sample_abstract_file

<Rec><Paragraph>prospective	data	on	the	efficacy	of	a	watch	and	wait	strategy	to	achieve	organ	preservation	in	patients	with	locally	advanced	rectal	cancer	treated	with	total	neoadjuvant	therapy	are	limited	in	this	prospective	randomized	phase	ii	trial	we	assessed	the	outcomes	of	324	patients	with	stage	ii	or	iii	rectal	adenocarcinoma	treated	with	induction	chemotherapy	followed	by	chemoradiotherapy	inct	crt	or	chemoradiotherapy	followed	by	consolidation	chemotherapy	crt	cnct	and	either	total	mesorectal	excision	tme	or	watch	and	wait	on	the	basis	of	tumor	response	patients	in	both	groups	received	4	months	of	infusional	fluorouracil	leucovorin	oxaliplatin	or	capecitabine	oxaliplatin	and	5	000	to	5	600	cgy	of	radiation	combined	with	either	continuous	infusion	fluorouracil	or	capecitabine	during	radiotherapy	the	trial	was	designed	as	two	stand	alone	studies	with	disease	free	survival	dfs	as	the	primary	end	point	for	both	groups	with	a	comparison	to	a	null	hypothesis	on	the	basis	of	historical	data	the	secondary	end	point	was	tme	free	survival	median	follow	up	was	3	years	three	year	dfs	was	76	95	ci	69	to	84	for	the	inct	crt	group	and	76	95	ci	69	to	83	for	the	crt	cnct	group	in	line	with	the	3	year	dfs	rate	75	observed	historically	three	year	tme	free	survival	was	41	95	ci	33	to	50	in	the	inct	crt	group	and	53	95	ci	45	to	62	in	the	crt	cnct	group	no	differences	were	found	between	groups	in	local	recurrence	free	survival	distant	metastasis	free	survival	or	overall	survival	patients	who	underwent	tme	after	restaging	and	patients	who	underwent	tme	after	regrowth	had	similar	dfs	rates	organ	preservation	is	achievable	in	half	of	the	patients	with	rectal	cancer	treated	with	total	neoadjuvant	therapy	without	an	apparent	detriment	in	survival	compared	with	historical	controls	treated	with	chemoradiotherapy	tme	and	postoperative	chemotherapy</Paragraph></Rec>
<Rec><Paragraph>in	clinical	practice	rectal	cancer	rc	is	classified	according	to	tumor	location	however	rc	s	genetic	characteristics	according	to	tumor	location	remain	unclear	therefore	we	aimed	to	compare	rc	s	genetic	characteristics	according	to	tumor	location	in	611	patients	with	surgically	resected	rc	we	performed	genetic	analyses	and	compared	the	results	between	low	and	other	rcs	low	rc	was	defined	according	to	the	european	society	for	medical	oncology	esmo	guidelines	and	japanese	classification	of	colorectal	appendiceal	and	anal	carcinoma	jccrc	kras	mutation	accumulation	was	significantly	higher	in	low	rc	under	the	esmo	classification	gene	expression	levels	significantly	differed	between	the	groups	for	ctnnb1	kras	and	erbb2	under	the	esmo	classification	and	for	tp53	kras	and	erbb2	under	the	jccrc	under	the	jccrc	low	rc	had	a	significantly	higher	prevalence	of	fusion	genes	such	as	eif3e	rspo2	ptprk	rspo3	and	vti1a	tcf7l2	consensus	molecular	subtype	cms	distribution	was	significantly	different	between	the	groups	under	both	classifications	in	particular	low	rc	had	lower	and	higher	frequencies	of	cms2	and	cms4	respectively	cms2	and	cms4	frequencies	in	low	rc	were	14	8	and	41	5	under	the	esmo	classification	and	14	5	and	41	6	under	the	jccrc	respectively	multivariate	cox	regression	analysis	demonstrated	that	pt3	4	pn1	2	and	cms4	were	associated	with	poor	relapse	free	survival	low	rc	exhibited	distinct	genetic	characteristics	from	other	rcs	in	particular	cms4	was	more	frequent	in	low	rc	and	was	a	risk	factor	for	poor	prognosis	these	findings	potentially	avail	further	information	regarding	tumor	biology	and	could	lead	to	improvements	in	rc	treatment</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	remains	the	third	most	common	cancer	in	the	us	with	15	of	cases	displaying	microsatellite	instability	msi	secondary	to	lynch	syndrome	ls	or	somatic	hypermethylation	of	the	mlh1	promoter	a	cohort	of	rhesus	macaques	from	our	institution	developed	spontaneous	mismatch	repair	deficient	mmrd	crc	with	a	notable	fraction	harboring	a	pathogenic	germline	mutation	in	mlh1	c	1029c	g	p	tyr343ter	our	study	aimed	to	provide	a	detailed	molecular	characterization	of	rhesus	crc	for	cross	comparison	with	human	mmrd	crc	we	performed	pcr	based	msi	testing	n	41	transcriptomics	analysis	n	35	reduced	representation	bisulfite	sequencing	rrbs	n	28	and	mlh1	dna	methylation	n	10	using	next	generation	sequencing	ngs	of	rhesus	crc	systems	biology	tools	were	used	to	perform	gene	set	enrichment	analysis	gsea	for	pathway	discovery	consensus	molecular	subtyping	cms	and	somatic	mutation	profiling	overall	the	majority	of	rhesus	tumors	displayed	high	levels	of	msi	msi	h	and	differential	gene	expression	profiles	that	were	consistent	with	known	deregulated	pathways	in	human	crc	dna	methylation	analysis	exposed	differentially	methylated	patterns	among	msi	h	msi	l	msi	low	mss	ms	stable	and	ls	tumors	with	mlh1	predominantly	inactivated	among	sporadic	msi	h	crcs	the	findings	from	this	study	support	the	use	of	rhesus	macaques	as	an	alternative	animal	model	to	mice	to	study	carcinogenesis	develop	immunotherapies	and	vaccines	and	implement	chemoprevention	approaches	relevant	to	sporadic	msi	h	and	ls	crc	in	humans</Paragraph></Rec>
<Rec><Paragraph>this	study	compared	changes	of	healthcare	quality	in	a	michigan	medicaid	population	before	and	after	physician	adoption	of	electronic	health	records	ehrs	via	the	meaningful	use	mu	program	for	selected	healthcare	effectiveness	data	and	information	set	hedis	quality	of	care	measures	healthcare	measures	included	well	child	visits	cancer	screening	and	chronic	illness	quality	measures	utilization	data	were	obtained	from	medicaid	paid	claims	and	encounter	data	with	providers	n	291	receiving	their	first	mu	incentive	in	2014	and	at	least	one	hedis	defined	outpatient	visit	with	a	michigan	medicaid	enrollee	paired	t	tests	with	a	repeated	measures	design	were	utilized	to	analyze	the	data	improvements	in	quality	of	infant	well	child	visits	mean	difference	10	2	and	colorectal	cancer	screening	mean	difference	8	0	percent	were	observed	we	found	no	change	or	slight	decreases	for	the	other	selected	measures	these	outcomes	inform	the	performance	and	ability	of	ehrs	to	improve	quality	of	healthcare	standards	particularly	as	technology	continues	to	evolve	under	the	centers	for	medicare	medicaid	services	cms	interoperability	and	patient	access	final	rule</Paragraph></Rec>
<Rec><Paragraph>metastasis	associated	in	colon	cancer	1	macc1	is	a	strong	prognostic	biomarker	inducing	proliferation	migration	invasiveness	and	metastasis	of	cancer	cells	the	context	of	macc1	dysregulation	in	cancers	is	however	still	poorly	understood	here	we	investigated	whether	chromosomal	instability	and	somatic	copy	number	alterations	scna	frequently	occurring	in	crc	contribute	to	macc1	dysregulation	with	prognostic	and	predictive	impacts	using	the	oncotrack	and	charité	crc	cohorts	of	crc	patients	we	showed	that	elevated	macc1	mrna	expression	was	tightly	dependent	on	increased	macc1	gene	scna	and	was	associated	with	metastasis	and	shorter	metastasis	free	survival	deep	analysis	of	the	coad	read	tcga	cohort	revealed	elevated	macc1	expression	due	to	scna	for	advanced	tumors	exhibiting	high	chromosomal	instability	cin	and	predominantly	classified	as	cms2	and	cms4	transcriptomic	subtypes	for	that	cohort	we	validated	that	elevated	macc1	mrna	expression	correlated	with	reduced	disease	free	and	overall	survival	in	conclusion	this	study	gives	insights	into	the	context	of	macc1	expression	in	crc	increased	macc1	expression	is	largely	driven	by	cin	scna	gains	and	molecular	subtypes	potentially	determining	the	molecular	risk	for	metastasis	that	might	serve	as	a	basis	for	patient	tailored	treatment	decisions</Paragraph></Rec>
<Rec><Paragraph>transcriptionally	informed	predictions	are	increasingly	important	for	sub	typing	cancer	patients	understanding	underlying	biology	and	to	inform	novel	treatment	strategies	for	instance	colorectal	cancers	crcs	can	be	classified	into	four	crc	consensus	molecular	subgroups	cms	or	five	intrinsic	cris	sub	types	that	have	prognostic	and	predictive	value	breast	cancer	brca	has	five	pam50	molecular	subgroups	with	similar	value	and	the	oncotypedx	test	provides	transcriptomic	based	clinically	actionable	treatment	risk	stratification	however	assigning	samples	to	these	subtypes	and	other	transcriptionally	inferred	predictions	is	time	consuming	and	requires	significant	bioinformatics	experience	there	is	no	universal	method	of	using	data	from	diverse	assay	sequencing	platforms	to	provide	subgroup	classification	using	the	established	classifier	sets	of	genes	cms	cris	pam50	oncotypedx	nor	one	which	in	provides	additional	useful	functional	annotations	such	as	cellular	composition	single	sample	gene	set	enrichment	analysis	or	prediction	of	transcription	factor	activity	to	address	this	bottleneck	we	developed	classifier	an	easy	to	use	r	shiny	based	web	application	that	supports	flexible	rapid	single	sample	annotation	of	transcriptional	profiles	derived	from	cancer	patient	samples	form	diverse	platforms	we	demonstrate	the	utility	of	the	classifier	framework	to	applications	focused	on	the	analysis	of	transcriptional	profiles	from	colorectal	classifierc	and	breast	classifierb	samples	are	annotated	with	disease	relevant	transcriptional	subgroups	cms	cris	sub	types	in	classifierc	and	pam50	inferred	oncotypedx	in	classifierb	estimation	of	cellular	composition	using	mcp	counter	and	xcell	single	sample	gene	set	enrichment	analysis	ssgsea	and	transcription	factor	activity	predictions	with	discriminant	regulon	expression	analysis	dorothea	classifier	provides	a	framework	which	enables	labs	without	access	to	a	dedicated	bioinformation	can	get	information	on	the	molecular	makeup	of	their	samples	providing	an	insight	into	patient	prognosis	druggability	and	also	as	a	tool	for	analysis	and	discovery	applications	are	hosted	online	at	https	generatr	qub	ac	uk	app	classifierc	and	https	generatr	qub	ac	uk	app	classifierb	after	signing	up	for	an	account	on	https	generatr	qub	ac	uk</Paragraph></Rec>
<Rec><Paragraph>in	the	last	years	several	efforts	have	been	made	to	classify	colorectal	cancer	crc	into	well	defined	molecular	subgroups	representing	the	intrinsic	inter	patient	heterogeneity	known	as	consensus	molecular	subtypes	cmss	in	this	work	we	performed	a	meta	analysis	of	crc	patients	stratified	into	four	cmss	we	identified	a	negative	correlation	between	a	high	level	of	anaplastic	lymphoma	kinase	alk	expression	and	relapse	free	survival	exclusively	in	cms1	subtype	stemming	from	this	observation	we	tested	cell	lines	patient	derived	organoids	and	mice	with	potent	alk	inhibitors	already	approved	for	clinical	use	alk	interception	strongly	inhibits	cell	proliferation	already	at	nanomolar	doses	specifically	in	cms1	cell	lines	while	no	effect	was	found	in	cms2	3	4	groups	furthermore	in	vivo	imaging	identified	a	role	for	alk	in	the	dynamic	formation	of	3d	tumor	spheroids	consistently	alk	appeares	constitutively	phosphorylated	in	cms1	and	it	signals	mainly	through	the	akt	axis	mechanistically	we	found	that	cms1	cells	display	several	copies	of	alkal2	ligand	and	alk	mrnas	suggesting	an	autocrine	loop	mediated	by	alkal2	in	the	activation	of	alk	pathway	responsible	for	the	invasive	phenotype	consequently	disruption	of	alk	axis	mediates	the	pro	apoptotic	action	of	cms1	cell	lines	both	in	2d	and	3d	and	enhanced	cell	cell	adhesion	and	e	cadherin	organization	in	agreement	with	all	these	findings	the	alk	signature	encompassing	65	genes	statistically	associated	with	worse	relapse	free	survival	in	cms1	subtype	finally	as	a	proof	of	concept	the	efficacy	of	alk	inhibition	was	demonstrated	in	both	patient	derived	organoids	and	in	tumor	xenografts	in	vivo	collectively	these	findings	suggest	that	alk	targeting	may	represent	an	attractive	therapy	for	crc	and	cms	classification	may	provide	a	useful	tool	to	identify	patients	who	could	benefit	from	this	treatment	these	findings	offer	rationale	and	pharmacological	strategies	for	the	treatment	of	cms1	crc</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	the	second	leading	cause	of	cancer	death	in	the	united	states	the	ras	pathway	is	activated	in	more	than	55	of	crc	and	has	been	targeted	for	therapeutic	intervention	with	mek	inhibitors	unfortunately	many	patients	have	de	novo	resistance	or	can	develop	resistance	to	this	new	class	of	drugs	we	have	hypothesized	that	much	of	this	resistance	may	pass	through	src	as	a	common	signal	transduction	node	and	that	inhibition	of	src	may	suppress	mek	inhibition	resistance	mechanisms	crc	tumors	of	the	consensus	molecular	subtype	cms	4	enriched	in	stem	cells	are	difficult	to	successfully	treat	and	have	been	suggested	to	evade	traditional	chemotherapy	agents	through	resistance	mechanisms	here	we	evaluate	targeting	two	pathways	simultaneously	to	produce	an	effective	treatment	by	overcoming	resistance	we	show	that	combining	trametinib	meki	with	dasatinib	srci	provides	enhanced	cell	death	in	8	of	the	16	tested	crc	cell	lines	compared	to	treatment	with	either	agent	alone	to	be	able	to	select	sensitive	cells	we	simultaneously	evaluated	a	validated	18	gene	ras	pathway	activation	signature	score	along	with	a	13	gene	meki	resistance	signature	score	which	we	hypothesize	predict	tumor	sensitivity	to	this	dual	targeted	therapy	we	found	the	cell	lines	that	were	sensitive	to	the	dual	treatment	were	predominantly	cms4	and	had	both	a	high	18	gene	and	a	high	13	gene	score	suggesting	these	cell	lines	had	potential	for	de	novo	meki	sensitivity	but	were	subject	to	the	rapid	development	of	meki	resistance	the	13	gene	score	is	highly	correlated	to	a	score	for	src	activation	suggesting	resistance	is	dependent	on	src	our	data	show	that	gene	expression	signature	scores	for	ras	pathway	activation	and	for	meki	resistance	may	be	useful	in	determining	which	crc	tumors	will	respond	to	the	novel	drug	combination	of	meki	and	srci</Paragraph></Rec>
<Rec><Paragraph>promising	single	agent	activity	from	sotorasib	and	adagrasib	in	kras	g12c	mutant	tumors	has	provided	clinical	evidence	of	effective	kras	signaling	inhibition	however	comprehensive	analysis	of	kras	variant	prevalence	genomic	alterations	and	the	relationship	between	kras	and	immuno	oncology	biomarkers	is	lacking	retrospective	analysis	of	deidentified	records	from	79	004	patients	with	various	cancers	who	underwent	next	generation	sequencing	was	performed	fisher	s	exact	test	evaluated	the	association	between	cancer	subtypes	and	kras	variants	logistic	regression	assessed	kras	g12c	comutations	with	other	oncogenes	and	the	association	between	kras	variants	and	immuno	oncology	biomarkers	of	the	79	004	samples	assessed	13	758	17	4	harbored	kras	mutations	with	1	632	11	9	harboring	kras	g12c	and	12	126	88	1	harboring	other	kras	variants	kras	non	g12c	compared	with	kras	non	g12c	across	all	tumor	subtypes	kras	g12c	was	more	prevalent	in	females	56	v	51	false	discovery	rate	adjusted	p	value	fdr	p	0006	current	or	prior	smokers	85	v	56	fdr	p	0001	and	patients	age	60	years	73	v	63	fdr	p	0001	the	most	frequent	kras	variants	across	all	subtypes	were	g12d	29	5	g12v	23	0	g12c	11	9	g13d	6	5	and	g12r	6	2	kras	g12c	was	most	prevalent	in	patients	with	non	small	cell	lung	cancer	9	appendiceal	3	9	colorectal	3	2	tumor	of	unknown	origin	1	6	small	bowel	1	43	and	pancreatic	1	3	cancers	compared	with	kras	non	g12c	mutated	kras	g12c	mutated	tumors	were	significantly	associated	with	tumor	mutational	burden	high	status	17	9	v	8	4	odds	ratio	or	2	38	fdr	p	0001	kras	g12c	mutated	tumors	exhibited	a	distinct	comutation	profile	from	kras	non	g12c	mutated	tumors	including	higher	comutations	of	stk11	20	59	v	5	95	or	4	10	fdr	p	01	and	keap1	15	38	v	4	61	or	3	76	fdr	p	01	this	study	presents	the	first	large	scale	pan	cancer	genomic	characterization	of	kras	g12c	the	kras	g12c	mutation	was	more	prevalent	in	females	and	older	patients	and	appeared	to	be	associated	with	smoking	status	kras	g12c	tumors	exhibited	a	distinct	comutation	profile	and	were	associated	with	tumor	mutational	burden	high	status</Paragraph></Rec>
<Rec><Paragraph>the	importance	of	the	tumour	microbiome	in	different	aspects	of	colorectal	cancer	crc	has	been	increasingly	recognised	but	many	questions	remain	the	aim	of	this	study	was	to	explore	the	effect	of	specific	crc	associated	microbes	on	the	tumour	immune	response	which	has	a	considerable	prognostic	value	in	crc	we	applied	specific	qpcr	to	detect	parvimonas	micra	and	fusobacterium	nucleatum	in	tumour	tissues	from	an	immunologically	well	characterised	cohort	of	69	crc	patients	this	cohort	included	detailed	analyses	of	immune	profiles	based	on	flow	cytometry	and	transcriptomics	in	tumour	tissue	and	blood	along	with	comprehensive	analyses	of	molecular	subtypes	p	micra	and	f	nucleatum	were	detected	in	24	and	64	of	tumour	tissues	respectively	we	found	a	significant	association	of	p	micra	with	high	grade	tumours	and	tumours	of	cms1	subtype	f	nucleatum	was	significantly	associated	with	right	sided	tumours	microsatellite	instability	and	cms1	tumours	the	immunological	analyses	revealed	significant	associations	of	p	micra	with	activated	cd69	t	lymphocytes	and	increased	antigen	presenting	hla	dr	b	lymphocytes	p	micra	was	also	positively	associated	with	m1	and	m2	macrophage	traits	the	impact	of	p	micra	tumour	colonisation	on	the	immune	response	was	further	assessed	using	transcriptomics	in	validation	of	our	findings	no	associations	were	found	between	f	nucleatum	and	immune	profiles	in	this	study	our	findings	support	novel	associations	between	p	micra	and	the	immune	response	in	crc	a	better	understanding	of	these	interactions	might	help	to	identify	important	predictive	and	prognostic	tools	as	well	as	new	targets	for	therapy</Paragraph></Rec>
<Rec><Paragraph>previously	colorectal	cancer	crc	has	been	classified	into	four	distinct	molecular	subtypes	based	on	transcriptome	data	these	consensus	molecular	subtypes	cmss	have	implications	for	our	understanding	of	tumor	heterogeneity	and	the	prognosis	of	patients	so	far	this	classification	has	been	based	on	the	use	of	messenger	rnas	mrnas	although	micrornas	mirnas	have	also	been	shown	to	play	a	role	in	tumor	heterogeneity	and	biological	differences	between	cmss	in	contrast	to	mrnas	mirnas	have	a	smaller	size	and	increased	stability	facilitating	their	detection	therefore	we	built	a	mirna	based	cms	classifier	by	converting	the	existing	mrna	based	cms	classification	using	machine	learning	training	dataset	of	n	271	the	performance	of	this	mirna	assigned	cms	classifier	cms	miracl	was	evaluated	in	several	datasets	achieving	an	overall	accuracy	of	0	72	0	6329	0	7987	in	the	largest	dataset	n	158	to	gain	insight	into	the	biological	relevance	of	cms	miracl	we	evaluated	the	most	important	features	in	the	classifier	we	found	that	mirnas	previously	reported	to	be	relevant	in	microsatellite	instable	crcs	or	wnt	signaling	were	important	features	for	cms	miracl	following	further	studies	to	validate	its	robustness	this	mirna	based	alternative	might	simplify	the	implementation	of	cms	classification	in	clinical	workflows</Paragraph></Rec>
<Rec><Paragraph>in	colorectal	cancer	crc	the	consensus	molecular	subtype	4	cms4	is	associated	with	therapy	resistance	and	poor	prognosis	clinical	diagnosis	of	cms4	is	hampered	by	locoregional	and	temporal	variables	influencing	cms	classification	diagnostic	tools	that	comprehensively	detect	cms4	are	therefore	urgently	needed	to	identify	targets	for	molecular	cms4	imaging	rna	sequencing	data	of	3232	primary	crc	patients	were	explored	heterogeneity	of	marker	expression	in	relation	to	cms4	status	was	assessed	by	analysing	3	5	tumour	regions	and	91	103	single	tumour	cells	7	and	29	tumours	respectively	candidate	marker	expression	was	validated	in	cms4	peritoneal	metastases	pm	n	59	molecular	imaging	was	performed	using	the	68	ga	dota	fapi	46	pet	tracer	fibroblast	activation	protein	fap	mrna	identified	cms4	with	very	high	sensitivity	and	specificity	auroc	0	91	and	was	associated	with	significantly	shorter	relapse	free	survival	p	0	0038	heterogeneous	expression	of	fap	among	and	within	tumour	lesions	correlated	with	cms4	heterogeneity	auroc	1	00	fap	expression	was	homogeneously	high	in	pm	a	near	homogeneous	cms4	entity	fapi	pet	identified	focal	and	diffuse	pm	that	were	missed	using	conventional	imaging	extra	peritoneal	metastases	displayed	extensive	heterogeneity	of	tracer	uptake	fap	expression	identifies	cms4	crc	fapi	pet	may	have	value	in	the	comprehensive	detection	of	cms4	tumours	in	crc	this	is	especially	relevant	in	patients	with	pm	for	whom	effective	imaging	tools	are	currently	lacking</Paragraph></Rec>
<Rec><Paragraph>to	evaluate	the	association	of	low	value	care	with	excess	out	of	pocket	expenditure	among	older	adults	diagnosed	with	incident	breast	prostate	colorectal	cancers	and	non	hodgkin	s	lymphoma	we	used	a	retrospective	cohort	study	design	with	12	month	baseline	and	follow	up	periods	we	identified	a	cohort	of	older	adults	age	66	years	diagnosed	with	breast	prostate	colorectal	cancers	or	non	hodgkin	s	lymphoma	between	january	2014	and	december	2014	we	assessed	low	value	care	and	patient	out	of	pocket	expenditure	in	the	follow	up	period	we	identified	relevant	low	value	services	using	icd9	icd10	and	cpt	hcpcs	codes	from	the	linked	health	claims	and	patient	out	of	pocket	expenditure	from	medicare	claim	files	and	expressed	expenditure	in	2016	usd	about	29	of	older	adults	received	at	least	one	low	value	care	procedure	during	the	follow	up	period	low	value	care	differed	by	gender	and	rates	were	higher	in	women	with	colorectal	cancer	32	7	vs	28	8	and	nhl	40	vs	39	compared	to	men	individuals	who	received	one	or	more	low	value	care	had	significantly	higher	mean	out	of	pocket	expenditure	8	726	7	214	vs	6	802	6	102	xgboost	a	machine	learning	algorithm	revealed	that	low	value	care	was	among	the	five	leading	predictors	of	oop	expenditure	one	in	four	older	adults	with	incident	cancer	received	low	value	care	in	12	months	after	a	cancer	diagnosis	across	all	cancer	populations	individuals	who	received	low	value	care	had	significantly	higher	out	of	pocket	expenditure	excess	out	of	pocket	expenditure	was	driven	by	low	value	care	fragmentation	of	care	and	an	increasing	number	of	pre	existing	chronic	conditions	this	study	focuses	on	health	policy	issues	specifically	value	based	care	and	its	findings	have	important	clinical	and	policy	implications	for	centers	for	medicare	and	medicaid	services	cms	which	has	issued	a	roadmap	for	states	to	accelerate	the	adoption	of	value	based	care	with	the	department	of	health	and	human	services	hhs	setting	a	goal	of	converting	50	of	traditional	medicare	payment	systems	to	alternative	payment	models	tied	to	value	based	care	by	2022</Paragraph></Rec>
<Rec><Paragraph>over	half	of	colorectal	cancers	crcs	are	hard	wired	to	ras	raf	mek	erk	pathway	oncogenic	signaling	however	the	promise	of	targeted	therapeutic	inhibitors	has	been	tempered	by	disappointing	clinical	activity	likely	due	to	complex	resistance	mechanisms	that	are	not	well	understood	this	study	aims	to	investigate	mek	inhibitor	associated	resistance	signaling	and	identify	subpopulation	s	of	crc	patients	who	may	be	sensitive	to	biomarker	driven	drug	combination	s	we	classified	2250	primary	and	metastatic	human	crc	tumors	by	consensus	molecular	subtypes	cms	for	each	tumor	we	generated	multiple	gene	expression	signature	scores	measuring	mek	pathway	activation	meki	bypass	resistance	src	activation	dasatinib	sensitivity	emt	pc1	hu	lgr5	isc	hu	ephb2	isc	hu	late	ta	hu	proliferation	and	wnt	activity	we	carried	out	correlation	survival	and	other	bioinformatic	analyses	validation	analyses	were	performed	in	two	independent	publicly	available	crc	tumor	datasets	n	585	and	n	677	and	a	crc	cell	line	dataset	n	154	here	we	report	a	central	role	of	src	in	mediating	bypass	resistance	to	mek	inhibition	meki	primarily	in	cancer	stem	cells	cscs	our	integrated	and	comprehensive	gene	expression	signature	analyses	in	2250	crc	tumors	reveal	that	meki	resistance	is	strikingly	correlated	with	src	activation	spearman	p	10	320	which	is	similarly	associated	with	emt	epithelial	to	mesenchymal	transition	regional	metastasis	and	disease	recurrence	with	poor	prognosis	deeper	analysis	shows	that	both	meki	resistance	and	src	activation	are	preferentially	associated	with	a	mesenchymal	csc	phenotype	this	association	is	validated	in	additional	independent	crc	tumor	and	cell	lines	datasets	the	cms	classification	analysis	demonstrates	the	strikingly	distinct	associations	of	cms1	4	subtypes	with	the	meki	resistance	and	src	activation	importantly	meki	srci	sensitivities	are	predicted	to	occur	predominantly	in	the	kras	mutant	mesenchymal	csc	like	cms4	crcs	large	human	tumor	gene	expression	datasets	representing	crc	heterogeneity	can	provide	deep	biological	insights	heretofore	not	possible	with	cell	line	models	suggesting	novel	repurposed	drug	combinations	we	identified	src	as	a	common	targetable	node	an	achilles	heel	in	meki	targeted	therapy	associated	resistance	in	mesenchymal	stem	like	crcs	which	may	help	development	of	a	biomarker	driven	drug	combination	meki	srci	to	treat	problematic	subpopulations	of	crc</Paragraph></Rec>
<Rec><Paragraph>in	colorectal	cancer	whereas	mucinous	adenocarcinoma	mac	has	several	poor	clinical	prognostic	factors	compared	to	adenocarcinoma	ac	the	prognosis	of	mac	remains	controversial	we	evaluated	the	prognosis	of	mac	without	distant	metastasis	and	the	effects	of	adjuvant	chemotherapy	using	health	insurance	registry	data	managed	by	south	korea	patients	with	colorectal	cancer	between	january	2014	and	december	2016	were	included	ac	22	050	96	8	mac	729	3	2	we	observed	no	difference	in	overall	survival	os	between	ac	and	mac	in	stages	i	and	ii	however	mac	showed	a	worse	os	than	ac	in	stage	iii	disease	especially	in	patients	administered	chemotherapy	p	0	001	these	findings	persisted	after	propensity	score	matching	of	clinical	characteristics	between	ac	and	mac	in	addition	transcriptome	analysis	of	the	cancer	genome	atlas	tcga	data	showed	increased	chemoresistance	associated	pathways	in	mac	compared	to	ac	in	consensus	molecular	subtypes	cms	classification	unlike	in	ac	cmss	1	3	and	4	comprised	most	of	mac	and	the	proportions	of	cmss	3	and	4	increased	with	stage	progression	these	results	suggest	clues	to	overcome	resistance	to	chemotherapy	and	develop	targeted	treatments	in	mac</Paragraph></Rec>
<Rec><Paragraph>transcriptomic	profiling	was	performed	for	microsatellite	instability	high	msi	h	mismatch	repair	deficient	dmmr	gastrointestinal	gi	tumors	to	determine	the	predictors	of	response	to	pd	1	blockade	thirty	six	patients	with	msi	h	dmmr	gi	tumors	including	gastric	cancer	colorectal	cancer	crc	cholangiocarcinoma	small	intestine	cancer	and	pancreatic	cancer	being	treated	with	pd	1	blockade	were	analyzed	we	conducted	the	transcriptomic	analysis	of	gi	tumors	using	rna	sequencing	data	including	the	consensus	molecular	subtypes	cms	of	crc	gene	set	enrichment	analysis	gsea	demonstrated	that	non	responders	had	upregulations	of	epithelial	mesenchymal	transition	angiogenesis	hypoxia	mtorc1	tnf	α	kras	wnt	β	catenin	tgf	β	and	various	metabolism	related	signaling	pathways	meanwhile	the	ifn	γ	pathway	was	enriched	in	responders	based	on	the	leading	edge	analysis	of	gsea	vegf	a	was	significantly	correlated	with	enriched	pathways	in	non	responders	patients	with	high	vegf	a	expression	compared	to	those	with	low	expression	had	significantly	shorter	progression	free	survival	pfs	median	4	8	months	vs	not	reached	nr	p	0	032	and	overall	survival	median	11	1	months	vs	nr	p	0	045	among	13	patients	with	crc	evaluable	for	cms	classification	the	objective	response	rate	was	100	0	0	and	16	7	in	cms1	cms2	cms3	and	cms4	respectively	patients	with	cms1	had	significantly	longer	pfs	nr	vs	4	8	months	p	0	017	than	those	with	cms2	cms3	or	cms4	several	transcriptomic	features	including	cms	classification	and	related	genes	were	associated	with	response	to	pd	1	blockade	in	msi	h	dmmr	gi	tumors	these	findings	can	help	develop	predictive	biomarkers	or	combination	immunotherapies</Paragraph></Rec>
<Rec><Paragraph>cancer	cells	reprogram	lipid	metabolism	to	fuel	cell	division	adaptation	to	stress	and	metastatic	dissemination	nf	κb	transcription	factors	control	this	mechanism	in	aggressive	consensus	molecular	subtype	cms	4	of	colorectal	carcinoma	crc	via	triacylglycerol	tag	lipase	carboxylesterase	1	ces1	thereby	linking	obesity	associated	inflammation	with	metabolic	adaptation	and	cytoprotection	from	lipid	induced	toxicity	our	findings	identify	a	potential	therapeutic	route	to	treat	patients	with	metastasis	prone	crc	and	provide	an	example	for	targeting	core	tumor	subtype	based	vulnerabilities	in	cancers	beyond	crc</Paragraph></Rec>
<Rec><Paragraph>the	oncology	care	model	ocm	is	an	episode	based	alternative	payment	model	for	cancer	care	that	seeks	to	reduce	medicare	spending	while	maintaining	care	quality	we	evaluated	the	impact	of	ocm	on	appropriate	use	of	supportive	care	medications	during	cancer	treatment	we	evaluated	chemotherapy	episodes	assigned	to	ocm	n	201	and	comparison	practices	n	534	using	medicare	claims	2013	2019	we	assessed	denosumab	use	for	beneficiaries	with	bone	metastases	from	breast	lung	or	prostate	cancer	prophylactic	wbc	growth	factor	use	for	beneficiaries	receiving	chemotherapy	for	breast	lung	or	colorectal	cancer	and	prophylactic	use	of	neurokinin	1	nk1	antagonists	and	long	acting	serotonin	antagonists	for	beneficiaries	receiving	chemotherapy	for	any	cancer	type	analyses	used	a	difference	in	difference	approach	after	its	launch	in	2016	ocm	led	to	a	relative	reduction	in	the	use	of	denosumab	for	beneficiaries	with	bone	metastases	receiving	bone	modifying	medications	eg	5	0	percentage	point	relative	reduction	in	breast	cancer	episodes	90	ci	7	1	to	2	8	there	was	no	ocm	impact	on	use	of	prophylactic	wbc	growth	factors	during	chemotherapy	with	high	or	low	risk	for	febrile	neutropenia	among	beneficiaries	receiving	chemotherapy	with	intermediate	febrile	neutropenia	risk	ocm	led	to	a	7	6	percentage	point	reduction	in	the	use	of	prophylactic	wbc	growth	factors	during	breast	cancer	episodes	90	ci	12	6	to	2	7	there	was	no	ocm	impact	in	lung	or	colorectal	cancer	episodes	among	beneficiaries	receiving	chemotherapy	with	high	or	moderate	emetic	risk	ocm	led	to	reductions	in	the	prophylactic	use	of	nk1	antagonists	and	long	acting	serotonin	antagonists	eg	6	0	percentage	point	reduction	in	the	use	of	nk1	antagonists	during	high	emetic	risk	chemotherapy	90	ci	9	0	to	3	1	ocm	led	to	the	reduced	use	of	some	high	cost	supportive	care	medications	suggesting	more	value	conscious	care</Paragraph></Rec>
<Rec><Paragraph>peritoneal	metastases	pm	in	colorectal	cancer	crc	are	associated	with	therapy	resistance	and	poor	survival	oxaliplatin	monotherapy	is	widely	applied	in	the	intraperitoneal	treatment	of	pm	but	fails	to	yield	clinical	benefit	we	aimed	to	identify	the	mechanism	s	underlying	pm	resistance	to	oxaliplatin	and	to	develop	strategies	overcoming	such	resistance	we	generated	a	biobank	consisting	of	35	primary	tumour	regions	and	59	paired	pm	from	12	patients	all	samples	were	analysed	by	rna	sequencing	we	also	generated	a	series	of	pm	derived	organoid	pmdo	cultures	and	used	these	to	design	and	test	strategies	to	overcome	resistance	to	oxaliplatin	pm	displayed	various	hallmarks	of	aggressive	crc	biology	the	vast	majority	of	pm	and	paired	primary	tumours	belonged	to	the	consensus	molecular	subtype	4	cms4	pmdo	cultures	were	resistant	to	oxaliplatin	and	expressed	high	levels	of	glutamate	cysteine	ligase	gclc	causing	detoxification	of	oxaliplatin	through	glutathione	synthesis	genetic	or	pharmacological	targeting	of	gclc	sensitised	pmdos	to	a	1	h	exposure	to	oxaliplatin	through	increased	platinum	dna	adduct	formation	these	results	link	oxaliplatin	resistance	of	colorectal	pm	to	their	cms4	status	and	high	reducing	capacity	inhibiting	the	reducing	capacity	of	pm	may	be	an	effective	strategy	to	overcome	pm	resistance	to	oxaliplatin</Paragraph></Rec>
<Rec><Paragraph>background	colorectal	cancer	crc	is	the	third	most	common	cancer	worldwide	in	which	aberrant	activation	of	the	ras	signaling	pathway	appears	frequently	rab	proteins	rabs	are	the	largest	ras	small	gtpases	superfamily	that	regulates	intracellular	membrane	trafficking	pathways	the	dysregulation	of	rabs	have	been	found	in	various	diseases	including	cancers	compared	with	other	members	of	ras	families	the	roles	of	rabs	in	colorectal	cancer	are	less	well	understood	methods	we	analyzed	the	differential	expression	and	clinicopathological	association	of	rabs	in	crc	using	rna	sequencing	and	genotyping	datasets	from	tcga	samples	moreover	the	biological	function	of	rab17	and	rab34	were	investigated	in	crc	cell	lines	and	patient	samples	results	of	the	62	rabs	we	analyzed	in	crc	seven	rab10	rab11a	rab15	rab17	rab19	rab20	and	rab25	were	significantly	upregulated	while	six	rab6b	rab9b	rab12	rab23	rab31	and	rab34	were	significantly	downregulated	in	tumor	tissues	as	compared	to	normal	we	found	that	the	upregulated	rabs	which	were	highly	expressed	in	metabolic	activated	crc	subtype	cms3	are	associated	with	cell	cycle	related	pathways	enrichment	and	positively	correlated	with	the	mismatch	repair	mmr	genes	in	crc	implying	their	role	in	regulating	cell	metabolism	and	tumor	growth	while	high	expression	of	the	downregulated	rabs	were	significantly	associated	with	poor	prognostic	crc	mesenchymal	subtypes	cms4	immune	checkpoint	genes	and	tumor	infiltrating	immune	cells	indicating	their	role	in	predicting	prognosis	and	immunotherapy	efficacy	interestingly	though	rab34	mrna	is	downregulated	in	crc	its	high	expression	is	significantly	associated	with	poor	prognosis	in	vitro	experiments	showed	that	rab17	overexpression	can	promote	cell	proliferation	via	cell	cycle	regulation	while	rab34	overexpression	can	promote	cell	migration	and	invasion	and	is	associated	with	pd	l1	pd	l2	expression	increase	in	crc	cells	conclusions	our	study	showed	that	rabs	may	play	important	roles	in	regulating	cell	cycle	and	immune	related	pathways	therefore	might	be	potential	biomarkers	in	predicting	prognosis	and	immunotherapy	response	in	crc</Paragraph></Rec>
<Rec><Paragraph>stemness	refers	to	the	capacities	of	self	renewal	and	repopulation	which	contributes	to	the	progression	relapse	and	drug	resistance	of	colorectal	cancer	crc	mounting	evidence	has	established	the	links	between	cancer	stemness	and	intratumoral	heterogeneity	across	cancer	currently	the	intertumoral	heterogeneity	of	cancer	stemness	remains	elusive	in	crc	this	study	enrolled	four	crc	datasets	two	immunotherapy	datasets	and	a	clinical	in	house	cohort	non	negative	matrix	factorization	nmf	was	performed	to	decipher	the	heterogeneity	of	cancer	stemness	multiple	machine	learning	algorithms	were	applied	to	develop	a	nine	gene	stemness	cluster	predictor	the	clinical	outcomes	multi	omics	landscape	potential	mechanisms	and	immune	features	of	the	stemness	clusters	were	further	explored	based	on	26	published	stemness	signatures	derived	by	alternative	approaches	we	decipher	two	heterogeneous	clusters	low	stemness	cluster	1	c1	and	high	stemness	cluster	2	c2	c2	possessed	a	higher	proportion	of	advanced	tumors	and	displayed	worse	overall	survival	and	relapse	free	survival	compared	with	c1	the	msi	h	and	cms1	tumors	tended	to	enrich	in	c1	and	the	mesenchymal	subtype	cms4	was	the	prevalent	subtype	of	c2	subsequently	we	developed	a	nine	gene	stemness	cluster	predictor	which	robustly	validated	and	reproduced	our	stemness	clusters	in	three	independent	datasets	and	an	in	house	cohort	c1	also	displayed	a	generally	superior	mutational	burden	and	c2	possessed	a	higher	burden	of	copy	number	deletion	further	investigations	suggested	that	c1	enriched	numerous	proliferation	related	biological	processes	and	abundant	immune	infiltration	while	c2	was	significantly	associated	with	mesenchyme	development	and	differentiation	given	results	derived	from	three	algorithms	and	two	immunotherapeutic	cohorts	we	observed	c1	could	benefit	more	from	immunotherapy	for	patients	with	c2	we	constructed	a	ridge	regression	model	and	further	identified	nine	latent	therapeutic	agents	which	might	improve	their	clinical	outcomes	this	study	proposed	two	stemness	clusters	with	stratified	prognosis	multi	omics	landscape	potential	mechanisms	and	treatment	options	current	work	not	only	provided	new	insights	into	the	heterogeneity	of	cancer	stemness	but	also	shed	light	on	optimizing	decision	making	in	immunotherapy	and	chemotherapy</Paragraph></Rec>
<Rec><Paragraph>the	landmark	centers	for	medicare	medicaid	services	cms	decision	memo	on	blood	based	biomarkers	to	screen	for	colorectal	cancer	crc	sets	thresholds	of	74	for	sensitivity	and	90	for	specificity	for	crc	this	approach	does	not	consider	detection	of	advanced	precancerous	lesions	as	true	positives	we	contrasted	the	impact	of	counting	advanced	precancerous	lesions	as	true	vs	false	positives	and	projected	crc	outcomes	under	contrasting	tests	in	a	validated	model	a	test	with	the	threshold	performance	set	by	cms	decreased	crc	incidence	by	30	and	crc	mortality	by	48	in	45	year	olds	if	this	test	also	detected	advanced	precancerous	lesions	with	30	sensitivity	crc	incidence	decreased	by	45	and	mortality	by	58	but	the	test	s	crc	specificity	of	only	88	would	not	satisfy	the	cms	threshold	cms	should	reconsider	its	definition	of	threshold	specificity	for	crc	screening	biomarkers	future	coverage	determinations	on	biomarkers	to	screen	for	cancer	should	consider	detection	of	relevant	precursor	lesions	and	projected	outcomes</Paragraph></Rec>
<Rec><Paragraph>local	invasion	is	the	initial	step	towards	metastasis	the	main	cause	of	cancer	mortality	in	human	colorectal	cancer	crc	malignant	cells	predominantly	invade	as	cohesive	collectives	and	may	undergo	partial	epithelial	mesenchymal	transition	pemt	at	the	invasive	front	how	this	particular	mode	of	stromal	infiltration	is	generated	is	unknown	here	we	investigated	the	impact	of	oncogenic	transformation	and	the	microenvironment	on	tumor	cell	invasion	using	genetically	engineered	organoids	as	crc	models	we	found	that	inactivation	of	the	apc	tumor	suppressor	combined	with	expression	of	oncogenic	kras	g12d	and	dominant	negative	trp53	r172h	did	not	cell	autonomously	induce	invasion	in	vitro	however	oncogenic	transformation	primed	organoids	for	activation	of	a	collective	invasion	program	upon	exposure	to	the	prototypical	microenvironmental	factor	tgfβ1	execution	of	this	program	co	depended	on	a	permissive	extracellular	matrix	which	was	further	actively	remodeled	by	invading	organoids	although	organoids	shed	some	epithelial	properties	particularly	at	the	invasive	edge	tgfβ1	stimulated	organoids	largely	maintained	epithelial	gene	expression	while	additionally	implementing	a	mesenchymal	transcription	pattern	resulting	in	a	pemt	phenotype	that	did	not	progress	to	a	fully	mesenchymal	state	notably	while	tgfβ1	induced	pemt	and	promoted	collective	invasion	it	abrogated	self	renewal	capacity	of	tka	organoids	which	correlated	with	the	downregulation	of	intestinal	stem	cell	isc	marker	genes	mechanistically	induction	of	the	non	progressive	pemt	required	canonical	tgfβ	signaling	mediated	by	smad	transcription	factors	tfs	whereas	the	emt	master	regulators	snail1	and	zeb1	were	dispensable	gene	expression	profiling	provided	further	evidence	for	pemt	of	tgfβ1	treated	organoids	and	showed	that	their	transcriptomes	resemble	those	of	human	poor	prognosis	cms4	cancers	which	likewise	exhibit	pemt	features	we	propose	that	collective	invasion	in	colorectal	carcinogenesis	is	triggered	by	microenvironmental	stimuli	through	activation	of	a	novel	transcription	mediated	form	of	non	progressive	pemt	independently	of	classical	emt	regulators</Paragraph></Rec>
<Rec><Paragraph>the	coronavirus	disease	2019	covid	19	pandemic	has	brought	significant	challenges	to	many	aspects	of	healthcare	delivery	since	the	first	reported	case	in	early	december	2019	once	in	the	body	sars	cov	2	can	spread	to	other	digestive	organs	such	as	the	liver	because	of	the	presence	of	ace2	receptors	colorectal	cancer	crc	remains	the	second	leading	cause	of	death	in	the	united	states	us	therefore	individuals	are	routinely	screened	using	either	endoscopic	methods	i	e	flexible	sigmoidoscopy	and	colonoscopy	or	stool	based	tests	as	per	the	published	guidelines	at	the	beginning	of	the	covid	19	pandemic	the	centers	for	medicare	and	medicaid	services	cms	recommended	that	all	non	urgent	surgical	and	medical	procedures	including	screening	colonoscopies	be	delayed	until	the	pandemic	stabilization	this	article	aims	to	review	the	impact	of	covid	19	on	crc	screening</Paragraph></Rec>
<Rec><Paragraph>the	molecular	pathogenesis	of	solid	tumour	was	first	assessed	in	colorectal	cancer	crc	to	date	100	genes	with	somatic	alterations	have	been	found	to	inter	connectively	promote	neoplastic	transformation	through	specific	pathways	the	process	of	colorectal	carcinogenesis	via	genome	landscape	is	reviewed	on	the	basis	of	an	adenoma	to	carcinoma	sequence	as	shown	by	serial	histological	and	epidemiological	observations	the	relevant	literatures	from	pubmed	1980	2021	have	been	reviewed	for	this	article	the	major	routes	of	crc	development	chromosomal	instability	cin	microsatellite	instability	msi	and	the	serrated	route	either	via	cin	or	msi	proceed	through	the	respective	molecular	pathway	of	colorectal	carcinogenesis	particular	aspects	of	crc	carcinogenesis	can	also	be	determined	by	evaluating	familial	crcs	fcrc	and	genotype	phenotype	correlations	specific	causative	gene	alterations	still	leave	to	be	identified	in	several	fcrcs	otherwise	recently	verified	fcrc	can	be	particularly	notable	for	example	epcam	associated	lynch	syndrome	polymerase	proofreading	associated	polyposis	rnf43	associated	polyposis	syndrome	or	nthl1	tumour	syndrome	and	hereditary	mixed	polyposis	syndrome	the	oncogenic	landscape	is	described	including	representative	pathway	genes	the	three	routes	of	carcinogenesis	familial	crcs	genotype	phenotype	correlations	the	identification	of	causative	genes	and	consensus	molecular	subtypes	cms	whole	genome	research	using	multi	gene	panels	mgps	has	facilitated	high	through	put	detection	of	previously	unidentified	genes	involved	in	colorectal	carcinogenesis	new	approaches	designed	to	identify	rare	variants	are	recommended	to	consider	their	alterations	implicated	in	the	molecular	pathogenesis</Paragraph></Rec>
<Rec><Paragraph>the	circadian	gene	timeless	tim	provides	a	molecular	bridge	between	circadian	and	cell	cycle	dna	replication	regulatory	systems	and	has	been	recently	involved	in	human	cancer	development	and	progression	however	its	functional	role	in	colorectal	cancer	crc	the	third	leading	cause	of	cancer	related	deaths	worldwide	has	not	been	fully	clarified	yet	here	the	analysis	of	two	independent	crc	patient	cohorts	total	1159	samples	reveals	that	loss	of	tim	expression	is	an	unfavorable	prognostic	factor	significantly	correlated	with	advanced	tumor	stage	metastatic	spreading	and	microsatellite	stability	status	genome	wide	expression	profiling	in	vitro	and	in	vivo	experiments	revealed	that	tim	knockdown	induces	the	activation	of	the	epithelial	to	mesenchymal	transition	emt	program	accordingly	the	analysis	of	a	large	set	of	human	samples	showed	that	tim	expression	inversely	correlated	with	a	previously	established	gene	signature	of	canonical	emt	markers	emt	score	and	its	ectopic	silencing	promotes	migration	invasion	and	acquisition	of	stem	like	phenotype	in	crc	cells	mechanistically	we	found	that	loss	of	tim	expression	unleashes	zeb1	expression	that	in	turn	drives	the	emt	program	and	enhances	the	aggressive	behavior	of	crc	cells	besides	the	deranged	tim	zeb1	axis	sets	off	the	accumulation	of	dna	damage	and	delays	dna	damage	recovery	furthermore	we	show	that	the	aggressive	and	genetically	unstable	cms4	colorectal	cancer	molecular	subtype	is	characterized	by	a	lower	expression	of	tim	and	that	patients	with	the	combination	of	low	tim	high	zeb1	expression	have	a	poorer	outcome	in	conclusion	our	results	as	a	whole	suggest	the	engagement	of	an	unedited	tim	zeb1	axis	in	key	pathological	processes	driving	malignant	phenotype	acquisition	in	colorectal	carcinogenesis	thus	tim	zeb1	expression	profiling	could	provide	a	robust	prognostic	biomarker	in	crc	patients	supporting	targeted	therapeutic	strategies	with	better	treatment	selection	and	patients	outcomes</Paragraph></Rec>
<Rec><Paragraph>the	epithelial	mesenchymal	transition	emt	is	associated	with	tumor	aggressiveness	and	increased	invasion	migration	metastasis	angiogenesis	and	drug	resistance	although	the	hct116	p21	cell	line	is	well	known	for	its	emt	associated	phenotype	with	high	vimentin	and	low	e	cadherin	protein	levels	the	gene	signature	of	this	rather	intermediate	emt	like	cell	line	has	not	been	determined	so	far	in	this	work	we	present	a	robust	molecular	and	bioinformatics	analysis	to	reveal	the	associated	gene	expression	profile	and	its	correlation	with	different	types	of	colorectal	cancer	tumors	we	compared	the	quantitative	signature	obtained	with	the	nanostring	platform	with	the	expression	profiles	of	colorectal	cancer	crc	consensus	molecular	subtypes	cms	as	identified	and	validated	the	results	in	a	large	independent	cohort	of	human	tumor	samples	the	expression	signature	derived	from	the	p21	cells	showed	consistent	and	reliable	numbers	of	upregulated	and	downregulated	genes	as	evaluated	with	two	machine	learning	methods	against	the	four	crc	subtypes	i	e	cms1	2	3	and	4	high	concordance	was	found	between	the	upregulated	gene	signature	of	hct116	p21	cells	and	the	signature	of	the	cms4	mesenchymal	subtype	at	the	same	time	the	upregulated	gene	signature	of	the	native	hct116	cells	was	similar	to	that	of	cms1	using	a	multivariate	cox	regression	model	to	analyze	the	survival	data	in	the	crc	tumor	cohort	we	selected	genes	that	have	a	predictive	risk	power	with	a	significant	gene	risk	incidence	score	a	set	of	genes	of	the	mesenchymal	signature	was	proven	to	be	significantly	associated	with	poor	survival	specifically	in	the	cms4	crc	human	cohort	we	suggest	that	the	gene	signature	of	hct116	p21	cells	could	be	a	suitable	metric	for	mechanistic	studies	regarding	the	cms4	signature	and	its	functional	consequences	in	crc	moreover	this	model	could	help	to	discover	the	molecular	mechanisms	of	intermediate	emt	which	is	known	to	be	associated	with	extraordinarily	high	stemness	and	drug	resistance</Paragraph></Rec>
<Rec><Paragraph>to	investigate	whether	a	panel	of	circulating	protein	biomarkers	would	improve	risk	assessment	for	lung	cancer	screening	in	combination	with	a	risk	model	on	the	basis	of	participant	characteristics	a	blinded	validation	study	was	performed	using	prostate	lung	colorectal	ovarian	plco	cancer	screening	trial	data	and	biospecimens	to	evaluate	the	performance	of	a	four	marker	protein	panel	4mp	consisting	of	the	precursor	form	of	surfactant	protein	b	cancer	antigen	125	carcinoembryonic	antigen	and	cytokeratin	19	fragment	in	combination	with	a	lung	cancer	risk	prediction	model	plcom2012	compared	with	current	us	preventive	services	task	force	uspstf	screening	criteria	the	4mp	was	assayed	in	1	299	sera	collected	preceding	lung	cancer	diagnosis	and	8	709	noncase	sera	the	4mp	alone	yielded	an	area	under	the	receiver	operating	characteristic	curve	of	0	79	95	ci	0	77	to	0	82	for	case	sera	collected	within	1	year	preceding	diagnosis	and	0	74	95	ci	0	72	to	0	76	among	the	entire	specimen	set	the	combined	4mp	plcom2012	model	yielded	an	area	under	the	receiver	operating	characteristic	curve	of	0	85	95	ci	0	82	to	0	88	for	case	sera	collected	within	1	year	preceding	diagnosis	the	benefit	of	the	4mp	in	the	combined	model	resulted	from	improvement	in	sensitivity	at	high	specificity	compared	with	the	uspstf2021	criteria	the	combined	4mp	plcom2012	model	exhibited	statistically	significant	improvements	in	sensitivity	and	specificity	among	plco	participants	with	10	smoking	pack	years	the	4mp	plcom2012	model	would	have	identified	for	annual	screening	9	2	more	lung	cancer	cases	and	would	have	reduced	referral	by	13	7	among	noncases	compared	with	uspstf2021	criteria	a	blood	based	biomarker	panel	in	combination	with	plcom2012	significantly	improves	lung	cancer	risk	assessment	for	lung	cancer	screening</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	leading	cause	of	cancer	related	deaths	with	a	5	5	year	survival	rate	for	metastatic	disease	yet	with	limited	therapeutic	advancements	due	to	insufficient	understanding	of	and	inability	to	accurately	capture	high	risk	crc	patients	who	are	most	likely	to	recur	we	aimed	to	improve	high	risk	classification	by	identifying	biological	pathways	associated	with	outcome	in	adjuvant	stage	ii	iii	crc	we	included	1062	patients	with	stage	iii	or	high	risk	stage	ii	colon	carcinoma	from	the	prospective	three	arm	randomized	phase	3	avant	trial	and	performed	expression	profiling	to	identify	a	prognostic	signature	data	from	validation	cohort	gse39582	the	cancer	genome	atlas	and	cell	lines	were	used	to	further	validate	the	prognostic	biology	our	retrospective	analysis	of	the	adjuvant	avant	trial	uncovered	a	prognostic	signature	capturing	three	biological	functions	stromal	proliferative	and	immune	that	outperformed	the	consensus	molecular	subtypes	cms	and	recurrence	prediction	signatures	like	oncotype	dx	in	an	independent	cohort	importantly	within	the	immune	component	high	granzyme	b	gzmb	expression	had	a	significant	prognostic	impact	while	other	individual	t	effector	genes	were	less	or	not	prognostic	in	addition	we	found	gzmb	to	be	endogenously	expressed	in	cms2	tumor	cells	and	to	be	prognostic	in	a	t	cell	independent	fashion	a	limitation	of	our	study	is	that	these	results	although	robust	and	derived	from	a	large	dataset	still	need	to	be	clinically	validated	in	a	prospective	study	this	work	furthers	our	understanding	of	the	underlying	biology	that	propagates	stage	ii	iii	crc	disease	progression	and	provides	scientific	rationale	for	future	high	risk	stratification	and	targeted	treatment	evaluation	in	biomarker	defined	subpopulations	of	resectable	high	risk	crc	our	results	also	shed	light	on	an	alternative	gzmb	source	with	context	specific	implications	on	the	disease	s	unique	biology</Paragraph></Rec>
<Rec><Paragraph>colorectal	liver	metastases	crlm	have	heterogenous	histopathological	and	immunohistochemical	phenotypes	which	are	associated	with	variable	responses	to	treatment	and	outcomes	however	this	information	is	usually	only	available	after	resection	and	therefore	of	limited	value	in	treatment	planning	improved	techniques	for	in	vivo	disease	assessment	which	can	characterise	the	variable	tumour	biology	would	support	further	personalization	of	management	strategies	advanced	imaging	of	crlm	including	multiparametric	mri	and	functional	imaging	techniques	have	the	potential	to	provide	clinically	actionable	phenotypic	characterisation	this	includes	assessment	of	the	tumour	liver	interface	internal	tumour	components	and	treatment	response	advanced	analysis	techniques	including	radiomics	and	machine	learning	now	have	a	growing	role	in	assessment	of	imaging	providing	high	dimensional	imaging	feature	extraction	which	can	be	linked	to	clinical	relevant	tumour	phenotypes	such	as	a	the	consensus	molecular	subtypes	cms	in	this	review	we	outline	how	imaging	techniques	could	reproducibly	characterize	the	histopathological	features	of	crlm	with	several	matched	imaging	and	histology	examples	to	illustrate	these	features	and	discuss	the	oncological	relevance	of	these	features	finally	we	discuss	the	future	challenges	and	opportunities	of	crlm	imaging	with	a	focus	on	the	potential	value	of	advanced	analytics	including	radiomics	and	artificial	intelligence	to	help	inform	future	research	in	this	rapidly	moving	field</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	heterogeneous	and	deadly	and	the	exact	cause	of	the	disease	is	unknown	recent	progress	indicated	that	crc	is	not	a	single	disease	but	a	group	of	diseases	with	significant	heterogeneity	three	previous	crc	subtyping	systems	microsatellite	instability	msi	consensus	molecular	subtypes	cms	and	tumor	node	metastases	tnm	stage	were	evaluated	for	their	molecular	and	clinical	implications	results	suggested	that	the	msi	and	cms	systems	are	prognostic	and	predictive	mostly	in	early	stage	crc	as	the	stage	remains	an	influential	factor	for	crc	subtype	analysis	we	developed	a	new	subtyping	system	named	stage	supervised	crc	subtypes	sscs	in	order	to	better	stratify	crc	biologically	and	clinically	our	subtyping	system	can	be	used	to	classify	crc	patients	into	five	subtypes	sscs1	5	sscs1	was	found	to	have	the	highest	frequency	of	msi	h	cases	compared	to	the	remaining	four	subtypes	sscs2	had	the	most	favorable	prognosis	whereas	the	worst	prognosis	was	seen	in	sscs4	sscs3	had	cell	cycle	and	metabolism	related	gene	sets	upregulation	and	sscs5	subtype	was	enriched	with	amplicon	associated	gene	sets	moreover	tumor	infiltrating	fibroblast	was	found	to	be	predictive	for	poor	disease	free	survival	dfs	only	within	the	sscs4	subtype	conventional	dendritic	cells	cdc	on	the	contrary	were	associated	with	favorable	dfs	in	the	sscs3	subtype	our	study	provides	a	new	subtyping	system	sscs	which	can	be	used	for	better	stratify	crc	patients	compared	to	current	standards	further	exploration	of	the	subtype	specific	cell	types	has	the	potential	to	be	novel	therapies	for	crc</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	manifests	as	gastrointestinal	tumors	with	high	intratumoral	heterogeneity	recent	studies	have	demonstrated	that	crc	may	consist	of	tumor	cells	with	different	consensus	molecular	subtypes	cms	the	advancements	in	single	cell	rna	sequencing	have	facilitated	the	development	of	gene	regulatory	networks	to	decode	key	regulators	for	specific	cell	types	herein	we	comprehensively	analyzed	the	cms	of	crc	patients	by	using	single	cell	rna	sequencing	data	cms	for	all	malignant	cells	were	assigned	using	cmscaller	gene	set	variation	analysis	showed	pathway	activity	differences	consistent	with	those	reported	in	previous	studies	cell	cell	communication	analysis	confirmed	that	cms1	was	more	closely	related	to	immune	cells	and	that	monocytes	and	macrophages	play	dominant	roles	in	the	crc	tumor	microenvironment	on	the	basis	of	the	constructed	gene	regulation	networks	grns	for	each	subtype	we	identified	that	the	critical	transcription	factor	erg	is	universally	activated	and	upregulated	in	all	cms	in	comparison	with	normal	cells	and	that	it	performed	diverse	roles	by	regulating	the	expression	of	different	downstream	genes	in	summary	molecular	subtyping	of	single	cell	rna	sequencing	data	for	colorectal	cancer	could	elucidate	the	heterogeneity	in	gene	regulatory	networks	and	identify	critical	regulators	of	crc</Paragraph></Rec>
<Rec><Paragraph>population	based	cancer	registries	pbcrs	are	critical	for	national	cancer	control	planning	yet	few	low	and	middle	income	countries	lmics	have	quality	pbcrs	the	central	america	four	region	represents	the	principal	lmic	region	in	the	western	hemisphere	we	describe	the	establishment	of	a	pbcr	in	rural	western	honduras	with	first	estimates	for	the	2013	2017	period	the	western	honduras	pbcr	was	established	through	a	collaboration	of	academic	institutions	and	the	honduras	ministry	of	health	for	collection	of	incident	cancer	data	from	public	and	private	health	services	data	were	recorded	using	the	research	electronic	data	capture	redcap	web	based	platform	with	data	monitoring	and	quality	checks	crude	and	age	standardized	rates	asrs	were	calculated	at	the	regional	level	following	who	methodology	the	web	based	platform	for	data	collection	available	ancillary	data	services	eg	endoscopy	and	technical	support	from	international	centers	united	states	and	colombia	were	instrumental	for	quality	control	crude	cancer	incidence	rates	were	112	2	69	8	and	154	6	per	100	000	habitants	overall	males	and	females	respectively	excluding	nonmelanoma	skin	cancer	the	adjusted	asrs	were	84	2	49	6	and	118	9	per	100	000	overall	habitants	males	and	females	respectively	the	most	common	sites	among	men	were	stomach	asr	26	0	52	4	colorectal	asr	5	11	10	15	and	prostate	asr	2	7	5	4	the	most	common	sites	in	women	were	cervix	asr	34	2	36	7	breast	asr	11	2	12	3	and	stomach	asr	10	8	11	7	the	copán	pbcr	represents	a	successful	model	to	develop	cancer	monitoring	in	rural	lmics	innovations	included	the	use	of	the	redcap	platform	and	leverage	of	health	ministry	resources	this	provides	the	first	pbcr	data	for	honduras	and	the	central	america	four	and	confirms	that	infection	driven	cancers	such	as	gastric	and	cervical	should	be	priority	targets	for	cancer	control	initiatives</Paragraph></Rec>
<Rec><Paragraph>colon	cancer	is	a	complex	heterogeneous	disease	the	colorectal	cancer	subtyping	consortium	reported	a	novel	classification	system	for	colon	cancer	in	2015	to	better	understand	its	heterogeneity	this	molecular	classification	system	divided	colon	cancer	into	four	distinct	consensus	molecular	subtypes	cms	1	2	3	and	4	however	the	characteristics	of	different	colon	cancer	molecular	subtypes	have	not	been	fully	elucidated	this	study	comprehensively	analyzed	the	molecular	characteristics	of	varying	colon	cancer	subtypes	using	multiple	databases	and	algorithms	including	the	cancer	genome	atlas	tcga	database	driverdbv3	database	cibersort	and	mcp	counter	algorithms	we	analyzed	the	alterations	in	the	subtype	specific	genes	of	different	colon	cancer	subtypes	such	as	the	rna	levels	and	dna	alterations	and	showed	that	specific	subtype	specific	genes	significantly	affected	prognosis	we	also	explored	the	changes	in	colon	cancer	driver	genes	and	representative	genes	of	10	signaling	pathways	in	different	subtypes	we	identified	genes	that	were	altered	in	specific	subtypes	we	further	detected	the	infiltration	of	22	immune	cell	types	in	four	colon	cancer	subtypes	and	the	infiltration	level	of	primary	immune	cells	among	these	subtypes	additionally	we	explored	changes	in	immune	checkpoint	genes	icgs	and	immunotherapy	responses	among	different	colon	cancer	subtypes	this	study	may	provide	clues	for	the	molecular	mechanism	of	tumorigenesis	and	progression	in	colon	cancer	it	also	offers	potential	biomarkers	and	targets	for	the	clinical	diagnosis	and	treatment	of	different	colon	cancer	subtypes</Paragraph></Rec>
<Rec><Paragraph>the	identification	of	several	genetic	mutations	in	colorectal	cancer	crc	has	allowed	a	better	comprehension	of	the	prognosis	and	response	to	different	antineoplastic	treatments	recently	through	a	systematic	process	consensus	molecular	subtypes	cms	have	been	described	to	characterize	genetic	and	molecular	mutations	in	crc	patients	through	cms	crc	patients	can	be	categorized	into	four	molecular	subtypes	of	crc	by	wide	transcriptional	genome	analysis	cms1	has	microsatellite	instability	and	mutations	in	cimp	and	braf	pathways	cms2	distinguished	by	mutations	in	specific	pathways	linked	to	cellular	metabolism	also	has	a	better	prognosis	cms3	has	a	kras	mutation	as	a	hallmark	cms4	presents	mutations	in	fibrogenesis	pathways	and	mesenchymal	epithelial	transition	associated	with	a	worse	prognosis	cms	classification	can	be	a	meaningful	step	in	providing	possible	answers	to	important	issues	in	crc	such	as	the	use	of	adjuvant	chemotherapy	in	stage	ii	personalized	first	line	chemotherapy	for	metastasic	crc	and	possible	new	target	treatments	that	address	specific	pathways	in	each	molecular	subtype	understanding	cms	is	a	crucial	step	in	personalized	medicine	although	prospective	clinical	trials	selecting	patients	by	cms	are	required	to	pass	proof	of	concept	before	becoming	a	routine	clinical	tool	in	oncology	routine	care</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancers	crcs	with	microsatellite	instability	high	msi	h	are	hypermutated	tumors	and	are	generally	regarded	as	immunogenic	however	their	heterogeneous	immune	responses	and	underlying	molecular	characteristics	remain	largely	unexplained	we	conducted	a	retrospective	analysis	of	73	primary	msi	h	crc	tissues	to	characterize	heterogeneous	immune	subgroups	based	on	combined	tumor	infiltrating	lymphocyte	til	immunoscore	and	tertiary	lymphoid	structure	tls	activity	msi	h	crcs	were	classified	into	immune	high	immune	intermediate	and	immune	low	subgroups	of	these	the	immune	high	and	immune	low	subgroups	were	further	analyzed	using	whole	exome	and	transcriptome	sequencing	we	found	considerable	variations	in	immune	parameters	between	msi	h	crcs	and	immune	subgrouping	of	msi	h	crcs	was	performed	accordingly	the	til	densities	and	tls	activities	of	immune	low	msi	h	crcs	were	comparable	to	those	of	an	immune	low	or	immune	intermediate	subgroup	of	microsatellite	stable	crcs	there	were	remarkable	differences	between	immune	high	and	immune	low	msi	h	crcs	including	their	pathological	features	medullary	vs	mucinous	genomic	alterations	tyrosine	kinase	fusions	vs	kras	mutations	and	activated	signaling	pathways	immune	related	vs	wnt	and	notch	signaling	whereas	no	significant	differences	were	found	in	tumor	mutational	burden	tmb	and	neoantigen	load	the	immune	low	msi	h	crcs	were	subdivided	by	the	consensus	molecular	subtype	cms1	vs	cms3	with	different	gene	expression	signatures	mesenchymal	stem	like	vs	epithelial	goblet	like	suggesting	distinct	immune	evasion	mechanisms	angiogenesis	and	cd200	were	identified	as	potential	therapeutic	targets	in	immune	low	cms1	and	cms3	msi	h	crcs	respectively	msi	h	crcs	are	immunologically	heterogeneous	regardless	of	tmb	the	unusual	immune	low	msi	h	crcs	are	characterized	by	mucinous	histology	kras	mutations	and	wnt	notch	activation	and	can	be	further	divided	into	distinct	gene	expression	subtypes	including	cms4	like	cms1	and	cms3	our	data	provide	novel	insights	into	precise	immunotherapeutic	strategies	for	subtypes	of	msi	h	tumors</Paragraph></Rec>
<Rec><Paragraph>molecular	characterization	of	colorectal	cancer	has	helped	us	understand	better	the	biology	of	the	disease	however	previous	efforts	have	yet	to	provide	significant	clinical	value	in	order	to	be	integrated	into	clinical	practice	for	patients	with	early	stage	colon	cancer	cc	the	purpose	of	this	study	was	to	assess	pd	l1	glut	1	e	cadherin	muc2	cdx2	and	microsatellite	instability	dmmr	and	to	propose	a	risk	panel	with	prognostic	capabilities	biomarkers	were	immunohistochemically	assessed	through	tissue	microarrays	in	a	cohort	of	144	patients	with	stage	ii	iii	colon	cancer	a	biomarker	panel	consisting	of	pd	l1	glut	1	dmmr	and	potentially	cdx2	was	constructed	that	divided	patients	into	low	medium	and	high	risk	of	overall	survival	or	disease	free	survival	dfs	in	equally	sized	groups	compared	with	low	risk	patients	medium	risk	patients	have	almost	twice	the	risk	of	death	hr	2	10	0	99	4	46	p	0	054	while	high	risk	patients	have	almost	four	times	the	risk	hr	3	79	1	77	8	11	p	0	001	the	multivariate	goodness	of	fit	was	0	756	and	was	correlated	with	kaplan	meier	curves	p	0	002	consistent	results	were	found	for	dfs	this	study	provides	a	critical	basis	for	the	future	development	of	an	immunohistochemical	assessment	capable	of	discerning	early	stage	cc	patients	as	a	function	of	their	prognosis	this	tool	may	aid	with	treatment	personalization	in	daily	clinical	practice	and	improve	survival	outcomes</Paragraph></Rec>
<Rec><Paragraph>palbociclib	is	a	cyclin	dependent	kinase	4	and	6	inhibitor	approved	for	advanced	breast	cancer	in	the	adjuvant	setting	the	potential	value	of	adding	palbociclib	to	endocrine	therapy	for	hormone	receptor	positive	breast	cancer	has	not	been	confirmed	in	the	prospective	randomized	phase	iii	pallas	trial	patients	with	hormone	receptor	positive	human	epidermal	growth	factor	receptor	2	negative	early	breast	cancer	were	randomly	assigned	to	receive	2	years	of	palbociclib	125	mg	orally	once	daily	days	1	21	of	a	28	day	cycle	with	adjuvant	endocrine	therapy	or	adjuvant	endocrine	therapy	alone	for	at	least	5	years	the	primary	end	point	of	the	study	was	invasive	disease	free	survival	idfs	secondary	end	points	were	invasive	breast	cancer	free	survival	distant	recurrence	free	survival	locoregional	cancer	free	survival	and	overall	survival	among	5	796	patients	enrolled	at	406	centers	in	21	countries	worldwide	over	3	years	5	761	were	included	in	the	intention	to	treat	population	at	the	final	protocol	defined	analysis	at	a	median	follow	up	of	31	months	idfs	events	occurred	in	253	of	2	884	8	8	patients	who	received	palbociclib	plus	endocrine	therapy	and	in	263	of	2	877	9	1	patients	who	received	endocrine	therapy	alone	with	similar	results	between	the	two	treatment	groups	idfs	at	4	years	84	2	v	84	5	hazard	ratio	0	96	ci	0	81	to	1	14	p	65	no	significant	differences	were	observed	for	secondary	time	to	event	end	points	and	subgroup	analyses	did	not	show	any	differences	by	subgroup	there	were	no	new	safety	signals	for	palbociclib	in	this	trial	at	this	final	analysis	of	the	pallas	trial	the	addition	of	adjuvant	palbociclib	to	standard	endocrine	therapy	did	not	improve	outcomes	over	endocrine	therapy	alone	in	patients	with	early	hormone	receptor	positive	breast	cancer</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	high	incidence	malignancy	worldwide	which	still	needs	better	therapy	options	therefore	the	aim	of	the	present	study	was	to	investigate	the	responses	of	normal	or	malignant	human	intestinal	epithelium	to	bone	morphogenetic	protein	bmp	9	and	to	find	out	whether	the	application	of	bmp	9	to	patients	with	crc	or	the	enhancement	of	its	synthesis	in	the	liver	could	be	useful	strategies	for	new	therapy	approaches	in	silico	analyses	of	crc	patient	cohorts	tcga	database	revealed	that	high	expression	of	the	bmp	target	gene	id1	especially	in	combination	with	low	expression	of	the	bmp	inhibitor	noggin	is	significantly	associated	with	better	patient	survival	organoid	lines	were	generated	from	human	biopsies	of	colon	cancer	t	orgs	and	corresponding	non	malignant	areas	n	orgs	of	three	patients	the	n	orgs	represented	tumours	belonging	to	three	different	consensus	molecular	subtypes	cms	of	crc	overall	bmp	9	stimulation	of	organoids	promoted	an	enrichment	of	tumour	suppressive	gene	expression	signatures	whereas	the	stimulation	with	noggin	had	the	opposite	effects	furthermore	treatment	of	organoids	with	bmp	9	induced	id1	expression	independently	of	high	noggin	levels	while	treatment	with	noggin	reduced	id1	in	summary	our	data	identify	the	ratio	between	id1	and	noggin	as	a	new	prognostic	value	for	crc	patient	outcome	we	further	show	that	by	inducing	id1	bmp	9	enhances	this	ratio	even	in	the	presence	of	noggin	thus	bmp	9	is	identified	as	a	novel	target	for	the	development	of	improved	anti	cancer	therapies	of	patients	with	crc</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	driven	in	part	by	dysregulated	wnt	ras	raf	mapk	tgf	β	and	pi3k	akt	signaling	the	progression	of	crc	is	also	promoted	by	molecular	alterations	and	heterogeneous	yet	interconnected	gene	mutations	chromosomal	instability	transcriptomic	subtypes	and	immune	signatures	genomic	alterations	of	crc	progression	lead	to	changes	in	rna	expression	which	support	crc	metastasis	an	rna	based	classification	system	used	for	crc	known	as	consensus	molecular	subtyping	cms	has	four	classes	cms1	has	the	lowest	survival	after	relapse	of	the	four	crc	cms	phenotypes	here	we	identify	gene	signatures	and	associated	coding	mrnas	that	are	co	expressed	during	cms1	crc	progression	using	rna	seq	data	from	crc	primary	tumor	samples	acquired	from	the	cancer	genome	atlas	tcga	we	identified	co	expression	gene	networks	significantly	correlated	with	cms1	crc	progression	cxcl13	cxcr5	il10	pik3r5	pik3ap1	ccl19	and	other	co	expressed	genes	were	identified	to	be	positively	correlated	with	cms1	the	co	expressed	eigengene	networks	for	cms1	were	significantly	and	positively	correlated	with	the	tnf	wnt	and	erk1	and	erk2	signaling	pathways	which	together	promote	cell	proliferation	and	survival	this	network	was	also	aligned	with	biological	characteristics	of	cms1	crc	being	positively	correlated	to	right	sided	tumors	microsatellite	instability	chemokine	mediated	signaling	pathways	and	immune	responses	cms1	also	differentially	expressed	genes	involved	in	pi3k	akt	signaling	our	findings	reveal	crc	gene	networks	related	to	oncogenic	signaling	cascades	cell	activation	and	positive	regulation	of	immune	responses	distinguishing	cms1	from	other	crc	subtypes</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	is	one	of	the	most	common	malignant	tumors	and	hence	has	become	one	of	the	most	important	public	health	issues	in	the	world	treatment	with	immune	checkpoint	inhibitors	icis	successfully	improves	the	survival	rate	of	patients	with	melanoma	non	small	cell	lung	cancer	and	other	malignancies	and	its	application	in	metastatic	colorectal	cancer	is	being	actively	explored	however	a	few	patients	develop	drug	resistance	predictive	molecular	markers	are	important	tools	to	precisely	screen	patient	groups	that	can	benefit	from	treatment	with	icis	the	current	article	focused	on	certain	important	predictive	molecular	markers	for	ici	treatment	in	colorectal	cancer	including	not	only	some	of	the	mature	molecular	markers	such	as	deficient	mismatch	repair	d	mmr	microsatellite	instability	high	msi	h	tumor	mutational	burden	tmb	programmed	death	ligand	1	pd	l1	tumor	immune	microenvironment	time	and	tumor	infiltrating	lymphocytes	tils	but	also	some	of	the	novel	molecular	markers	such	as	dna	polymerase	epsilon	pole	polymerase	delta	1	pold1	circulating	tumor	dna	ctdna	and	consensus	molecular	subtypes	cms	we	have	reviewed	these	markers	in	depth	and	presented	the	results	from	certain	important	studies	which	suggest	their	applicability	in	crc	and	indicate	their	advantages	and	disadvantages	we	hope	this	article	is	helpful	for	clinicians	and	researchers	to	systematically	understand	these	markers	and	can	guide	the	treatment	of	colorectal	cancer</Paragraph></Rec>
<Rec><Paragraph>background	acyl	coa	dehydrogenase	short	chain	acads	is	a	crucial	enzyme	in	the	fatty	acid	metabolism	pathway	located	in	mitochondria	however	the	expression	level	and	prognostic	value	of	acads	in	colorectal	cancer	crc	remain	unclear	methods	the	mrna	and	protein	expression	data	of	acads	was	obtained	from	the	cancer	genome	atlas	tcga	clinical	proteomic	tumor	analysis	consortium	cptac	and	oncomine	prognostic	values	of	acads	were	calculated	using	kaplan	meier	survival	analysis	correlations	between	acads	and	immune	infiltration	were	estimated	using	timer	cibersort	epic	quantiseq	and	xcell	the	ualcan	and	mexpress	databases	were	utilized	for	methylation	analysis	the	co	expression	analysis	based	on	mrna	expression	and	interaction	network	of	acads	were	performed	via	several	online	tools	gene	ontology	go	and	kyoto	encyclopedia	of	genes	and	genomes	kegg	analysis	on	acads	co	expressed	genes	were	performed	using	the	metascape	results	the	expression	analysis	demonstrated	that	acads	was	down	regulated	in	crc	tissues	compared	with	paired	normal	tissue	expression	of	acads	was	found	to	be	significantly	associated	with	clinical	cancer	stages	and	the	consensus	molecular	subgroups	cms	constituent	ratio	in	crc	patients	besides	lower	acads	expression	was	found	to	predict	poor	prognosis	and	be	significantly	associated	with	common	immune	checkpoint	genes	and	mmr	genes	in	crc	acads	expression	levels	were	positively	related	to	b	cells	cd4	t	cells	cd8	t	cells	m1	macrophages	neutrophils	and	tregs	while	negatively	correlated	with	m0	macrophages	m2	macrophages	the	methylation	level	of	acads	in	normal	tissues	was	significantly	higher	than	that	in	tumor	tissues	and	several	methylation	sites	were	identified	the	enrichment	analysis	suggested	the	co	expressed	genes	mainly	enriched	in	cell	mitochondrial	metabolism	conclusions	the	present	study	provided	multilevel	evidences	for	expression	of	acads	in	crc	and	the	function	of	acads	in	prognostic	prediction	immune	infiltration	and	methylation	acads	might	have	the	potential	as	the	novel	biomarker	and	therapeutic	target	in	crc	patients</Paragraph></Rec>
<Rec><Paragraph>recently	it	was	suggested	that	consensus	molecular	subtyping	cms	may	aide	in	predicting	response	to	egfr	inhibitor	cetuximab	therapies	we	recently	identified	that	apc	and	tp53	as	two	tumor	suppressor	genes	when	mutated	may	enhance	cetuximab	sensitivity	and	may	represent	easily	measured	biomarkers	in	tumors	or	blood	our	study	aimed	to	use	apc	and	tp53	mutations	ap	to	refine	the	cms	classification	to	better	predict	responses	to	cetuximab	in	total	433	crc	tumors	were	classified	into	cms1	4	subtypes	the	cetuximab	sensitivity	ctx	s	signature	scores	of	ap	vs	non	ap	tumors	were	determined	across	each	of	the	cms	classes	tumors	harboring	combined	ap	mutations	were	predominantly	enriched	in	the	cms2	class	and	to	a	lesser	degree	in	the	cms4	class	on	the	other	hand	ap	mutated	crcs	had	significantly	higher	ctx	s	scores	compared	to	non	ap	crcs	across	all	cms	classes	similar	results	were	also	obtained	in	independent	tcga	tumor	collections	n	531	and	in	pdmr	pdx	pdo	pdc	models	n	477	in	addition	the	in	vitro	cetuximab	growth	inhibition	was	preferentially	associated	with	the	cms2	cell	lines	harboring	a	p	genotypes	in	conclusion	the	ap	mutation	signature	represents	a	convenient	biomarker	that	refines	the	cms	classification	to	identify	crc	subpopulations	predicted	to	be	sensitive	to	egfr	targeted	therapies</Paragraph></Rec>
<Rec><Paragraph>the	heterogenous	nature	of	colorectal	cancer	crc	renders	it	a	major	clinical	challenge	increasing	genomic	understanding	of	crc	has	improved	our	knowledge	of	this	heterogeneity	and	the	main	cancer	drivers	with	significant	improvements	in	clinical	outcomes	comprehensive	molecular	characterization	has	allowed	clinicians	a	more	precise	range	of	treatment	options	based	on	biomarker	selection	furthermore	this	deep	molecular	understanding	likely	extends	therapeutic	options	to	a	larger	number	of	patients	the	biological	associations	of	consensus	molecular	subtypes	cms	with	clinical	outcomes	in	localized	crc	have	been	validated	in	retrospective	clinical	trials	the	prognostic	role	of	cms	has	also	been	confirmed	in	the	metastatic	setting	with	cms2	having	the	best	prognosis	whereas	cms1	tumors	are	associated	with	a	higher	risk	of	progression	and	death	after	chemotherapy	similarly	according	to	mesenchymal	features	and	immunosuppressive	molecules	cms1	responds	to	immunotherapy	whereas	cms4	has	a	poorer	prognosis	suggesting	that	a	cms1	signature	could	identify	patients	who	may	benefit	from	immune	checkpoint	inhibitors	regardless	of	microsatellite	instability	msi	status	the	main	goal	of	these	comprehensive	analyses	is	to	switch	from	one	marker	one	drug	to	multi	marker	drug	combinations	allowing	oncologists	to	give	the	right	drug	to	the	right	patient	despite	the	revealing	data	from	transcriptomic	analyses	the	high	rate	of	intra	tumoral	heterogeneity	across	the	different	cms	subgroups	limits	its	incorporation	as	a	predictive	biomarker	in	clinical	practice	when	feasible	comprehensive	genomic	tests	should	be	performed	to	identify	potentially	targetable	alterations	particularly	in	ras	braf	wild	type	msi	and	right	sided	tumors	furthermore	cms	has	not	only	been	associated	with	clinical	outcomes	and	specific	tumor	and	patient	phenotypes	but	also	with	specific	microbiome	patterns	future	steps	will	include	the	integration	of	clinical	features	genomics	transcriptomics	and	microbiota	to	select	the	most	accurate	biomarkers	to	identify	optimal	treatments	improving	individual	clinical	outcomes	in	summary	cms	is	context	specific	identifies	a	level	of	heterogeneity	beyond	standard	genomic	biomarkers	and	offers	a	means	of	maximizing	personalized	therapy</Paragraph></Rec>
<Rec><Paragraph>young	patients	with	colorectal	cancer	crc	exhibit	poor	prognoses	compared	to	older	patients	due	to	the	difficulty	in	early	diagnosis	and	treatment	however	the	underlying	molecular	characteristics	are	still	unclear	we	conducted	a	comprehensive	analysis	of	49	crc	patients	without	hereditary	crc	using	the	whole	exome	and	rna	sequencing	with	tumor	and	matched	normal	samples	a	total	of	594	tcga	samples	and	4	patient	derived	cells	were	utilized	for	validation	consensus	molecular	subtype	4	cms4	53	85	and	cms2	38	46	were	enriched	in	the	young	40	years	and	old	60	years	age	groups	respectively	a	cms4	associated	gene	platelet	derived	growth	factor	receptor	α	pdgfra	was	significantly	upregulated	in	young	patients	with	crc	fc	3	21	p	0	0001	and	was	negatively	correlated	with	age	p	0	0001	r	0	526	moreover	pdgfra	showed	a	positive	co	expression	with	metastasis	related	genes	in	young	crc	patients	in	vitro	validation	confirmed	that	young	patient	derived	cells	pdcs	showed	an	enriched	expression	of	pdgfra	compared	to	old	pdcs	and	a	reduced	proliferation	rate	by	knockdown	of	pdgfra	furthermore	young	crc	patients	were	more	sensitive	to	regorafenib	a	pdgfra	targeting	drug	than	old	crc	patients	our	study	suggests	that	crc	in	young	patients	is	associated	with	cms4	and	pdgfra	in	addition	pdgfra	may	serve	potential	of	novel	therapeutic	strategies	and	represent	a	predictive	biomarker	of	response	to	regorafenib	for	young	crc	patients</Paragraph></Rec>
<Rec><Paragraph>new	tumor	biomarkers	are	needed	to	improve	the	management	of	colon	cancer	cc	the	second	leading	cause	of	cancer	related	deaths	in	the	united	states	carcinoembryonic	antigen	cea	the	translated	protein	of	carcinoembryonic	antigen	related	cell	adhesion	molecule	5	ceacam5	gene	is	used	as	a	biomarker	for	cc	cartilage	oligomeric	matrix	protein	comp	is	overexpressed	in	cc	compared	to	normal	colon	tissues	this	study	aims	to	evaluate	the	expression	of	comp	by	disease	stage	consensus	molecular	subtype	cms	its	impact	on	disease	outcomes	and	comparison	to	ceacam5	rna	seq	data	from	456	cc	the	cancer	genome	atlas	samples	and	41	matching	control	samples	were	analyzed	for	comp	expression	and	ceacam5	expression	we	stratified	tumor	samples	by	stage	i	iv	subtype	cms1	cms4	tumor	location	and	kirsten	rat	sarcoma	kras	mutant	status	and	three	quartiles	were	established	based	on	comp	expression	kaplan	meier	survival	outcomes	were	evaluated	comp	expression	was	significantly	higher	in	tumor	samples	with	elevation	of	expression	occurring	in	stage	i	and	significantly	increasing	in	stage	iv	increased	comp	expression	occurs	in	cms4	with	relatively	low	expression	in	cms3	no	significant	expression	difference	was	attributed	to	tumor	location	and	kras	mutant	status	compared	to	ceacam5	comp	was	a	stronger	molecular	marker	across	stages	and	subtypes	cms4	was	associated	with	the	high	comp	expression	and	higher	levels	of	comp	were	associated	with	poorer	overall	survival	disease	specific	survival	and	tumor	progression	free	intervals	cms2	and	3	were	associated	with	low	expression	and	better	survival	comp	is	a	potential	molecular	biomarker	for	cc	and	may	be	superior	to	cea	as	an	indicator	of	cc</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancers	crc	can	be	classified	into	four	consensus	molecular	subtypes	cms	among	which	cms1	has	the	best	prognosis	contrasting	with	cms4	that	has	the	worst	outcome	cms4	crc	is	notoriously	resistant	against	therapeutic	interventions	as	demonstrated	by	preclinical	studies	and	retrospective	clinical	observations	here	we	report	the	finding	that	two	clinically	employed	agents	everolimus	eve	and	plicamycin	pli	efficiently	target	the	prototypic	cms4	cell	line	mdst8	as	compared	to	the	prototypic	cms1	cell	line	lovo	mdst8	cells	treated	with	eve	or	pli	demonstrated	stronger	cytostatic	and	cytotoxic	effects	increased	signs	of	apoptosis	and	autophagy	as	well	as	a	more	pronounced	inhibition	of	dna	to	rna	transcription	and	rna	to	protein	translation	moreover	nontoxic	doses	of	eve	and	pli	induced	the	shrinkage	of	mdst8	tumors	in	mice	yet	had	only	minor	tumor	growth	reducing	effects	on	lovo	tumors	altogether	these	results	suggest	that	eve	and	pli	should	be	evaluated	for	their	clinical	activity	against	cms4	crc</Paragraph></Rec>
<Rec><Paragraph>the	implications	of	intratumor	heterogeneity	on	the	four	consensus	molecular	subtypes	cms	of	colorectal	cancer	crc	are	not	well	known	here	we	use	single	cell	rna	sequencing	scrnaseq	to	build	an	algorithm	to	assign	cms	classification	to	individual	cells	which	we	use	to	explore	the	distributions	of	cmss	in	tumor	and	non	tumor	cells	a	dataset	of	colorectal	tumors	with	bulk	rnaseq	n	3232	was	used	to	identify	cms	specific	marker	gene	sets	these	gene	sets	were	then	applied	to	a	discovery	dataset	of	scrnaseq	profiles	n	10	to	develop	an	algorithm	for	single	cell	cms	sccms	assignment	which	recapitulated	the	intrinsic	biology	of	all	four	cmss	the	single	cell	cms	assignment	algorithm	was	used	to	explore	the	scrnaseq	profiles	of	two	prospective	crc	tumors	with	mixed	cms	via	bulk	sequencing	we	find	that	every	crc	tumor	contains	individual	cells	of	each	sccms	as	well	as	many	individual	cells	that	have	enrichment	for	features	of	more	than	one	sccms	called	mixed	cells	sccms4	and	sccms1	cells	dominate	stroma	and	immune	cell	clusters	respectively	but	account	for	less	than	3	epithelial	cells	these	data	imply	that	cms1	and	cms4	are	driven	by	the	transcriptomic	contribution	of	immune	and	stromal	cells	respectively	not	tumor	cells</Paragraph></Rec>
<Rec><Paragraph>recent	advances	in	anticancer	therapy	have	shown	dramatic	improvements	in	clinical	outcomes	and	adoptive	cell	therapy	has	emerged	as	a	type	of	immunotherapy	that	can	modulate	immune	responses	by	transferring	engineered	immune	cells	however	a	small	percentage	of	responders	and	their	toxicity	remain	as	challenges	three	dimensional	3d	in	vitro	models	of	the	tumor	microenvironment	tme	have	the	potential	to	provide	a	platform	for	assessing	and	predicting	responses	to	therapy	this	paper	describes	an	in	vitro	3d	tumor	model	that	incorporates	clusters	of	colorectal	cancer	crc	cells	around	perfusable	vascular	networks	to	validate	immune	cell	mediated	cytotoxicity	against	cancer	cells	the	platform	is	based	on	an	injection	molded	3d	co	culture	model	and	composed	of	28	microwells	where	separate	identical	vascularized	cancer	models	can	be	formed	it	allows	robust	hydrogel	patterning	for	3d	culture	that	enables	high	throughput	experimentation	the	uniformity	of	the	devices	resulted	in	reproducible	experiments	that	allowed	10	more	experiments	to	be	performed	when	compared	to	conventional	polydimethylsiloxane	pdms	based	microfluidic	devices	to	demonstrate	its	capability	primary	natural	killer	nk	cells	were	introduced	into	the	vascularized	tumor	network	and	their	activities	were	monitored	using	live	cell	imaging	extravasation	migration	and	cytotoxic	activity	against	six	types	of	crc	cell	lines	were	tested	and	compared	the	consensus	molecular	subtypes	cms	of	crc	with	distinct	immune	responses	resulted	in	the	highest	nk	cell	cytotoxicity	against	cms1	cancer	cells	these	results	show	the	potential	of	our	vascularized	tumor	model	for	understanding	various	steps	involved	in	the	immune	response	for	the	assessment	of	adoptive	cell	therapy</Paragraph></Rec>
<Rec><Paragraph>strict	clinical	criteria	used	by	medicare	for	germline	testing	for	lynch	syndrome	ls	could	lead	to	missed	diagnoses	of	hereditary	cancer	syndromes	given	variable	individual	and	family	phenotypes	the	aim	of	this	study	was	to	compare	rates	and	spectrum	of	pathogenic	or	likely	pathogenic	p	lp	variants	in	ls	and	other	hereditary	cancer	genes	on	the	basis	of	meeting	medicare	ls	testing	criteria	retrospective	review	of	medicare	beneficiaries	who	had	multigene	panel	testing	with	an	indication	of	personal	or	family	history	of	colorectal	cancer	crc	was	performed	ordering	providers	determined	if	medicare	ls	criteria	were	met	the	results	of	genetic	testing	were	compared	on	the	basis	of	whether	or	not	medicare	testing	criteria	were	met	among	639	medicare	beneficiaries	495	77	5	met	testing	criteria	overall	rates	of	p	lp	variant	identification	were	similar	between	those	meeting	and	not	meeting	testing	criteria	18	4	v	11	8	p	06	ls	was	diagnosed	more	frequently	among	those	meeting	testing	criteria	10	1	v	4	9	p	05	no	statistical	differences	were	found	in	rates	of	p	lp	variant	identification	for	non	ls	crc	genes	5	3	v	5	6	p	89	or	non	crc	genes	4	2	v	2	1	p	23	pms2	mutyh	and	atm	p	lp	variants	were	found	at	higher	rates	among	those	outside	of	criteria	among	medicare	beneficiaries	undergoing	genetic	testing	for	suspected	ls	rates	of	p	lp	variants	in	actionable	cancer	genes	were	similar	regardless	of	whether	testing	criteria	were	met	current	testing	criteria	fail	to	identify	individuals	with	p	lp	variants	in	pms2	and	other	actionable	cancer	genes	relaxing	ls	testing	criteria	could	improve	identification	of	individuals	with	hereditary	cancer	syndromes	among	medicare	beneficiaries</Paragraph></Rec>
<Rec><Paragraph>the	role	of	the	proangiogenic	factor	olfactomedin	like	3	olfml3	in	cancer	is	unclear	to	characterize	olfml3	expression	in	human	cancer	and	its	role	during	tumor	development	we	undertook	tissue	expression	studies	gene	expression	analyses	of	patient	tumor	samples	in	vivo	studies	in	mouse	cancer	models	and	in	vitro	coculture	experiments	olfml3	was	expressed	at	high	levels	mainly	in	blood	vessels	in	multiple	human	cancers	we	focused	on	colorectal	cancer	crc	as	elevated	expression	of	olfml3	mrna	correlated	with	shorter	relapse	free	survival	higher	tumor	grade	and	angiogenic	microsatellite	stable	consensus	molecular	subtype	4	cms4	treatment	of	multiple	in	vivo	tumor	models	with	olfml3	blocking	antibodies	and	deletion	of	the	olfml3	gene	from	mice	decreased	lymphangiogenesis	pericyte	coverage	and	tumor	growth	antibody	mediated	blockade	of	olfml3	and	deletion	of	host	olfml3	decreased	the	recruitment	of	tumor	promoting	tumor	associated	macrophages	and	increased	infiltration	of	the	tumor	microenvironment	by	nkt	cells	importantly	targeting	olfml3	increased	the	antitumor	efficacy	of	anti	pd	1	checkpoint	inhibitor	therapy	taken	together	the	results	demonstrate	that	olfml3	is	a	promising	candidate	therapeutic	target	for	crc</Paragraph></Rec>
<Rec><Paragraph>to	study	the	impact	of	transarterial	yttrium	90	radioembolization	tare	in	combination	with	second	line	systemic	chemotherapy	for	colorectal	liver	metastases	clm	in	this	international	multicenter	open	label	phase	iii	trial	patients	with	clm	who	progressed	on	oxaliplatin	or	irinotecan	based	first	line	therapy	were	randomly	assigned	1	1	to	receive	second	line	chemotherapy	with	or	without	tare	the	two	primary	end	points	were	progression	free	survival	pfs	and	hepatic	pfs	hpfs	assessed	by	blinded	independent	central	review	random	assignment	was	performed	using	a	web	or	voice	based	system	stratified	by	unilobar	or	bilobar	disease	oxaliplatin	or	irinotecan	based	first	line	chemotherapy	and	kras	mutation	status	four	hundred	twenty	eight	patients	from	95	centers	in	north	america	europe	and	asia	were	randomly	assigned	to	chemotherapy	with	or	without	tare	this	represents	the	intention	to	treat	population	and	included	215	patients	in	the	tare	plus	chemotherapy	group	and	213	patients	in	the	chemotherapy	alone	group	the	hazard	ratio	hr	for	pfs	was	0	69	95	ci	0	54	to	0	88	1	sided	p	0013	with	a	median	pfs	of	8	0	95	ci	7	2	to	9	2	and	7	2	95	ci	5	7	to	7	6	months	respectively	the	hr	for	hpfs	was	0	59	95	ci	0	46	to	0	77	1	sided	p	0001	with	a	median	hpfs	of	9	1	95	ci	7	8	to	9	7	and	7	2	95	ci	5	7	to	7	6	months	respectively	objective	response	rates	were	34	0	95	ci	28	0	to	40	5	and	21	1	95	ci	16	2	to	27	1	1	sided	p	0019	for	the	tare	and	chemotherapy	groups	respectively	median	overall	survival	was	14	0	95	ci	11	8	to	15	5	and	14	4	months	95	ci	12	8	to	16	4	1	sided	p	7229	with	a	hr	of	1	07	95	ci	0	86	to	1	32	for	tare	and	chemotherapy	groups	respectively	grade	3	adverse	events	were	reported	more	frequently	with	tare	68	4	v	49	3	both	groups	received	full	chemotherapy	dose	intensity	the	addition	of	tare	to	systemic	therapy	for	second	line	clm	led	to	longer	pfs	and	hpfs	further	subset	analyses	are	needed	to	better	define	the	ideal	patient	population	that	would	benefit	from	tare</Paragraph></Rec>
<Rec><Paragraph>consensus	molecular	subtypes	cmss	can	guide	precision	treatment	of	colorectal	cancer	crc	we	aim	to	identify	methylation	markers	to	distinguish	between	cms2	and	cms3	in	patients	with	crc	for	which	an	easy	test	is	currently	lacking	to	this	aim	fresh	frozen	tumor	tissue	of	239	patients	with	stage	i	iii	crc	was	analyzed	methylation	profiles	were	obtained	using	the	infinium	humanmethylation450	beadchip	we	performed	adaptive	group	regularized	logistic	ridge	regression	with	post	hoc	group	weighted	elastic	net	marker	selection	to	build	prediction	models	for	classification	of	cms2	and	cms3	the	cancer	genome	atlas	tcga	data	were	used	for	validation	group	regularization	of	the	probes	was	done	based	on	their	location	either	relative	to	a	cpg	island	or	relative	to	a	gene	present	in	the	cms	classifier	resulting	in	two	different	prediction	models	and	subsequently	different	marker	panels	for	both	panels	even	when	using	only	five	markers	accuracies	were	90	in	our	cohort	and	in	the	tcga	validation	set	our	methylation	marker	panel	accurately	distinguishes	between	cms2	and	cms3	this	enables	development	of	a	targeted	assay	to	provide	a	robust	and	clinically	relevant	classification	tool	for	crc	patients</Paragraph></Rec>
<Rec><Paragraph>the	xelaviri	trial	compared	sequential	fluoropyrimidine	and	bevacizumab	irinotecan	iri	at	progression	versus	initial	combination	therapy	fluoropyrimidine	bevacizumab	iri	of	treatment	naïve	metastatic	colorectal	cancer	mcrc	in	the	confirmatory	analysis	the	primary	end	point	non	inferiority	of	sequential	therapy	regarding	time	to	failure	of	strategy	tfs	was	not	met	nevertheless	significant	differences	regarding	treatment	efficacy	were	observed	according	to	ras	status	here	we	evaluate	the	consensus	molecular	subtypes	cms	as	additional	biomarkers	for	sequential	versus	combination	therapy	gene	expression	was	measured	using	nanostring	after	mrna	extraction	from	formalin	fixed	paraffin	embedded	tumour	specimens	cms	were	predicted	using	multinomial	regression	and	correlated	with	updated	data	for	tfs	overall	os	and	progression	free	survival	cms	were	predicted	in	337	of	421	80	0	patients	cms1	18	4	cms2	51	6	cms3	2	7	cms4	27	3	cms2	together	with	ras	braf	wild	type	status	was	identified	as	potential	predictive	marker	of	benefit	from	initial	combination	therapy	for	os	hr	0	56	95	ci	0	33	0	96	p	0	036	and	progression	free	survival	hr	0	28	95	ci	0	29	0	79	p	0	004	and	also	trending	in	tfs	hr	0	63	90	ci	0	41	0	95	p	0	066	in	patients	with	ras	mutated	mcrc	cms1	was	associated	with	longer	os	after	initial	combination	therapy	hr	0	43	95	ci	0	20	0	95	p	0	038	interaction	testing	two	sided	of	cms	and	ras	braf	status	in	favour	of	the	combination	treatment	strategy	was	significant	for	os	p	0	012	conclusions	in	patients	with	ras	braf	wild	type	mcrc	cms2	may	serve	as	an	additional	biomarker	of	benefit	from	the	initial	combination	therapy	including	iri	trial	registration	id	clinicaltrials	gov	nct01249638</Paragraph></Rec>
<Rec><Paragraph>transcriptomic	based	subtyping	consensus	molecular	subtyping	cms	and	colorectal	cancer	intrinsic	subtyping	cris	identify	a	patient	subpopulation	with	mesenchymal	traits	cms4	cris	b	and	poorer	outcome	here	we	investigated	the	relationship	between	prevalence	of	fusobacterium	nucleatum	fn	and	fusobacteriales	cms	cris	subtyping	cell	type	composition	immune	infiltrates	and	host	contexture	to	refine	patient	stratification	and	to	identify	druggable	context	specific	vulnerabilities	we	coupled	cell	culture	experiments	with	characterisation	of	fn	fusobacteriales	prevalence	and	host	biology	microenviroment	in	tumours	from	two	independent	colorectal	cancer	patient	cohorts	taxonomy	n	140	colon	and	rectal	cases	of	the	cancer	genome	atlas	tcga	coad	read	cohort	n	605	in	vitro	fn	infection	induced	inflammation	via	nuclear	factor	kappa	light	chain	enhancer	of	activated	b	cells	tumour	necrosis	factor	alpha	in	hct116	and	ht29	cancer	cell	lines	in	patients	high	fn	fusobacteriales	were	found	in	cms1	microsatellite	unstable	tumours	with	infiltration	of	m1	macrophages	reduced	m2	macrophages	and	high	interleukin	il	6	il	8	il	1β	signalling	analysis	of	the	taxonomy	cohort	suggested	that	fn	was	prognostic	for	cms4	cris	b	patients	despite	having	lower	fn	load	than	cms1	patients	in	the	tcga	coad	read	cohort	we	likewise	identified	a	differential	association	between	fusobacteriales	relative	abundance	and	outcome	when	stratifying	patients	in	mesenchymal	either	cms4	and	or	cris	b	versus	non	mesenchymal	neither	cms4	nor	cris	b	patients	with	mesenchymal	tumours	and	high	fusobacteriales	had	approximately	twofold	higher	risk	of	worse	outcome	these	associations	were	null	in	non	mesenchymal	patients	modelling	the	three	way	association	between	fusobacteriales	prevalence	molecular	subtyping	and	host	contexture	with	logistic	models	with	an	interaction	term	disentangled	the	pathogen	host	signalling	relationship	and	identified	aberrations	including	notch	csf1	3	and	il	6	il	8	as	candidate	targets	this	study	identifies	cms4	cris	b	patients	with	high	fn	fusobacteriales	prevalence	as	a	high	risk	subpopulation	that	may	benefit	from	therapeutics	targeting	mesenchymal	biology</Paragraph></Rec>
<Rec><Paragraph>the	backbone	of	all	colorectal	cancer	classifications	including	the	consensus	molecular	subtypes	cms	highlights	microsatellite	instability	msi	as	a	key	molecular	pathway	although	mucinous	histology	generally	defined	as	50	extracellular	mucin	to	tumor	area	is	a	typical	feature	of	msi	it	is	not	limited	to	this	subgroup	here	we	investigate	the	association	of	cms	classification	and	mucin	to	tumor	area	quantified	using	a	deep	learning	algorithm	and	the	expression	of	specific	mucins	in	predicting	cms	groups	and	clinical	outcome	a	weakly	supervised	segmentation	method	was	developed	to	quantify	extracellular	mucin	to	tumor	area	in	h	e	images	performance	was	compared	to	two	pathologists	scores	then	applied	to	two	cohorts	1	tcga	n	871	slides	412	patients	used	for	mucin	cms	group	correlation	and	2	bern	n	775	slides	517	patients	for	histopathological	correlations	and	next	generation	tissue	microarray	construction	tcga	and	cptac	n	85	patients	were	used	to	further	validate	mucin	detection	and	cms	classification	by	gene	and	protein	expression	analysis	for	muc2	muc4	muc5ac	and	muc5b	an	excellent	inter	observer	agreement	between	pathologists	scores	and	the	algorithm	was	obtained	icc	0	92	in	tcga	mucinous	tumors	were	predominantly	cms1	25	7	cms3	24	6	and	cms4	16	2	average	mucin	in	cms2	was	1	8	indicating	negligible	amounts	rna	and	protein	expression	of	muc2	muc4	muc5ac	and	muc5b	were	low	to	absent	in	cms2	muc5ac	protein	expression	correlated	with	aggressive	tumor	features	e	g	distant	metastases	p	0	0334	braf	mutation	p	0	0001	mismatch	repair	deficiency	p	0	0001	and	unfavorable	5	year	overall	survival	44	versus	65	for	positive	negative	staining	muc2	expression	showed	the	opposite	trend	correlating	with	less	lymphatic	p	0	0096	and	venous	vessel	invasion	p	0	0023	no	impact	on	survival	the	absence	of	mucin	expressing	tumors	in	cms2	provides	an	important	phenotype	genotype	correlation	together	with	msi	mucinous	histology	may	help	predict	cms	classification	using	only	histopathology	and	should	be	considered	in	future	image	classifiers	of	molecular	subtypes</Paragraph></Rec>
<Rec><Paragraph>regorafenib	reg	is	approved	for	the	treatment	of	metastatic	colorectal	cancer	but	has	modest	survival	benefit	and	associated	toxicities	robust	predictive	early	response	biomarkers	to	aid	patient	stratification	are	outstanding	we	have	exploited	biological	pathway	analyses	in	a	patient	derived	xenograft	pdx	trial	to	study	reg	response	mechanisms	and	elucidate	putative	biomarkers	molecularly	subtyped	pdxs	were	annotated	for	reg	response	subtyping	was	based	on	gene	expression	cms	consensus	molecular	subtype	and	copy	number	alteration	cna	baseline	tumor	vascularization	apoptosis	and	proliferation	signatures	were	studied	to	identify	predictive	biomarkers	within	subtypes	phospho	proteomic	analysis	was	used	to	identify	novel	classifiers	supervised	rna	sequencing	analysis	was	performed	on	pdxs	that	progressed	or	did	not	progress	following	reg	treatment	improved	reg	response	was	observed	in	cms4	although	intra	subtype	response	was	variable	tumor	vascularity	did	not	correlate	with	outcome	in	cms4	tumors	reduced	proliferation	and	higher	sensitivity	to	apoptosis	at	baseline	correlated	with	response	reverse	phase	protein	array	rppa	analysis	revealed	4	phospho	proteomic	clusters	one	of	which	was	enriched	with	non	progressor	models	a	classification	decision	tree	trained	on	rppa	and	cms	based	assignments	discriminated	non	progressors	from	progressors	with	92	overall	accuracy	97	sensitivity	67	specificity	supervised	rna	sequencing	revealed	that	higher	basal	epha2	expression	is	associated	with	reg	resistance	subtype	classification	systems	represent	canonical	termini	a	quo	starting	points	to	support	reg	biomarker	identification	and	provide	a	platform	to	identify	resistance	mechanisms	and	novel	contexts	of	vulnerability	incorporating	functional	characterization	of	biological	systems	may	optimize	the	biomarker	identification	process	for	multitargeted	kinase	inhibitors</Paragraph></Rec>
<Rec><Paragraph>obesity	is	a	strong	risk	factor	for	cancer	progression	posing	obesity	related	cancer	as	one	of	the	leading	causes	of	death	nevertheless	the	molecular	mechanisms	that	endow	cancer	cells	with	metastatic	properties	in	patients	affected	by	obesity	remain	unexplored	here	we	show	that	il	6	and	hgf	secreted	by	tumor	neighboring	visceral	adipose	stromal	cells	v	ascs	expand	the	metastatic	colorectal	cr	cancer	cell	compartment	cd44v6	which	in	turn	secretes	neurotrophins	such	as	ngf	and	nt	3	and	recruits	adipose	stem	cells	within	tumor	mass	visceral	adipose	derived	factors	promote	vasculogenesis	and	the	onset	of	metastatic	dissemination	by	activation	of	stat3	which	inhibits	mir	200a	and	enhances	zeb2	expression	effectively	reprogramming	crc	cells	into	a	highly	metastatic	phenotype	notably	obesity	associated	tumor	microenvironment	provokes	a	transition	in	the	transcriptomic	expression	profile	of	cells	derived	from	the	epithelial	consensus	molecular	subtype	cms2	crc	patients	towards	a	mesenchymal	subtype	cms4	stat3	pathway	inhibition	reduces	zeb2	expression	and	abrogates	the	metastatic	growth	sustained	by	adipose	released	proteins	together	our	data	suggest	that	targeting	adipose	factors	in	colorectal	cancer	patients	with	obesity	may	represent	a	therapeutic	strategy	for	preventing	metastatic	disease</Paragraph></Rec>
<Rec><Paragraph>two	distinct	genetic	mutational	pathways	characterized	by	either	chromosomal	instability	or	high	frequency	microsatellite	instability	msi	h	are	recognized	in	the	pathogenesis	of	colorectal	cancer	crc	recently	it	has	been	shown	that	patients	with	primary	crc	that	displays	msi	h	have	a	significant	stage	independent	multivariate	survival	advantage	biological	properties	of	cms1	msi	h	type	can	affect	therapeutic	efficiencies	of	agents	used	in	the	treatment	of	crc	and	therefore	become	a	new	predictive	factor	of	the	treatment	but	the	predictive	impact	of	msi	h	status	for	adjuvant	chemotherapy	remains	controversial	this	study	will	assess	whether	there	is	any	unnecessary	or	inappropriate	use	of	treatment	agents	recommended	for	adjuvant	therapy	of	stage	2	and	3	of	disease	and	for	palliative	or	curative	treatment	of	liver	metastatic	disease	in	microsatellite	instability	high	group	a	molecular	subtype	of	colon	cancer	within	this	scope	the	efficiencies	of	fluorouracil	and	oxaliplatin	based	chemotherapeutic	agents	will	be	shown	on	stage	3	microsatellite	instability	high	colon	tumor	cell	lines	first	and	then	a	microfluidic	model	will	be	created	imitating	the	metastasis	of	colon	cancer	to	the	liver	in	the	microfluidic	chip	model	we	will	create	in	liver	tissue	where	the	metastasis	of	microsatellite	instability	high	colon	cancer	will	be	simulated	the	effectiveness	of	chemotherapeutic	agents	immunotherapy	agents	and	targeted	agents	on	tumor	cells	as	well	as	drug	response	will	be	assessed	according	to	cell	viability	through	released	biomarkers	from	the	cells	the	proposed	hypothesis	study	includes	the	modeling	and	treatment	of	patient	derived	post	metastatic	liver	cancer	in	microfluidics	which	has	priority	at	the	global	and	our	region	and	consequently	develop	personal	medication</Paragraph></Rec>
<Rec><Paragraph>to	establish	an	artificial	intelligence	assisted	diagnosis	system	for	molecular	subtyping	of	colorectal	cancer	crc	812	whole	slide	images	wsis	of	422	patients	were	selected	from	the	database	of	the	cancer	genome	atlas	tcga	and	were	put	into	the	training	set	75	and	the	test	set	25	the	slides	were	stored	in	the	www	paiwsit	com	database	we	preprocessed	and	segmented	the	slides	based	on	the	labelling	results	of	experienced	pathologists	to	generate	a	training	set	of	more	than	4	million	labeled	samples	finally	deep	learning	models	were	adopted	for	training	after	training	with	several	convolutional	neural	network	models	we	tested	the	performance	of	the	trained	deep	learning	model	on	the	test	set	of	203	wsis	from	110	patients	and	our	model	achieved	an	accuracy	of	53	04	at	patch	level	and	51	72	at	slide	level	while	the	accuracy	of	cms2	one	of	a	consensus	of	four	subtypes	for	crc	at	slide	level	was	as	high	as	75	00	this	study	is	of	great	significance	to	the	promotion	of	colorectal	cancer	screening	and	precision	treatment</Paragraph></Rec>
<Rec><Paragraph>lynch	syndrome	ls	is	caused	by	a	pathogenic	heterozygous	germline	variant	in	one	of	the	dna	mismatch	repair	mmr	genes	mlh1	msh2	msh6	or	pms2	ls	associated	colorectal	carcinomas	crcs	are	characterized	by	mmr	deficiency	and	by	accumulation	of	multiple	insertions	deletions	at	coding	microsatellites	cms	mmr	deficiency	induced	variants	at	defined	cms	loci	have	a	driver	function	and	promote	tumorigenesis	notably	pms2	variant	carriers	face	only	a	slightly	increased	risk	of	developing	crc	here	we	investigate	whether	this	lower	penetrance	is	also	reflected	by	differences	in	molecular	features	and	cms	variant	patterns	tumor	dna	was	extracted	from	formalin	fixed	paraffin	embedded	ffpe	tissue	cores	or	sections	n	90	tumors	originated	from	genetically	proven	germline	pathogenic	mmr	variant	carriers	including	14	pms2	deficient	tumors	the	mutational	spectrum	was	analyzed	using	fluorescently	labeled	primers	specific	for	18	cms	previously	described	as	mutational	targets	in	mmr	deficient	tumors	immune	cell	infiltration	was	analyzed	by	immunohistochemical	detection	of	t	cells	on	ffpe	tissue	sections	the	cms	spectrum	of	pms2	deficient	crcs	did	not	show	any	significant	differences	from	mlh1	msh2	deficient	crcs	pms2	deficient	tumors	however	displayed	lower	cd3	positive	t	cell	infiltration	compared	to	other	mmr	deficient	cancers	28	00	vs	55	00	per	0	1	mm	2	p	0	0025	our	study	demonstrates	that	the	spectrum	of	potentially	immunogenic	cms	variants	in	crcs	from	pms2	gene	variant	carriers	is	similar	to	that	observed	in	crcs	from	other	mmr	gene	variant	carriers	lower	immune	cell	infiltration	observed	in	pms2	deficient	crcs	could	be	the	result	of	alternative	mechanisms	of	immune	evasion	or	immune	cell	exclusion	similar	to	those	seen	in	mmr	proficient	tumors</Paragraph></Rec>
<Rec><Paragraph>intratumor	heterogeneity	ith	is	described	as	the	presence	of	various	clones	within	one	tumor	each	with	their	own	unique	features	in	terms	of	morphology	inflammation	genetics	or	transcriptomics	heterogeneity	provides	the	fuel	for	drug	resistance	therefore	an	accurate	assessment	of	tumor	heterogeneity	is	essential	for	the	development	of	effective	therapies	the	purpose	of	this	study	was	to	dissect	morphologic	and	molecular	ith	in	colorectal	adenocarcinoma	a	series	of	120	v600e	braf	mutated	v600e	brafmt	consecutive	metastatic	colorectal	adenocarcinomas	was	assessed	for	morphologic	heterogeneity	the	two	heterogeneous	components	of	each	specimen	underwent	a	histopathological	immunohistochemical	and	molecular	characterization	to	evaluate	histologic	variant	grading	tumor	infiltrating	lymphocytes	tils	mismatch	repair	proteins	expression	kras	braf	nras	mutations	microsatellite	instability	msi	status	and	consensus	molecular	subtype	cms	thirty	one	out	of	120	25	8	v600e	brafmt	primary	colorectal	adenocarcinomas	presented	a	heterogeneous	morphology	among	these	eight	cases	had	adequate	material	for	molecular	profiling	five	out	of	the	eight	62	5	cases	resulted	instable	at	msi	testing	the	majority	62	5	of	the	samples	showed	a	cms4	phenotype	based	on	gene	expression	profiling	heterogeneity	in	cms	classification	was	observed	in	four	out	of	eight	cases	one	out	of	eight	cases	presented	significant	heterogeneity	in	the	number	of	tils	between	the	two	components	of	the	tumor	although	the	distribution	of	the	immune	infiltrate	appears	relatively	conserved	among	heterogeneous	areas	of	the	same	tumor	changes	in	gene	expression	profile	and	cms	occur	in	50	of	v600e	brafmt	adenocarcinoma	cases	in	our	small	series	and	might	contribute	to	variability	in	response	to	anticancer	therapy	and	clinical	outcomes	assessment	of	morphological	and	molecular	ith	is	needed	to	improve	colorectal	cancer	classification	and	to	tailor	anticancer	treatments	and	should	be	included	in	the	pathology	report</Paragraph></Rec>
<Rec><Paragraph>gene	expression	based	subtypes	of	colorectal	cancer	have	clinical	relevance	but	the	representativeness	of	primary	tumors	and	the	consensus	molecular	subtypes	cms	for	metastatic	cancers	is	not	well	known	we	investigated	the	metastatic	heterogeneity	of	cms	the	best	approach	to	subtype	translation	was	delineated	by	comparisons	of	transcriptomic	profiles	from	317	primary	tumors	and	295	liver	metastases	including	multi	metastatic	samples	from	45	patients	and	14	primary	metastasis	sets	associations	were	validated	in	an	external	data	set	n	618	projection	of	metastases	onto	principal	components	of	primary	tumors	showed	that	metastases	were	depleted	of	cms1	immune	cms3	metabolic	signals	enriched	for	cms4	mesenchymal	stromal	signals	and	heavily	influenced	by	the	microenvironment	the	tailored	cms	classifier	available	in	an	updated	version	of	the	r	package	cmscaller	therefore	implemented	an	approach	to	regress	out	the	liver	tissue	background	the	majority	of	classified	metastases	were	either	cms2	or	cms4	nonetheless	subtype	switching	and	inter	metastatic	cms	heterogeneity	were	frequent	and	increased	with	sampling	intensity	poor	prognostic	value	of	cms1	3	metastases	was	consistent	in	the	context	of	intra	patient	tumor	heterogeneity</Paragraph></Rec>
<Rec><Paragraph>this	pilot	study	aimed	to	evaluate	the	congruency	in	consensus	molecular	subtypes	cms	of	primary	colorectal	cancer	and	corresponding	hepatic	metastasis	hm	rna	was	extracted	from	both	primary	colorectal	cancer	and	hm	from	ten	patients	sequenced	to	establish	gene	expression	profiles	and	classified	into	cms	clinical	data	were	collected	retrospectively	of	the	ten	patients	recruited	nine	had	primary	tumors	that	were	classifiable	seven	were	cms2	one	was	cms3	and	one	was	cms4	five	had	incongruent	classification	in	the	corresponding	hm	three	out	of	the	five	patients	with	incongruent	classification	had	received	adjuvant	chemotherapy	prior	to	hepatic	resection	a	change	in	cms	type	between	matched	primary	and	metastatic	colorectal	tumors	is	common	and	may	be	attributable	to	chemotherapy</Paragraph></Rec>
<Rec><Paragraph>nodal	an	embryonic	morphogen	in	tgf	β	family	is	related	with	tumorigenicity	and	progression	in	various	tumors	including	colorectal	cancer	crc	however	the	difference	of	nodal	expression	between	crc	and	colorectal	polyps	has	not	yet	been	investigated	besides	whether	nodal	can	be	used	as	a	marker	for	consensus	molecular	subtype	classification	4	cms4	of	crc	is	also	worth	studying	we	analyzed	nodal	expression	in	patients	of	crc	161	high	grade	intraepithelial	neoplasia	hgin	28	and	five	types	of	colorectal	polyps	116	the	nodal	expression	difference	among	groups	and	the	association	between	nodal	expression	and	clinicopathological	features	were	analyzed	two	categories	logistic	regression	model	was	used	to	predict	the	odds	ratio	or	of	risk	factors	for	high	tumor	stroma	percentage	tsp	and	roc	curve	was	used	to	assess	the	diagnostic	value	of	nodal	in	predicting	high	tsp	in	crc	we	found	that	nodal	expression	was	significantly	elevated	in	crc	and	hgin	p	0	0001	the	increased	expression	of	nodal	was	related	with	high	tsp	mismatch	repair	proficient	pmmr	status	lymph	node	metastasis	and	advanced	ajcc	stage	p	0	05	besides	nodal	expression	was	the	only	risk	factor	for	high	tsp	or	6	94	p	0	001	and	roc	curve	demonstrated	that	nodal	expression	was	able	to	efficiently	distinguish	high	and	low	tsp	in	conclusion	different	expression	of	nodal	between	crc	hgin	and	benign	lesions	is	suggestive	of	a	promoting	role	for	nodal	in	colorectal	tumor	progression	besides	nodal	might	also	be	used	as	a	potential	marker	for	cms4	subtype	of	crc</Paragraph></Rec>
<Rec><Paragraph>patient	selection	for	addition	of	anti	egfr	therapy	to	chemotherapy	for	patients	with	ras	and	braf	wildtype	metastatic	colorectal	cancer	can	still	be	optimised	here	we	investigate	the	effect	of	anti	egfr	therapy	on	survival	in	different	consensus	molecular	subtypes	cmss	and	stratified	by	primary	tumour	location	retrospective	analyses	using	the	immunohistochemistry	based	cms	classifier	were	performed	in	the	coin	first	line	oxaliplatin	backbone	with	or	without	cetuximab	and	piccolo	trial	second	line	irinotecan	with	or	without	panitumumab	tumour	tissue	was	available	for	323	patients	20	and	349	41	respectively	when	using	an	irinotecan	backbone	anti	egfr	therapy	is	effective	in	both	cms2	3	and	cms4	in	left	sided	primary	tumours	progression	free	survival	pfs	hr	0	44	95	ci	0	26	0	75	p	0	003	and	hr	0	12	95	ci	0	04	0	36	p	0	001	respectively	and	in	cms4	right	sided	tumours	pfs	hr	0	17	95	ci	0	04	0	71	p	0	02	efficacy	using	an	oxaliplatin	backbone	was	restricted	to	left	sided	cms2	3	tumours	hr	0	57	95	ci	0	36	0	96	p	0	034	the	subtype	specific	efficacy	of	anti	egfr	therapy	is	dependent	on	the	chemotherapy	backbone	this	may	provide	the	possibility	of	subtype	specific	treatment	strategies	for	a	more	optimal	use	of	anti	egfr	therapy</Paragraph></Rec>
<Rec><Paragraph>the	cms4	mesenchymal	subtype	of	colorectal	cancer	crc	is	associated	with	poor	prognosis	and	resistance	to	treatment	the	cellular	prion	protein	prp	c	is	overexpressed	in	cms4	tumors	and	controls	the	expression	of	a	panel	of	cms4	specific	genes	in	crc	cell	lines	here	we	sought	to	investigate	prp	c	downstream	pathways	that	may	underlie	its	role	in	cms4	crc	by	combining	gene	set	enrichment	analyses	and	gain	and	loss	of	function	approaches	in	crc	cell	lines	we	identify	the	integrin	linked	kinase	ilk	as	a	proximal	effector	of	prp	c	that	mediates	its	control	on	the	cms4	phenotype	we	further	leveraged	three	independent	large	crc	cohorts	to	assess	correlations	in	gene	expression	pattern	with	patient	outcomes	and	found	that	ilk	is	overexpressed	in	cms4	mesenchymal	tumors	and	confers	a	poor	prognosis	especially	when	combined	with	high	expression	of	the	prp	c	encoding	gene	prnp	of	note	we	discovered	that	the	prp	c	ilk	signaling	axis	controls	the	expression	and	activity	of	the	tryptophan	metabolizing	enzyme	indoleamine	2	3	dioxygenase	ido1	a	key	player	in	immune	tolerance	in	addition	we	monitored	alterations	in	the	levels	of	tryptophan	and	its	metabolites	of	the	kynurenine	pathway	in	the	plasma	of	metastatic	crc	patients	n	325	and	we	highlight	their	prognostic	value	in	combination	with	plasma	prp	c	levels	thus	the	prp	c	ilk	ido1	axis	plays	a	key	role	in	the	mesenchymal	subtype	of	crc	prp	c	and	ido1	targeted	strategies	may	represent	new	avenues	for	patient	stratification	and	treatment	in	crc</Paragraph></Rec>
<Rec><Paragraph>regular	colonoscopy	even	with	short	intervals	does	not	prevent	all	colorectal	cancers	crc	in	lynch	syndrome	ls	in	the	present	study	we	asked	whether	cancers	detected	under	regular	colonoscopy	surveillance	incident	cancers	are	phenotypically	different	from	cancers	detected	at	first	colonoscopy	prevalent	cancers	we	analyzed	clinical	histological	immunological	and	mutational	characteristics	including	panel	sequencing	and	high	throughput	coding	microsatellite	cms	analysis	in	28	incident	and	67	prevalent	ls	crcs	n	total	95	incident	cancers	presented	with	lower	uicc	and	t	stage	compared	to	prevalent	cancers	p	0	0005	the	majority	of	incident	cancers	21	28	were	detected	after	previous	colonoscopy	without	any	pathological	findings	on	the	molecular	level	incident	cancers	presented	with	a	significantly	lower	kras	codon	12	13	1	23	4	3	vs	11	21	52	p	0	0005	and	pathogenic	tp53	mutation	frequency	0	17	0	vs	7	21	33	3	p	0	0108	compared	to	prevalent	cancers	10	17	58	8	incident	cancers	harbored	one	or	more	truncating	apc	mutations	all	showing	mutational	signatures	of	mismatch	repair	mmr	deficiency	the	proportion	of	mmr	deficiency	related	mutational	events	was	significantly	higher	in	incident	compared	to	prevalent	crc	p	0	018	in	conclusion	our	study	identifies	a	set	of	features	indicative	of	biological	differences	between	incident	and	prevalent	cancers	in	ls	which	should	further	be	monitored	in	prospective	ls	screening	studies	to	guide	towards	optimized	prevention	protocols</Paragraph></Rec>
<Rec><Paragraph>the	consensus	molecular	subtypes	cms	represent	a	significant	advance	in	the	understanding	of	intertumor	heterogeneity	in	colon	cancer	intratumor	heterogeneity	ith	is	the	new	frontier	for	refining	prognostication	and	understanding	treatment	resistance	this	study	aims	at	deciphering	the	transcriptomic	ith	of	colon	cancer	and	understanding	its	potential	prognostic	implications	we	deconvoluted	the	transcriptomic	profiles	of	1	779	tumors	from	the	petacc8	trial	and	155	colon	cancer	cell	lines	as	weighted	sums	of	the	four	cmss	using	the	weighted	in	silico	pathology	wisp	algorithm	we	assigned	to	each	tumor	and	cell	line	a	combination	of	up	to	three	cms	subtypes	with	a	threshold	above	20	over	55	of	tumors	corresponded	to	mixtures	of	at	least	two	cmss	demonstrating	pervasive	ith	in	colon	cancer	of	note	ith	was	associated	with	shorter	disease	free	survival	dfs	and	overall	survival	hr	1	34	95	confidence	interval	ci	1	12	1	59	1	40	95	ci	1	14	1	71	respectively	moreover	we	uncovered	specific	combinations	of	cms	associated	with	dismal	prognosis	in	multivariate	analysis	ith	represents	the	third	parameter	explaining	dfs	variance	after	t	and	n	stages	at	a	cellular	level	combined	wisp	and	single	cell	transcriptomic	analysis	revealed	that	most	colon	cancer	cell	lines	are	a	mixture	of	cells	falling	into	different	cmss	indicating	that	ith	may	correspond	to	distinct	functional	statuses	of	colon	cancer	cells	this	study	shows	that	cms	based	transcriptomic	ith	is	frequent	in	colon	cancer	and	impacts	its	prognosis	cms	based	transcriptomic	ith	may	correspond	to	distinct	functional	statuses	of	colon	cancer	cells	suggesting	plasticity	between	cms	related	cell	populations	transcriptomic	ith	deserves	further	assessment	in	the	context	of	personalized	medicine</Paragraph></Rec>
<Rec><Paragraph>to	explore	the	potential	value	of	consensus	molecular	subtypes	cms	in	stage	ii	colon	cancer	treatment	selection	we	carried	out	an	early	cost	effectiveness	assessment	of	a	cms	based	strategy	for	adjuvant	chemotherapy	we	used	a	markov	cohort	model	to	evaluate	three	selection	strategies	i	the	dutch	guideline	strategy	mss	pt4	ii	the	mutation	based	strategy	mss	plus	a	braf	and	or	kras	mutation	or	mss	plus	pt4	and	iii	the	cms	based	strategy	cms4	or	pt4	outcomes	were	number	of	colon	cancer	deaths	per	1	000	patients	total	discounted	costs	per	patient	pp	and	quality	adjusted	life	years	qaly	pp	the	analyses	were	conducted	from	a	dutch	societal	perspective	the	robustness	of	model	predictions	was	assessed	in	sensitivity	analyses	to	evaluate	the	value	of	future	research	we	performed	a	value	of	information	voi	analysis	the	dutch	guideline	strategy	resulted	in	8	10	qalys	pp	and	total	costs	of	23	660	pp	the	cms	based	and	mutation	based	strategies	were	more	effective	and	more	costly	with	8	12	and	8	13	qalys	pp	and	24	643	and	24	542	pp	respectively	assuming	a	threshold	of	50	000	qaly	the	mutation	based	strategy	was	considered	as	the	optimal	strategy	in	an	incremental	analysis	however	the	voi	analysis	showed	substantial	decision	uncertainty	driven	by	the	molecular	markers	expected	value	of	partial	perfect	information	18m	on	the	basis	of	current	evidence	our	analyses	suggest	that	the	mutation	based	selection	strategy	would	be	the	best	use	of	resources	however	the	extensive	decision	uncertainty	for	the	molecular	markers	does	not	allow	selection	of	an	optimal	strategy	at	present	future	research	is	needed	to	eliminate	decision	uncertainty	driven	by	molecular	markers</Paragraph></Rec>
<Rec><Paragraph>the	consensus	molecular	subtypes	cmss	of	colorectal	cancer	crc	capture	tumor	heterogeneity	at	the	gene	expression	level	currently	a	restricted	number	of	molecular	features	are	used	to	guide	treatment	for	crc	we	summarize	the	evidence	on	the	clinical	value	of	the	cmss	we	systematically	identified	studies	in	medline	and	embase	that	evaluated	the	prognostic	and	predictive	value	of	cmss	in	crc	patients	a	random	effect	meta	analysis	was	performed	on	prognostic	data	predictive	data	were	summarized	in	local	disease	cms4	tumors	were	associated	with	worse	overall	survival	os	compared	with	cms1	hazard	ratio	hr	3	28	95	confidence	interval	1	27	to	8	47	and	cms2	cancers	hr	2	60	95	confidence	interval	1	93	to	3	50	in	metastatic	disease	cms1	consistently	had	worse	survival	than	cms2	4	os	hr	range	0	33	0	55	progression	free	survival	hr	range	0	53	0	89	adjuvant	chemotherapy	in	stage	ii	and	iii	crc	was	most	beneficial	for	os	in	cms2	and	cms3	hr	range	0	16	0	45	and	not	effective	in	cms4	tumors	in	metastatic	cms4	cancers	an	irinotecan	based	regimen	improved	outcome	compared	with	oxaliplatin	hr	range	0	31	0	72	the	addition	of	bevacizumab	seemed	beneficial	in	cms1	and	anti	epidermal	growth	factor	receptor	therapy	improved	outcome	for	kras	wild	type	cms2	patients	the	cms	classification	holds	clear	potential	for	clinical	use	in	predicting	both	prognosis	and	response	to	systemic	therapy	which	seems	to	be	independent	of	the	classifier	used	prospective	studies	are	warranted	to	support	implementation	of	the	cms	taxonomy	in	clinical	practice</Paragraph></Rec>
<Rec><Paragraph>enhancer	aberrations	are	beginning	to	emerge	as	a	key	epigenetic	feature	of	colorectal	cancers	crc	however	a	comprehensive	knowledge	of	chromatin	state	patterns	in	tumour	progression	heterogeneity	of	these	patterns	and	imparted	therapeutic	opportunities	remain	poorly	described	we	performed	comprehensive	epigenomic	characterisation	by	mapping	222	chromatin	profiles	from	69	samples	33	colorectal	adenocarcinomas	4	adenomas	21	matched	normal	tissues	and	11	colon	cancer	cell	lines	for	six	histone	modification	marks	h3k4me3	for	pol	ii	bound	and	cpg	rich	promoters	h3k4me1	for	poised	enhancers	h3k27ac	for	enhancers	and	transcriptionally	active	promoters	h3k79me2	for	transcribed	regions	h3k27me3	for	polycomb	repressed	regions	and	h3k9me3	for	heterochromatin	we	demonstrate	that	h3k27ac	marked	active	enhancer	state	could	distinguish	between	different	stages	of	crc	progression	by	epigenomic	editing	we	present	evidence	that	gains	of	tumour	specific	enhancers	for	crucial	oncogenes	such	as	ascl2	and	fzd10	was	required	for	excessive	proliferation	consistently	combination	of	mek	plus	bromodomain	inhibition	was	found	to	have	synergistic	effects	in	crc	patient	derived	xenograft	models	probing	intertumour	heterogeneity	we	identified	four	distinct	enhancer	subtypes	epigenome	based	classification	epic	three	of	which	correlate	well	with	previously	defined	transcriptomic	subtypes	consensus	molecular	subtypes	cmss	importantly	cms2	can	be	divided	into	two	epic	subgroups	with	significant	survival	differences	leveraging	such	correlation	we	devised	a	combinatorial	therapeutic	strategy	of	enhancer	blocking	bromodomain	inhibitors	with	pathway	specific	inhibitors	parpi	egfri	tgfβi	mtori	and	srci	for	epic	groups	our	data	suggest	that	the	dynamics	of	active	enhancer	underlies	crc	progression	and	the	patient	specific	enhancer	patterns	can	be	leveraged	for	precision	combination	therapy</Paragraph></Rec>
<Rec><Paragraph>phenotypic	plasticity	represents	the	most	relevant	hallmark	of	the	carcinoma	cell	as	it	bestows	it	with	the	capacity	of	transiently	altering	its	morphological	and	functional	features	while	en	route	to	the	metastatic	site	however	the	study	of	phenotypic	plasticity	is	hindered	by	the	rarity	of	these	events	within	primary	lesions	and	by	the	lack	of	experimental	models	here	we	identified	a	subpopulation	of	phenotypic	plastic	colon	cancer	cells	epcam	lo	cells	are	motile	invasive	chemo	resistant	and	highly	metastatic	epcam	lo	bulk	and	single	cell	rnaseq	analysis	indicated	1	enhanced	wnt	β	catenin	signaling	2	a	broad	spectrum	of	degrees	of	epithelial	to	mesenchymal	transition	emt	activation	including	hybrid	e	m	states	partial	emt	with	highly	plastic	features	and	3	high	correlation	with	the	cms4	subtype	accounting	for	colon	cancer	cases	with	poor	prognosis	and	a	pronounced	stromal	component	of	note	a	signature	of	genes	specifically	expressed	in	epcam	lo	cancer	cells	is	highly	predictive	of	overall	survival	in	tumors	other	than	cms4	thus	highlighting	the	relevance	of	quasi	mesenchymal	tumor	cells	across	the	spectrum	of	colon	cancers	enhanced	wnt	and	the	downstream	emt	activation	represent	key	events	in	eliciting	phenotypic	plasticity	along	the	invasive	front	of	primary	colon	carcinomas	distinct	sets	of	epithelial	and	mesenchymal	genes	define	transcriptional	trajectories	through	which	state	transitions	arise	pemt	cells	often	earmarked	by	the	extracellular	matrix	glycoprotein	sparc	together	with	nuclear	zeb1	and	β	catenin	along	the	invasive	front	of	primary	colon	carcinomas	are	predicted	to	represent	the	origin	of	these	de	differentiation	routes	through	biologically	distinct	cellular	states	and	to	underlie	the	phenotypic	plasticity	of	colon	cancer	cells</Paragraph></Rec>
<Rec><Paragraph>immunotherapy	has	achieved	efficacy	for	advanced	colorectal	cancer	crc	patients	with	a	mismatch	repair	deficient	dmmr	subtype	however	little	immunotherapy	efficacy	was	observed	in	patients	with	the	mismatch	repair	proficient	pmmr	subtype	and	hence	identifying	new	immune	therapeutic	targets	is	imperative	for	those	patients	in	this	study	transcriptome	data	of	stage	iii	iv	crc	patients	were	retrieved	from	the	gene	expression	omnibus	database	the	cibersort	algorithm	was	used	to	quantify	immune	cellular	compositions	and	the	results	revealed	that	m2	macrophage	fractions	were	higher	in	pmmr	patients	as	compared	with	those	with	the	dmmr	subtype	moreover	pmmr	patients	with	higher	m2	macrophage	fractions	experienced	shorter	overall	survival	os	subsequently	weighted	gene	co	expression	network	analysis	and	protein	protein	interaction	network	analysis	identified	six	hub	genes	related	to	m2	macrophage	infiltrations	in	pmmr	crc	patients	cald1	col6a1	col1a2	timp3	dcn	and	sparc	univariate	and	multivariate	cox	regression	analyses	then	determined	cald1	as	the	independent	prognostic	biomarker	for	os	cald1	was	upregulated	specifically	the	in	cms4	crc	subtype	and	single	sample	gene	set	enrichment	analysis	ssgsea	revealed	that	cald1	was	significantly	correlated	with	angiogenesis	and	tgf	β	signaling	gene	sets	enrichment	scores	in	stage	iii	iv	pmmr	crc	samples	the	estimation	of	stromal	and	immune	cells	in	malignant	tumor	tissues	using	expression	data	estimate	algorithm	and	correlation	analysis	revealed	that	cald1	was	significantly	associated	with	multiple	immune	and	stromal	components	in	a	tumor	microenvironment	in	addition	gsea	demonstrated	that	high	expression	of	cald1	was	significantly	correlated	with	antigen	processing	and	presentation	chemokine	signaling	leukocyte	transendothelial	migration	vascular	smooth	muscle	contraction	cytokine	cytokine	receptor	interaction	cell	adhesion	molecules	focal	adhesion	mapk	and	tgf	beta	signaling	pathways	furthermore	the	proliferation	invasion	and	migration	abilities	of	cancer	cells	were	suppressed	after	reducing	cald1	expression	in	crc	cell	lines	taken	together	multiple	bioinformatics	analyses	and	cell	level	assays	demonstrated	that	cald1	could	serve	as	a	prognostic	biomarker	and	a	prospective	therapeutic	target	for	stage	iii	iv	pmmr	crcs</Paragraph></Rec>
<Rec><Paragraph>constitutional	mismatch	repair	deficiency	syndrome	cmmrd	is	a	lethal	cancer	predisposition	syndrome	characterized	by	early	onset	synchronous	and	metachronous	multiorgan	tumors	we	designed	a	surveillance	protocol	for	early	tumor	detection	in	these	individuals	data	were	collected	from	patients	with	confirmed	cmmrd	who	were	registered	in	the	international	replication	repair	deficiency	consortium	tumor	spectrum	efficacy	of	the	surveillance	protocol	and	malignant	transformation	of	low	grade	lesions	were	examined	for	the	entire	cohort	survival	outcomes	were	analyzed	for	patients	followed	prospectively	from	the	time	of	surveillance	implementation	a	total	of	193	malignant	tumors	in	110	patients	were	identified	median	age	of	first	cancer	diagnosis	was	9	2	years	range	1	7	39	5	years	for	patients	undergoing	surveillance	all	gi	and	other	solid	tumors	and	75	of	brain	cancers	were	detected	asymptomatically	by	contrast	only	16	of	hematologic	malignancies	were	detected	asymptomatically	p	001	eighty	nine	patients	were	followed	prospectively	and	used	for	survival	analysis	five	year	overall	survival	os	was	90	95	ci	78	6	to	100	and	50	95	ci	39	2	to	63	7	when	cancer	was	detected	asymptomatically	and	symptomatically	respectively	p	001	patient	outcome	measured	by	adherence	to	the	surveillance	protocol	revealed	4	year	os	of	79	95	ci	54	8	to	90	9	for	patients	undergoing	full	surveillance	55	95	ci	28	5	to	74	5	for	partial	surveillance	and	15	95	ci	5	2	to	28	8	for	those	not	under	surveillance	p	0001	of	the	64	low	grade	tumors	detected	the	cumulative	likelihood	of	transformation	from	low	to	high	grade	was	81	for	gi	cancers	within	8	years	and	100	for	gliomas	in	6	years	surveillance	and	early	cancer	detection	are	associated	with	improved	os	for	individuals	with	cmmrd</Paragraph></Rec>
<Rec><Paragraph>the	lack	of	specific	targeting	therapy	to	precisely	identify	and	kill	malignant	cells	while	sparing	others	is	a	great	challenge	in	colorectal	cancer	crc	treatment	in	the	era	of	molecular	classification	of	tumors	crc	has	been	grouped	into	four	consensus	molecular	subtypes	accounting	for	37	of	all	types	the	cms2	group	canonical	type	shows	distinguishing	features	wnt	and	myc	signaling	activation	in	this	study	we	designed	an	rna	only	delivery	kill	switch	to	specifically	eliminate	cms2	type	crc	cells	the	sensing	and	logic	processing	functions	are	integrated	by	the	newly	engineered	l7ae	which	can	not	only	detect	the	stability	of	β	catenin	protein	and	the	presence	of	cytoplasm	located	myc	myc	nick	but	also	do	logic	computation	the	circuit	specifically	eliminated	hct	116	cells	while	sparing	other	kinds	of	cells	showing	a	proof	of	principle	approach	to	precisely	target	cms2	type	crc</Paragraph></Rec>
<Rec><Paragraph>there	is	a	patent	need	to	better	characterize	early	stage	colorectal	cancer	crc	patients	pd	1	ligand	pd	l1	expression	has	been	proposed	as	a	prognostic	factor	but	yields	mixed	results	in	different	settings	the	consensus	molecular	subtype	cms	classification	has	yet	to	be	integrated	into	clinical	practice	we	sought	to	evaluate	the	prognostic	value	of	pd	l1	expression	overall	and	within	cms	in	early	stage	colon	cancer	patients	in	the	hope	of	assisting	treatment	choice	in	this	setting	tissue	microarrays	were	constructed	from	tumor	samples	of	162	stage	ii	iii	crc	patients	they	underwent	automatic	immunohistochemical	staining	for	pd	l1	and	the	proposed	cms	panel	primary	endpoints	were	overall	survival	os	and	disease	free	survival	dfs	pd	l1	expression	was	significantly	and	independently	associated	with	better	prognosis	hr	0	46	0	26	0	82	p	0	009	and	was	mostly	seen	in	immune	cells	of	the	tumor	related	stroma	cms4	five	folds	the	risk	of	mortalitycompared	with	cms1	hr	5	58	1	36	22	0	p	0	034	in	the	subgroup	cms2	cms3	analysis	pd	l1	expression	significantly	differentiated	individuals	with	better	os	p	0	004	and	dfs	p	0	001	our	study	suggests	that	pd	l1	expression	is	an	independent	prognostic	factor	in	patients	with	stage	ii	iii	colon	cancer	additionally	it	successfully	differentiates	patients	with	better	prognosis	in	the	cms2	cms3	group	and	may	prove	significant	for	the	clinical	relevance	of	the	cms	classification</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	heterogeneous	disease	which	in	part	explains	the	differential	response	to	chemotherapy	observed	in	the	clinic	bh3	mimetics	which	target	anti	apoptotic	bcl	2	family	members	have	shown	potential	in	the	treatment	of	hematological	malignancies	and	offer	promise	for	the	treatment	of	solid	tumors	as	well	to	gain	a	comprehensive	understanding	of	the	response	to	bh3	mimetics	in	crc	and	the	underlying	molecular	factors	predicting	sensitivity	we	screened	a	panel	of	crc	cell	lines	with	four	bh3	mimetics	targeting	distinct	anti	apoptotic	bcl	2	proteins	treatment	with	compounds	alone	and	in	combination	revealed	potent	efficacy	of	combined	mcl	1	and	bcl	xl	inhibition	in	inducing	crc	cell	death	irrespective	of	molecular	features	importantly	expression	of	the	anti	apoptotic	protein	target	of	bh3	mimetics	on	its	own	did	not	predict	sensitivity	however	the	analysis	did	identify	consensus	molecular	subtype	cms	specific	response	patterns	such	as	higher	resistance	to	single	and	combined	bcl	2	and	mcl	1	inhibition	in	cms2	cell	lines	furthermore	analysis	of	mutation	status	revealed	that	kras	mutant	cell	lines	were	more	resistant	to	mcl	1	inhibition	conclusively	we	find	that	crc	cell	lines	presented	with	distinct	responses	to	bh3	mimetics	that	can	in	part	be	predicted	by	their	cms	profile	and	kras	braf	mutations	overall	almost	all	crc	lines	share	sensitivity	in	the	nanomolar	range	to	combined	mcl	1	and	bcl	xl	targeting	suggesting	that	this	would	be	the	preferred	approach	to	target	these	cancers</Paragraph></Rec>
<Rec><Paragraph>inter	hospital	transfer	iht	may	help	reduce	failure	to	rescue	ftr	by	transferring	patients	to	centers	with	a	higher	level	of	expertise	than	the	index	hospital	we	sought	to	identify	factors	associated	with	an	iht	and	examine	if	iht	was	associated	with	improved	outcomes	after	complex	gastrointestinal	cancer	surgery	medicare	inpatient	standard	analytic	files	were	utilized	to	identify	patients	with	1	postoperative	complication	following	resection	for	esophageal	pancreatic	liver	or	colorectal	cancer	between	2013	and	2017	multivariable	logistic	regression	was	used	to	examine	the	association	of	different	factors	with	the	chance	of	iht	as	well	as	the	impact	of	iht	on	failure	to	rescue	ftr	and	expenditures	among	39	973	patients	with	1	postoperative	complications	3090	7	7	patients	were	transferred	to	a	secondary	hospital	the	median	los	at	the	index	hospital	prior	to	iht	was	10	days	iqr	6	17	days	patients	who	underwent	iht	more	often	had	experienced	multiple	complications	at	the	index	hospital	compared	with	non	iht	patients	57	7	vs	38	9	p	0	001	transferred	patients	more	commonly	had	undergone	surgery	at	a	low	volume	index	hospital	n	218	60	2	compared	with	non	iht	n	10	351	25	9	patients	p	0	001	on	multivariate	analysis	hospital	volume	remained	strongly	associated	with	transfer	to	an	acute	care	hospital	ach	or	5	53	95	ci	3	91	7	84	p	0	001	as	did	multiple	complications	or	2	01	95	ci	1	56	2	57	the	incidence	of	ftr	was	much	higher	among	iht	ach	patients	20	2	versus	non	iht	patients	11	5	or	1	51	95	ci	1	11	2	05	p	0	001	medicare	expenditures	were	higher	among	patients	who	had	iht	ach	72	1k	usd	iqr	48	1k	116	7k	versus	non	iht	38	5k	usd	iqr	28	1k	59	2k	usd	p	0	001	approximately	1	in	13	patients	had	an	iht	after	complex	gastrointestinal	cancer	surgery	iht	was	associated	with	high	rates	of	ftr	which	was	more	pronounced	among	patients	who	underwent	surgery	at	an	index	low	volume	hospital	iht	was	associated	with	higher	overall	cms	expenditures</Paragraph></Rec>
<Rec><Paragraph>the	treatment	and	prognosis	of	advanced	colorectal	cancer	crc	remain	a	challenging	clinical	research	focus	here	we	describe	a	new	crc	tumor	suppressor	and	potential	therapeutic	target	thymocyte	selection	associated	high	mobility	group	box	tox	protein	the	expression	of	tox	was	lower	in	crc	than	para	crc	with	the	increase	of	tumor	stage	tox	expression	decreased	indicating	the	presence	of	tox	relates	to	better	overall	survival	os	tox	suppressed	the	mechanistic	target	of	rapamycin	kinase	mtor	signaling	to	inhibit	cell	proliferation	migration	invasion	and	change	the	epithelial	mesenchymal	transition	emt	process	in	addition	tox	promoted	apoptosis	as	tumor	mutation	burden	and	tumor	microenvironment	play	vital	roles	in	the	occurrence	and	development	of	tumors	we	analyzed	the	tox	expression	in	the	immune	microenvironment	of	crc	the	high	tox	expression	was	negatively	correlated	with	tumorpurity	moreover	it	was	positively	related	to	immunescore	stromalscore	microsatellite	instability	msi	status	and	consensus	molecular	subtypes	cms	3	typing	based	on	gene	set	enrichment	analysis	gsea	the	reduced	expression	of	tox	activated	mtor	we	found	rapamycin	a	mtor	inhibitor	partly	inhibited	cell	proliferation	invasion	and	migration	in	shtox	hct116	cells	lastly	tox	suppressed	tumorigenesis	and	lung	metastasis	of	crc	in	vivo	rapamycin	alone	or	combined	with	pd1	inhibitor	is	more	effective	than	pd1	inhibitor	alone	in	a	tumor	model	taken	together	these	findings	highlight	the	tumor	suppressive	role	of	tox	in	crc	especially	in	msi	crc	and	provide	valuable	information	that	rapamycin	alone	or	combined	with	pd1	inhibitor	has	therapeutic	potential	in	crc</Paragraph></Rec>
<Rec><Paragraph>the	ability	to	adapt	to	low	nutrient	microenvironments	is	essential	for	tumor	cell	survival	and	progression	in	solid	cancers	such	as	colorectal	carcinoma	crc	signaling	by	the	nf	κb	transcription	factor	pathway	associates	with	advanced	disease	stages	and	shorter	survival	in	patients	with	crc	nf	κb	has	been	shown	to	drive	tumor	promoting	inflammation	cancer	cell	survival	and	intestinal	epithelial	cell	iec	dedifferentiation	in	mouse	models	of	crc	however	whether	nf	κb	affects	the	metabolic	adaptations	that	fuel	aggressive	disease	in	patients	with	crc	is	unknown	here	we	identified	carboxylesterase	1	ces1	as	an	essential	nf	κb	regulated	lipase	linking	obesity	associated	inflammation	with	fat	metabolism	and	adaptation	to	energy	stress	in	aggressive	crc	ces1	promoted	crc	cell	survival	via	cell	autonomous	mechanisms	that	fuel	fatty	acid	oxidation	fao	and	prevent	the	toxic	build	up	of	triacylglycerols	we	found	that	elevated	ces1	expression	correlated	with	worse	outcomes	in	overweight	patients	with	crc	accordingly	nf	κb	drove	ces1	expression	in	crc	consensus	molecular	subtype	4	cms4	which	is	associated	with	obesity	stemness	and	inflammation	ces1	was	also	upregulated	by	gene	amplifications	of	its	transcriptional	regulator	hnf4a	in	cms2	tumors	reinforcing	its	clinical	relevance	as	a	driver	of	crc	this	subtype	based	distribution	and	unfavorable	prognostic	correlation	distinguished	ces1	from	other	intracellular	triacylglycerol	lipases	and	suggest	ces1	could	provide	a	route	to	treat	aggressive	crc</Paragraph></Rec>
<Rec><Paragraph>consensus	molecular	subtypes	cmss	are	emerging	as	critical	factor	for	prognosis	and	treatment	of	colorectal	cancer	gene	regulators	including	chromatin	regulator	rna	binding	protein	and	transcriptional	factor	are	critical	modulators	of	cancer	hallmark	yet	little	is	known	regarding	the	underlying	functional	mechanism	in	cmss	herein	we	identified	a	core	set	of	235	functional	gene	regulators	fgrs	by	integrating	genome	epigenome	transcriptome	and	interactome	of	cmss	fgrs	exhibited	significant	multi	omics	alterations	and	impacts	on	cell	lines	growth	as	well	as	significantly	enriched	cancer	driver	genes	and	pathways	moreover	common	fgrs	played	different	roles	in	the	context	of	cmss	in	accordance	with	the	immune	characteristics	of	cmss	we	found	that	the	anti	tumor	immune	pathways	were	mainly	activated	by	fgrs	e	g	stat1	and	crebbp	in	cms1	while	inhibited	by	fgrs	in	cms2	4	fgrs	mediated	aberrant	expression	of	ligands	which	bind	to	receptor	on	immune	cells	and	modulated	tumor	immune	microenvironment	of	subtypes	intriguingly	systematic	exploration	of	datasets	using	genomic	and	transcriptome	co	similarity	reveals	the	coordinated	manner	in	fgrs	act	in	cmss	to	orchestrate	their	pathways	and	patients	prognosis	expression	signatures	of	the	fgrs	revealed	an	optimized	cms	classifier	which	demonstrated	88	concordance	with	the	gold	standard	classifier	but	avoiding	the	influence	of	sample	composition	overall	our	integrative	analysis	identified	fgrs	to	regulate	core	tumorigenic	processes	pathways	across	cmss</Paragraph></Rec>
<Rec><Paragraph>the	presence	of	peritoneal	metastases	pm	in	patients	with	colorectal	cancer	crc	is	associated	with	an	extremely	poor	prognosis	the	diagnosis	of	pm	is	challenging	resulting	in	an	underestimation	of	their	true	incidence	while	surgery	can	be	curative	in	a	small	percentage	of	patients	effective	treatment	for	non	operable	pm	is	lacking	and	clinical	and	pre	clinical	studies	are	relatively	sparse	here	we	have	defined	the	major	clinical	challenges	in	the	areas	of	risk	assessment	detection	and	treatment	recent	developments	in	the	field	include	the	application	of	organoid	technology	which	has	generated	highly	relevant	pre	clinical	pm	models	the	application	of	diffusion	weighted	mri	which	has	greatly	improved	pm	detection	and	the	design	of	small	clinical	proof	of	concept	studies	which	allows	the	efficient	testing	of	new	treatment	strategies	together	these	developments	set	the	stage	for	starting	to	address	the	clinical	challenges	to	help	structure	these	efforts	a	translational	research	framework	is	presented	in	which	clinical	trial	design	is	based	on	the	insight	gained	from	direct	tissue	analyses	and	pre	clinical	organoid	models	derived	from	crc	patients	with	pm	this	feed	forward	approach	in	which	a	thorough	understanding	of	the	disease	drives	innovation	in	its	clinical	management	has	the	potential	to	improve	outcome	in	the	years	to	come</Paragraph></Rec>
<Rec><Paragraph>the	heterogeneity	of	colorectal	cancer	crc	poses	a	significant	challenge	to	the	precise	treatment	of	patients	crc	has	been	divided	into	4	consensus	molecular	subtypes	cmss	with	distinct	biological	and	clinical	characteristics	of	which	cms4	has	the	mesenchymal	identity	and	the	highest	relapse	rate	autophagy	plays	a	vital	role	in	crc	development	and	therapeutic	response	the	gene	expression	profiles	collected	from	6	datasets	were	applied	to	this	study	network	analysis	was	applied	to	integrate	the	subtype	specific	molecular	modalities	and	autophagy	signature	to	establish	an	autophagy	based	prognostic	signature	for	crc	apscrc	network	analysis	revealed	that	6	prognostic	autophagy	genes	vamp7	dlc1	fkbp1b	pea15	pex14	and	dnajb1	predominantly	regulated	the	mesenchymal	modalities	of	crc	the	apscrc	was	constructed	by	these	6	core	genes	and	applied	for	risk	calculation	patients	were	divided	into	high	and	low	risk	groups	based	on	apscrc	score	in	all	cohorts	patients	within	the	high	risk	group	showed	an	unfavorable	prognosis	in	multivariate	analysis	the	apscrc	remained	an	independent	predictor	of	prognosis	moreover	the	apscrc	achieved	higher	prognostic	power	than	commercialized	multigene	signatures	we	proposed	and	validated	an	autophagy	based	signature	which	is	a	promising	prognostic	biomarker	of	crc	patients	further	prospective	studies	are	warranted	to	test	and	validate	its	efficiency	for	clinical	application</Paragraph></Rec>
<Rec><Paragraph>signet	ring	cell	carcinoma	srcc	is	a	rare	pathological	type	of	colorectal	cancer	of	which	the	clinicopathological	features	and	genetic	background	have	not	yet	been	fully	investigated	previous	research	has	focused	on	the	optimization	of	colorectal	cancer	treatment	utilizing	consensus	molecular	subtyping	cms	however	it	is	not	known	what	type	of	cms	would	be	designated	to	srcc	treatment	in	the	current	study	of	1	350	patients	diagnosed	with	colorectal	cancer	who	underwent	surgery	14	were	diagnosed	with	srcc	the	case	control	cohort	that	fit	the	clinical	background	of	the	srcc	case	was	constructed	statistical	comparison	between	the	srcc	group	and	the	case	control	cohort	was	performed	among	clinicopathological	variables	srcc	and	well	to	moderately	adenocarcinoma	case	mrna	were	submitted	to	microarray	analysis	and	cms	analysis	compared	with	the	case	control	cohort	the	srcc	group	was	located	more	in	the	right	sided	colon	the	lymphatic	invasion	was	more	severe	and	the	peritoneal	dissemination	was	more	frequent	the	cancer	specific	survival	and	the	progression	free	survival	were	significantly	worse	in	the	srcc	group	compared	with	the	case	control	cohort	microarray	and	cms	analysis	identified	that	one	srcc	case	was	significantly	well	assigned	in	the	cms	4	group	and	the	other	case	was	assigned	in	the	cms	1	group	gene	set	analysis	revealed	the	upregulation	of	emt	related	genes	and	the	downregulation	of	fatty	acid	glycolysis	differentiation	myc	hnf4a	dna	repair	genes	in	conclusion	the	clinical	characteristics	of	srcc	are	severe	but	there	is	a	possibility	of	the	presence	of	different	phenotypes	according	to	cms	analysis</Paragraph></Rec>
<Rec><Paragraph>defective	dna	damage	response	ddr	is	a	hallmark	of	cancer	leading	to	genomic	instability	and	is	associated	with	chemosensitivity	although	the	mismatch	repair	system	has	been	extensively	studied	the	clinical	implications	of	other	mechanisms	associated	with	ddr	alterations	in	patients	with	colorectal	cancer	remain	unclear	this	study	aimed	to	understand	ddr	pathways	alterations	and	their	association	with	common	clinical	features	in	patients	with	colorectal	cancer	next	generation	sequencing	and	whole	transcriptome	sequencing	were	conducted	using	formalin	fixed	paraffin	embedded	samples	submitted	to	a	commercial	clinical	laboratory	improvement	amendments	certified	laboratory	samples	with	pathogenic	or	presumed	pathogenic	mutations	in	29	specific	ddr	related	genes	were	considered	as	ddr	mutant	ddr	mt	and	the	remaining	samples	as	ddr	wild	type	ddr	wt	of	9	321	patients	with	colorectal	cancer	1	290	13	8	were	ddr	mt	the	frequency	of	ddr	mt	was	significantly	higher	in	microsatellite	instability	high	msi	h	cases	than	in	microsatellite	stable	cases	76	4	vs	9	5	the	ddr	mt	genotype	was	higher	in	the	right	sided	ras	wild	braf	mutant	and	cms1	subgroups	however	these	associations	were	primarily	confounded	by	the	distribution	of	msi	status	compared	with	the	ddr	wt	tumors	the	ddr	mt	tumors	had	a	higher	mutational	burden	and	gene	expression	levels	in	the	immune	related	pathway	which	were	independent	of	msi	status	we	characterized	a	distinct	subgroup	of	patients	with	colorectal	cancer	with	tumors	harboring	mutations	in	the	ddr	related	genes	these	patients	more	commonly	had	msi	h	tumors	and	exhibited	an	activated	immune	signature	regardless	of	their	tumor	s	msi	status	these	findings	warrant	further	investigations	to	develop	personalized	treatment	strategies	in	this	significant	subgroup	of	patients	with	colorectal	cancer</Paragraph></Rec>
<Rec><Paragraph>a	substantial	fraction	of	patients	with	stage	i	iii	colorectal	adenocarcinoma	crc	experience	disease	relapse	after	surgery	with	curative	intent	however	biomarkers	for	predicting	the	likelihood	of	crc	relapse	have	not	been	fully	explored	therefore	we	assessed	the	association	between	tumor	infiltration	by	a	broad	array	of	innate	and	adaptive	immune	cell	types	and	crc	relapse	risk	we	implemented	a	discovery	validation	design	including	a	discovery	dataset	from	moffitt	cancer	center	mcc	tampa	fl	and	three	independent	validation	datasets	1	gse41258	2	the	molecular	epidemiology	of	colorectal	cancer	mecc	study	and	3	gse39582	infiltration	by	22	immune	cell	types	was	inferred	from	tumor	gene	expression	data	and	the	association	between	immune	infiltration	by	each	cell	type	and	relapse	free	survival	was	assessed	using	cox	proportional	hazards	regression	within	each	of	the	four	independent	cohorts	cd4	memory	activated	t	cell	hr	0	93	95	ci	0	90	0	96	fdr	0	0001	infiltration	was	associated	with	longer	time	to	disease	relapse	independent	of	stage	microsatellite	instability	and	adjuvant	therapy	based	on	our	meta	analysis	across	the	four	datasets	10	innate	and	adaptive	immune	cell	types	associated	with	disease	relapse	of	which	2	were	internally	validated	using	multiplex	immunofluorescence	moreover	immune	cell	type	infiltration	was	a	better	predictors	of	disease	relapse	than	consensus	molecular	subtype	cms	and	other	expression	based	biomarkers	immune	aicmcc	238	1	238	9	cms	aicmcc	241	0	these	data	suggest	that	transcriptome	derived	immune	profiles	are	prognostic	indicators	of	crc	relapse	and	quantification	of	both	innate	and	adaptive	immune	cell	types	may	serve	as	candidate	biomarkers	for	predicting	prognosis	and	guiding	frequency	and	modality	of	disease	surveillance</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	heterogeneous	disease	with	different	genetic	and	molecular	backgrounds	leading	to	a	diverse	patient	prognosis	and	treatment	response	four	consensus	molecular	subtypes	cms	1	4	have	recently	been	proposed	based	on	transcriptome	profiling	a	clinically	practical	immunohistochemistry	ihc	based	cms	classifier	consisting	of	the	four	markers	frmd6	zeb1	htr2b	and	cdx2	was	then	demonstrated	however	the	ihc	cms	classifier	did	not	distinguish	between	cms2	and	cms3	tumours	in	this	study	we	have	applied	the	proposed	transcriptome	based	and	ihc	based	cms	classifiers	in	a	crc	cohort	of	65	patients	and	found	a	concordance	of	77	5	further	we	modified	the	ihc	cms	classifier	by	analysing	the	differentially	expressed	genes	between	cms2	and	cms3	tumours	using	rna	sequencing	data	from	the	tcga	dataset	the	result	showed	that	wnt	signalling	was	among	the	most	upregulated	pathways	in	cms2	tumours	and	the	expression	level	of	ctnnb1	encoding	β	catenin	a	wnt	pathway	hallmark	was	significantly	upregulated	p	1	15	10	6	we	therefore	introduced	nuclear	β	catenin	staining	to	the	ihc	cms	classifier	using	the	modified	classifier	in	our	cohort	we	found	a	71	4	concordance	between	the	ihc	and	rna	sequencing	based	cms	classifiers	moreover	β	catenin	staining	could	classify	16	out	of	the	19	cms2	3	tumours	into	cms2	or	cms3	thereby	showing	an	84	2	concordance	with	the	rna	sequencing	based	classifier	in	conclusion	we	evaluated	cms	classifiers	based	on	transcriptome	and	ihc	analysis	we	present	a	modified	ihc	panel	that	categorizes	crc	tumours	into	the	four	cms	groups	to	our	knowledge	this	is	the	first	study	using	ihc	to	identify	all	four	cms	groups</Paragraph></Rec>
<Rec><Paragraph>the	consensus	molecular	subtypes	cms	demonstrated	prognostic	value	in	metastatic	colorectal	cancer	mcrc	similarly	a	prognostic	impact	was	suggested	for	the	pre	consensus	crcassigner	crca	classifier	in	early	stages	the	potential	predictive	role	of	these	classifiers	with	regard	to	the	choice	of	the	first	line	therapy	has	not	been	established	we	investigated	the	prognostic	and	predictive	impact	of	cms	and	crca	subtypes	among	mcrc	patients	treated	in	the	tribe2	study	among	679	randomized	patients	426	and	428	63	samples	were	profiled	according	to	cms	and	crca	classifications	respectively	the	prognostic	and	predictive	impact	of	both	cms	and	crca	subtypes	was	investigated	with	univariate	and	multivariate	analyses	for	progression	free	survival	pfs	pfs	2	pfs2	and	overall	survival	os	significant	associations	of	cms	and	crca	subtypes	with	pfs	pfs2	and	os	were	demonstrated	the	cms	classifier	confirmed	its	independent	prognostic	value	in	the	multivariable	model	p	value	for	pfs	pfs2	os	0	01	0	07	0	08	the	effect	of	treatment	intensification	was	independent	of	cms	subtypes	p	value	for	interaction	for	pfs	pfs2	os	0	88	0	75	0	55	a	significant	interaction	effect	between	crca	subtypes	and	treatment	arm	was	demonstrated	in	pfs	p	0	02	pfs2	p	0	01	and	os	p	0	008	the	benefit	of	folfoxiri	seemed	more	relevant	in	the	stem	like	pfs	hazard	ratio	0	60	p	0	03	and	mixed	subtypes	hazard	ratio	0	44	p	0	002	these	findings	were	confirmed	in	a	subgroup	of	patients	of	the	previous	tribe	study	we	confirmed	the	independent	prognostic	role	of	cms	classification	in	mcrc	independently	of	ras	braf	status	crca	classification	may	help	identifying	subgroups	of	patients	who	may	derive	more	benefit	from	folfoxiri	bevacizumab</Paragraph></Rec>
<Rec><Paragraph>the	intestinal	epithelium	fulfils	pleiotropic	functions	in	nutrient	uptake	waste	elimination	and	immune	surveillance	while	also	forming	a	barrier	against	luminal	toxins	and	gut	resident	microbiota	incessantly	barraged	by	extraneous	stresses	the	intestine	must	continuously	replenish	its	epithelial	lining	and	regenerate	the	full	gamut	of	specialized	cell	types	that	underpin	its	functions	homeostatic	remodelling	is	orchestrated	by	the	intestinal	stem	cell	isc	niche	a	convergence	of	epithelial	and	stromal	derived	cues	which	maintains	iscs	in	a	multipotent	state	following	demise	of	homeostatic	iscs	post	injury	plasticity	is	pervasive	among	multiple	populations	of	reserve	stem	like	cells	lineage	committed	progenitors	and	or	fully	differentiated	cell	types	all	of	which	can	contribute	to	regeneration	and	repair	failure	to	restore	the	epithelial	barrier	risks	seepage	of	toxic	luminal	contents	resulting	in	inflammation	and	likely	predisposing	to	tumour	formation	here	we	explore	how	homeostatic	niche	signalling	pathways	are	subverted	in	tumorigenesis	enabling	iscs	to	gain	autonomy	from	niche	restraints	isc	emancipation	and	transform	into	cancer	stem	cells	capable	of	driving	tumour	initiation	progression	and	therapy	resistance	we	further	consider	the	implications	of	the	pervasive	plasticity	of	the	intestinal	epithelium	for	the	trajectory	of	colorectal	cancer	the	emergence	of	distinct	molecular	subtypes	the	propensity	to	metastasize	and	the	development	of	effective	therapeutic	strategies</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	heterogeneous	disease	that	can	currently	be	subdivided	into	four	distinct	consensus	molecular	subtypes	cms	based	on	gene	expression	profiling	the	cms4	subtype	is	marked	by	high	expression	of	mesenchymal	genes	and	is	associated	with	a	worse	overall	prognosis	compared	to	other	cmss	importantly	this	subtype	responds	poorly	to	the	standard	therapies	currently	used	to	treat	crc	we	set	out	to	explore	what	regulatory	signalling	networks	underlie	the	cms4	phenotype	of	cancer	cells	specifically	by	analysing	which	kinases	were	more	highly	expressed	in	this	subtype	compared	to	others	we	found	akt3	to	be	expressed	in	the	cancer	cell	epithelium	of	crc	specimens	patient	derived	xenograft	pdx	models	and	in	primary	cell	cultures	representing	cms4	importantly	chemical	inhibition	or	knockout	of	this	gene	hampers	outgrowth	of	this	subtype	as	akt3	controls	expression	of	the	cell	cycle	regulator	p27	kip1	furthermore	high	akt3	expression	was	associated	with	high	expression	of	epithelial	mesenchymal	transition	emt	genes	and	this	observation	could	be	expanded	to	cell	lines	representing	other	carcinoma	types	more	importantly	this	association	allowed	for	the	identification	of	crc	patients	with	a	high	propensity	to	metastasise	and	an	associated	poor	prognosis	high	akt3	expression	in	the	tumour	epithelial	compartment	may	thus	be	used	as	a	surrogate	marker	for	emt	and	may	allow	for	a	selection	of	crc	patients	that	could	benefit	from	akt3	targeted	therapy</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	is	the	2nd	leading	cause	of	cancer	related	deaths	in	the	world	the	mechanisms	underlying	crc	development	progression	and	resistance	to	treatment	are	complex	and	not	fully	understood	the	immune	response	in	the	tumor	microenvironment	has	been	shown	to	play	a	significant	role	in	many	cancers	including	colorectal	cancer	colony	stimulating	factor	3	csf3	has	been	associated	with	changes	to	the	immune	environment	in	colorectal	cancer	animal	models	we	hypothesized	that	csf3	signaling	would	correlate	with	pro	tumor	tumor	microenvironment	changes	associated	with	immune	infiltrate	and	response	we	utilized	publicly	available	datasets	to	guide	future	mechanistic	studies	of	the	role	csf3	and	its	receptor	csf3r	play	in	colorectal	cancer	development	and	progression	here	we	use	bioinformatics	data	and	mrna	from	patients	with	colon	n	242	or	rectal	n	92	cancers	obtained	from	the	cancer	genome	atlas	firehose	legacy	dataset	we	examined	correlations	of	csf3	and	csf3r	expression	with	patient	demographics	tumor	stage	and	consensus	molecular	subtype	classification	gene	expression	correlations	cell	type	enrichment	estimation	of	stromal	and	immune	cells	in	malignant	tumor	tissues	using	expression	data	scores	and	gene	ontology	were	used	to	analyze	expression	of	receptor	and	ligand	tumor	microenvironment	infiltration	of	immune	cells	and	alterations	in	biological	pathways	we	found	that	csf3	and	csf3r	expression	is	highest	in	consensus	molecular	subtype	1	and	consensus	molecular	subtype	4	ligand	and	receptor	expression	are	also	correlated	with	changes	in	t	cell	and	macrophage	signatures	csf3r	significantly	correlates	with	a	large	number	of	genes	that	are	associated	with	poor	colorectal	cancer	prognosis</Paragraph></Rec>
<Rec><Paragraph>a	critical	obstacle	in	the	field	of	colorectal	cancer	crc	is	the	establishment	of	precise	tumor	subtypes	to	facilitate	the	development	of	targeted	therapeutic	regimens	while	dysregulated	mucin	production	is	a	histopathological	feature	of	multiple	crc	subtypes	it	is	not	clear	how	well	these	pathologies	are	associated	with	the	proportion	of	goblet	cells	in	the	tumor	or	whether	or	not	this	proportion	is	variable	across	all	crc	this	study	demonstrates	that	consensus	molecular	subtype	3	cms3	crc	tumors	and	cell	lines	are	enriched	for	the	expression	of	goblet	cell	marker	genes	further	the	proportion	of	goblet	cells	in	the	tumor	is	associated	with	the	probability	of	cms3	subtype	assignment	and	these	cms3	subtype	tumors	are	mutually	exclusive	from	mucinous	adenocarcinoma	pathologies	this	study	provides	proof	of	principle	for	the	use	of	machine	learning	classification	systems	to	subtype	tumors	based	on	cellular	content	and	provides	further	context	regarding	the	features	weighing	cms3	subtype	assignment</Paragraph></Rec>
<Rec><Paragraph>a	subset	of	colorectal	cancer	crc	with	a	mesenchymal	phenotype	cms4	displays	an	aggressive	disease	with	an	increased	risk	of	recurrence	after	surgery	reduced	survival	and	resistance	to	standard	treatments	it	has	been	shown	that	the	axl	and	tgfβ	signaling	pathways	are	involved	in	epithelial	to	mesenchymal	transition	migration	metastatic	spread	and	unresponsiveness	to	targeted	therapies	however	the	prognostic	role	of	the	combination	of	these	biomarkers	and	the	anti	tumor	effect	of	axl	and	tgfβ	inhibition	in	crc	still	has	to	be	assessed	to	evaluate	the	role	of	axl	and	tgfβ	as	negative	biomarker	in	crc	we	conducted	an	in	depth	in	silico	analysis	of	crc	samples	derived	from	the	gene	expression	omnibus	we	found	that	axl	and	tgfβ	receptors	are	upregulated	in	cms4	tumors	and	are	correlated	with	an	increased	risk	of	recurrence	after	surgery	in	stage	ii	iii	crc	and	a	reduced	overall	survival	moreover	we	showed	that	axl	receptor	is	differently	expressed	in	human	crc	cell	lines	dual	treatment	with	the	tgfβ	galunisertib	and	the	axl	inhibitor	bemcentinib	significantly	reduced	colony	formation	and	migration	capabilities	of	tumor	cells	and	displayed	a	strong	anti	tumor	activity	in	3d	spheroid	cultures	derived	from	patients	with	advanced	crc	our	work	shows	that	axl	and	tgfβ	receptors	identify	a	subgroup	of	crc	with	a	mesenchymal	phenotype	and	correlate	with	poor	prognosis	dual	inhibition	of	axl	and	tgfβ	could	represent	a	novel	therapeutic	strategy	for	patients	with	this	aggressive	disease</Paragraph></Rec>
<Rec><Paragraph>the	four	major	rna	adenosine	modifications	i	e	m	6	a	m	1	a	alternative	polyadenylation	and	adenosine	to	inosine	rna	editing	are	mediated	mostly	by	the	writer	enzymes	and	constitute	critical	mechanisms	of	epigenetic	regulation	in	immune	response	and	tumorigenesis	however	the	cross	talk	and	potential	roles	of	these	writers	in	the	tumor	microenvironment	tme	drug	sensitivity	and	immunotherapy	remain	unknown	we	systematically	characterized	mrna	expression	and	genetic	alterations	of	26	rna	modification	writers	in	colorectal	cancer	crc	and	evaluated	their	expression	pattern	in	1697	crc	samples	from	8	datasets	we	used	an	unsupervised	clustering	method	to	assign	the	samples	into	two	patterns	of	expression	of	rna	modification	writers	subsequently	we	constructed	the	rna	modification	writer	score	wm	score	model	based	on	differentially	expressed	genes	degs	responsible	for	the	rna	modification	patterns	to	quantify	the	rna	modification	related	subtypes	of	individual	tumors	furthermore	we	performed	association	analysis	for	wm	score	and	characteristics	of	tme	consensus	molecular	subtypes	cmss	clinical	features	transcriptional	and	post	transcriptional	regulation	drug	response	and	the	efficacy	of	immunotherapy	we	demonstrated	that	multi	layer	alterations	of	rna	modification	writer	are	associated	with	patient	survival	and	tme	cell	infiltrating	characteristics	we	identified	two	distinct	rna	modification	patterns	characterized	by	a	high	and	a	low	wm	score	the	wm	score	high	group	was	associated	with	worse	patient	overall	survival	and	with	the	infiltration	of	inhibitory	immune	cells	such	as	m2	macrophages	emt	activation	and	metastasis	while	the	wm	score	low	group	was	associated	with	a	survival	advantage	apoptosis	and	cell	cycle	signaling	pathways	wm	score	correlated	highly	with	the	regulation	of	transcription	and	post	transcriptional	events	contributing	to	the	development	of	crc	in	response	to	anti	cancer	drugs	wm	score	highly	negatively	correlated	drug	sensitive	with	drugs	which	targeted	oncogenic	related	pathways	such	as	mapk	egfr	and	mtor	signaling	pathways	positively	correlated	drug	resistance	with	drugs	which	targeted	in	apoptosis	and	cell	cycle	importantly	the	wm	score	was	associated	with	the	therapeutic	efficacy	of	pd	l1	blockade	suggesting	that	the	development	of	potential	drugs	targeting	these	writers	to	aid	the	clinical	benefits	of	immunotherapy	our	study	is	the	first	to	provide	a	comprehensive	analysis	of	four	rna	modifications	in	crc	we	revealed	the	potential	function	of	these	writers	in	tme	transcriptional	and	post	transcriptional	events	and	identified	their	therapeutic	liability	in	targeted	therapy	and	immunotherapy	this	work	highlights	the	cross	talk	and	potential	clinical	utility	of	rna	modification	writers	in	cancer	therapy</Paragraph></Rec>
<Rec><Paragraph>targeted	therapeutic	strategies	for	advanced	colorectal	cancer	crc	have	been	limited	sting	is	crucial	to	the	antitumor	immunotherapy	for	it	stimulates	ifn	signaling	to	mediate	the	crosstalk	between	innate	and	adaptive	immune	responses	emerging	evidence	suggests	that	sting	also	contributes	to	the	prognosis	of	crc	however	prognostic	models	relating	to	sting	have	not	yet	been	explored	a	total	of	431	crc	samples	from	the	tcga	database	were	analyzed	to	explore	the	prognostic	value	of	sting	related	genes	we	trained	prognostic	models	using	the	multivariate	cox	regression	a	sting	related	prognostic	score	sps	was	calculated	as	the	gene	expression	multiplied	by	the	corresponding	coefficients	of	the	final	model	a	backward	stepaic	strategy	was	adopted	to	select	the	optimal	model	a	nomogram	was	used	to	personalize	medical	decisions	for	crc	the	expression	level	of	sting	was	upregulated	in	the	cms1	subtype	p	0	036	among	sting	related	genes	dhx9	hr	0	72	p	0	01	irf2	hr	1	34	p	0	022	and	polr1d	hr	1	23	p	0	038	showed	significant	prognostic	value	the	sps	was	proven	to	be	an	independent	risk	factor	training	hr	2	9	p	0	00013	validation	hr	3	02	p	0	01	and	outperformed	random	classifiers	in	identifying	high	risk	crc	the	high	sps	group	was	characterized	by	less	genomic	aberrations	upregulated	il6	jak	stat3	and	il2	stat5	signaling	pathways	increased	expression	of	tim	3	increased	infiltration	of	regulatory	t	treg	cells	and	t	helper	17	th17	cells	and	decreased	infiltration	of	m0	macrophages	finally	the	nomogram	based	on	the	sps	and	clinical	factors	showed	good	performance	in	crc	sps	is	an	independent	risk	factor	that	could	identify	high	risk	crc	while	icbs	may	benefit	patients	of	the	cms1	subtype	for	the	cms2	cms3	and	cms4	subtypes	in	the	high	sps	group	sting	agonists	and	immunotherapies	targeting	the	th17	axis	may	be	beneficial	finally	the	sps	based	nomogram	could	help	advance	personalized	medical	decisions	for	crc</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	among	the	deadliest	cancers	wherein	early	dissemination	of	tumor	cells	and	consequently	metastasis	formation	are	the	main	causes	of	mortality	and	poor	prognosis	cofilin	1	cfl	1	and	its	modulators	limk1	ssh1	play	key	roles	in	mediating	the	invasiveness	by	driving	actin	cytoskeleton	reorganization	in	various	cancer	types	however	their	clinical	significance	and	prognostic	value	in	crc	has	not	been	fully	explored	here	we	evaluated	the	clinical	contribution	of	these	actin	regulators	according	to	tnm	and	consensus	molecular	subtypes	cmss	classification	cfl	1	limk1	and	ssh1	mrna	protein	levels	were	assessed	by	real	time	pcr	and	immunohistochemical	analyses	using	normal	adjacent	and	tumor	tissues	obtained	from	a	clinical	cohort	of	crc	patients	the	expression	levels	of	these	proteins	were	associated	with	clinicopathological	features	by	using	the	chi	square	test	in	addition	using	rna	seq	data	of	crc	patients	from	the	cancer	genome	atlas	tcga	database	we	determine	how	these	actin	regulators	are	expressed	and	distributed	according	to	tnm	and	cmss	classification	based	on	gene	expression	profiling	kaplan	meier	survival	analysis	was	used	to	evaluated	overall	survival	bioinformatic	analysis	revealed	that	limk1	expression	was	upregulated	in	all	tumor	stages	patients	with	high	levels	of	limk1	demonstrated	significantly	lower	overall	survival	rates	and	exhibited	greater	lymph	node	metastatic	potential	in	a	clinical	cohort	in	contrast	cfl	1	and	ssh1	have	expression	downregulated	in	all	tumor	stages	however	immunohistochemical	analyses	showed	that	patients	with	high	protein	levels	of	cfl	1	and	ssh1	exhibited	greater	lymph	node	metastatic	potential	and	greater	depth	of	local	invasion	in	addition	using	the	cmss	classification	to	evaluate	different	biological	phenotypes	of	crc	we	observed	that	limk1	and	ssh1	genes	are	upregulated	in	immune	cms1	and	mesenchymal	cms4	subtypes	however	patients	with	high	levels	of	limk1	also	demonstrated	significantly	lower	overall	survival	rates	in	canonical	cms2	and	metabolic	cms3	subtypes	we	demonstrated	that	cfl	1	and	its	modulators	limk1	ssh1	are	differentially	expressed	and	associated	with	lymph	node	metastasis	in	crc	finally	this	expression	profile	may	be	useful	to	predict	patients	with	aggressive	signatures	particularly	the	immune	and	mesenchymal	subtypes	of	crc</Paragraph></Rec>
<Rec><Paragraph>at	rich	interactive	domain	1a	arid1a	is	commonly	mutated	in	colorectal	cancer	frequently	resulting	in	truncation	and	loss	of	protein	expression	arid1a	recruits	msh2	for	mismatch	repair	during	dna	replication	arid1a	deficiency	promotes	hypermutability	and	immune	activation	in	preclinical	models	but	its	role	in	patients	with	colorectal	cancer	is	being	explored	the	dna	sequencing	and	gene	expression	profiling	of	patients	with	colorectal	cancer	were	extracted	from	the	cancer	genome	atlas	and	md	anderson	cancer	center	databases	with	validation	utilizing	external	databases	and	correlation	between	arid1a	and	immunologic	features	ihc	for	t	cell	markers	was	performed	on	a	separate	cohort	of	patients	twenty	eight	of	417	patients	with	microsatellite	stable	mss	colorectal	cancer	6	7	had	arid1a	mutation	among	58	genes	most	commonly	mutated	in	colorectal	cancer	arid1a	mutation	had	the	highest	increase	with	frameshift	mutation	rates	in	mss	cases	8	fold	p	0	001	in	mss	arid1a	mutation	was	enriched	in	immune	subtype	cms1	and	had	a	strong	correlation	with	ifnγ	expression	δz	score	1	91	p	0	001	compared	with	arid1a	wild	type	statistically	significant	higher	expression	for	key	checkpoint	genes	e	g	pd	l1	ctla4	and	pdcd1	and	gene	sets	e	g	antigen	presentation	cytotoxic	t	cell	function	and	immune	checkpoints	was	observed	in	mutant	cases	this	was	validated	by	unsupervised	differential	expression	of	genes	related	to	immune	response	and	further	confirmed	by	higher	infiltration	of	t	cells	in	ihc	of	tumors	with	arid1a	mutation	p	0	01	the	immunogenicity	of	arid1a	mutant	cases	is	likely	due	to	an	increased	level	of	neoantigens	resulting	from	increased	tumor	mutational	burden	and	frameshift	mutations	tumors	with	arid1a	mutation	may	be	more	susceptible	to	immune	therapy	based	treatment	strategies	and	should	be	recognized	as	a	unique	molecular	subgroup	in	future	immune	therapy	trials</Paragraph></Rec>
<Rec><Paragraph>despite	the	advancements	in	new	therapies	for	colorectal	cancer	crc	chemotherapy	still	constitutes	the	mainstay	of	the	medical	treatment	for	this	reason	new	strategies	to	increase	the	efficacy	of	chemotherapy	are	desirable	poly	adp	ribose	polymerase	inhibitors	parpi	have	shown	to	increase	the	activity	of	dna	damaging	chemotherapeutics	used	in	the	treatment	of	crc	however	previous	clinical	trials	failed	to	validate	these	results	and	pointed	out	dose	limiting	toxicities	that	hamper	the	use	of	such	combinations	in	unselected	crc	patients	nevertheless	in	these	studies	little	attention	was	paid	to	the	mutational	status	of	homologous	recombination	repair	hrr	genes	we	tested	the	combination	of	the	parpi	niraparib	with	either	5	fluorouracil	oxaliplatin	or	irinotecan	sn38	in	a	panel	of	12	molecularly	annotated	crc	cell	lines	encompassing	the	4	consensus	molecular	subtypes	cmss	synergism	was	calculated	using	the	chou	talalay	method	for	drug	interaction	a	correlation	between	synergism	and	genetic	alterations	in	genes	involved	in	homologous	recombination	hr	repair	was	performed	we	used	clonogenic	assays	mice	xenograft	models	and	patient	derived	3d	spheroids	to	validate	the	results	the	induction	of	dna	damage	was	studied	by	immunofluorescence	we	showed	that	human	crc	cell	lines	as	well	as	patient	derived	3d	spheroids	harboring	pathogenic	atm	mutations	are	significantly	vulnerable	to	parpi	chemotherapy	combination	at	low	doses	regardless	of	consensus	molecular	subtypes	cms	and	microsatellite	status	the	strongest	synergism	was	shown	for	the	combination	of	niraparib	with	irinotecan	and	the	presence	of	atm	mutations	was	associated	to	a	delay	in	the	resolution	of	double	strand	breaks	dsbs	through	hrr	and	dna	damage	persistence	this	work	demonstrates	that	a	numerically	relevant	subset	of	crcs	carrying	heterozygous	atm	mutations	may	benefit	from	the	combination	treatment	with	low	doses	of	niraparib	and	irinotecan	suggesting	a	new	potential	approach	in	the	treatment	of	atm	mutated	crc	that	deserves	to	be	prospectively	validated	in	clinical	trials</Paragraph></Rec>
<Rec><Paragraph>intra	tumor	heterogeneity	ith	of	colorectal	cancer	crc	complicates	molecular	tumor	classification	such	as	transcriptional	subtyping	differences	in	cellular	states	biopsy	cell	composition	and	tumor	microenvironment	may	all	lead	to	ith	here	we	analyze	ith	at	the	transcriptomic	and	proteomic	levels	to	ascertain	whether	subtype	discordance	between	multiregional	biopsies	reflects	relevant	biological	ith	or	lack	of	classifier	robustness	further	we	study	the	impact	of	tumor	location	on	ith	multiregional	biopsies	from	stage	ii	and	iii	crc	tumors	were	analyzed	by	rna	sequencing	41	biopsies	14	tumors	and	multiplex	immune	protein	analysis	89	biopsies	29	tumors	crc	subtyping	was	performed	using	consensus	molecular	subtypes	cms	crc	intrinsic	subtypes	cris	and	tumor	types	ith	scores	and	network	maps	were	defined	to	determine	the	origin	of	heterogeneity	a	validation	cohort	was	used	with	one	biopsy	per	tumor	162	tumors	overall	inter	tumor	transcriptional	variation	exceeded	ith	and	subtyping	calls	were	frequently	concordant	between	multiregional	biopsies	still	some	tumors	had	high	transcriptional	ith	and	were	classified	discordantly	subtyping	of	proximal	mss	tumors	were	discordant	for	50	of	the	tumors	this	ith	was	related	to	differences	in	the	microenvironment	subtyping	of	distal	mss	tumors	were	less	discordant	here	the	ith	was	more	cancer	cell	related	the	subtype	discordancy	reflected	actual	molecular	ith	within	the	tumors	the	relevance	of	the	subtypes	was	reflected	at	protein	level	where	several	inflammation	markers	were	significantly	increased	in	immune	related	transcriptional	subtypes	which	was	verified	in	an	independent	cohort	wilcoxon	rank	sum	test	p	0	05	unsupervised	hierarchical	clustering	of	the	protein	data	identified	large	ith	at	protein	level	as	the	multiregional	biopsies	clustered	together	for	only	9	out	of	29	tumors	our	transcriptomic	and	proteomic	analyses	show	that	the	tumor	location	along	the	colorectum	influence	the	ith	of	crc	which	again	influence	the	concordance	of	subtyping</Paragraph></Rec>
<Rec><Paragraph>to	clarify	the	function	of	cyclin	a2	in	colon	homeostasis	and	colorectal	cancer	crc	we	generated	mice	deficient	for	cyclin	a2	in	colonic	epithelial	cells	cecs	colons	of	these	mice	displayed	architectural	changes	in	the	mucosa	and	signs	of	inflammation	as	well	as	increased	proliferation	of	cecs	associated	with	the	appearance	of	low	and	high	grade	dysplasias	the	main	initial	events	triggering	those	alterations	in	cyclin	a2	deficient	cecs	appeared	to	be	abnormal	mitoses	and	dna	damage	cyclin	a2	deletion	in	cecs	promoted	the	development	of	dysplasia	and	adenocarcinomas	in	a	murine	colitis	associated	cancer	model	we	next	explored	the	status	of	cyclin	a2	expression	in	clinical	crc	samples	at	the	mrna	and	protein	levels	and	found	higher	expression	in	tumors	of	patients	with	stage	1	or	2	crc	compared	with	those	of	patients	with	stage	3	or	4	crc	a	meta	analysis	of	11	transcriptome	data	sets	comprising	2239	primary	crc	tumors	revealed	different	expression	levels	of	ccna2	the	mrna	coding	for	cyclin	a2	among	the	crc	tumor	subtypes	with	the	highest	expression	detected	in	consensus	molecular	subtype	1	cms1	and	the	lowest	in	cms4	tumors	moreover	we	found	high	expression	of	ccna2	to	be	a	new	independent	prognosis	factor	for	crc	tumors</Paragraph></Rec>
<Rec><Paragraph>to	understand	the	relationship	between	patient	experience	as	measured	by	scores	on	the	consumer	assessment	of	healthcare	providers	and	systems	cahps	survey	and	clinical	and	financial	outcomes	among	older	cancer	survivors	we	analyzed	the	records	of	all	fee	for	service	ffs	medicare	beneficiaries	66	years	and	older	who	completed	one	cahps	survey	from	2001	to	2004	or	2007	2013	with	one	of	the	five	following	cancer	types	breast	bladder	colorectal	lung	or	prostate	and	completed	a	cahps	survey	within	5	years	of	cancer	diagnosis	date	we	conducted	a	multivariate	analysis	controlling	for	clinical	and	demographic	variables	to	evaluate	the	association	between	excellent	cahps	scores	and	the	following	clinical	and	financial	outcomes	mortality	emergency	department	visits	and	total	healthcare	expenditures	a	total	of	7395	individuals	were	present	in	our	cohort	with	57	being	male	and	85	7	non	hispanic	white	breakdown	of	the	cohort	by	cancer	site	is	as	follows	prostate	40	4	breast	28	6	colorectal	14	0	lung	9	4	and	bladder	7	6	when	looking	at	the	relationship	between	cahps	scores	and	clinical	outcomes	there	was	no	significant	difference	between	excellent	and	non	excellent	cahps	score	respondents	in	all	three	of	the	clinical	outcomes	studied	furthermore	there	was	no	association	between	ed	utilization	and	patient	experience	scores	when	stratifying	by	cancer	site	and	race	ethnicity	among	this	cohort	in	this	cohort	a	highly	rated	patient	experience	as	measured	by	responses	on	the	cahps	survey	is	not	associated	with	improved	clinical	outcomes	among	older	cancer	survivors</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	is	a	molecularly	heterogeneous	disease	responses	to	genotoxic	chemotherapy	in	the	adjuvant	or	palliative	setting	vary	greatly	between	patients	and	colorectal	cancer	cells	often	resist	chemotherapy	by	evading	apoptosis	antagonists	of	an	inhibitor	of	apoptosis	proteins	iaps	can	restore	defective	apoptosis	signaling	by	degrading	ciap1	and	ciap2	proteins	and	by	inhibition	of	xiap	due	to	the	multiple	molecular	mechanisms	of	action	of	these	targets	responses	to	iap	antagonist	may	differ	between	molecularly	distinct	colon	cancer	cells	in	this	study	responses	to	the	iap	antagonist	birinapant	and	oxaliplatin	5	fluorouracil	5	fu	were	investigated	in	14	colon	cancer	cell	lines	representing	the	consensus	molecular	subtypes	cms	treatment	with	birinapant	alone	did	not	result	in	a	substantial	increase	in	apoptotic	cells	in	this	cell	line	panel	annexin	v	pi	assays	quantified	by	flow	cytometry	and	high	content	screening	showed	that	birinapant	increased	responses	of	cms1	and	partially	cms3	cell	lines	to	oxaliplatin	5	fu	whereas	cms2	cells	were	not	effectively	sensitized	fret	based	imaging	of	caspase	8	and	3	activation	validated	these	differences	at	the	single	cell	level	with	cms1	cells	displaying	sustained	activation	of	caspase	8	like	activity	during	birinapant	and	oxaliplatin	5	fu	co	treatment	ultimately	activating	the	intrinsic	mitochondrial	apoptosis	pathway	in	cms2	cell	lines	birinapant	exhibited	synergistic	effects	in	combination	with	tnfα	suggesting	that	birinapant	can	restore	extrinsic	apoptosis	signaling	in	the	context	of	inflammatory	signals	in	this	subtype	to	explore	this	further	we	co	cultured	cms2	and	cms1	colon	cancer	cells	with	peripheral	blood	mononuclear	cells	we	observed	increased	cell	death	during	birinapant	single	treatment	in	these	co	cultures	which	was	abrogated	by	anti	tnfα	neutralizing	antibodies	collectively	our	study	demonstrates	that	iap	inhibition	is	a	promising	modulator	of	response	to	oxaliplatin	5	fu	in	colorectal	cancers	of	the	cms1	subtype	and	may	show	promise	as	in	the	cms2	subtype	suggesting	that	molecular	subtyping	may	aid	as	a	patient	stratification	tool	for	iap	antagonists	in	this	disease</Paragraph></Rec>
<Rec><Paragraph>cancer	associated	fibroblasts	cafs	promote	tumor	malignancy	but	the	precise	transcriptional	mechanisms	regulating	the	acquisition	of	the	caf	phenotype	are	not	well	understood	we	show	that	the	upregulation	of	sox2	is	central	to	this	process	which	is	repressed	by	protein	kinase	cζ	pkcζ	pkcζ	deficiency	activates	the	reprogramming	of	colonic	fibroblasts	to	generate	a	predominant	sox2	dependent	caf	population	expressing	the	wnt	regulator	sfrp2	as	its	top	biomarker	sox2	directly	binds	the	sfrp1	2	promoters	and	the	inactivation	of	sox2	or	sfrp1	2	in	cafs	impaired	the	induction	of	migration	and	invasion	of	colon	cancer	cells	as	well	as	their	tumorigenicity	in	vivo	importantly	recurrence	free	and	overall	survival	of	colorectal	cancer	crc	patients	negatively	correlates	with	stromal	pkcζ	levels	also	sox2	expression	in	the	stroma	is	associated	with	crc	t	invasion	and	worse	prognosis	of	recurrence	free	survival	therefore	the	pkcζ	sox2	axis	emerges	as	a	critical	step	in	the	control	of	caf	pro	tumorigenic	potential</Paragraph></Rec>
<Rec><Paragraph>the	development	and	progression	of	solid	tumors	such	as	colorectal	cancer	crc	are	known	to	be	affected	by	the	immune	system	and	cell	types	such	as	t	cells	natural	killer	nk	cells	and	natural	killer	t	nkt	cells	are	emerging	as	interesting	targets	for	immunotherapy	and	clinical	biomarker	research	in	addition	cd3	and	cd8	t	cell	distribution	in	tumors	has	shown	positive	prognostic	value	in	stage	i	iii	crc	recent	developments	in	digital	computational	pathology	support	not	only	classical	cell	density	based	tumor	characterization	but	also	a	more	comprehensive	analysis	of	the	spatial	cell	organization	in	the	tumor	immune	microenvironment	time	leveraging	that	methodology	in	the	current	study	we	tried	to	address	the	question	of	how	the	distribution	of	myeloid	derived	suppressor	cells	in	time	of	primary	crc	affects	the	function	and	location	of	cytotoxic	t	cells	we	applied	multicolored	immunohistochemistry	to	identify	monocytic	cd11b	cd14	and	granulocytic	cd11b	cd15	myeloid	cell	populations	together	with	proliferating	and	non	proliferating	cytotoxic	t	cells	cd8	ki67	through	automated	object	detection	and	image	registration	using	halo	software	indicalabs	we	applied	dedicated	spatial	statistics	to	measure	the	extent	of	overlap	between	the	areas	occupied	by	myeloid	and	t	cells	with	this	approach	we	observed	distinct	spatial	organizational	patterns	of	immune	cells	in	tumors	obtained	from	74	treatment	naive	crc	patients	detailed	analysis	of	inter	cell	distances	and	myeloid	t	cell	spatial	overlap	combined	with	integrated	gene	expression	data	allowed	to	stratify	patients	irrespective	of	their	mismatch	repair	mmr	status	or	consensus	molecular	subgroups	cms	classification	in	addition	generation	of	cell	distance	derived	gene	signatures	and	their	mapping	to	the	tcga	data	set	revealed	associations	between	spatial	immune	cell	distribution	in	time	and	certain	subsets	of	cd8	and	cd4	t	cells	the	presented	study	sheds	a	new	light	on	myeloid	and	t	cell	interactions	in	time	in	crc	patients	our	results	show	that	crc	tumors	present	distinct	distribution	patterns	of	not	only	t	effector	cells	but	also	tumor	resident	myeloid	cells	thus	stressing	the	necessity	of	more	comprehensive	characterization	of	time	in	order	to	better	predict	cancer	prognosis	this	research	emphasizes	the	importance	of	a	multimodal	approach	by	combining	computational	pathology	with	its	detailed	spatial	statistics	and	gene	expression	profiling	finally	our	study	presents	a	novel	approach	to	cancer	patients	characterization	that	can	potentially	be	used	to	develop	new	immunotherapy	strategies	not	based	on	classical	biomarkers	related	to	crc	biology</Paragraph></Rec>
<Rec><Paragraph>tumor	heterogeneity	is	a	major	challenge	to	the	treatment	of	colorectal	cancer	crc	recently	a	transcriptome	based	classification	was	developed	segregating	crc	into	four	consensus	molecular	subtypes	cms	with	distinct	biological	and	clinical	characteristics	here	we	applied	the	cms	classification	on	crc	cell	lines	to	identify	novel	subtype	specific	drug	vulnerabilities	we	combined	publicly	available	transcriptome	data	from	multiple	resources	to	assign	157	crc	cell	lines	to	cms	by	integrating	results	from	large	scale	drug	screens	we	discovered	that	the	cms1	subtype	is	highly	vulnerable	to	the	birc5	suppressor	ym155	we	confirmed	our	results	using	an	independent	panel	of	crc	cell	lines	and	demonstrated	a	100	fold	higher	sensitivity	of	cms1	this	vulnerability	was	specific	to	ym155	and	not	observed	for	commonly	used	chemotherapeutic	agents	in	cms1	crc	low	concentrations	of	ym155	induced	apoptosis	and	expression	signatures	associated	with	er	stress	mediated	apoptosis	signaling	using	a	genome	wide	crispr	cas9	screen	we	further	discovered	a	novel	role	of	genes	involved	in	ldl	receptor	trafficking	as	modulators	of	ym155	sensitivity	in	the	crc	cell	line	hct116	our	work	shows	that	combining	drug	response	data	with	cms	classification	in	cell	lines	can	reveal	selective	vulnerabilities	and	proposes	ym155	as	a	novel	subtype	specific	drug</Paragraph></Rec>
<Rec><Paragraph>cancer	immunotherapies	have	achieved	great	progress	in	colorectal	cancer	crc	however	only	a	small	subset	of	crc	patients	with	microsatellite	instability	msi	can	obtain	benefits	from	immune	checkpoint	inhibitors	icis	nearly	85	of	all	crc	patients	have	microsatellite	stable	mss	disease	which	does	not	respond	to	icis	increasing	evidence	has	revealed	that	cd14	promotes	tumor	growth	and	induces	an	immunosuppressive	environment	through	cd14	immunosuppressive	cells	however	a	systematic	exploration	of	cd14	in	crc	is	lacking	a	total	of	644	samples	with	transcriptome	data	and	566	samples	with	microarray	data	were	investigated	in	this	study	including	tcga	rna	seq	and	gse39582	microarray	r	software	was	the	main	tool	for	graphical	work	and	statistical	analysis	cd14	was	upregulated	in	the	msi	h	braf	mutant	right	sided	disease	and	hypermethylation	groups	cases	with	high	cd14	expression	were	related	to	the	cms4	subtype	and	had	frequent	mutation	of	driver	oncogenes	cd14	expression	was	associated	with	the	regulation	of	immune	system	processes	in	gene	ontology	analysis	the	cytokine	cytokine	receptor	interaction	was	associated	with	cd14	expression	moreover	cd14	was	associated	with	high	immune	and	stromal	infiltration	and	cd14	synergized	with	immune	checkpoints	additionally	cd14	was	involved	in	immune	and	inflammatory	responses	finally	high	cd14	expression	predicted	worse	outcomes	and	was	an	independent	negative	indicator	of	prognosis	in	crc	which	was	further	confirmed	in	tissue	microarray	our	findings	indicated	that	cd14	expression	was	associated	with	specific	clinical	characteristics	high	cd14	expression	might	represent	pre	existing	immunity	and	have	a	high	correlation	with	immune	checkpoints	moreover	cd14	correlated	with	poor	clinical	outcomes	in	crc	therefore	the	cd14	molecule	promises	to	be	a	potential	target	to	enhance	the	immunotherapy	of	colorectal	cancers</Paragraph></Rec>
<Rec><Paragraph>semaphorin	4c	sema4c	is	an	important	regulator	of	axonal	guidance	and	aggravates	tumor	development	however	the	roles	and	prognostic	value	of	sema4c	in	colorectal	cancer	crc	remain	unclear	here	bioinformatics	analyses	of	transcriptome	data	from	multiple	crc	patient	datasets	and	immunohistochemical	staining	of	a	crc	tissue	microarray	tma	n	83	showed	that	sema4c	mrna	and	protein	expression	were	higher	in	crc	tissues	than	normal	colorectal	tissues	sema4c	mrna	and	protein	expression	correlated	with	pathologic	stage	and	metastasis	in	crc	patients	higher	sema4c	expression	was	associated	with	shorter	overall	survival	consensus	molecular	subtype	4	cms4	and	dna	hypomethylation	of	sema4c	in	crc	patients	multivariate	cox	regression	analyses	revealed	that	sema4c	expression	was	an	independent	prognostic	predictor	in	crc	patients	gene	set	expression	analysis	gsea	illustrated	that	sema4c	expression	had	remarkable	correlations	with	epithelial	mesenchymal	transition	emt	as	well	as	hedgehog	wnt	β	catenin	tgf	β	and	notch	signaling	pathways	receiver	operating	characteristic	roc	curve	analysis	demonstrated	that	sema4c	expression	accurately	distinguished	between	the	cms4	and	cms1	3	subtypes	of	crc	patients	by	inhibiting	emt	sema4c	silencing	reduced	in	vitro	proliferation	migration	and	invasion	by	crc	cells	these	findings	suggest	that	sema4c	is	a	cms4	associated	gene	that	enhances	crc	progression	by	inducing	emt</Paragraph></Rec>
<Rec><Paragraph>recent	advance	in	the	characterization	of	the	heterogeneity	of	colorectal	cancer	has	led	to	the	definition	of	a	consensus	molecular	classification	within	four	cms	subgroups	each	associated	with	specific	molecular	and	clinical	features	investigating	the	signalling	pathways	that	drive	colorectal	cancer	progression	in	relation	to	the	cms	classification	may	help	design	therapeutic	strategies	tailored	for	each	cms	subtype	the	two	main	effectors	of	the	hippo	pathway	yap	and	its	paralogue	taz	have	been	intensively	scrutinized	for	their	contribution	to	colon	carcinogenesis	here	we	review	the	knowledge	of	yap	taz	implication	in	colorectal	cancer	from	the	perspective	of	the	cms	framework	we	identify	gaps	in	our	current	understanding	and	delineate	research	avenues	for	future	work</Paragraph></Rec>
<Rec><Paragraph>consensus	molecular	subtyping	cms	of	colorectal	cancer	has	potential	to	reshape	the	colorectal	cancer	landscape	we	developed	and	validated	an	assay	that	is	applicable	on	formalin	fixed	paraffin	embedded	ffpe	samples	of	colorectal	cancer	and	implemented	the	assay	in	a	clinical	laboratory	improvement	amendments	clia	certified	laboratory	we	performed	an	in	silico	experiment	to	build	an	optimal	cms	classifier	using	a	training	set	of	1	329	samples	from	12	studies	and	validation	set	of	1	329	samples	from	14	studies	we	constructed	an	assay	on	the	basis	of	nanostring	codesets	for	the	top	472	genes	and	performed	analyses	on	paired	flash	frozen	ff	ffpe	samples	from	175	colorectal	cancers	to	adapt	the	classifier	to	ffpe	samples	using	a	subset	of	genes	found	to	be	concordant	between	ff	and	ffpe	tested	the	classifier	s	reproducibility	and	repeatability	and	validated	in	a	clia	certified	laboratory	we	assessed	prognostic	significance	of	cms	in	345	patients	pooled	across	three	clinical	trials	the	best	classifier	was	weighted	support	vector	machine	with	high	accuracy	across	platforms	and	gene	lists	0	95	and	the	472	gene	model	outperforming	existing	classifiers	we	constructed	subsets	of	99	and	200	genes	with	high	ff	ffpe	concordance	and	adapted	ffpe	based	classifier	that	had	strong	classification	accuracy	80	relative	to	gold	standard	cms	the	classifier	was	reproducible	to	sample	type	and	rna	quality	and	demonstrated	poor	prognosis	for	cms1	3	and	good	prognosis	for	cms2	in	metastatic	colorectal	cancer	p	0	001	we	developed	and	validated	a	colorectal	cancer	cms	assay	that	is	ready	for	use	in	clinical	trials	to	assess	prognosis	in	standard	of	care	settings	and	explore	as	predictor	of	therapy	response</Paragraph></Rec>
<Rec><Paragraph>the	serious	side	effect	of	current	conventional	treatments	for	patients	with	metastatic	colorectal	cancer	crc	highlights	the	requirement	of	an	alternative	treatment	strategy	natural	compounds	such	as	curcumin	have	been	gained	much	attention	due	to	its	low	toxicity	and	anti	tumor	effect	qpcr	and	western	blot	were	used	to	measure	the	molecular	changes	induced	by	curcumin	wound	healing	assay	and	transwell	assay	were	conducted	to	study	the	effect	on	cell	migration	and	invasion	rt	1	pcr	array	was	performed	to	identify	the	mirnas	involved	in	curcumin	repressed	emt	three	algorithms	and	luciferase	reporter	assay	were	used	to	identify	epm5	as	a	target	of	mir	200c	the	bioinformatical	analysis	of	tcga	coad	and	other	crc	cohorts	were	used	to	examine	the	association	of	epm5	with	emt	signatures	and	clinical	relevance	the	ectopic	expression	or	sirna	mediated	knockdown	of	epm5	was	applied	to	study	the	role	of	epm5	in	crc	treatment	with	curcumin	changed	the	epithelial	mesenchymal	transition	emt	related	gene	expression	repressed	cell	migration	and	invasion	in	crc	cells	its	anti	tumor	capability	required	the	upregulation	of	mir	200c	epm5	was	a	direct	target	of	mir	200c	and	enriched	in	the	consensus	molecular	subtype	cms	4	of	crc	ectopic	expression	of	epm5	alone	was	sufficient	to	induce	emt	in	crc	downregulation	of	epm5	was	necessary	for	curcumin	repressed	emt	migration	and	invasion	higher	expression	of	epm5	was	associated	with	the	advanced	tnm	stages	and	poor	survival	in	crc	our	data	provide	the	first	evidence	that	the	curcumin	inhibits	emt	in	crc	by	upregulation	of	mir	200c	and	downregulation	of	epm5	and	the	use	of	curcumin	might	be	able	to	prevent	or	delay	crc	progression</Paragraph></Rec>
<Rec><Paragraph>lume	colon	1	nct02149108	was	a	global	placebo	controlled	phase	iii	study	of	nintedanib	in	advanced	colorectal	cancer	crc	pre	specified	biomarker	analyses	investigated	the	association	of	crc	consensus	molecular	subtypes	cms	and	tumor	genomic	and	circulating	biomarkers	with	clinical	outcomes	archival	tumor	tissue	cell	free	dna	cfdna	and	plasma	samples	were	collected	for	genomic	transcriptomic	and	proteomic	analyses	to	investigate	potential	associations	between	crc	cms	and	other	biomarkers	with	nintedanib	response	and	clinical	outcomes	of	the	765	treated	patients	735	245	and	192	patient	samples	were	analyzed	in	the	circulating	protein	tumor	tissue	and	cfdna	datasets	respectively	patients	were	classified	as	cms1	1	7	cms2	27	7	cms3	0	9	cms4	51	5	or	unclassified	18	2	unclassified	mixed	cms	was	associated	with	longer	overall	survival	os	with	nintedanib	vs	cms2	or	cms4	interaction	p	value	0086	no	association	was	observed	for	cms4	gene	expression	based	pathway	analysis	revealed	an	association	between	vascular	endothelial	growth	factor	related	signaling	and	os	for	nintedanib	p	0498	the	most	frequently	detected	somatic	mutations	were	apc	72	0	tumor	tissue	vs	56	8	cfdna	tp53	47	1	vs	34	9	kras	40	8	vs	28	6	and	pik3ca	16	6	vs	11	5	concordance	rates	were	80	median	os	differences	were	observed	for	apc	and	tp53	mutations	vs	wild	type	in	cfdna	indicating	a	potential	prognostic	value	circulating	ang	2	ca	9	ceacam1	collagen	iv	igfbp	1	icam	1	il	8	and	upar	were	potentially	prognostic	for	both	os	and	progression	free	survival	we	demonstrated	the	feasibility	of	large	scale	biomarker	analyses	and	cms	classification	within	a	global	clinical	trial	and	identified	signals	suggesting	a	potential	for	greater	nintedanib	treatment	response	in	the	unclassified	mixed	cms	subgroup	despite	these	tumors	showing	heterogeneous	patterns	of	cms	mixtures	our	results	revealed	a	high	degree	of	concordance	in	somatic	mutations	between	tumor	tissue	and	cfdna	associations	with	prognosis	for	cfdna	somatic	mutations	as	well	as	several	protein	based	biomarkers	may	warrant	further	investigation	in	future	trials</Paragraph></Rec>
<Rec><Paragraph>the	classification	of	colorectal	cancer	crc	plays	a	pivotal	role	in	predicting	a	patient	s	prognosis	and	determining	treatment	strategies	the	consensus	molecular	subtype	cms	classification	system	was	constructed	by	analyzing	genetic	information	from	18	crc	data	sets	containing	4151	crc	samples	crc	was	classified	into	four	subtypes	with	distinct	molecular	and	biological	characteristics	cms1	microsatellite	instability	immune	cms2	canonical	cms3	metabolic	and	cms4	mesenchymal	since	their	designation	in	2015	these	classifications	have	been	applied	to	basic	and	translational	research	of	crc	with	the	hope	that	understanding	these	subsets	will	influence	a	clinician	s	approach	to	therapeutic	treatment	and	improve	clinical	outcomes	we	reviewed	crc	investigations	in	accordance	with	cmss	published	in	the	last	5	years	to	further	explore	the	clinical	significance	of	these	subtypes	and	identify	underlying	trends	that	may	direct	relevant	future	research	we	determined	that	cmss	linked	common	features	of	crc	cell	lines	and	pdx	models	in	various	studies	furthermore	associations	between	prognosis	and	clinicopathological	findings	including	pathological	grade	and	the	stage	of	carcinogenesis	tumor	budding	and	tumor	location	were	correlated	with	cms	classification	novel	prognostic	factors	were	identified	and	the	relationship	between	chemotherapeutic	drug	resistance	and	cms	has	been	fortified	by	our	compilation	of	research	thus	indicating	that	this	review	provides	advanced	insight	into	clinical	questions	and	treatment	strategies	for	crc</Paragraph></Rec>
<Rec><Paragraph>colon	cancer	cc	is	a	heterogeneous	disease	novel	prognostic	factors	beyond	pathological	staging	are	required	to	accurately	identify	patients	at	higher	risk	of	relapse	integrating	these	new	biological	factors	such	as	plasma	circulating	tumour	dna	ctdna	cdx2	staining	inflammation	associated	cytokines	and	transcriptomic	consensus	molecular	subtypes	cms	classification	into	a	multimodal	approach	may	improve	our	accuracy	in	determining	risk	of	recurrence	one	hundred	and	fifty	patients	consecutively	diagnosed	with	localised	cc	were	prospectively	enrolled	in	our	study	ctdna	was	tracked	to	detect	minimal	residual	disease	by	droplet	digital	pcr	cdx2	expression	was	analysed	by	immunostaining	plasma	levels	of	cytokines	potentially	involved	in	disease	progression	were	measured	using	elisas	a	96	custom	gene	panel	for	ncounter	assay	was	used	to	classify	cc	into	colorectal	cancer	assigner	and	cms	most	patients	were	classified	into	cms4	37	and	cms2	28	followed	by	cms1	20	and	cms3	15	groups	cdx2	negative	tumours	were	enriched	in	cms1	and	cms4	subtypes	in	univariable	analysis	prognosis	was	influenced	by	primary	tumour	location	stage	vascular	and	perineural	invasion	together	with	high	interleukin	6	plasma	levels	at	baseline	tumours	belonging	to	cms	1	vs	cms2	cms3	ctdna	presence	in	plasma	and	cdx2	loss	however	only	positive	ctdna	in	plasma	samples	hr	13	64	p	0	002	and	lack	of	cdx2	expression	hr	23	12	p	0	001	were	found	to	be	independent	prognostic	factors	for	disease	free	survival	in	the	multivariable	model	ctdna	detection	after	surgery	and	lack	of	cdx2	expression	identified	patients	at	very	high	risk	of	recurrence	in	localised	cc</Paragraph></Rec>
<Rec><Paragraph>the	immune	system	can	recognize	and	attack	cancer	cells	especially	those	with	a	high	load	of	mutation	induced	neoantigens	such	neoantigens	are	abundant	in	dna	mismatch	repair	mmr	deficient	microsatellite	unstable	msi	cancers	mmr	deficiency	leads	to	insertion	deletion	indel	mutations	at	coding	microsatellites	cms	and	to	neoantigen	inducing	translational	frameshifts	here	we	develop	a	tool	to	quantify	frameshift	mutations	in	msi	colorectal	and	endometrial	cancer	our	results	show	that	frameshift	mutation	frequency	is	negatively	correlated	to	the	predicted	immunogenicity	of	the	resulting	peptides	suggesting	counterselection	of	cell	clones	with	highly	immunogenic	frameshift	peptides	this	correlation	is	absent	in	tumors	with	beta	2	microglobulin	mutations	and	hla	a	02	01	status	is	related	to	cms	mutation	patterns	importantly	certain	outlier	mutations	are	common	in	msi	cancers	despite	being	related	to	frameshift	peptides	with	functionally	confirmed	immunogenicity	suggesting	a	possible	driver	role	during	msi	tumor	evolution	neoantigens	resulting	from	shared	mutations	represent	promising	vaccine	candidates	for	prevention	of	msi	cancers</Paragraph></Rec>
<Rec><Paragraph>changes	in	protein	levels	in	different	components	of	the	apical	junctional	complex	occur	in	colorectal	cancer	crc	claudin	3	is	one	of	the	main	constituents	of	tight	junctions	and	its	overexpression	can	increase	the	paracellular	flux	of	macromolecules	as	well	as	the	malignant	potential	of	crc	cells	the	aim	of	this	study	was	to	investigate	the	molecular	mechanisms	involved	in	the	regulation	of	claudin	3	and	its	prognostic	value	in	crc	in	silico	evaluation	in	each	of	the	crc	consensus	molecular	subtypes	cmss	revealed	that	high	expression	levels	of	cldn3	gene	encoding	claudin	3	in	cms2	and	cms3	worsened	the	patients	long	term	survival	whereas	a	decrease	in	claudin	3	levels	concomitant	with	a	reduction	in	phosphorylation	levels	of	epidermal	growth	factor	receptor	egfr	and	insulin	like	growth	factor	1	receptor	igf1r	could	be	achieved	by	inhibiting	n	glycan	biosynthesis	in	crc	cells	we	also	observed	that	specific	inactivation	of	these	receptor	tyrosine	kinases	rtks	led	to	a	decrease	in	claudin	3	levels	and	this	regulation	seems	to	be	mediated	by	phospholipase	c	plc	and	signal	transducer	and	activator	of	transcription	3	stat3	in	crc	cells	rtks	are	modulated	by	their	n	linked	glycans	and	inhibition	of	n	glycan	biosynthesis	decreased	the	claudin	3	levels	therefore	we	evaluated	the	correlation	between	n	glycogenes	and	cldn3	expression	levels	in	each	of	the	crc	molecular	subtypes	the	cms1	msi	immune	subtype	concomitantly	exhibited	low	expression	levels	of	cldn3	and	n	glycogenes	mgat5	st6gal1	and	b3gnt8	whereas	cms2	canonical	exhibited	high	gene	expression	levels	of	cldn3	and	n	glycogenes	st6gal1	and	b3gnt8	a	robust	positive	correlation	was	also	observed	between	cldn3	and	b3gnt8	expression	levels	in	all	cmss	these	results	support	the	hypothesis	of	a	mechanism	integrating	rtk	signaling	and	n	glycosylation	for	the	regulation	of	claudin	3	levels	in	crc	and	they	suggest	that	cldn3	expression	can	be	used	to	predict	the	prognosis	of	patients	identified	as	cms2	or	cms3</Paragraph></Rec>
<Rec><Paragraph>for	stage	ii	colorectal	cancer	crc	the	efficacy	of	adjuvant	chemotherapy	remains	controversial	consensus	molecular	subtype	cms	has	been	validated	to	be	a	prognostic	tool	for	crcs	in	this	study	cms	status	was	investigated	as	a	prognostic	biomarker	for	the	efficacy	of	adjuvant	chemotherapy	for	stage	ii	colorectal	cancer	the	tissue	microarray	was	retrospectively	constructed	of	165	nonconsecutive	primary	and	sporadic	stage	ii	crcs	cms	status	was	determined	by	immunohistochemistry	staining	of	cdx2	htr2b	frmd6	and	zeb1	combining	with	microsatellite	instability	testing	the	prognostic	for	adjuvant	chemotherapy	efficacy	of	cms	status	was	calculated	by	kaplan	meier	curves	and	cox	regression	analysis	subgroup	analyses	were	conducted	according	to	tumor	location	kaplan	meier	curves	indicated	that	cms	was	associated	with	overall	survival	os	and	disease	free	survival	for	stage	ii	crcs	cox	regression	analysis	showed	that	cms	was	an	independent	risk	factor	for	os	among	high	risk	clinicopathological	factors	patients	with	cms2	3	hazard	ratio	hr	0	445	95	confidence	interval	ci	0	227	0	875	left	sided	tumors	hr	0	488	95	ci	0	247	0	968	or	fewer	than	12	lymph	nodes	examined	hr	0	307	95	ci	0	097	0	974	had	survival	benefit	from	adjuvant	chemotherapy	subgroup	analysis	showed	that	adjuvant	chemotherapy	only	improved	os	for	patients	with	left	sided	tumors	of	cms2	3	subtype	regardless	of	cms	right	sided	tumors	had	no	benefit	from	adjuvant	chemotherapy	cms	is	a	better	prognostic	factor	for	adjuvant	chemotherapy	for	stage	ii	crcs	together	with	tumor	location	cms	classification	will	aid	in	personalized	treatment	for	stage	ii	crcs	for	stage	ii	colorectal	cancer	crc	the	efficacy	of	adjuvant	chemotherapy	remains	controversial	in	that	its	minimal	benefit	no	more	than	5	on	average	is	considered	not	worth	the	toxic	effects	of	the	drugs	there	are	still	no	effective	prognostic	and	predictive	biomarkers	this	study	showed	that	consensus	molecular	subtype	cms	status	is	a	predictive	marker	for	adjuvant	chemotherapy	efficacy	patients	with	left	sided	tumors	of	cms2	3	subtype	have	survival	benefit	by	receiving	adjuvant	chemotherapy	which	will	aid	in	personalized	treatment	for	stage	ii	crcs	moreover	this	test	of	cms	based	on	immunohistochemistry	is	cheap	not	time	consuming	and	easily	conducted	in	the	laboratories	of	most	hospitals</Paragraph></Rec>
<Rec><Paragraph>there	are	profound	individual	differences	in	clinical	outcomes	between	colorectal	cancers	crcs	presenting	with	identical	stage	of	disease	molecular	stratification	in	conjunction	with	the	traditional	tnm	staging	is	a	promising	way	to	predict	patient	outcomes	we	investigated	the	interconnectivity	between	tumor	stage	and	tumor	biology	reflected	by	the	consensus	molecular	subtypes	cmss	in	crc	and	explored	the	possible	value	of	these	insights	in	patients	with	stage	ii	colon	cancer	we	performed	a	retrospective	analysis	using	clinical	records	and	gene	expression	profiling	in	a	meta	cohort	of	1040	crc	patients	the	interconnectivity	of	tumor	biology	and	disease	stage	was	assessed	by	investigating	the	association	between	cmss	and	tnm	classification	in	order	to	validate	the	clinical	applicability	of	our	findings	we	employed	a	meta	cohort	of	197	stage	ii	colon	cancers	cms4	was	significantly	more	prevalent	in	advanced	stages	of	disease	stage	i	9	8	versus	stage	iv	38	5	p	0	001	the	observed	differential	gene	expression	between	cancer	stages	is	at	least	partly	explained	by	the	biological	differences	as	reflected	by	cms	subtypes	gene	signatures	for	stage	iii	iv	and	cms4	were	highly	correlated	r	0	77	p	0	001	cms4	cancers	showed	an	increased	progression	rate	to	more	advanced	stages	cms4	compared	to	cms2	1	25	95	ci	1	08	1	46	patients	with	a	cms4	cancer	had	worse	survival	in	the	high	risk	stage	ii	tumors	compared	to	the	total	stage	ii	cohort	5	year	dfs	41	7	versus	100	0	p	0	008	considerable	interconnectivity	between	tumor	biology	and	tumor	stage	in	crc	exists	this	implies	that	the	tnm	stage	in	addition	to	the	stage	of	progression	might	also	reflect	distinct	biological	disease	entities	these	insights	can	potentially	be	utilized	to	optimize	identification	of	high	risk	stage	ii	colon	cancers</Paragraph></Rec>
<Rec><Paragraph>we	hypothesise	that	the	nrf2	transcription	factor	would	act	a	biomarker	of	poor	prognosis	in	colorectal	cancer	we	derived	and	validated	an	mrna	based	metagene	signature	of	nrf2	signalling	and	validated	it	in	1360	patients	from	4	different	datasets	as	an	independent	biomarker	of	poor	prognosis	this	is	a	novel	insight	into	the	molecular	signalling	of	colorectal	cancer	nrf2	over	activity	confers	poor	prognosis	in	some	cancers	but	its	prognostic	role	in	colorectal	cancer	crc	is	unknown	as	a	transcription	factor	we	hypothesise	a	signature	of	nrf2	regulated	genes	could	act	as	a	prognostic	biomarker	in	crc	and	reveal	novel	biological	insights	using	known	nrf2	regulated	genes	differentially	expressed	in	crc	we	defined	a	signature	of	nrf2	pathway	activity	using	principal	component	analysis	and	cox	proportional	hazard	models	and	tested	it	in	four	independent	mrna	datasets	profiled	on	three	different	mrna	platforms	36	genes	comprised	the	final	nrf2	signature	1360	patients	were	included	in	the	validation	high	nrf2	was	associated	with	worse	disease	free	survival	dfs	and	or	overall	survival	os	in	all	datasets	gse14333	hr	1	55	95	c	i	1	2	2	004	p	0	0008	gse39582	hr	1	24	95	c	i	1	086	1	416	p	0	001	gse87211	hr	1	431	95	c	i	1	06	1	93	p	0	056	mrc	focus	trial	hr	1	14	95	c	i	1	04	1	26	p	0	008	in	multivariate	analyses	nrf2	remained	significant	when	adjusted	for	stage	and	adjuvant	chemotherapy	in	stage	i	iii	disease	and	braf	v600e	mutation	and	sidedness	in	stage	iv	disease	nrf2	activity	was	particularly	enriched	in	consensus	molecular	subtype	cms	4	for	the	first	time	nrf2	is	shown	to	be	a	consistent	robust	prognostic	biomarker	across	all	stages	of	colorectal	cancer	with	additional	clinical	value	to	current	known	prognostic	biomarkers	high	nrf2	signalling	in	cms	4	further	refines	the	molecular	taxonomy	of	crc	a	new	biological	insight	suggesting	avenues	of	further	study</Paragraph></Rec>
<Rec><Paragraph>lung	cancer	screening	with	chest	computed	tomography	ct	reduces	lung	cancer	death	centers	for	medicare	medicaid	services	cms	eligibility	criteria	for	lung	cancer	screening	with	ct	require	detailed	smoking	information	and	miss	many	incident	lung	cancers	an	automated	deep	learning	approach	based	on	chest	radiograph	images	may	identify	more	smokers	at	high	risk	for	lung	cancer	who	could	benefit	from	screening	with	ct	to	develop	and	validate	a	convolutional	neural	network	cxr	lc	that	predicts	long	term	incident	lung	cancer	using	data	commonly	available	in	the	electronic	medical	record	emr	chest	radiograph	age	sex	and	whether	currently	smoking	risk	prediction	study	u	s	lung	cancer	screening	trials	the	cxr	lc	model	was	developed	in	the	plco	prostate	lung	colorectal	and	ovarian	cancer	screening	trial	n	41	856	the	final	cxr	lc	model	was	validated	in	additional	plco	smokers	n	5615	12	year	follow	up	and	nlst	national	lung	screening	trial	heavy	smokers	n	5493	6	year	follow	up	results	are	reported	for	validation	data	sets	only	up	to	12	year	lung	cancer	incidence	predicted	by	cxr	lc	the	cxr	lc	model	had	better	discrimination	area	under	the	receiver	operating	characteristic	curve	auc	for	incident	lung	cancer	than	cms	eligibility	plco	auc	0	755	vs	0	634	p	0	001	the	cxr	lc	model	s	performance	was	similar	to	that	of	plcom2012	a	state	of	the	art	risk	score	with	11	inputs	in	both	the	plco	data	set	cxr	lc	auc	of	0	755	vs	plcom2012	auc	of	0	751	and	the	nlst	data	set	0	659	vs	0	650	when	compared	in	equal	sized	screening	populations	cxr	lc	was	more	sensitive	than	cms	eligibility	in	the	plco	data	set	74	9	vs	63	8	p	0	012	and	missed	30	7	fewer	incident	lung	cancers	on	decision	curve	analysis	cxr	lc	had	higher	net	benefit	than	cms	eligibility	and	similar	benefit	to	plcom2012	validation	in	lung	cancer	screening	trials	and	not	a	clinical	setting	the	cxr	lc	model	identified	smokers	at	high	risk	for	incident	lung	cancer	beyond	cms	eligibility	and	using	information	commonly	available	in	the	emr	none</Paragraph></Rec>
<Rec><Paragraph>in	this	issue	of	jem	varga	et	al	https	doi	org	10	1084	jem	20191515	describe	a	mouse	model	of	invasive	and	metastatic	colorectal	cancer	crc	closely	resembling	the	human	consensus	molecular	subtype	cms	4	associated	with	the	poorest	overall	survival	of	the	four	cmss	transcriptomic	and	bioinformatic	analysis	combined	with	pharmacological	and	genetic	studies	identified	notch3	as	a	promoter	of	tumor	progression	and	metastasis	notch3	expression	was	up	regulated	in	cms4	crc	patients	and	associated	with	tumor	staging	lymph	node	and	distant	metastasis	these	findings	feature	notch3	as	putative	therapeutic	target	for	advanced	cms4	crc	patients</Paragraph></Rec>
<Rec><Paragraph>carcinoma	development	in	colorectal	cancer	is	driven	by	genetic	alterations	in	numerous	signaling	pathways	alterations	in	the	ras	erk1	2	pathway	are	associated	with	the	shortest	overall	survival	for	patients	after	diagnosis	of	colorectal	cancer	metastatic	disease	yet	how	ras	erk	signaling	regulates	colorectal	cancer	metastasis	remains	unknown	in	this	study	we	used	an	unbiased	screening	approach	based	on	selection	of	highly	liver	metastatic	colorectal	cancer	cells	in	vivo	to	determine	genes	associated	with	metastasis	from	this	an	erk1	2	controlled	metastatic	gene	set	emgs	was	defined	emgs	was	associated	with	increased	recurrence	and	reduced	survival	in	patients	with	colorectal	cancer	tumors	higher	levels	of	emgs	expression	were	detected	in	the	colorectal	cancer	subsets	consensus	molecular	subtype	cms	1	and	cms4	angpt2	and	cxcr4	two	genes	within	the	emgs	were	subjected	to	gain	of	function	and	loss	of	function	studies	in	several	colorectal	cancer	cell	lines	and	then	tested	in	clinical	samples	the	ras	erk1	2	axis	controlled	expression	of	the	cytokine	angpt2	and	the	cytokine	receptor	cxcr4	in	colorectal	cancer	cells	which	facilitated	development	of	liver	but	not	lung	metastases	suggesting	that	angpt2	and	cxcr4	are	important	for	metastatic	outgrowth	in	the	liver	cxcr4	controlled	the	expression	of	cytokines	il10	and	cxcl1	providing	evidence	for	a	causal	role	of	il10	in	supporting	liver	colonization	in	summary	these	studies	demonstrate	that	amplification	of	erk1	2	signaling	in	kras	mutated	colorectal	cancer	cells	affects	the	cytokine	milieu	of	the	tumors	possibly	affecting	tumor	stroma	interactions	and	favoring	liver	metastasis	formation	significance	these	findings	identify	amplified	erk1	2	signaling	in	kras	mutated	colorectal	cancer	cells	as	a	driver	of	tumor	stroma	interactions	that	favor	formation	of	metastases	in	the	liver</Paragraph></Rec>
<Rec><Paragraph>it	is	estimated	that	around	15	30	of	patients	with	early	stage	colon	cancer	benefit	from	adjuvant	chemotherapy	we	are	currently	not	capable	of	upfront	selection	of	patients	who	benefit	from	chemotherapy	which	indicates	the	need	for	additional	predictive	markers	for	response	to	chemotherapy	it	has	been	shown	that	the	consensus	molecular	subtypes	cmss	defined	by	rna	profiling	have	prognostic	and	or	predictive	value	due	to	postoperative	timing	of	chemotherapy	in	current	guidelines	tumor	response	to	chemotherapy	per	cms	is	not	known	which	makes	the	differentiation	between	the	prognostic	and	predictive	value	impossible	therefore	we	propose	to	assess	the	tumor	response	per	cms	in	the	neoadjuvant	chemotherapy	setting	this	will	provide	us	with	clear	data	on	the	predictive	value	for	chemotherapy	response	of	the	cmss	in	this	prospective	single	arm	multicenter	intervention	study	262	patients	with	resectable	microsatellite	stable	ct3	4nxm0	colon	cancer	will	be	treated	with	two	courses	of	neoadjuvant	and	two	courses	of	adjuvant	capecitabine	and	oxaliplatin	the	primary	endpoint	is	the	pathological	tumor	response	to	neoadjuvant	chemotherapy	per	cms	secondary	endpoints	are	radiological	tumor	response	the	prognostic	value	of	these	responses	for	recurrence	free	survival	and	overall	survival	and	the	differences	in	cms	classification	of	the	same	tumor	before	and	after	neoadjuvant	chemotherapy	the	study	is	scheduled	to	be	performed	in	8	10	dutch	hospitals	the	first	patient	was	included	in	february	2020	patient	selection	for	adjuvant	chemotherapy	in	early	stage	colon	cancer	is	far	from	optimal	the	cms	classification	is	a	promising	new	biomarker	but	a	solid	chemotherapy	response	assessment	per	subtype	is	lacking	in	this	study	we	will	investigate	whether	cms	classification	can	be	of	added	value	in	clinical	decision	making	by	analyzing	the	predictive	value	for	chemotherapy	response	this	study	can	provide	the	results	necessary	to	proceed	to	future	studies	in	which	neo	adjuvant	chemotherapy	may	be	withhold	in	patients	with	a	specific	cms	subtype	who	show	no	benefit	from	chemotherapy	and	for	whom	possible	new	treatments	can	be	investigated	this	study	has	been	registered	in	the	netherlands	trial	register	nl8177	at	11	26	2019	https	www	trialregister	nl	trial	8177	the	study	has	been	approved	by	the	medical	ethics	committee	utrecht	mec18	712</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	heterogeneous	disease	representing	a	therapeutic	challenge	which	is	further	complicated	by	the	common	occurrence	of	several	molecular	alterations	that	confer	resistance	to	standard	chemotherapy	and	targeted	agents	mechanisms	of	resistance	have	been	identified	at	multiple	levels	in	the	epidermal	growth	factor	receptor	egfr	pathway	including	mutations	in	kras	nras	and	braf	v600e	and	in	the	her2	and	met	receptors	these	alterations	represent	oncogenic	drivers	that	may	co	exist	in	the	same	tumor	with	other	primary	and	acquired	alterations	via	a	clonal	selection	process	other	molecular	alterations	include	dna	damage	repair	mechanisms	and	rare	kinase	fusions	potentially	offering	a	rationale	for	new	therapeutic	strategies	in	recent	years	genomic	analysis	has	been	expanded	by	a	more	complex	study	of	epigenomic	transcriptomic	and	microenvironment	features	the	consensus	molecular	subtype	cms	classification	describes	four	crc	subtypes	with	distinct	biological	characteristics	that	show	prognostic	and	potential	predictive	value	in	the	clinical	setting	here	we	review	the	panorama	of	actionable	targets	in	crc	and	the	developments	in	more	recent	molecular	tests	such	as	liquid	biopsy	analysis	which	are	increasingly	offering	clinicians	a	means	of	ensuring	optimal	tailored	treatments	for	patients	with	metastatic	crc	according	to	their	evolving	molecular	profile	and	treatment	history</Paragraph></Rec>
<Rec><Paragraph>recently	a	transcriptome	based	consensus	molecular	subtype	cms	classification	of	colorectal	cancer	crc	has	been	established	which	may	ultimately	help	to	individualize	crc	therapy	however	the	lack	of	animal	models	that	faithfully	recapitulate	the	different	molecular	subtypes	impedes	adequate	preclinical	testing	of	stratified	therapeutic	concepts	here	we	demonstrate	that	constitutive	akt	activation	in	intestinal	epithelial	cells	markedly	enhances	tumor	invasion	and	metastasis	in	trp53δiec	mice	trp53δiecakte17k	upon	challenge	with	the	carcinogen	azoxymethane	gene	expression	profiling	indicates	that	trp53δiecakte17k	tumors	resemble	the	human	mesenchymal	colorectal	cancer	subtype	cms4	which	is	characterized	by	the	poorest	survival	rate	among	the	four	cmss	trp53δiecakte17k	tumor	cells	are	characterized	by	notch3	up	regulation	and	treatment	of	trp53δiecakte17k	mice	with	a	notch3	inhibiting	antibody	reduces	invasion	and	metastasis	in	crc	patients	notch3	expression	correlates	positively	with	tumor	grading	and	the	presence	of	lymph	node	as	well	as	distant	metastases	and	is	specifically	up	regulated	in	cms4	tumors	therefore	we	suggest	notch3	as	a	putative	target	for	advanced	cms4	crc	patients</Paragraph></Rec>
<Rec><Paragraph>appendiceal	adenocarcinoma	aa	is	an	orphan	disease	with	unique	clinical	attributes	but	often	treated	as	colorectal	cancer	crc	understanding	key	molecular	differences	between	aa	and	crc	is	critical	we	performed	retrospective	analyses	of	aa	patients	n	266	with	tumour	and	or	blood	next	generation	sequencing	ngs	2013	2018	with	in	depth	clinicopathological	annotation	overall	survival	os	was	examined	for	comparison	crc	cohorts	annotated	for	sidedness	consensus	molecular	subtypes	cms	and	mutations	n	3283	were	used	blood	ngs	identified	less	ras	gnas	mutations	compared	to	tissue	ngs	4	2	vs	60	9	p	0	0001	and	showed	poor	concordance	with	tissue	for	well	moderately	differentiated	tumours	ras	56	2	gnas	28	1	and	tp53	26	9	were	most	frequent	mutations	well	moderately	differentiated	tumours	harboured	more	ras	69	2	64	0	vs	40	5	and	gnas	48	7	32	0	vs	10	1	while	moderate	poorly	differentiated	tumours	had	more	tp53	26	0	27	8	vs	7	7	mutations	appendiceal	adenocarcinoma	compared	to	crc	harboured	significantly	fewer	apc	9	1	vs	55	4	and	tp53	26	9	vs	67	5	and	more	gnas	mutations	28	1	vs	2	0	p	0	0001	appendiceal	adenocarcinoma	mutation	profile	did	not	resemble	either	right	sided	crc	or	any	of	the	four	cms	in	crc	high	grade	but	no	mutation	was	independently	predictive	of	survival	integrated	clinico	molecular	profiling	of	aa	identified	key	molecular	drivers	distinct	from	crc	appendiceal	adenocarcinoma	has	a	predominantly	grade	driven	biology	that	trumps	mutations</Paragraph></Rec>
<Rec><Paragraph>tumor	budding	has	been	found	to	be	of	prognostic	significance	for	several	cancers	including	colorectal	cancer	crc	additionally	the	molecular	classification	of	crc	has	led	to	the	identification	of	different	immune	microenvironments	linked	to	distinct	prognosis	and	therapeutic	response	however	the	association	between	tumor	budding	and	the	different	molecular	subtypes	of	crc	and	distinct	immune	profiles	have	not	been	fully	elucidated	this	study	focused	firstly	on	the	validation	of	derived	xenograft	models	pdxs	for	the	evaluation	of	tumor	budding	and	their	human	counterparts	and	secondly	on	the	association	between	tumor	budding	and	the	immune	tumor	microenvironment	by	the	analysis	of	gene	expression	signatures	of	immune	checkpoints	toll	like	receptors	tlrs	and	chemokine	families	clinical	crc	samples	with	different	grades	of	tumor	budding	and	their	corresponding	pdxs	were	included	in	this	study	tumor	budding	grade	was	reliably	reproduced	in	early	passages	of	pdxs	and	high	grade	tumor	budding	was	intimately	related	with	a	poor	prognosis	cms4	mesenchymal	subtype	in	addition	an	upregulation	of	negative	regulatory	immune	checkpoints	pdl1	tim	3	nox2	and	ido1	tlrs	tlr1	tlr3	tlr4	and	tlr6	and	chemokine	receptors	and	ligands	cxcr2	cxcr4	cxcl1	cxcl2	cxcl6	and	cxcl9	was	detected	in	high	grade	tumor	budding	in	both	human	samples	and	their	corresponding	xenografts	our	data	support	a	close	link	between	high	grade	tumor	budding	in	crc	and	a	distinctive	immune	suppressive	microenvironment	promoting	tumor	invasion	which	may	have	a	determinant	role	in	the	poor	prognosis	of	the	cms4	mesenchymal	subtype	in	addition	our	study	demonstrates	that	pdx	models	may	constitute	a	robust	preclinical	platform	for	the	development	of	novel	therapies	directed	against	tumor	budding	in	crc</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	tumors	can	be	partitioned	into	four	biologically	distinct	consensus	molecular	subtypes	cms1	4	using	gene	expression	evidence	is	accumulating	that	tumors	in	different	subtypes	are	likely	to	respond	differently	to	treatments	however	to	date	there	is	no	clinical	diagnostic	test	for	cms	subtyping	in	this	study	we	used	novel	methodology	in	a	multi	cohort	training	domain	n	1	214	to	develop	the	colotype	scores	and	classifier	to	predict	cms1	4	based	on	expression	of	40	genes	in	three	validation	cohorts	n	1	744	in	total	representing	three	distinct	gene	expression	measurement	technologies	colotype	predicted	gold	standard	cms	subtypes	with	accuracies	0	90	0	91	0	88	respectively	to	accommodate	for	potential	intratumoral	heterogeneity	and	tumors	of	mixed	subtypes	colotype	was	designed	to	report	continuous	scores	measuring	the	prevalence	of	each	of	cms1	4	in	a	tumor	in	addition	to	specifying	the	most	prevalent	subtype	for	analysis	of	clinical	specimens	colotype	was	also	implemented	with	targeted	rna	sequencing	illumina	ampliseq	in	a	series	of	formalin	fixed	paraffin	embedded	crc	samples	n	49	colotype	by	targeted	rna	sequencing	agreed	with	subtypes	predicted	by	two	independent	methods	with	accuracies	0	92	0	82	respectively	with	further	validation	colotype	by	targeted	rna	sequencing	may	enable	clinical	application	of	cms	subtyping	with	widely	available	and	cost	effective	technology</Paragraph></Rec>
<Rec><Paragraph>this	is	a	phase	i	ii	trial	to	assess	the	efficacy	and	safety	of	napabucasin	plus	pembrolizumab	for	metastatic	colorectal	cancer	mcrc	phase	i	was	conducted	to	determine	the	recommended	phase	2	dose	rp2d	in	a	dose	escalation	design	of	napabucasin	240	to	480	mg	twice	daily	with	200	mg	pembrolizumab	every	3	weeks	phase	ii	included	cohort	a	n	10	microsatellite	instability	high	msi	h	and	cohort	b	n	40	microsatellite	stable	mss	the	primary	endpoint	was	immune	related	objective	response	rate	irorr	pd	l1	combined	positive	score	cps	genomic	profiles	and	the	consensus	molecular	subtypes	cms	of	colorectal	cancer	were	assessed	a	total	of	55	patients	were	enrolled	in	this	study	in	phase	i	no	patients	experienced	dose	limiting	toxicities	and	napabucasin	480	mg	was	determined	as	rp2d	the	irorr	was	50	0	in	cohort	a	and	10	0	in	cohort	b	in	cohort	b	the	irorr	was	0	5	3	and	42	9	in	cps	1	1	cps	10	and	cps	10	respectively	patients	with	objective	response	tended	to	have	higher	tumor	mutation	burden	than	those	without	of	evaluable	18	patients	for	cms	classification	in	cohort	b	the	irorr	was	33	3	0	33	3	and	33	3	in	cms1	cms2	cms3	and	cms4	respectively	the	common	grade	3	or	higher	treatment	related	adverse	events	included	fever	10	0	in	cohort	a	and	decreased	appetite	7	5	and	diarrhea	5	0	in	cohort	b	napabucasin	with	pembrolizumab	showed	antitumor	activity	with	acceptable	toxicities	for	patients	with	mss	mcrc	as	well	as	msi	h	mcrc	although	it	did	not	meet	the	primary	end	point	the	impact	of	related	biomarkers	on	the	efficacy	warrants	further	investigations	in	the	additional	cohort	see	related	commentary	by	nusrat	p	5775</Paragraph></Rec>
<Rec><Paragraph>complex	phenotypes	captured	on	histological	slides	represent	the	biological	processes	at	play	in	individual	cancers	but	the	link	to	underlying	molecular	classification	has	not	been	clarified	or	systematised	in	colorectal	cancer	crc	histological	grading	is	a	poor	predictor	of	disease	progression	and	consensus	molecular	subtypes	cmss	cannot	be	distinguished	without	gene	expression	profiling	we	hypothesise	that	image	analysis	is	a	cost	effective	tool	to	associate	complex	features	of	tissue	organisation	with	molecular	and	outcome	data	and	to	resolve	unclassifiable	or	heterogeneous	cases	in	this	study	we	present	an	image	based	approach	to	predict	crc	cms	from	standard	h	e	sections	using	deep	learning	training	and	evaluation	of	a	neural	network	were	performed	using	a	total	of	n	1206	tissue	sections	with	comprehensive	multi	omic	data	from	three	independent	datasets	training	on	focus	trial	n	278	patients	test	on	rectal	cancer	biopsies	grampian	cohort	n	144	patients	and	the	cancer	genome	atlas	tcga	n	430	patients	ground	truth	cms	calls	were	ascertained	by	matching	random	forest	and	single	sample	predictions	from	cms	classifier	image	based	cms	imcms	accurately	classified	slides	in	unseen	datasets	from	tcga	n	431	slides	auc	0	84	and	rectal	cancer	biopsies	n	265	slides	auc	0	85	imcms	spatially	resolved	intratumoural	heterogeneity	and	provided	secondary	calls	correlating	with	bioinformatic	prediction	from	molecular	data	imcms	classified	samples	previously	unclassifiable	by	rna	expression	profiling	reproduced	the	expected	correlations	with	genomic	and	epigenetic	alterations	and	showed	similar	prognostic	associations	as	transcriptomic	cms	this	study	shows	that	a	prediction	of	rna	expression	classifiers	can	be	made	from	h	e	images	opening	the	door	to	simple	cheap	and	reliable	biological	stratification	within	routine	workflows</Paragraph></Rec>
<Rec><Paragraph>the	aim	of	the	study	was	to	investigate	the	effect	of	chemo	radiation	on	the	genetic	and	immunological	status	of	rectal	cancer	patients	who	were	treated	with	preoperative	chemoradiotherapy	crt	the	expression	of	immune	response	associated	genes	was	compared	between	rectal	cancer	patients	treated	n	9	and	not	treated	n	10	with	preoperative	crt	using	volcano	plot	analysis	apoptosis	and	epithelial	to	mesenchymal	transition	emt	marker	genes	were	analysed	by	quantitative	pcr	qpcr	other	markers	associated	with	the	tumor	microenvironment	tme	such	as	tumor	infiltrating	lymphocytes	til	and	immune	checkpoint	molecules	were	investigated	using	immunohistochemistry	ihc	the	clinical	responses	of	preoperative	crt	for	9	rectal	cancer	patients	were	all	rated	as	stable	disease	while	the	pathological	tumor	regression	score	trg	revealed	6	cases	of	grade2	and	3	cases	of	grade1	according	to	the	genetic	signature	of	colon	cancers	treated	tumors	belonged	to	consensus	molecular	subtype	cms	4	while	not	treated	tumors	had	signatures	of	cms2	or	3	crt	treated	tumors	showed	significant	upregulation	of	emt	associated	genes	such	as	cdh2	tgf	beta	and	fgf	and	cancer	stem	cell	associated	genes	additionally	qpcr	and	ihc	demonstrated	a	suppressive	immunological	status	derived	from	the	upregulation	of	inflammatory	cytokines	il	6	il	10	and	tgf	beta	and	immune	checkpoint	genes	b7	h3	and	b7	h5	and	from	m2	type	macrophage	accumulation	in	the	tumor	the	induction	of	emt	and	immune	suppressive	status	in	the	tumor	after	strong	crt	treatment	urges	the	development	of	a	novel	combined	therapy	that	restores	immune	suppression	and	inhibits	emt	ultimately	leading	to	distant	metastasis	control</Paragraph></Rec>
<Rec><Paragraph>due	to	high	potency	and	low	toxicity	desflurane	has	been	widely	used	during	surgery	recent	evidence	that	the	use	of	desflurane	was	associated	with	colorectal	cancer	crc	tumor	metastasis	and	poor	prognosis	raising	concerns	about	the	safety	of	desflurane	however	the	mechanism	was	uncovered	crc	cells	were	exposed	to	desflurane	the	changes	in	morphology	and	epithelial	mesenchymal	transition	emt	related	genes	were	evaluated	transwell	assay	was	used	to	study	the	migration	and	invasion	effect	xenograft	was	performed	to	study	the	tumor	formation	ability	of	desflurane	treated	cells	in	vivo	dual	luciferase	reporter	assay	was	conducted	to	verify	the	target	of	microrna	mir	34a	knockdown	or	overexpression	of	loxl3	was	used	to	investigate	the	mechanism	of	desflurane	induced	emt	the	association	of	loxl3	with	crc	molecular	subtypes	and	clinical	relevance	was	studied	by	analysis	of	public	datasets	exposure	to	desflurane	induced	emt	migration	and	invasion	in	crc	cells	mice	injected	with	desflurane	treated	cells	formed	more	tumors	in	the	lungs	downregulation	of	mir	34a	and	upregulation	of	loxl3	were	required	for	desflurane	induced	emt	in	crc	cells	loxl3	was	a	direct	target	of	mir	34a	overexpression	of	loxl3	rescued	mir	34a	repressed	emt	after	exposure	to	desflurane	elevated	expression	of	loxl3	was	enriched	in	cms4	and	cris	b	subtypes	patients	with	high	expression	of	loxl3	showed	more	lymph	node	metastasis	as	well	as	poor	survival	desflurane	induced	emt	and	metastasis	in	crc	through	deregulation	of	mir	34a	loxl3	axis	clinical	mir	34a	mimic	or	inhibitor	targeting	loxl3	might	have	a	potential	protective	role	when	patients	with	crc	anesthetized	by	desflurane</Paragraph></Rec>
<Rec><Paragraph>risk	stratification	in	stage	ii	and	iii	colorectal	cancer	crc	patients	is	critical	as	it	allows	patient	selection	for	adjuvant	chemotherapy	in	view	of	the	inadequacy	of	current	clinicopathological	features	for	risk	stratification	we	undertook	a	systematic	and	comprehensive	biomarker	discovery	effort	to	develop	a	risk	assessment	signature	in	crc	patients	the	biomarker	discovery	phase	examined	853	crc	patients	and	identified	a	gene	signature	for	predicting	recurrence	free	survival	rfs	this	signature	was	validated	in	a	meta	analysis	of	1212	patients	from	nine	independent	datasets	and	its	performance	was	compared	against	established	prognostic	signatures	and	consensus	molecular	subtypes	cms	in	addition	a	risk	prediction	model	was	trained	n	142	and	subsequently	validated	in	an	independent	clinical	cohort	n	286	as	a	result	this	mesenchymal	associated	transcriptomic	signature	mats	identified	high	risk	crc	patients	with	poor	rfs	in	the	discovery	hazard	ratio	hr	1	79	and	nine	validation	cohorts	hr	1	86	in	multivariate	analysis	mats	was	the	most	significant	predictor	of	rfs	compared	to	established	prognostic	signatures	and	cms	subtypes	intriguingly	mats	robustly	identified	cms4	subtype	in	multiple	crc	cohorts	auc	0	92	0	99	in	the	two	clinical	cohorts	mats	stratified	low	and	high	risk	groups	with	a	5	year	rfs	in	the	training	hr	4	11	and	validation	cohorts	hr	2	55	as	well	as	predicted	response	to	adjuvant	therapy	in	stage	ii	and	iii	crc	patients	we	report	a	novel	prognostic	and	predictive	biomarker	signature	in	crc	which	is	superior	to	currently	used	approaches	and	have	the	potential	for	clinical	translation	in	near	future</Paragraph></Rec>
<Rec><Paragraph>akr1b1	and	akr1b10	members	of	the	aldo	keto	reductase	family	of	enzymes	that	participate	in	the	polyol	pathway	of	aldehyde	metabolism	are	aberrantly	expressed	in	colon	cancer	we	previously	showed	that	high	expression	of	akr1b1	akr1b1high	was	associated	with	enhanced	motility	inflammation	and	poor	clinical	outcome	in	colon	cancer	patients	using	publicly	available	datasets	and	ex	vivo	gene	expression	analysis	n	51	ankara	cohort	we	have	validated	our	previous	in	silico	finding	that	akr1b1high	was	associated	with	worse	overall	survival	os	compared	with	patients	with	low	expression	of	akr1b1	akr1b1low	samples	a	combined	signature	of	akr1b1high	and	akr1b10low	was	significantly	associated	with	worse	recurrence	free	survival	rfs	in	microsatellite	stable	mss	patients	and	in	patients	with	distal	colon	tumors	as	well	as	a	higher	mesenchymal	signature	when	compared	with	akr1b1low	akr1b10high	tumors	when	the	patients	were	stratified	according	to	consensus	molecular	subtypes	cms	akr1b1high	akr1b10low	samples	were	primarily	classified	as	cms4	with	predominantly	mesenchymal	characteristics	while	akr1b1low	akr1b10high	samples	were	primarily	classified	as	cms3	which	is	associated	with	metabolic	deregulation	reverse	phase	protein	array	carried	out	using	protein	samples	from	the	ankara	cohort	indicated	that	akr1b1high	akr1b10low	tumors	showed	aberrant	activation	of	metabolic	pathways	western	blot	analysis	of	akr1b1high	akr1b10low	colon	cancer	cell	lines	also	suggested	aberrant	activation	of	nutrient	sensing	pathways	collectively	our	data	suggest	that	the	akr1b1high	akr1b10low	signature	may	be	predictive	of	poor	prognosis	aberrant	activation	of	metabolic	pathways	and	can	be	considered	as	a	novel	biomarker	for	colon	cancer	prognostication</Paragraph></Rec>
<Rec><Paragraph>advanced	colorectal	cancer	crc	consensus	molecular	subtype	4	cms4	or	crc	with	a	low	immunoscore	is	associated	with	shorter	survival	times	non	metastatic	crc	with	microsatellite	instability	msi	is	associated	with	a	lower	risk	of	recurrence	we	evaluated	outcome	lymph	node	metastases	lnm	or	cancer	recurrence	in	these	tumor	subtypes	in	patients	with	surgically	removed	non	pedunculated	t1	crc	by	performing	a	multicenter	case	cohort	study	we	included	all	patients	in	13	hospitals	in	the	netherlands	from	2000	2014	n	651	we	randomly	selected	a	subgroup	of	patients	n	223	and	all	patients	with	lnm	or	recurrence	n	63	and	median	follow	up	of	44	months	we	centrally	reviewed	tumor	slides	and	constructed	and	immunostained	tissue	microarrays	determining	msi	cms	msi	cms1	cms2	3	or	cms4	and	immunoscore	i	low	i	high	we	used	weighted	cox	proportional	hazard	models	to	evaluate	the	association	of	msi	cms	and	immunoscore	with	lnm	or	recurrence	adjusting	for	conventional	histologic	risk	factors	in	the	randomly	selected	subgroup	of	patients	7	1	of	tumors	were	msi	cms1	91	0	cms2	3	1	8	cms4	and	25	i	low	in	the	case	cohort	patients	with	cms4	tumors	had	an	increased	risk	for	lnm	or	recurrence	compared	with	patients	with	tumors	of	other	cmss	adjusted	hazard	ratio	hr	3	97	95	ci	1	12	14	06	p	0	03	albeit	not	significant	tumors	with	msi	had	a	lower	risk	for	lnm	or	recurrence	than	other	tumor	subtypes	adjusted	hr	0	52	95	ci	0	12	2	30	p	0	39	whereas	tumors	with	a	low	immunoscore	had	an	increased	risk	for	lnm	or	recurrence	adjusted	hr	1	30	95	ci	0	68	2	48	p	0	43	in	conclusion	in	a	case	cohort	study	of	patients	with	non	pedunculated	t1	crc	msi	and	immunoscore	were	not	significantly	associated	with	adverse	outcome	after	surgery	cms4	substantially	increased	the	risk	of	adverse	outcome	however	cms4	is	rare	in	t1	crcs	limiting	its	value	for	determining	the	risk	in	patients</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	has	been	divided	into	4	consensus	molecular	subtypes	cmss	of	which	cms4	has	the	mesenchymal	identity	and	the	highest	relapse	rate	our	goal	is	to	develop	a	prognostic	signature	by	integrating	the	immune	system	and	mesenchymal	modalities	involved	in	cms4	the	gene	expression	profiles	collected	from	5	public	datasets	were	applied	to	this	study	including	1280	samples	totally	network	analysis	was	applied	to	integrate	the	mesenchymal	modalities	and	immune	signature	to	establish	an	immune	based	prognostic	signature	for	crc	ipscrc	we	identified	6	immune	genes	as	key	factors	of	cms4	and	established	the	ipscrc	the	ipscrc	could	significantly	divide	patients	into	high	and	low	risk	groups	in	terms	of	relapse	free	survival	rfs	and	overall	survival	os	and	in	discovery	rfs	p	0001	and	4	independent	validation	sets	rfs	range	p	01	to	0001	os	range	p	02	0004	after	stage	stratification	the	ipscrc	could	still	distinguish	poor	prognosis	patients	in	discovery	rfs	p	04	and	validation	cohorts	rfs	range	p	04	007	within	stage	ii	in	terms	of	rfs	further	in	multivariate	analysis	the	ipscrc	remained	an	independent	predictor	of	prognosis	moreover	macrophage	m2	was	significantly	enriched	in	the	high	risk	group	while	plasma	cells	enriched	in	the	low	risk	group	we	propose	an	immune	based	signature	identified	by	network	analysis	which	is	a	promising	prognostic	biomarker	and	help	for	the	selection	of	crc	patients	who	might	benefit	from	more	rigorous	therapies	further	prospective	studies	are	warranted	to	test	and	validate	its	efficiency	for	clinical	application</Paragraph></Rec>
<Rec><Paragraph>colon	cancer	is	one	of	the	most	frequently	diagnosed	malignancies	in	adults	considering	both	its	incidence	and	prevalence	anatomically	the	right	colon	is	considered	as	being	from	the	cecum	to	the	splenic	flexure	and	the	left	colon	is	from	the	splenic	flexure	to	the	rectum	sidedness	is	a	surrogate	of	a	wide	spectrum	of	colorectal	cancer	crc	biology	features	embryology	microbiome	methylation	microsatellite	instability	msi	braf	aging	kras	consensus	molecular	subtypes	cms	etc	which	result	in	prognostic	factors	different	molecular	subtypes	have	been	identified	according	to	genomic	and	transcriptomic	criteria	a	subgroup	harboring	a	braf	mutation	has	been	described	and	represents	approximately	10	of	the	patients	diagnosed	with	colon	cancer	this	subgroup	has	morphological	clinical	and	therapeutic	characteristics	that	differ	substantially	from	patients	who	do	not	carry	this	genetic	alteration	unfortunately	there	is	no	established	standard	of	care	for	this	particular	cohort	of	patients	this	manuscript	aims	to	study	the	biology	of	this	subgroup	of	colon	cancer	to	understand	the	current	approach	in	clinical	research</Paragraph></Rec>
<Rec><Paragraph>dna	mismatch	repair	mmr	deficiency	is	a	hallmark	of	lynch	syndrome	the	most	common	inherited	cancer	syndrome	mmr	deficient	cancer	cells	accumulate	numerous	insertion	deletion	mutations	at	microsatellites	mutations	of	coding	microsatellites	cms	lead	to	the	generation	of	immunogenic	frameshift	peptide	fsp	neoantigens	as	the	evolution	of	mmr	deficient	cancers	is	triggered	by	mutations	inactivating	defined	cms	containing	tumor	suppressor	genes	distinct	fsp	neoantigens	are	shared	by	most	mmr	deficient	cancers	to	evaluate	safety	and	immunogenicity	of	an	fsp	based	vaccine	we	performed	a	clinical	phase	i	iia	trial	micoryx	the	trial	comprised	three	cycles	of	four	subcutaneous	vaccinations	fsp	neoantigens	derived	from	mutant	aim2	ht001	taf1b	genes	mixed	with	montanide	isa	51	vg	over	6	months	inclusion	criteria	were	history	of	mmr	deficient	colorectal	cancer	uicc	stage	iii	or	iv	and	completion	of	chemotherapy	phase	i	evaluated	safety	and	toxicity	as	primary	endpoint	six	patients	phase	iia	addressed	cellular	and	humoral	immune	responses	16	patients	vaccine	induced	humoral	and	cellular	immune	responses	were	observed	in	all	patients	vaccinated	per	protocol	three	patients	developed	grade	2	local	injection	site	reactions	no	vaccination	induced	severe	adverse	events	occurred	one	heavily	pretreated	patient	with	bulky	metastases	showed	stable	disease	and	stable	cea	levels	over	7	months	fsp	neoantigen	vaccination	is	systemically	well	tolerated	and	consistently	induces	humoral	and	cellular	immune	responses	thus	representing	a	promising	novel	approach	for	treatment	and	even	prevention	of	mmr	deficient	cancer</Paragraph></Rec>
<Rec><Paragraph>in	chronic	peritoneal	diseases	mesothelial	mesenchymal	transition	is	determined	by	cues	from	the	extracellular	environment	rather	than	just	the	cellular	genome	the	transformation	of	peritoneal	mesothelial	cells	and	other	host	cells	into	myofibroblasts	is	mediated	by	cell	membrane	receptors	transforming	growth	factor	β1	tgf	β1	src	and	hypoxia	inducible	factor	hif	this	article	provides	a	narrative	review	of	the	reprogramming	of	mesothelial	mesenchymal	transition	in	chronic	peritoneal	diseases	drawing	on	the	similarities	in	pathophysiology	between	encapsulating	peritoneal	sclerosis	and	peritoneal	metastasis	with	a	particular	focus	on	tgf	β1	signaling	and	estrogen	receptor	modulators	estrogen	receptors	act	at	the	cell	membrane	cytosol	as	tyrosine	kinases	that	can	phosphorylate	src	in	a	similar	way	to	other	receptor	tyrosine	kinases	or	can	activate	the	estrogen	response	element	via	nuclear	translocation	tamoxifen	can	modulate	estrogen	membrane	receptors	and	has	been	shown	to	be	a	potent	inhibitor	of	mesothelial	mesenchymal	transition	mmt	peritoneal	mesothelial	cell	migration	stromal	fibrosis	and	neoangiogenesis	in	the	treatment	of	encapsulating	peritoneal	sclerosis	with	a	known	side	effect	and	safety	profile	the	ability	of	tamoxifen	to	inhibit	the	transduction	pathways	of	tgf	β1	and	hif	and	achieve	a	quiescent	peritoneal	stroma	makes	it	a	potential	candidate	for	use	in	cancer	treatments	this	is	relevant	to	tumors	that	spread	to	the	peritoneum	particularly	those	with	mesenchymal	phenotypes	such	as	colorectal	cms4	and	mss	emt	gastric	cancers	and	pancreatic	cancer	with	its	desmoplastic	stroma	morphological	changes	observed	during	mesothelial	mesenchymal	transition	can	be	treated	with	estrogen	receptor	modulation	and	tgf	β1	inhibition	which	may	enable	the	regression	of	encapsulating	peritoneal	sclerosis	and	peritoneal	metastasis</Paragraph></Rec>
<Rec><Paragraph>background	colorectal	cancer	crc	is	one	of	the	most	common	types	of	cancer	in	the	world	metastatic	disease	is	still	incurable	in	most	of	these	patients	but	the	survival	rate	has	improved	by	treatment	with	novel	systemic	chemotherapy	and	targeted	therapy	in	combination	with	surgery	new	knowledge	of	its	complex	heterogeneity	in	terms	of	genetics	epigenetics	transcriptomics	and	microenvironment	including	prognostic	and	clinical	characteristics	led	to	its	classification	into	various	molecular	subtypes	of	metastatic	crc	called	consensus	molecular	subtypes	cms	the	cms	classification	thus	enables	the	medical	oncologists	to	adjust	the	treatment	from	case	to	case	they	can	determine	which	type	of	systemic	chemotherapy	or	targeted	therapy	is	best	suited	to	a	specific	patient	what	dosages	are	needed	and	in	what	order	conclusions	cms	in	metastatic	crc	are	the	new	tool	to	include	the	knowledge	of	molecular	factors	tumour	stroma	and	signalling	pathways	for	personalized	patient	orientated	systemic	treatment	in	precision	medicine</Paragraph></Rec>
<Rec><Paragraph>to	date	no	systematic	analyses	are	available	assessing	concordance	of	molecular	classifications	between	primary	tumors	pt	and	matched	liver	metastases	lm	of	metastatic	colorectal	cancer	mcrc	we	investigated	concordance	between	pt	and	lm	for	four	clinically	relevant	crc	gene	signatures	twenty	seven	fresh	and	55	formalin	fixed	paraffin	embedded	pairs	of	pt	and	synchronous	lm	of	untreated	mcrc	patients	were	retrospectively	collected	and	classified	according	to	the	msi	like	braf	like	tgfb	activated	like	and	the	consensus	molecular	subtypes	cms	classification	we	investigated	classification	concordance	between	pt	and	lm	and	association	of	tgfba	like	and	cms	classification	with	overall	survival	fifty	one	successfully	profiled	matched	pairs	were	used	for	analyses	pt	and	matched	lm	were	highly	concordant	in	terms	of	braf	like	and	msi	like	signatures	90	2	and	98	concordance	respectively	in	contrast	40	to	70	of	pt	that	were	classified	as	mesenchymal	like	based	on	the	cms	and	the	tgfba	like	signature	respectively	lost	this	phenotype	in	their	matched	lm	60	8	and	76	5	concordance	respectively	this	molecular	switch	was	independent	of	the	microenvironment	composition	in	addition	the	significant	change	in	subtypes	was	observed	also	by	using	methods	developed	to	detect	cancer	cell	intrinsic	subtypes	more	importantly	the	molecular	switch	did	not	influence	the	survival	pt	classified	as	mesenchymal	had	worse	survival	as	compared	to	nonmesenchymal	pt	cms4	vs	cms2	hazard	ratio	hr	5	2	95	ci	1	5	18	5	p	0048	tgfba	like	vs	tgfbi	like	hr	2	5	95	ci	1	1	5	6	p	028	the	same	was	not	true	for	lm	our	study	highlights	that	the	origin	of	the	tissue	may	have	major	consequences	for	precision	medicine	in	mcrc</Paragraph></Rec>
<Rec><Paragraph>dna	microarrays	such	as	the	consensus	molecular	subtype	cms	classification	using	600	genes	are	used	to	predict	cancer	patient	prognosis	we	recently	constructed	a	simple	55	gene	classifier	55gc	system	to	risk	stratify	colon	cancer	cc	here	we	validate	the	55gc	specifically	for	stage	ii	cc	and	compare	it	with	cms	categories	tissue	sections	from	232	stage	ii	cc	patients	who	underwent	curative	surgery	without	adjuvant	chemotherapy	between	2009	and	2012	were	subjected	to	dna	microarray	analysis	based	on	the	55gc	patients	were	classified	into	microsatellite	instability	like	27	chromosomal	instability	like	41	and	stromal	32	subtypes	with	5	year	relapse	free	survival	rfs	rates	of	88	5	83	3	and	71	2	respectively	stromal	vs	others	p	0	0049	multivariate	analysis	by	cox	s	proportional	hazard	model	revealed	that	the	stromal	subtype	pt4	and	the	number	of	lymph	nodes	examined	12	were	independent	poor	prognostic	factors	the	overall	concordance	rate	between	55gc	and	cms	was	72	and	5	year	rfs	rates	of	patients	with	cms1	cms2	cms3	and	cms4	cancers	were	100	85	5	92	3	and	73	0	respectively	p	0	0113	we	conclude	that	the	55gc	is	a	useful	and	reproducible	grading	system	for	stage	ii	cc	recurrence	risk	stratification</Paragraph></Rec>
<Rec><Paragraph>angiopoietin	2	angpt2	is	a	prognostic	factor	in	metastatic	colorectal	cancer	crc	nevertheless	it	remains	to	be	elucidated	which	molecular	characteristics	make	up	the	angpt2	related	poor	prognosis	crc	subset	public	transcriptomic	datasets	were	collected	from	gene	expression	omnibus	geo	and	with	the	tcgabiolinks	r	package	for	the	tcga	after	appropriate	normalization	differential	expression	analysis	was	performed	using	benjamini	and	hochberg	method	for	false	discovery	rate	plasma	from	two	prospective	clinical	trials	were	used	to	investigate	the	clinical	impact	of	angpt2	related	biomarkers	in	the	935	samples	included	in	four	annotated	platforms	gpl	and	derived	from	localized	crc	angpt2	hi	expression	conferred	a	worst	overall	survival	hr	1	20	p	0	02	crc	stage	angpt2	hi	expression	but	not	consortium	molecular	subtype	cms	predict	overall	survival	in	multivariate	analysis	angpt2	expression	was	not	correlated	with	a	specific	cms	nor	to	ras	raf	msi	p53	cin	cimp	genomic	alterations	gene	expression	analysis	revealed	that	angpt2	hi	crc	subset	is	characterized	by	angiogenesis	related	gene	expression	presence	of	myeloid	cells	stromal	organization	and	resistance	to	chemotherapy	a	prognostic	model	was	proposed	using	seric	levels	of	angpt2	stc1	and	cd138	in	97	mcrc	patients	our	results	provide	evidence	that	angpt2	is	a	prognostic	factor	in	localized	crc	and	defined	a	specific	crc	subset	with	potential	clinical	implementation</Paragraph></Rec>
<Rec><Paragraph>quiescent	slow	cycling	cells	have	been	identified	in	several	tumors	and	correlated	with	therapy	resistance	however	the	features	of	chemoresistant	populations	and	the	molecular	factors	linking	quiescence	to	chemoresistance	are	largely	unknown	a	population	of	chemoresistant	quiescent	slow	cycling	cells	was	isolated	through	pkh26	staining	which	allows	to	separate	cells	on	the	basis	of	their	proliferation	rate	from	colorectal	cancer	crc	xenografts	and	subjected	to	global	gene	expression	and	pathway	activation	analyses	factors	expressed	by	the	quiescent	slow	cycling	population	were	analyzed	through	lentiviral	overexpression	approaches	for	their	ability	to	induce	a	dormant	chemoresistant	state	both	in	vitro	and	in	mouse	xenografts	the	correlation	between	quiescence	associated	factors	crc	consensus	molecular	subtype	and	cancer	prognosis	was	analyzed	in	large	patient	datasets	untreated	colorectal	tumors	contain	a	population	of	quiescent	slow	cycling	cells	with	stem	cell	features	quiescent	cancer	stem	cells	qcscs	characterized	by	a	predetermined	mesenchymal	like	chemoresistant	phenotype	qcscs	expressed	increased	levels	of	zeb2	a	transcription	factor	involved	in	stem	cell	plasticity	and	epithelial	mesenchymal	transition	emt	and	of	antiapototic	factors	pcraf	and	pask1	zeb2	overexpression	upregulated	pcraf	pask1	levels	resulting	in	increased	chemoresistance	enrichment	of	cells	with	stemness	emt	traits	and	proliferative	slowdown	of	tumor	xenografts	in	parallel	chemotherapy	treatment	of	tumor	xenografts	induced	the	prevalence	of	qcscs	with	a	stemness	emt	phenotype	and	activation	of	the	zeb2	pcraf	pask1	axis	resulting	in	a	chemotherapy	unresponsive	state	in	crc	patients	increased	zeb2	levels	correlated	with	worse	relapse	free	survival	and	were	strongly	associated	to	the	consensus	molecular	subtype	4	cms4	characterized	by	dismal	prognosis	decreased	proliferative	rates	and	upregulation	of	emt	genes	these	results	show	that	chemotherapy	naive	tumors	contain	a	cell	population	characterized	by	a	coordinated	program	of	chemoresistance	quiescence	stemness	and	emt	such	population	becomes	prevalent	upon	drug	treatment	and	is	responsible	for	chemotherapy	resistance	thus	representing	a	key	target	for	more	effective	therapeutic	approaches</Paragraph></Rec>
<Rec><Paragraph>the	efficacy	of	checkpoint	blockade	immunotherapies	in	colorectal	cancer	is	currently	restricted	to	a	minority	of	patients	diagnosed	with	mismatch	repair	deficient	tumors	having	high	mutation	burden	however	this	observation	does	not	exclude	the	existence	of	neoantigen	specific	t	cells	in	colorectal	cancers	with	low	mutation	burden	and	the	exploitation	of	their	anti	cancer	potential	for	immunotherapy	therefore	we	investigated	whether	autologous	neoantigen	specific	t	cell	responses	could	also	be	observed	in	patients	diagnosed	with	mismatch	repair	proficient	colorectal	cancers	whole	exome	and	transcriptome	sequencing	were	performed	on	cancer	and	normal	tissues	from	seven	colorectal	cancer	patients	diagnosed	with	mismatch	repair	proficient	tumors	to	detect	putative	neoantigens	corresponding	neo	epitopes	were	synthesized	and	tested	for	recognition	by	in	vitro	expanded	t	cells	that	were	isolated	from	tumor	tissues	tumor	infiltrating	lymphocytes	and	from	peripheral	mononuclear	blood	cells	stimulated	with	tumor	material	neoantigen	specific	t	cell	reactivity	was	detected	to	several	neo	epitopes	in	the	tumor	infiltrating	lymphocytes	of	three	patients	while	their	respective	cancers	expressed	15	21	and	30	non	synonymous	variants	cell	sorting	of	tumor	infiltrating	lymphocytes	based	on	the	co	expression	of	cd39	and	cd103	pinpointed	the	presence	of	neoantigen	specific	t	cells	in	the	cd39	cd103	t	cell	subset	strikingly	the	tumors	containing	neoantigen	reactive	til	were	classified	as	consensus	molecular	subtype	4	cms4	which	is	associated	with	tgf	β	pathway	activation	and	worse	clinical	outcome	we	have	detected	neoantigen	targeted	reactivity	by	autologous	t	cells	in	mismatch	repair	proficient	colorectal	cancers	of	the	cms4	subtype	these	findings	warrant	the	development	of	specific	immunotherapeutic	strategies	that	selectively	boost	the	activity	of	neoantigen	specific	t	cells	and	target	the	tgf	β	pathway	to	reinforce	t	cell	reactivity	in	this	patient	group</Paragraph></Rec>
<Rec><Paragraph>fire	3	compared	first	line	therapy	with	folfiri	plus	either	cetuximab	or	bevacizumab	in	592	kras	exon	2	wild	type	metastatic	colorectal	cancer	mcrc	patients	the	consensus	molecular	subgroups	cms	are	grouping	crc	samples	according	to	their	gene	signature	in	four	different	subtypes	relevance	of	cms	for	the	treatment	of	mcrc	has	yet	to	be	defined	in	this	exploratory	analysis	patients	were	grouped	according	to	the	previously	published	tumor	crc	cmss	objective	response	rates	orr	were	compared	using	chi	square	test	overall	survival	os	and	progression	free	survival	pfs	times	were	compared	using	kaplan	meier	estimation	log	rank	tests	hazard	ratios	hr	were	estimated	according	to	the	cox	proportional	hazard	method	cms	classification	could	be	determined	in	438	out	of	514	specimens	available	from	the	intent	to	treat	itt	population	n	592	frequencies	for	the	remaining	438	samples	were	as	follows	cms1	14	cms2	37	cms3	15	cms4	34	for	the	315	ras	wild	type	tumors	frequencies	were	as	follows	cms1	12	cms2	41	cms3	11	cms4	34	cms	distribution	in	right	versus	vs	left	sided	primary	tumors	was	as	follows	cms1	27	versus	11	cms2	28	versus	45	cms3	10	versus	12	cms4	35	versus	32	independent	of	the	treatment	cms	was	a	strong	prognostic	factor	for	orr	p	0	051	pfs	p	0	001	and	os	p	0	001	within	the	ras	wild	type	population	os	observed	in	cms4	significantly	favored	folfiri	cetuximab	over	folfiri	bevacizumab	in	cms3	os	showed	a	trend	in	favor	of	the	cetuximab	arm	while	os	was	comparable	in	cms1	and	cms2	independent	of	targeted	therapy	cms	classification	is	prognostic	for	mcrc	prolonged	os	induced	by	folfiri	plus	cetuximab	versus	folfiri	plus	bevacizumab	in	the	fire	3	study	appears	to	be	driven	by	cms3	and	cms4	cms	classification	provides	deeper	insights	into	the	biology	to	crc	but	at	present	time	has	no	direct	impact	on	clinical	decision	making	the	fire	3	aio	krk	0306	study	had	been	registered	at	clinicaltrials	gov	nct00433927</Paragraph></Rec>
<Rec><Paragraph>molecular	mechanisms	driving	acquired	resistance	to	anti	egfr	therapies	in	metastatic	colorectal	cancer	mcrc	are	complex	but	generally	involve	the	activation	of	the	downstream	ras	raf	mek	mapk	pathway	nevertheless	even	if	inhibition	of	egfr	and	mek	could	be	a	strategy	for	overcoming	anti	egfr	resistance	its	use	is	limited	by	the	development	of	mek	inhibitor	meki	resistance	we	have	generated	in	vitro	and	in	vivo	different	crc	models	in	order	to	underline	the	mechanisms	of	meki	resistance	the	three	different	in	vitro	meki	resistant	models	two	generated	by	human	crc	cells	quadruple	wild	type	for	kras	nras	braf	pi3kca	genes	sw48	mr	and	lim1215	mr	and	one	by	human	crc	cells	harboring	kras	mutation	hct116	mr	showed	features	related	to	the	gene	signature	of	colorectal	cancer	cms4	with	up	regulation	of	immune	pathway	as	confirmed	by	microarray	and	western	blot	analysis	in	particular	the	meki	phenotype	was	associated	with	the	loss	of	epithelial	features	and	acquisition	of	mesenchymal	markers	and	morphology	the	change	in	morphology	was	accompanied	by	up	regulation	of	pd	l1	expression	and	activation	of	egfr	and	its	downstream	pathway	independently	to	ras	mutation	status	to	extend	these	in	vitro	findings	we	have	obtained	mouse	colon	cancer	mc38	and	ct26	meki	resistant	syngeneic	models	mc38	mr	and	ct26	mr	combined	treatment	with	meki	egfr	inhibitor	egfri	and	pd	l1	inhibitor	pd	l1i	resulted	in	a	marked	inhibition	of	tumor	growth	in	both	models	these	results	suggest	a	strategy	to	potentially	improve	the	efficacy	of	mek	inhibition	by	co	treatment	with	egfr	and	pd	l1	inhibitors	via	modulation	of	host	immune	responses</Paragraph></Rec>
<Rec><Paragraph>increased	expression	of	trefoil	factor	3	tff3	has	been	reported	in	colorectal	carcinoma	crc	being	correlated	with	distant	metastasis	and	poor	clinical	outcomes	amongst	the	crc	subtypes	mesenchymal	cms4	crc	is	associated	with	the	worst	survival	outcome	herein	the	functional	roles	of	tff3	and	the	pharmacological	inhibition	of	tff3	by	a	novel	specific	small	molecule	tff3	inhibitor	2	amino	4	4	6	fluoro	5	methylpyridin	3	yl	phenyl	5	oxo	4h	5h	pyrano	3	2	c	chromene	3	carbonitrile	ampc	in	cms4	crc	was	explored	forced	expression	of	tff3	in	cms4	crc	cells	promoted	cell	proliferation	cell	survival	foci	formation	invasion	migration	cancer	stem	cell	like	behaviour	and	growth	in	3d	matrigel	in	contrast	sirna	mediated	depletion	of	tff3	or	ampc	inhibition	of	tff3	in	cms4	crc	cells	decreased	oncogenic	behaviour	as	indicated	by	the	above	cell	function	assays	ampc	also	inhibited	tumour	growth	in	vivo	the	tff3	stimulated	oncogenic	behaviour	of	cms4	crc	cells	was	dependent	on	tff3	activation	of	the	p44	42	mapk	erk1	2	pathway	furthermore	the	forced	expression	of	tff3	decreased	the	sensitivity	of	cms4	crc	cells	to	5	fluorouracil	5	fu	while	depleted	tff3	expression	enhanced	5	fu	sensitivity	in	cms4	crc	cells	5	fu	treatment	induced	tff3	expression	in	cms4	crc	cells	ampc	when	used	in	combination	with	5	fu	in	cms4	crc	cells	exhibited	a	synergistic	inhibitory	effect	in	summary	this	study	provides	functional	evidence	for	tff3	as	a	therapeutic	target	in	cms4	crc</Paragraph></Rec>
<Rec><Paragraph>angiogenesis	is	an	essential	step	in	cancer	progression	and	metastasis	changes	in	the	microrna	mirna	or	mir	expression	profiles	of	endothelial	cells	ecs	elicited	by	cancer	cells	promote	angiogenesis	vascular	endothelial	growth	factor	vegf	a	key	pro	angiogenic	factor	influences	mirna	expression	in	ecs	however	the	exact	role	that	vegf	serves	in	mirna	regulation	during	angiogenesis	is	poorly	defined	the	present	study	aimed	to	demonstrate	the	differential	angiogenic	effects	on	human	umbilical	vein	endothelial	cells	huvecs	of	five	different	colorectal	cancer	crc	cell	lines	by	in	vitro	huvec	migration	and	angiogenesis	assays	in	response	to	crc	conditioned	medium	cm	among	the	tested	cms	lovo	was	the	most	effective	cell	line	in	eliciting	huvec	angiogenic	phenotypes	at	least	partially	due	to	its	high	vegf	level	it	was	also	observed	that	pro	angiogenesis	regulatory	mirnas	angio	mirna	mir	296	mir	132	mir	105	and	mir	200	were	upregulated	in	the	vegf	rich	lovo	cm	compared	with	the	vegf	scarce	sw620	cm	in	addition	treatment	with	vegf	receptor	2	inhibitor	downregulated	the	pro	angio	mirnas	with	the	exception	of	mir	132	suggesting	that	vegf	as	well	as	additional	signaling	is	required	for	angio	mirna	expression	quantitative	analyses	on	pro	angio	mirna	target	expression	suggested	that	independent	pathways	may	be	involved	in	the	regulation	of	their	expression	overall	the	data	from	the	present	study	indicated	that	multiple	paracrine	factors	including	vegf	secreted	by	crcs	effectively	modulated	angio	mirna	expression	thus	impacting	their	target	expression	and	the	angiogenic	phenotypes	of	huvecs</Paragraph></Rec>
<Rec><Paragraph>cancer	remains	a	leading	health	threat	in	the	united	states	and	cardiovascular	drug	toxicity	is	a	primary	cause	to	eliminate	a	drug	from	fda	approval	as	a	result	the	demand	to	develop	new	anticancer	drugs	without	cardiovascular	toxicity	is	high	human	induced	pluripotent	stem	ips	cell	derived	tissue	chips	provide	potentially	a	cost	effective	preclinical	drug	testing	platform	including	potential	avenues	for	personalized	medicine	we	have	developed	a	three	dimensional	microfluidic	device	that	simultaneously	cultures	tumor	cell	spheroids	with	ips	derived	cardiomyocytes	ips	cms	and	ips	derived	endothelial	cells	ips	ec	the	ips	derived	cells	include	a	gcamp6	fluorescence	reporter	to	allow	real	time	imaging	to	monitor	intracellular	calcium	transients	the	multiple	chambered	tissue	chip	features	electrodes	for	pacing	of	the	cardiac	tissue	to	assess	cardiomyocyte	function	such	as	the	maximum	capture	rate	and	conduction	velocity	we	measured	the	inhibition	concentration	ic50	of	the	anticancer	drugs	doxorubicin	0	1	μm	and	oxaliplatin	4	2	μm	on	the	tissue	chip	loaded	with	colon	cancer	cells	sw620	we	simultaneously	evaluated	the	cardiotoxicity	of	these	anticancer	drugs	by	assessing	the	drug	effect	on	the	spontaneous	beat	frequency	and	conduction	velocity	of	ips	derived	cardiac	tissue	consistent	with	in	vivo	observations	doxorubicin	reduced	the	spontaneous	beating	rate	and	maximum	capture	rate	at	or	near	the	ic50	0	04	and	0	22	μm	respectively	whereas	the	toxicity	of	oxaliplatin	was	only	observed	at	concentrations	beyond	the	ic50	33	and	9	9	μm	respectively	our	platform	demonstrates	the	feasibility	to	simultaneously	assess	cardiac	toxicity	and	antitumor	effects	of	drugs	and	could	be	used	to	enhance	personalized	drug	testing	safety	and	efficacy	impact	statement	drug	development	using	murine	models	for	preclinical	testing	is	no	longer	adequate	nor	acceptable	both	financially	for	the	pharmaceutical	industry	as	well	as	for	generalized	or	personalized	assessment	of	safety	and	efficacy	innovative	solutions	using	human	cells	and	tissues	provide	exciting	new	opportunities	in	this	study	we	report	on	the	creation	of	a	3d	microfluidic	device	that	simultaneously	cultures	human	tumor	cell	spheroids	with	cardiomyocytes	and	endothelial	cells	derived	from	the	same	induced	pluripotent	stem	cell	line	the	platform	provides	the	opportunity	to	assess	efficacy	of	anticancer	agents	while	simultaneously	screening	for	potential	cardiovascular	toxicity	in	a	format	conducive	for	personalized	medicine</Paragraph></Rec>
<Rec><Paragraph>the	centers	for	medicare	and	medicaid	services	cms	hospital	compare	star	rating	system	has	been	proposed	as	a	means	to	assess	hospital	quality	performance	the	current	study	aimed	to	investigate	outcomes	and	payments	among	patients	undergoing	surgery	for	colorectal	lung	esophageal	pancreatic	and	liver	cancer	across	hospital	star	rating	groups	the	medicare	standard	analytic	files	saf	from	2013	to	2015	were	used	to	derive	the	analytic	cohort	the	association	of	star	ratings	to	perioperative	outcomes	and	expenditures	was	examined	among	119	854	patients	the	majority	underwent	surgery	at	a	3	star	n	34	901	29	1	or	4	star	n	30	492	25	4	hospital	only	12	2	n	14	732	were	treated	at	a	5	star	hospital	across	all	procedures	examined	patients	who	underwent	surgery	at	a	1	star	hospital	had	greater	odds	of	death	within	90	days	than	patients	who	had	surgery	at	a	5	star	hospital	colorectal	1	41	95	confidence	interval	ci	1	25	1	60	lung	1	97	95	ci	1	56	2	48	esophagectomy	1	83	95	ci	0	81	4	16	pancreatectomy	1	70	95	ci	1	20	2	41	hepatectomy	1	63	95	ci	0	96	2	77	a	similar	trend	was	noted	for	failure	to	rescue	ftr	with	the	greatest	odds	of	ftr	associated	with	1	star	hospitals	the	median	expenditure	associated	with	an	abdominal	operation	was	1661	more	at	a	1	star	hospital	than	at	a	5	star	hospital	1	star	17	399	vs	5	star	15	738	a	similar	trend	was	noted	for	thoracic	operations	the	risk	of	ftr	90	day	mortality	and	increased	hospital	expenditure	were	all	higher	at	a	1	star	hospital	further	research	is	needed	to	investigate	barriers	to	care	at	5	star	rated	hospitals	and	to	target	specific	interventions	to	improve	outcomes	at	1	star	hospitals</Paragraph></Rec>
<Rec><Paragraph>post	surgical	staging	is	the	mainstay	of	prognostic	stratification	for	colorectal	cancer	crc	here	we	compare	tnm	staging	to	consensus	molecular	subtyping	cms	and	assess	the	value	of	subtyping	in	addition	to	stratification	by	tnm	three	hundred	and	eight	treatment	naïve	colorectal	tumours	were	accessed	from	our	institutional	tissue	bank	cms	typing	was	carried	out	using	tumour	gene	expression	data	post	surgical	tnm	staging	and	cms	were	analysed	with	respect	to	clinicopathologic	variables	and	patient	outcome	cms	alone	was	not	associated	with	survival	while	tnm	stage	significantly	explained	mortality	addition	of	cms	to	tnm	stratified	tumours	showed	a	prognostic	effect	in	stage	2	tumours	cms3	tumours	had	a	significantly	lower	overall	survival	p	0	006	stage	2	patients	with	a	good	prognosis	showed	immune	activation	and	up	regulation	of	tumour	suppressor	genes	although	stratification	using	cms	does	not	outperform	tnm	staging	as	a	prognostic	indicator	gene	expression	based	subtyping	shows	promise	for	improved	prognostication	in	stage	2	crc</Paragraph></Rec>
<Rec><Paragraph>despite	the	well	known	prognostic	value	of	the	tumor	immune	microenvironment	time	in	colorectal	cancers	objective	and	readily	applicable	methods	for	quantifying	tumor	infiltrating	lymphocytes	til	and	the	tumor	stroma	ratio	tsr	are	not	yet	available	we	established	an	open	source	software	based	analytic	pipeline	for	quantifying	tils	and	the	tsr	from	whole	slide	images	obtained	after	cd3	and	cd8	ihc	staining	using	a	random	forest	classifier	the	method	separately	quantified	intraepithelial	tils	itil	and	stromal	tils	stil	we	applied	this	method	to	discovery	and	validation	cohorts	of	578	and	283	stage	iii	or	high	risk	stage	ii	colorectal	cancers	patients	respectively	who	were	subjected	to	curative	surgical	resection	and	oxlaliplatin	based	adjuvant	chemotherapy	automatic	quantification	of	itils	and	stils	showed	a	moderate	concordance	with	that	obtained	after	visual	inspection	by	a	pathologist	the	k	means	based	consensus	clustering	of	197	time	parameters	that	showed	robustness	against	interobserver	variations	caused	colorectal	cancers	to	be	grouped	into	five	distinctive	subgroups	reminiscent	of	those	for	consensus	molecular	subtypes	cms1	4	and	mixed	intermediate	group	in	accordance	with	the	original	cms	report	the	cms4	like	subgroup	cluster	4	was	significantly	associated	with	a	worse	5	year	relapse	free	survival	and	proved	to	be	an	independent	prognostic	factor	the	clinicopathologic	and	prognostic	features	of	the	time	subgroups	have	been	validated	in	an	independent	validation	cohort	machine	learning	based	image	analysis	can	be	useful	for	extracting	quantitative	information	about	the	time	using	whole	slide	histopathologic	images	this	information	can	classify	colorectal	cancers	into	clinicopathologically	relevant	subgroups	without	performing	a	molecular	analysis	of	the	tumors</Paragraph></Rec>
<Rec><Paragraph>predicting	the	risk	of	liver	metastasis	can	have	important	prognostic	and	therapeutic	implications	given	the	availability	of	liver	directed	therapy	uveal	melanoma	has	a	striking	predisposition	for	liver	metastasis	despite	the	absence	of	anatomical	proximity	understanding	its	biology	may	uncover	factors	promoting	liver	metastasis	in	other	malignancies	we	quantified	gene	expression	by	rnaseq	in	76	uveal	melanomas	and	combined	with	public	data	in	a	meta	analysis	of	196	patients	the	meta	analysis	of	uveal	melanoma	gene	expression	identified	63	genes	which	remained	prognostic	after	adjustment	for	chromosome	3	status	two	genes	ptp4a3	and	jph1	were	selected	by	l1	penalized	regression	and	combined	in	a	prognostic	score	the	score	predicted	liver	specific	relapse	in	a	public	pan	cancer	dataset	and	in	two	public	colorectal	cancer	datasets	the	score	varied	between	colorectal	consensus	molecular	subtypes	cms	as	did	the	risk	of	liver	relapse	which	was	lowest	in	cms1	additional	prospective	validation	was	done	by	real	time	pcr	in	463	breast	cancer	patients	the	score	was	significantly	correlated	with	liver	relapse	in	hormone	receptor	positive	tumors	in	conclusion	the	expression	of	ptp4a3	and	jph1	correlates	with	risk	of	liver	metastasis	in	colorectal	cancer	and	breast	cancer	the	underlying	biological	mechanism	is	an	interesting	area	for	further	research</Paragraph></Rec>
<Rec><Paragraph>celiac	disease	cd	is	a	risk	factor	for	developing	small	bowel	carcinoma	with	a	14	fold	higher	risk	compared	with	general	population	as	small	bowel	carcinomas	associated	with	cd	cd	sbcs	are	extremely	rare	very	few	molecular	data	are	available	about	their	pathogenesis	and	information	about	their	transcriptomic	profiling	is	lacking	we	generated	rna	seq	data	on	13	cd	sbcs	taken	from	the	largest	well	characterized	series	published	so	far	collected	by	the	small	bowel	cancer	italian	consortium	and	compared	the	tumor	transcriptional	signatures	with	the	four	consensus	molecular	subtypes	cms	of	colorectal	carcinoma	by	applying	the	cms	classifier	cpg	island	methylator	phenotype	cimp	was	evaluated	using	methylation	sensitive	multiple	ligation	dependent	probe	amplification	up	to	12	of	13	cancers	fell	within	the	two	main	subtypes	exhibiting	high	immune	and	inflammatory	signatures	i	e	subtypes	1	and	4	the	first	and	predominant	subset	was	commonly	microsatellite	unstable	and	exhibited	cimp	and	high	cd3	and	cd8	t	cell	infiltration	moreover	it	showed	increased	expression	of	genes	associated	with	t	helper	1	and	natural	killer	cell	infiltration	as	well	as	upregulation	of	apoptosis	cell	cycle	progression	and	proteasome	pathways	by	contrast	cancers	falling	in	subtype	4	showed	prominent	transforming	growth	factor	β	activation	and	were	characterized	by	complement	associated	inflammation	matrix	remodeling	cancer	associated	stroma	production	and	angiogenesis	parallel	histologic	and	histochemical	analysis	confirmed	such	tumor	subtyping	in	conclusion	two	molecular	subtypes	have	been	consistently	identified	in	our	series	of	cd	sbcs	a	microsatellite	instability	immune	and	a	mesenchymal	subtype	the	former	likely	associated	with	an	indolent	and	the	latter	with	a	worse	tumor	behavior</Paragraph></Rec>
<Rec><Paragraph>recommendations	vary	regarding	the	maximum	age	at	which	to	stop	lung	cancer	screening	80	years	according	to	the	u	s	preventive	services	task	force	uspstf	77	years	according	to	the	centers	for	medicare	medicaid	services	cms	and	74	years	according	to	the	national	lung	screening	trial	nlst	to	compare	the	cost	effectiveness	of	different	stopping	ages	for	lung	cancer	screening	by	using	shared	inputs	for	smoking	behavior	costs	and	quality	of	life	4	independently	developed	microsimulation	models	evaluated	the	health	and	cost	outcomes	of	annual	lung	cancer	screening	with	low	dose	computed	tomography	ldct	the	nlst	prostate	lung	colorectal	and	ovarian	cancer	screening	trial	seer	surveillance	epidemiology	and	end	results	program	nurses	health	study	and	health	professionals	follow	up	study	and	u	s	smoking	history	generator	current	former	and	never	smokers	aged	45	years	from	the	1960	u	s	birth	cohort	45	years	health	care	sector	annual	ldct	according	to	nlst	cms	and	uspstf	criteria	incremental	cost	effectiveness	ratios	icers	with	a	willingness	to	pay	threshold	of	100	000	per	quality	adjusted	life	year	qaly	the	4	models	showed	that	the	nlst	cms	and	uspstf	screening	strategies	were	cost	effective	with	icers	averaging	49	200	68	600	and	96	700	per	qaly	respectively	increasing	the	age	at	which	to	stop	screening	resulted	in	a	greater	reduction	in	mortality	but	also	led	to	higher	costs	and	overdiagnosis	rates	probabilistic	sensitivity	analysis	showed	that	the	nlst	and	cms	strategies	had	higher	probabilities	of	being	cost	effective	98	and	77	respectively	than	the	uspstf	strategy	52	scenarios	assumed	100	screening	adherence	and	models	extrapolated	beyond	clinical	trial	data	all	3	sets	of	lung	cancer	screening	criteria	represent	cost	effective	programs	despite	underlying	uncertainty	the	nlst	and	cms	screening	strategies	have	high	probabilities	of	being	cost	effective	cisnet	cancer	intervention	and	surveillance	modeling	network	lung	group	national	cancer	institute</Paragraph></Rec>
<Rec><Paragraph>solid	tumour	growth	is	the	consequence	of	a	complex	interplay	between	cancer	cells	and	their	microenvironment	recently	a	new	global	transcriptomic	immune	classification	of	solid	tumours	has	identified	six	immune	subtypes	iss	c1	c6	our	aim	was	to	specifically	characterise	iss	in	colorectal	cancer	crc	and	assess	their	interplay	with	the	consensus	molecular	subtypes	cmss	clinical	and	molecular	information	including	cmss	and	iss	were	obtained	from	the	cancer	genome	atlas	tcga	n	625	immune	cell	populations	differential	gene	expression	and	gene	set	enrichment	analysis	were	performed	to	characterise	iss	in	the	global	crc	population	by	using	cmss	only	5	iss	were	identified	in	crc	predominantly	c1	wound	healing	77	and	c2	ifn	γ	dominant	17	cms1	showed	the	highest	proportion	of	c2	53	whereas	c1	was	particularly	dominant	in	cms2	91	cms3	had	the	highest	representation	of	c3	inflammatory	7	and	c4	lymphocyte	depleted	iss	4	whereas	all	c6	tgf	β	dominant	cases	belonged	to	cms4	2	3	prognostic	relevance	of	iss	in	crc	substantially	differed	from	that	reported	for	the	global	tcga	and	iss	had	a	greater	ability	to	stratify	the	prognosis	of	crc	patients	than	cms	classification	c2	had	higher	densities	of	cd8	cd4	activated	follicular	helper	t	cells	regulatory	t	cells	and	neutrophils	and	the	highest	m1	m2	polarisation	c2	had	a	heightened	activation	of	pathways	related	to	the	immune	system	apoptosis	and	dna	repair	mtor	signalling	and	oxidative	phosphorylation	whereas	c1	was	more	dependent	of	metabolic	pathways	the	correlation	of	is	and	cms	allows	a	more	precise	categorisation	of	patients	with	relevant	clinical	and	biological	implications	which	may	be	valuable	tools	to	improve	tailored	therapeutic	interventions	in	crc	patients</Paragraph></Rec>
<Rec><Paragraph>molecular	subtypes	based	therapies	offer	new	potential	framework	for	desired	and	precise	outcome	in	clinical	settings	current	treatment	strategies	in	colorectal	cancer	are	largely	one	drug	fit	all	model	for	patients	that	display	same	pathological	conditions	however	crc	is	a	very	heterogenous	set	of	malignancy	that	does	not	support	for	above	criteria	each	subtype	displays	different	pathological	and	genetic	signatures	based	on	these	features	therapeutic	stratification	for	individual	patients	may	be	designed	which	may	ultimately	lead	to	improved	therapeutic	outcomes	in	this	comprehensive	review	we	have	attempted	to	briefly	outline	major	crc	pathways	a	detailed	overview	of	molecular	subtypes	and	their	clinical	significance	has	been	discussed	present	and	future	methods	governing	crc	subtyping	in	the	era	of	personalized	therapy	with	a	special	emphasis	on	cms	subtypes	of	crc	has	been	reviewed	together	discovery	and	validation	of	new	crc	patient	stratification	methods	screening	for	novel	therapeutic	targets	and	enhanced	diagnosis	of	crc	may	improve	the	treatment	outcome</Paragraph></Rec>
<Rec><Paragraph>in	recent	years	an	increasing	number	of	studies	have	shown	that	elevated	expression	of	cyclin	dependent	kinase	cdk5	contributes	to	the	oncogenic	initiation	and	progression	of	many	types	of	cancers	in	this	study	we	investigated	the	expression	pattern	of	cdk5	in	colorectal	cancer	crc	cell	lines	and	in	a	large	number	of	tumor	samples	in	order	to	evaluate	its	relevance	in	this	pathogenesis	and	possible	use	as	a	prognostic	marker	we	found	that	cdk5	is	highly	expressed	and	activated	in	crc	cell	lines	and	that	silencing	of	the	kinase	decreases	their	migration	ability	in	tumor	tissues	cdk5	is	overexpressed	compared	to	normal	tissues	due	to	a	copy	number	gain	in	patients	with	localized	disease	we	found	that	high	cdk5	levels	correlate	with	poor	prognosis	while	in	the	metastatic	setting	this	was	only	the	case	for	patients	receiving	an	oxaliplatin	based	treatment	when	exploring	the	cdk5	levels	in	the	consensus	molecular	subtypes	cms	we	found	the	lowest	levels	in	subtype	1	where	high	cdk5	again	was	associated	with	a	poorer	prognosis	in	conclusion	we	confirm	that	cdk5	is	involved	in	crc	and	disease	progression	and	that	it	could	serve	as	a	prognostic	and	predictive	biomarker	in	this	disease</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	heterogeneous	disease	that	includes	both	hereditary	and	sporadic	types	of	tumors	tumor	initiation	and	growth	is	driven	by	mutational	or	epigenetic	changes	that	alter	the	function	or	expression	of	multiple	genes	the	genes	predominantly	encode	components	of	various	intracellular	signaling	cascades	in	this	review	we	present	mouse	intestinal	cancer	models	that	include	alterations	in	the	wnt	hippo	p53	epidermal	growth	factor	egf	and	transforming	growth	factor	β	tgfβ	pathways	models	of	impaired	dna	mismatch	repair	and	chemically	induced	tumorigenesis	are	included	based	on	their	molecular	biology	characteristics	and	mutational	and	epigenetic	status	human	colorectal	carcinomas	were	divided	into	four	so	called	consensus	molecular	subtype	cms	groups	it	was	shown	subsequently	that	the	cms	classification	system	could	be	applied	to	various	cell	lines	derived	from	intestinal	tumors	and	tumor	derived	organoids	although	the	cms	system	facilitates	characterization	of	human	crc	individual	mouse	models	were	not	assigned	to	some	of	the	cms	groups	thus	we	also	indicate	the	possible	assignment	of	described	animal	models	to	the	cms	group	this	might	be	helpful	for	selection	of	a	suitable	mouse	strain	to	study	a	particular	type	of	crc</Paragraph></Rec>
<Rec><Paragraph>gene	expression	based	consensus	molecular	subtypes	cms	and	non	negative	matrix	factorization	nmf	sub	clusters	are	robust	colon	cancer	classification	systems	although	the	molecular	features	are	clear	colon	cancer	subgroups	based	interventions	are	limited	to	address	this	problem	we	analyze	the	cms	and	nmf	subgroup	guided	drug	sensitivity	in	colon	cancer	cell	lines	cms3	subtype	cells	are	sensitive	to	5	fluorouracil	while	cms4	subtype	cells	are	sensitive	to	cisplatin	treatment	in	nmf	classification	a	sub	cluster	is	specifically	sensitive	to	chemotherapy	braf	inhibitors	pi3k	mtor	inhibitors	and	notch	inhibitor	treatment	this	sub	cluster	has	low	frequency	of	tp53	pole	pik3ca	and	braf	mutation	transcriptional	analysis	demonstrates	low	notch	signaling	activity	low	cdx2	and	vdr	expression	in	this	sub	cluster	cdx2	and	vdr	are	significantly	associated	with	the	sensitivity	of	chemotherapy	braf	inhibitors	and	pi3k	mtor	inhibitors	moreover	a	positive	correlation	between	vdr	and	cdx2	is	identified	vdr	and	cdx2	mediated	regulatory	networks	are	constructed	at	last	three	or	four	sub	clusters	classification	is	validated	in	colon	cancer	patients	overall	our	results	suggest	a	molecular	sub	cluster	of	colon	cancer	cells	with	low	cdx2	and	vdr	expression	is	sensitive	to	chemotherapy	braf	inhibitors	and	pi3k	mtor	inhibitors	treatment	and	provide	an	example	of	translation	of	cancer	classification	to	subgroup	guided	therapies</Paragraph></Rec>
<Rec><Paragraph>despite	intense	research	and	clinical	efforts	patients	affected	by	advanced	colorectal	cancer	crc	have	still	a	poor	prognosis	the	discovery	of	colorectal	cr	cancer	stem	cell	csc	as	the	cell	compartment	responsible	for	tumor	initiation	and	propagation	may	provide	new	opportunities	for	the	development	of	new	therapeutic	strategies	given	the	reduced	sensitivity	of	cr	cscs	to	chemotherapy	and	the	ability	of	bone	morphogenetic	proteins	bmp	to	promote	colonic	stem	cell	differentiation	we	aimed	to	investigate	whether	an	enhanced	variant	of	bmp7	bmp7v	could	sensitize	to	chemotherapy	resistant	crc	cells	and	tumors	thirty	five	primary	human	cultures	enriched	in	cr	cscs	including	four	from	chemoresistant	metastatic	lesions	were	used	for	in	vitro	studies	and	to	generate	cr	csc	based	mouse	avatars	to	evaluate	tumor	growth	and	progression	upon	treatment	with	bmp7v	alone	or	in	combination	with	standard	therapy	or	pi3k	inhibitors	bmp7v	treatment	promotes	cr	csc	differentiation	and	recapitulates	the	cell	differentiation	related	gene	expression	profile	by	suppressing	wnt	pathway	activity	and	reducing	mesenchymal	traits	and	survival	of	cr	cscs	moreover	in	cr	csc	based	mouse	avatars	bmp7v	exerts	an	antiangiogenic	effect	and	sensitizes	tumor	cells	to	standard	chemotherapy	regardless	of	the	mutational	msi	and	cms	profiles	of	note	tumor	harboring	pik3ca	mutations	were	affected	to	a	lower	extent	by	the	combination	of	bmp7v	and	chemotherapy	however	the	addition	of	a	pi3k	inhibitor	to	the	bmp7v	based	combination	potentiates	pik3ca	mutant	tumor	drug	response	and	reduces	the	metastatic	lesion	size	these	data	suggest	that	bmp7v	treatment	may	represent	a	useful	antiangiogenic	and	prodifferentiation	agent	which	renders	cscs	sensitive	to	both	standard	and	targeted	therapies</Paragraph></Rec>
<Rec><Paragraph>approximately	half	of	colorectal	cancer	crc	patients	experience	disease	recurrence	and	metastasis	and	these	individuals	frequently	fail	to	respond	to	treatment	due	to	their	clinical	and	biological	diversity	here	we	aimed	to	identify	a	prognostic	signature	consisting	of	a	small	gene	group	for	precisely	predicting	crc	heterogeneity	we	performed	transcriptomic	profiling	using	rna	seq	data	generated	from	the	primary	tissue	samples	of	130	crc	patients	a	prognostic	index	pi	based	on	recurrence	associated	genes	was	developed	and	validated	in	two	larger	independent	crc	patient	cohorts	n	795	the	association	between	the	pi	and	prognosis	of	crc	patients	was	evaluated	using	kaplan	meier	plots	log	rank	tests	a	cox	regression	analysis	and	a	rt	pcr	analysis	transcriptomic	profiling	in	130	crc	patients	identified	two	distinct	subtypes	associated	with	systemic	recurrence	pathway	enrichment	and	rt	pcr	analyses	revealed	an	eleven	gene	signature	incorporated	into	the	pi	system	which	was	a	significant	prognostic	indicator	of	crc	multivariate	and	subset	analyses	showed	that	pi	was	an	independent	risk	factor	hr	1	812	95	ci	1	342	2	448	p	0	001	with	predictive	value	to	identify	low	risk	stage	ii	patients	who	responded	the	worst	to	adjuvant	chemotherapy	finally	a	comparative	analysis	with	previously	reported	consensus	molecular	subgroup	cms	high	risk	patients	classified	by	the	pi	revealed	a	distinct	molecular	property	similar	to	cms4	associated	with	a	poor	prognosis	this	novel	pi	predictor	based	on	an	eleven	gene	signature	likely	represents	a	surrogate	diagnostic	tool	for	identifying	high	risk	crc	patients	and	for	predicting	the	worst	responding	patients	for	adjuvant	chemotherapy</Paragraph></Rec>
<Rec><Paragraph>the	metastatic	process	of	colorectal	cancer	crc	is	not	fully	understood	and	effective	therapies	are	lacking	we	show	that	activation	of	notch1	signaling	in	the	murine	intestinal	epithelium	leads	to	highly	penetrant	metastasis	100	metastasis	with	80	liver	metastases	in	kras	g12d	driven	serrated	cancer	transcriptional	profiling	reveals	that	epithelial	notch1	signaling	creates	a	tumor	microenvironment	tme	reminiscent	of	poorly	prognostic	human	crc	subtypes	cms4	and	cris	b	and	drives	metastasis	through	transforming	growth	factor	tgf	β	dependent	neutrophil	recruitment	importantly	inhibition	of	this	recruitment	with	clinically	relevant	therapeutic	agents	blocks	metastasis	we	propose	that	notch1	signaling	is	key	to	crc	progression	and	should	be	exploited	clinically</Paragraph></Rec>
<Rec><Paragraph>it	remains	unknown	to	what	extent	consensus	molecular	subtype	cms	groups	and	immune	stromal	infiltration	patterns	improve	our	ability	to	predict	outcomes	over	tumor	node	metastasis	tnm	staging	and	microsatellite	instability	msi	status	in	early	stage	colorectal	cancer	crc	we	carried	out	a	comprehensive	retrospective	biomarker	analysis	of	prognostic	markers	in	adjuvant	chemotherapy	untreated	n	1656	and	treated	n	980	stage	ii	n	1799	and	iii	n	837	crcs	we	defined	cms	scores	and	estimated	cd8	cytotoxic	lymphocytes	cytolym	and	cancer	associated	fibroblasts	caf	infiltration	scores	from	bulk	tumor	tissue	transcriptomes	cmsclassifier	and	mcpcounter	r	packages	constructed	a	stratified	multivariable	cox	model	for	disease	free	survival	dfs	and	calculated	the	relative	proportion	of	explained	variation	by	each	marker	clinicopathological	clinpath	genomics	gen	msi	braf	and	kras	mutations	cms	scores	cms	and	microenvironment	cells	microcells	cytolym	caf	in	multivariable	models	only	clinpath	and	microcells	remained	significant	prognostic	factors	with	both	cytolym	and	caf	infiltration	scores	improving	survival	prediction	beyond	other	markers	the	explained	variation	for	dfs	models	of	clinpath	microcells	gen	markers	and	cms4	scores	was	77	14	5	3	and	3	7	respectively	in	stage	ii	and	55	9	35	1	4	1	and	0	9	respectively	in	stage	iii	patients	whose	tumors	were	cytolym	high	caf	low	had	better	dfs	than	other	strata	hr	0	71	0	6	0	9	p	0	004	microsatellite	stable	tumors	had	the	strongest	signal	for	improved	outcomes	with	cytolym	high	scores	interaction	p	0	04	and	the	poor	prognosis	linked	to	high	caf	scores	was	limited	to	stage	iii	disease	interaction	p	0	04	our	results	confirm	that	tumor	microenvironment	infiltration	patterns	represent	potent	determinants	of	the	risk	for	distant	dissemination	in	early	stage	crc	multivariable	models	suggest	that	the	prognostic	value	of	msi	and	cms	groups	is	largely	explained	by	cytolym	and	caf	infiltration	patterns</Paragraph></Rec>
<Rec><Paragraph>the	benefit	of	adjuvant	chemotherapy	has	been	clearly	established	in	the	adjuvant	setting	for	node	positive	colon	cancer	a	number	of	trials	in	the	adjuvant	setting	have	analyzed	the	efficacy	of	multiple	agent	combinations	including	irinotecan	oxaliplatin	bevacizumab	and	cetuximab	only	oxaliplatin	added	to	fluorouracil	capecitabine	has	been	shown	to	be	superior	beyond	a	fluropyrimidine	alone	in	the	adjuvant	setting	as	such	standard	treatment	options	include	fluorouracil	fu	or	capecitabine	with	or	without	oxaliplatin	however	oxaliplatin	is	associated	with	cumulative	dose	dependent	neurotoxicity	characterized	by	distal	or	perioral	paresthesias	or	dysesthesias	for	this	reason	in	this	review	we	discuss	the	results	of	the	international	duration	evaluation	of	adjuvant	chemotherapy	idea	trial	the	idea	trail	is	the	largest	prospective	clinical	trial	ever	conducted	in	colorectal	cancer	wherein	patients	were	treated	with	either	3	months	or	6	months	of	adjuvant	chemotherapy	in	the	era	of	cancer	gene	expression	based	subtyping	the	colorectal	cancer	subtyping	consortium	has	proposed	a	four	subgroup	molecular	classification	system	for	colorectal	cancer	consisting	of	cms1	immune	cms2	canonical	cms3	metabolic	and	cms4	mesenchymal	in	this	review	we	present	and	analyze	the	available	data	on	efficacy	and	toxicity	of	the	combination	regimen	approved	for	treatment	of	resected	colon	cancer	and	discuss	the	questions	of	when	how	and	how	long	we	need	to	treat	such	patients</Paragraph></Rec>
<Rec><Paragraph>in	2014	the	centers	for	medicare	and	medicaid	services	cms	began	covering	a	multitarget	stool	dna	mtsdna	test	for	colorectal	cancer	crc	screening	of	medicare	beneficiaries	in	this	study	we	evaluated	whether	mtsdna	testing	is	a	cost	effective	alternative	to	other	crc	screening	strategies	reimbursed	by	cms	and	if	not	under	what	conditions	it	could	be	we	use	three	independently	developed	microsimulation	models	to	simulate	a	cohort	of	previously	unscreened	us	65	year	olds	who	are	screened	with	triennial	mtsdna	testing	or	one	of	six	other	reimbursed	screening	strategies	main	outcome	measures	are	discounted	life	years	gained	lyg	and	lifetime	costs	cms	perspective	threshold	reimbursement	rates	and	threshold	adherence	rates	outcomes	are	expressed	as	the	median	and	range	across	models	compared	to	no	screening	triennial	mtsdna	screening	resulted	in	82	range	79	88	lyg	per	1	000	simulated	individuals	this	was	more	than	for	five	yearly	sigmoidoscopy	80	range	71	89	lyg	but	fewer	than	for	every	other	simulated	strategy	at	its	2017	reimbursement	rate	of	512	mtsdna	was	the	most	costly	strategy	and	even	if	adherence	were	30	higher	than	with	other	strategies	it	would	not	be	a	cost	effective	alternative	at	a	substantially	reduced	reimbursement	rate	6	18	two	models	found	that	triennial	mtsdna	testing	was	an	efficient	and	potentially	cost	effective	screening	option	compared	to	no	screening	triennial	mtsdna	screening	reduces	crc	incidence	and	mortality	at	acceptable	costs	however	compared	to	nearly	all	other	crc	screening	strategies	reimbursed	by	cms	it	is	less	effective	and	considerably	more	costly	making	it	an	inefficient	screening	option</Paragraph></Rec>
<Rec><Paragraph>v600e	braf	mutated	metastatic	colorectal	cancer	mcrc	is	a	subtype	10	with	overall	poor	prognosis	but	the	clinical	experience	suggests	a	great	heterogeneity	in	survival	it	is	still	unexplored	the	real	distribution	of	traditional	and	innovative	biomarkers	among	v600e	braf	mutated	mcrc	and	which	is	their	role	in	the	improvement	of	clinical	prediction	of	survival	outcomes	data	and	tissue	specimens	from	155	v600e	braf	mutated	mcrc	patients	treated	at	eight	italian	units	of	oncology	were	collected	specimens	were	analysed	by	means	of	immunohistochemistry	profiling	performed	on	tissue	microarrays	primary	endpoint	was	overall	survival	os	cdx2	loss	conferred	worse	os	hr	1	72	95	ci	1	03	2	86	p	0	036	as	well	as	high	ck7	expression	hr	2	17	95	ci	1	10	4	29	p	0	026	according	to	consensus	molecular	subtypes	cms	cms1	patients	had	better	os	compared	to	cms2	3	cms4	hr	0	37	95	ci	0	19	0	71	p	0	003	samples	showing	less	tils	had	worse	os	hr	1	72	95	ci	1	16	2	56	p	0	007	progression	free	survival	analyses	led	to	similar	results	at	multivariate	analysis	ck7	and	cms	subgrouping	retained	their	significant	correlation	with	os	the	present	study	provides	new	evidence	on	how	several	well	established	biomarkers	perform	in	a	homogenous	v600e	braf	mutated	mcrc	population	with	important	and	independent	information	added	to	standard	clinical	prognosticators	these	data	could	be	useful	to	inform	further	translational	research	for	patients	stratification	in	clinical	trials	and	in	routine	clinical	practice	to	better	estimate	patients	prognosis</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	is	one	of	the	top	three	causes	of	cancer	related	mortality	globally	but	no	predictive	molecular	biomarkers	are	currently	available	for	identifying	the	disease	stage	of	colorectal	cancer	patients	common	molecular	patterns	in	the	disease	beyond	superficial	manifestations	can	be	significant	in	determining	treatment	choices	in	this	study	we	used	microarray	data	from	colorectal	cancer	and	adjacent	normal	tissue	from	the	geo	database	these	data	were	categorized	into	four	consensus	molecular	subtypes	based	on	distinct	gene	expression	signatures	weighted	gene	based	protein	protein	interaction	network	analysis	was	performed	for	each	subtype	nusap1	cd44	and	col4a1	modules	were	found	to	be	statistically	significant	and	present	among	all	the	subtypes	and	displayed	though	similar	but	not	identical	functional	enrichment	results	reference	of	the	characteristics	of	the	subtypes	to	functional	modules	is	necessary	since	the	latter	can	stay	resistant	to	platform	changes	and	technique	noise	when	compared	with	other	analyses	the	cms4	mesenchymal	group	which	currently	has	a	poor	prognosis	was	examined	in	the	study	it	is	composed	mainly	of	genes	involved	in	immune	and	stromal	expression	with	modules	focused	on	ecm	dysregulation	and	chemokine	biological	processes	hub	genes	detection	and	its	mapping	into	the	protein	protein	interaction	network	can	be	indicative	of	possible	targets	against	specific	modules	this	approach	identified	subtypes	using	enrichment	oriented	analysis	in	functional	modules	proper	annotation	of	functional	analysis	of	modules	from	different	subtypes	of	crc	might	be	directive	for	finding	extra	options	for	treatment	targets	and	guiding	clinical	routines</Paragraph></Rec>
<Rec><Paragraph>gene	set	analysis	gsa	has	become	the	common	methodology	for	analyzing	transcriptomics	data	however	self	contained	gsa	techniques	are	rarely	if	ever	used	for	proteomics	data	analysis	here	we	present	a	self	contained	proteome	level	gsa	of	four	consensus	molecular	subtypes	cmss	previously	established	by	transcriptome	dissection	of	colon	carcinoma	specimens	despite	notable	difference	in	structure	of	proteomics	and	transcriptomics	data	many	pathway	wide	characteristic	features	of	cmss	found	at	the	mrna	level	were	reproduced	at	the	protein	level	in	particular	cms1	features	show	heavy	involvement	of	immune	system	as	well	as	the	pathways	related	to	mismatch	repair	dna	replication	and	functioning	of	proteasome	while	cms4	tumors	upregulate	complement	pathway	and	proteins	participating	in	epithelial	to	mesenchymal	transition	emt	in	addition	protein	level	gsa	yielded	a	set	of	novel	observations	visible	at	the	proteome	but	not	at	the	transcriptome	level	including	possible	involvement	of	major	histocompatibility	complex	ii	mhc	ii	antigens	in	the	known	immunogenicity	of	cms1	and	a	connection	between	cholesterol	trafficking	and	the	regulation	of	integrin	linked	kinase	ilk	in	cms3	overall	this	study	proves	utility	of	self	contained	gsa	approaches	as	a	critical	tool	for	analyzing	proteomics	data	in	general	and	dissecting	protein	level	molecular	portraits	of	human	tumors	in	particular</Paragraph></Rec>
<Rec><Paragraph>gremlin1	grem1	is	a	secreted	glycoprotein	member	of	the	differential	screening	selected	gene	in	aberrant	neuroblastoma	dan	family	of	bone	morphogenetic	protein	bmp	antagonists	which	binds	to	bmps	preventing	their	receptor	engagement	previous	studies	have	identified	that	stage	ii	colorectal	cancer	crc	patients	with	high	levels	of	grem1	gene	expression	in	their	tumour	tissue	have	a	poorer	prognosis	using	a	series	of	in	silico	and	in	situ	methodologies	we	demonstrate	that	grem1	gene	expression	is	significantly	higher	p	0	0001	in	crc	consensus	molecular	subtype	4	cms4	compared	to	the	other	cms	subtypes	and	correlates	p	0	0001	with	levels	of	cancer	associated	fibroblasts	cafs	within	the	crc	tumour	microenvironment	tme	our	optimised	immunohistochemistry	protocol	identified	endogenous	grem1	protein	expression	in	both	the	muscularis	mucosa	and	adjacent	colonic	crypt	bases	in	mouse	intestine	in	contrast	to	rna	expression	which	was	shown	to	localise	specifically	to	the	muscularis	mucosa	as	determined	by	in	situ	hybridisation	importantly	we	demonstrate	that	cells	with	high	levels	of	grem1	expression	display	low	levels	of	phospho	smad1	5	consistent	with	reduced	bmp	signalling	taken	together	these	data	highlight	a	novel	paracrine	signalling	circuit	which	involves	uptake	of	mature	grem1	protein	by	colonic	crypt	cells	following	secretion	from	neighbouring	fibroblasts	in	the	tme</Paragraph></Rec>
<Rec><Paragraph>epigenetic	clock	or	dna	methylation	age	has	been	shown	to	highly	correlate	with	chronologic	age	epigenetic	age	acceleration	the	difference	between	dna	methylation	age	and	individual	s	chronologic	age	was	observed	in	colorectal	cancer	however	the	association	of	epigenetic	age	acceleration	with	colorectal	cancer	tumor	molecular	characteristics	clinical	characteristics	and	patient	outcomes	has	not	been	systematically	investigated	dna	methylation	ages	of	345	patients	with	colorectal	cancer	from	the	cancer	genome	atlas	tcga	were	computed	using	the	horvath	age	prediction	model	multivariate	linear	regression	was	used	to	assess	the	association	of	epigenetic	age	acceleration	with	molecular	and	clinical	features	of	colorectal	cancer	including	consensus	molecular	subtypes	cms1	cms4	and	tumor	stage	cox	proportional	hazards	regression	was	used	to	assess	the	association	of	epigenetic	age	acceleration	with	survival	epigenetic	age	acceleration	is	significantly	associated	with	cms	compared	with	cms2	epigenetic	age	acceleration	for	cms1	cms3	and	cms4	was	23	90	years	p	5	55e	11	95	confidence	interval	ci	17	10	30	69	9	16	years	p	5	84e	03	95	ci	2	68	15	65	and	6	05	years	p	2	69e	02	95	ci	0	70	11	41	respectively	furthermore	epigenetic	age	acceleration	is	statistically	significantly	and	positively	associated	with	total	mortality	hr	1	97	95	ci	1	14	3	39	p	0	014	epigenetic	age	acceleration	is	associated	with	colorectal	cancer	tumor	molecular	characteristics	and	a	significant	predictor	of	overall	survival	of	colorectal	cancer	along	with	age	and	tumor	stage	combining	information	of	colonic	tissue	epigenetic	age	acceleration	and	tumor	molecular	characteristics	may	improve	prognosis	prediction	in	colorectal	cancer</Paragraph></Rec>
<Rec><Paragraph>accumulating	evidence	suggests	immunomodulatory	and	context	dependent	effects	of	tp53	mutations	in	cancer	we	performed	an	exploratory	analysis	of	the	transcriptional	immunobiological	and	prognostic	associations	of	tp53	mutations	within	the	gene	expression	based	consensus	molecular	subtypes	cmss	of	colorectal	cancer	crc	in	a	single	hospital	series	of	401	stage	i	iv	primary	crcs	we	sequenced	the	whole	coding	region	of	tp53	and	analysed	cms	dependent	transcriptional	consequences	of	the	mutations	by	gene	expression	profiling	immunomodulatory	associations	were	validated	by	multiplex	fluorescence	based	immunohistochemistry	of	immune	cell	markers	prognostic	associations	of	tp53	mutations	were	analysed	in	an	aggregated	series	of	635	patients	classified	according	to	cms	including	publicly	available	data	from	a	french	multicentre	cohort	gse39582	tp53	mutations	were	found	in	60	of	the	crcs	however	gene	set	enrichment	analyses	indicated	that	their	transcriptional	consequences	varied	among	the	cmss	and	were	most	pronounced	in	cms1	immune	and	cms4	mesenchymal	subtype	specificity	was	primarily	seen	as	an	upregulation	of	gene	sets	reflecting	cell	cycle	progression	in	cms4	and	a	downregulation	of	t	cell	activity	in	cms1	the	subtype	dependent	immunomodulatory	associations	were	reinforced	by	significant	depletion	of	several	immune	cell	populations	in	mutated	tumours	compared	with	wild	type	wt	tumours	exclusively	in	cms1	including	cytotoxic	lymphocytes	adjusted	p	value	in	cms1	0	002	and	cms2	4	0	9	microenvironment	cell	populations	mcp	counter	algorithm	this	was	validated	by	immunohistochemistry	based	quantification	of	tumour	infiltrating	cd8	cells	within	cms1	the	immunomodulatory	association	of	tp53	mutations	was	strongest	among	microsatellite	stable	mss	tumours	and	this	translated	into	a	propensity	for	metastatic	disease	and	poor	prognostic	value	of	the	mutations	specifically	in	the	cms1	mss	subtype	both	series	overall	survival	tp53	mutation	vs	wt	hr	5	52	p	0	028	integration	of	tp53	mutation	status	with	the	cms	framework	in	primary	crc	suggested	subtype	dependent	immunobiological	associations	with	prognostic	and	potentially	immunotherapeutic	implications	warranting	independent	validation</Paragraph></Rec>
<Rec><Paragraph>about	80	of	colorectal	cancers	crcs	have	chromosomal	instability	which	is	an	integral	part	of	aggressive	malignancy	development	but	the	importance	of	specific	copy	number	aberrations	cnas	in	modulating	gene	expression	particularly	within	the	framework	of	clinically	relevant	molecular	subtypes	remains	mostly	elusive	we	performed	dna	copy	number	profiling	of	257	stage	i	iv	primary	crcs	and	integrative	gene	expression	analysis	in	151	microsatellite	stable	mss	tumors	focusing	on	high	level	amplifications	and	the	effect	of	cnas	on	the	characteristics	of	the	gene	expression	based	consensus	molecular	subtypes	cms	the	results	were	validated	in	323	mss	tumors	from	tcga	novel	recurrent	high	level	amplifications	15	additional	copies	with	a	major	impact	on	gene	expression	were	found	for	tox3	16q	at	1	5	frequency	as	well	as	for	ccnd2	12p	and	anxa11	10q	at	1	frequency	in	addition	to	the	well	known	targets	erbb2	17q	and	myc	8q	focal	amplifications	with	15	or	5	additional	copies	of	at	least	one	of	these	regions	were	associated	with	a	poor	overall	survival	among	patients	with	stage	i	iii	mss	crcs	multivariable	hazard	ratio	3	2	p	0	01	all	high	level	amplifications	were	focal	and	had	a	more	consistent	relationship	with	gene	expression	than	lower	amplitude	and	or	broad	range	amplifications	suggesting	specific	targeting	during	carcinogenesis	genome	wide	copy	number	driven	gene	expression	was	enriched	for	pathways	characteristic	of	the	cms2	epithelial	canonical	subtype	including	dna	repair	and	cell	cycle	progression	furthermore	50	of	upregulated	genes	in	cms2	epithelial	canonical	mss	crcs	were	driven	by	cnas	an	enrichment	compared	with	the	other	cms	groups	and	associated	with	the	stronger	correspondence	between	cnas	and	gene	expression	in	malignant	epithelial	cells	than	in	the	cells	of	the	tumor	microenvironment	fibroblasts	endothelial	cells	leukocytes	in	conclusion	we	identify	novel	recurrent	amplifications	with	impact	on	gene	expression	in	crc	and	provide	the	first	evidence	that	cms2	may	have	a	stronger	copy	number	related	genetic	basis	than	subtypes	more	heavily	influenced	by	gene	expression	signals	from	the	tumor	microenvironment</Paragraph></Rec>
<Rec><Paragraph>approximately	20	of	colorectal	cancer	patients	with	colorectal	adenocarcinomas	present	with	metastases	at	the	time	of	diagnosis	and	therapies	that	specially	target	these	metastases	are	lacking	we	present	a	novel	approach	for	investigating	transcriptomic	differences	between	primary	colorectal	adenocarcinoma	and	distant	metastases	which	may	help	to	identify	primary	tumors	with	high	risk	for	future	dissemination	and	to	inform	the	development	of	metastasis	targeted	therapies	to	effectively	compare	the	transcriptomes	of	primary	colorectal	adenocarcinoma	and	metastatic	lesions	at	both	the	gene	and	pathway	levels	we	eliminated	tissue	specificity	of	the	host	organs	where	tumors	are	located	and	adjusted	for	confounders	such	as	exposure	to	chemotherapy	and	radiation	and	identified	that	metastases	were	characterized	by	reduced	epithelial	mesenchymal	transition	emt	but	increased	myc	target	and	dna	repair	pathway	activities	fbn2	and	mmp3	were	the	most	differentially	expressed	genes	between	primary	tumors	and	metastases	the	two	subtypes	of	colorectal	adenocarcinoma	metastases	that	were	identified	emt	inflammatory	and	proliferative	were	distinct	from	the	consensus	molecular	subtype	cms	3	suggesting	subtype	exclusivity	in	summary	this	study	highlights	transcriptomic	differences	between	primary	tumors	and	colorectal	adenocarcinoma	metastases	and	delineates	pathways	that	are	activated	in	metastases	that	could	be	targeted	in	colorectal	adenocarcinoma	patients	with	metastatic	disease	significance	these	findings	identify	a	colorectal	adenocarcinoma	metastasis	specific	gene	expression	signature	that	is	free	from	potentially	confounding	background	signals	coming	from	treatment	exposure	and	the	normal	host	tissue	that	the	metastasis	is	now	situated	within</Paragraph></Rec>
<Rec><Paragraph>identification	of	previously	unreported	metabolites	so	called	unknowns	in	untargeted	metabolomic	data	has	become	an	increasingly	active	area	of	research	considerably	less	attention	however	has	been	dedicated	to	identifying	unknown	metabolic	pathways	yet	for	each	unknown	metabolite	structure	there	is	potentially	a	yet	to	be	discovered	chemical	transformation	elucidating	these	biochemical	connections	is	essential	to	advancing	our	knowledge	of	cellular	metabolism	and	can	be	achieved	by	tracking	an	isotopically	labeled	precursor	to	an	unexpected	product	in	addition	to	their	role	in	mapping	metabolic	fates	isotopic	labels	also	provide	critical	insight	into	pathway	dynamics	i	e	metabolic	fluxes	that	cannot	be	obtained	from	conventional	label	free	metabolomic	analyses	when	labeling	is	compared	quantitatively	between	conditions	for	example	isotopic	tracers	can	enable	relative	pathway	activities	to	be	inferred	to	discover	unexpected	chemical	transformations	or	unanticipated	differences	in	metabolic	pathway	activities	we	have	developed	x	13	cms	a	platform	for	analyzing	liquid	chromatography	mass	spectrometry	lc	ms	data	at	the	systems	level	after	providing	cells	animals	or	patients	with	an	isotopically	enriched	metabolite	e	g	13	c	15	n	or	2	h	x	13	cms	identifies	compounds	that	have	incorporated	the	isotopic	tracer	and	reports	the	extent	of	labeling	for	each	the	analysis	can	be	performed	with	a	single	condition	or	isotopic	fates	can	be	compared	between	multiple	conditions	the	choice	of	which	metabolite	to	enrich	and	which	isotopic	label	to	use	is	highly	context	dependent	but	13	c	glucose	and	13	c	glutamine	are	often	applied	because	they	feed	a	large	number	of	metabolic	pathways	x	13	cms	is	freely	available</Paragraph></Rec>
<Rec><Paragraph>reimbursement	for	colonic	pathology	by	the	centers	for	medicare	and	medicaid	services	cms	are	grouped	in	the	medicare	severity	diagnosis	related	groups	ms	drg	with	limited	available	data	we	sought	to	compare	the	relative	impact	of	malignant	vs	benign	colonic	pathology	on	reimbursement	under	the	ms	drg	system	we	used	5	national	medicare	data	from	2011	to	2014	patients	were	classified	as	having	benign	disease	or	malignancy	descriptive	statistics	and	multivariate	regression	analysis	were	used	to	evaluate	the	surgical	approach	and	health	resource	utilization	of	10	928	patients	most	were	non	hispanic	white	women	the	majority	underwent	open	colectomy	in	both	cohorts	p	001	colectomy	for	benign	disease	was	associated	with	higher	total	charges	p	001	and	a	longer	length	of	stay	p	0002	despite	higher	charges	payments	were	not	significantly	different	between	the	cohorts	p	434	both	inpatient	mortality	and	discharge	to	a	rehab	facility	were	higher	in	the	oncologic	group	p	001	payment	methodology	for	colectomy	under	the	cms	ms	drg	system	does	not	appear	to	accurately	reflect	the	episode	cost	of	care	the	data	suggest	that	inpatient	costs	are	not	fully	compensated	a	transition	to	value	based	payments	with	expanded	episode	duration	will	require	a	better	understanding	of	unique	costs	before	adoption</Paragraph></Rec>
<Rec><Paragraph>previously	we	classified	colorectal	cancers	crcs	into	five	crcassigner	crca	subtypes	with	different	prognoses	and	potential	treatment	responses	later	consolidated	into	four	consensus	molecular	subtypes	cms	here	we	demonstrate	the	analytical	development	and	validation	of	a	custom	nanostring	ncounter	platform	based	biomarker	assay	nanocrca	to	stratify	crcs	into	subtypes	to	reduce	costs	we	switched	from	the	standard	ncounter	protocol	to	a	custom	modified	protocol	the	assay	included	a	reduced	38	gene	panel	that	was	selected	using	an	in	house	machine	learning	pipeline	we	applied	nanocrca	to	413	samples	from	355	crc	patients	from	the	fresh	frozen	samples	n	237	a	subset	had	matched	microarray	rnaseq	profiles	n	47	or	formalin	fixed	paraffin	embedded	ffpe	samples	n	58	we	also	analyzed	a	further	118	ffpe	samples	we	compared	the	assay	results	with	the	cms	classifier	different	platforms	microarrays	rnaseq	and	gene	set	classifiers	38	and	the	original	786	genes	the	standard	and	modified	protocols	showed	high	correlation	0	88	for	gene	expression	technical	replicates	were	highly	correlated	0	96	nanocrca	classified	fresh	frozen	and	ffpe	samples	into	all	five	crca	subtypes	with	consistent	classification	of	selected	matched	fresh	frozen	ffpe	samples	we	demonstrate	high	and	significant	subtype	concordance	across	protocols	100	gene	sets	95	platforms	87	and	with	cms	subtypes	75	when	evaluated	across	multiple	datasets	overall	our	nanocrca	assay	with	further	validation	may	facilitate	prospective	validation	of	crc	subtypes	in	clinical	trials	and	beyond</Paragraph></Rec>
<Rec><Paragraph>we	propose	a	working	hypothesis	that	integrates	data	from	the	calgb	swog	80405	and	fire	3	studies	to	explain	apparent	discrepancies	in	their	results	both	trials	assessed	the	combination	of	either	cetuximab	or	bevacizumab	with	a	different	chemotherapy	backbone	irinotecan	in	all	patients	in	the	fire	3	study	or	oxaliplatin	in	75	of	the	patients	in	the	calgb	swog	80405	study	the	hypothesis	is	divided	into	three	parts	firstly	in	addition	to	the	biology	or	microenvironment	of	the	tumour	and	the	selection	of	the	biologically	targeted	agents	common	to	both	trials	chemotherapy	itself	is	an	important	variable	that	determines	treatment	efficacy	because	of	a	complex	interplay	between	the	biological	therapy	the	chemotherapy	and	the	microenvironment	secondly	the	tumour	microenvironment	as	defined	by	the	consensus	molecular	subtypes	cms	classification	determines	the	interaction	of	chemotherapeutic	agents	with	biologically	targeted	agents	such	as	bevacizumab	and	cetuximab	whereas	irinotecan	synergises	with	cetuximab	across	all	cms	subtypes	oxaliplatin	might	have	variable	effects	synergising	with	cetuximab	in	fibroblast	poor	microenvironments	such	as	cms2	and	cms3	but	activating	fibroblast	rich	microenvironments	such	as	cms1	and	cms4	to	release	cytokines	that	might	antagonise	some	of	the	cetuximab	effects	thirdly	the	previous	assumptions	integrate	into	a	final	concept	which	is	that	overall	survival	is	determined	not	only	by	the	biological	therapy	or	the	first	line	treatment	but	specifically	by	the	sequence	of	first	line	and	second	line	regimens	and	the	degree	of	synergism	between	them	in	a	clinical	setting	the	optimal	first	line	combination	of	biological	therapy	and	chemotherapy	predetermines	the	crossover	to	a	specific	second	line	treatment	which	affects	the	overall	survival	of	a	patient	with	a	specific	tumour	subtype	our	working	hypothesis	suggests	that	the	calgb	swog	80405	and	fire	3	studies	are	complementary	rather	than	discrepant	and	it	provides	an	explanation	for	their	opposing	interpretations	in	conclusion	proper	interpretation	of	the	calgb	swog	80405	and	fire	3	results	requires	an	in	depth	examination	of	the	complex	interplay	not	only	between	the	targeted	biological	agents	and	chemotherapeutic	drugs	but	also	between	therapies	and	the	tumour	biology	and	microenvironment	for	each	line	of	treatment</Paragraph></Rec>
<Rec><Paragraph>to	determine	the	predictive	and	prognostic	value	of	the	consensus	molecular	subtypes	cmss	of	colorectal	cancer	crc	that	represent	a	merging	of	gene	expression	based	features	largely	in	primary	tumors	from	six	independent	classification	systems	and	provide	a	framework	for	capturing	the	intrinsic	heterogeneity	of	crc	in	patients	enrolled	in	calgb	swog	80405	calgb	swog	80405	is	a	phase	iii	trial	that	compared	the	addition	of	bevacizumab	or	cetuximab	to	infusional	fluorouracil	leucovorin	and	oxaliplatin	or	fluorouracil	leucovorin	and	irinotecan	as	first	line	treatment	of	advanced	crc	we	characterized	the	cms	classification	using	a	novel	nanostring	gene	expression	panel	on	primary	crcs	from	581	patients	enrolled	in	this	study	to	assess	the	prognostic	and	predictive	value	of	cmss	in	these	patients	the	cmss	are	highly	prognostic	for	overall	survival	os	p	001	and	progression	free	survival	pfs	p	001	furthermore	cmss	were	predictive	for	both	os	p	for	interaction	001	and	pfs	p	for	interaction	0032	in	the	cms1	cohort	patients	treated	with	bevacizumab	had	a	significantly	longer	os	than	those	treated	with	cetuximab	p	001	in	the	cms2	cohort	patients	treated	with	cetuximab	had	a	significantly	longer	os	than	patients	treated	with	bevacizumab	p	0046	these	findings	highlight	the	possible	clinical	utility	of	cmss	and	suggests	that	refinement	of	the	cms	classification	may	provide	a	path	toward	identifying	patients	with	metastatic	crc	who	are	most	likely	to	benefit	from	specific	targeted	therapy	as	part	of	the	initial	treatment</Paragraph></Rec>
<Rec><Paragraph>four	consensus	molecular	subtypes	cms1	4	of	colorectal	cancer	were	identified	in	primary	tumors	and	found	to	be	associated	with	distinctive	biological	features	and	clinical	outcomes	given	that	distant	metastasis	largely	accounts	for	colorectal	cancer	related	mortality	we	examined	the	molecular	and	clinical	attributes	of	cms	in	metastatic	colorectal	cancer	mcrc	we	developed	a	colorectal	cancer	focused	nanostring	based	cms	classifier	that	is	ideally	suited	to	interrogate	archival	tissues	we	successfully	used	this	panel	in	the	cms	classification	of	formalin	fixed	paraffin	embedded	ffpe	tissues	from	mcrc	cohorts	one	of	which	is	composed	of	paired	primary	tumors	and	metastases	finally	we	developed	novel	mouse	implantation	models	to	enable	modeling	of	colorectal	cancer	in	vivo	at	relevant	sites	using	our	classifier	we	find	that	the	biological	hallmarks	of	mcrc	including	cms	are	in	general	highly	similar	to	those	observed	in	nonmetastatic	early	stage	disease	importantly	our	data	demonstrate	that	cms1	has	the	worst	outcome	in	relapsed	disease	compared	with	other	cms	assigning	cms	to	primary	tumors	and	their	matched	metastases	reveals	mostly	concordant	subtypes	between	primary	and	metastasis	molecular	analysis	of	matched	discordant	pairs	reveals	differences	in	stromal	composition	at	each	site	the	development	of	two	novel	in	vivo	orthotopic	implantation	models	further	reinforces	the	notion	that	extrinsic	factors	may	impact	on	cms	identification	in	matched	primary	and	metastatic	colorectal	cancer	we	describe	the	utility	of	a	nanostring	panel	for	cms	classification	of	ffpe	clinical	samples	our	work	reveals	the	impact	of	intrinsic	and	extrinsic	factors	on	colorectal	cancer	heterogeneity	during	disease	progression</Paragraph></Rec>
<Rec><Paragraph>braf	mutations	are	grouped	in	activating	ras	independent	signaling	as	monomers	class	1	v600e	or	as	dimers	class	2	codons	597	601	and	ras	dependent	with	impaired	kinase	activity	class	3	codons	594	596	although	clinical	pathologic	and	molecular	features	of	v600e	braf	mutated	metastatic	colorectal	cancer	mcrc	are	well	known	limited	data	are	available	from	the	two	other	classes	data	from	117	patients	with	braf	92	class	1	12	class	2	and	13	class	3	mutated	mcrc	were	collected	a	total	of	540	braf	wt	mcrcs	were	included	as	control	ihc	profiling	was	performed	to	determine	the	consensus	molecular	subtypes	cms	cytokeratin	7	20	profiles	tumor	infiltrating	lymphocyte	infiltration	and	bm1	bm2	categorization	overall	survival	os	and	progression	free	survival	were	evaluated	by	kaplan	meier	and	log	rank	test	class	3	braf	mutated	mcrc	was	more	frequently	left	sided	p	0	0028	pn0	p	0	0159	and	without	peritoneal	metastases	p	0	0176	compared	with	class	1	whereas	class	2	cases	were	similar	to	class	1	hazard	ratio	for	os	as	compared	with	braf	wt	was	2	38	95	confidence	interval	ci	1	61	3	54	for	class	1	1	90	95	ci	0	85	4	26	for	class	2	and	0	93	95	ci	0	51	1	69	for	class	3	p	0	0001	class	2	and	3	tumors	were	all	assigned	to	cms2	3	a	higher	median	cd3	cd8	positive	lymphocyte	infiltration	was	observed	in	braf	mutated	class	2	p	0	033	compared	with	class	3	cases	for	the	first	time	different	clinical	and	pathologic	features	and	outcome	data	were	reported	according	to	the	three	braf	mutation	classes	in	mcrc	specific	targeted	treatment	strategies	should	be	identified	in	the	near	future	for	such	patients</Paragraph></Rec>
<Rec><Paragraph>cpg	island	methylator	phenotype	cimp	is	found	in	15	20	of	malignant	colorectal	tumors	and	is	characterized	by	strong	cpg	hypermethylation	over	the	genome	the	molecular	mechanisms	of	this	phenomenon	are	not	still	fully	understood	the	development	of	cimp	is	followed	by	global	gene	expression	alterations	and	metabolic	changes	in	particular	cimp	low	colon	adenocarcinoma	coad	predominantly	corresponded	to	consensus	molecular	subtype	3	cms3	metabolic	subgroup	according	to	coad	molecular	classification	is	associated	with	elevated	expression	of	genes	participating	in	metabolic	pathways	we	performed	bioinformatics	analysis	of	rna	seq	data	from	the	cancer	genome	atlas	tcga	project	for	cimp	high	and	non	cimp	coad	samples	with	deseq2	clusterprofiler	and	topgo	r	packages	obtained	results	were	validated	on	a	set	of	fourteen	coad	samples	with	matched	morphologically	normal	tissues	using	quantitative	pcr	qpcr	upregulation	of	multiple	genes	involved	in	glycolysis	and	related	processes	eno2	pfkp	hk3	pkm	eno1	hk2	pgam1	gapdh	aldoa	gpi	tpi1	and	hk1	was	revealed	in	cimp	high	tumors	compared	to	non	cimp	ones	most	remarkably	the	expression	of	the	pklr	gene	encoding	for	pyruvate	kinase	participating	in	gluconeogenesis	was	decreased	approximately	20	fold	up	to	8	fold	decrease	in	the	expression	of	ogdhl	gene	involved	in	tricarboxylic	acid	tca	cycle	was	observed	in	cimp	high	tumors	using	qpcr	we	confirmed	the	increase	4	fold	in	the	eno2	expression	and	decrease	2	fold	in	the	ogdhl	mrna	level	on	a	set	of	coad	samples	we	demonstrated	the	association	between	cimp	high	status	and	the	energy	metabolism	changes	at	the	transcriptomic	level	in	colorectal	adenocarcinoma	against	the	background	of	immune	pathway	activation	differential	methylation	of	at	least	nine	cpg	sites	in	ogdhl	promoter	region	as	well	as	decreased	ogdhl	mrna	level	can	potentially	serve	as	an	additional	biomarker	of	the	cimp	high	status	in	coad</Paragraph></Rec>
<Rec><Paragraph>primary	tumour	location	is	regarded	as	a	reliable	surrogate	of	colorectal	cancer	biology	sensitivity	to	anti	egfrs	epidermal	growth	factor	receptor	of	metastatic	transverse	colon	cancers	mtccs	has	usually	been	assumed	similar	to	right	sided	tumours	however	evidence	about	the	clinical	behaviour	of	mtcc	is	limited	thus	to	verify	sensitivity	of	mtcc	to	anti	egfrs	we	conducted	the	present	study	patients	with	ras	braf	wild	type	microsatellite	stable	mss	mtcc	receiving	anti	egfr	monotherapy	or	in	combination	with	irinotecan	if	clearly	irinotecan	refractory	were	included	hypothesising	an	overall	response	rate	orr	of	35	11	patients	of	whom	at	least	3	were	responders	were	necessary	to	be	able	to	reject	the	null	hypothesis	of	an	orr	of	5	with	α	and	β	errors	of	0	05	and	0	20	pressing	panel	and	consensus	molecular	subtypes	cms	were	assessed	on	tumour	samples	whereas	in	silico	data	were	obtained	from	tcga	dataset	among	nine	eligible	patients	four	and	three	achieved	response	and	disease	stabilisation	orr	44	at	a	median	follow	up	of	23	1	months	median	progression	free	survival	and	overall	survival	were	7	3	95	ci	3	9	to	na	and	15	0	months	95	ci	10	0	to	na	respectively	a	met	amplification	and	an	erbb4	s303f	substitution	were	detected	in	patients	with	rapid	disease	progression	while	others	had	pressing	panel	negative	tumours	with	cms2	or	cms4	subtypes	ras	braf	wild	type	mss	mtccs	may	be	sensitive	to	anti	egfrs	as	confirmed	by	molecular	analyses</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	complex	and	heterogeneous	disease	with	four	consensus	molecular	subtypes	cms1	4	ltbp2	is	a	member	of	the	fibrillin	ltbp	super	family	and	plays	a	critical	role	in	tumorigenesis	by	activating	tgf	β	in	the	cms4	crc	subtype	so	far	the	expression	and	prognostic	significance	of	ltbp2	in	crc	remains	obscure	in	this	study	we	aimed	to	analyze	the	mrna	and	protein	expression	levels	of	ltbp2	in	crc	tissues	and	then	estimate	their	values	as	a	potential	prognostic	biomarker	we	detected	the	mrna	expression	of	ltbp2	in	28	cases	of	fresh	crc	tissues	and	4	crc	cell	lines	and	the	protein	expression	of	ltbp2	in	483	samples	of	crc	tissues	matched	tumor	adjacent	tissues	and	benign	colorectal	diseases	ltbp2	protein	expression	was	then	correlated	to	patients	clinical	features	and	overall	survival	both	ltbp2	mrna	and	protein	expression	levels	in	crc	tissues	were	remarkably	superior	to	those	in	adjacent	normal	colorectal	tissues	p	0	0071	and	p	0	001	respectively	according	to	tcga	dataset	of	crc	high	ltbp2	protein	expression	was	correlated	with	tnm	stage	p	0	001	t	stage	p	0	001	n	stage	p	0	001	and	m	stage	p	0	001	high	ltbp2	protein	expression	was	related	to	poor	overall	survival	in	crc	patients	and	was	an	independent	prognostic	factor	for	crc	ltbp2	mrna	expression	was	especially	higher	in	the	cms4	subtype	p	0	001	which	was	confirmed	in	crc	cell	lines	our	data	suggested	that	ltbp2	may	act	as	an	oncogene	in	the	development	of	colorectal	cancer	and	have	important	significance	in	predicting	crc	prognosis	ltbp2	could	be	a	novel	biomarker	and	potential	therapeutic	target	for	mesenchymal	colorectal	cancer	and	can	improve	the	outcome	of	high	risk	crc</Paragraph></Rec>
<Rec><Paragraph>disparities	in	outcomes	exist	for	breast	colon	and	lung	cancer	among	diverse	populations	particularly	racial	and	ethnic	underrepresented	minorities	urms	and	individuals	from	lower	socioeconomic	status	for	example	blacks	experience	mortality	rates	up	to	about	42	higher	than	whites	for	these	cancers	furthermore	although	overall	death	rates	have	been	declining	the	differential	access	to	screening	and	care	has	aggravated	disparities	our	purpose	is	to	assess	how	the	coverage	policies	of	cms	and	the	united	states	preventive	services	task	force	uspstf	influence	these	disparities	additionally	barriers	are	often	encountered	in	accessing	screening	tests	and	receiving	prompt	treatment	to	narrow	and	potentially	eliminate	outcomes	disparities	cms	and	uspstf	could	consider	revising	their	decision	making	processes	regarding	coverage	some	options	include	1	extending	their	evidence	base	to	include	observational	studies	that	involve	groups	at	higher	risk	2	lowering	the	threshold	ages	for	screening	to	encompass	differences	in	incidence	3	cms	approving	screening	ct	colonography	coverage	which	can	even	increase	compliance	with	other	screening	tests	4	clarifying	and	streamlining	guidelines	5	supporting	research	on	improving	access	to	screening	and	6	encouraging	the	development	of	more	navigation	services	for	urms</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	heterogeneous	disease	that	can	be	classified	into	distinct	molecular	subtypes	the	aims	of	this	study	were	1	to	compare	claudin	cldn	gene	expression	in	crc	samples	and	normal	colon	mucosa	and	then	in	the	different	crc	molecular	subtypes	and	2	to	assess	their	prognostic	value	cldn	expression	in	crc	samples	was	analyzed	using	gene	expression	data	for	a	cohort	of	143	primary	crc	samples	and	compared	in	the	same	crc	samples	classified	into	different	molecular	subtypes	c1	to	c6	according	to	the	marisa	s	classification	and	cms1	to	cms4	of	the	consensus	classification	comparison	of	cldn	expression	in	normal	and	tumor	colon	samples	was	also	made	on	a	smaller	number	of	samples	then	the	relationship	between	cldn	expression	profiles	and	overall	survival	os	and	progression	free	survival	was	examined	compared	with	normal	mucosa	cldn1	and	cldn2	were	upregulated	whereas	cldn5	7	8	and	23	were	downregulated	in	crc	samples	variations	in	cldn	expression	profiles	were	observed	mainly	in	the	cms2	c1	and	cms4	c4	subtypes	overall	expression	of	cldn2	or	cldn4	alone	had	a	strong	prognostic	value	that	increased	when	they	were	associated	in	the	cms4	c4	subtypes	lower	expressions	of	cldn11	cldn12	and	cldn23	were	associated	with	longer	os	conversely	in	the	cms2	and	c1	subtypes	low	cldn23	expression	was	associated	with	shorter	os	and	progression	free	survival	suggesting	a	dual	role	for	cldn23	as	a	tumor	suppressor	promoter	in	crc	cldn6	and	cldn11	had	a	prognostic	value	in	the	cms2	and	c4	subtypes	respectively	this	analysis	of	cldn	gene	expression	profiles	and	prognostic	value	in	crc	samples	classified	according	to	their	molecular	subtype	shows	that	crc	heterogeneity	must	be	taken	into	account	when	assessing	cldn	potential	value	as	prognostic	markers	or	therapeutic	targets</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	incidence	is	increasing	in	adults	younger	than	50	years	this	study	evaluated	clinical	and	molecular	features	to	identify	those	features	unique	to	early	onset	crc	that	differentiate	these	patients	from	patients	50	years	old	or	older	baseline	characteristics	were	evaluated	according	to	the	crc	onset	age	with	3	independent	cohorts	a	fourth	cohort	was	used	to	describe	the	impact	of	age	on	the	consensus	molecular	subtype	cms	prevalence	this	retrospective	review	of	more	than	36	000	patients	with	crc	showed	that	early	onset	patients	were	more	likely	to	have	microsatellite	instability	p	038	synchronous	metastatic	disease	p	009	primary	tumors	in	the	distal	colon	or	rectum	p	0001	and	fewer	braf	v600	mutations	p	001	in	comparison	with	patients	50	years	old	or	older	patients	aged	18	to	29	years	had	fewer	adenomatous	polyposis	coli	apc	mutations	odds	ratio	or	0	56	95	confidence	interval	ci	0	35	0	90	p	015	and	an	increased	prevalence	of	signet	ring	histology	or	4	89	95	ci	3	23	7	39	p	0001	in	comparison	with	other	patients	younger	than	50	years	in	patients	younger	than	40	years	cms1	was	the	most	common	subtype	whereas	cms3	and	cms4	were	uncommon	p	003	cms2	was	relatively	stable	across	age	groups	early	onset	patients	with	inflammatory	bowel	disease	were	more	likely	to	have	mucinous	or	signet	ring	histology	or	5	54	95	ci	2	24	13	74	p	0004	and	less	likely	to	have	apc	mutations	or	0	24	95	ci	0	07	0	75	p	019	in	comparison	with	early	onset	patients	without	predisposing	conditions	early	onset	crc	is	not	only	distinct	from	traditional	crc	special	consideration	should	be	given	to	and	further	investigations	should	be	performed	for	both	very	young	patients	with	crc	18	29	years	and	those	with	predisposing	conditions	the	etiology	of	the	high	rate	of	cms1	in	patients	younger	than	40	years	deserves	further	exploration</Paragraph></Rec>
<Rec><Paragraph>the	early	events	by	which	inflammation	promotes	cancer	are	still	not	fully	defined	the	mcc	gene	is	silenced	by	promoter	methylation	in	colitis	associated	and	sporadic	colon	tumors	but	its	functional	significance	in	precancerous	lesions	or	polyps	is	not	known	here	we	aimed	to	determine	the	impact	of	mcc	deletion	on	the	cellular	pathways	and	carcinogenesis	associated	with	inflammation	in	the	mouse	proximal	colon	we	generated	knockout	mice	with	deletion	of	mcc	in	the	colonic	intestinal	epithelial	cells	mcc	δiec	or	in	the	whole	body	mcc	δ	δ	drug	induced	lesions	were	analyzed	by	transcriptome	profiling	at	10	weeks	and	histopathology	at	20	weeks	cell	cycle	phases	and	dna	damage	proteins	were	analyzed	by	flow	cytometry	and	western	blot	of	hydrogen	peroxide	treated	mouse	embryo	fibroblasts	transcriptome	profiling	of	the	lesions	showed	a	strong	response	to	colon	barrier	destruction	such	as	up	regulation	of	key	inflammation	and	cancer	associated	genes	as	well	as	28	interferon	γ	induced	guanosine	triphosphatase	genes	including	the	homologs	of	crohn	s	disease	susceptibility	gene	irgm	these	features	were	shared	by	both	mcc	expressing	and	mcc	deficient	mice	and	many	of	the	altered	gene	expression	pathways	were	similar	to	the	mesenchymal	colorectal	cancer	subtype	known	as	consensus	molecular	subtype	4	cms4	however	mcc	deletion	was	required	for	increased	carcinogenesis	in	the	lesions	with	adenocarcinoma	in	59	of	mcc	δiec	compared	with	19	of	mcc	expressing	mice	p	002	this	was	not	accompanied	by	hyperactivation	of	β	catenin	but	mcc	deletion	caused	down	regulation	of	dna	repair	genes	and	a	disruption	of	dna	damage	signaling	loss	of	mcc	may	promote	cancer	through	a	failure	to	repair	inflammation	induced	dna	damage	we	provide	a	comprehensive	transcriptome	data	set	of	early	colorectal	lesions	and	evidence	for	the	in	vivo	significance	of	mcc	silencing	in	colorectal	cancer</Paragraph></Rec>
<Rec><Paragraph>radiofrequency	ablation	rfa	therapy	has	proven	to	be	effective	and	feasible	for	early	stage	hepatocellular	carcinoma	hcc	however	rapid	progression	of	residual	tumor	cells	after	rfa	has	been	confirmed	but	the	molecular	mechanisms	of	this	phenomenon	are	poorly	understood	this	study	evaluated	the	effect	of	the	lipid	raft	proteins	known	as	flotillins	on	the	invasive	and	metastatic	potential	of	residual	hcc	the	human	hcc	cell	line	hcclm3	was	used	to	establish	insufficient	rfa	models	in	vivo	and	in	vitro	changes	in	cellular	morphology	soft	agar	colony	formation	motility	metastasis	and	epithelial	mesenchymal	transition	emt	markers	after	insufficient	rfa	intervention	in	vitro	and	in	vivo	were	detected	by	real	time	pcr	western	blotting	immunohistochemistry	and	transwell	assays	the	results	showed	that	flotillin	1	and	flotillin	2	expression	were	upregulated	in	hcclm3	cells	following	45	c	heat	treatment	and	in	residual	hcclm3	xenografts	cells	after	insufficient	rfa	knocking	down	flotillin	1	or	flotillin	2	in	hcclm3	cells	by	shrna	significantly	lowered	insufficient	rfa	induced	tumor	growth	emt	changes	and	metastasis	in	vitro	and	in	vivo	furthermore	mechanism	studies	indicated	that	flotillins	altered	the	emt	status	and	metastatic	potential	of	heat	treated	hcclm3	cells	by	activating	the	akt	wnt	β	catenin	signaling	pathway	our	findings	present	new	evidence	that	flotillins	play	a	key	role	in	the	aggressive	behaviors	of	residual	cancer	cells	after	insufficient	rfa	and	provide	new	insights	into	the	regulatory	mechanism	of	wnt	β	catenin	signaling</Paragraph></Rec>
<Rec><Paragraph>the	colorectal	cancer	subtyping	consortium	identified	four	gene	expression	consensus	molecular	subtypes	cms1	immune	cms2	canonical	cms3	metabolic	and	cms4	mesenchymal	using	multiple	microarray	or	rna	sequencing	datasets	of	primary	tumor	samples	mainly	from	early	stage	colon	cancer	patients	consequently	rectal	tumors	and	stage	iv	tumors	possibly	reflective	of	more	aggressive	disease	were	underrepresented	and	no	chemo	and	or	radiotherapy	pretreated	samples	or	metastatic	lesions	were	included	in	view	of	their	possible	effect	on	gene	expression	and	consequently	subtype	classification	sample	source	and	treatments	received	by	the	patients	before	collection	must	be	carefully	considered	when	applying	the	classifier	to	new	datasets	recently	several	correlative	analyses	of	clinical	trials	demonstrated	the	applicability	of	this	classification	to	the	metastatic	setting	confirmed	the	prognostic	value	of	cms	subtypes	after	relapse	and	hinted	at	differential	sensitivity	to	treatments	here	we	discuss	why	contexts	and	equivocal	factors	need	to	be	taken	into	account	when	analyzing	clinical	trial	data	including	potential	selection	biases	type	of	platform	and	type	of	algorithm	used	for	subtype	prediction	this	perspective	article	facilitates	both	our	clinical	and	research	understanding	of	the	application	of	this	classifier	to	expedite	subtype	based	clinical	trials</Paragraph></Rec>
<Rec><Paragraph>constitutive	wnt	activation	upon	loss	of	adenoma	polyposis	coli	apc	acts	as	main	driver	of	colorectal	cancer	crc	targeting	wnt	signaling	has	proven	difficult	because	the	pathway	is	crucial	for	homeostasis	and	stem	cell	renewal	to	distinguish	oncogenic	from	physiological	wnt	activity	we	have	performed	transcriptome	and	proteome	profiling	in	isogenic	human	colon	organoids	culture	in	the	presence	or	absence	of	exogenous	ligand	allowed	us	to	discriminate	receptor	mediated	signaling	from	the	effects	of	crispr	cas9	induced	apc	loss	we	could	catalog	two	nonoverlapping	molecular	signatures	that	were	stable	at	distinct	levels	of	stimulation	newly	identified	markers	for	normal	stem	progenitor	cells	and	adenomas	were	validated	by	immunohistochemistry	and	flow	cytometry	we	found	that	oncogenic	wnt	signals	are	associated	with	good	prognosis	in	tumors	of	the	consensus	molecular	subtype	2	cms2	in	contrast	receptor	mediated	signaling	was	linked	to	cms4	tumors	and	poor	prognosis	together	our	data	represent	a	valuable	resource	for	biomarkers	that	allow	more	precise	stratification	of	wnt	responses	in	crc</Paragraph></Rec>
<Rec><Paragraph>the	current	histopathological	risk	stratification	criteria	in	colorectal	cancer	crc	patients	following	a	curative	surgery	remain	inadequate	in	this	study	we	undertook	a	systematic	genomewide	biomarker	discovery	approach	to	identify	and	validate	key	emt	associated	genes	that	may	facilitate	recurrence	prediction	in	crc	genomewide	rna	expression	profiling	results	from	two	datasets	gse17538	n	173	and	gse41258	n	307	were	used	for	biomarker	discovery	these	results	were	independently	validated	in	two	large	clinical	cohorts	testing	cohort	n	201	and	validation	cohort	n	468	we	performed	gene	set	enrichment	analysis	gsea	for	understanding	the	function	of	the	candidate	markers	and	evaluated	their	correlation	with	the	mesenchymal	cms4	subtype	we	identified	integrin	subunit	beta	like	1	itgbl1	as	a	promising	candidate	biomarker	and	its	high	expression	associated	with	poor	overall	survival	os	in	stage	i	iv	patients	and	relapse	free	survival	rfs	in	stage	i	iii	patients	subgroup	validation	in	multiple	independent	patient	cohorts	confirmed	these	findings	and	demonstrated	that	high	itgbl1	expression	correlated	with	shorter	rfs	in	stage	ii	patients	we	developed	a	rfs	prediction	model	which	robustly	predicted	rfs	the	area	under	the	receiver	operating	curve	auroc	0	74	hazard	ratio	hr	2	72	in	crc	patients	itgbl1	is	a	promising	emt	associated	biomarker	for	recurrence	prediction	in	crc	patients	which	may	contribute	to	improved	risk	stratification	in	crc</Paragraph></Rec>
<Rec><Paragraph>this	review	seeks	to	provide	an	informed	prospective	on	the	advances	in	molecular	profiling	and	analysis	of	colorectal	cancer	crc	the	goal	is	to	provide	a	historical	context	and	current	summary	on	how	advances	in	gene	and	protein	sequencing	technology	along	with	computer	capabilities	led	to	our	current	bioinformatic	advances	in	the	field	an	explosion	of	knowledge	has	occurred	regarding	genetic	epigenetic	and	biochemical	alterations	associated	with	the	evolution	of	colorectal	cancer	this	has	led	to	the	realization	that	crc	is	a	heterogeneous	disease	with	molecular	alterations	often	dictating	natural	history	response	to	treatment	and	outcome	the	consensus	molecular	subtypes	cms	classification	classifies	crc	into	four	molecular	subtypes	with	distinct	biological	characteristics	which	may	form	the	basis	for	clinical	stratification	and	subtype	based	targeted	intervention	this	review	summarizes	new	developments	of	a	field	moving	back	to	the	future	crc	molecular	subtyping	will	better	identify	key	subtype	specific	therapeutic	targets	and	responses	to	therapy</Paragraph></Rec>
<Rec><Paragraph>nearly	1	5	million	clinicians	in	the	united	states	will	be	affected	by	centers	for	medicare	and	medicaid	services	cms	new	payment	program	the	merit	based	incentive	program	mips	where	clinicians	will	be	penalized	or	rewarded	based	on	the	health	care	expenditures	of	their	patients	we	therefore	examined	expenditures	for	major	cancer	surgery	to	understand	physician	specific	variation	in	episode	payments	we	used	surveillance	epidemiology	and	end	results	medicare	data	to	identify	patients	aged	66	99	y	who	underwent	a	prostatectomy	nephrectomy	lung	or	colorectal	resection	for	cancer	from	2008	to	2012	we	calculated	90	d	episode	payments	attributed	each	episode	to	a	physician	and	evaluated	physician	level	payment	variation	next	we	determined	which	component	index	admission	readmission	physician	services	postacute	care	hospice	drove	differences	in	payments	finally	we	evaluated	payments	by	geographic	region	number	of	comorbidities	and	cancer	stage	we	identified	39	109	patients	who	underwent	surgery	by	1	of	7182	providers	there	was	wide	variation	in	payments	for	each	procedure	prostatectomy	7046	40	687	nephrectomy	8855	82	489	lung	resection	11	167	223	467	colorectal	resection	9711	199	480	the	largest	component	difference	in	episode	payments	varied	by	condition	physician	payments	for	prostatectomy	29	postacute	care	for	nephrectomy	38	and	colorectal	resections	38	and	index	hospital	admission	for	lung	resections	43	but	were	fairly	stable	across	region	comorbidity	number	and	cancer	stage	for	patients	undergoing	major	cancer	surgery	90	d	episode	payments	vary	widely	across	surgeons	the	components	driving	such	variation	differ	by	condition	but	remain	stable	across	region	number	of	comorbidities	and	cancer	stage	these	data	suggest	that	programs	to	reduce	specific	component	payments	may	have	advantages	over	those	targeting	individual	physicians	for	decreasing	health	care	expenditures</Paragraph></Rec>
<Rec><Paragraph>health	care	reform	is	changing	preventive	services	delivery	this	study	explored	trajectories	in	colorectal	cancer	crc	testing	over	a	5	year	period	that	included	implementation	of	16	medicaid	accountable	care	organizations	acos	2012	and	medicaid	expansion	2014	two	provisions	of	the	affordable	care	act	aca	within	the	state	of	oregon	usa	retrospective	analysis	of	oregon	s	medicaid	claims	for	enrollee	s	eligible	for	crc	screening	50	64	years	spanning	january	2010	through	december	2014	our	analysis	was	conducted	and	refined	april	2016	through	june	2018	the	analysis	assessed	the	annual	probability	of	patients	receiving	crc	testing	and	the	modality	used	e	g	colonoscopy	fecal	testing	relative	to	a	baseline	year	2010	we	hypothesized	that	crc	testing	would	increase	following	medicaid	aco	formation	called	coordinated	care	organizations	ccos	a	total	of	132	424	unique	medicaid	enrollees	representing	255	192	person	years	met	inclusion	criteria	over	the	5	year	study	controlling	for	demographic	and	regional	factors	the	predicted	probability	of	crc	testing	was	significantly	higher	in	2014	1	4	percentage	points	p	0	001	compared	to	the	2010	baseline	but	not	in	2012	or	2013	increased	fecal	testing	using	fecal	occult	blood	tests	fobt	or	fecal	immunochemical	tests	fit	played	a	prominent	role	in	2014	the	uptick	in	statewide	fecal	testing	appears	driven	primarily	by	a	subset	of	ccos	observed	crc	testing	did	not	immediately	increase	following	the	transition	to	ccos	in	2012	however	increased	testing	in	2014	may	reflect	a	delay	in	implementation	of	interventions	to	increase	crc	screening	and	or	a	strong	desire	by	newly	insured	medicaid	cco	members	to	receive	preventive	care</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	the	second	most	common	cancer	in	europe	and	a	leading	cause	of	death	worldwide	patient	derived	xenograft	pdx	models	maintain	complex	intratumoral	biology	and	heterogeneity	and	therefore	remain	the	platform	of	choice	for	translational	drug	discovery	in	this	study	we	implanted	37	primary	crc	tumors	and	five	crc	cell	lines	into	nu	j	mice	to	develop	xenograft	models	primary	tumors	and	established	xenografts	were	histologically	assessed	and	surveyed	for	genetic	variants	and	gene	expression	using	a	panel	of	409	cancer	related	genes	and	rna	seq	respectively	more	than	half	of	crc	tumors	20	out	of	37	54	developed	into	a	pdx	histological	assessment	confirmed	that	pdx	grading	stromal	components	inflammation	and	budding	were	consistent	with	those	of	the	primary	tumors	dna	sequencing	identified	an	average	of	0	14	variants	per	gene	per	sample	the	percentage	of	mutated	variants	in	pdxs	increased	with	successive	passages	indicating	a	decrease	in	clonal	heterogeneity	gene	ontology	analyses	of	4180	differentially	expressed	transcripts	adj	p	value	0	05	revealed	overrepresentation	of	genes	involved	in	cell	division	and	catabolic	processes	among	the	transcripts	upregulated	in	pdxs	downregulated	transcripts	were	associated	with	go	terms	related	to	extracellular	matrix	organization	immune	responses	and	angiogenesis	neither	a	transcriptome	based	consensus	molecular	subtype	cms	classifier	nor	three	other	predictors	reliably	matched	pdx	molecular	subtypes	with	those	of	the	primary	tumors	in	sum	both	genetic	and	transcriptomic	profiles	differed	between	donor	tumors	and	pdxs	likely	as	a	consequence	of	subclonal	evolution	at	the	early	phase	of	xenograft	development	making	molecular	stratification	of	pdxs	challenging</Paragraph></Rec>
<Rec><Paragraph>next	generation	immunotherapies	have	limited	efficacy	in	colorectal	cancer	immune	checkpoints	inhibitors	demonstrated	their	benefit	in	mismatch	repair	deficient	tumors	which	also	exhibit	microsatellite	instability	msi	the	consensual	molecular	subtype	cms	classification	has	been	recently	proposed	and	highlights	specific	immune	escape	mechanisms	for	each	subtype	cms1	immune	subtype	is	hypermutated	with	a	favorable	immune	microenvironment	for	immune	checkpoints	inhibitors	activity	importantly	cms1	is	not	restricted	to	msi	tumors	and	includes	also	exonucleasic	domain	pole	mutated	tumors	which	are	good	candidates	for	immunotherapy	the	scope	of	this	comprehensive	review	is	to	described	immune	anomalies	and	propose	immunomodulating	strategies	for	each	cms	subtype	in	colorectal	cancer	finally	the	potential	interest	of	tumor	mutation	burden	and	the	immunoscore	in	colorectal	cancer	is	discussed	taking	into	account	the	molecular	classification	and	obstacles	to	antitumoral	immune	activity</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancers	crc	belonging	to	the	consensus	molecular	subtype	2	cms2	have	the	highest	incidence	rate	affect	mainly	the	distal	colon	and	rectum	and	are	characterized	by	marked	wnt	β	catenin	transcription	factor	7	like	2	tcf7l2	pathway	activation	and	also	by	activation	of	epidermal	growth	factor	receptor	egfr	signalling	despite	having	the	highest	overall	survival	cms2	tumours	are	often	diagnosed	at	stage	iii	when	an	adjuvant	chemotherapy	based	regimen	is	recommended	nevertheless	colorectal	cancer	stem	cells	cscs	and	circulating	tumour	cells	may	still	evade	the	current	therapeutic	options	and	metastasize	stressing	the	need	to	develop	more	tailored	therapeutic	strategies	for	example	activation	of	egfr	signalling	is	being	used	as	a	target	for	tailored	therapy	however	therapy	resistance	is	frequently	observed	therefore	targeting	the	wnt	signalling	axis	represents	an	additional	therapeutic	strategy	considering	that	cms2	tumours	are	wnt	addicted	several	efforts	have	been	made	to	identify	wnt	antagonists	either	of	synthetic	or	natural	origin	however	an	inverse	gradient	of	wnt	β	catenin	tcf7l2	signalling	activity	during	crc	progression	has	been	suggested	with	early	stage	and	metastatic	tumours	displaying	high	and	low	wnt	signalling	activities	respectively	which	lead	us	to	revisit	the	just	right	signalling	model	this	may	pinpoint	the	use	of	wnt	signalling	agonists	instead	of	antagonists	for	treatment	of	metastatic	stages	in	a	context	dependent	fashion	moreover	the	poor	immunogenicity	of	these	tumours	challenges	the	use	of	recently	emerged	immunotherapies	this	chapter	makes	a	journey	about	cms2	tumour	characterization	their	conventional	treatment	and	how	modulation	of	wnt	signalling	or	immune	response	may	be	applied	to	crc	therapy	it	describes	the	newest	findings	in	this	field	and	indicates	where	more	research	is	required</Paragraph></Rec>
<Rec><Paragraph>cancer	cells	rewire	their	metabolism	in	order	to	boost	growth	survival	proliferation	and	chemoresistance	the	common	event	of	this	aberrant	metabolism	is	the	increased	glucose	uptake	and	fermentation	of	glucose	to	lactate	this	phenomenon	is	observed	even	in	the	presence	of	o2	and	completely	functioning	mitochondria	this	is	known	as	the	warburg	effect	and	it	is	a	hallmark	in	cancer	up	to	40	of	all	crc	s	are	known	to	have	a	mutated	abnormal	kras	gene	found	at	differing	frequencies	in	all	consensus	molecular	subtypes	cms	cms3	colon	cancer	molecular	subtype	contains	the	so	called	metabolic	tumours	which	represents	13	of	total	cr	cases	these	tumours	display	remarkable	metabolic	deregulation	often	showing	kras	mutations	68	unfortunately	patients	harbouring	mutated	kras	are	unlikely	to	benefit	from	anti	egfr	therapies	moreover	it	remains	unclear	that	patients	with	kras	wild	type	crc	will	definitely	respond	to	such	therapies	although	some	clinically	designed	strategies	to	modulate	kras	aberrant	activation	have	been	designed	all	attempts	to	target	kras	have	failed	in	the	clinical	assays	and	kras	has	been	assumed	to	be	invulnerable	to	chemotherapeutic	attack	quest	for	metabolic	inhibitors	with	anti	tumour	activity	may	constitute	a	novel	and	hopeful	approach	in	order	to	handle	kras	dependent	chemoresistance	in	colon	cancer</Paragraph></Rec>
<Rec><Paragraph>broad	copy	number	aberrations	bcnas	represent	a	common	form	of	genome	instability	in	colorectal	cancer	crc	crcs	show	large	variations	in	their	level	of	aneuploidy	microsatellite	instable	msi	tumors	are	known	to	have	a	near	diploid	karyotype	while	microsatellite	stable	mss	tumors	show	high	level	of	chromosomal	instability	however	mss	tumors	have	great	heterogeneity	in	the	number	of	bcnas	with	a	minor	percentage	of	samples	showing	an	almost	normal	karyotype	in	the	present	work	we	subdivided	mss	crcs	according	to	a	bcna	score	and	characterized	their	transcriptome	profiles	considered	as	a	proxy	to	their	phenotypic	features	microsatellite	testing	genome	wide	dna	copy	number	and	whole	transcript	expression	analysis	hta	were	performed	on	33	tumor	samples	and	25	normal	colonic	tissue	samples	from	32	crc	patients	15	1	of	the	samples	were	msi	tumors	n	5	whereas	84	9	were	mss	tumors	n	28	gene	expression	data	of	34	additional	msi	tumors	was	retrieved	from	a	public	functional	genomics	data	repository	using	as	a	threshold	the	first	quartile	of	the	bcna	score	distribution	mss	samples	were	classified	as	low	bcna	lb	n	7	or	high	bcna	hb	n	21	lb	tumors	were	enriched	for	mucinous	crcs	and	their	gene	expression	profile	resembled	that	of	msi	samples	for	what	concerns	a	subset	of	genes	involved	in	secretory	processes	mucosal	protection	and	extracellular	matrix	remodeling	hb	tumors	were	predominantly	non	mucinous	adenocarcinomas	and	showed	overexpression	of	a	subset	of	genes	typical	of	surface	colonocytes	and	egf	signaling	a	large	percentage	of	unclassified	samples	according	to	the	consensus	molecular	subtypes	cms	classifier	was	found	in	the	lb	group	43	whereas	76	hb	tumors	belonged	to	cms2	a	classification	of	colorectal	tumors	based	on	the	number	of	bcnas	identifies	two	groups	of	mss	tumors	which	differ	for	histopathology	and	gene	expression	profile	such	information	can	be	exploited	for	its	translational	relevance	in	different	aspects	of	crc	clinical	management</Paragraph></Rec>
<Rec><Paragraph>the	trillions	of	microbes	collectively	referred	to	as	the	human	microbiota	inhabit	the	human	body	and	establish	a	beneficial	relationship	with	the	host	it	is	clear	however	that	dysbiosis	impacting	microbial	diversity	in	the	gut	may	lead	to	development	of	inflammatory	and	malignant	gastrointestinal	diseases	including	colorectal	cancer	crc	we	provide	a	literature	review	of	the	recent	influx	of	information	related	to	the	alterations	in	gut	microbiota	composition	that	influences	crc	incidence	and	progression	a	growing	body	of	evidence	implicates	altered	gut	microbiota	in	the	development	of	crc	profiles	of	crc	associated	microbiota	have	been	shown	to	differ	from	those	in	healthy	subjects	and	bacterial	phylotypes	vary	depending	on	the	primary	tumor	location	the	compositional	variation	in	the	microbial	profile	is	not	restricted	to	cancerous	tissue	however	and	is	different	between	cancers	of	the	proximal	and	distal	colons	respectively	more	recently	studies	have	shed	light	on	the	driver	passenger	model	for	crc	wherein	driver	bacteria	cause	inflammation	increased	cell	proliferation	and	production	of	genotoxic	substances	to	contribute	towards	mutational	acquisition	associated	with	adenoma	carcinoma	sequence	these	changes	facilitate	gradual	replacement	of	driver	bacteria	by	passengers	that	either	promote	or	suppress	tumor	progression	significant	advances	have	also	been	made	in	associating	individual	bacterial	species	to	consensus	molecular	subtypes	cms	of	crc	and	this	remarkable	development	is	expected	to	galvanize	scientific	community	into	advancing	therapeutic	strategies	for	crc	increasing	evidence	suggests	a	link	between	the	intestinal	microbiota	and	crc	development	although	the	mechanisms	through	which	the	bacterial	constituents	of	the	microbiome	contribute	towards	crc	are	complex	and	yet	to	be	fully	fathomed	thus	more	exhaustive	and	mechanistic	studies	are	needed	to	identify	key	interactions	amongst	diet	microbial	community	and	metabolites	that	help	facilitate	the	adenoma	carcinoma	sequence	evolution	in	crc	it	is	expected	that	development	of	therapeutics	based	on	microbial	association	with	cms	will	likely	facilitate	the	translation	of	molecular	subtypes	into	the	clinic	for	crcs	and	potentially	other	malignancies</Paragraph></Rec>
<Rec><Paragraph>elevated	mir	31	expression	is	associated	with	poor	outcome	in	colorectal	cancer	crc	whether	the	prognostic	information	is	independent	of	known	molecular	subgroups	and	gene	expression	based	consensus	molecular	subtypes	cms	is	currently	unknown	to	investigate	this	we	analyzed	nearly	2000	crc	biopsies	and	preclinical	models	the	expression	of	mir	31	5p	and	its	host	transcript	long	noncoding	rna	mir31hg	was	strongly	correlated	spearman	s	ρ	0	80	mir31hg	outlier	expression	was	observed	in	158	1265	12	of	pcrcs	and	was	associated	with	depletion	of	cms2	canonical	subgroup	odds	ratio	0	21	0	11	0	35	and	shorter	relapse	free	survival	rfs	in	multivariable	analysis	adjusted	hazard	ratio	2	2	1	6	3	0	for	stage	ii	disease	5	year	rfs	for	patients	with	mir31hg	outlier	status	was	49	compared	to	77	for	those	with	normal	like	expression	mir31hg	outlier	status	was	associated	with	inferior	outcome	also	within	clinical	high	risk	groups	and	within	the	poor	prognostic	cms4	mesenchymal	gene	expression	subtype	specifically	preclinical	models	with	mir31hg	outlier	expression	were	characterized	by	reduced	expression	of	myc	targets	as	well	as	elevated	epithelial	mesenchymal	transition	tnf	α	nfκb	tgf	β	and	ifn	α	γ	gene	expression	signatures	indicating	cancer	cell	intrinsic	properties	resembling	the	cms4	subgroup	associations	which	were	recapitulated	in	patient	biopsies	moreover	the	prognostic	value	of	mir31hg	outlier	status	was	independent	of	cytotoxic	t	lymphocyte	and	fibroblast	infiltration	we	here	present	evidence	that	mir31hg	expression	provides	clinical	stratification	beyond	major	gene	expression	phenotypes	and	tumor	immune	and	stromal	cell	infiltration	and	propose	a	model	where	increased	expression	is	an	indicator	of	a	cellular	state	conferring	intrinsic	invasive	and	or	immuno	evasive	capabilities</Paragraph></Rec>
<Rec><Paragraph>gene	expression	based	profiling	of	colorectal	cancer	crc	can	be	used	to	identify	four	molecularly	homogeneous	consensus	molecular	subtype	cms	groups	with	unique	biologic	features	however	its	applicability	to	colorectal	premalignant	lesions	remains	unknown	we	assembled	the	largest	transcriptomic	premalignancy	dataset	by	integrating	different	public	and	proprietary	cohorts	of	adenomatous	and	serrated	polyps	from	sporadic	n	311	and	hereditary	n	78	patient	populations	and	carried	out	a	comprehensive	analysis	of	carcinogenesis	pathways	using	the	cms	random	forest	rf	classifier	overall	transcriptomic	subtyping	of	sporadic	and	hereditary	polyps	revealed	cms2	and	cms1	subgroups	as	the	predominant	molecular	subtypes	in	premalignancy	pathway	enrichment	analysis	showed	that	adenomatous	polyps	from	sporadic	or	hereditary	cases	including	lynch	syndrome	displayed	a	cms2	like	phenotype	with	wnt	and	myc	activation	whereas	hyperplastic	and	serrated	polyps	with	cms1	like	phenotype	harbored	prominent	immune	activation	rare	adenomas	with	cms4	like	phenotype	showed	significant	enrichment	for	stromal	signatures	along	with	transforming	growth	factor	β	activation	there	was	a	strong	association	of	cms1	like	polyps	with	serrated	pathology	right	sided	anatomic	location	and	braf	mutations	based	on	our	observations	made	in	premalignancy	we	propose	a	model	of	pathway	activation	associated	with	cms	classification	in	colorectal	carcinogenesis	specifically	while	adenomatous	polyps	are	largely	cms2	most	hyperplastic	and	serrated	polyps	are	cms1	and	may	transition	into	other	cms	groups	during	evolution	into	carcinomas	our	findings	shed	light	on	the	transcriptional	landscape	of	premalignant	colonic	polyps	and	may	help	guide	the	development	of	future	biomarkers	or	preventive	treatments	for	crc</Paragraph></Rec>
<Rec><Paragraph>tumour	budding	is	an	important	prognostic	factor	in	colorectal	cancer	crc	molecular	profiling	of	tumour	buds	suggests	partial	epithelial	mesenchymal	transition	and	cancer	stem	cell	phenotype	similarly	described	in	the	mesenchymal	consensus	molecular	subtype	4	cms4	which	identifies	a	particularly	poor	prognostic	subgroup	here	we	determine	the	association	of	tumour	budding	with	cms	classification	prognosis	and	response	to	therapy	amc	ajccii	90	cohort	n	76	stage	ii	was	evaluated	for	peritumoural	budding	on	h	e	slides	lumc	n	270	stage	i	iv	cairo	n	504	metastatic	crc	and	cairo2	n	472	metastatic	crc	cohorts	were	investigated	for	intratumoural	budding	using	pan	cytokeratin	stained	tissue	microarrays	budding	was	scored	as	count	area	then	classified	as	5	or	5	buds	for	all	cohorts	cms	classifications	were	available	gene	expression	immunohistochemistry	based	classifiers	high	5	budding	predicted	a	worse	outcome	in	multivariate	analysis	in	amc	ajccii	90	p	0	018	lumc	p	0	0001	and	cairo	p	0	03	and	in	cairo2	continuous	variable	p	0	02	tumour	budding	counts	were	higher	in	cms4	compared	to	epithelial	cms2	3	cancers	p	0	01	all	and	associated	with	kras	braf	mutations	p	0	01	amc	ajccii	90	cairo	cairo2	tumour	budding	is	an	adverse	prognostic	factor	across	all	crc	stages	and	is	associated	with	the	mesenchymal	cms4	phenotype	kras	braf	mutations	are	strongly	correlated	with	tumour	budding	suggesting	their	involvement	in	the	regulation	of	this	process</Paragraph></Rec>
<Rec><Paragraph>alterations	in	cellular	energy	metabolism	play	a	critical	role	in	colorectal	cancer	crc	which	has	been	identified	as	the	definition	of	consensus	molecular	subtypes	cmss	and	cms3	tumors	exhibit	energy	metabolism	signatures	along	with	kirsten	rat	sarcoma	viral	oncogene	homolog	kras	activating	mutations	this	review	summarizes	the	relationship	between	cms3	tumors	associated	with	mutated	kras	and	energy	metabolism	in	crc	especially	for	the	dysregulated	energy	metabolism	that	affects	tumor	cell	proliferation	invasion	and	migration	furthermore	this	review	concentrates	on	the	role	of	metabolic	genes	and	factors	and	signaling	pathways	which	coupled	with	a	primary	energy	source	connected	with	the	cms3	associated	with	mutated	kras	induce	metabolic	alterations	the	strategies	to	target	energy	metabolism	for	the	metabolic	alterations	in	mutated	kras	crc	are	also	introduced	in	conclusion	dysregulated	energy	metabolism	has	a	close	relationship	with	mutated	kras	in	cms3	tumors	therefore	selective	inhibitors	or	agents	against	metabolic	targets	or	kras	signaling	may	be	clinically	useful	for	cms3	tumor	treatment	through	a	personalized	approach	for	patients	with	cancer</Paragraph></Rec>
<Rec><Paragraph>surgical	management	of	malignant	bowel	obstruction	carries	with	high	morbidity	and	mortality	placement	of	a	trans	anal	decompression	tube	tdt	has	traditionally	been	used	for	malignant	bowel	obstruction	as	a	bridge	to	surgery	recently	colonic	metallic	stent	cms	as	a	bridge	to	surgery	for	malignant	bowel	obstruction	particularly	left	sided	malignant	large	bowel	obstruction	lmlbo	caused	by	colorectal	cancer	has	been	reported	to	be	both	a	safe	and	feasible	option	the	aim	of	this	retrospective	study	is	to	evaluate	the	clinical	effects	of	cms	for	lmlbo	as	a	bridge	to	surgery	compared	to	tdt	between	january	2000	and	december	2015	we	retrospectively	evaluated	outcomes	of	59	patients	with	lmlbo	we	compared	the	outcomes	of	26	patients	with	cms	for	lmlbo	between	2013	and	2015	cms	group	with	those	of	33	patients	managed	with	tdt	between	2003	and	2011	tdt	group	by	the	historical	study	lmlbo	was	defined	as	a	large	bowel	obstruction	due	to	a	colorectal	cancer	that	was	diagnosed	by	computed	tomography	and	required	emergent	decompression	all	patients	in	the	cms	group	were	successfully	decompressed	p	0	03	and	could	initiate	oral	intake	after	the	procedure	p	0	01	outcomes	in	the	cms	group	were	superior	to	the	tdt	group	in	the	following	areas	duration	of	tube	placement	p	0	01	surgical	approach	p	0	01	operation	time	p	0	01	number	of	resected	lymph	nodes	p	0	001	and	rate	of	curative	resection	p	0	01	however	no	significant	differences	were	found	in	the	overall	postoperative	complication	rate	p	0	151	surgical	site	infection	rate	p	0	685	hospital	length	of	stay	p	0	502	and	the	need	for	permanent	ostomy	p	0	745	the	3	year	overall	survival	rate	of	patients	in	the	cms	and	tdt	groups	was	73	0	and	80	9	respectively	and	this	was	not	significant	p	0	423	treatment	with	cms	for	patients	with	lmlbo	as	a	bridge	to	surgery	is	safe	and	demonstrated	higher	rates	of	resumption	of	solid	food	intake	and	temporary	discharge	prior	to	elective	surgery	compared	to	tdt	oncological	outcomes	during	mid	term	were	equivalent</Paragraph></Rec>
<Rec><Paragraph>increased	copy	number	alterations	cnas	indicative	of	chromosomal	instability	cin	have	been	associated	with	poor	cancer	outcome	here	we	study	cnas	as	potential	biomarkers	of	bevacizumab	bvz	response	in	metastatic	colorectal	cancer	mcrc	we	cluster	409	mcrcs	in	three	subclusters	characterized	by	different	degrees	of	cin	tumors	belonging	to	intermediate	to	high	instability	clusters	have	improved	outcome	following	chemotherapy	plus	bvz	versus	chemotherapy	alone	in	contrast	low	instability	tumors	which	amongst	others	consist	of	pole	mutated	and	microsatellite	instable	tumors	derive	no	further	benefit	from	bvz	this	is	confirmed	in	81	mcrc	tumors	from	the	phase	2	moma	study	involving	bvz	cna	clusters	overlap	with	crc	consensus	molecular	subtypes	cms	cms2	4	xenografts	correspond	to	intermediate	to	high	instability	clusters	and	respond	to	folfox	chemotherapy	plus	mouse	avastin	b20	while	cms1	3	xenografts	match	with	low	instability	clusters	and	fail	to	respond	overall	we	identify	copy	number	load	as	a	novel	potential	predictive	biomarker	of	bvz	combination	therapy</Paragraph></Rec>
<Rec><Paragraph>human	cancers	can	be	classified	based	on	gene	signatures	quantifying	the	degree	of	cell	proliferation	and	tissue	remodelling	pr	however	the	specific	factors	that	drive	the	increased	tissue	remodelling	in	tumours	are	not	fully	understood	here	we	address	this	question	using	colorectal	cancer	as	a	case	study	we	reanalysed	a	reported	cohort	of	colorectal	cancer	patients	the	patients	were	stratified	based	on	gene	signatures	of	cell	proliferation	and	tissue	remodelling	putative	transcription	factors	activity	was	inferred	using	gene	expression	profiles	and	annotations	of	transcription	factor	targets	as	input	we	demonstrate	that	the	pr	classification	performs	better	than	the	currently	adopted	consensus	molecular	subtyping	cms	although	cms	classification	differentiates	patients	with	a	mesenchymal	signature	it	cannot	distinguish	the	remaining	patients	based	on	survival	we	demonstrate	that	the	missing	factor	is	cell	proliferation	which	is	indicative	of	good	prognosis	we	also	uncover	a	klf4	transcription	factor	activity	score	associated	with	the	tissue	remodelling	gene	signature	we	further	show	that	the	klf4	activity	score	is	significantly	higher	in	colorectal	tumours	with	predicted	infiltration	of	cells	from	the	myeloid	lineage	the	klf4	activity	score	is	associated	with	tissue	remodelling	myeloid	cell	infiltration	and	poor	prognosis	in	colorectal	cancer</Paragraph></Rec>
<Rec><Paragraph>cetuximab	ctx	is	a	monoclonal	antibody	targeting	the	epidermal	growth	factor	receptor	egfr	commonly	used	to	treat	patients	with	metastatic	colorectal	cancer	mcrc	unfortunately	objective	remissions	occur	only	in	a	minority	of	patients	and	are	of	short	duration	with	a	population	of	cells	surviving	the	treatment	and	eventually	enabling	ctx	resistance	our	previous	study	on	crc	xenopatients	associated	poor	response	to	ctx	with	increased	abundance	of	a	set	of	pro	inflammatory	cytokines	including	the	interleukins	il	1a	il	1b	and	il	8	stemming	from	these	observations	our	current	work	aimed	to	assess	the	role	of	il	1	pathway	activity	in	ctx	resistance	we	employed	a	recombinant	decoy	trap	il	1	a	soluble	protein	combining	the	human	immunoglobulin	fc	portion	linked	to	the	extracellular	region	of	the	il	1	receptor	il	1r1	able	to	sequester	il	1	directly	from	the	medium	we	generated	stable	clones	expressing	and	secreting	a	functional	trap	il	1	into	the	culture	medium	our	results	show	that	il	1r1	inhibition	leads	to	a	decreased	cell	proliferation	and	a	dampened	mapk	and	akt	axes	moreover	crc	patients	not	responding	to	ctx	blockage	displayed	higher	levels	of	il	1r1	than	responsive	subjects	and	abundant	il	1r1	is	predictive	of	survival	in	patient	datasets	specifically	for	the	consensus	molecular	subtype	1	cms1	we	conclude	that	il	1r1	abundance	may	represent	a	therapeutic	marker	for	patients	who	become	refractory	to	monoclonal	antibody	therapy	while	inhibition	of	il	1r1	by	trap	il	1	may	offer	a	novel	therapeutic	strategy</Paragraph></Rec>
<Rec><Paragraph>the	consensus	molecular	subtypes	cms	is	a	transcriptome	based	classification	of	colorectal	cancer	crc	initially	described	in	early	stage	cohorts	but	the	associations	of	cms	with	treatment	outcomes	in	the	metastatic	setting	are	yet	to	be	established	this	study	aimed	to	evaluate	the	prognostic	impact	of	cms	classification	and	its	predictive	effects	for	bevacizumab	benefit	in	metastatic	crc	by	correlative	analysis	of	the	agitg	max	trial	the	max	trial	previously	reported	improved	progression	free	survival	pfs	for	the	addition	of	bevacizumab	b	to	chemotherapy	capecitabine	c	mitomycin	m	archival	primary	tumours	from	237	patients	50	of	trial	population	underwent	gene	expression	profiling	and	classification	into	cms	groups	cms	groups	were	correlated	to	pfs	and	overall	survival	os	the	interaction	of	cms	with	treatment	was	assessed	by	proportional	hazards	model	the	distribution	of	cms	in	max	were	cms1	18	cms2	47	cms3	12	cms4	23	cms1	was	the	predominant	subtype	in	right	sided	primary	tumours	while	cms2	was	the	predominant	subtype	in	left	sided	cms	was	prognostic	of	os	p	0	008	with	cms2	associated	with	the	best	outcome	and	cms1	the	worst	cms	remained	an	independent	prognostic	factor	in	a	multivariate	analysis	there	was	a	significant	interaction	between	cms	and	treatment	p	interaction	0	03	for	pfs	with	hazard	ratios	95	ci	for	cb	cbm	versus	c	arms	in	cms1	2	3	and	4	0	83	0	43	1	62	0	50	0	33	0	76	0	31	0	13	0	75	and	1	24	0	68	2	25	respectively	this	exploratory	study	found	that	cms	stratified	os	outcomes	in	metastatic	crc	regardless	of	first	line	treatment	with	prognostic	effects	of	cms	groups	distinct	from	those	previously	reported	in	early	stage	cohorts	in	cms	associations	with	treatment	cms2	and	possibly	cms3	tumours	may	preferentially	benefit	from	the	addition	of	bevacizumab	to	first	line	capecitabine	based	chemotherapy	compared	with	other	cms	groups	validation	of	these	findings	in	additional	cohorts	is	warranted	this	is	a	molecular	sub	study	of	max	clinical	trial	nct00294359</Paragraph></Rec>
<Rec><Paragraph>spontaneous	tumors	in	pet	dogs	represent	a	valuable	but	undercharacterized	cancer	model	to	better	use	this	resource	we	performed	an	initial	global	comparison	between	proliferative	and	invasive	colorectal	tumors	from	20	canine	cases	and	evaluated	their	molecular	homology	to	human	colorectal	cancer	crc	first	proliferative	canine	tumors	harbor	overactivated	wnt	β	catenin	pathways	and	recurrent	ctnnb1	β	catenin	mutations	s45f	p	d32y	and	g34e	invasive	canine	tumors	harbor	prominent	fibroblast	proliferation	and	overactivated	stroma	both	groups	have	recurrent	tp53	mutations	we	observed	three	invasion	patterns	in	canine	tumors	collective	crypt	like	and	epithelial	mesenchymal	transition	emt	we	detected	enriched	helicobacter	bilis	and	alistipes	finegoldii	in	proliferative	and	crypt	like	tumors	but	depleted	mucosa	microbes	in	the	emt	tumor	second	guided	by	our	canine	findings	we	classified	79	of	478	human	colon	cancers	from	the	cancer	genome	atlas	into	four	subtypes	primarily	proliferative	or	with	collective	crypt	like	or	emt	invasion	features	their	molecular	characteristics	match	those	of	canine	tumors	we	showed	that	consensus	molecular	subtype	4	mesenchymal	of	human	crc	should	be	further	divided	into	emt	and	crypt	like	subtypes	which	differ	in	tgf	β	activation	and	mucosa	microbe	content	our	canine	tumors	share	the	same	pathogenic	pathway	as	human	crcs	dog	human	integration	identifies	three	crc	invasion	patterns	and	improves	crc	subtyping</Paragraph></Rec>
<Rec><Paragraph>the	mucinous	histologic	subtype	accounts	for	5	to	20	of	colorectal	cancer	crc	cases	but	remains	poorly	characterized	the	present	study	characterized	the	baseline	characteristics	mutational	profile	and	clinical	outcomes	of	patients	diagnosed	with	mucinous	crc	we	identified	1877	patients	with	metastatic	crc	with	available	histologic	findings	and	molecular	profiling	and	summarized	the	baseline	clinical	and	pathologic	characteristics	and	overall	survival	os	stratified	by	the	histologic	type	the	data	from	separate	cohorts	with	consensus	molecular	subtype	cms	and	cpg	island	methylator	information	were	also	summarized	the	mucinous	histologic	type	was	found	in	277	of	the	1877	patients	14	8	and	was	associated	with	an	increased	prevalence	of	microsatellite	instability	p	001	and	a	right	sided	primary	p	001	an	increased	frequency	of	cms1	microsatellite	instability	immune	and	lower	rates	of	cms2	canonical	were	identified	with	mucinous	compared	with	nonmucinous	adenocarcinoma	p	0001	mutations	in	smad4	p	001	gnas	p	001	erbb2	p	02	braf	p	001	and	kras	p	001	occurred	at	greater	frequencies	in	the	mucinous	crc	cases	and	tp53	p	001	apc	p	001	and	nras	mutations	p	03	were	less	common	univariate	hazard	ratio	hr	1	38	95	confidence	interval	ci	1	17	1	63	p	001	and	multivariate	analysis	hr	1	36	95	ci	1	12	1	64	p	002	demonstrated	that	the	mucinous	histologic	type	is	associated	with	worse	os	the	features	associated	with	the	mucinous	histologic	subtype	were	independent	predictors	for	shorter	os	including	braf	hr	1	74	95	ci	1	35	2	25	p	001	and	kras	hr	1	42	95	ci	1	22	1	65	p	001	mutations	right	sided	location	hr	1	20	95	ci	1	04	1	39	p	01	and	synchronous	metastases	hr	2	92	95	ci	2	49	3	42	p	001	compared	with	nonmucinous	adenocarcinoma	the	mucinous	histologic	type	is	associated	with	a	worse	prognosis	even	when	controlling	for	known	prognostic	features	this	unique	biologic	behavior	should	be	considered	in	the	treatment	and	prognostic	assessment	of	patients	with	crc</Paragraph></Rec>
<Rec><Paragraph>patient	derived	xenograft	pdx	models	have	become	an	important	asset	in	translational	cancer	research	however	to	provide	a	robust	preclinical	platform	pdxs	need	to	accommodate	the	tumor	heterogeneity	that	is	observed	in	patients	colorectal	cancer	crc	can	be	stratified	into	four	consensus	molecular	subtypes	cms	with	distinct	biological	and	clinical	features	surprisingly	using	a	set	of	crc	patients	we	revealed	the	partial	representation	of	tumor	heterogeneity	in	pdx	models	the	epithelial	subtypes	the	largest	subgroups	of	crc	subtype	were	very	ineffective	in	establishing	pdxs	indicating	the	need	for	further	optimization	to	develop	an	effective	personalized	therapeutic	approach	to	crc	moreover	we	showed	that	tumor	cell	proliferation	was	associated	with	successful	pdx	establishment	and	able	to	distinguish	patient	with	poor	clinical	outcomes	within	cms2	group</Paragraph></Rec>
<Rec><Paragraph>transcriptomic	profiling	of	colorectal	cancer	crc	has	led	to	identification	of	four	consensus	molecular	subtypes	cms1	4	which	have	prognostic	value	in	stage	ii	iii	disease	more	recently	the	colorectal	cancer	intrinsic	subtypes	cris	classification	system	has	helped	to	define	the	biology	specific	to	the	epithelial	component	of	colorectal	tumors	however	the	clinical	value	of	these	classifications	in	predicting	response	to	standard	of	care	adjuvant	chemotherapy	remains	unknown	using	samples	from	4	european	sites	we	assembled	a	novel	stage	ii	iii	crc	patient	cohort	and	performed	transcriptomic	profiling	on	156	samples	targeted	sequencing	and	generated	a	tissue	microarray	to	enable	integrated	multi	omics	analyses	we	also	accessed	data	from	2	published	stage	ii	iii	crc	patient	cohorts	gse39582	and	gse14333	479	and	185	samples	respectively	the	epithelial	rich	cms2	subtype	of	crc	benefitted	significantly	from	adjuvant	chemotherapy	treatment	in	both	stage	ii	and	iii	disease	p	0	02	and	p	0	0001	respectively	while	the	cms3	subtype	significantly	benefitted	in	stage	iii	only	p	0	00073	following	cris	sub	stratification	of	cms2	we	observed	that	only	the	cris	c	subtype	significantly	benefitted	from	adjuvant	chemotherapy	in	stage	ii	and	iii	disease	p	0	0081	and	p	0	0001	respectively	while	cris	d	significantly	benefitted	in	stage	iii	only	p	0	0034	we	also	observed	that	cris	c	patients	with	low	levels	of	cd8	tumor	infiltrating	lymphocytes	were	most	at	risk	of	relapse	in	both	stage	ii	and	iii	disease	p	0	0031	patient	stratification	using	a	combination	of	transcriptional	subtyping	and	cd8	immunohistochemistry	analyses	is	capable	of	identifying	poor	prognostic	stage	ii	iii	patients	who	benefit	from	adjuvant	standard	of	care	chemotherapy	these	findings	are	particularly	relevant	for	stage	ii	disease	where	the	overall	benefit	of	adjuvant	chemotherapy	is	marginal</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	heterogeneous	disease	entity	in	terms	of	both	molecular	carcinogenesis	and	morphologic	carcinogenesis	multistep	pathways	considerable	heterogeneity	exists	within	crc	due	to	the	varied	genetic	and	epigenetic	mechanisms	involved	in	different	carcinogenesis	pathways	a	better	understanding	of	pathophysiology	of	tumors	is	necessary	to	develop	modern	and	successful	means	of	treatment	in	metastatic	crc	over	the	last	5	years	there	has	been	a	surge	in	interest	in	the	molecular	classification	of	colorectal	cancer	as	its	clinical	importance	both	for	predicting	prognosis	and	in	guiding	personalized	treatment	had	been	acknowledged	recently	the	colorectal	cancer	subtyping	consortium	identified	four	consensus	molecular	subtypes	cms	1	4	in	crc	however	attempts	to	stratify	crc	using	molecular	features	for	prognostic	and	predictive	purposes	in	clinical	conditions	had	limited	success	in	this	review	we	focused	on	molecularly	defined	subtypes	of	crc	including	specific	mutations	and	discuss	implications	for	current	and	future	patient	management	in	metastatic	crc	to	achieve	the	maximal	therapeutic	response	for	each	patient	while	reducing	adverse	side	effects	of	therapy</Paragraph></Rec>
<Rec><Paragraph>annexin	a2	anxa2	is	upregulated	in	several	malignancies	including	colorectal	cancer	crc	however	there	is	little	knowledge	on	the	molecular	mechanisms	involved	to	its	upregulation	the	aim	of	this	study	was	to	identify	the	mechanism	through	which	anxa2	overexpression	leads	to	crc	progression	and	evaluate	its	potential	prognostic	value	we	used	human	crc	samples	to	analyse	the	correlation	between	anxa2	levels	and	tumour	staging	anxa2	expression	was	increased	in	crc	tissues	compared	to	normal	colon	tissues	in	addition	we	observe	increased	anxa2	levels	in	stage	iv	tumours	and	metastasis	when	compared	to	stage	i	iii	whereas	e	cadherin	an	epithelial	marker	decreased	in	stage	ii	iv	and	increased	in	metastasis	we	ve	also	shown	that	tgf	β	a	classic	emt	inductor	caused	upregulation	of	anxa2	and	internalization	of	both	e	cadherin	and	anxa2	in	crc	cells	anxa2	silencing	hindered	tgf	β	induced	invasiveness	and	inhibitors	of	the	src	anxa2	stat3	pathway	reversed	the	emt	in	silico	analysis	confirmed	overexpression	of	anxa2	and	association	to	the	consensus	moleculars	subtypes	cms	with	the	worst	prognosis	therefore	anxa2	overexpression	play	a	pivotal	role	in	crc	invasiveness	through	src	anxa2	stat3	pathway	activation	the	association	of	anxa2	to	distinct	cmss	suggests	the	possible	use	of	anxa2	as	a	prognostic	marker	or	directed	target	therapy</Paragraph></Rec>
<Rec><Paragraph>consensus	molecular	subtyping	is	an	rna	expression	based	classification	system	for	colorectal	cancer	crc	genomic	alterations	accumulate	during	crc	pathogenesis	including	the	premalignant	adenoma	stage	leading	to	changes	in	rna	expression	only	a	minority	of	adenomas	progress	to	malignancies	a	transition	that	is	associated	with	specific	dna	copy	number	aberrations	or	microsatellite	instability	msi	we	aimed	to	investigate	whether	colorectal	adenomas	can	already	be	stratified	into	consensus	molecular	subtype	cms	classes	and	whether	specific	cms	classes	are	related	to	the	presence	of	specific	dna	copy	number	aberrations	associated	with	progression	to	malignancy	rna	sequencing	was	performed	on	62	adenomas	and	59	crcs	msi	status	was	determined	with	polymerase	chain	reaction	based	methodology	dna	copy	number	was	assessed	by	low	coverage	dna	sequencing	n	30	or	array	comparative	genomic	hybridisation	n	32	adenomas	were	classified	into	cms	classes	together	with	crcs	from	the	study	cohort	and	from	the	cancer	genome	atlas	n	556	by	use	of	the	established	cms	classifier	as	a	result	54	of	62	87	adenomas	were	classified	according	to	the	cms	the	cms3	metabolic	subtype	which	was	least	common	among	crcs	was	most	prevalent	among	adenomas	n	45	73	one	of	the	two	adenomas	showing	msi	was	classified	as	cms1	2	the	msi	immune	subtype	eight	adenomas	13	were	classified	as	the	canonical	cms2	no	adenomas	were	classified	as	the	mesenchymal	cms4	consistent	with	the	fact	that	adenomas	lack	invasion	associated	stroma	the	distribution	of	the	cms	classes	among	adenomas	was	confirmed	in	an	independent	series	cms3	was	enriched	with	adenomas	at	low	risk	of	progressing	to	crc	whereas	relatively	more	high	risk	adenomas	were	observed	in	cms2	we	conclude	that	adenomas	can	be	stratified	into	the	cms	classes	considering	that	cms1	and	cms2	expression	signatures	may	mark	adenomas	at	increased	risk	of	progression	the	distribution	of	the	cms	classes	among	adenomas	is	consistent	with	the	proportion	of	adenomas	expected	to	progress	to	crc	2018	the	authors	the	journal	of	pathology	published	by	john	wiley	sons	ltd	on	behalf	of	pathological	society	of	great	britain	and	ireland</Paragraph></Rec>
<Rec><Paragraph>mismatch	repair	mmr	deficient	cancers	accumulate	multiple	insertion	deletion	mutations	at	coding	microsatellites	cms	which	give	rise	to	frameshift	peptide	neoantigens	the	high	mutational	neoantigen	load	of	mmr	deficient	cancers	is	reflected	by	pronounced	anti	tumoral	immune	responses	of	the	host	and	high	responsiveness	towards	immune	checkpoint	blockade	however	immune	evasion	mechanisms	can	interfere	with	the	immune	response	against	mmr	deficient	tumors	we	here	performed	a	comprehensive	analysis	of	immune	evasion	in	mmr	deficient	colorectal	cancers	focusing	on	hla	class	i	mediated	antigen	presentation	72	of	mmr	deficient	colorectal	cancers	of	the	dfci	database	harbored	alterations	affecting	genes	involved	in	hla	class	i	mediated	antigen	presentation	and	54	of	these	mutations	were	predicted	to	abrogate	function	mutations	affecting	the	hla	class	i	transactivator	nlrc5	were	observed	as	a	potential	new	immune	evasion	mechanism	in	26	6	abrogating	of	the	analyzed	tumors	nlrc5	mutations	in	mmr	deficient	cancers	were	associated	with	decreased	levels	of	hla	class	i	antigen	expression	in	summary	the	majority	of	mmr	deficient	cancers	display	mutations	interfering	with	hla	class	i	antigen	presentation	that	reflect	active	immune	surveillance	and	immunoselection	during	tumor	development	clinical	studies	focusing	on	immune	checkpoint	blockade	in	msi	cancer	should	account	for	the	broad	variety	of	immune	evasion	mechanisms	as	potential	biomarkers	of	therapy	success</Paragraph></Rec>
<Rec><Paragraph>to	reduce	colorectal	cancer	crc	screening	disparities	it	is	important	to	understand	correlates	of	different	types	of	cancer	worry	among	ethnically	diverse	individuals	the	current	study	examined	the	prevalence	of	three	types	of	cancer	worry	i	e	general	cancer	worry	crc	specific	worry	and	worry	about	crc	test	results	as	well	as	sociodemographic	and	health	related	predictors	for	each	type	of	cancer	worry	participants	were	aged	50	75	at	average	crc	risk	nonadherent	to	crc	screening	guidelines	and	enrolled	in	a	randomized	controlled	trial	to	increase	crc	screening	participants	completed	a	baseline	questionnaire	assessing	sociodemographics	health	beliefs	healthcare	experiences	and	three	cancer	worry	measures	associations	between	study	variables	were	examined	with	separate	univariate	and	multivariable	logistic	regression	models	responses	from	a	total	of	416	participants	were	used	of	these	47	reported	experiencing	moderate	to	high	levels	of	general	cancer	worry	predictors	of	general	cancer	worry	were	salience	and	coherence	aor	1	1	95	ci	1	0	1	3	perceived	susceptibility	aor	1	2	95	ci	1	1	1	3	and	social	influence	aor	1	1	95	ci	1	0	0	1	fewer	23	reported	moderate	to	high	levels	of	crc	specific	worry	or	crc	test	worry	35	predictors	of	crc	worry	were	perceived	susceptibility	aor	1	4	95	ci	1	3	1	6	and	social	influence	aor	1	1	95	ci	1	0	1	2	predictors	of	crc	test	result	worry	were	perceived	susceptibility	aor	1	2	95	ci	1	1	1	3	and	marital	status	aor	2	0	95	ci	1	1	3	7	for	married	partnered	vs	single	and	aor	2	3	95	ci	1	3	4	1	for	divorced	widowed	vs	single	perceived	susceptibility	consistently	predicted	the	three	types	of	cancer	worry	whereas	other	predictors	varied	between	cancer	worry	types	and	in	magnitude	of	association	the	three	types	of	cancer	worry	were	generally	predicted	by	health	beliefs	suggesting	potential	malleability	future	research	should	include	multiple	measures	of	cancer	worry	and	clear	definitions	of	how	cancer	worry	is	measured</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	one	of	the	leading	causes	of	cancer	related	deaths	worldwide	similar	to	many	other	malignancies	crc	is	a	heterogeneous	disease	making	it	a	clinical	challenge	for	optimization	of	treatment	modalities	in	reducing	the	morbidity	and	mortality	associated	with	this	disease	a	more	precise	understanding	of	the	biological	properties	that	distinguish	patients	with	colorectal	tumors	especially	in	terms	of	their	clinical	features	is	a	key	requirement	towards	a	more	robust	targeted	drug	design	and	implementation	of	individualized	therapies	in	the	recent	decades	extensive	studies	have	reported	distinct	crc	subtypes	with	a	mutation	centered	view	of	tumor	heterogeneity	however	more	recently	the	paradigm	has	shifted	towards	transcriptome	based	classifications	represented	by	six	independent	crc	taxonomies	in	2015	the	colorectal	cancer	subtyping	consortium	reported	the	identification	of	four	consensus	molecular	subtypes	cmss	providing	thus	far	the	most	robust	classification	system	for	crc	in	this	review	we	summarize	the	historical	timeline	of	crc	classification	approaches	discuss	their	salient	features	and	potential	limitations	that	may	require	further	refinement	in	near	future	in	other	words	in	spite	of	the	recent	encouraging	progress	several	major	challenges	prevent	translation	of	molecular	knowledge	gleaned	from	cmss	into	the	clinic	herein	we	summarize	some	of	these	potential	challenges	and	discuss	exciting	new	opportunities	currently	emerging	in	related	fields	we	believe	close	collaborations	between	basic	researchers	bioinformaticians	and	clinicians	are	imperative	for	addressing	these	challenges	and	eventually	paving	the	path	for	crc	subtyping	into	routine	clinical	practice	as	we	usher	into	the	era	of	personalized	medicine</Paragraph></Rec>
<Rec><Paragraph>the	consensus	molecular	subtypes	cms	classification	is	one	of	the	most	robust	colorectal	cancer	crc	classifications	based	on	comprehensive	gene	expression	profiles	this	study	aimed	to	clarify	whether	the	cms	is	a	predictive	factor	for	therapeutic	effects	of	standard	chemotherapies	for	metastatic	crc	mcrc	we	retrospectively	enrolled	193	patients	with	mcrcs	and	using	comprehensive	gene	expression	data	classified	them	into	4	subtypes	cms1	cms4	the	associations	between	the	subtypes	and	treatment	outcomes	were	analyzed	regarding	first	line	chemotherapy	irinotecan	iri	based	chemotherapy	was	significantly	superior	to	oxaliplatin	ox	based	chemotherapy	for	progression	free	survival	pfs	hazard	ratio	hr	0	31	95	confidence	interval	ci	0	13	0	64	and	overall	survival	os	hr	0	45	95	ci	0	19	0	99	in	cms4	regarding	the	anti	epidermal	growth	factor	receptor	anti	egfr	therapy	cms1	showed	particularly	worse	pfs	hr	2	50	95	ci	1	31	4	39	and	os	hr	4	23	95	ci	1	83	9	04	and	cms2	showed	particularly	good	pfs	hr	0	67	95	ci	0	44	1	01	and	os	hr	0	49	95	ci	0	27	0	87	compared	with	the	other	subtypes	the	biological	characteristics	of	cms	may	influence	the	efficacy	of	chemotherapy	cms	might	be	a	new	predictive	factor	for	the	efficacy	of	chemotherapy	against	mcrcs</Paragraph></Rec>
<Rec><Paragraph>despite	growing	therapeutic	relevance	of	erbb2	amplifications	in	colorectal	cancer	crc	little	is	known	about	erbb2	erbb3	mutations	we	aimed	to	characterize	these	subsets	of	crc	we	performed	a	retrospective	analysis	of	419	crc	patients	from	md	anderson	mdacc	and	619	patients	from	the	nurses	health	study	nhs	health	professionals	follow	up	study	hpfs	with	tissue	sequencing	clinicopathologic	mutational	and	consensus	molecular	subtype	cms	profiles	of	erbb2	erbb3	mutant	patients	a	third	cohort	of	1623	crc	patients	with	ctdna	assays	characterized	the	ctdna	profile	of	erbb2	mutants	all	statistical	tests	were	two	sided	erbb2	mutations	occurred	in	4	1	95	confidence	interval	ci	2	4	to	6	4	5	8	95	ci	4	1	to	8	0	and	5	1	95	ci	4	0	to	6	2	of	mdacc	nhs	hpfs	and	ctdna	patients	respectively	erbb3	mutations	occurred	in	5	7	95	ci	3	7	to	8	4	95	ci	4	0	to	7	8	of	patients	in	both	tissue	cohorts	age	stage	and	tumor	location	were	not	associated	with	either	mutation	microsatellite	instability	msi	was	associated	with	erbb2	odds	ratio	or	5	98	95	ci	2	47	to	14	49	p	001	or	5	13	95	ci	2	38	to	11	05	p	001	and	erbb3	mutations	or	3	48	95	ci	1	51	to	8	02	p	002	or	3	40	95	ci	1	05	to	10	96	p	03	in	both	tissue	cohorts	neither	gene	was	associated	with	tp53	apc	kras	nras	or	braf	mutations	in	tissue	however	pik3ca	mutations	were	strongly	associated	with	erbb2	mutations	in	all	three	cohorts	or	3	68	95	ci	1	83	to	7	41	p	001	or	2	25	95	ci	1	11	to	4	58	p	02	or	2	11	95	ci	1	25	to	3	58	p	004	and	erbb3	mutations	in	the	mdacc	cohort	or	13	26	95	ci	5	27	to	33	33	p	001	erbb2	p	0	08	and	erbb3	p	008	mutations	were	associated	with	cms1	subtype	erbb2	hazard	ratio	hr	1	82	95	ci	1	23	to	4	03	p	009	but	not	erbb3	hr	0	88	95	ci	0	45	to	1	73	p	73	mutations	were	associated	with	worse	overall	survival	msi	and	pik3ca	mutations	are	associated	with	erbb2	erbb3	mutations	co	occurring	pik3ca	mutations	may	represent	a	second	hit	to	oncogenic	signaling	that	needs	consideration	when	targeting	erbb2	erbb3</Paragraph></Rec>
<Rec><Paragraph>novel	immune	therapeutic	tools	are	rapidly	expanding	the	anticancer	arsenal	despite	this	progress	patients	with	colorectal	cancer	crc	that	spreads	to	vital	parts	of	the	body	still	have	a	dismal	outcome	transforming	growth	factor	β	tgf	β	plays	a	pivotal	role	in	the	development	of	crc	and	metastasis	important	new	work	by	tauriello	and	colleagues	has	revealed	that	inhibition	of	tgf	β	prevents	tumor	metastasis	by	enhancing	a	cytotoxic	t	cell	response	suggesting	that	tgf	β	inhibition	is	a	promising	pro	immunogenic	therapy</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	heterogeneous	disease	which	can	be	categorized	into	distinct	consensus	molecular	subtypes	cmss	these	subtypes	differ	in	both	clinical	as	well	as	biological	properties	the	gold	standard	classification	strategy	relies	on	genome	wide	expression	data	which	hampers	widespread	implementation	here	we	describe	an	immunohistochemical	ihc	mini	classifier	a	practical	tool	that	in	combination	with	microsatellite	instability	testing	delivers	objective	and	accurate	scoring	to	classify	crc	patients	into	the	main	molecular	disease	subtypes	it	is	a	robust	immunohistochemical	based	assay	containing	four	specific	stainings	frmd6	zeb1	htr2b	and	cdx2	in	combination	with	cytokeratin	we	also	describe	an	online	tool	for	classification	of	individual	samples	based	on	scoring	parameters	of	these	stainings</Paragraph></Rec>
<Rec><Paragraph>the	prognostic	impact	of	kras	and	brafv600e	mutations	in	primary	colorectal	cancer	crc	varies	with	microsatellite	instability	msi	status	the	gene	expression	based	consensus	molecular	subtypes	cmss	of	crc	define	molecularly	and	clinically	distinct	subgroups	and	represent	a	novel	stratification	framework	in	biomarker	analysis	we	investigated	the	prognostic	value	of	these	mutations	within	the	cms	groups	totally	1197	primary	tumors	from	a	norwegian	series	of	crc	stage	i	iv	were	analyzed	for	msi	and	mutation	status	in	hotspots	in	kras	codons	12	13	and	61	and	braf	codon	600	a	subset	was	analyzed	for	gene	expression	and	confident	cms	classification	was	obtained	for	317	samples	this	cohort	was	expanded	with	clinical	and	molecular	data	including	cms	classification	from	514	patients	in	the	publically	available	dataset	gse39582	gene	expression	signatures	associated	with	kras	and	brafv600e	mutations	were	used	to	evaluate	differential	impact	of	mutations	on	gene	expression	among	the	cms	groups	brafv600e	and	kras	mutations	were	both	associated	with	inferior	5	year	overall	survival	os	exclusively	in	mss	tumors	brafv600e	mutation	versus	kras	braf	wild	type	hazard	ratio	hr	2	85	p	0	001	kras	mutation	versus	kras	braf	wild	type	hr	1	30	p	0	013	brafv600e	mutated	mss	tumors	were	strongly	enriched	and	associated	with	metastatic	disease	in	cms1	leading	to	negative	prognostic	impact	in	this	subtype	os	brafv600e	mutation	versus	wild	type	hr	7	73	p	0	001	in	contrast	the	poor	prognosis	of	kras	mutations	was	limited	to	mss	tumors	with	cms2	cms3	epithelial	like	gene	expression	profiles	os	kras	mutation	versus	wild	type	hr	1	51	p	0	011	the	subtype	specific	prognostic	associations	were	substantiated	by	differential	effects	of	brafv600e	and	kras	mutations	on	gene	expression	signatures	according	to	the	msi	status	and	cms	group	brafv600e	mutations	are	enriched	and	associated	with	metastatic	disease	in	cms1	mss	tumors	leading	to	poor	prognosis	in	this	subtype	kras	mutations	are	associated	with	adverse	outcome	in	epithelial	cms2	cms3	mss	tumors</Paragraph></Rec>
<Rec><Paragraph>metformin	hydrochloride	mf	repurposing	as	adjuvant	anticancer	therapy	for	colorectal	cancer	crc	proved	effective	several	studies	attempted	to	develop	mf	loaded	nanoparticles	nps	however	the	entrapment	efficiency	ee	was	poor	thus	the	present	study	aimed	at	the	facile	development	of	a	new	series	of	chitosan	cs	based	semi	interpenetrating	network	semi	ipn	nps	incorporating	pluronic	nanomicelles	as	nanocarriers	for	enhanced	entrapment	and	sustained	release	of	mf	for	efficient	treatment	of	crc	the	nps	were	prepared	by	ionic	gelation	and	subsequently	characterized	using	ftir	dsc	tem	and	dls	a	full	factorial	design	was	also	adopted	to	study	the	effect	of	various	formulation	variables	on	ee	particle	size	and	zeta	potential	of	nps	nps	had	a	spherical	shape	and	a	mean	particle	size	ranging	between	135	and	220	nm	ftir	and	dsc	studies	results	were	indicative	of	successful	ionic	gelation	with	the	drug	being	dispersed	in	its	amorphous	form	within	cs	pluronic	matrix	maximum	ee	reaching	57	00	12	90	was	achieved	using	pluronic	123	based	nps	nps	exhibited	a	sustained	release	profile	over	48	h	the	mf	loaded	nps	sensitized	rko	crc	cells	relative	to	drug	alone	the	reported	results	highlighted	the	novel	utility	of	the	developed	nps	in	the	arena	of	colon	cancer	treatment</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	biopsies	underpin	accurate	diagnosis	but	are	also	relevant	for	patient	stratification	in	molecularly	guided	clinical	trials	the	consensus	molecular	subtypes	cmss	and	colorectal	cancer	intrinsic	subtypes	criss	transcriptional	signatures	have	potential	clinical	utility	for	improving	prognostic	predictive	patient	assignment	however	their	ability	to	provide	robust	classification	particularly	in	pretreatment	biopsies	from	multiple	regions	or	at	different	time	points	remains	untested	in	this	study	we	undertook	a	comprehensive	assessment	of	the	robustness	of	crc	transcriptional	signatures	including	cris	and	cms	using	a	range	of	tumour	sampling	methodologies	currently	employed	in	clinical	and	translational	research	these	include	analyses	using	i	laser	capture	microdissected	crc	tissue	ii	eight	publically	available	rectal	cancer	biopsy	data	sets	n	543	iii	serial	biopsies	from	axebeam	trial	nct00828672	n	10	iv	multi	regional	biopsies	from	colon	tumours	n	29	biopsies	n	7	tumours	and	v	pretreatment	biopsies	from	the	phase	ii	rectal	cancer	trial	coperncius	nct01263171	n	44	compared	to	previous	results	obtained	using	crc	resection	material	we	demonstrate	that	cms	classification	in	biopsy	tissue	is	significantly	less	capable	of	reliably	classifying	patient	subtype	43	unknown	in	biopsy	versus	13	unknown	in	resections	p	0	0001	in	contrast	there	was	no	significant	difference	in	classification	rate	between	biopsies	and	resections	when	using	the	cris	classifier	additionally	we	demonstrated	that	cris	provides	significantly	better	spatially	and	temporally	robust	classification	of	molecular	subtypes	in	crc	primary	tumour	tissue	compared	to	cms	p	0	003	and	p	0	02	respectively	these	findings	have	potential	to	inform	ongoing	biopsy	based	patient	stratification	in	crc	enabling	robust	and	stable	assignment	of	patients	into	clinically	informative	arms	of	prospective	multi	arm	multi	stage	clinical	trials	2018	the	authors	the	journal	of	pathology	published	by	john	wiley	sons	ltd	on	behalf	of	pathological	society	of	great	britain	and	ireland</Paragraph></Rec>
<Rec><Paragraph>tumour	infiltrating	lymphocyte	til	response	and	deficient	dna	mismatch	repair	dmmr	are	determinants	of	prognosis	in	colorectal	cancer	although	highly	correlated	evidence	suggests	that	these	are	independent	predictors	of	outcome	however	the	prognostic	significance	of	combined	til	mmr	classification	and	how	this	compares	to	the	major	genomic	and	transcriptomic	subtypes	remain	unclear	a	prospective	cohort	of	1265	patients	with	stage	ii	iii	cancer	was	examined	for	til	mmr	status	and	braf	kras	mutations	consensus	molecular	subtype	cms	status	was	determined	for	142	cases	associations	with	5	year	disease	free	survival	dfs	were	evaluated	and	validated	in	an	independent	cohort	of	602	patients	tumours	were	categorised	into	four	subtypes	based	on	til	and	mmr	status	til	low	proficient	mmr	pmmr	61	3	of	cases	til	high	pmmr	14	8	til	low	dmmr	8	6	and	til	high	dmmr	15	2	compared	with	til	high	dmmr	tumours	with	the	most	favourable	prognosis	both	til	low	dmmr	hr	3	53	95	ci	1	88	to	6	64	pmultivariate	0	001	and	til	low	pmmr	tumours	hr	2	67	95	ci	1	47	to	4	84	pmultivariate	0	001	showed	poor	dfs	outcomes	of	patients	with	til	low	dmmr	and	til	low	pmmr	tumours	were	similar	til	high	pmmr	tumours	showed	intermediate	survival	rates	these	findings	were	validated	in	an	independent	cohort	til	mmr	status	was	a	more	significant	predictor	of	prognosis	than	national	comprehensive	cancer	network	high	risk	features	and	was	a	superior	predictor	of	prognosis	compared	with	genomic	dmmr	pmmr	braf	wt	kras	wt	pmmr	braf	mut	kras	wt	pmmr	braf	wt	kras	mut	and	transcriptomic	cms	1	4	subtypes	til	mmr	classification	identified	subtypes	of	stage	ii	iii	colorectal	cancer	associated	with	different	outcomes	although	dmmr	status	is	generally	considered	a	marker	of	good	prognosis	we	found	this	to	be	dependent	on	the	presence	of	tils	prognostication	based	on	til	mmr	subtypes	was	superior	compared	with	histopathological	genomic	and	transcriptomic	subtypes</Paragraph></Rec>
<Rec><Paragraph>patients	with	colorectal	peritoneal	carcinomatosis	have	a	very	poor	prognosis	the	recently	developed	consensus	molecular	subtype	cms	classification	of	primary	colorectal	cancer	categorizes	tumours	into	four	robust	subtypes	which	could	guide	subtype	targeted	therapy	cms4	also	known	as	the	mesenchymal	subtype	has	the	greatest	propensity	to	form	distant	metastases	cms4	status	and	histopathological	features	of	colorectal	peritoneal	carcinomatosis	were	investigated	in	this	study	fresh	frozen	tissue	samples	from	primary	colorectal	cancer	and	paired	peritoneal	metastases	from	patients	who	underwent	cytoreductive	surgery	combined	with	hyperthermic	intraperitoneal	chemotherapy	were	collected	histopathological	features	were	analysed	and	a	reverse	transcriptase	quantitative	pcr	test	was	used	to	assess	cms4	status	of	all	collected	lesions	colorectal	peritoneal	carcinomatosis	was	associated	with	adverse	histopathological	characteristics	including	a	high	percentage	of	stroma	in	both	primary	tumours	and	metastases	and	poor	differentiation	grade	and	high	grade	tumour	budding	in	primary	tumours	furthermore	cms4	was	significantly	enriched	in	primary	tumours	with	peritoneal	metastases	compared	with	unselected	stage	i	iv	tumours	60	per	cent	12	of	20	versus	23	per	cent	p	0	002	the	majority	of	peritoneal	metastases	75	per	cent	21	of	28	were	also	classified	as	cms4	considerable	intrapatient	subtype	heterogeneity	was	observed	notably	15	of	16	patients	with	paired	tumours	had	at	least	one	cms4	positive	tumour	location	significant	enrichment	for	cms4	was	observed	in	colorectal	peritoneal	carcinomatosis	surgical	relevance	cytoreductive	surgery	combined	with	hyperthermic	intraperitoneal	chemotherapy	crs	hipec	improves	survival	of	selected	patients	with	colorectal	peritoneal	carcinomatosis	but	recurrence	is	common	histopathological	and	molecular	analysis	of	colorectal	peritoneal	carcinomatosis	could	provide	clues	for	development	of	novel	therapies	in	this	study	colorectal	peritoneal	carcinomatosis	was	found	to	be	enriched	for	tumours	with	high	stromal	content	and	cms4	positive	status	to	further	improve	prognosis	for	patients	with	colorectal	peritoneal	carcinomatosis	therapies	that	target	tumour	stroma	interaction	could	be	added	to	crs	hipec</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	highly	heterogeneous	disease	both	from	a	molecular	and	clinical	perspective	several	distinct	molecular	entities	such	as	microsatellite	instability	msi	have	been	defined	that	make	up	biologically	distinct	subgroups	with	their	own	clinical	course	recent	data	indicated	that	crc	can	be	best	segregated	into	four	groups	called	consensus	molecular	subtypes	cms1	4	each	of	which	has	a	unique	biology	and	gene	expression	pattern	in	order	to	develop	improved	subtype	specific	therapies	and	to	gain	insight	into	the	molecular	wiring	and	origin	of	these	subtypes	reliable	models	are	needed	this	study	was	designed	to	determine	the	heterogeneity	and	identify	the	presence	of	cmss	in	a	large	panel	of	crc	cell	lines	primary	cultures	and	patient	derived	xenografts	pdx	we	provide	a	repository	encompassing	this	heterogeneity	and	moreover	describe	that	a	large	part	of	the	models	can	be	robustly	assigned	to	one	of	the	four	cmss	independent	of	the	stromal	contribution	we	subsequently	validate	our	cms	stratification	by	functional	analysis	which	for	instance	shows	mesenchymal	enrichment	in	cms4	and	metabolic	dysregulation	in	cms3	finally	we	observe	a	clear	difference	in	sensitivity	to	chemotherapy	induced	apoptosis	specifically	between	cms2	and	cms4	this	relates	to	the	in	vivo	efficacy	of	chemotherapy	which	delays	outgrowth	of	cms2	but	not	cms4	xenografts	combined	our	data	indicate	that	molecular	subtypes	are	faithfully	modelled	in	crc	cell	cultures	and	pdxs	representing	tumour	cell	intrinsic	and	stable	features	this	repository	provides	researchers	with	a	platform	to	study	crc	using	the	existing	heterogeneity</Paragraph></Rec>
<Rec><Paragraph>recent	large	scale	expression	based	subtyping	has	advanced	our	understanding	of	the	genomic	landscape	of	colorectal	cancer	crc	and	resulted	in	a	consensus	molecular	classification	that	enables	the	categorization	of	most	crc	tumors	into	one	of	four	consensus	molecular	subtypes	cms	currently	major	progress	in	characterization	of	immune	landscape	of	tumor	associated	microenvironment	has	been	made	especially	with	respect	to	microsatellite	status	of	crcs	while	these	studies	profoundly	improved	the	understanding	of	molecular	and	immunological	profile	of	crcs	heterogeneity	less	is	known	about	repertoire	of	the	tumor	infiltrating	immune	cells	of	each	cms	in	order	to	comprehensively	characterize	the	immune	landscape	of	crc	we	re	analyzed	a	total	of	15	crc	genome	wide	expression	data	sets	encompassing	1597	tumors	and	125	normal	adjacent	colon	tissues	after	quality	filtering	crc	clusters	were	discovered	using	a	combination	of	multiple	clustering	algorithms	and	multiple	validity	metrics	cibersort	algorithm	was	used	to	compute	relative	proportions	of	22	human	leukocyte	subpopulations	across	crc	clusters	and	normal	colon	tissue	subsequently	differential	expression	specific	to	tumor	epithelial	cells	was	calculated	to	characterize	mechanisms	of	tumor	escape	from	immune	surveillance	occurring	in	particular	crc	clusters	our	results	not	only	characterize	the	common	and	cluster	specific	influx	of	immune	cells	into	crcs	but	also	identify	several	deregulated	gene	targets	that	may	contribute	to	improvement	of	immunotherapeutic	strategies	in	crc</Paragraph></Rec>
<Rec><Paragraph>we	have	previously	identified	the	long	non	coding	rna	linc01021	as	a	direct	p53	target	hünten	et	al	mol	cell	proteomics	2015	14	2609	2629	here	we	show	that	linc01021	is	up	regulated	in	colorectal	cancer	crc	cell	lines	upon	various	p53	activating	treatments	the	linc01021	promoter	and	the	p53	binding	site	lie	within	a	mer61c	ltr	which	originated	from	insertion	of	endogenous	retrovirus	1	erv1	sequences	deletion	of	this	mer61c	element	by	a	crispr	cas9	approach	as	well	as	sirna	mediated	knockdown	of	linc01021	rna	significantly	enhanced	the	sensitivity	of	the	crc	cell	line	hct116	towards	the	chemotherapeutic	drugs	doxorubicin	and	5	fu	suggesting	that	linc01021	is	an	integral	part	of	the	p53	mediated	response	to	dna	damage	inactivation	of	linc01021	and	also	its	ectopic	expression	did	not	affect	p53	protein	expression	and	transcriptional	activity	implying	that	linc01021	does	not	feedback	to	p53	furthermore	in	crc	patient	samples	linc01021	expression	positively	correlated	with	a	wild	type	p53	associated	gene	expression	signature	linc01021	expression	was	increased	in	primary	colorectal	tumors	and	displayed	a	bimodal	distribution	that	was	particularly	pronounced	in	the	mesenchymal	cms4	consensus	molecular	subtype	of	crcs	cms4	tumors	with	low	linc01021	expression	were	associated	with	poor	patient	survival	our	results	suggest	that	the	genomic	redistribution	of	erv1	derived	p53	response	elements	and	generation	of	novel	p53	inducible	lncrna	encoding	genes	was	selected	for	during	primate	evolution	as	integral	part	of	the	cellular	response	to	various	forms	of	genotoxic	stress</Paragraph></Rec>
<Rec><Paragraph>purpose	response	to	standard	oncologic	treatment	is	limited	in	colorectal	cancer	the	gene	expression	based	consensus	molecular	subtypes	cms	provide	a	new	paradigm	for	stratified	treatment	and	drug	repurposing	however	drug	discovery	is	currently	limited	by	the	lack	of	translation	of	cms	to	preclinical	models	experimental	design	we	analyzed	cms	in	primary	colorectal	cancers	cell	lines	and	patient	derived	xenografts	pdx	for	classification	of	preclinical	models	we	developed	an	optimized	classifier	enriched	for	cancer	cell	intrinsic	gene	expression	signals	and	performed	high	throughput	in	vitro	drug	screening	n	459	drugs	to	analyze	subtype	specific	drug	sensitivities	results	the	distinct	molecular	and	clinicopathologic	characteristics	of	each	cms	group	were	validated	in	a	single	hospital	series	of	409	primary	colorectal	cancers	the	new	cancer	cell	adapted	classifier	was	found	to	perform	well	in	primary	tumors	and	applied	to	a	panel	of	148	cell	lines	and	32	pdxs	these	colorectal	cancer	models	were	shown	to	recapitulate	the	biology	of	the	cms	groups	drug	screening	of	33	cell	lines	demonstrated	subtype	dependent	response	profiles	confirming	strong	response	to	egfr	and	her2	inhibitors	in	the	cms2	epithelial	canonical	group	and	revealing	strong	sensitivity	to	hsp90	inhibitors	in	cells	with	the	cms1	microsatellite	instability	immune	and	cms4	mesenchymal	phenotypes	this	association	was	validated	in	vitro	in	additional	cms	predicted	cell	lines	combination	treatment	with	5	fluorouracil	and	luminespib	showed	potential	to	alleviate	chemoresistance	in	a	cms4	pdx	model	an	effect	not	seen	in	a	chemosensitive	cms2	pdx	model	conclusions	we	provide	translation	of	cms	classification	to	preclinical	models	and	uncover	a	potential	for	targeted	treatment	repurposing	in	the	chemoresistant	cms4	group	clin	cancer	res	24	4	794	806	2017	aacr</Paragraph></Rec>
<Rec><Paragraph>we	tested	the	association	of	colon	tumour	sidedness	with	prognosis	and	with	molecular	subtypes	recently	shown	to	be	predictive	of	oxaliplatin	benefit	in	stage	iii	colon	cancer	nsabp	nrg	c	07	trial	n	1603	was	used	to	determine	association	of	tumour	sidedness	with	molecular	subtypes	and	recurrence	free	survival	rfs	and	overall	survival	os	sidedness	was	associated	with	molecular	subtypes	except	stem	like	cms4	subtype	patients	with	stage	iii	left	sided	tumours	showed	superior	os	but	not	rfs	sidedness	was	not	associated	with	prediction	of	oxaliplatin	benefit	when	combined	with	5	fu	lv	however	greater	benefit	from	oxaliplatin	was	observed	in	a	small	subset	of	stage	iii	patients	with	left	sided	enterocyte	subtype	tumours	interaction	hr	0	17	p	0	01	sidedness	was	associated	with	molecular	subtypes	and	was	predictive	of	os	in	stage	iii	colon	cancer	but	was	not	predictive	of	rfs	or	oxaliplatin	benefit	in	c	07	molecular	subtypes	may	provide	more	predictive	value	for	oxaliplatin	benefit	than	tumour	sidedness</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancers	crcs	can	be	divided	into	four	gene	expression	based	biologically	distinct	consensus	molecular	subtypes	cms	this	classification	provides	a	potential	framework	for	stratified	treatment	but	to	identify	novel	cms	drug	associations	translation	of	the	subtypes	to	pre	clinical	models	is	essential	the	currently	available	classifier	is	dependent	on	gene	expression	signals	from	the	immune	and	stromal	compartments	of	tumors	and	fails	to	identify	the	poor	prognostic	cms4	mesenchymal	group	in	immortalized	cell	lines	patient	derived	organoids	and	xenografts	to	address	this	we	present	a	novel	cms	classifier	based	on	a	filtered	set	of	cancer	cell	intrinsic	subtype	enriched	gene	expression	markers	this	new	classifier	referred	to	as	cmscaller	recapitulated	the	subtypes	in	both	in	vitro	and	in	vivo	models	551	in	total	importantly	by	analyzing	public	drug	response	data	from	patient	derived	xenografts	and	cell	lines	we	show	that	the	subtypes	are	predictive	of	response	to	standard	crc	drugs	cmscaller	is	available	as	an	r	package</Paragraph></Rec>
<Rec><Paragraph>purpose	colorectal	cancers	are	classified	as	right	left	sided	based	on	whether	they	occur	before	after	the	splenic	flexure	with	established	differences	in	molecular	subtypes	and	outcomes	however	it	is	unclear	if	this	division	is	optimal	and	whether	precise	tumor	location	provides	further	information	experimental	design	in	1	876	patients	with	colorectal	cancer	we	compared	mutation	prevalence	and	overall	survival	os	according	to	side	and	location	consensus	molecular	subtype	cms	was	compared	in	a	separate	cohort	of	608	patients	results	mutation	prevalence	differed	by	side	and	location	for	tp53	kras	brafv600	pik3ca	smad4	ctnnb1	gnas	and	pten	within	left	and	right	sided	tumors	there	remained	substantial	variations	in	mutation	rates	for	example	within	right	sided	tumors	ras	mutations	decreased	from	70	for	cecal	to	43	for	hepatic	flexure	location	p	0	0001	while	brafv600	mutations	increased	from	10	to	22	between	the	same	locations	p	0	0001	within	left	sided	tumors	the	sigmoid	and	rectal	region	had	more	tp53	mutations	p	0	027	less	pik3ca	p	0	0009	braf	p	0	0033	or	ctnnb1	mutations	p	0	0001	and	less	msi	p	0	0001	than	other	left	sided	locations	despite	this	a	left	right	division	preceding	the	transverse	colon	maximized	prognostic	differences	by	side	and	transverse	colon	tumors	had	k	modes	mutation	clustering	that	appeared	more	left	than	right	sided	cms	profiles	showed	a	decline	in	cms1	and	cms3	and	rise	in	cms2	prevalence	moving	distally	conclusions	current	right	left	classifications	may	not	fully	recapitulate	regional	variations	in	tumor	biology	specifically	the	sigmoid	rectal	region	appears	unique	and	the	transverse	colon	is	distinct	from	other	right	sided	locations	clin	cancer	res	24	5	1062	72	2017	aacrsee	related	commentary	by	dienstmann	p	989</Paragraph></Rec>
<Rec><Paragraph>surgical	removal	of	colorectal	cancer	crc	liver	metastases	generates	areas	of	tissue	hypoxia	hypoxia	imposes	a	stem	like	phenotype	on	residual	tumor	cells	and	promotes	tumor	recurrence	moreover	in	primary	crc	gene	expression	signatures	reflecting	hypoxia	and	a	stem	like	phenotype	are	highly	expressed	in	the	aggressive	consensus	molecular	subtype	4	cms4	therapeutic	strategies	eliminating	hypoxic	stem	like	cells	may	limit	recurrence	following	resection	of	primary	tumors	or	metastases	here	we	show	that	expression	of	dna	repair	genes	is	strongly	suppressed	in	cms4	and	inversely	correlated	with	hypoxia	inducible	factor	1	alpha	hif1α	and	hif	2α	co	expression	signatures	tumors	with	high	expression	of	hif	signatures	and	low	expression	of	repair	proteins	showed	the	worst	survival	in	human	tumors	expression	of	the	repair	proteins	rad51	ku70	and	rif1	was	strongly	suppressed	in	hypoxic	peri	necrotic	tumor	areas	experimentally	induced	hypoxia	in	patient	derived	colonospheres	in	vitro	or	in	vivo	through	vascular	clamping	was	sufficient	to	downregulate	repair	protein	expression	and	caused	dna	damage	hypoxia	induced	dna	damage	was	prevented	by	expressing	the	hydroperoxide	scavenging	enzyme	glutathione	peroxidase	2	gpx2	indicating	that	reactive	oxygen	species	mediate	hypoxia	induced	dna	damage	finally	the	hypoxia	activated	prodrug	tirapazamine	greatly	augmented	dna	damage	and	reduced	the	fraction	of	stem	like	aldefluor	bright	tumor	cells	in	vitro	and	in	vivo	following	vascular	clamping	we	conclude	that	decreased	expression	of	dna	repair	proteins	and	increased	dna	damage	in	hypoxic	tumor	areas	may	be	therapeutically	exploited	with	hypoxia	activated	prodrugs	and	that	such	drugs	reduce	the	fraction	of	aldefluor	bright	stem	like	tumor	cells</Paragraph></Rec>
<Rec><Paragraph>metastatic	colorectal	cancer	crc	is	associated	with	highly	variable	clinical	outcome	and	response	to	therapy	the	recently	identified	consensus	molecular	subtypes	cms1	4	have	prognostic	and	therapeutic	implications	in	primary	crc	but	whether	these	subtypes	are	valid	for	metastatic	disease	is	unclear	we	performed	multi	level	analyses	of	resectable	crc	liver	metastases	clm	to	identify	molecular	characteristics	of	metastatic	disease	and	evaluate	the	clinical	relevance	in	this	ancillary	study	to	the	oslo	comet	trial	clm	and	tumor	adjacent	liver	tissue	from	46	patients	were	analyzed	by	profiling	mutations	targeted	sequencing	genome	wide	copy	number	alteration	cnas	and	gene	expression	somatic	mutations	and	cnas	detected	in	clm	were	similar	to	reported	primary	crc	profiles	while	cna	profiles	of	eight	metastatic	pairs	suggested	intra	patient	divergence	a	cms	classifier	tool	applied	to	gene	expression	data	revealed	the	cohort	to	be	highly	enriched	for	cms2	hierarchical	clustering	of	genes	with	highly	variable	expression	identified	two	subgroups	separated	by	high	or	low	expression	of	55	genes	with	immune	related	and	metabolic	functions	importantly	induction	of	genes	and	pathways	associated	with	immunogenic	cell	death	icd	was	identified	in	metastases	exposed	to	neoadjuvant	chemotherapy	nact	the	uniform	classification	of	clm	by	cms	subtyping	may	indicate	that	novel	class	discovery	approaches	need	to	be	explored	to	uncover	clinically	useful	stratification	of	clm	detected	gene	expression	signatures	support	the	role	of	metabolism	and	chemotherapy	in	shaping	the	immune	microenvironment	of	clm	furthermore	the	results	point	to	rational	exploration	of	immune	modulating	strategies	in	clm	particularly	by	exploiting	nact	induced	icd</Paragraph></Rec>
<Rec><Paragraph>the	immune	system	has	a	substantial	effect	on	colorectal	cancer	crc	progression	additionally	the	response	to	immunotherapeutics	and	conventional	treatment	options	e	g	chemotherapy	radiotherapy	and	targeted	therapies	is	influenced	by	the	immune	system	the	molecular	characterization	of	colorectal	cancer	crc	has	led	to	the	identification	of	favorable	and	unfavorable	immunological	attributes	linked	to	clinical	outcome	with	the	definition	of	consensus	molecular	subtypes	cmss	based	on	transcriptomic	profiles	multiple	characteristics	have	been	proposed	to	be	responsible	for	the	development	of	the	tumor	immune	microenvironment	and	corresponding	mechanisms	of	immune	escape	in	this	review	a	detailed	description	of	proposed	immune	phenotypes	as	well	as	their	interaction	with	different	therapeutic	modalities	will	be	provided	finally	possible	strategies	to	shift	the	crc	immune	phenotype	towards	a	reactive	anti	tumor	orientation	are	proposed	per	cms</Paragraph></Rec>
<Rec><Paragraph>purpose	kras	mutation	is	a	common	canonical	mutation	in	colorectal	cancer	found	at	differing	frequencies	in	all	consensus	molecular	subtypes	cms	the	independent	immunobiological	impacts	of	ras	mutation	and	cms	are	unknown	thus	we	explored	the	immunobiological	effects	of	kras	mutation	across	the	cms	spectrum	experimental	design	expression	analysis	of	immune	genes	signatures	was	performed	using	the	cancer	genome	atlas	tcga	rna	seq	and	the	kfsyscc	microarray	datasets	multivariate	analysis	included	kras	status	cms	tumor	location	msi	status	and	neoantigen	load	protein	expression	of	stat1	hla	class	ii	and	cxcl10	was	analyzed	by	digital	ihc	results	the	th1	centric	co	ordinate	immune	response	cluster	circ	was	significantly	albeit	modestly	reduced	in	kras	mutant	colorectal	cancer	in	both	datasets	cytotoxic	t	cells	neutrophils	and	the	ifnγ	pathway	were	suppressed	in	kras	mutant	samples	the	expressions	of	stat1	and	cxcl10	were	reduced	at	the	mrna	and	protein	levels	in	multivariate	analysis	kras	mutation	cms2	and	cms3	were	independently	predictive	of	reduced	circ	expression	immune	response	was	heterogeneous	across	kras	mutant	colorectal	cancer	kras	mutant	cms2	samples	have	the	lowest	circ	expression	reduced	expression	of	the	ifnγ	pathway	stat1	and	cxcl10	and	reduced	infiltration	of	cytotoxic	cells	and	neutrophils	relative	to	cms1	and	cms4	and	to	kras	wild	type	cms2	samples	in	the	tcga	these	trends	held	in	the	kfsyscc	dataset	conclusions	kras	mutation	is	associated	with	suppressed	th1	cytotoxic	immunity	in	colorectal	cancer	the	extent	of	the	effect	being	modulated	by	cms	subtype	these	results	add	a	novel	immunobiological	dimension	to	the	biological	heterogeneity	of	colorectal	cancer	clin	cancer	res	24	1	224	33	2017	aacr</Paragraph></Rec>
<Rec><Paragraph>immune	checkpoint	ick	expression	might	represent	a	surrogate	measure	of	tumor	infiltrating	t	cell	ctl	exhaustion	and	therefore	be	a	more	accurate	prognostic	biomarker	for	colorectal	cancer	crc	patients	than	ctl	enumeration	as	measured	by	the	immunoscore	the	expression	of	icks	th1	ctls	cytotoxicity	related	genes	and	metagenes	including	immunoscore	like	metagenes	were	evaluated	in	three	independent	cohorts	of	crc	samples	260	microsatellite	instable	msi	971	non	msi	their	associations	with	patient	survival	were	analyzed	by	cox	models	taking	into	account	the	microsatellite	instability	msi	status	and	affiliation	with	various	consensus	molecular	subgroups	cms	pd	l1	and	cd8	expression	were	examined	on	a	subset	of	tumors	with	immunohistochemistry	all	statistical	tests	were	two	sided	the	expression	of	immunoscore	like	metagenes	was	statistically	significantly	associated	with	improved	outcome	in	non	msi	tumors	displaying	low	levels	of	both	ctls	and	immune	checkpoints	icks	cms2	and	cms3	hazard	ratio	hr	0	63	95	confidence	interval	ci	0	43	to	0	92	p	02	and	hr	0	55	95	ci	0	34	to	0	90	p	02	respectively	but	clearly	had	no	prognostic	relevance	in	crcs	displaying	higher	levels	of	ctls	and	icks	cms1	and	cms4	hr	0	46	95	ci	0	10	to	2	10	p	32	and	hr	1	13	95	ci	0	79	to	1	63	p	50	respectively	including	msi	tumors	ick	metagene	expression	was	statistically	significantly	associated	with	worse	prognosis	independent	of	tumor	staging	in	msi	tumors	hr	3	46	95	ci	1	41	to	8	49	p	007	ick	expression	had	a	negative	impact	on	the	proliferation	of	infiltrating	cd8	t	cells	in	msi	neoplasms	median	0	56	in	ick	low	vs	median	0	34	in	ick	high	p	004	ick	expression	cancels	the	prognostic	relevance	of	ctls	in	highly	immunogenic	colon	tumors	and	predicts	a	poor	outcome	in	msi	crc	patients</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	heterogeneous	disease	and	recent	advances	in	subtype	classification	have	successfully	stratified	the	disease	using	molecular	profiling	the	contribution	of	bacterial	species	to	crc	development	is	increasingly	acknowledged	and	here	we	sought	to	analyse	crc	microbiomes	and	relate	them	to	tumour	consensus	molecular	subtypes	cms	in	order	to	better	understand	the	relationship	between	bacterial	species	and	the	molecular	mechanisms	associated	with	crc	subtypes	we	classified	34	tumours	into	crc	subtypes	using	rna	sequencing	derived	gene	expression	and	determined	relative	abundances	of	bacterial	taxonomic	groups	using	16s	rrna	amplicon	metabarcoding	16s	rrna	analysis	showed	enrichment	of	fusobacteria	and	bacteroidetes	and	decreased	levels	of	firmicutes	and	proteobacteria	in	cms1	a	more	detailed	analysis	of	bacterial	taxa	using	non	human	rna	sequencing	reads	uncovered	distinct	bacterial	communities	associated	with	each	molecular	subtype	the	most	highly	enriched	species	associated	with	cms1	included	fusobacterium	hwasookii	and	porphyromonas	gingivalis	cms2	was	enriched	for	selenomas	and	prevotella	species	while	cms3	had	few	significant	associations	targeted	quantitative	pcr	validated	these	findings	and	also	showed	an	enrichment	of	fusobacterium	nucleatum	parvimonas	micra	and	peptostreptococcus	stomatis	in	cms1	in	this	study	we	have	successfully	associated	individual	bacterial	species	to	crc	subtypes	for	the	first	time</Paragraph></Rec>
<Rec><Paragraph>the	colorectal	cancer	crc	subtyping	consortium	has	unified	six	independent	molecular	classification	systems	based	on	gene	expression	data	into	a	single	consensus	system	with	four	distinct	groups	known	as	the	consensus	molecular	subtypes	cms	clinical	implications	are	discussed	in	this	review	this	article	is	based	on	a	literature	review	relevant	to	the	cms	of	crc	indexed	in	pubmed	us	national	library	of	medicine	as	well	as	the	authors	own	published	data	the	cms	were	determined	and	correlated	with	epigenomic	transcriptomic	microenvironmental	genetic	prognostic	and	clinical	characteristics	the	cms1	subtype	is	immunogenic	and	hypermutated	cms2	tumors	are	activated	by	the	wnt	β	catenin	pathway	and	have	the	highest	overall	survival	cms3	feature	a	metabolic	cancer	phenotype	and	cms4	cancers	have	the	worst	survival	and	have	a	strong	stromal	gene	signature	the	consensus	molecular	subtypes	of	crc	may	better	inform	clinicians	of	prognosis	therapeutic	response	and	potential	novel	therapeutic	strategies</Paragraph></Rec>
<Rec><Paragraph>this	study	aimed	to	coat	lipid	based	nanocarriers	with	chitosan	to	encapsulate	nutraceuticals	minimize	opsonization	and	facilitate	passive	targeting	phase	one	was	concerned	with	standardization	according	to	the	world	health	organization	qualitative	analysis	using	liquid	chromatography	high	resolution	mass	spectrometry	lc	hrms	ms	investigated	the	active	constituents	especially	reported	cytotoxic	agents	cinnamaldehyde	and	rosmarinic	acid	were	selected	to	be	quantified	using	high	performance	liquid	chromatography	phase	two	was	aimed	to	encapsulate	both	extracts	in	solid	lipid	nanoparticles	core	and	chitosan	shell	to	gain	the	advantages	of	both	materials	properties	the	developed	experimental	model	suggested	an	optimum	formulation	with	2	lipid	2	3	surfactant	and	0	4	chitosan	to	achieve	a	particle	size	of	254	77	nm	polydispersity	index	of	0	28	zeta	potential	of	15	26	and	entrapment	efficiency	percentage	of	77	3	and	69	1	for	cinnamon	and	oregano	respectively	phase	three	was	focused	on	the	evaluation	of	cytotoxic	activity	unencapsulated	encapsulated	cinnamon	and	oregano	extracts	with	without	5	fluorouracil	on	hct	116	cells	this	study	confirmed	the	success	of	the	suggested	combination	with	5	fluorouracil	for	treating	human	colon	carcinoma	with	a	low	dose	leading	to	decreasing	side	effects	and	allowing	uninterrupted	therapy</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	an	heterogeneous	disease	three	carcinogenic	pathways	determine	its	molecular	profile	microsatellite	instability	msi	chromosomal	instability	cin	and	cpg	island	methylator	phenotype	cimp	based	on	the	new	molecular	classification	four	consensus	crc	molecular	subtypes	cms	are	established	which	are	related	to	clinical	pathological	and	biological	characteristics	of	the	tumor	to	classify	chilean	patients	with	sporadic	crc	according	to	the	new	consensus	molecular	subtypes	of	carcinogenic	pathways	prospective	analytical	study	of	53	patients	with	a	mean	age	of	70	years	55	males	with	crc	operated	at	a	private	clinic	without	neoadjuvant	treatment	from	normal	and	tumor	tissue	dna	of	each	patient	cin	msi	and	cimp	were	analyzed	combining	these	variables	tumors	were	classified	as	cms1	msi	immune	cms2	canonical	cms3	metabolic	and	cms4	mesenchymal	cms1	tumors	19	were	located	in	the	right	colon	were	in	early	stages	had	mmr	complex	deficiencies	and	67	had	an	activating	mutation	of	the	braf	oncogene	cms2	tumors	31	were	located	in	the	left	colon	had	moderate	differentiation	absence	of	vascular	invasion	lymphatic	and	mucin	cms3	tumors	29	were	also	left	sided	with	absence	of	vascular	and	lymphatic	invasion	and	29	had	an	activating	mutation	of	the	kras	oncogene	cms4	tumors	21	showed	advanced	stages	and	presence	of	metastases	this	new	molecular	classification	contributes	to	understanding	the	heterogeneity	of	tumors	it	is	possible	to	differentiate	molecular	subgroups	of	a	single	pathological	diagnosis	of	adenocarcinoma	opening	the	door	to	personalized	medicine</Paragraph></Rec>
<Rec><Paragraph>the	study	was	carried	out	to	evaluate	the	early	outcomes	using	radiofrequency	ablation	rfa	for	unresectable	liver	metastases	in	the	management	of	metastatic	colorectal	cancer	mcrc	from	an	area	of	low	endemicity	60	patients	with	unresectable	colorectal	liver	metastases	had	undergone	88	sessions	of	rfa	from	january	2007	till	december	2013	the	results	were	retrospectively	analysed	to	evaluate	the	outcomes	in	terms	of	efficacy	and	survival	rates	the	median	follow	up	of	patients	in	our	series	was	24	8months	35	52	67	3	patients	had	complete	response	at	3	months	while	8	patients	were	lost	to	follow	up	of	the	17	patients	who	had	recurrence	4	23	5	were	at	the	ablated	site	while	13	patients	76	4	progressed	elsewhere	abdominal	pain	was	commonest	post	procedural	symptom	20	there	was	no	procedure	related	mortality	or	any	major	complications	mean	disease	free	interval	and	progression	free	survival	was	6	7	and	13	1	months	estimated	median	survival	in	patients	with	liver	limited	disease	and	those	with	small	lesion	3cm	was	3	79	years	and	3	45	years	respectively	median	survival	in	patients	with	lesion	size	3	5	cms	was	1	5	years	annual	survival	rates	would	be	94	5	55	2	and	26	2	for	1	3	and	5	years	radiofrequency	ablation	of	unresectable	liver	metastases	is	effective	in	treatment	of	mcrc	estimated	survival	rates	and	annual	survival	rates	at	our	institute	from	the	low	endemic	region	also	follow	the	global	trend	size	of	the	lesion	was	an	important	predictor	of	efficacy	of	rfa	presence	of	extrahepatic	disease	and	lesion	size	3	cm	was	associated	with	decreased	survival</Paragraph></Rec>
<Rec><Paragraph>cancer	is	a	heterogeneous	disease	and	many	cancer	types	do	not	represent	a	single	entity	but	are	composed	of	biologically	and	clinically	diverse	subtypes	the	subtype	affiliation	can	influence	prognosis	and	response	to	therapy	recently	a	multicenter	colorectal	cancer	crc	subtyping	consortium	introduced	a	consensus	molecular	classification	system	for	crc	this	will	be	of	great	benefit	for	future	basic	and	clinical	research	since	it	enables	uniform	categorization	of	crc	specimens	across	different	institutes	and	studies	the	biological	conformity	observed	within	each	consensus	molecular	subtype	cms	holds	promise	for	the	design	of	subtype	specific	treatment	regimens	herein	we	review	the	cmss	of	crc	with	a	focus	on	how	multiple	parameters	such	as	the	origin	developmental	route	and	microenvironmental	regulation	shape	distinct	subtypes</Paragraph></Rec>
<Rec><Paragraph>somatic	copy	number	aberrations	cnas	are	common	acquired	changes	in	cancer	cells	having	an	important	role	in	the	progression	of	colon	cancer	colorectal	cancer	crc	this	study	aimed	to	perform	a	characterisation	of	cna	and	their	impact	in	gene	expression	copy	number	aberrations	were	inferred	from	snp	array	data	in	a	series	of	99	crc	copy	number	aberration	events	were	calculated	and	used	to	assess	the	association	between	copy	number	dosage	clinical	and	molecular	characteristics	of	the	tumours	and	gene	expression	changes	all	analyses	were	adjusted	for	the	quantity	of	stroma	in	each	sample	which	was	inferred	from	gene	expression	data	high	heterogeneity	among	samples	was	observed	the	proportion	of	altered	genome	ranged	between	0	04	and	26	6	recurrent	cna	regions	with	gains	were	frequent	in	chromosomes	7p	8q	13q	and	20	whereas	8p	17p	and	18	cumulated	losses	a	significant	positive	correlation	was	observed	between	the	number	of	somatic	mutations	and	total	cna	spearman	s	r	0	42	p	0	006	approximately	37	of	genes	located	in	cna	regions	changed	their	level	of	expression	and	the	average	partial	correlation	adjusted	for	stromal	content	with	copy	number	was	0	54	interquartile	range	0	20	to	0	81	altered	genes	showed	enrichment	in	pathways	relevant	for	crc	tumours	classified	as	cms2	and	cms4	by	the	consensus	molecular	subtyping	showed	higher	frequency	of	cna	losses	of	one	small	region	in	1p36	33	with	gene	cdk11b	were	associated	with	poor	prognosis	more	than	66	of	the	recurrent	cna	were	validated	in	the	the	cancer	genome	atlas	tcga	data	when	analysed	with	the	same	procedure	furthermore	79	of	the	genes	with	altered	expression	in	our	data	were	validated	in	the	tcga	although	cna	are	frequent	events	in	microsatellite	stable	crc	few	focal	recurrent	regions	were	found	these	aberrations	have	strong	effects	on	gene	expression	and	contribute	to	deregulate	relevant	cancer	pathways	owing	to	the	diploid	nature	of	stromal	cells	it	is	important	to	consider	the	purity	of	tumour	samples	to	accurately	calculate	cna	events	in	crc</Paragraph></Rec>
<Rec><Paragraph>the	consensus	molecular	subtypes	cms	in	colorectal	cancer	crc	represent	distinct	molecular	subcategories	of	disease	as	reflected	by	comprehensive	molecular	profiling	the	four	cms	subtypes	represent	unique	biology	cms1	represents	high	immune	infiltration	cms2	demonstrates	upregulation	of	canonical	pathways	such	as	wnt	signaling	widespread	metabolic	changes	are	seen	in	cms3	cms4	represents	a	mesenchymal	phenotype	with	hallmark	features	including	complement	activation	matrix	remodeling	angiogenesis	epithelial	mesechymal	transition	emt	integrin	upregulation	and	stromal	infiltration	in	contrast	to	this	new	paradigm	a	number	of	observations	regarding	crc	remain	disconnected	cancers	are	associated	with	thrombocytosis	venous	thromboembolic	events	are	more	likely	in	malignancy	and	may	signify	worse	prognosis	aspirin	an	anti	platelet	agent	has	been	linked	in	large	observational	studies	to	decrease	incidence	of	adenocarcinoma	and	less	advanced	presentations	of	cancer	in	particular	crc	inflammatory	bowel	disease	is	a	risk	factor	for	crc	gross	markers	to	recognize	the	immunothrombotic	link	such	as	the	platelet	to	lymphocyte	ratio	are	associated	with	poorer	outcomes	in	many	cancers	platelets	are	increasingly	recognized	for	their	dual	roles	in	coordinating	the	immune	response	in	addition	to	hemostasis	here	we	explore	how	these	different	but	related	observations	coalesce	platelets	as	first	responders	to	pathogens	and	injury	form	the	link	between	hemostasis	and	immunity	we	outline	how	platelets	contribute	to	tumorigenesis	and	how	some	disconnected	ideas	may	be	linked	through	inflammation	cms4	through	its	shared	mechanisms	has	predicted	platelet	activation	as	a	hallmark	feature	we	demonstrate	a	platelet	gene	expression	signature	that	predicts	platelet	presence	within	cms4	tumors</Paragraph></Rec>
<Rec><Paragraph>metastatic	colorectal	cancer	mcrc	is	one	of	the	major	causes	of	cancer	related	death	despite	the	substantial	progress	in	mcrc	management	it	remains	important	to	identify	new	therapeutic	options	and	biological	markers	for	personalized	medicine	here	we	investigated	the	expression	of	claudin	1	cldn1	a	major	tight	junction	transmembrane	protein	in	the	different	colorectal	cancer	crc	molecular	subtypes	and	then	assessed	the	anti	tumor	effect	of	a	new	anti	cldn1	monoclonal	antibody	mab	gene	expression	profiling	and	immunochemistry	analysis	of	normal	and	tumor	tissue	samples	from	patients	with	stage	iv	crc	were	used	to	determine	cldn1	gene	expression	then	the	6f6	mab	against	cldn1	extracellular	part	was	generated	its	effect	on	crc	cell	cycle	proliferation	survival	and	migration	was	assessed	in	vitro	using	a	3d	cell	culture	system	flow	cytometry	clonogenic	and	migration	assays	in	vivo	6	f6	mab	efficacy	was	evaluated	in	nude	mice	after	subcutaneous	xenografts	or	intrasplenic	injection	of	crc	cells	compared	with	normal	mucosa	where	it	was	almost	exclusively	cytoplasmic	in	crc	samples	cldn1	was	overexpressed	p	0	001	and	mainly	localized	at	the	membrane	moreover	it	was	differentially	expressed	in	the	various	crc	molecular	subtypes	the	strongest	expressions	were	found	in	the	consensus	molecular	subtype	cms2	p	0	001	the	transit	ampliflying	p	0	001	and	the	c5	subtypes	p	0	001	lower	cldn1	expression	predicted	a	better	outcome	in	the	molecular	subtypes	c3	and	c5	p	0	012	and	p	0	004	respectively	cldn1	targeting	with	the	6	f6	mab	led	to	reduction	of	survival	growth	and	migration	of	cldn1	positive	cells	in	preclinical	mouse	models	the	6f6	mab	decreased	tumor	growth	and	liver	metastasis	formation	our	data	indicate	that	cldn1	targeting	with	an	anti	cldn1	mab	results	in	decreased	growth	and	survival	of	crc	cells	this	suggests	that	cldn1	could	be	a	new	potential	therapeutic	target</Paragraph></Rec>
<Rec><Paragraph>prior	studies	have	shown	higher	screening	mammography	rates	for	beneficiaries	in	capitated	managed	care	medicare	advantage	ma	plans	compared	with	traditional	fee	for	service	medicare	the	aim	of	this	study	was	to	explore	variation	in	screening	mammography	rates	at	the	level	of	ma	managed	care	plans	using	the	2016	ma	healthcare	effectiveness	data	and	information	set	public	use	file	screening	mammography	rates	were	identified	for	all	385	reporting	ma	plans	associations	were	explored	with	a	range	of	plan	characteristics	from	this	file	as	well	as	from	the	cms	part	c	and	part	d	medicare	star	ratings	data	file	medicare	advantage	plan	directory	and	medicare	monthly	enrollment	by	plan	file	overall	ma	plan	screening	rates	were	high	mean	72	6	9	4	but	varied	substantially	among	plans	range	14	3	91	8	screening	rates	were	higher	in	nonprofit	versus	for	profit	plans	77	3	versus	71	8	p	001	as	well	as	in	health	maintenance	organization	or	local	preferred	provider	organization	plans	versus	private	fee	for	service	or	regional	preferred	provider	organization	plans	71	9	73	2	versus	65	5	66	8	p	001	among	parent	organizations	with	five	or	more	plans	screening	rates	were	highest	for	kaiser	foundation	median	88	4	and	lowest	for	molina	healthcare	median	65	3	screening	rates	showed	small	but	significant	associations	with	plans	contract	lengths	enrolled	populations	and	counties	served	screening	rates	showed	strong	associations	r	0	796	0	798	with	colorectal	cancer	screening	and	annual	flu	vaccine	rates	and	showed	moderate	associations	r	0	283	0	365	with	ambulatory	and	preventive	care	visits	osteoporosis	screenings	body	mass	index	assessments	and	nonrecommended	prostate	specific	antigen	screenings	after	age	70	screening	mammography	rates	vary	considerably	among	ma	plans	with	increased	federal	interest	in	promoting	the	ma	program	enhanced	transparency	will	be	necessary	to	ensure	appropriate	medicare	beneficiary	participation	decision	making</Paragraph></Rec>
<Rec><Paragraph>the	cerebrospinal	fluid	csf	levels	of	total	tau	t	tau	and	aβ1	42	are	potential	early	diagnostic	markers	for	probable	alzheimer	s	disease	ad	the	influence	of	genetic	variation	on	these	csf	biomarkers	has	been	investigated	in	candidate	or	genome	wide	association	studies	gwas	however	the	investigation	of	statistically	modest	associations	in	gwas	in	the	context	of	biological	networks	is	still	an	under	explored	topic	in	ad	studies	the	main	objective	of	this	study	is	to	gain	further	biological	insights	via	the	integration	of	statistical	gene	associations	in	ad	with	physical	protein	interaction	networks	the	csf	and	genotyping	data	of	843	study	subjects	199	cn	85	smc	239	emci	207	lmci	113	ad	from	the	alzheimer	s	disease	neuroimaging	initiative	adni	were	analyzed	plink	was	used	to	perform	gwas	on	the	t	tau	aβ1	42	ratio	using	quality	controlled	genotype	data	including	563	980	single	nucleotide	polymorphisms	snps	with	age	sex	and	diagnosis	as	covariates	gene	level	p	values	were	obtained	by	vegas2	genes	with	p	value	0	05	were	mapped	on	to	a	protein	protein	interaction	ppi	network	9	617	nodes	39	240	edges	from	the	hprd	database	we	integrated	a	consensus	model	strategy	into	the	ipinbpa	network	analysis	framework	and	named	it	as	cm	ipinbpa	four	consensus	modules	cms	were	discovered	by	cm	ipinbpa	and	were	functionally	annotated	using	the	pathway	analysis	tool	enrichr	the	intersection	of	four	cms	forms	a	common	subnetwork	of	29	genes	including	those	related	to	tau	phosphorylation	gsk3b	sumo1	akap5	calm1	and	dlg4	amyloid	beta	production	casp8	pik3r1	ppa1	parp1	csnk2a1	ngfr	and	rhoa	and	ad	bcl3	cflar	smad1	and	hif1a	this	study	coupled	a	consensus	module	cm	strategy	with	the	ipinbpa	network	analysis	framework	and	applied	it	to	the	gwas	of	csf	t	tau	aβ1	42	ratio	in	an	ad	study	the	genome	wide	network	analysis	yielded	4	enriched	cms	that	share	not	only	genes	related	to	tau	phosphorylation	or	amyloid	beta	production	but	also	multiple	genes	enriching	several	kegg	pathways	such	as	alzheimer	s	disease	colorectal	cancer	gliomas	renal	cell	carcinoma	huntington	s	disease	and	others	this	study	demonstrated	that	integration	of	gene	level	associations	with	cms	could	yield	statistically	significant	findings	to	offer	valuable	biological	insights	e	g	functional	interaction	among	the	protein	products	of	these	genes	and	suggest	high	confidence	candidates	for	subsequent	analyses</Paragraph></Rec>
<Rec><Paragraph>approximately	15	of	primary	colorectal	cancers	have	dna	mismatch	repair	deficiency	causing	a	complex	genome	with	thousands	of	small	mutations	the	microsatellite	instability	msi	phenotype	we	investigated	molecular	heterogeneity	and	tumor	immunogenicity	in	relation	to	clinical	endpoints	within	this	distinct	subtype	of	colorectal	cancers	a	total	of	333	primary	msi	colorectal	tumors	from	multiple	cohorts	were	analyzed	by	multilevel	genomics	and	computational	modeling	including	mutation	profiling	clonality	modeling	and	neoantigen	prediction	in	a	subset	of	the	tumors	as	well	as	gene	expression	profiling	for	consensus	molecular	subtypes	cms	and	immune	cell	infiltration	novel	frequent	frameshift	mutations	in	four	cancer	critical	genes	were	identified	by	deep	exome	sequencing	including	in	crtc1	bcl9	jak1	and	ptch1	jak1	loss	of	function	mutations	were	validated	with	an	overall	frequency	of	20	in	norwegian	and	british	patients	and	mutated	tumors	had	up	regulation	of	transcriptional	signatures	associated	with	resistance	to	anti	pd	1	treatment	clonality	analyses	revealed	a	high	level	of	intra	tumor	heterogeneity	however	this	was	not	associated	with	disease	progression	among	the	msi	tumors	the	total	mutation	load	correlated	with	the	number	of	predicted	neoantigens	p	4	10	5	but	not	with	immune	cell	infiltration	this	was	dependent	on	the	cms	class	msi	tumors	in	cms1	were	highly	immunogenic	compared	to	msi	tumors	in	cms2	4	both	jak1	mutations	and	cms1	were	favorable	prognostic	factors	hazard	ratios	0	2	0	05	0	9	and	0	4	0	2	0	9	respectively	p	0	03	and	0	02	multilevel	genomic	analyses	of	msi	colorectal	cancer	revealed	molecular	heterogeneity	with	clinical	relevance	including	tumor	immunogenicity	and	a	favorable	patient	outcome	associated	with	jak1	mutations	and	the	transcriptomic	subgroup	cms1	emphasizing	the	potential	for	prognostic	stratification	of	this	clinically	important	subtype	see	related	research	highlight	by	samstein	and	chan	10	1186	s13073	017	0438	9</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	characterized	by	major	inter	tumor	diversity	that	complicates	the	prediction	of	disease	and	treatment	outcomes	recent	efforts	help	resolve	this	by	sub	classification	of	crc	into	natural	molecular	subtypes	however	this	strategy	is	not	yet	able	to	provide	clinicians	with	improved	tools	for	decision	making	we	here	present	an	extended	framework	for	crc	stratification	that	specifically	aims	to	improve	patient	prognostication	using	transcriptional	profiles	from	1	100	crcs	including	300	previously	unpublished	samples	we	identify	cancer	cell	and	tumor	archetypes	and	suggest	the	tumor	microenvironment	as	a	major	prognostic	determinant	that	can	be	influenced	by	the	microbiome	notably	our	subtyping	strategy	allowed	identification	of	archetype	specific	prognostic	biomarkers	that	provided	information	beyond	and	independent	of	uicc	tnm	staging	msi	status	and	consensus	molecular	subtyping	the	results	illustrate	that	our	extended	subtyping	framework	combining	subtyping	and	subtype	specific	biomarkers	could	contribute	to	improved	patient	prognostication	and	may	form	a	strong	basis	for	future	studies</Paragraph></Rec>
<Rec><Paragraph>individualizing	adjuvant	chemotherapy	is	important	in	patients	with	advanced	colorectal	cancers	crcs	and	the	ability	to	identify	molecular	subtypes	predictive	of	good	prognosis	for	stage	iii	crcs	after	adjuvant	chemotherapy	could	be	highly	beneficial	we	performed	microarray	based	gene	expression	analysis	on	101	fresh	frozen	primary	samples	from	patients	with	stage	iii	crcs	treated	with	folfox	adjuvant	chemotherapy	and	35	matched	non	neoplastic	mucosal	tissues	crc	samples	were	classified	into	four	molecular	subtypes	using	nonnegative	matrix	factorization	and	for	comparison	we	also	grouped	crc	samples	using	the	proposed	consensus	molecular	subtypes	cmss	of	the	101	cases	80	were	classified	into	a	cms	group	which	shows	a	79	correlation	between	the	cms	classification	and	our	four	molecular	subtypes	we	found	that	two	of	our	subtypes	showed	significantly	higher	disease	free	survival	and	overall	survival	than	the	others	group	2	in	particular	which	showed	no	disease	recurrence	or	death	was	characterized	by	high	microsatellite	instability	msi	h	6	21	abundant	mucin	production	12	21	and	right	sided	location	12	21	this	group	strongly	correlated	with	cms1	microsatellite	instability	immune	type	we	further	identified	the	molecular	characteristics	of	each	group	and	selected	10	potential	biomarker	genes	from	each	when	these	were	compared	to	the	previously	reported	molecular	classifier	genes	we	found	that	31	out	of	40	selected	genes	were	matched	with	those	previously	reported	our	findings	indicate	that	molecular	classification	can	reveal	specific	molecular	subtypes	correlating	with	clinicopathologic	features	of	crcs	and	can	have	predictive	value	for	the	prognosis	for	stage	iii	crcs	with	folfox	adjuvant	chemotherapy</Paragraph></Rec>
<Rec><Paragraph>the	identification	of	four	consensus	molecular	subtypes	cms1	4	of	colorectal	cancer	forms	a	new	paradigm	for	the	design	and	evaluation	of	subtype	directed	therapeutic	strategies	the	most	aggressive	subtype	cms4	has	the	highest	chance	of	disease	recurrence	novel	adjuvant	therapies	for	patients	with	cms4	tumours	are	therefore	urgently	needed	cms4	tumours	are	characterized	by	expression	of	mesenchymal	and	stem	like	genes	previous	pre	clinical	work	has	shown	that	targeting	platelet	derived	growth	factor	receptors	pdgfrs	and	the	related	kit	receptor	with	imatinib	is	potentially	effective	against	mesenchymal	type	colon	cancer	in	the	present	study	we	aim	to	provide	proof	for	the	concept	that	imatinib	can	reduce	the	aggressive	phenotype	of	primary	cms4	colon	cancer	tumour	biopsies	from	patients	with	newly	diagnosed	stage	i	iii	colon	cancer	will	be	analysed	with	a	novel	rt	qpcr	test	to	pre	select	patients	with	cms4	tumours	selected	patients	n	27	will	receive	treatment	with	imatinib	400	mg	per	day	starting	two	weeks	prior	to	planned	tumour	resection	to	assess	treatment	induced	changes	in	the	aggressive	cms4	phenotype	rna	sequencing	will	be	performed	on	pre	and	post	treatment	tissue	samples	the	development	of	effective	adjuvant	therapy	for	primary	colon	cancer	is	hindered	by	multiple	factors	first	new	drugs	that	may	have	value	in	the	prevention	of	early	distant	recurrence	are	almost	always	first	tested	in	patients	with	heavily	pre	treated	metastatic	disease	second	measuring	on	target	drug	effects	and	biological	consequences	in	tumour	tissue	is	not	commonly	a	part	of	the	study	design	third	due	to	the	lack	of	patient	selection	tools	clinical	trials	in	the	adjuvant	setting	require	large	patient	populations	finally	the	evaluation	of	recurrence	prevention	requires	a	long	term	follow	up	in	the	impacct	trial	these	issues	are	addressed	by	including	newly	diagnosed	pre	selected	patients	with	cms4	tumours	prior	to	primary	tumour	resection	rather	than	non	selected	patients	with	late	stage	disease	by	making	use	of	the	pre	operative	window	period	the	biological	effect	of	imatinib	treatment	on	cms4	tumours	can	be	rapidly	assessed	delivering	proof	of	concept	for	drug	action	in	early	stage	disease	should	form	the	basis	for	the	design	of	future	trials	with	subtype	targeted	therapies	in	colon	cancer	patients	clinicaltrials	gov	nct02685046	registration	date	february	9	2016</Paragraph></Rec>
<Rec><Paragraph>consensus	molecular	subtype	4	cms4	is	a	recently	identified	aggressive	colon	cancer	subtype	for	which	platelet	derived	growth	factor	receptors	pdgfrs	and	kit	are	potential	therapeutic	targets	we	aimed	to	develop	a	clinically	applicable	cms4	reverse	transcription	polymerase	chain	reaction	rt	qpcr	test	to	select	patients	for	pdgfr	kit	targeted	therapy	we	used	logistic	regression	to	develop	a	cms4	prediction	rule	based	on	microarray	expression	values	of	pdgfra	pdgfrb	pdgfc	and	kit	566	training	and	1259	test	samples	using	the	273	gene	random	forest	classifier	as	cms4	reference	standard	we	next	translated	the	prediction	rule	into	a	single	sample	rt	qpcr	test	which	we	independently	validated	in	29	fresh	tumor	samples	to	study	intratumor	cms4	heterogeneity	we	used	the	rt	qpcr	test	to	analyze	five	random	regions	of	20	colon	tumors	the	microarray	based	prediction	rule	diagnosed	cms4	type	tumors	extremely	well	in	both	training	and	independent	test	samples	training	area	under	the	curve	auc	0	95	95	confidence	interval	ci	0	94	to	0	97	test	auc	0	95	95	ci	0	94	to	0	96	with	excellent	calibration	and	approximately	80	overall	net	benefit	over	a	large	threshold	range	translation	into	an	rt	qpcr	test	did	not	affect	discrimination	auc	0	97	95	ci	0	93	to	1	00	independent	validation	rt	qpcr	analysis	of	five	random	tumor	regions	revealed	extensive	intratumor	cms4	heterogeneity	in	nine	out	of	20	tumors	at	least	two	regions	likely	have	to	be	analyzed	to	identify	patients	that	are	predominantly	cms4	positive	50	average	cms4	chance	the	cms4	rt	qpcr	test	is	a	promising	clinical	tool	for	selecting	individual	patients	for	cms4	subtype	targeted	therapy</Paragraph></Rec>
<Rec><Paragraph>caudal	type	homeobox	transcription	factor	2	cdx2	is	involved	in	colon	cancer	cc	oncogenesis	and	has	been	proposed	as	a	prognostic	biomarker	in	patients	with	stage	ii	or	iii	cc	we	analyzed	cdx2	expression	in	a	series	of	469	cc	typed	for	the	new	international	consensus	molecular	subtype	cms	classification	and	we	confirmed	results	in	a	series	of	90	cc	here	we	show	that	lack	of	cdx2	expression	is	only	present	in	the	mesenchymal	subgroup	cms4	and	in	msi	immune	tumors	cms1	and	not	in	cms2	and	cms3	colon	cancer	although	cdx2	expression	was	a	globally	independent	prognostic	factor	loss	of	cdx2	expression	is	not	associated	with	a	worse	prognosis	in	the	cms1	group	but	is	highly	prognostic	in	cms4	patients	for	both	relapse	free	and	overall	survival	similarly	lack	of	cdx2	expression	was	a	bad	prognostic	factor	in	mss	patients	but	not	in	msi	our	work	suggests	that	combination	of	the	consensual	cms	classification	and	lack	of	cdx2	expression	could	be	a	useful	marker	to	identify	cms4	cdx2	negative	patients	with	a	very	poor	prognosis</Paragraph></Rec>
<Rec><Paragraph>cd95	is	best	known	for	its	ability	to	induce	apoptosis	via	a	well	characterized	pathway	involving	caspase	mediated	proteolytic	events	however	in	apoptosis	resistant	cell	lines	of	diverse	cancer	types	stimulation	of	cd95	primarily	has	pro	tumorigenic	effects	that	affect	many	of	the	hallmarks	of	cancer	for	instance	in	colon	cancer	cells	with	a	mutant	kras	gene	cd95	primarily	promotes	invasion	and	metastasis	in	the	current	study	we	further	investigated	the	context	dependency	of	the	consequences	of	cd95	activation	in	colon	cancer	we	used	a	series	of	patient	derived	three	dimensional	colon	cancer	cultures	and	studied	their	response	to	stimulation	with	cd95	ligand	cd95l	cd95l	had	a	strong	inhibitory	effect	on	the	clone	forming	capacity	of	five	out	of	nine	cultures	in	line	with	previous	work	these	cultures	all	had	a	wild	type	kras	gene	and	expressed	high	levels	of	cd95	furthermore	the	most	sensitive	cultures	were	characterized	by	microsatellite	instability	msi	and	deficient	mismatch	repair	the	reduced	clonogenic	growth	of	msi	type	colonospheres	resulting	from	chronic	cd95	stimulation	was	only	partly	due	to	apoptosis	as	many	tumor	cells	survived	treatment	yet	were	unable	to	regenerate	clones	cd95	stimulation	caused	an	irreversible	cell	cycle	arrest	which	was	associated	with	cytokine	secretion	similar	to	the	senescence	associated	secretory	phenotype	sasp	and	expression	of	senescence	associated	β	galactosidase	in	human	colon	cancer	cohorts	cd95	expression	was	strongly	correlated	with	the	recently	identified	consensus	molecular	subtype	1	cms1	which	mainly	consists	of	msi	high	tumors	and	with	two	independent	sasp	signatures	mechanistically	cd95	induced	senescence	was	caused	by	chronic	dna	damage	via	caspase	activated	dnase	resulting	in	p53	activation	and	p21	expression	with	a	minor	contribution	of	the	sasp	we	conclude	that	induction	of	senescence	is	a	hitherto	unrecognized	consequence	of	high	cd95	expression	which	appears	to	be	most	relevant	for	cms1</Paragraph></Rec>
<Rec><Paragraph>although	clinical	management	of	colon	cancer	generally	has	not	accounted	for	the	primary	tumor	site	left	sided	and	right	sided	colon	cancers	harbor	different	clinical	and	biologic	characteristics	right	sided	colon	cancers	are	more	likely	to	have	genome	wide	hypermethylation	via	the	cpg	island	methylator	phenotype	cimp	hypermutated	state	via	microsatellite	instability	and	braf	mutation	there	are	also	differential	exposures	to	potential	carcinogenic	toxins	and	microbiota	in	the	right	and	left	colon	gene	expression	analyses	further	shed	light	on	distinct	biologic	subtypes	of	colorectal	cancers	crcs	with	4	consensus	molecular	subtypes	cmss	identified	importantly	these	subtypes	are	differentially	distributed	between	right	and	left	sided	crcs	with	greater	proportions	of	the	microsatellite	unstable	immune	cms1	and	the	metabolic	cms3	subtypes	found	in	right	sided	colon	cancers	this	review	summarizes	important	biologic	distinctions	between	right	and	left	sided	crcs	that	likely	impact	prognosis	and	may	predict	for	differential	responses	to	biologic	therapy	given	the	inferior	prognosis	of	stage	iii	iv	right	sided	crcs	and	emerging	data	suggesting	that	anti	epidermal	growth	factor	receptor	antibody	therapy	is	associated	with	worse	survival	in	right	sided	stage	iv	crcs	compared	with	left	sided	cancers	these	biologic	differences	between	right	and	left	sided	crcs	provide	critical	context	and	may	provide	opportunities	to	personalize	therapy</Paragraph></Rec>
<Rec><Paragraph>tumour	budding	described	as	the	presence	of	single	cells	or	small	clusters	of	up	to	five	tumour	cells	at	the	invasive	margin	is	established	as	a	prognostic	marker	in	colorectal	carcinoma	in	the	present	study	we	aimed	to	investigate	the	molecular	signature	of	tumour	budding	cells	and	the	corresponding	tumour	bulk	tumour	bulk	and	budding	areas	were	microdissected	and	processed	for	rna	sequencing	as	little	rna	was	obtained	from	budding	cells	a	special	low	input	mrna	library	preparation	protocol	was	used	gene	expression	profiles	of	budding	as	compared	with	tumour	bulk	were	investigated	for	established	emt	signatures	consensus	molecular	subtype	cms	gene	set	enrichment	and	pathway	analysis	a	total	of	296	genes	were	differentially	expressed	with	an	fdr	0	05	and	a	twofold	change	between	tumour	bulk	and	budding	regions	genes	that	were	upregulated	in	the	budding	signature	were	mainly	involved	in	cell	migration	and	survival	while	downregulated	genes	were	important	for	cell	proliferation	supervised	clustering	according	to	an	established	emt	gene	signature	categorised	budding	regions	as	emt	positive	whereas	tumour	bulk	was	considered	emt	negative	furthermore	a	shift	from	cms2	epithelial	to	cms4	mesenchymal	was	observed	as	tumour	cells	transit	from	the	tumour	bulk	to	the	budding	regions	tumour	budding	regions	are	characterised	by	a	phenotype	switch	compared	with	the	tumour	bulk	involving	the	acquisition	of	migratory	characteristics	and	a	decrease	in	cell	proliferation	in	particular	most	tumour	budding	signatures	were	emt	positive	and	switched	from	an	epithelial	subtype	cms2	in	the	tumour	bulk	to	a	mesenchymal	subtype	cms4	in	budding	cells</Paragraph></Rec>
<Rec><Paragraph>multiple	gene	expression	based	subtypes	have	been	proposed	for	the	molecular	subdivision	of	colon	cancer	in	the	last	decade	we	aimed	to	cross	validate	these	classifiers	to	explore	their	concordance	and	their	power	to	predict	survival	a	gene	chip	based	database	comprising	2	166	samples	from	12	independent	datasets	was	set	up	a	total	of	22	different	molecular	subtypes	were	re	trained	including	the	cchs	cin25	cms	cologuideex	cologuidepro	crcassigner	mda114	meta163	odxcolon	oncodefender	tca19	and	v7rhs	classifiers	as	well	as	subtypes	established	by	budinska	chang	desousa	marisa	merlos	popovici	schetter	yuen	and	watanabe	first	authors	correlation	with	survival	was	assessed	by	cox	proportional	hazards	regression	for	each	classifier	using	relapse	free	survival	data	the	highest	efficacy	at	predicting	survival	in	stage	2	3	patients	was	achieved	by	yuen	p	3	9e	05	hr	2	9	marisa	p	2	6e	05	hr	2	6	and	chang	p	9e	09	hr	2	35	finally	61	colon	cancer	cell	lines	from	four	independent	studies	were	assigned	to	the	closest	molecular	subtype</Paragraph></Rec>
<Rec><Paragraph>in	present	investigation	initially	curcumin	was	complexed	with	2	hp	β	cd	curcumin	2	hp	β	cd	complex	in	1	1	ratio	and	later	amalgamated	with	chitosan	microspheres	curcumin	2	hp	β	cd	cms	for	selective	delivery	in	colon	only	through	oral	route	of	administration	various	analytical	spectral	and	in	silico	docking	techniques	revealed	that	the	curcumin	was	deeply	inserted	in	the	2	hp	β	cd	cavity	with	apparent	stability	constant	of	3	35	10	3	m	furthermore	the	mean	particle	size	of	6	8	2	6μm	and	39	2	4	1mv	surface	charge	of	curcumin	2	hp	β	cd	complex	cms	in	addition	to	encapsulation	efficiency	of	about	79	8	6	3	exhibited	that	the	tailored	microspheres	were	optimum	for	colon	delivery	of	curcumin	this	was	also	demonstrated	in	dissolution	testing	and	standard	cell	proliferation	assay	in	which	curcumin	2	hp	β	cd	complex	cms	exhibited	maximum	release	in	simulated	colonic	fluid	scf	ph	7	0	8	0	almond	emulsion	β	glucosidase	with	improved	therapeutic	index	in	ht	29	cells	consistently	curcumin	2	hp	β	cd	complex	cms	successively	enhanced	the	colonic	bio	distribution	of	curcumin	by	8	36	folds	as	compared	to	curcumin	suspension	in	preclinical	pharmacokinetic	studies	in	conclusion	curcumin	2	hp	β	cd	complex	cms	warrant	further	in	vivo	tumor	regression	study	to	establish	its	therapeutic	efficacy	in	experimental	colon	cancer</Paragraph></Rec>
<Rec><Paragraph>angiogenesis	is	important	in	cancer	progression	and	can	be	influenced	by	tumor	associated	myofibroblasts	we	addressed	the	hypothesis	that	glucocorticoids	indirectly	affect	angiogenesis	by	altering	the	release	of	pro	angiogenic	factors	from	colon	cancer	derived	myofibroblasts	our	study	shows	that	glucocorticoids	reduced	prostanoids	urokinase	type	plasminogen	activator	upa	and	angiopoietin	like	protein	2	angptl2	levels	but	increased	angiogenin	ang	in	supernatant	from	human	ct5	3htert	colon	cancer	derived	myofibroblasts	conditioned	medium	from	solvent	cms	and	dexamethasone	dex	treated	cmd	myofibroblasts	increased	human	umbilical	vein	endothelial	cell	huvec	proliferation	but	did	not	affect	expression	of	pro	angiogenic	factors	or	tube	like	structure	formation	by	huvecs	or	human	aortic	ecs	in	a	huvec	scratch	assay	cms	induced	acceleration	of	wound	healing	was	blunted	by	cmd	treatment	moreover	cms	induced	neovessel	growth	in	mouse	aortic	rings	ex	vivo	was	also	blunted	using	cmd	the	latter	effect	could	be	ascribed	to	both	dex	driven	reduction	of	secreted	factors	and	potential	residual	dex	present	in	cmd	indicated	using	a	dexamethasone	spiked	cms	control	a	similar	control	in	the	scratch	assay	however	revealed	that	altered	levels	of	factors	in	the	cmd	and	not	potential	residual	dex	were	responsible	for	decreased	wound	closure	in	conclusion	our	results	suggest	that	glucocorticoids	indirectly	alter	endothelial	cell	function	during	tumor	development	in	vivo</Paragraph></Rec>
<Rec><Paragraph>fatty	acid	binding	protein	1	fabp1	is	an	intracellular	protein	responsible	for	the	transportation	of	long	chain	fatty	acids	aside	from	its	functions	in	lipid	metabolism	and	cellular	differentiation	fabp1	also	plays	a	role	in	inflammation	through	its	interaction	with	peroxisome	proliferator	activated	receptors	ppars	previously	we	compared	expression	of	colonic	epithelium	genes	in	a	subset	of	microsatellite	instable	msi	colorectal	carcinomas	medullary	carcinomas	to	normal	colonic	mucosa	and	found	that	fabp1	expression	was	markedly	decreased	in	the	tumors	further	analysis	of	rna	expression	in	the	colorectal	subtypes	and	the	cancer	genome	atlas	data	set	found	that	fabp1	expression	is	decreased	in	the	cms1	subset	of	colorectal	carcinomas	which	is	characterized	by	microsatellite	instability	as	msi	colorectal	carcinomas	are	known	for	their	robust	immune	response	we	then	aimed	to	link	fabp1	to	the	immune	microenvironment	of	msi	carcinomas	to	confirm	the	gene	expression	results	we	performed	immunohistochemical	analysis	of	a	cohort	of	colorectal	carcinomas	fabp1	was	preferentially	lost	in	msi	carcinomas	123	133	93	compared	with	microsatellite	stable	carcinomas	240	562	43	p	0	0001	in	addition	higher	numbers	of	tumor	infiltrating	lymphocytes	were	present	in	tumors	with	loss	of	fabp1	p	0	0001	decreased	expression	of	the	fatty	acid	storage	and	glucose	regulator	pparγ	was	associated	with	the	loss	of	fabp1	p	0	0001	colorectal	cancer	cell	lines	treated	with	interferon	γ	exhibited	decreased	expression	of	fabp1	fabp1	expression	was	partially	recovered	with	the	treatment	of	the	cell	lines	with	rosiglitazone	a	pparγ	agonist	this	study	demonstrated	that	the	loss	of	fabp1	expression	is	associated	with	msi	carcinomas	and	that	interferon	γ	stimulation	plays	a	role	in	this	process	via	its	interaction	with	pparγ</Paragraph></Rec>
<Rec><Paragraph>purpose	apoptosis	is	essential	for	chemotherapy	responses	in	this	discovery	and	validation	study	we	evaluated	the	suitability	of	a	mathematical	model	of	apoptosis	execution	apopto	cell	as	a	stand	alone	signature	and	as	a	constituent	of	further	refined	prognostic	stratification	tools	experimental	design	apoptosis	competency	of	primary	tumor	samples	from	patients	with	stage	iii	colorectal	cancer	n	120	was	calculated	by	apopto	cell	from	measured	protein	concentrations	of	procaspase	3	procaspase	9	smac	and	xiap	an	enriched	apopto	cell	signature	apopto	cell	pc3	was	synthesized	to	capture	apoptosome	independent	effects	of	caspase	3	furthermore	a	machine	learning	random	forest	approach	was	applied	to	apopto	cell	pc3	and	available	molecular	and	clinicopathologic	data	to	identify	a	further	enhanced	signature	association	of	the	signature	with	prognosis	was	evaluated	in	an	independent	colon	adenocarcinoma	cohort	tcga	coad	n	136	results	we	identified	3	prognostic	biomarkers	p	0	04	p	0	006	and	p	0	0004	for	apopto	cell	apopto	cell	pc3	and	random	forest	signatures	respectively	with	increasing	stratification	accuracy	for	patients	with	stage	iii	colorectal	cancer	the	apopto	cell	pc3	signature	ranked	highest	among	all	features	the	prognostic	value	of	the	signatures	was	independently	validated	in	stage	iii	tcga	coad	patients	p	0	01	p	0	04	and	p	0	02	for	apopto	cell	apopto	cell	pc3	and	random	forest	signatures	respectively	the	signatures	provided	further	stratification	for	patients	with	cms1	3	molecular	subtype	conclusions	the	integration	of	a	systems	biology	based	biomarker	for	apoptosis	competency	with	machine	learning	approaches	is	an	appealing	and	innovative	strategy	toward	refined	patient	stratification	the	prognostic	value	of	apoptosis	competency	is	independent	of	other	available	clinicopathologic	and	molecular	factors	with	tangible	potential	of	being	introduced	in	the	clinical	management	of	patients	with	stage	iii	colorectal	cancer	clin	cancer	res	23	5	1200	12	2016	aacr</Paragraph></Rec>
<Rec><Paragraph>despite	the	current	evidence	of	preventive	screening	effectiveness	rates	of	breast	cervical	and	colorectal	cancer	in	the	united	states	fall	below	national	targets	we	evaluated	the	efficacy	and	feasibility	of	combining	practice	facilitation	and	academic	detailing	quality	improvement	qi	strategies	to	help	primary	care	practices	increase	breast	cervical	and	colorectal	cancer	screening	among	patients	practices	received	a	1	hour	academic	detailing	session	addressing	current	cancer	screening	guidelines	and	best	practices	followed	by	6	months	of	practice	facilitation	to	implement	evidence	based	interventions	aimed	at	increasing	patient	screening	one	way	repeated	measures	analysis	of	variance	compared	screening	rates	before	and	after	the	intervention	provider	surveys	and	translate	model	scores	qualitative	data	were	gathered	via	participant	focus	groups	and	interviews	twenty	three	practices	enrolled	in	the	project	4	federally	qualified	health	centers	10	practices	affiliated	with	larger	health	systems	4	physician	owned	practices	4	university	hospital	clinics	and	1	nonprofit	clinic	average	screening	rates	for	breast	cancer	increased	by	13	p	001	and	rates	for	colorectal	cancer	increased	by	5	6	p	001	practices	implemented	a	mix	of	electronic	health	record	data	cleaning	workflows	provider	audits	and	feedback	reminder	systems	streamlining	and	patient	education	and	outreach	interventions	practice	facilitators	assisted	practices	in	tailoring	interventions	to	practice	specific	priorities	and	constraints	and	in	connecting	with	community	resources	practices	with	resource	constraints	benefited	from	the	engagement	of	all	levels	of	staff	in	the	quality	improvement	processes	and	from	team	based	adaptations	to	office	workflows	and	policies	many	practices	aligned	quality	improvement	interventions	in	this	project	with	patient	centered	medical	home	and	other	regulatory	reporting	targets	combining	practice	facilitation	and	academic	detailing	is	1	method	through	which	primary	care	practices	can	achieve	systems	level	changes	to	better	manage	patient	population	health</Paragraph></Rec>
<Rec><Paragraph>ccn2	also	known	as	connective	tissue	growth	factor	ctgf	is	a	transcriptional	target	of	tgf	β	signaling	unlike	its	original	name	ctgf	suggested	ccn2	is	not	an	actual	growth	factor	but	a	matricellular	protein	that	plays	an	important	role	in	fibrosis	inflammation	and	connective	tissue	remodeling	in	a	variety	of	diseases	including	cancer	in	pancreatic	ductal	adenocarcinoma	ccn2	signaling	induces	stromal	infiltration	and	facilitates	a	strong	tumor	stromal	interaction	in	many	types	of	cancer	ccn2	overexpression	has	been	associated	with	poor	outcome	cms4	consensus	molecular	subtype	4	is	a	recently	identified	aggressive	colorectal	cancer	subtype	that	is	characterized	by	up	regulation	of	genes	involved	in	epithelial	to	mesenchymal	transition	tgf	β	signaling	angiogenesis	complement	activation	and	extracellular	matrix	remodeling	in	addition	a	high	influx	of	stromal	fibroblasts	contributes	to	the	mesenchymal	like	gene	expression	profile	of	this	subtype	furthermore	compared	with	the	other	three	cms	groups	cms4	tumors	have	the	worst	prognosis	based	on	these	observations	we	postulated	that	ccn2	might	contribute	to	colorectal	cancer	progression	especially	in	the	cms4	subtype	this	review	discusses	the	available	literature	on	the	role	of	ccn2	in	colorectal	cancer	with	a	focus	on	the	fibrotic	subtype	cms4</Paragraph></Rec>
<Rec><Paragraph>cancer	cells	including	colorectal	cancer	ones	crc	release	high	amounts	of	nanovesicles	exosomes	delivering	biochemical	messages	for	paracrine	or	systemic	crosstalk	mesenchymal	stromal	cells	mscs	have	been	shown	to	play	contradicting	roles	in	tumor	progression	crc	exosomes	induce	in	cmscs	i	atypical	morphology	higher	proliferation	migration	and	invasion	ii	formation	of	spheroids	iii	an	acidic	extracellular	environment	associated	with	iv	a	plasma	membrane	redistribution	of	vacuolar	h	atpase	and	increased	expression	of	cea	colon	cancer	derived	mscs	which	were	isolated	from	tumor	masses	produce	umbilicated	spheroids	a	future	frequently	observed	in	the	inner	core	of	rapidly	growing	tumors	and	recapitulate	the	changes	observed	in	normal	colonic	mscs	exposed	to	crc	exosomes	tissue	specific	colonic	c	mscs	were	exposed	to	primary	or	metastatic	crc	exosomes	and	analysed	by	light	and	electron	microscopy	proliferation	in	2d	and	3d	cultures	migration	and	invasion	assays	western	blot	and	confocal	microscopy	for	vacuolar	h	atpase	expression	crc	exosomes	are	able	to	induce	morphological	and	functional	changes	in	colonic	mscs	which	may	favour	tumor	growth	and	its	malignant	progression	our	results	suggest	that	exosomes	are	actively	involved	in	cancer	progression	and	that	inhibiting	tumor	exosome	release	may	represent	a	way	to	interfere	with	cancer</Paragraph></Rec>
<Rec><Paragraph>in	a	previous	national	central	review	project	74	of	the	rectal	cancer	clinical	target	volumes	ctvs	needed	a	modification	in	a	follow	up	initiative	we	evaluated	whether	the	use	of	refined	international	consensus	guidelines	improves	the	uniformity	of	ctv	delineation	in	clinical	practice</Paragraph></Rec>
<Rec><Paragraph>this	review	reports	3	of	recently	published	molecular	classifications	of	the	3	main	gastro	intestinal	cancers	gastric	pancreatic	and	colorectal	adenocarcinoma	in	colorectal	adenocarcinoma	6	independent	classifications	were	combined	to	finally	hold	4	molecular	sub	groups	consensus	molecular	subtypes	cms	1	4	linked	to	various	clinical	molecular	and	survival	data	cms1	14	msi	with	immune	activation	cms2	37	canonical	with	epithelial	differentiation	and	activation	of	the	wnt	myc	pathway	cms3	13	metabolic	with	epithelial	differentiation	and	ras	mutation	cms4	23	mesenchymal	with	activation	of	tgfβ	pathway	and	angiogenesis	with	stromal	invasion	in	gastric	adenocarcinoma	4	groups	were	established	subtype	ebv	9	high	frequency	of	pik3ca	mutations	hypermetylation	and	amplification	of	jak2	pd	l1	and	pd	l2	subtype	msi	22	high	rate	of	mutation	subtype	genomically	stable	tumor	20	diffuse	histology	type	and	mutations	of	ras	and	genes	encoding	integrins	and	adhesion	proteins	including	cdh1	and	subtype	tumors	with	chromosomal	instability	50	intestinal	type	aneuploidy	and	receptor	tyrosine	kinase	amplification	in	pancreatic	adenocarcinomas	a	classification	in	four	sub	groups	has	been	proposed	stable	subtype	20	aneuploidy	locally	rearranged	subtype	30	focal	event	on	one	or	two	chromosoms	scattered	subtype	36	200	structural	variation	events	and	unstable	subtype	14	200	structural	variation	events	defects	in	dna	maintenance	although	currently	away	from	the	care	of	patients	these	classifications	open	the	way	to	à	la	carte	treatment	depending	on	molecular	biology</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	shows	variable	underlying	molecular	changes	with	two	major	mechanisms	of	genetic	instability	chromosomal	instability	and	microsatellite	instability	this	review	aims	to	delineate	the	different	pathways	of	colorectal	carcinogenesis	and	provide	an	overview	of	the	most	recent	advances	in	molecular	pathological	classification	systems	for	colorectal	cancer	two	molecular	pathological	classification	systems	for	crc	have	recently	been	proposed	integrated	molecular	analysis	by	the	cancer	genome	atlas	project	is	based	on	a	wide	ranging	genomic	and	transcriptomic	characterisation	study	of	crc	using	array	based	and	sequencing	technologies	this	approach	classified	crc	into	two	major	groups	consistent	with	previous	classification	systems	1	16	hypermutated	cancers	with	either	microsatellite	instability	msi	due	to	defective	mismatch	repair	13	or	ultramutated	cancers	with	dna	polymerase	epsilon	proofreading	mutations	3	and	2	84	non	hypermutated	microsatellite	stable	mss	cancers	with	a	high	frequency	of	dna	somatic	copy	number	alterations	which	showed	common	mutations	in	apc	tp53	kras	smad4	and	pik3ca	the	recent	consensus	molecular	subtypes	cms	consortium	analysing	crc	expression	profiling	data	from	multiple	studies	described	four	cms	groups	almost	all	hypermutated	msi	cancers	fell	into	the	first	category	cms1	msi	immune	14	with	the	remaining	mss	cancers	subcategorised	into	three	groups	of	cms2	canonical	37	cms3	metabolic	13	and	cms4	mesenchymal	23	with	a	residual	unclassified	group	mixed	features	13	although	further	research	is	required	to	validate	these	two	systems	they	may	be	useful	for	clinical	trial	designs	and	future	post	surgical	adjuvant	treatment	decisions	particularly	for	tumours	with	aggressive	features	or	predicted	responsiveness	to	immune	checkpoint	blockade</Paragraph></Rec>
<Rec><Paragraph>oxaliplatin	added	to	fluorouracil	plus	leucovorin	therapy	for	patients	with	colon	cancer	has	been	shown	to	provide	significant	but	modest	absolute	benefit	for	disease	free	survival	however	acute	and	chronic	neurotoxic	effects	from	this	regimen	underscore	the	need	for	markers	that	predict	oxaliplatin	benefit	to	test	our	hypothesis	that	molecular	subtypes	of	colon	cancer	would	be	associated	with	differential	prognosis	and	benefit	from	oxaliplatin	added	to	fluorouracil	plus	leucovorin	therapy	participants	in	the	nsabp	c	07	trial	were	divided	into	discovery	n	848	and	validation	n	881	cohorts	based	on	the	order	of	tissue	block	submission	a	reestimated	centroid	using	72	genes	was	used	to	determine	colorectal	cancer	assigner	subtypes	and	their	association	with	oxaliplatin	benefit	in	the	discovery	cohort	the	validation	cohort	was	examined	with	a	locked	down	algorithm	for	subtype	classification	and	statistical	analysis	plan	post	hoc	analysis	included	examination	of	the	entire	cohort	with	colorectal	cancer	assigner	colorectal	cancer	subtype	ccs	and	consensus	molecular	subtype	cms	methods	fluorouracil	plus	leucovorin	with	or	without	oxaliplatin	percent	recurrence	free	survival	among	1729	patients	744	43	were	female	and	mean	sd	age	was	58	11	years	although	c	07	participants	with	stage	iii	disease	with	an	enterocyte	subtype	showed	a	statistically	significant	benefit	from	oxaliplatin	in	the	discovery	cohort	hazard	ratio	0	22	95	ci	0	09	0	56	p	001	n	65	no	statistically	significant	benefit	was	observed	in	the	validation	cohort	hazard	ratio	0	53	95	ci	0	22	1	24	p	14	n	70	the	stemlike	subtype	was	associated	with	poor	prognosis	and	lack	of	benefit	from	oxaliplatin	treatment	hr	0	99	95	ci	0	73	1	34	p	96	n	367	examination	of	the	different	subtyping	methods	shows	that	all	3	methods	robustly	identified	patients	with	poor	prognosis	stemlike	ccs	3	and	cms	4	in	both	stage	ii	and	iii	patients	with	stemlike	tumors	may	be	appropriate	for	clinical	trials	testing	experimental	therapies	because	stemlike	tumors	were	robustly	identified	and	associated	with	a	poor	prognosis	regardless	of	stage	or	chemotherapy	regimen	the	clinical	utility	of	using	subtyping	for	the	identification	of	patients	for	treatment	with	oxaliplatin	requires	validation	in	independent	clinical	trial	cohorts	clinicaltrials	gov	identifier	nct00004931</Paragraph></Rec>
<Rec><Paragraph>in	2009	the	centers	for	medicare	and	medicaid	services	cms	underwent	a	national	coverage	determination	on	computed	tomography	colonography	ctc	to	screen	for	colorectal	cancer	the	cancer	intervention	surveillance	network	developed	decision	models	to	inform	this	decision	the	purpose	of	our	study	was	to	investigate	the	role	of	models	in	this	decision	we	performed	a	descriptive	case	study	we	conducted	semistructured	telephone	interviews	with	members	of	the	cms	coverage	and	analysis	group	cag	and	medicare	coverage	and	analysis	advisory	committee	medcac	panelists	informed	by	previously	published	literature	we	developed	a	coding	scheme	to	analyze	interview	transcripts	medcac	meeting	transcripts	and	the	final	cms	decision	memo	four	members	of	the	cag	and	8	medcac	panelists	were	interviewed	the	total	number	of	codes	across	all	study	documents	was	772	we	found	evidence	that	decision	makers	believed	in	the	adequacy	of	models	to	inform	decision	making	in	interview	transcripts	the	code	models	are	adequate	to	inform	was	more	frequent	than	the	code	models	are	inadequate	to	inform	47	times	v	5	discussion	of	model	conceptualization	dominated	the	medcac	meeting	model	conceptualization	assigned	113	times	and	was	frequently	discussed	during	interviews	model	conceptualization	assigned	84	times	we	also	found	evidence	that	the	models	helped	to	focus	the	policy	discussion	across	study	documents	the	codes	focus	on	cost	focus	on	clinical	health	impact	and	focus	on	inadequacy	of	evidence	base	were	assigned	99	98	and	97	times	respectively	decision	makers	involved	in	the	ctc	decision	believed	in	the	adequacy	of	models	to	inform	coverage	decisions	the	model	played	a	role	in	focusing	the	ctc	coverage	policy	discussion</Paragraph></Rec>
<Rec><Paragraph>the	heterogeneous	nature	of	colorectal	cancer	crc	complicates	prognosis	and	is	suggested	to	be	a	determining	factor	in	the	efficacy	of	adjuvant	therapy	for	individual	patients	based	on	gene	expression	profiling	crc	is	currently	classified	into	four	consensus	molecular	subtypes	cmss	characterized	by	specific	biological	programs	thus	suggesting	the	existence	of	unifying	developmental	drivers	for	each	cms	using	human	organoid	cultures	we	investigated	the	role	of	such	developmental	drivers	at	the	premalignant	stage	of	distinct	crc	subtypes	and	found	that	tgfβ	plays	an	important	role	in	the	development	of	the	mesenchymal	cms4	which	is	of	special	interest	due	to	its	association	with	dismal	prognosis	we	show	that	in	tubular	adenomas	tas	which	progress	to	classical	crcs	the	dominating	response	to	tgfβ	is	death	by	apoptosis	by	contrast	induction	of	a	mesenchymal	phenotype	upon	tgfβ	treatment	prevails	in	a	genetically	engineered	organoid	culture	carrying	a	braf	v	600e	mutation	constituting	a	model	system	for	sessile	serrated	adenomas	ssas	our	data	indicate	that	tgfβ	signaling	is	already	active	in	ssa	precursor	lesions	and	that	tgfβ	is	a	critical	cue	for	directing	ssas	to	the	mesenchymal	poor	prognosis	cms4	of	crc</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	heterogeneous	disease	posing	a	challenge	for	accurate	classification	and	treatment	of	this	malignancy	there	is	no	common	genetic	molecular	feature	that	would	allow	for	the	identification	of	patients	at	risk	for	developing	recurrences	and	thus	selecting	patients	who	would	benefit	from	more	stringent	therapies	still	poses	a	major	clinical	challenge	recently	an	international	multicenter	consortium	crc	subtyping	consortium	was	established	aiming	at	the	classification	of	crc	patients	in	biologically	homogeneous	crc	subtypes	four	consensus	molecular	subtypes	cmss	were	identified	of	which	the	mesenchymal	cms4	presented	with	worse	prognosis	signifying	the	importance	of	identifying	these	patients	despite	the	large	number	of	samples	analyzed	and	their	clear	association	with	unifying	biological	programs	and	clinical	features	single	driver	mutations	could	not	be	identified	and	patients	are	heterogeneous	with	regard	to	currently	used	clinical	markers	we	therefore	set	out	to	define	the	regulatory	mechanisms	underlying	the	distinct	gene	expression	profiles	using	a	network	based	approach	involving	multiple	molecular	modalities	such	as	gene	expression	methylation	levels	and	microrna	mir	expression	the	mir	200	family	presented	as	the	most	powerful	determinant	of	cms4	specific	gene	expression	tuning	the	majority	of	genes	differentially	expressed	in	the	poor	prognosis	subtype	including	genes	associated	with	the	epithelial	mesenchymal	transition	program	furthermore	our	data	show	that	two	epigenetic	marks	namely	the	methylation	of	the	two	mir	200	promoter	regions	can	identify	tumors	belonging	to	the	mesenchymal	subtype	and	is	predictive	of	disease	free	survival	in	crc	patients	importantly	epigenetic	silencing	of	the	mir	200	family	is	also	detected	in	epithelial	crc	cell	lines	that	belong	to	the	mesenchymal	cms	we	thus	show	that	determining	regulatory	networks	is	a	powerful	strategy	to	define	drivers	of	distinct	cancer	subtypes	which	possess	the	ability	to	identify	subtype	affiliation	and	to	shed	light	on	biological	behavior</Paragraph></Rec>
<Rec><Paragraph>the	colorectal	cancer	crc	subtyping	consortium	crcsc	recently	published	four	consensus	molecular	subtypes	cms	s	representing	the	underlying	biology	in	crc	the	microsatellite	instable	msi	immune	group	cms1	has	a	favorable	prognosis	in	early	stage	disease	but	paradoxically	has	the	worst	prognosis	following	relapse	suggesting	the	presence	of	factors	enabling	neoplastic	cells	to	circumvent	this	immune	response	to	identify	the	genes	influencing	subsequent	poor	prognosis	in	cms1	we	analyzed	this	subtype	centered	on	risk	of	relapse	in	a	cohort	of	early	stage	colon	cancer	n	460	we	examined	in	silico	changes	in	gene	expression	within	the	cms1	subtype	and	demonstrated	for	the	first	time	the	favorable	prognostic	value	of	chemokine	like	factor	cklf	gene	expression	in	the	adjuvant	disease	setting	hr	0	18	ci	0	04	0	89	in	addition	using	transcription	profiles	originating	from	cell	sorted	crc	tumors	we	delineated	the	source	of	cklf	transcription	within	the	colorectal	tumor	microenvironment	to	the	leukocyte	component	of	these	tumors	further	to	this	we	confirmed	that	cklf	gene	expression	is	confined	to	distinct	immune	subsets	in	whole	blood	samples	and	primary	cell	lines	highlighting	cklf	as	a	potential	immune	cell	derived	factor	promoting	tumor	immune	surveillance	of	nascent	neoplastic	cells	particularly	in	cms1	tumors	building	on	the	recently	reported	crcsc	data	we	provide	compelling	evidence	that	leukocyte	infiltrate	derived	cklf	expression	is	a	candidate	biomarker	of	favorable	prognosis	specifically	in	msi	immune	stage	ii	iii	disease</Paragraph></Rec>
<Rec><Paragraph>the	aim	of	our	study	was	to	compare	the	efficacy	of	the	circular	compression	stapler	and	the	circular	mechanical	stapler	in	transanal	colorectal	anastomosis	after	left	colectomy	or	anterior	rectal	resection	we	performed	a	retrospective	analysis	of	10	patients	with	disease	of	the	sigmoid	colon	or	rectum	carcinoma	or	diverticular	disease	who	underwent	left	colectomy	or	anterior	rectal	resection	with	end	to	side	transanal	colorectal	anastomosis	a	follow	up	was	planned	for	all	patients	at	1	3	and	6	months	after	surgery	and	the	anastomosis	was	evaluated	by	colonoscopy	at	1	year	in	all	patients	an	end	to	side	transanal	colorectal	anastomosis	was	performed	using	a	circular	compression	stapler	ccs	group	or	circular	mechanical	staplers	with	titanium	staples	cms	group	the	mean	distance	of	the	anastomosis	from	the	anal	margin	was	6	4	1	5	cm	in	the	ccs	group	and	18	2	11	2	cm	in	the	cms	group	all	patients	in	the	ccs	group	expelled	the	ring	after	a	mean	time	of	8	2	postoperative	days	at	12	months	colonoscopy	revealed	that	all	ccs	patients	had	a	satisfactory	anastomosis	with	mean	size	of	the	colic	lumen	at	the	level	of	anastomotic	line	of	26	3	mm	in	our	experience	the	circular	compression	stapler	a	valuable	alternative	to	the	circular	mechanical	stapler	for	the	creation	of	transanal	colorectal	anastomosis	in	line	with	the	relevant	literature	anastomotic	leakage	anastomotic	stenosis	circular	compression	stapler	circular	mechanical	stapler	transanal	colorectal	anastomosis	lo	scopo	del	nostro	studio	è	confrontare	l	efficacia	della	suturatrice	circolare	a	compressione	rispetto	alla	suturatrice	circolare	meccanica	negli	interventi	di	emicolectomia	sinistra	e	resezione	anteriore	del	retto	è	stata	effettuata	un	analisi	retrospettiva	di	10	pazienti	affetti	da	patologie	del	colon	discendente	sigma	o	retto	carcinoma	o	malattia	diverticolare	sottoposti	a	emicolectomia	sinistra	o	resezione	anteriore	del	retto	con	anastomosi	colorettale	transanale	termino	laterale	il	follow	up	è	stato	effettuato	in	tutti	i	pazienti	a	1	3	e	6	mesi	dopo	l	intervento	chirurgico	e	l	anastomosi	è	stata	valutata	mediante	endoscopia	a	1	anno	in	tutti	i	pazienti	è	stata	effettuata	un	anastomosi	colorettale	transanale	termino	laterale	utilizzando	la	suturatrice	circolare	a	compressione	gruppo	ccs	o	la	suturatrice	meccanica	circolare	con	clip	di	titanio	gruppo	cms	la	distanza	media	dell	anastomosi	dal	margine	anale	è	di	6	4	1	5	centimetri	nel	gruppo	ccs	e	di	18	2	11	2	centimetri	nel	gruppo	cms	tutti	i	pazienti	del	gruppo	ccs	hanno	espulso	l	anello	dopo	un	tempo	medio	di	8	2	giorni	postoperatori	un	anastomosi	soddisfacente	è	stata	rilevata	nei	pazienti	del	gruppo	ccs	valutati	endoscopicamente	a	12	mesi	con	calibro	medio	del	lume	colico	a	livello	della	linea	anastomotica	di	26	3	mm	nella	nostra	esperienza	il	dispositivo	a	compressione	si	è	rivelato	valido	quanto	la	suturatrice	circolare	meccanica	tradizionale	per	il	confezionamento	di	anastomosi	colorettale	transanale	in	linea	con	gli	studi	presenti	in	letteratura</Paragraph></Rec>
<Rec><Paragraph>the	tumor	microenvironment	is	formed	by	many	distinct	and	interacting	cell	populations	and	its	composition	may	predict	patients	prognosis	and	response	to	therapies	colorectal	cancer	is	a	heterogeneous	disease	in	which	immune	classifications	and	four	consensus	molecular	subgroups	cms	have	been	described	our	aim	was	to	integrate	the	composition	of	the	tumor	microenvironment	with	the	consensus	molecular	classification	of	colorectal	cancer	we	retrospectively	analyzed	the	composition	and	the	functional	orientation	of	the	immune	fibroblastic	and	angiogenic	microenvironment	of	1	388	colorectal	cancer	tumors	from	three	independent	cohorts	using	transcriptomics	we	validated	our	findings	using	immunohistochemistry	we	report	that	colorectal	cancer	molecular	subgroups	and	microenvironmental	signatures	are	highly	correlated	out	of	the	four	molecular	subgroups	two	highly	express	immune	specific	genes	the	good	prognosis	microsatellite	instable	enriched	subgroup	cms1	is	characterized	by	overexpression	of	genes	specific	to	cytotoxic	lymphocytes	in	contrast	the	poor	prognosis	mesenchymal	subgroup	cms4	expresses	markers	of	lymphocytes	and	of	cells	of	monocytic	origin	the	mesenchymal	subgroup	also	displays	an	angiogenic	inflammatory	and	immunosuppressive	signature	a	coordinated	pattern	that	we	also	found	in	breast	n	254	ovarian	n	97	lung	n	80	and	kidney	n	143	cancers	pathologic	examination	revealed	that	the	mesenchymal	subtype	is	characterized	by	a	high	density	of	fibroblasts	that	likely	produce	the	chemokines	and	cytokines	that	favor	tumor	associated	inflammation	and	support	angiogenesis	resulting	in	a	poor	prognosis	in	contrast	the	canonical	cms2	and	metabolic	cms3	subtypes	with	intermediate	prognosis	exhibit	low	immune	and	inflammatory	signatures	the	distinct	immune	orientations	of	the	colorectal	cancer	molecular	subtypes	pave	the	way	for	tailored	immunotherapies	clin	cancer	res	22	16	4057	66	2016	aacr</Paragraph></Rec>
<Rec><Paragraph>most	colorectal	polyps	can	be	reliably	assigned	to	one	of	the	known	polyp	categories	but	a	subset	of	polyps	named	colonic	mucosubmucosal	elongated	polyps	cmseps	do	not	fall	into	any	of	these	categories	first	described	in	the	japanese	literature	cmseps	seem	to	be	under	recognized	in	the	western	literature	the	aims	of	this	study	were	to	describe	the	clinicopathological	features	of	14	cmseps	discuss	potential	pathogenetic	mechanisms	and	increase	awareness	of	this	entity	among	pathologists	fourteen	pedunculated	colorectal	polyps	that	met	the	histopathological	criteria	for	cmsep	as	described	by	matake	et	al	and	alizart	et	al	were	assessed	12	males	and	two	females	mean	age	59	7	years	five	polyps	were	located	in	the	sigmoid	colon	four	in	the	rectum	two	in	the	descending	colon	and	three	in	the	colon	not	otherwise	specified	nine	of	14	polyps	were	discovered	incidentally	two	of	nine	on	routine	screening	colonoscopy	two	of	nine	on	surveillance	colonoscopy	for	inflammatory	bowel	disease	ibd	and	five	of	nine	upon	surgical	intervention	for	carcinoma	or	ibd	none	coexisted	with	diverticular	disease	the	polyps	were	long	and	slender	varied	from	5	to	30	mm	in	length	mean	15	9	mm	and	showed	a	normal	looking	colonic	mucosal	layer	and	underlying	loose	submucosa	with	thick	walled	and	congested	blood	vessels	and	lymphatics	cmseps	show	subtle	but	distinctive	pathological	features	and	occur	in	normal	and	diseased	colons	pathologists	need	to	be	aware	of	this	entity	to	avoid	confusion	with	other	more	commonly	encountered	colorectal	polyps	with	increasing	colon	cancer	screening	programmes	and	surveillance	colonoscopy	it	is	likely	that	cmseps	will	be	encountered	more	often</Paragraph></Rec>
<Rec><Paragraph>increasing	use	of	oral	chemotherapy	drugs	increases	the	challenges	for	drug	and	patient	management	an	oral	chemotherapy	management	clinic	was	developed	to	provide	patients	with	oral	chemotherapy	management	concurrent	medication	cm	education	and	symptom	management	services	this	evaluation	aims	to	measure	the	need	and	effectiveness	of	this	practice	model	due	to	scarce	published	data	this	is	a	case	series	report	of	all	patients	referred	to	the	oral	chemotherapy	management	clinic	data	collected	included	patient	demographics	depression	scores	cms	and	types	of	intervention	including	detection	and	management	outcomes	collected	at	baseline	3	day	7	day	and	3	month	follow	ups	persistence	rate	was	monitored	secondary	analysis	assessed	potential	cost	avoidance	a	total	of	86	evaluated	patients	32	men	and	54	women	mean	age	of	63	4	years	did	not	show	a	high	risk	for	medication	nonadherence	the	3	most	common	cancer	diagnoses	were	rectal	pancreatic	and	breast	with	capecitabine	most	prescribed	patients	had	an	average	of	13	7	cms	a	total	of	125	interventions	detection	and	management	of	adverse	drug	event	detection	compliance	drug	interactions	medication	error	and	symptom	management	occurred	in	201	visits	with	more	than	75	of	interventions	occurring	within	the	first	14	days	a	persistence	rate	was	observed	in	78	of	41	evaluable	patients	the	total	estimated	annual	cost	avoidance	per	1	0	full	time	employee	fte	was	125	761	93	this	evaluation	demonstrated	the	need	for	additional	support	for	patients	receiving	oral	chemotherapy	within	standard	of	care	medical	service	a	comprehensive	oral	chemotherapy	management	referral	service	can	optimize	patient	care	delivery	via	early	interventions	for	adverse	drug	events	drug	interactions	and	medication	errors	up	to	3	months	after	initiation	of	treatment</Paragraph></Rec>
<Rec><Paragraph>deficient	dna	mismatch	repair	mmr	boosts	the	accumulation	of	frameshift	mutations	in	genes	encompassing	coding	microsatellites	cms	this	results	in	the	translation	of	proteins	with	mutation	induced	frameshift	peptides	neoantigens	rendering	microsatellite	unstable	msi	cancers	highly	immunogenic	msi	cancers	express	a	defined	set	of	neoantigens	resulting	from	functionally	relevant	driver	mutations	which	are	shared	by	most	msi	cancers	patients	with	msi	cancers	and	healthy	individuals	affected	by	lynch	syndrome	an	inherited	predisposition	for	msi	cancers	develop	specific	immune	responses	against	these	neoantigens	in	this	review	we	summarize	our	current	understanding	of	the	immune	biology	of	msi	cancers	and	outline	new	concepts	and	research	directions	to	develop	not	only	therapeutic	treatments	but	also	preventive	vaccines	based	on	the	msi	cancer	genome	landscapes</Paragraph></Rec>
<Rec><Paragraph>the	aim	of	this	technical	note	is	to	describe	a	three	step	technique	for	expeditious	and	complete	mobilization	of	the	splenic	flexure	cmsf	during	single	docking	totally	robotic	rectal	cancer	surgery	a	prospectively	maintained	database	was	searched	for	all	patients	who	underwent	single	docking	totally	robotic	rectal	cancer	surgery	with	cmsf	through	a	stepwise	technique	we	studied	89	patients	underwent	cmsf	during	single	docking	totally	robotic	lower	anterior	resection	for	rectal	cancer	the	technique	demonstrates	that	cmsf	can	be	performed	with	a	standardized	approach	using	the	natural	embryological	planes	of	surgery	moreover	this	technique	does	not	involve	any	change	in	patient	s	position	on	the	operating	table	or	undocking	the	robotic	system	we	have	included	an	intra	operative	video	recording	to	demonstrate	the	technique</Paragraph></Rec>
<Rec><Paragraph>the	aim	of	this	study	was	to	analyze	the	impact	of	the	mutanome	in	the	prognosis	of	microsatellite	stable	stage	ii	crc	tumors	the	exome	of	42	stage	ii	microsatellite	stable	colon	tumors	21	of	them	relapse	and	their	paired	mucosa	were	sequenced	and	analyzed	although	some	pathways	accumulated	more	mutations	in	patients	exhibiting	good	or	poor	prognosis	no	single	somatic	mutation	was	associated	with	prognosis	exome	sequencing	data	is	also	valuable	to	infer	tumor	neoantigens	able	to	elicit	a	host	immune	response	hence	putative	neoantigens	were	identified	by	combining	information	about	missense	mutations	in	each	tumor	and	hlas	genotypes	of	the	patients	under	the	hypothesis	that	neoantigens	should	be	correctly	presented	in	order	to	activate	the	immune	response	expression	levels	of	genes	involved	in	the	antigen	presentation	machinery	were	also	assessed	in	addition	cd8a	level	as	a	marker	of	t	cell	infiltration	was	measured	we	found	that	tumors	with	better	prognosis	showed	a	tendency	to	generate	a	higher	number	of	immunogenic	epitopes	and	up	regulated	genes	involved	in	the	antigen	processing	machinery	moreover	tumors	with	higher	t	cell	infiltration	also	showed	better	prognosis	stratifying	by	consensus	molecular	subtype	cms4	tumors	showed	the	highest	association	of	expression	levels	of	genes	involved	in	the	antigen	presentation	machinery	with	prognosis	thus	we	hypothesize	that	a	subset	of	stage	ii	microsatellite	stable	crc	tumors	are	able	to	generate	an	immune	response	in	the	host	via	mhc	class	i	antigen	presentation	directly	related	with	a	better	prognosis</Paragraph></Rec>
<Rec><Paragraph>recently	colorectal	cancer	crc	subtyping	consortium	identified	four	consensus	molecular	subtypes	cms1	4	cms1	is	enriched	for	deficient	mismatch	repair	dmmr	and	braf	v600e	tumors	intriguingly	this	subtype	has	better	relapse	free	survival	but	worse	overall	survival	after	relapse	compared	with	the	other	subtypes	growing	evidence	is	accumulating	on	the	benefit	of	specific	therapeutic	strategies	such	as	immune	checkpoint	inhibition	therapy	in	dmmr	tumors	and	mitogen	activated	protein	kinase	mapk	pathway	targeted	therapy	in	tumors	harboring	braf	v600e	mutation	after	reviewing	dmmr	prognostic	value	immune	checkpoints	as	major	targets	for	dmmr	carcinomas	will	be	highlighted	following	braf	v600e	prognostic	impact	will	be	reviewed	and	therapeutic	strategies	with	the	combination	of	cytotoxic	agents	and	especially	the	combinations	of	braf	and	mapk	inhibitors	will	be	discussed</Paragraph></Rec>
<Rec><Paragraph>china	has	entered	a	period	of	high	incidence	of	colorectal	cancer	the	year	of	2015	is	the	start	of	precision	medicine	colorectal	cancer	precision	medicine	is	based	on	the	analysis	of	the	cancer	genome	sequencing	and	information	analysis	interprets	the	mechanism	of	the	occurrence	development	invasion	metastasis	and	recurrence	of	colorectal	cancer	and	helps	to	implement	targeted	individual	treatment	the	experts	of	the	world	s	colorectal	cancer	subtyping	consortium	integrated	the	past	genetic	testing	based	on	the	classification	of	colorectal	cancer	subtypes	refered	to	the	indices	of	gene	mutation	copy	number	methylation	microrna	and	proteomics	and	coalesce	the	types	of	colorectal	cancer	into	four	consensus	molecular	subtypes	cmss	with	distinguishing	features	cmss	may	be	the	most	powerful	classification	system	of	colorectal	cancer	because	of	its	clear	biological	interpretation	and	is	expected	to	provide	a	reference	basis	for	the	establishment	of	clinical	precision	treatment	system</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	a	frequently	lethal	disease	with	heterogeneous	outcomes	and	drug	responses	to	resolve	inconsistencies	among	the	reported	gene	expression	based	crc	classifications	and	facilitate	clinical	translation	we	formed	an	international	consortium	dedicated	to	large	scale	data	sharing	and	analytics	across	expert	groups	we	show	marked	interconnectivity	between	six	independent	classification	systems	coalescing	into	four	consensus	molecular	subtypes	cmss	with	distinguishing	features	cms1	microsatellite	instability	immune	14	hypermutated	microsatellite	unstable	and	strong	immune	activation	cms2	canonical	37	epithelial	marked	wnt	and	myc	signaling	activation	cms3	metabolic	13	epithelial	and	evident	metabolic	dysregulation	and	cms4	mesenchymal	23	prominent	transforming	growth	factor	β	activation	stromal	invasion	and	angiogenesis	samples	with	mixed	features	13	possibly	represent	a	transition	phenotype	or	intratumoral	heterogeneity	we	consider	the	cms	groups	the	most	robust	classification	system	currently	available	for	crc	with	clear	biological	interpretability	and	the	basis	for	future	clinical	stratification	and	subtype	based	targeted	interventions</Paragraph></Rec>
<Rec><Paragraph>recently	a	new	entity	has	been	described	a	colonic	muco	submucosal	elongated	polyp	cmsep	that	did	not	fall	into	traditional	classification	of	colorectal	polyps	the	cmsep	is	endoscopically	characterised	by	elongated	worm	like	appearance	with	a	normal	overlying	mucosa	histologic	characteristics	of	the	cmsep	comprise	mucosa	and	expanded	submucosa	with	dilated	vasculature	and	lymphatics	herein	we	report	a	case	of	cmsep	that	to	the	best	of	our	knowledge	has	not	been	previously	described	in	our	literature	with	regard	to	the	on	going	national	colorectal	cancer	screening	programme	our	intention	is	to	draw	attention	of	gastrointestinal	pathologists	and	endoscopists	to	this	distinctive	and	very	rare	phenomenon</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	the	third	most	commonly	diagnosed	cancer	and	the	second	leading	cause	of	cancer	death	among	men	and	women	combined	in	the	usa	although	the	benefits	of	early	crc	detection	are	widely	recognized	screening	rates	are	suboptimal	cologuard	is	a	multitarget	stool	dna	screening	test	that	offers	a	unique	non	invasive	option	for	crc	screening	cologuard	was	the	first	product	to	be	reviewed	under	a	pilot	parallel	review	program	jointly	conducted	by	the	us	fda	and	the	centers	for	medicare	medicaid	services	cms	this	parallel	review	process	shortened	the	overall	review	for	cologuard	and	resulted	in	a	preliminary	national	coverage	determination	that	coincided	with	fda	approval</Paragraph></Rec>
<Rec><Paragraph>to	describe	the	clinicopathological	features	of	gastrointestinal	stromal	tumors	gist	diagnosed	in	our	section	and	to	perform	risk	stratification	of	our	cases	by	assigning	them	to	specific	risk	categories	and	groups	for	disease	progression	based	on	proposals	by	fletcher	et	al	and	miettinen	and	lasota	we	retrieved	255	cases	of	gist	diagnosed	between	2003	and	2014	over	59	were	male	the	age	range	was	16	to	83	years	with	a	mean	of	51	years	over	70	occurred	between	40	and	70	years	of	age	average	diameter	of	tumors	was	10	cms	the	stomach	was	the	most	common	site	accounting	for	about	40	egists	constituted	about	16	on	histologic	examination	spindle	cell	morphology	was	seen	in	almost	of	85	cases	cd117	was	the	most	useful	immunohistochemical	antibody	positive	in	98	risk	stratification	was	possible	for	220	cases	based	on	fletcher	s	consensus	proposal	62	3	gastric	81	8	duodenal	68	small	intestinal	72	colorectal	and	89	egists	were	assigned	to	the	high	risk	category	while	based	on	miettinen	and	lasota	s	algorithm	about	48	gastric	100	duodenal	76	small	intestinal	100	colorectal	and	100	egists	in	our	study	were	associated	with	high	risk	for	disease	progression	tumor	metastasis	and	tumor	related	death	follow	up	was	available	in	95	patients	26	were	dead	and	69	alive	at	follow	up	most	of	the	patients	who	died	had	high	risk	disease	and	on	average	death	occurred	just	a	few	months	to	a	maximum	of	one	to	two	years	after	initial	surgical	resection	epidemiological	and	morphologic	findings	in	our	study	were	similar	to	international	published	data	the	majority	of	cases	in	our	study	belonged	to	the	high	risk	category</Paragraph></Rec>
<Rec><Paragraph>colorectal	cancer	crc	is	the	second	leading	cause	of	cancer	related	mortality	in	france	recently	colorectal	cancer	subtyping	consortium	crcsc	identified	4	consensus	molecular	subtypes	cms	cms1	is	enriched	for	crc	with	deficient	dna	mismatch	repair	system	dmmr	and	tumors	with	mutated	braf	intriguingly	cms1	is	characterized	by	better	relapse	free	survival	but	worse	survival	after	relapse	compared	with	the	other	subtypes	in	this	review	we	provide	a	comprehensive	overview	of	prognostic	and	predictive	impacts	of	mmr	and	braf	status	we	highlight	immune	checkpoints	inhibitors	as	potentially	future	therapeutics	for	crc	with	deficient	mmr	we	also	focus	on	the	management	of	braf	mutant	metastatic	crc	with	a	particular	interest	on	targeted	therapies</Paragraph></Rec>
<Rec><Paragraph>although	tumor	infiltrating	lymphocyte	til	density	is	prognostic	and	predictive	in	colorectal	cancer	crc	the	impact	of	tumor	genetics	upon	colorectal	immunobiology	is	unclear	identification	of	genetic	factors	that	influence	the	tumor	immunophenotype	is	essential	to	improve	the	effectiveness	of	stratified	immunotherapy	approaches	we	carried	out	a	bioinformatics	analysis	of	crc	data	in	the	cancer	genome	atlas	tcga	involving	two	dimensional	hierarchical	clustering	to	define	an	immune	signature	that	we	used	to	characterize	the	immune	response	across	key	patient	groups	an	immune	signature	termed	the	co	ordinate	immune	response	cluster	circ	comprising	28	genes	was	coordinately	regulated	across	the	patient	population	four	patient	groups	were	delineated	on	the	basis	of	cluster	expression	group	a	which	was	heavily	enriched	for	patients	with	microsatellite	instability	msi	h	and	pol	mutations	exhibited	high	circ	expression	including	the	presence	of	several	inhibitory	molecules	ctla4	pdl1	pdl2	lag3	and	tim3	in	contrast	ras	mutation	was	enriched	in	patient	groups	with	lower	circ	expression	this	work	links	the	genetics	and	immunobiology	of	colorectal	tumorigenesis	with	implications	for	the	development	of	stratified	immunotherapeutic	approaches	microsatellite	instability	and	pol	mutations	are	linked	with	high	mutational	burden	and	high	immune	infiltration	but	the	coordinate	expression	of	inhibitory	pathways	observed	suggests	combination	checkpoint	blockade	therapy	may	be	required	to	improve	efficacy	in	contrast	ras	mutant	tumors	predict	for	a	relatively	poor	immune	infiltration	and	low	inhibitory	molecule	expression	in	this	setting	checkpoint	blockade	may	be	less	efficacious	highlighting	a	requirement	for	novel	strategies	in	this	patient	group</Paragraph></Rec>
<Rec><Paragraph>since	1990	the	national	cancer	institute	nci	and	centers	for	medicare	and	medicaid	services	cms	have	collaborated	to	create	linked	data	resources	to	improve	our	understanding	of	patterns	of	care	health	care	costs	and	trends	in	utilization	however	existing	data	linkages	have	not	included	measures	of	patient	experiences	with	care	to	describe	a	new	resource	for	quality	of	care	research	based	on	a	linkage	between	the	medicare	consumer	assessment	of	healthcare	providers	and	systems	cahps	patient	surveys	and	the	nci	s	surveillance	epidemiology	and	end	results	seer	data	this	is	an	observational	study	of	cahps	respondents	and	includes	both	fee	for	service	and	medicare	advantage	beneficiaries	with	and	without	cancer	the	data	linkage	includes	cahps	survey	data	collected	between	1998	and	2010	to	assess	patient	reports	on	multiple	aspects	of	their	care	such	as	access	to	needed	and	timely	care	doctor	communication	as	well	as	patients	global	ratings	of	their	personal	doctor	specialists	overall	health	care	and	their	health	plan	seer	registry	data	1973	2007	on	cancer	site	stage	treatment	death	information	and	patient	demographics	and	longitudinal	medicare	claims	data	2002	2011	for	fee	for	service	beneficiaries	on	utilization	and	costs	of	care	in	total	150	750	respondents	were	in	the	cancer	cohort	and	571	318	were	in	the	non	cancer	cohort	the	data	linkage	includes	seer	data	on	cancer	site	stage	treatment	death	information	and	patient	demographics	in	addition	to	longitudinal	data	from	medicare	claims	and	information	on	patient	experiences	from	cahps	surveys	sizable	proportions	of	cases	from	common	cancers	e	g	breast	colorectal	prostate	and	short	term	survival	cancers	e	g	pancreas	by	time	since	diagnosis	enable	comparisons	across	the	cancer	care	trajectory	by	ma	vs	ffs	coverage	seer	cahps	is	a	valuable	resource	for	information	about	medicare	beneficiaries	experiences	of	care	across	different	diagnoses	and	treatment	modalities	and	enables	comparisons	by	type	of	insurance</Paragraph></Rec>
<Rec><Paragraph>the	brief	family	history	questionnaire	bfhq	was	developed	to	identify	endometrial	cancer	patients	whose	family	histories	suggest	lynch	syndrome	ls	we	compared	the	bfhq	extended	family	history	questionnaire	efhq	and	dictated	medical	records	dmrs	to	determine	which	family	history	screening	strategy	is	superior	in	identifying	ls	in	unselected	women	with	newly	diagnosed	endometrial	cancer	that	have	undergone	universal	germline	testing	prospective	cohort	study	recruited	women	with	newly	diagnosed	endometrial	cancer	to	evaluate	screening	strategies	to	identify	ls	participants	completed	bfhq	and	efhq	had	tumor	assessed	with	immunohistochemistry	ihc	for	mismatch	repair	proteins	mmr	and	micro	satellite	instability	testing	and	underwent	universal	germline	testing	for	ls	the	sensitivity	specificity	positive	and	negative	predictive	values	ppv	npv	were	compared	between	the	family	history	screening	strategies	as	well	as	ihc	118	of	182	eligible	patients	65	consented	87	patients	74	were	evaluable	with	both	family	history	and	germline	mutation	status	median	age	was	61years	range	26	91	all	7	patients	with	confirmed	ls	were	correctly	identified	by	bfhq	compared	to	5	and	4	by	efhq	and	dmr	respectively	the	sensitivity	specificity	ppv	and	npv	values	of	bfhq	were	100	76	5	25	9	and	100	respectively	performing	similar	to	ihc	testing	while	efhq	was	more	specific	than	bfhq	86	7	vs	76	5	p	0	007	2	cases	of	ls	were	missed	the	patient	administered	bfhq	effectively	identified	women	with	confirmed	ls	and	is	a	good	screening	tool	to	triage	women	with	endometrial	cancer	for	further	genetic	assessment</Paragraph></Rec>
<Rec><Paragraph>the	butyrate	g	protein	coupled	receptors	gpcrs	gpr41	and	gpr43	have	been	implicated	in	colorectal	cancer	and	leptin	production	to	date	their	function	has	not	been	elucidated	as	low	levels	of	protein	expression	and	difficulties	in	producing	diffraction	quality	crystals	have	hindered	their	structural	determination	in	meso	crystallization	which	uses	an	artificial	lipid	membrane	matrix	to	facilitate	crystal	growth	is	becoming	an	increasingly	successful	crystallization	technique	particularly	for	gpcrs	we	report	herein	the	lipid	membrane	matrix	structural	characterization	for	gpr41	and	gpr43	within	two	lipid	self	assembly	systems	monoolein	and	phytantriol	commonly	used	for	in	meso	crystallization	and	comment	on	their	suitability	for	crystallizing	these	gpcrs	synchrotron	small	angle	x	ray	scattering	saxs	studies	were	used	to	determine	the	initial	phase	and	uptake	of	these	receptors	within	the	lipid	matrix	and	investigate	the	role	of	cholesterol	in	this	process	the	self	assembled	lipid	nanostructure	was	retained	in	the	presence	of	gpr43	for	both	lipids	but	was	destabilized	for	gpr41	in	the	phytantriol	lipid	system	the	structural	changes	to	the	lipid	matrix	upon	protein	incorporation	were	greater	for	cholesterol	doped	systems	potentially	indicative	of	increased	receptor	uptake</Paragraph></Rec>
<Rec><Paragraph>in	colorectal	cancer	crc	evidence	shows	that	expanding	ras	testing	to	analyze	more	mutations	may	better	predict	benefit	from	anti	egfr	therapy	the	economic	implications	of	expanding	ras	testing	for	metastatic	crc	were	analyzed	estimates	of	standard	kras	exon	2	testing	were	based	on	the	centers	for	medicare	and	medicaid	services	cms	2014	diagnostic	laboratory	fee	schedule	and	expanded	ras	testing	was	estimated	using	a	sensitivity	analysis	done	with	various	potential	cost	scenarios	1	2	10	and	30	times	the	cost	of	the	standard	kras	test	the	cost	estimates	for	cetuximab	and	panitumumab	were	based	on	the	cms	payment	allowance	limits	for	medicare	part	b	a	total	of	28	692	patients	with	metastatic	crc	were	estimated	to	be	eligible	annually	for	ras	testing	for	cetuximab	the	societal	cost	of	standard	kras	testing	plus	the	drug	versus	expanded	testing	plus	the	drug	would	be	1	16	billion	versus	816	million	if	the	cost	of	the	tests	were	the	same	if	the	cost	of	the	expanded	ras	test	were	30	times	the	cost	of	the	standard	test	then	the	societal	cost	of	standard	kras	testing	plus	the	drug	versus	expanded	testing	plus	the	drug	would	be	1	16	billion	versus	980	million	a	continued	savings	of	more	than	184	million	annually	similar	savings	were	seen	with	panitumumab	the	increased	societal	cost	of	expanded	ras	testing	versus	standard	approved	kras	exon	2	testing	was	inconsequential	when	compared	with	the	amount	of	money	saved	by	not	treating	the	additional	18	of	patients	who	harbor	additional	ras	mutations	beyond	exon	2	with	anti	egfr	therapy</Paragraph></Rec>
<Rec><Paragraph>the	effectiveness	of	the	cms	nonpayment	policy	for	certain	hospital	acquired	conditions	hac	is	debated	since	their	preventability	is	questionable	in	several	groups	of	patients	this	study	aimed	to	determine	the	rate	of	the	three	most	common	hac	in	major	surgical	resections	for	cancer	surgical	site	infection	ssi	urinary	tract	infection	uti	and	venous	thromboembolism	vte	additionally	the	association	of	hac	with	patients	characteristics	and	their	effect	on	post	operative	outcomes	were	investigated	patients	who	underwent	surgical	resection	for	esophageal	gastric	hepato	biliary	pancreatic	colorectal	and	lung	cancer	were	identified	using	the	acs	nsqip	database	2005	2012	early	surgical	outcomes	were	compared	between	hac	and	non	hac	patients	modified	poisson	regression	was	used	to	identify	risk	factors	for	developing	hac	seventy	four	thousand	three	hundred	eighty	one	patients	were	identified	of	whom	9	479	12	74	developed	one	or	more	hac	hac	patients	had	significantly	higher	rates	of	30	day	mortality	return	to	operating	room	30	day	readmission	had	longer	los	and	were	less	likely	to	be	discharged	home	several	peri	operative	patients	factors	were	significantly	associated	with	hac	our	data	show	that	the	development	of	hac	is	strongly	associated	to	pre	operative	patients	characteristics	and	not	only	to	sub	optimal	peri	operative	care	therefore	suggesting	that	the	nonpayment	policy	might	be	excessively	penalizing</Paragraph></Rec>
<Rec><Paragraph>in	2008	results	from	the	landmark	american	college	of	radiology	imaging	network	acrin	trial	provided	evidence	supporting	the	use	computed	tomography	colonography	ctc	as	a	comparable	alternative	to	colonoscopy	for	colorectal	cancer	crc	screening	subsequently	however	the	united	states	preventive	task	force	decided	against	a	recommendation	in	support	of	ctc	for	crc	screening	following	soon	after	the	centers	for	medicare	and	medicaid	services	cms	made	noncoverage	decision	for	the	use	of	ctc	in	crc	screening	since	that	decision	there	have	been	a	number	of	publications	on	ctc	and	crc	screening	with	a	strong	push	from	the	radiology	community	to	reassess	ctc	as	a	viable	option	the	purpose	of	this	review	was	to	address	focused	questions	concerning	the	use	of	ctc	in	crc	screening	through	an	analysis	of	the	available	scientific	evidence	in	an	effort	to	provide	recommendations	for	clinicians	patients	and	payors	who	may	evaluate	the	role	of	ctc	for	crc	screening</Paragraph></Rec>
<Rec><Paragraph>after	a	comprehensive	review	of	the	evidence	the	united	states	preventive	services	task	force	recently	endorsed	screening	with	low	dose	computed	tomography	as	an	early	detection	approach	that	has	the	potential	to	significantly	reduce	deaths	due	to	lung	cancer	prudent	implementation	of	lung	cancer	screening	as	a	high	quality	preventive	health	service	is	a	complex	challenge	the	clinical	evaluation	and	management	of	high	risk	cohorts	in	the	absence	of	symptoms	mandates	an	approach	that	differs	significantly	from	that	of	symptom	detected	lung	cancer	as	with	other	cancer	screenings	it	is	essential	to	provide	to	informed	at	risk	individuals	a	safe	high	quality	cost	effective	and	accessible	service	in	this	review	the	components	of	a	successful	screening	program	are	discussed	as	we	begin	to	disseminate	lung	cancer	screening	as	a	national	resource	to	improve	outcomes	with	this	lethal	cancer	this	information	about	lung	cancer	screening	will	assist	clinicians	with	communications	about	the	potential	benefits	and	harms	of	this	service	for	high	risk	individuals	considering	participation	in	the	screening	process</Paragraph></Rec>
<Rec><Paragraph>to	describe	a	dosimetric	method	using	an	anterior	dose	avoidance	structure	adas	during	the	treatment	planning	process	for	intensity	modulated	radiation	therapy	imrt	for	patients	with	anal	canal	and	rectal	carcinomas	a	total	of	20	patients	were	planned	on	the	elekta	cms	xio	treatment	planning	system	version	4	5	1	maryland	heights	mo	with	a	superposition	algorithm	for	each	patient	2	plans	were	created	one	employing	an	adas	adas	plan	and	the	other	replanned	without	an	adas	non	adas	plan	the	adas	was	defined	to	occupy	the	volume	between	the	inguinal	nodes	and	primary	target	providing	a	single	organ	at	risk	that	is	completely	outside	of	the	target	volume	each	plan	used	the	same	beam	parameters	and	was	analyzed	by	comparing	target	coverage	overall	plan	dose	conformity	using	a	conformity	number	cn	equation	bowel	dose	volume	histograms	and	the	number	of	segments	daily	treatment	duration	and	global	maximum	dose	the	adas	and	non	adas	plans	were	equivalent	in	target	coverage	mean	global	maximum	dose	and	sparing	of	small	bowel	in	low	dose	regions	5	10	15	and	20	gy	the	mean	difference	between	the	cn	value	for	the	non	adas	plans	and	adas	plans	was	0	04	0	03	p	0	001	the	mean	difference	in	the	number	of	segments	was	15	7	12	7	p	0	001	in	favor	of	adas	plans	the	adas	plan	delivery	time	was	shorter	by	2	0	1	5	minutes	p	0	001	than	the	non	adas	one	the	adas	has	proven	to	be	a	powerful	tool	when	planning	rectal	and	anal	canal	imrt	cases	with	critical	structures	partially	contained	inside	the	target	volume</Paragraph></Rec>
<Rec><Paragraph>in	saudi	arabia	colorectal	cancers	crcs	are	registered	as	the	second	most	common	cancers	however	no	data	has	been	reported	about	correlation	of	the	severity	of	the	anemia	and	pretreatment	platelets	level	with	clinicopathological	features	of	crcs	we	aimed	to	evaluate	the	association	between	pretreatment	hemoglobin	and	platelets	level	and	the	clinicopathological	features	of	crc	patients	in	saudi	arabia	between	september	2005	and	november	2011	one	hundred	and	fifty	four	confirmed	crc	patients	underwent	thorough	physical	examination	blood	investigations	endoscopic	ultrasonography	eus	and	computed	tomography	ct	for	staging	before	surgery	findings	of	physical	assessment	eus	ct	and	pathological	specimens	were	correlated	with	pretreatment	hemoglobin	and	platelets	levels	the	pearson	kendall	tau	correlative	coefficients	the	mean	age	of	cohort	was	56	6	years	range	26	89	left	sided	crc	were	predominant	97	patients	63	mean	size	of	primary	tumor	was	6	cms	1	18	sd	3	55	mean	values	of	hemoglobin	red	blood	cells	hematocrit	white	blood	cells	and	platelets	were	11	9	sd	2	3	35	5	sd	5	7	4	43	10	6	ml	sd	0	6	7	67	10	6	ml	sd	2	44	and	343	10	3	ml	sd	164	4	respectively	pretreatment	hemoglobin	was	inversely	correlated	with	primary	tumor	size	r	0	71	r2	1	55	p	0	0001	and	nodal	status	r	0	02	r2	0	05	p	0	01	right	sided	crc	had	significantly	low	pretreatment	hemoglobin	levels	p	0	001	interestingly	pretreatment	thrombocytosis	was	seen	only	in	right	sided	crc	p	0	0001	pretreatment	anemia	and	thrombocytosis	were	found	mainly	in	right	sided	crcs	and	advanced	primary	and	nodal	stages	pretreatment	hemoglobin	and	thrombocytosis	can	be	considered	as	useful	prognostic	markers	in	crc	patients</Paragraph></Rec>
<Rec><Paragraph>ct	colonography	has	been	shown	to	be	an	effective	method	to	screen	for	colorectal	cancer	however	at	present	full	endorsement	and	reimbursement	for	screening	ct	colonography	particularly	by	the	us	preventive	services	task	force	and	cms	respectively	are	absent	so	this	screening	option	is	infrequently	used	and	optical	colonoscopy	remains	the	de	facto	standard	screening	option	the	authors	summarize	the	past	accomplishments	that	led	to	the	current	state	of	reimbursement	and	outline	the	remaining	challenges	and	road	to	full	acceptance	and	reimbursement	of	screening	ct	colonography	nationally</Paragraph></Rec>
<Rec><Paragraph>the	increase	in	chronic	health	conditions	among	medicare	beneficiaries	has	implications	for	the	medicare	system	the	objective	of	this	study	was	to	use	the	us	department	of	health	and	human	services	strategic	framework	on	multiple	chronic	conditions	as	a	basis	to	examine	the	prevalence	of	multiple	chronic	conditions	among	medicare	beneficiaries	we	analyzed	centers	for	medicare	and	medicaid	services	administrative	claims	data	for	medicare	beneficiaries	enrolled	in	the	fee	for	service	program	in	2010	we	included	approximately	31	million	medicare	beneficiaries	and	examined	15	chronic	conditions	a	beneficiary	was	considered	to	have	a	chronic	condition	if	a	medicare	claim	indicated	that	the	beneficiary	received	a	service	or	treatment	for	the	condition	we	defined	the	prevalence	of	multiple	chronic	conditions	as	having	2	or	more	chronic	conditions	overall	68	4	of	medicare	beneficiaries	had	2	or	more	chronic	conditions	and	36	4	had	4	or	more	chronic	conditions	the	prevalence	of	multiple	chronic	conditions	increased	with	age	and	was	more	prevalent	among	women	than	men	across	all	age	groups	non	hispanic	black	and	hispanic	women	had	the	highest	prevalence	of	4	or	more	chronic	conditions	whereas	asian	or	pacific	islander	men	and	women	in	general	had	the	lowest	the	prevalence	of	multiple	chronic	conditions	among	the	medicare	fee	for	service	population	varies	across	demographic	groups	multiple	chronic	conditions	appear	to	be	more	prevalent	among	women	particularly	non	hispanic	black	and	hispanic	women	and	among	beneficiaries	eligible	for	both	medicare	and	medicaid	benefits	our	findings	can	help	public	health	researchers	target	prevention	and	management	strategies	to	improve	care	and	reduce	costs	for	people	with	multiple	chronic	conditions</Paragraph></Rec>
<Rec><Paragraph>although	the	centers	for	medicare	and	medicaid	services	cms	denied	coverage	for	screening	computed	tomography	colonography	ctc	in	march	2009	little	is	understood	about	whether	ctc	was	targeted	to	the	appropriate	patient	population	prior	to	this	decision	evaluate	patient	characteristics	and	known	relative	clinical	indications	for	screening	ctc	among	patients	who	received	ctc	compared	to	optical	colonoscopy	oc	cross	sectional	study	of	all	10	538	asymptomatic	medicare	beneficiaries	who	underwent	ctc	between	january	2007	and	december	2008	compared	to	a	cohort	of	160	113	asymptomatic	beneficiaries	who	underwent	oc	matched	on	county	of	residence	and	year	of	examination	patient	characteristics	and	known	relative	appropriate	and	inappropriate	clinical	indications	for	screening	ctc	ctc	utilization	was	higher	among	women	patients	65	years	of	age	white	patients	and	those	with	household	income	75	p	0	001	patients	with	relatively	appropriate	clinical	indications	for	screening	ctc	were	more	likely	to	undergo	ctc	than	oc	including	presumed	incomplete	oc	or	80	7	95	ci	76	01	85	63	sedation	risk	or	1	11	95	ci	1	05	1	17	and	chronic	anticoagulation	risk	or	1	46	95	ci	1	38	1	54	after	adjusting	for	patient	characteristics	and	known	clinical	indications	conversely	patients	undergoing	high	risk	screening	an	inappropriate	indication	were	less	likely	to	receive	ctc	or	0	4	95	ci	0	37	0	42	overall	83	of	asymptomatic	patients	referred	to	ctc	had	at	least	one	clinical	indication	relatively	appropriate	for	ctc	8	772	10	538	during	the	2	years	preceding	cms	denial	for	screening	ctc	was	targeted	to	asymptomatic	patients	with	relatively	appropriate	clinical	indications	for	ctc	not	receiving	oc	however	ctc	utilization	was	lower	among	certain	demographic	groups	including	minority	patients	these	findings	raise	the	possibility	that	future	coverage	of	screening	ctc	might	exacerbate	disparities	in	colorectal	cancer	screening	while	increasing	overall	screening	rates</Paragraph></Rec>
<Rec><Paragraph>some	escherichia	coli	strains	produce	toxins	designated	cyclomodulins	cms	which	interfere	with	the	eukaryotic	cell	cycle	of	host	cells	suggesting	a	possible	link	between	these	bacteria	and	cancers	there	are	relatively	few	data	available	concerning	the	colonization	of	colon	tumors	by	cyclomodulin	and	genotoxic	producing	e	coli	we	did	a	qualitative	and	phylogenetic	analysis	of	mucosa	associated	e	coli	harboring	cyclomodulin	encoding	genes	from	38	patients	with	colorectal	cancer	crc	and	31	with	diverticulosis	the	functionality	of	these	genes	was	investigated	on	cell	cultures	and	the	genotoxic	activity	of	strains	devoid	of	known	cm	encoding	gene	was	investigated	results	showed	a	higher	prevalence	of	b2	phylogroup	e	coli	harboring	the	colibatin	producing	genes	in	biopsies	of	patients	with	crc	55	3	than	in	those	of	patients	with	diverticulosis	19	3	p	0	01	likewise	a	higher	prevalence	of	b2	e	coli	harboring	the	cnf1	encoding	genes	in	biopsies	of	patients	with	crc	39	5	than	in	those	of	patients	with	diverticulosis	12	9	p	0	01	functional	analysis	revealed	that	the	majority	of	these	genes	were	functional	analysis	of	the	ability	of	e	coli	to	adhere	to	intestinal	epithelial	cells	int	407	indicated	that	highly	adherent	e	coli	strains	mostly	belonged	to	a	and	d	phylogroups	whatever	the	origin	of	the	strains	crc	or	diverticulosis	and	that	most	e	coli	strains	belonging	to	b2	phylogroup	displayed	very	low	levels	of	adhesion	in	addition	27	6	n	21	76	e	coli	strains	devoid	of	known	cyclomodulin	encoding	genes	induced	dna	damage	in	vitro	as	assessed	by	the	comet	assay	in	contrast	to	cyclomodulin	producing	e	coli	these	strains	mainly	belonged	to	a	or	d	e	coli	phylogroups	and	exhibited	a	non	significant	difference	in	the	distribution	of	crc	and	diverticulosis	specimens	22	versus	32	5	p	0	91	in	conclusion	cyclomodulin	producing	e	coli	belonging	mostly	to	b2	phylogroup	colonize	the	colonic	mucosa	of	patients	with	crc</Paragraph></Rec>
<Rec><Paragraph>previous	studies	have	focused	on	the	treatment	received	by	rural	cancer	patients	and	have	not	examined	their	diagnostic	pathways	as	reasons	for	poorer	outcomes	in	rural	australia	to	compare	and	explore	symptom	appraisal	and	help	seeking	behaviour	in	patients	with	breast	lung	prostate	or	colorectal	cancer	from	rural	western	australia	wa	a	mixed	methods	study	of	people	recently	diagnosed	with	breast	lung	prostate	or	colorectal	cancer	from	rural	wa	the	time	from	first	symptom	to	diagnosis	i	e	total	diagnostic	interval	tdi	was	calculated	from	interviews	and	medical	records	sixty	six	participants	were	recruited	24	breast	20	colorectal	14	prostate	and	8	lung	cancer	patients	there	was	a	highly	significant	difference	in	time	from	symptom	onset	to	seeking	help	between	cancers	p	0	006	geometric	mean	symptom	appraisal	for	colorectal	cancer	was	significantly	longer	than	that	for	breast	and	lung	cancers	geometric	mean	differences	2	58	95	confidence	interval	ci	0	64	4	53	p	0	01	3	97	1	63	6	30	p	0	001	respectively	there	was	a	significant	overall	difference	in	arithmetic	mean	tdi	p	0	046	breast	cancer	tdi	was	significantly	shorter	than	colorectal	or	prostate	cancer	tdi	mean	difference	266	3	days	95	ci	45	9	486	8	p	0	019	277	0	days	32	1	521	9	p	0	027	respectively	these	differences	were	explained	by	the	nature	and	personal	interpretation	of	symptoms	perceived	as	well	as	real	problems	of	access	to	health	care	optimism	stoicism	machismo	fear	embarrassment	and	competing	demands	longer	symptom	appraisal	was	observed	for	colorectal	cancer	participants	defined	core	characteristics	of	rural	australians	as	optimism	stoicism	and	machismo	these	features	as	well	as	access	to	health	care	contribute	to	later	presentation	of	cancer</Paragraph></Rec>
<Rec><Paragraph>case	management	cm	models	based	on	experienced	nurses	are	increasingly	used	to	improve	coordination	and	continuity	of	care	for	patients	with	complex	health	care	needs	anyway	little	is	known	about	the	effects	of	hospital	based	cm	in	cancer	care	aim	to	analyse	the	effects	of	hospital	based	cm	on	i	gps	evaluation	of	information	from	the	hospital	and	collaboration	with	the	hospital	staff	and	ii	patients	contacts	with	gps	during	daytime	and	out	of	hours	a	randomized	controlled	trial	allocated	280	colorectal	cancer	patients	1	1	to	either	a	control	group	or	cm	intervention	patients	were	recruited	at	a	danish	surgical	department	an	ad	hoc	piloted	questionnaire	was	sent	to	all	patients	gps	30	weeks	after	patients	recruitment	and	the	responses	from	the	two	groups	of	gps	were	compared	registry	data	on	patients	contacts	with	general	practice	during	daytime	and	out	of	hours	were	collected	9	months	after	recruitment	and	the	data	from	the	two	groups	were	compared	quarterly	cm	was	associated	with	an	overall	tendency	towards	more	positive	gp	evaluations	which	for	3	of	20	items	reached	statistical	significance	statistically	significantly	fewer	gps	of	cm	patients	reported	contacting	the	hospital	cm	did	not	affect	the	number	of	patient	contacts	with	the	gps	during	the	daytime	but	cm	patients	showed	a	tendency	towards	more	contacts	to	the	out	of	hours	gp	services	than	non	cm	patients	cm	was	appreciated	by	the	gps	and	reduced	their	need	for	subsequent	hospital	contact	cm	increased	the	number	of	patient	contacts	to	the	out	of	hours	gp	services</Paragraph></Rec>
<Rec><Paragraph>transverse	abdominal	wall	incisions	are	favoured	as	part	of	enhanced	recovery	programmes	we	explored	the	use	of	rectus	preserving	extraction	site	incisions	in	laparoscopic	right	colectomy	the	approach	involved	minimal	anterior	abdominal	wall	disruption	with	preservation	of	the	rectus	abdominis	muscle	the	rectus	abdominis	muscle	extraction	site	rames	in	15	patients	a	rames	was	used	electively	in	right	colectomy	for	malignancy	the	median	wound	length	was	6	cms	there	was	no	clinical	or	radiological	evidence	of	incisional	herniation	in	the	15	patients	at	12	month	and	in	the	12	survivors	at	24	month	follow	up	an	anatomical	dissection	at	specimen	extraction	site	reduces	early	incisional	herniation	rates	and	should	be	of	benefit	in	the	longer	term</Paragraph></Rec>
<Rec><Paragraph>a	colonic	muco	submucosal	elongated	polyp	cmsep	was	identified	at	colonoscopy	in	a	53	year	old	male	patient	with	lower	gastrointestinal	bleeding	non	polypoid	depressed	type	of	early	cancer	was	noted	at	the	tip	of	the	colonic	polyp	the	cmsep	is	very	rare	and	incidentally	found	in	most	cases	moreover	its	association	with	colonic	neoplasia	is	extremely	rare	to	our	knowledge	this	is	the	second	case	report	of	cmsep	associated	with	a	cancerous	transformation</Paragraph></Rec>
<Rec><Paragraph>we	sought	to	determine	the	accuracy	with	which	medicare	billing	data	documents	elderly	medicare	cancer	patients	receipt	of	common	multiagent	chemotherapy	regimens	we	merged	gold	standard	clinical	trial	data	from	406	elderly	cancer	patients	known	to	be	treated	on	1	of	6	cancer	and	leukemia	group	b	calgb	breast	colorectal	and	lung	cancer	trials	trial	numbers	9344	9730	9235	9732	80203	89803	with	their	medicare	claims	data	from	centers	for	medicare	and	medicaid	services	cms	comparing	cms	chemotherapy	codes	to	gold	standard	calgb	treatment	data	we	estimated	medicare	data	s	sensitivity	at	measuring	the	correct	drugs	and	schedule	for	each	of	the	multiagent	chemotherapy	regimens	overall	92	375	406	of	calgb	patients	had	contemporaneous	cms	claims	indicating	receipt	of	chemotherapy	the	overall	sensitivity	of	cms	ambulatory	claims	for	documenting	treatment	with	the	correct	drugs	and	on	the	correct	schedule	ie	all	drugs	had	to	be	billed	on	the	same	day	for	the	5	common	multiagent	chemotherapy	regimens	was	78	275	354	for	those	potentially	treated	in	the	ambulatory	setting	the	sensitivity	was	similar	for	all	treatment	regimens	carboplatin	and	paclitaxel	83	5	fluorouracil	and	leucovorin	80	fluorouracil	leucovorin	and	irinotecan	folfiri	76	doxorubicin	and	cyclophosphamide	75	and	cisplatin	and	etoposide	75	we	correctly	identified	at	least	3	quarters	of	elderly	medicare	cancer	patients	treated	on	a	clinical	trial	with	standard	first	line	multiagent	chemotherapy	regimens	in	the	ambulatory	setting	by	applying	coding	algorithms	to	their	cms	claims	the	algorithms	may	be	useful	in	identifying	cohorts	of	elderly	medicare	patients	for	observational	studies	of	the	comparative	effectiveness	of	standard	multiagent	chemotherapy	regimens</Paragraph></Rec>
<Rec><Paragraph>presacral	venous	haemorrhage	during	rectal	movement	is	low	but	is	often	massive	and	even	fatal	our	objective	is	the	in	vitro	determination	of	the	results	of	electrocoagulation	applied	to	a	fragment	of	muscle	on	the	sacral	bone	surface	during	rectal	resection	due	to	a	malignant	neoplasm	of	the	rectum	single	pole	coagulation	was	applied	in	vitro	with	the	selector	at	maximum	power	on	a	2	2	cms	muscle	fragment	applied	to	the	anterior	side	of	the	iv	sacral	vertebra	until	reaching	boiling	point	the	method	was	used	on	6	patients	with	bleeding	of	the	presacral	venous	plexus	in	the	in	vitro	study	boiling	point	was	reached	in	90	seconds	from	applying	the	single	pole	current	on	the	muscle	fragment	electrocoagulation	was	applied	to	a	2	2	cm	rectal	muscle	fragment	in	6	patients	with	presacral	venous	haemorrhage	using	pressure	on	the	surface	of	the	presacral	bone	with	the	stopping	of	the	bleeding	being	achieved	in	all	cases	the	use	of	indirect	electrocoagulation	on	a	fragment	of	the	rectus	abdominis	muscle	is	a	straightforward	and	highly	effective	technique	for	controlling	presacral	venous	haemorrhage</Paragraph></Rec>
<Rec><Paragraph>in	july	2007	the	centers	for	medicare	and	medicaid	services	cms	limited	coverage	of	erythropoiesis	stimulating	agents	esas	in	cancer	patients	with	chemotherapy	induced	anemia	cia	through	a	national	coverage	determination	ncd	the	primary	objective	of	this	study	was	to	compare	transfusion	rates	in	patients	with	cia	with	lung	breast	or	colorectal	cancer	before	and	after	the	ncd	adult	medicare	patients	with	cia	treated	at	49	community	oncology	clinics	were	selected	from	two	time	periods	based	on	clinics	ncd	implementation	date	chart	data	were	abstracted	for	12	weeks	post	cia	episode	start	defined	as	hemoglobin	hb	level	11	g	dl	while	receiving	chemotherapy	or	within	60	days	of	the	last	chemotherapy	dose	multivariate	analyses	were	used	to	calculate	the	odds	of	transfusion	and	to	assess	the	units	of	blood	transfused	controlling	for	differences	in	demographics	clinical	history	and	chemotherapy	eight	hundred	pre	ncd	and	994	post	ncd	patients	from	49	sites	were	selected	of	the	patients	56	used	esas	post	ncd	vs	88	pre	ncd	p	0	0001	the	duration	of	esa	use	decreased	in	the	post	ncd	32	1	days	vs	pre	ncd	48	4	days	p	0	0001	group	the	post	ncd	group	reported	significantly	lower	hb	levels	higher	odds	of	receiving	a	transfusion	odds	ratio	1	41	95	ci	1	05	1	89	p	0	0238	and	increased	blood	utilization	of	53	units	transfused	or	1	53	95	ci	1	15	2	04	p	0	0034	decreased	frequency	and	duration	of	esa	administration	were	reported	in	the	post	ncd	vs	pre	ncd	period	findings	were	accompanied	by	a	modest	but	statistically	significant	increase	in	transfusions	and	a	decrease	in	hb	values</Paragraph></Rec>
<Rec><Paragraph>abdominoperineal	resection	apr	is	not	free	of	complications	in	particular	complications	due	to	the	occupation	of	the	pelvis	by	the	small	bowel	after	surgery	a	number	of	surgical	techniques	have	been	described	to	prevent	the	small	bowel	from	entering	and	adhering	to	the	pelvis	pelvic	partition	but	there	is	no	agreement	concerning	their	use	the	aim	of	this	study	was	to	evaluate	the	feasibility	effectiveness	and	safety	of	using	an	absorbable	synthetic	prosthetic	material	for	pelvic	partitioning	after	apr	a	prospective	non	randomised	longitudinal	pilot	study	was	carried	out	on	a	series	of	10	patients	who	underwent	apr	due	to	lower	third	rectal	cancer	in	order	to	evaluate	the	feasibility	safety	and	efficacy	of	pelvic	partitioning	with	an	absorbable	synthetic	prosthetic	material	in	all	the	patients	it	was	possible	to	perform	a	radical	resection	and	to	install	the	prosthesis	after	a	mean	follow	up	of	9	months	range	4	18	months	no	abdominal	or	perineal	complications	were	detected	one	patient	10	suffered	chronic	pelvic	pain	pelvic	partition	after	apr	of	the	rectum	with	an	absorbable	synthetic	prosthesis	is	feasible	effective	and	safe</Paragraph></Rec>
<Rec><Paragraph>the	authors	present	the	novel	and	successful	use	of	an	air	filled	breast	prosthesis	for	extra	pelvic	exclusion	of	small	bowel	to	facilitate	adjuvant	radiotherapy	following	resection	of	recurrent	adenocarcinoma	of	the	ascending	bowel	the	therapeutic	use	of	radiotherapy	in	colon	cancer	can	cause	acute	or	chronic	radiation	enteropathy	mobile	small	bowel	can	be	sequestered	in	dead	space	or	by	adhesions	exposing	it	to	adjuvant	radiotherapy	a	variety	of	pelvic	partitioning	methods	have	been	described	to	exclude	bowel	from	radiation	fields	using	both	native	and	prosthetic	materials	in	this	case	a	68	year	old	presented	with	ascending	colon	adenocarcinoma	invading	the	peritoneum	and	underwent	en	bloc	peritoneal	resection	thirty	seven	months	later	surveillance	ct	identified	a	local	recurrence	subsequent	resection	resulted	in	a	large	iliacus	muscle	defect	which	would	sequester	small	bowel	loops	thus	exposing	the	patient	to	radiation	enteropathy	the	lateral	position	of	the	defect	precluded	the	use	of	traditional	pelvic	partitioning	methods	which	would	be	unlikely	to	remain	in	place	long	enough	to	allow	radiotherapy	a	lightweight	air	filled	breast	prosthesis	allergan	133	fv	750	cms	secured	in	place	with	an	omentoplasty	was	used	to	fill	the	defect	following	well	tolerated	radiotherapy	the	prosthesis	was	deflated	under	ultrasound	guidance	and	removed	via	a	7	cm	transverse	incision	above	the	right	iliac	crest	the	patient	is	disease	free	18	months	later	with	no	evidence	of	treatment	related	morbidity	the	use	of	a	malleable	air	filled	prosthesis	for	pelvic	partitioning	allows	specific	tailoring	of	the	prosthesis	size	and	shape	for	individual	patient	defects	it	is	also	lightweight	enough	to	be	secured	in	place	using	an	omentoplasty	to	prevent	movement	related	prosthesis	migration	in	the	absence	of	adequate	omentum	a	mesh	sling	may	be	considered	to	allow	fixation	in	this	case	the	anatomy	of	the	prosthesis	position	allowed	for	its	removal	without	the	need	for	repeat	laparotomy	pre	operative	deflation	of	the	air	filled	prosthesis	under	ultrasound	guidance	also	reduces	the	size	of	the	incision	required	for	removal	this	technique	may	be	valuable	to	prevent	collateral	small	bowel	irradiation	following	resection	of	renal	or	retroperitoneal	malignancy</Paragraph></Rec>
<Rec><Paragraph>frameshift	mutations	in	microsatellite	instability	high	msi	high	colorectal	cancers	are	a	potential	source	of	targetable	neo	antigens	many	nonsense	transcripts	are	subject	to	rapid	degradation	due	to	nonsense	mediated	decay	nmd	but	nonsense	transcripts	with	a	cms	in	the	last	exon	or	near	the	last	exon	exon	junction	have	intrinsic	resistance	to	nonsense	mediated	decay	nmd	nmd	resistant	transcripts	are	therefore	a	likely	source	of	expressed	mutant	proteins	in	msi	high	tumours	using	antibodies	to	the	conserved	n	termini	of	predicted	mutant	proteins	we	analysed	msi	high	colorectal	cancer	cell	lines	for	examples	of	naturally	expressed	mutant	proteins	arising	from	frameshift	mutations	in	coding	microsatellites	cms	by	immunoprecipitation	and	western	blot	experiments	detected	mutant	protein	bands	from	nmd	resistant	transcripts	were	further	validated	by	gene	specific	short	interfering	rna	sirna	knockdown	a	genome	wide	search	was	performed	to	identify	cms	containing	genes	likely	to	generate	nmd	resistant	transcripts	that	could	encode	for	antigenic	expressed	mutant	proteins	in	msi	high	colon	cancers	these	genes	were	screened	for	cms	mutations	in	the	msi	high	colon	cancer	cell	lines	mutant	protein	bands	of	expected	molecular	weight	were	detected	in	mutated	msi	high	cell	lines	for	nmd	resistant	transcripts	crebbp	ep300	ttk	but	not	nmd	sensitive	transcripts	bax	casp5	msh3	expression	of	the	mutant	crebbp	and	ep300	proteins	was	confirmed	by	sirna	knockdown	five	cms	bearing	genes	identified	from	the	genome	wide	search	and	without	existing	mutation	data	sfrs12ip1	med8	asxl1	fbxl3	and	rgs12	were	found	to	be	mutated	in	at	least	5	of	11	45	of	the	msi	high	cell	lines	tested	nmd	resistant	transcripts	can	give	rise	to	expressed	mutant	proteins	in	msi	high	colon	cancer	cells	if	commonly	expressed	in	primary	msi	high	colon	cancers	msi	derived	mutant	proteins	could	be	useful	as	cancer	specific	immunological	targets	in	a	vaccine	targeting	msi	high	colonic	tumours</Paragraph></Rec>
<Rec><Paragraph>despite	the	advances	in	the	treatment	of	cancer	of	the	rectum	and	the	expansion	of	the	multimodal	therapeutic	technique	abdominoperineal	resection	apr	still	needs	to	be	performed	as	radical	treatment	in	20	30	of	cases	apr	of	the	rectum	involves	a	significant	morbidity	including	intestinal	obstruction	and	wound	complications	with	radiotherapy	induced	enteritis	being	able	to	develop	in	15	of	cases	subjected	to	post	operative	radiotherapy	furthermore	with	the	aim	of	improving	local	oncology	results	an	extended	apr	is	recommended	a	technique	that	requires	a	perineal	reconstruction	technique	that	allows	a	tension	free	closure	in	a	previously	radiated	tissue	and	may	prevent	perineal	hernias	developing	the	objective	of	this	article	is	to	review	pelvic	and	perineal	repair	methods	after	apr	due	to	cancer	with	special	attention	to	the	new	prosthetic	repair	techniques</Paragraph></Rec>
<Rec><Paragraph>working	with	a	group	of	key	stakeholders	the	authors	developed	an	episode	based	resource	use	measure	focused	on	the	use	of	colonoscopy	this	measure	is	intended	to	identify	differences	in	health	care	resource	use	in	a	short	time	frame	surrounding	the	colonoscopy	the	ultimate	intent	in	the	development	of	this	measure	was	to	pair	it	with	a	measure	of	quality	so	that	both	the	cost	and	quality	of	care	can	be	evaluated	together	in	initial	testing	the	authors	found	the	use	of	general	anesthesia	with	colonoscopy	to	be	associated	with	higher	episode	costs	eventually	when	paired	with	quality	measures	it	is	hoped	this	measure	will	provide	actionable	information	for	health	care	payers	and	providers	to	more	efficiently	provide	colonoscopy	services	without	compromising	quality</Paragraph></Rec>
<Rec><Paragraph>the	centers	for	medicare	and	medicaid	services	cms	considered	whether	to	reimburse	computed	tomographic	colonography	ctc	for	colorectal	cancer	screening	of	medicare	enrollees	to	help	inform	its	decision	we	evaluated	the	reimbursement	rate	at	which	ctc	screening	could	be	cost	effective	compared	with	the	colorectal	cancer	screening	tests	that	are	currently	reimbursed	by	cms	and	are	included	in	most	colorectal	cancer	screening	guidelines	namely	annual	fecal	occult	blood	test	fobt	flexible	sigmoidoscopy	every	5	years	flexible	sigmoidoscopy	every	5	years	in	conjunction	with	annual	fobt	and	colonoscopy	every	10	years	we	used	three	independently	developed	microsimulation	models	to	assess	the	health	outcomes	and	costs	associated	with	ctc	screening	and	with	currently	reimbursed	colorectal	cancer	screening	tests	among	the	average	risk	medicare	population	we	assumed	that	ctc	was	performed	every	5	years	using	test	characteristics	from	either	a	department	of	defense	ctc	study	or	the	national	ctc	trial	and	that	individuals	with	findings	of	6	mm	or	larger	were	referred	to	colonoscopy	we	computed	incremental	cost	effectiveness	ratios	for	the	currently	reimbursed	screening	tests	and	calculated	the	maximum	cost	per	scan	ie	the	threshold	cost	for	the	ctc	strategy	to	lie	on	the	efficient	frontier	sensitivity	analyses	were	performed	on	key	parameters	and	assumptions	assuming	perfect	adherence	with	all	tests	the	undiscounted	number	life	years	gained	from	ctc	screening	ranged	from	143	to	178	per	1000	65	year	olds	which	was	slightly	less	than	the	number	of	life	years	gained	from	10	yearly	colonoscopy	152	185	per	1000	65	year	olds	and	comparable	to	that	from	5	yearly	sigmoidoscopy	with	annual	fobt	149	177	per	1000	65	year	olds	if	ctc	screening	was	reimbursed	at	488	per	scan	slightly	less	than	the	reimbursement	for	a	colonoscopy	without	polypectomy	it	would	be	the	most	costly	strategy	ctc	screening	could	be	cost	effective	at	108	205	per	scan	depending	on	the	microsimulation	model	used	sensitivity	analyses	showed	that	if	relative	adherence	to	ctc	screening	was	25	higher	than	adherence	to	other	tests	it	could	be	cost	effective	if	reimbursed	at	488	per	scan	ctc	could	be	a	cost	effective	option	for	colorectal	cancer	screening	among	medicare	enrollees	if	the	reimbursement	rate	per	scan	is	substantially	less	than	that	for	colonoscopy	or	if	a	large	proportion	of	otherwise	unscreened	persons	were	to	undergo	screening	by	ctc</Paragraph></Rec>
<Rec><Paragraph>to	investigate	early	adoption	and	potential	predictors	of	postoperative	utilization	of	fluorine	18	fluorodeoxyglucose	fdg	positron	emission	tomography	pet	in	patients	who	underwent	colorectal	cancer	resection	between	july	2001	and	december	2002	the	first	18	months	of	centers	for	medicare	and	medicaid	services	cms	coverage	for	fdg	pet	and	who	were	observed	for	2	years	from	the	date	of	surgery	this	hipaa	compliant	study	was	exempt	from	institutional	review	board	approval	informed	consent	was	waived	this	was	a	retrospective	cohort	study	of	fdg	pet	utilization	in	patients	with	colorectal	cancer	following	resection	between	july	1	2001	and	december	31	2002	utilization	data	were	drawn	from	the	surveillance	epidemiology	and	end	results	medicare	files	during	the	first	2	years	following	colorectal	surgery	the	primary	outcome	measure	was	fdg	pet	utilization	covariates	included	disease	patient	and	hospital	level	characteristics	as	well	as	computed	tomography	ct	utilization	univariate	and	multiple	regression	analysis	were	performed	of	10630	patients	mean	age	77	5	years	who	underwent	resection	for	colorectal	cancer	during	the	study	period	1056	10	patients	underwent	at	least	one	fdg	pet	examination	in	the	2	year	period	following	surgery	a	41	relative	increase	in	utilization	of	fdg	pet	was	found	among	patients	who	underwent	resection	early	in	the	study	period	compared	with	those	who	underwent	resection	late	in	the	study	period	this	was	a	significant	difference	p	001	there	was	no	change	in	ct	utilization	between	these	two	groups	p	302	the	highest	utilization	of	fdg	pet	was	during	the	first	6	months	following	surgery	significant	predictors	of	higher	fdg	pet	utilization	included	rectal	cancer	later	date	of	initial	surgery	higher	disease	stage	older	age	marital	status	and	lower	comorbidity	substantial	growth	in	utilization	of	fdg	pet	within	2	years	of	surgery	was	found	among	patients	who	underwent	surgery	during	the	first	18	months	of	approved	cms	coverage	with	the	highest	rates	of	utilization	occurring	within	6	months	of	surgery	and	lower	rates	occurring	subsequently	over	the	2	year	period	following	resection</Paragraph></Rec>
<Rec><Paragraph>every	year	more	than	one	million	new	patients	are	diagnosed	with	colon	cancer	worldwide	although	multiple	prospective	randomized	trials	and	observational	studies	have	demonstrated	that	mortality	from	colon	cancer	can	be	reduced	with	screening	and	removal	of	adenomatous	polyps	compliance	with	screening	guidelines	remains	low	recent	ct	colonography	ctc	trials	have	shown	that	ctc	is	capable	of	demonstrating	adenomatous	polyps	or	10	mm	and	in	most	cases	or	6	mm	with	sensitivities	comparable	to	those	for	optical	colonoscopy	based	on	these	results	at	least	two	expert	panels	have	recommended	ctc	as	an	option	for	colorectal	cancer	screening	despite	these	endorsements	the	centers	for	medicare	and	medicaid	services	cms	in	the	united	states	recently	decided	to	deny	coverage	of	ctc	for	colorectal	cancer	screening	this	article	addresses	the	reservations	raised	by	cms	and	provides	a	perspective	on	whether	ctc	is	ready	for	routine	use	as	a	colorectal	cancer	screening	test</Paragraph></Rec>
<Rec><Paragraph>to	review	the	current	status	and	rationale	of	the	updated	acr	practice	guidelines	for	ct	colonography	ctc	clinical	validation	trials	in	both	the	united	states	and	europe	are	reviewed	key	technical	aspects	of	the	ctc	examination	are	emphasized	including	low	dose	protocols	proper	insufflation	and	bowel	preparation	important	issues	of	implementation	are	discussed	including	training	and	certification	definition	of	the	target	lesion	reporting	of	colonic	and	extracolonic	findings	quality	metrics	reimbursement	and	cost	effectiveness	successful	validation	trials	in	screening	cohorts	both	in	the	united	states	with	acrin	and	in	germany	demonstrated	sensitivity	or	90	for	patients	with	polyps	10	mm	proper	technique	is	critical	including	low	dose	techniques	in	screening	cohorts	with	an	upper	limit	of	the	ct	dose	index	by	volume	of	12	5	mgy	per	examination	training	new	readers	includes	the	requirement	of	interactive	workstation	training	with	2	d	and	3	d	image	display	techniques	the	target	lesion	is	defined	as	a	polyp	or	6	mm	consistent	with	the	american	cancer	society	joint	guidelines	five	quality	metrics	have	been	defined	for	ctc	with	pilot	data	entered	although	the	cms	national	noncoverage	decision	in	may	2009	was	a	disappointment	multiple	third	party	payers	are	reimbursing	for	screening	ctc	cost	effective	modeling	has	shown	ctc	to	be	a	dominant	strategy	including	in	a	medicare	cohort	supported	by	third	party	payer	reimbursement	for	screening	ctc	will	continue	to	further	transition	into	community	practice	and	can	provide	an	important	adjunctive	examination	for	colorectal	screening</Paragraph></Rec>
<Rec><Paragraph>approximately	15	of	small	intestinal	adenocarcinomas	show	inactivation	of	dna	mismatch	repair	mmr	and	display	high	level	microsatellite	instability	msi	h	msi	h	tumors	progress	as	a	result	of	mutations	affecting	coding	microsatellites	coding	microsatellite	instability	cmsi	that	may	result	in	a	functional	inactivation	of	the	encoded	proteins	and	provide	a	selective	growth	advantage	for	the	affected	cell	to	investigate	the	cmsi	selection	in	small	intestinal	carcinogenesis	56	adenocarcinomas	were	tested	for	msi	eleven	msi	h	carcinomas	19	6	were	identified	and	subjected	to	cmsi	analysis	in	24	potentially	tumor	relevant	genes	mutation	frequencies	were	similar	to	those	observed	in	colorectal	cancer	crc	beside	high	frequencies	of	cmsi	in	tgfbetar2	acvr2	and	aim2	we	detected	marcks	mutations	in	10	out	of	11	91	tumors	with	a	30	share	of	biallelic	mutations	since	little	is	known	about	marcks	expression	in	the	intestine	we	analyzed	marcks	protein	expression	in	31	carcinomas	in	non	neoplastic	mucosa	marcks	was	found	to	be	expressed	with	a	concentration	gradient	along	the	crypt	villus	axis	in	line	with	cmsi	induced	functional	inactivation	of	marcks	8	out	of	11	msi	h	adenocarcinomas	showed	regional	or	complete	loss	of	the	protein	in	microsatellite	stable	mss	small	bowel	adenocarcinoma	loss	of	marcks	expression	was	seen	in	2	out	of	20	tumors	10	in	conclusion	we	herein	present	a	cmsi	profile	of	msi	h	small	intestinal	adenocarcinomas	identifying	marcks	as	a	frequent	target	of	mutation	loss	of	marcks	protein	expression	suggests	a	significant	role	of	marcks	inactivation	in	the	pathogenesis	of	small	intestinal	adenocarcinomas</Paragraph></Rec>
<Rec><Paragraph>gastrointestinal	carcinoma	is	affected	environmental	factors	however	it	remains	to	be	determined	whether	neonatal	administration	of	an	estrogenic	endocrine	disruptor	such	as	diethylstilbestrol	des	affects	gastrointestinal	carcinogenesis	the	effects	of	neonatally	administered	des	on	gastrointestinal	tumorigenesis	induced	by	7	12	dimethylbenz	a	anthracene	dmba	were	investigated	in	male	and	female	rats	male	and	female	rats	in	group	i	were	daily	administered	oil	alone	from	0	14	days	after	birth	male	and	female	rats	in	groups	ii	and	iii	were	daily	administered	des	at	1	and	10	microg	rat	respectively	the	administration	periods	of	des	in	subgroups	a	iia	and	iiia	b	iib	and	iiib	and	c	iic	and	iiic	were	from	0	14	0	5	and	6	14	days	after	birth	respectively	at	28	42	and	56	days	after	birth	all	male	rats	were	given	10	mg	of	dmba	at	50	days	after	birth	all	female	rats	were	given	10	mg	of	dmba	in	the	digestive	tracts	of	male	rats	forestomach	masses	fms	in	all	groups	13	58	small	intestine	masses	in	group	iiia	17	and	colon	masses	cms	in	groups	iiia	8	and	iiib	33	were	observed	although	there	were	no	significant	changes	in	the	incidence	and	number	in	the	digestive	tracts	of	female	rats	fms	in	groups	i	10	iia	13	iib	33	iic	25	and	iiic	33	cms	in	groups	iia	6	and	iiia	6	were	seen	although	there	were	no	significant	changes	in	the	incidence	aberrant	crypt	foci	acf	in	the	colon	and	rectum	were	seen	in	all	male	and	female	rats	the	neonatal	administration	of	des	in	male	rats	increased	the	number	of	acf	while	that	in	female	rats	did	not	these	results	suggest	that	neonatal	administration	of	des	may	affect	male	colorectal	carcinogenesis</Paragraph></Rec>
<Rec><Paragraph>to	compare	the	medicare	managed	care	mc	and	fee	for	service	ffs	sectors	on	stage	at	diagnosis	and	treatment	patterns	for	prostate	female	breast	and	colorectal	cancers	and	to	examine	patterns	across	mc	plans	surveillance	epidemiology	and	end	results	medicare	linked	data	among	cases	diagnosed	at	ages	65	79	between	1998	and	2002	we	selected	all	mc	enrollees	n	42	467	and	beneficiaries	in	ffs	n	82	998	who	resided	in	the	same	counties	mc	and	ffs	samples	were	compared	using	logistic	regression	adjusting	for	demographic	geographic	and	clinical	covariates	the	percentage	of	late	stage	cases	was	similar	in	mc	and	ffs	for	prostate	and	colorectal	cancers	there	were	slightly	fewer	late	stage	breast	cancer	cases	in	mc	after	adjustment	7	3	vs	8	5	p	0	001	within	mc	radical	prostatectomy	was	performed	less	frequently	for	clinically	localized	prostate	cancer	18	3	vs	22	4	p	0	0001	and	12	or	more	lymph	nodes	were	examined	less	often	for	resected	colon	cancer	cases	40	9	vs	43	0	p	0	05	treatment	patterns	for	early	stage	breast	cancer	were	similar	in	mc	and	ffs	analyses	of	treatment	patterns	at	the	individual	plan	level	revealed	significant	variation	among	plans	as	well	as	within	the	ffs	sector	for	all	3	types	of	cancer	on	average	there	are	few	significant	differences	in	cancer	diagnosis	and	treatment	between	mc	and	ffs	such	comparisons	however	mask	the	wide	variability	among	mc	plans	as	well	as	ffs	providers	observed	variation	in	patterns	of	care	may	be	related	to	patient	selection	but	can	potentially	lead	to	outcome	differences	these	findings	support	the	need	for	quality	measures	to	evaluate	plan	practices	and	performance</Paragraph></Rec>
<Rec><Paragraph>there	are	very	few	symptom	assessment	instruments	in	chinese	we	present	the	validity	and	reliability	of	the	memorial	symptom	assessment	scale	short	form	msas	sf	and	the	condensed	form	msas	cmsas	in	chinese	cancer	patients	the	chinese	version	of	the	32	item	msas	sf	a	self	report	measure	for	assessing	symptom	distress	and	frequency	in	cancer	patients	was	administered	to	256	chinese	patients	with	colorectal	cancer	at	a	clinical	oncology	outpatient	unit	highly	prevalent	symptoms	included	worrying	59	dry	mouth	54	lack	of	energy	54	feeling	sad	48	feeling	irritable	48	and	pain	41	both	the	msas	sf	and	cmsas	demonstrated	good	validity	and	reliability	for	the	msas	sf	subscales	cronbach	alphas	ranged	from	0	84	to	0	91	and	for	cmsas	subscales	from	0	79	to	0	87	moderate	to	high	correlations	of	msas	sf	and	cmsas	subscales	with	appropriate	european	organization	for	research	and	treatment	of	cancer	eortc	qlq	c30	subscales	0	42	0	71	ps	0	001	indicated	acceptable	convergent	validity	low	correlations	with	the	rosenberg	self	esteem	and	optimism	scale	0	22	p	0	001	indicated	divergent	validity	msas	subscales	varied	as	expected	with	other	chinese	scales	the	chinese	health	questionnaire	chq	and	the	life	orientation	scale	construct	validity	of	both	msas	versions	was	demonstrated	by	effective	differentiation	between	clinically	distinct	patient	groups	karnofsky	scores	80	vs	or	80	p	0	001	no	active	treatment	vs	active	treatment	p	0	002	0	034	chq	12	scores	or	4	vs	chq	12	scores	4	p	0	001	the	number	of	symptoms	subscale	correlated	appropriately	with	the	eortc	qlq	c30	function	0	46	to	0	60	p	0	001	and	symptom	scales	0	31	0	64	p	0	001	the	average	time	to	complete	the	msas	sf	was	six	minutes	the	chinese	versions	of	the	msas	sf	and	cmsas	are	valid	and	practical	measures	further	validation	is	needed	for	chinese	patients	with	other	cancer	types	and	with	other	symptom	instruments</Paragraph></Rec>
<Rec><Paragraph>patterns	of	gi	endoscopy	are	influenced	by	the	underlying	epidemiology	of	gi	disease	as	well	as	by	policy	and	practice	guidelines	to	compare	practice	patterns	of	gi	endoscopy	between	two	large	national	databases	of	the	united	states	descriptive	database	analysis	a	5	sample	of	the	entire	u	s	medicare	population	centers	for	medicare	and	medicaid	services	cms	data	files	and	endoscopic	data	repository	of	u	s	gastroenterology	practices	clinical	outcomes	research	initiative	cori	database	from	1999	to	2003	the	study	population	included	1	121	215	medicare	and	635	573	cori	patients	undergoing	various	types	of	gi	endoscopy	egd	colonoscopy	and	flexible	sigmoidoscopy	patient	demographics	endoscopic	diagnoses	time	trends	of	diagnoses	a	colonoscopy	was	the	most	common	endoscopic	procedure	performed	cms	53	cori	58	followed	by	an	egd	37	32	and	a	flexible	sigmoidoscopy	10	10	in	the	cms	data	women	accounted	for	59	of	the	egds	57	of	the	colonoscopies	and	56	of	the	flexible	sigmoidoscopies	and	in	the	cori	data	the	corresponding	numbers	were	57	55	and	54	respectively	compared	with	their	distribution	in	the	u	s	census	population	nonwhite	patients	in	both	databases	underwent	relatively	more	egds	and	fewer	colonoscopies	the	most	common	upper	gi	diagnosis	was	gerd	followed	by	gi	bleeding	gastric	ulcer	and	duodenal	ulcer	the	most	common	lower	gi	diagnosis	was	colorectal	polyp	over	the	period	of	1999	to	2003	the	rates	of	colorectal	cancer	diagnosed	with	colonoscopy	declined	only	a	limited	amount	of	information	about	individual	patients	was	retrievable	from	the	electronic	databases	a	colonoscopy	is	now	the	most	common	endoscopic	procedure	in	the	united	states	women	undergo	both	upper	and	lower	endoscopic	procedures	more	often	than	men	nonwhite	patients	are	underrepresented	in	the	use	of	colonoscopy	relative	to	the	prevalence	of	nonwhite	persons	in	the	u	s	population	increased	use	of	a	colonoscopy	for	colon	screening	and	surveillance	has	been	associated	with	a	decreased	rate	of	cancer	diagnosis</Paragraph></Rec>
<Rec><Paragraph>managed	care	weighs	advances	and	associated	costs	to	determine	whether	the	combination	of	longer	life	at	sometimes	significantly	increased	cost	represents	value	the	price	of	treatment	is	only	1	factor	to	review	treatment	decision	processes	for	oncologic	agents	in	managed	care	environments	price	can	be	exceptionally	high	for	individuals	but	if	the	population	size	is	low	the	per	member	per	month	pmpm	impact	can	be	almost	negligible	unlike	treatments	that	have	moderate	costs	but	are	used	ubiquitously	cancer	therapies	have	for	the	most	part	escaped	managed	care	s	notice	for	2007	the	national	cancer	institute	projects	that	antineoplastic	agents	will	consume	almost	a	quarter	of	the	overall	drug	spend	the	medicare	population	is	a	unique	concern	with	regard	to	cancer	traditionally	medicare	reimbursement	of	chemotherapeutic	agents	was	based	on	average	wholesale	price	awp	discounting	not	the	oncologist	s	purchasing	cost	this	allowed	oncologists	to	use	reimbursement	for	infusions	to	support	their	medical	practices	the	proposed	plan	of	the	center	for	medicare	medicaid	services	cms	to	use	average	sales	price	asp	plus	6	to	reimburse	for	drugs	used	in	the	office	setting	leads	to	significant	problems	pharmacy	and	therapeutics	committees	will	also	face	challenges	fewer	data	are	available	for	some	agents	because	they	have	become	available	through	the	u	s	food	and	drug	administration	s	fast	track	priority	review	or	accelerated	approval	processes	oncology	disease	management	programs	must	reach	out	to	patients	and	not	necessarily	deal	with	oncology	issues	directly	but	address	tangential	issues	that	impact	care	especially	depression	and	pain	management</Paragraph></Rec>
<Rec><Paragraph>medicare	covers	costs	far	more	than	50	of	all	cancer	patients	and	most	private	payers	follow	medicare	s	lead	on	coverage	and	benefits	for	cancer	care	medicare	and	private	payers	are	legally	required	by	federal	statute	to	cover	anticancer	chemotherapeutic	products	based	on	u	s	food	and	drug	administration	approved	labeling	and	indicate	how	off	label	uses	are	covered	to	review	reimbursement	issues	unique	to	medicare	with	regard	to	oncology	drugs	currently	the	centers	for	medicare	medicaid	services	cms	recognizes	2	compendia	for	purposes	of	evaluating	off	label	uses	of	drugs	coverage	determinations	can	be	pursued	nationally	locally	and	case	by	case	because	of	the	impact	and	scope	of	colorectal	cancer	on	the	national	budget	cms	initiated	a	process	to	establish	national	coverage	determinations	this	and	other	such	medicare	reforms	will	have	significant	repercussions	for	clinicians	who	work	with	oncology	patients	major	administrative	and	access	challenges	for	both	health	care	providers	and	beneficiaries	include	a	diverse	array	of	plan	choices	in	terms	of	medicare	part	d	the	25	of	patients	who	are	chronically	ill	and	prescribed	expensive	therapies	including	antineoplastics	and	supportive	care	agents	may	find	the	coverage	gap	donut	hole	challenging	and	even	prohibitive	in	their	access	to	appropriate	care	lack	of	coverage	could	potentially	affect	therapy	compliance	and	managed	care	must	pursue	additional	payment	or	coverage	support	mechanisms	evaluating	formularies	will	be	critical	for	cancer	patients	and	those	who	use	specialty	drugs	as	they	select	their	part	d	plans	in	the	future	oncologists	and	their	patients	are	left	with	difficult	choices	regarding	not	only	the	clinical	efficacy	of	a	treatment	but	also	the	financial	considerations	of	the	treatment</Paragraph></Rec>
<Rec><Paragraph>mismatch	repair	mmr	deficiency	is	a	major	mechanism	of	colorectal	tumorigenesis	that	is	observed	in	10	15	of	sporadic	colorectal	cancers	and	those	associated	with	the	hereditary	nonpolyposis	colorectal	cancer	hnpcc	syndrome	mmr	deficiency	leads	to	the	accumulation	of	mutations	mainly	at	short	repetitive	sequences	termed	microsatellites	constituting	the	high	level	microsatellite	instability	msi	h	phenotype	in	recent	years	several	genes	have	been	described	that	harbor	microsatellites	in	their	coding	region	coding	microsatellites	cms	and	are	frequently	affected	by	mutations	in	mmr	deficient	cancers	however	evidence	for	a	functional	role	of	most	of	the	known	cms	containing	genes	is	missing	and	further	analyses	are	needed	for	a	better	understanding	of	msi	tumorigenesis	here	we	examined	in	detail	alterations	of	the	absent	in	melanoma	2	aim2	gene	that	shows	a	high	frequency	of	cms	frameshift	mutations	in	msi	h	colorectal	gastric	and	endometrial	tumors	aim2	belongs	to	the	hin	200	family	of	interferon	ifn	inducible	proteins	its	role	in	colon	carcinogenesis	however	is	unknown	sequencing	of	the	entire	coding	region	of	aim2	revealed	a	high	frequency	of	frameshift	and	missense	mutations	in	primary	msi	h	colon	cancers	9	20	and	cell	lines	9	15	biallelic	aim2	alterations	were	detected	in	8	msi	h	colon	tumors	and	cell	lines	in	addition	aim2	promoter	hypermethylation	conferred	insensitivity	to	ifn	gamma	induced	aim2	expression	of	three	msi	h	colon	cancer	cell	lines	these	results	demonstrate	that	inactivation	of	aim2	by	genetic	and	epigenetic	mechanisms	is	frequent	in	mmr	deficient	colorectal	cancers	thus	suggesting	that	aim2	is	a	mutational	target	relevant	for	the	progression	of	msi	h	colorectal	cancers</Paragraph></Rec>
<Rec><Paragraph>blacks	are	more	likely	to	be	diagnosed	at	a	later	stage	of	colorectal	cancer	crc	and	have	poorer	survival	than	whites	colorectal	cancer	crc	is	usually	curable	when	diagnosed	at	an	early	stage	we	compare	the	use	of	crc	tests	for	screening	between	whites	and	blacks	and	compare	the	use	of	crc	tests	for	either	screening	or	diagnosis	and	further	check	the	test	results	for	a	diagnosis	of	crc	the	data	we	use	are	from	physician	claims	files	provided	by	the	centers	for	medicare	and	medicaid	services	cms	1996	2000	for	a	closed	cohort	of	all	tennesseans	eligible	for	medicare	in	1996	age	or	6	half	as	many	blacks	as	whites	were	screened	with	fecal	occult	blood	testing	fobt	sigmoidoscopy	and	colonoscopy	significantly	fewer	blacks	had	any	colorectal	procedures	sigmoidoscopy	colonoscopy	and	or	barium	enema	for	screening	or	diagnosis	however	the	test	results	show	that	more	blacks	were	diagnosed	with	crc	than	whites	the	use	of	crc	tests	is	low	regardless	of	race	only	24	of	beneficiaries	used	at	least	one	of	the	four	procedures	during	the	five	years	during	the	five	years	fobt	and	barium	enema	use	decreased	significantly	for	both	blacks	and	whites	while	colonoscopy	use	increased	significantly	sigmoidoscopy	use	was	highest	in	1998	which	corresponds	to	the	change	of	medicare	coverage	policy	in	1998	removal	of	financial	barriers	to	screening	alone	has	failed	to	substantially	improve	the	use	of	colorectal	procedures	lack	of	vigilance	and	lack	of	access	to	good	quality	of	care	contribute	to	the	fact	that	blacks	are	more	likely	to	be	diagnosed	at	a	late	stage	of	crc	than	whites</Paragraph></Rec>
<Rec><Paragraph>traditionally	patients	with	a	high	rectosigmoid	carcinoma	and	a	synchronous	large	distal	rectal	adenoma	would	be	treated	by	low	anterior	resection	with	associated	loss	of	rectal	function	four	patients	with	a	carcinoma	of	the	upper	rectum	or	distal	sigmoid	colon	and	a	synchronous	distal	rectal	adenoma	were	treated	by	high	anterior	resection	followed	by	staged	transanal	endoscopic	microsurgery	tem	thus	conserving	the	distal	rectum	preoperative	and	postoperative	rectal	function	was	assessed	using	the	st	mark	s	incontinence	score	the	proximal	carcinomas	and	distal	adenomas	were	12	18	cms	and	0	5	9	cms	respectively	from	the	dentate	line	the	mean	surface	area	of	the	distal	adenomas	was	9	7	cms2	there	were	no	deaths	or	major	complications	there	were	no	recurrences	after	a	mean	follow	up	of	31	5	months	rectal	function	was	unchanged	in	three	patients	with	a	minor	increase	in	the	score	in	one	staged	high	anterior	resection	and	rem	offers	effective	treatment	of	synchronous	rectosigmoid	carcinoma	and	distal	rectal	adenoma	with	preservation	of	rectal	function</Paragraph></Rec>
<Rec><Paragraph>dna	methylation	is	an	epigenetic	mark	crucial	in	regulation	of	gene	expression	aberrant	dna	methylation	causes	silencing	of	tumor	suppressor	genes	and	promotes	chromosomal	instability	in	human	cancers	most	of	previous	studies	for	dna	methylation	have	focused	on	limited	genomic	regions	such	as	selected	genes	or	promoter	cpg	islands	cgis	containing	recognition	sites	of	methylation	sensitive	restriction	enzymes	here	we	describe	a	method	for	high	resolution	analysis	of	dna	methylation	using	oligonucleotide	tiling	arrays	the	input	material	is	methylated	dna	immunoprecipitated	with	anti	methylcytosine	antibodies	we	examined	the	encode	region	approximately	1	of	human	genome	in	three	human	colorectal	cancer	cell	lines	and	identified	over	700	candidate	methylated	sites	cms	where	24	of	25	cms	selected	randomly	were	subsequently	verified	by	bisulfite	sequencing	cms	were	enriched	in	the	5	regulatory	regions	and	the	3	regions	of	genes	we	also	compared	dna	methylation	patterns	with	histone	h3	and	h4	acetylation	patterns	in	the	hoxa	cluster	region	our	analysis	revealed	no	acetylated	histones	in	the	hypermethylated	region	demonstrating	reciprocal	relationship	between	dna	methylation	and	histone	h3	and	h4	acetylation	our	method	recognizes	dna	methylation	with	little	bias	by	genomic	location	and	therefore	is	useful	for	comprehensive	high	resolution	analysis	of	dna	methylation	providing	new	findings	in	the	epigenomics</Paragraph></Rec>
<Rec><Paragraph>the	water	residence	time	and	diffusional	water	permeability	in	colonic	epithelial	t84	cancer	cells	was	measured	using	1	h	nmr	spectroscopy	the	values	estimated	were	35	2	2	8	ms	and	7	4	0	6	x10	3	cms	1	respectively	water	permeability	was	inhibited	to	approximately	10	of	its	original	value	by	the	mercurial	diuretic	p	chloromercuribenzenesulfonate	pcmbs	1mm	and	fully	restored	by	dithiothreitol	dtt	1mm	the	permeability	was	also	inhibited	reversibly	to	approximately	55	by	extracellular	glibenclamide	1mm	an	inhibitor	of	some	atp	binding	cassette	abc	transporters	including	the	cystic	fibrosis	transmembrane	conductance	regulator	cftr	addition	of	the	phosphodiesterase	inhibitor	3	isobutyl	1	methylxanthine	imbx	0	1	1mm	and	the	adenylate	cyclase	activator	forskolin	0	1	1mm	did	not	alter	water	permeability	it	is	concluded	that	in	t84	cells	water	diffuses	through	the	membrane	lipid	bilayer	and	via	channels	that	are	inhibited	by	pcmbs	including	the	channels	that	are	known	to	be	inhibited	by	glibenclamide</Paragraph></Rec>
<Rec><Paragraph>in	colorectal	cancer	the	immune	response	is	particularly	pronounced	against	tumors	displaying	the	high	microsatellite	instability	msi	h	phenotype	msi	h	tumors	accumulate	mutations	affecting	microsatellites	located	within	protein	encoding	regions	coding	microsatellites	cms	which	lead	to	translational	shifts	of	the	respective	reading	frames	consequently	novel	tumor	specific	frameshift	derived	neopeptides	fsp	are	generated	and	presented	by	msi	h	tumor	cells	thus	eliciting	effective	cytotoxic	immune	responses	to	analyze	whether	the	immunoselective	pressure	was	reflected	by	the	phenotype	of	msi	h	colorectal	cancer	cells	we	compared	here	the	expression	of	antigen	processing	machinery	apm	components	and	human	leukocyte	antigen	hla	class	i	antigen	subunits	in	20	msi	h	and	20	microsatellite	stable	mss	colorectal	cancer	using	a	panel	of	newly	developed	apm	component	specific	monoclonal	antibodies	in	addition	we	did	a	systematic	analysis	of	mutations	at	cms	located	within	apm	genes	and	beta2	microglobulin	beta2m	total	hla	class	i	antigen	loss	was	observed	in	12	60	0	of	the	20	msi	h	lesions	compared	with	only	6	30	0	of	the	20	mss	colorectal	cancer	lesions	moreover	total	loss	of	membraneous	hla	a	staining	was	significantly	more	frequent	in	msi	h	colorectal	cancer	p	0	0024	mutations	at	cms	of	beta2m	and	genes	encoding	apm	components	tap1	and	tap2	were	detected	in	at	least	7	35	0	of	20	msi	h	colorectal	cancers	but	in	none	of	the	mss	colorectal	cancers	p	0	0002	these	data	show	that	defects	of	hla	class	i	antigen	processing	and	presentation	seem	to	be	significantly	more	frequent	in	msi	h	than	in	mss	colorectal	cancer	suggesting	that	in	msi	h	colorectal	cancer	the	immunoselective	pressure	leads	to	the	outgrowth	of	cells	with	defects	of	antigen	presentation</Paragraph></Rec>
<Rec><Paragraph>radiofrequency	ablation	rfa	provides	an	effective	technique	for	minimally	invasive	tissue	destruction	an	alternating	current	delivered	via	a	needle	electrode	causes	localised	ionic	agitation	and	frictional	heating	of	the	tissue	around	the	needle	image	guided	percutaneous	ablation	techniques	have	been	developed	in	most	parts	of	the	body	but	the	most	widely	accepted	applications	are	for	the	treatment	of	hepatocellular	carcinoma	hcc	in	early	cirrhosis	limited	but	inoperable	colorectal	liver	metastases	inoperable	renal	cell	carcinoma	and	inoperable	primary	or	secondary	lung	tumours	the	procedures	are	well	tolerated	and	the	complication	rates	low	patients	with	coexistent	morbidity	who	are	not	suitable	for	surgery	are	often	able	to	undergo	rfa	most	treatments	in	the	lung	kidney	and	for	hcc	are	performed	under	conscious	sedation	with	an	overnight	hospital	stay	or	as	a	day	case	larger	more	complicated	ablations	for	example	in	hepatic	metastases	may	require	general	anaesthesia	limitations	of	rfa	include	the	volume	of	tissue	that	can	be	ablated	in	a	timely	fashion	that	is	most	centres	will	treat	3	5	tumours	up	to	4	5	cms	in	diameter	early	series	reporting	technical	success	and	complications	are	available	for	lung	and	renal	ablation	liver	ablation	is	better	established	and	5	year	survival	figures	are	available	from	several	centres	in	patients	with	limited	but	inoperable	colorectal	metastases	the	5	year	survival	ranges	from	26	to	30	and	for	hcc	it	is	just	under	50	in	summary	rfa	provides	the	opportunity	for	localised	tissue	destruction	of	limited	volumes	of	tumour	it	can	be	offered	to	nonsurgical	candidates	and	used	in	conjunction	with	systemic	therapy</Paragraph></Rec>
<Rec><Paragraph>microsatellite	instability	msi	occurs	in	most	hereditary	nonpolyposis	colorectal	cancers	hnpcc	and	less	frequently	in	sporadic	tumors	as	the	result	of	dna	mismatch	repair	mmr	deficiency	instability	at	coding	microsatellites	cms	in	specific	target	genes	causes	frameshift	mutations	and	functional	inactivation	of	affected	proteins	thereby	providing	a	selective	growth	advantage	to	mmr	deficient	cells	at	present	little	is	known	about	selective	target	gene	frameshift	mutations	in	preneoplastic	lesions	in	this	study	we	examined	30	hnpcc	associated	msi	h	colorectal	adenomas	of	different	grades	of	dysplasia	for	frameshift	mutations	in	26	cms	bearing	genes	which	according	to	our	previous	model	represent	selective	target	genes	of	msi	about	30	8	26	of	these	genes	showed	a	high	mutation	frequency	or	50	in	colorectal	adenomas	similar	to	the	frequencies	reported	for	colorectal	carcinomas	mutations	in	one	gene	pthl3	occurred	significantly	less	frequently	in	msi	adenomas	compared	to	published	mutation	rates	in	msi	carcinomas	36	0	vs	85	7	p	0	023	biallelic	inactivation	was	observed	in	nine	genes	thus	emphasizing	the	functional	impact	of	cms	instability	on	msi	tumorigenesis	some	genes	showed	a	high	frequency	of	frameshift	mutations	already	at	early	stages	of	msi	colorectal	tumorigenesis	that	increased	with	grade	of	dysplasia	and	transition	to	carcinoma	these	include	known	target	genes	like	bax	and	tgfbr2	as	well	as	three	novel	candidates	macs	ndufc2	and	taf1b	overall	we	have	identified	genes	of	potential	relevance	for	the	initiation	and	progression	of	msi	tumorigenesis	thus	representing	promising	candidates	for	novel	diagnostic	and	therapeutic	approaches	directed	towards	mmr	deficient	tumors</Paragraph></Rec>
<Rec><Paragraph>rapid	and	efficient	symptom	assessment	is	an	important	aspect	of	palliative	care	the	objective	was	to	determine	whether	a	smaller	number	of	symptoms	from	the	32	item	memorial	symptom	assessment	scale	short	form	msas	sf	could	convey	equivalent	quality	of	life	qol	information	responses	from	479	medical	oncology	patients	who	completed	the	msas	sf	and	the	functional	assessment	cancer	therapy	fact	g	were	analyzed	canonical	correlations	were	performed	to	assess	the	relationships	of	32	msas	sf	symptoms	to	quality	of	life	fact	g	domains	and	clinical	variables	age	karnofsky	performance	status	kps	stage	of	disease	and	inpatient	status	the	relation	of	the	subscales	of	the	condensed	msas	cmsas	and	fact	g	to	survival	was	assessed	in	a	multivariate	model	the	median	age	was	67	years	range	20	89	and	median	kps	was	80	range	20	100	primary	sites	were	prostate	in	141	29	patients	lung	in	121	26	patients	colorectal	in	53	11	patients	hematologic	in	50	10	patients	head	and	neck	in	30	6	patients	and	other	in	84	18	patients	median	survival	was	245	days	range	1	2	215	days	canonical	correlation	analyses	identified	a	five	dimensional	qol	factor	structure	symptoms	important	for	qol	also	correlated	significantly	with	survival	and	provided	the	basis	for	the	cmsas	with	14	symptoms	and	3	subscales	cmsas	sum	cmsas	phys	and	cmsas	psych	in	multivariate	analyses	the	cmsas	psych	predicted	survival	independently	of	stage	performance	status	and	qol	the	cmsas	takes	2	4	minutes	to	complete	the	cmsas	contains	both	qol	and	survival	information	approximately	equivalent	to	the	original	32	items</Paragraph></Rec>
<Rec><Paragraph>about	15	of	all	human	colorectal	gastric	and	endometrial	tumors	and	the	majority	of	tumors	in	patients	suffering	from	hereditary	nonpolyposis	colorectal	cancer	syndrome	are	caused	by	loss	of	dna	mismatch	repair	functions	in	the	affected	cancer	cells	this	results	in	insertion	or	deletion	mutations	at	short	repetitive	dna	sequences	referred	to	as	microsatellites	such	mutations	in	coding	microsatellites	cms	cause	translational	frameshifts	that	may	destroy	gene	function	these	frameshift	mutations	could	also	cause	the	translation	of	immunogenic	neopeptides	at	the	carboxy	terminus	several	such	mutations	have	been	identified	recently	however	since	none	of	the	frameshift	induced	neopeptides	identified	so	far	is	generated	in	all	cancer	cells	with	microsatellite	instability	msi	we	aim	to	define	a	broad	but	comprehensive	set	of	frameshift	peptides	fsps	that	might	be	combined	in	a	multivalent	vaccine	for	msi	cancers	here	we	characterize	the	immunogenic	properties	of	five	additional	hla	a0201	restricted	frameshift	induced	neopeptides	derived	from	mutations	in	three	cms	containing	genes	caspase	5	taf	1b	and	ht001	that	are	frequently	hit	in	msi	cancer	cells	one	caspase	5	derived	fsp	67	fliiwqntm	fsp26	was	identified	as	a	novel	hla	a0201	restricted	ctl	epitope	fsp26	specific	ctls	efficiently	lysed	colon	carcinoma	cells	expressing	hla	a0201	and	the	underlying	1	mutation	this	mutation	in	an	a	10	cms	is	observed	in	up	to	66	of	msi	colorectal	cancers	thus	this	newly	identified	ctl	epitope	may	be	another	essential	component	of	a	multivalent	vaccine	against	cancers	with	msi</Paragraph></Rec>
<Rec><Paragraph>to	report	our	initial	experience	with	hand	assisted	laparoscopic	surgery	hals	for	colorectal	malignancies	using	a	specially	designed	laparoscopic	hand	cannula	nine	caucasians	patients	with	colorectal	malignancies	underwent	hals	which	included	02	right	hemicolectomies	01	transverse	colectomy	03	sigmoid	colectomies	01	anterior	resection	and	02	low	anterior	resections	there	were	4	males	and	5	females	the	mean	length	of	incision	for	placement	of	the	cannula	was	7	cms	range	7	8	cms	the	mean	operating	time	was	180	minutes	postoperatively	on	an	average	patients	were	ambulatory	by	day	2	range	1	4	and	taking	oral	fluids	by	day	3	range	1	4	there	were	no	conversions	to	laparotomy	furthermore	there	was	no	operative	mortality	and	no	complication	directly	related	to	the	use	of	the	device	hals	appears	to	be	a	useful	adjuvant	for	laparoscopic	colectomy	due	to	advantages	provided	by	tactile	sensation	a	curative	resection	for	malignancy	can	be	performed	without	compromising	oncological	principles</Paragraph></Rec>
<Rec><Paragraph>aproximately	one	third	of	node	negative	colorectal	cancer	recur	suggesting	the	presence	of	micrometastasis	not	detected	by	conventional	histopathologic	methods	we	think	that	the	role	of	enzymes	like	cathepsin	b	play	in	the	process	of	invasion	and	metastasis	in	colorectal	cancer	might	identify	at	earlier	stages	patients	with	high	risk	of	shorter	survival	and	who	need	more	aggressive	treatment	our	porpuse	is	to	evaluate	the	prognostic	significance	of	preoperative	serum	and	inmunohistochemical	levels	of	cathepsin	b	to	identify	colorectal	carcinomas	with	worse	prognostic	fifty	five	patients	undergoing	surgical	treatment	for	colorectal	cancer	from	1998	to	2000	as	a	control	group	sera	from	23	patients	with	acute	appendicitis	serum	levels	of	cathepsin	b	were	obtained	preoperatively	krka	novo	slovenia	ng	ml	cathepsin	b	inmunoreactivity	was	determinated	after	surgical	treatment	c	19	santa	cruz	biotechnology	serum	levels	of	cea	inmulit	2000	cea	and	ca	19	9	inmulite	gi	ma	diagnostic	products	corporation	los	angeles	ca	and	p53	expression	dako	were	determinated	in	patients	with	colorectal	cancer	survival	analysis	was	realized	using	cox	and	kaplan	meier	methods	spss	10	0	for	windows	the	mean	age	of	patients	with	colorectal	cancer	was	68	years	range	39	87	years	29	males	and	26	females	tumor	size	was	4	6	cms	range	1	12	rectal	localization	32	2	moderately	differentiated	49	1	the	median	serum	and	inmunohistochemical	levels	of	cathepsin	b	were	5	74	ng	ml	and	29	56	in	patients	with	acute	appendicitis	respectively	preoperative	serum	levels	in	patients	with	colorectal	cancer	were	cea	46	04	ng	ml	range	0	21	7	32	ca	19	9	110	52	ui	ml	range	2	5	1920	and	cathepsin	b	6	94	ng	ml	range	3	57	11	6	inmunohistochemical	results	were	p53	44	36	range	0	95	cathepsin	b	66	9	range	10	90	serum	and	inmunhistochemical	values	were	significantly	increased	in	patients	with	colorectal	cancer	when	compared	with	control	group	p	0	011	and	p	0	000	high	serum	levels	of	cathepsib	b	were	significantly	associated	wiyh	shorter	survival	of	patients	with	colorectal	cancer	in	univariate	and	multivariate	methods	p	0	041	hr	1	281	95	ci	1	043	1	716	and	p	0	022	hr	1	338	955	ci	1	043	1	716	cathepsin	b	can	be	used	like	an	independent	prognostic	tumoral	marker	in	colorectal	cancer	preoperative	serum	levels	over	6	94	ng	ml	are	associated	with	worse	prognostic	and	shorter	survival</Paragraph></Rec>
<Rec><Paragraph>this	final	rule	with	comment	period	refines	the	resource	based	practice	expense	relative	value	units	rvus	and	makes	other	changes	to	medicare	part	b	payment	policy	in	addition	as	required	by	statute	we	are	announcing	the	physician	fee	schedule	update	for	cy	2003	the	update	to	the	physician	fee	schedule	occurs	as	a	result	of	a	calculation	methodology	specified	by	law	that	law	required	the	department	to	set	annual	updates	based	in	part	on	estimates	of	several	factors	although	subsequent	after	the	fact	data	indicate	that	actual	increases	were	different	to	some	degree	from	earlier	estimates	the	law	does	not	permit	those	estimates	to	be	revised	a	subsequent	law	required	estimates	to	be	revised	for	fy	2000	and	beyond	although	we	have	exhaustively	examined	opportunities	for	a	different	interpretation	of	law	that	would	allow	us	to	correct	the	flaw	in	the	formula	administratively	current	law	does	not	permit	such	an	interpretation	accordingly	without	congressional	action	to	address	the	current	legal	framework	the	department	is	compelled	to	announce	herein	a	physician	fee	schedule	update	for	cy	2003	of	4	4	percent	because	the	department	would	adopt	a	change	in	the	formula	that	determines	the	physician	update	if	the	law	permitted	it	we	have	examined	how	proper	adjustments	to	past	data	could	result	in	a	positive	update	the	department	believes	that	revisions	of	estimates	used	to	establish	the	sustainable	growth	rates	sgr	for	fiscal	years	fy	1998	and	1999	and	medicare	volume	performance	standards	mvps	for	1990	1996	would	under	present	calculations	result	in	a	positive	update	the	department	intends	to	work	closely	with	congress	to	develop	legislation	that	could	permit	a	positive	update	and	hopes	that	such	legislation	can	be	passed	before	the	negative	update	takes	effect	because	the	department	wishes	to	change	the	update	promptly	in	the	event	that	congress	provides	the	department	legal	authority	to	do	so	we	are	requesting	comments	regarding	how	physician	fee	schedule	rates	could	and	should	be	recalculated	prospectively	in	the	event	that	congress	provides	the	department	with	legal	authority	to	revise	estimates	used	to	establish	the	sustainable	growth	rates	sgr	and	for	1998	and	1999	and	the	nvps	for	1990	1996	the	other	policy	changes	concern	the	pricing	of	the	technical	component	for	positron	emission	tomography	pet	scans	medicare	qualifications	for	clinical	nurse	specialists	a	process	to	add	or	delete	services	to	the	definition	of	telehealth	the	definition	for	zzz	global	periods	global	period	for	surface	radiation	and	an	endoscopic	base	for	urology	codes	in	addition	this	rule	updates	the	codes	subject	to	physician	self	referral	prohibitions	we	are	expanding	the	definition	of	a	screening	fecal	occult	blood	test	and	are	modifying	our	regulations	to	expand	coverage	for	additional	colorectal	cancer	screening	tests	through	our	national	coverage	determination	process	we	also	make	revisions	to	the	sustainable	growth	rate	the	anesthesia	conversion	factor	and	the	work	values	for	some	gastroenterologic	services	we	are	making	these	changes	to	ensure	that	our	payment	systems	are	updated	to	reflect	changes	in	medical	practice	and	the	relative	value	of	services	this	final	rule	also	clarifies	the	enrollment	of	physical	and	occupational	therapists	as	therapists	in	private	practice	and	clarifies	the	policy	regarding	services	and	supplies	incident	to	a	physician	s	professional	services	in	addition	this	final	rule	discusses	physical	and	occupational	therapy	payment	caps	and	makes	technical	changes	to	the	definition	of	outpatient	rehabilitation	services	in	addition	we	are	finalizing	the	calendar	year	cy	2002	interim	rvus	and	are	issuing	interim	rvus	for	new	and	revised	procedure	codes	for	calendar	year	cy	2003	as	required	by	the	statute	we	are	announcing	that	the	physician	fee	schedule	update	for	cy	2003	is	4	4	percent	the	initial	estimate	of	the	sustainable	growth	rate	for	cy	2003	is	7	6	percent	and	the	conversion	factor	for	cy	2003	is	34	5920	this	final	rule	will	also	allow	registered	nurses	rns	to	provide	emergency	care	in	certain	critical	access	hospitals	cahs	in	frontier	areas	an	area	with	fewer	than	six	residents	per	square	mile	or	remote	locations	locations	designated	in	a	state	s	rural	health	plan	that	we	have	approved	this	policy	applies	if	the	state	following	consultation	with	the	state	boards	of	medicine	and	nursing	and	in	accordance	with	state	law	requests	that	rns	be	included	along	with	a	doctor	of	medicine	or	osteopathy	a	physician	s	assistant	or	a	nurse	practitioner	with	training	or	experience	in	emergency	care	as	personnel	authorized	to	provide	emergency	services	in	cahs	in	frontier	areas	or	remote	locations</Paragraph></Rec>
<Rec><Paragraph>microsensors	provide	instruments	particularly	suited	for	the	rapid	noninvasive	and	on	line	analysis	of	cell	and	tissue	cultures	the	microsensor	system	presented	in	this	paper	is	a	modular	arrangement	of	various	planar	and	nonplanar	sensor	elements	for	the	measurement	of	physiological	parameters	of	cell	cultures	an	optic	access	to	the	cultures	e	g	for	light	microscopy	and	spectrophotometric	techniques	is	also	provided	for	a	parallel	and	comparative	data	acquisition	the	system	was	originally	designed	for	biomedical	research	in	chemotherapy	predicative	chemotherapy	assays	and	pharmacology	but	it	turned	out	to	be	also	an	effective	tool	for	toxicological	and	environmental	research</Paragraph></Rec>
<Rec><Paragraph>apc	adenomatous	polyposis	coli	protein	is	differentially	expressed	in	the	normal	colonic	crypt	and	believed	to	be	involved	in	colonic	cell	maturation	in	this	work	we	investigated	whether	expression	of	the	apc	protein	is	associated	with	cell	death	in	colonic	epithelial	cells	we	have	previously	reported	an	in	vitro	system	to	study	apoptosis	briefly	cells	attached	to	the	flask	have	a	low	frequency	of	apoptosis	1	3	whereas	cells	that	detach	from	the	flask	and	float	in	the	medium	have	a	high	proportion	of	apoptotic	cells	36	96	depending	on	the	cell	line	the	full	length	300	kda	or	truncated	apc	protein	normally	expressed	by	the	attached	cells	detected	using	the	fe9	antibody	was	found	to	be	lost	in	the	floating	apoptotic	cells	in	8	11	colon	tumour	cell	lines	examined	in	addition	the	apc	antibody	fe9	detected	a	90	kda	protein	in	the	floating	apoptotic	cells	of	all	cell	lines	investigated	which	was	not	present	in	attached	cells	furthermore	loss	of	full	length	apc	and	gain	of	the	90	kda	protein	was	observed	in	the	apoptotic	cells	of	2	cell	lines	derived	from	other	tissues	the	sv40	transformed	fibroblast	cell	line	cmsv40fib	and	the	lymphoblastoid	b	cell	line	bja	b	in	cells	repeatedly	frozen	and	thawed	believed	to	induce	necrotic	cell	death	full	length	or	truncated	apc	was	also	lost	though	a	95	kda	protein	distinct	from	that	in	apoptotic	cells	was	observed	specific	loss	of	full	length	or	truncated	apc	resulting	in	a	90	kda	protein	in	apoptotic	cells	but	a	95	kda	protein	in	necrotic	cells	is	therefore	associated	with	cell	death	our	findings	suggest	a	possible	role	for	apc	in	cell	survival</Paragraph></Rec>
<Rec><Paragraph>to	study	whether	digital	examination	preceding	anal	manometry	causes	significant	alteration	of	maximum	resting	pressure	reading	and	to	quantify	the	discrepancies	78	individuals	64	incontinent	14	controls	were	investigated	recordings	of	maximum	resting	pressure	were	taken	before	and	after	digital	rectal	examination	there	was	a	mean	discrepancy	of	only	1	8	cms	h2o	between	the	readings	and	excellent	correlation	but	analysis	of	agreement	revealed	a	bias	that	tended	to	be	greater	with	smaller	measurements	and	unacceptable	variability	between	test	results	furthermore	the	bias	was	not	related	to	age	gender	the	grade	of	incontinence	maximum	voluntary	contraction	functional	anal	canal	length	and	threshold	volume	digital	rectal	examination	prior	to	manometry	causes	unpredictable	results	especially	in	patients	with	lower	maximum	resting	pressures	and	should	strictly	be	avoided</Paragraph></Rec>
<Rec><Paragraph>to	compare	the	effect	of	cancer	prevention	of	china	medical	stone	cms	and	ge	132	rats	were	subcutaneously	injected	with	dimethylhydrazine	for	15	weeks	and	orally	administered	with	10	china	medical	stone	soak	and	ge	132	for	27	weeks	colorectal	cancer	incidence	in	cms	was	found	significantly	lower	than	in	ge	132	and	controls	p	0	05	0	01	in	ge	132	only	the	mean	cancer	foci	and	the	mean	cancer	volumes	rat	were	found	significantly	less	than	controls	p	0	01	it	was	shown	by	endoscopy	that	a	precancerous	lesion	of	the	bowel	resulted	from	carcinogen	was	more	mild	in	cms	and	ge	132	than	in	controls	serum	gamma	interferon	titer	and	nk	activity	of	spleen	cells	were	significantly	elevated	in	cms	and	ge	132	researches	explained	that	the	effect	of	cancer	prevention	of	cms	was	better	than	that	of	ge	132</Paragraph></Rec>
<Rec><Paragraph>statin	a	non	proliferation	specific	nuclear	antigen	was	used	here	to	assess	the	colonic	crypt	kinetics	of	the	mucosa	bordering	a	human	colon	cancer	mucosal	strips	adjacent	to	a	colon	cancer	obtained	from	operative	specimens	were	immediately	cut	into	five	one	cm	segments	and	stored	in	liquid	nitrogen	an	immunohistological	technique	using	the	statin	antibody	as	a	nuclear	marker	was	used	to	determine	the	labelling	indices	of	the	non	cycling	compartment	at	the	varying	distances	optical	density	measurements	of	the	nuclear	reaction	product	served	to	objectively	identify	the	statin	positive	nucleus	the	results	indicate	that	there	is	a	statistically	significant	reduction	p	0	0001	in	the	statin	positive	labelling	index	in	the	entire	crypt	length	for	a	distance	of	three	cms	the	division	of	the	entire	crypt	into	four	levels	a	b	c	and	d	demonstrates	that	this	effect	is	principally	due	to	the	upward	extension	of	the	statin	negative	cell	mass	into	levels	b	and	c	with	a	corresponding	decrease	in	the	labelling	index	of	the	statin	positive	nuclei	in	these	levels	the	in	vivo	expression	of	nuclear	statin	demonstrates	its	usefulness	in	accurately	determining	the	size	of	the	non	proliferative	compartment	in	the	human	colonic	crypt	adjacent	to	a	colon	cancer</Paragraph></Rec>
<Rec><Paragraph>the	clinical	experience	with	the	use	in	colorectal	surgery	of	a	new	compression	anastomotic	device	developed	by	the	authors	is	reported	from	may	1986	through	june	1990	95	patients	underwent	large	bowel	anastomosis	using	this	device	operations	performed	included	51	left	hemicolectomies	or	anterior	resections	of	the	sigmoid	and	rectum	23	left	colon	resections	19	right	hemicolectomies	and	two	total	colectomies	twenty	nine	anastomoses	were	performed	below	the	pelvic	peritoneal	reflection	and	18	5	of	them	resulted	less	than	4	cms	from	the	anal	verge	while	20	were	located	between	4	5	and	8	cms	five	5	2	intraoperative	diverting	colostomies	were	needed	the	rings	were	evacuated	postoperatively	after	a	mean	of	10	9	days	with	none	or	very	little	discomfort	operative	mortality	was	1	0	one	patient	died	of	myocardial	infarction	anastomotic	complications	included	five	5	2	clinical	and	four	4	2	subclinical	leakages	no	haemorrhages	or	stenoses	were	observed	this	initial	clinical	experience	shows	the	anastomotic	device	is	reliable	and	justifies	further	experimentation</Paragraph></Rec>
<Rec><Paragraph>the	authors	report	their	results	in	surgical	treatments	of	carcinoma	localized	in	the	low	two	thirds	of	the	rectum	done	between	1980	and	1988	the	number	of	patients	was	150	resectability	119	150	79	33	per	cent	lethality	4	119	3	3	per	cent	seventy	three	of	the	patients	61	per	cent	had	sphincter	saving	procedures	and	46	of	them	38	7	per	cent	had	abdominoperineal	excision	out	of	the	64	low	anterior	resection	2	patients	l	2	64	3	1	per	cent	and	out	of	the	46	abdominoperineal	excision	also	2	patients	l	2	46	4	5	per	cent	were	lost	in	the	sphincter	saving	group	the	distal	clearance	margin	was	decreased	to	below	3	cms	at	29	patients	without	having	local	recurrence	in	many	cases	of	the	carcinoma	localized	in	the	middle	third	of	the	rectum	at	82	per	cent	of	our	own	patients	the	sphincter	can	be	saved	without	having	more	local	recurrences	decreasing	the	distal	clearance	margin	to	2	5	cms	does	not	increase	the	possibility	of	local	recurrence	if	we	do	it	cranially	the	same	way	as	at	miles	operation	and	remove	the	mesorectum	caudally	and	laterally</Paragraph></Rec>