PMID: 28693246 (None)   Terms: , rat
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0		Genetic alterations in Japanese extrahepatic biliary tract cancer .
1		Biliary tract cancer ( BTC ) is one of the most devastating types of malignant neoplasms worldwide .
2		However , the mechanisms underlying the development and progression of BTC remain unresolved .
3		BTC includes extrahepatic bile duct carcinoma ( EBDC ) , gallbladder carcinoma ( GBC ) and ampulla of Vater carcinoma ( AVC ) , named according to the location of the tumor .
4		Although genetic alterations of intrahepatic cholangiocarcinoma have been investigated , those of EBDC , GBC and AVC have not yet been fully understood .
5	Μ	The present study analyzed somatic mutations of 50 cancer-associated genes in 27 Japanese BTC cells , including : 11 EBDC , 14 GBC and 2 AVC .
6	Μ	Next-generation sequencing using an Ion AmpliSeq Cancer Panel identified a total of 44 somatic mutations across 14 cancer-associated genes .
7		Among the 44 mutations , 42 were judged as pathological mutations .
8	Μ	Frequent mutations were identified in tumor protein 53 ( TP53 ) ( 14/27 ) , SMAD family member 4 ( SMAD4 ) ( 6/27 ) , phosphatidylinositol-4,5-bisphosphate 3 - kinase , catalytic subunit alpha (PIK3CA) ( 6/27 ) , and Kirsten rat sarcoma ( KRAS ) ( 6/27 ) ; no significant differences were identified between EBDC and GBC tissues .
9		Notably , the frequency of the PIK3CA mutation was higher when compared with previous reports .
10		This result may suggest that the activation of the PIK3CA-protein kinase B signaling pathway , in addition to the abrogation of p53 , SMAD4 and RAS mitogen -activated protein kinase may have a crucial role in the carcinogenesis of Japanese BTC .
11		These findings may be useful for the development of personalized therapies for BTC .

PMID: 28401006 (None)   Terms: In vitro
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0		Genomic and proteomic characterization of ARID1A chromatin remodeller in ampullary tumors .
1		AT rich interactive domain 1A ( ARID1A ) is one of the most commonly mutated genes in a broad variety of tumors .
2		The mechanisms that involve ARID1A in ampullary cancer progression remains elusive .
3		Here , we evaluated the frequency of ARID1A and KRAS mutations in ampullary adenomas and adenocarcinomas and in duodenal adenocarcinomas from two cohorts of patients from Singapore and Romania , correlated with clinical and pathological tumor features , and assessed the functional role of ARID1A .
4		In the ampullary adenocarcinomas , the frequency of KRAS and ARID1A mutations was 34.7% and 8.2% respectively , with a loss or reduction of ARID1A protein in 17.2% of the cases .
5		ARID1A mutational status was significantly correlated with ARID1A protein expression level ( P = 0023 ) .
6		There was a significant difference in frequency of ARID1A mutation between Romania and Singapore ( 27% versus 25% , P = 004 ) , suggestive of different etiologies .
7	Μ	One somatic mutation was detected in the ampullary adenoma group .
8		In vitro studies indicated the tumor suppressive role of ARID1A .
9		Our results warrant further investigation of this chromatin remodeller as a potential early biomarker of the disease , as well as identification of therapeutic targets in ARID1A mutated ampullary cancers .

PMID: 28214200 (Patient)   Terms:
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0		Concurrent MET copy number gain and KRAS mutation is a poor prognostic factor in pancreatobiliary subtype ampullary cancers .
1		Hepatocyte growth factor ( HGF ) and MET are candidates of targeted therapies for cancer patients .
2	Μ	Although MET and HGF are commonly expressed in biliary tract cancers , their expression and gene copy number status and their association with KRAS mutations have not been investigated in pancreatobiliary-type ampullary adenocarcinomas ( A-ACs ) , one of the aggressive periampullary cancers .
3		MET and HGF expressions and MET copy number status were examined by performing immunohistochemistry ( IHC ) and silver in situ hybridization ( SISH ) in 62 surgically resected , paraffin-embedded tumors , respectively .
4	Μ	High MET and HGF protein expressions were detected in 24 ( 387% ) and 15 ( 242% ) tumors .
5		High MET expression was associated with KRAS mutation .
6		However , there were no associations of high MET/HGF expression alone with other clinicopathological feature or survival .
7	Μ	MET SISH positivity was detected in 19 tumors ( 306% ) , where 84.2% were due to high trisomy or polysomy and only 3 cases ( 158% ) were MET gene amplification .
8		The overall MET protein overexpression was well correlated with MET SISH positivity .
9		The concurrent MET SISH positivity and KRAS mutation , not each alone , was an independent poor prognostic factor of disease-free survival only in pancreatobiliary subtype of A-ACs , but not in intestinal subtype .
10		Concurrent MET SISH positivity and KRAS mutation may predict a high risk of recurrence in pancreatobiliary subtype of A-ACs , indicating those markers could be potent candidates for a new therapeutic target in this cancer type .
11		MET IHC can be used as a reliable tool screening for MET copy number status in ampullary cancers .

PMID: 27984236 (Patient)   Terms: retrospective
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0		Duodenal Neoplasms of Gastric Phenotype : An Immunohistochemical and Genetic Study With a Practical Approach to the Classification .
1		Duodenal neoplasm of gastric phenotype ( DNGP ) is very rare , and details of its histopathologic , genetic , and biological features are still unclear .
2		Frequent gene mutations in GNAS , KRAS , and APC have been reported in pyloric gland adenomas and fundic gland-type neoplasms ( initially reported as low-grade adenocarcinomas ) of the stomach .
3		Here we retrospectively analyzed 16 cases of extra-ampullary DNGP ( benign to malignant ) , and we examined the mucin immunoprofile and oncogene mutations ( GNAS , KRAS , APC , BRAF , and CTNNB1 ) .
4		The 16 DNGPs were histologically classified into adenomas ( 5 pyloric gland adenomas and 2 foveolar-type adenomas ) , neoplasms of uncertain malignant potential ( NUMPs , n = 6 ) , and invasive adenocarcinomas ( n = 3 ) .
5		NUMPs consisted of slightly atypical epithelial cells with pale , eosinophilic , or basophilic cytoplasm growing in an anastomosing or branching glandular pattern , often with expansive submucosal extension .
6		In contrast to invasive adenocarcinomas , NUMPs lacked significant nuclear irregularity , desmoplastic stromal reaction , lymphovascular invasion , and metastasis ; their features were reminiscent of fundic gland-type neoplasms of the stomach .
7		Immunophenotypically , most of NUMPs were predominantly positive for MUC6 with variable expressions of pepsinogen-I , HKATPase , human gastric mucin , and MUC5AC .
8	Μ	Molecular analyses revealed the gene mutations of GNAS in 6 ( 38% ) of 16 DNGPs ( 4 [57%] adenomas , 1 [16%] NUMP , and 1 [33%] invasive adenocarcinoma ) and APC in 4 of 15 ( 27% ) DNGPs : no adenomas , 2 ( 33% ) NUMPs , and 2 ( 67% ) invasive adenocarcinomas .
9		BRAF mutation was present in only 1 ( 16% ) NUMP , and KRAS and CTNNB1 mutations were absent .
10		In conclusion , gastric-phenotype adenomas and NUMPs of the duodenum are similar to their counterparts of the stomach , in terms of histologic , genetic , and clinicopathologic features .
11		We propose the term "NUMP" as an intermediate category between adenoma and definitely invasive adenocarcinoma .
12		Our findings may provide novel insights into the classification of undescribed but distinctive duodenal tumors showing similarity to gastric-phenotype neoplasms of the stomach .

PMID: 27611608 (None)   Terms: , rat
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0		Ampulla of Vater Carcinoma : Sequencing Analysis Identifies TP53 Status as a Novel Independent Prognostic Factor and Potentially Actionable ERBB , PI3K , and WNT Pathways Gene Mutations .
1		OBJECTIVE :
2	Μ	To identify molecular prognostic factors and potentially actionable mutations in ampulla of Vater cancer ( AVC ) .
3		BACKGROUND :
4		The largely variable outcomes of AVCs make clinical decisions difficult regarding the need of postsurgical therapy , which is based on morphological and immunohistochemical classification that do not adequately consider the varying degrees of heterogeneity present in many AVCs .
5		No approved targeted therapies for AVC exist , but some show promising results requiring better molecular characterization to identify potential responders .
6		METHODS :
7		We assessed 80 AVCs for the prognostic value of mutations of kirsten rat sarcoma ( KRAS ) , neuroblastoma RAS ( NRAS ) , B rapidly accelerated fibrosarcoma ( BRAF ) , TP53 , and 4 membrane erythroblastosis oncogene B ( ERBB ) receptor tyrosine kinases ( EGFR-ERBB1 , HER2-ERBB2 , HER3-ERBB3 , HER4-ERBB4 ) amenable to pharmacological inhibition .
8		Moreover , we evaluated mutations in 16 key components of rat sarcoma ( RAS ) , phosphatidylinositol-4,5-bisphosphate 3-kinase ( PI3K ) , protein 53 ( P53 ) , transforming growth factor beta ( TGF-beta ) , and wingless/integrated ( WNT ) pathways , recently associated to AVC by whole-exome sequencing .
9		RESULTS :
10		TP53 and KRAS were mutated in 41% and 35% of cases , respectively , and emerged as independent prognostic factors together with tumor stage and regardless of the histotype ( TP53 : P = 0.0006 ; KRAS : P = 0.0018 ; stage IIB : P = 0.0117 ; stage III-IV : P = 0.0020 ) .
11		ERBB , WNT and PI3K pathway genes were mutated in 37.5% of cases .
12		CONCLUSIONS :
13	✓	KRAS and TP53 mutations are negative predictors of survival in AVCs , regardless of histotype .	GM-MRK-RO, GN-MRK-RO
14		Potentially actionable mutations in ERBB , WNT , and PI3K signaling pathway genes are present in 37.5% of all cases .
15	Μ	These might be amenable to target therapy using available drugs like Everolimus in PI3K-mutated cases or compounds under active screening against ERBB and WNT signaling .

PMID: 27602165 (Patient)   Terms: , rat
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0		APC promoter is frequently methylated in pancreatic juice of patients with pancreatic carcinomas or periampullary tumors .
1		Early detection of pancreatic and periampullary neoplasms is critical to improve their clinical outcome .
2		The present authors previously demonstrated that DNA hypermethylation of adenomatous polyposis coli ( APC ) , histamine receptor H2 ( HRH2 ) , cadherin 13 ( CDH13 ) , secreted protein acidic and cysteine rich ( SPARC ) and engrailed-1 ( EN-1 ) promoters is frequently detected in pancreatic tumor cells .
3		The aim of the present study was to assess their prevalence in pancreatic juice of carcinomas of the pancreas and periampullary area .
4		A total of 135 pancreatic juices obtained from 85 pancreatic cancer ( PC ) , 26 ampullary carcinoma ( AC ) , 10 intraductal papillary mucinous neoplasm ( IPMN ) and 14 chronic pancreatitis ( CP ) patients were analyzed .
5		The methylation status of the APC , HRH2 , CDH13 , SPARC and EN-1 promoters was analyzed using methylation specific-melting curve analysis ( MS-MCA ) .
6		rat Kirsten sarcoma viral oncogene homolog ( KRAS ) mutations were also tested with allele -specific quantitative polymerase chain reaction amplification .
7		Out of the 5 promoters analyzed , APC ( 71% ) and HRH2 ( 65% ) were the most frequently methylated in PC juice .
8	Μ	APC methylation was also detected at a high frequency in AC ( 76% ) and IPMN ( 80% ) , but only occasionally observed in CP ( 7% ) .
9		APC methylation had a high sensitivity ( 71-80% ) for all types of cancer analyzed .
10		The panel ( where a sample scored as positive when >/ = 2 markers were methylated ) did not outperform APC as a single marker .
11		Finally , KRAS detection in pancreatic juice offered a lower sensitivity ( 50% ) and specificity ( 71% ) for detection of any cancer .
12		APC hypermethylation in pancreatic juice , as assessed by MS-MCA , is a frequent event of potential clinical usefulness in the diagnosis of pancreatic and periampullary neoplasms .

PMID: 27517148 (Patient)   Terms: meta-analysis
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0	✓	KRAS mutation as a prognostic factor in ampullary adenocarcinoma : a meta-analysis and review .	GM-MRK-DS
1		Ampullary adenocarcinoma ( A-AC ) is a rare malignancy arising from the ampulla of Vater .
2	Μ	KRAS mutation is detected in 30-40% of patients with A-AC , but its clinical implication and prognostic value are not well described .
3		We conducted this meta-analysis to investigate the association between KRAS mutation and prognosis in patients with A-AC .
4		We searched Pubmed , MEDLINE , EMBASE , and the Cochrane Library databases for articles including following terms in their titles , abstracts , or keywords : 'ampullary or periampullary or ampulla of vater' , 'cancer or carcinoma' , and 'KRAS' .
5		There were five studies with survival data of patients .
6		A total of 388 patients with A-AC from the 5 studies were included in the overall survival ( OS ) analysis , and 169 patients from 2 studies were eligible for the relapse-free-survival ( RFS ) analysis .
7		Out of 388 patients , 175 ( 45% ) had KRAS mutation .
8	✓	There was no association between KRAS mutation and OS ( HR = 1.06 , 95% CI : 0.87-1.29 , P = 0.58 ) .	GM-ASS-RO
9	✓	However , there was a significant correlation between KRAS mutation and worse RFS ( HR = 2.74 , 95% CI : 1.52-4.92 , P = 0.0008 ) .	GM-ASS-RO
10	✓	In conclusion , this meta-analysis indicates that KRAS mutation is associated with poor RFS , but not with OS in patients with A-AC .	GM-ASS-RO

PMID: 27267833 (Patient)   Terms: clinical trial
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0		Genomic Alterations in Biliary Tract Cancer Using Targeted Sequencing .
1		BACKGROUND :
2		Biliary tract cancers ( BTCs ) are rare and heterogeneous group of tumors classified anatomically into intrahepatic and extrahepatic bile ducts and gallbladder adenocarcinomas .
3		Patient-derived tumor cell ( PDC ) models with genome analysis can be a valuable platform to develop a method to overcome the clinical barrier on BTCs .
4		MATERIAL AND METHODS :
5		Between January 2012 and June 2015 , 40 BTC patients' samples were collected .
6		PDCs were isolated and cultured from surgical specimens , biopsy tissues , or malignant effusions including ascites and pleural fluid .
7		Genome analysis using targeted panel sequencing as well as digital multiplexed gene analysis was applied to PDCs as well as primary tumors .
8		RESULTS :
9		Extrahepatic cholangiocarcinoma ( N = 15 , 375% ) , intrahepatic cholangiocarcinoma ( N = 10 , 250% ) , gallbladder cancer ( N = 14 , 350% ) , and ampulla of Vater cancer ( N = 1 , 25% ) were included .
10	Μ	We identified 15 mutations with diverse genetic alterations in 19 cases of BTC from primary tumor specimens .
11		The most common molecular alterations were in TP53 ( 8/19 , 421% ) , including missense mutations such as C242Y , E285K , G112S , P19T , R148T , R248Q , and R273L .
12	Μ	We also detected two NRAS mutations ( G12C and Q61L ) , two KRAS mutations ( G12A and G12S ) , two ERBB2 mutations ( V777L and pM774delinsMA ) and amplification , and three PIK3CA mutations ( N345K , E545K , and E521K ) .
13		PDC models were successfully established in 27 of 40 samples ( 675% ) , including 22/24 from body fluids ( 917% ) and 5/16 from tissue specimens ( 313% ) .
14		CONCLUSIONS :
15		PDC models are promising tools for uncovering driver mutations and identifying rational therapeutic strategies in BTC .
16		Application of this model is expected to inform clinical trials of drugs for molecular-based targeted therapy .

PMID: 27203738 (Patient)   Terms:
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0		Targeted next generation sequencing of endoscopic ultrasound acquired cytology from ampullary and pancreatic adenocarcinoma has the potential to aid patient stratification for optimal therapy selection .
1		BACKGROUND & ; AIMS : Less than 10% of registered drug intervention trials for pancreatic ductal adenocarcinoma ( PDAC ) include a biomarker stratification strategy .
2	Μ	The ability to identify distinct mutation subsets via endoscopic ultrasound fine needle aspiration ( EUS FNA ) molecular cytology could greatly aid clinical trial patient stratification and offer predictive markers .
3		We identified chemotherapy treatment naive ampullary adenocarcinoma and PDAC patients who underwent EUS FNA to assess multigene mutational frequency and diversity with a surgical resection concordance assessment , where available .
4		METHODS :
5		Following strict cytology smear screening criteria , targeted next generation sequencing ( NGS ) using a 160 cancer gene panel was performed .
6		RESULTS :
7	Μ	Complete sequencing was achieved in 29 patients , whereby 83 pathogenic alterations were identified in 21 genes .
8	Μ	Cytology genotyping revealed that the majority of mutations were identified in KRAS ( 93% ) , TP53 ( 72% ) , SMAD4 ( 31% ) , and GNAS ( 10% ) .
9		There was 100% concordance for the following pathogenic alterations : KRAS , TP53 , SMAD4 , KMT2D , NOTCH2 , MSH2 , RB1 , SMARCA4 , PPP2R1A , PIK3R1 , SCL7A8 , ATM , and FANCD2 .
10		Absolute multigene mutational concordance was 83% .
11	Μ	Incremental cytology smear mutations in GRIN2A , GATA3 and KDM6A were identified despite re-examination of raw sequence reads in the corresponding resection specimens .
12		CONCLUSIONS :
13	Μ	EUS FNA cytology genotyping using a 160 cancer gene NGS panel revealed a broad spectrum of pathogenic alterations .
14		The fidelity of cytology genotyping to that of paired surgical resection specimens suggests that EUS FNA represents a suitable surrogate and may complement the conventional stratification criteria in decision making for therapies and may guide future biomarker driven therapeutic development .

PMID: 27132476 (Patient)   Terms:
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0		Phenotypic characterization and clinical outcome in ampullary adenocarcinoma .
1		BACKGROUND :
2		Although various features of ampullary adenocarcinoma have been reported , the impact of genetic alterations and rare subtypes on clinical outcome remains unclear .
3		METHODS :
4		We determined the expression of proteins , including MUC1 , MUC2 , p53 , p16 , Smad/Dpc4 , and beta-catenin , and genetic mutations such as KRAS , BRAF , and GNAS mutations in 69 patients with ampullary adenocarcinoma to clarify their relationships with clinicopathological findings and subtypes .
5		RESULTS :
6		Kaplan-Meier survival analysis indicated that abnormal p53 labeling was significantly associated with a shorter overall survival .
7	✓	MUC1-positive and MUC2-negative expressions were significantly associated with lymphatic invasion , pancreatic invasion , lymph node metastasis , and advanced UICC stage .	GE-ASS-RO
8	✓	The KRAS mutation was significantly associated with large tumor size and pancreatic invasion .	GM-ASS-RO
9		There were 35 intestinal ( 50% ) , 15 pancreatobiliary ( 22% ) , and 11 mixed subtype ( 16% ) tumors .
10		Patients with the mixed subtype showed significantly poor outcome .
11	Μ	The invasiveness of the mixed subtype was similar to that of the pancreatobiliary subtype ; moreover , the mixed subtype showed a high incidence of abnormal beta-catenin immunolabeling ( 73% ) .
12		CONCLUSIONS :
13		Protein expression and genetic mutation are clinically associated with the characteristics of ampullary adenocarcinoma .
14		The mixed subtype may have a distinct tumor nature as compared to other two major subtypes .
15		J .
16		Surg .
17		Oncol. 2016 ; 114 : 119-127 .
18		(c) 2016 Wiley Periodicals , Inc .

PMID: 26997442 (Patient)   Terms:
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0		Low incidence of KRAS , BRAF , and PIK3CA mutations in adenocarcinomas of the ampulla of Vater and their prognostic value .
1		Ampullary adenocarcinomas ( A-ACs ) are rare malignancies with considerable importance because of their high curable resection rate and improved survival rate among periampullary cancers .
2		The RAS-RAF-MAPK pathway is involved in the development of A-ACs and is a potential therapeutic target .
3		However , molecular profiles of A-ACs and their prognostic impact are poorly understood .
4	Μ	Peptide nucleic acid -mediated polymerase chain reaction clamping and Mutyper were used to detect KRAS , BRAF , and PIK3CA mutations in 62 paraffinized samples of A-ACs .
5		Of 62 A-ACs , 30.6% had KRAS mutations , but no BRAF mutations and low frequency ( 16% ) of PIK3CA mutation were detected .
6	✓	KRAS mutation was correlated with poor tumor differentiation and was a predictor of shorter recurrence-free survival period in overall A-ACs , whereas the prognosis according to the histologic subtypes was not affected by KRAS mutation .	GM-MRK-RO, GM-INV-RO
7		Lymph node metastasis was an independent prognostic factor of poor overall survival .
8		Intestinal - and pancreatobiliary-type A-ACs had similar prognosis .
9		Intestinal - and pancreatobiliary-type A-ACs had different prognostic factors ; tumor differentiation and lymph node metastasis strongly predicted overall survival and recurrence-free survival in pancreatobiliary-type tumors , respectively , whereas no independent prognostic factors were demonstrated for intestinal-type tumors .
10		Low incidence of KRAS mutations and their strong prognostic value in A-ACs may suggest the potential of survival benefit depending on the epidermal growth factor receptor -targeted therapy .
11		Much lower frequencies of BRAF and PIK3CA mutations may suggest that they do not play a major role in the tumorigenesis of A-ACs .
12		Different therapeutic protocols should be considered for treating pancreatobiliary - and intestinal-type A-ACs .

PMID: 26806338 (Patient)   Terms:
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0		Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma .
1		Ampullary carcinomas are highly malignant neoplasms that can have either intestinal or pancreatobiliary differentiation .
2	Μ	To characterize somatic alterations in ampullary carcinomas , we performed whole-exome sequencing and DNA copy-number analysis on 60 ampullary carcinomas resected from clinically well-characterized Japanese and American patients .
3		We next selected 92 genes and performed targeted sequencing to validate significantly mutated genes in an additional 112 cancers .
4	Μ	The prevalence of driver gene mutations in carcinomas with the intestinal phenotype is different from those with the pancreatobiliary phenotype .
5	Μ	We identified a characteristic significantly mutated driver gene (ELF3) as well as previously known driver genes ( TP53 , KRAS , APC , and others ) .
6		Functional studies demonstrated that ELF3 silencing in normal human epithelial cells enhances their motility and invasion .

PMID: 26348463 (None)   Terms: clinical trial
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0		Advances in Molecular Pathology and Treatment of Periampullary Cancers .
1		OBJECTIVES :
2		Periampullary cancers ( PACs ) include the following 4 traditional anatomic subtypes : pancreatic , ampullary , biliary , or duodenal cancers .
3		This review was performed to highlight recent advances in the genomic and molecular understanding of each PAC subtype and the advances in chemotherapeutic and molecular trials in these cancer subtypes .
4		RESULTS :
5		Recent advances have highlighted differences in the genomic and molecular features within each PAC subtype .
6		Ampullary cancers can now be further defined accurately into their intestinal and pancreatobiliary subtypes using histomolecular profiling .
7	Μ	K-ras mutation , which occurs in most pancreatic cancers , is found to occur less frequently in ampullary ( 42%-52% ) , biliary ( 22%-23% ) , and duodenal cancers ( 32%-35% ) , suggesting crucial differences in targetable mutations in these cancer subtypes .
8		Ampullary cancers of intestinal subtype and duodenal cancers seem to share similarities with colorectal cancer , given that they respond to similar chemotherapeutic regimens .
9		This has potential implications for clinical trials and treatment selection , where PACs are often considered together .
10		CONCLUSIONS :
11		Future trials should be designed in view of our increased understanding of the different anatomic and histomolecularly profiled subtypes of PAC cancers , which respects their individual molecular characteristics , phenotype , and response to treatment .

PMID: 25975284 (Patient)   Terms:
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0		Sequencing of 279 cancer genes in ampullary carcinoma reveals trends relating to histologic subtypes and frequent amplification and overexpression of ERBB2 (HER2) .
1		The biological relevance of histological subtyping of ampullary carcinoma into intestinal versus pancreaticobiliary types remains to be determined .
2		In an effort to molecularly profile these subtypes of ampullary carcinomas , we conducted a two-phase study .
3		In the discovery phase , we identified 18 pancreatobiliary-type ampullary carcinomas and 14 intestinal-type ampullary carcinomas using stringent pathologic criteria and performed next-generation sequencing targeting 279 cancer-associated genes on these tumors .
4	Μ	Although the results showed overlapping of genomic alterations between the two subtypes , trends including more frequent KRAS alterations in pancreatobiliary-type ampullary carcinoma ( 61 versus 29% ) and more frequent mutations in APC in intestinal-type ampullary carcinoma ( 43 versus 17% ) were observed .
5	Μ	Of the entire cohort of 32 tumors , the most frequently mutated gene was TP53 ( n = 17 ) ; the most frequently amplified gene was ERBB2 ( n = 5 ) ; and the most frequently deleted gene was CDKN2A ( n = 6 ) .
6		In the second phase of the study , we aimed at validating our observation on ERBB2 and assessed ERBB2 amplification and protein overexpression in a series of 100 ampullary carcinomas .
7	✓ Μ	We found that (1) gene amplification and immunohistochemical overexpression of ERBB2 occurred in 13% of all ampullary carcinomas , therefore providing a potential target for anti-HER2 therapy in these tumors ; (2) amplification and immunohistochemical expression correlated in all cases , thus indicating that immunohistochemistry could be used to screen tumors ; and (3) none of the 14 ERBB2-amplified tumors harbored any downstream driver mutations in KRAS/NRAS , whereas 56% of the cases negative for ERBB2 amplification did , an observation clinically pertinent as downstream mutations may cause primary resistance to inhibition of EGFR family members .

PMID: 25971870 (Patient)   Terms: prospective
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0		Endoscopic papillectomy and KRAS expression in the treatment of adenoma in the major duodenal papilla .
1		OBJECTIVE :
2		The use of endoscopic papillectomy for resecting adenomas in the major duodenal papilla is increasing .
3		This study focuses on the following three issues : Can endoscopic papillectomy be performed as a safe diagnostic and/or therapeutic procedure in biopsy-verified or suspected ampullary adenoma? Does expression of mutated KRAS in resected adenomatous tissue predict long-term outcome? What other factors may affect long-term outcome and should , therefore , be considered in decision making prior to endoscopic papillectomy? MATERIAL AND METHODS : Thirty-six prospectively collected patients who underwent endoscopic papillectomy at Karolinska University Hospital between 2005 and 2014 were analyzed .
4		RESULTS :
5		The rate of exact agreement between the histomorphological grading of the endoscopic biopsies and the papillectomy specimens was low ( 48% ) .
6		Obstructive jaundice at presentation increased the risk of undetected adenocarcinoma ( RR = 398 ; 95% CI = 146-1085 , p = 0007 ) .
7		Lesions with malignancies were significantly larger ( mean 306 mm ) than those where only adenomas were found ( mean 144 mm , p = 0001 ) .
8	Μ	Mutated KRAS was detected in 9 of the 36 post-papillectomy specimens , including 4 of the 5 cases of ampullary adenocarcinoma .
9		Eighteen cases were endoscopically cured after a mean follow-up period of 47 months ( range 16-92 months ) .
10		CONCLUSIONS :
11		Endoscopic papillectomy is a valuable staging tool because of the limitations of endoscopic biopsy .
12		Endoscopic papillectomy concomitantly offers a curative treatment for most patients with adenoma in the major duodenal papilla .
13		Jaundice at presentation and large adenomas may indicate the presence of more advanced disease .
14		Determination of mutated KRAS seems to be of limited value in predicting long-term outcome .

PMID: 25616942 (Patient)   Terms:
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0		Survival in ampullary cancer : potential role of different KRAS mutations .
1		OBJECTIVE :
2		The prognosis of ampullary adenocarcinoma ( AA ) usually is favorable ; however , a subset of AA have poor biology and outcomes similar to pancreatic cancer .
3		Patients in this subset will have early recurrence and death usually within 2 years .
4		To date , there are no genetic markers to identify these patients .
5	Μ	This study identifies the high-risk subset of AA and evaluates the mutational status of KRAS in predicting poor outcome .
6		METHODS :
7		The tumor registry of an academic center was reviewed for data on patients managed operatively with AA .
8		KRAS genotypes were determined for these patients using a polymerase chain reaction-based assay on clinical specimens .
9		Analysis of variance and chi(2) tests was used to categorize continuous and categorical variables .
10		Univariate and multivariate survival analyses were performed using Kaplan-Meier and Cox methods , respectively .
11		RESULTS :
12		A total of 146 patients were identified with AA between 1982 and 2008 .
13		After stringent pathologic review , 97 patients were confirmed with AA , of whom 75 had tissue specimens available for analysis .
14		Genotyping revealed 67% were wild-type ( KRAS (WT) ) , and 33% were mutant for KRAS .
15	✓	Patients with KRAS (G12D) ( n = 9 ) , the most common mutational genotype , had poorer median survival ( 62 months ) compared with those with KRAS ( non-G12D ) mutants ( median survival not reached , mean 145 months ) and KRAS (WT) patients ( 155 months , P = 05 ) .	GM-ASS-RO, RO-ASS-GM
16		Patients with survival KRAS (G12D) , 56% were in this high-risk subset , compared with 18% of KRAS (WT) ( P = 02 ) and 31% of KRAS ( non-G12D ) ( P >05 ) populations .
17		Patients with KRAS (G12D) also were more likely to present with advanced T stage .
18		CONCLUSION :
19		The KRAS (G12D) mutation identifies a subset of AA patients with poor prognoses and may be used to identify patients at risk of early recurrence and poorer survival who may benefit from adjuvant therapy .

PMID: 25127237 (Patient)   Terms:
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0		Reporting tumor molecular heterogeneity in histopathological diagnosis .
1		BACKGROUND :
2		Detection of molecular tumor heterogeneity has become of paramount importance with the advent of targeted therapies .
3		Analysis for detection should be comprehensive , timely and based on routinely available tumor samples .
4		AIM :
5		To evaluate the diagnostic potential of targeted multigene next-generation sequencing ( TM-NGS ) in characterizing gastrointestinal cancer molecular heterogeneity .
6		METHODS :
7		35 gastrointestinal tract tumors , five of each intestinal type gastric carcinomas , pancreatic ductal adenocarcinomas , pancreatic intraductal papillary mucinous neoplasms , ampulla of Vater carcinomas , hepatocellular carcinomas , cholangiocarcinomas , pancreatic solid pseudopapillary tumors were assessed for mutations in 46 cancer-associated genes , using Ion Torrent semiconductor-based TM-NGS .
8		One ampulla of Vater carcinoma cell line and one hepatic carcinosarcoma served to assess assay sensitivity .
9		TP53 , PIK3CA , KRAS , and BRAF mutations were validated by conventional Sanger sequencing .
10		RESULTS :
11		TM-NGS yielded overlapping results on matched fresh-frozen and formalin-fixed paraffin-embedded ( FFPE ) tissues , with a mutation detection limit of 1% for fresh-frozen high molecular weight DNA and 2% for FFPE partially degraded DNA .
12	Μ	At least one somatic mutation was observed in all tumors tested ; multiple alterations were detected in 20/35 ( 57% ) tumors .
13		Seven cancers displayed significant differences in allelic frequencies for distinct mutations , indicating the presence of intratumor molecular heterogeneity ; this was confirmed on selected samples by immunohistochemistry of p53 and Smad4 , showing concordance with mutational analysis .
14		CONCLUSIONS :
15	Μ	TM-NGS is able to detect and quantitate multiple gene alterations from limited amounts of DNA , moving one step closer to a next-generation histopathologic diagnosis that integrates morphologic , immunophenotypic , and multigene mutational analysis on routinely processed tissues , essential for personalized cancer therapy .

PMID: 25076327 (None)   Terms:
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0		Biological identification of ampullary adenocarcinomas .
1		Ampullary adenocarcinomas have unique biologic and clinical features that result in its improved prognosis versus adenocarcinomas that arise from the distal bile ducts and pancreas .
2		However the histological differentiation and identification of these tumors is not easily accomplished .
3		Two abstracts at this year's ASCO Annual Meeting describe attempts to identify unique methods for distinguishing these tumors .
4		Abstract #4141 described a 92 gene RT-PCR assay that was used for molecular classification of patients with ampullary adenocarcinomas while Abstract #e15175 looked at mutational status of K-ras in patients with these tumors .
5		The results of their abstracts will be discussed .

PMID: 24525507 (Patient)   Terms:
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0		GNAS sequencing identifies IPMN-specific mutations in a subgroup of diminutive pancreatic cysts referred to as "incipient IPMNs" .
1		Incipient intraductal papillary mucinous neoplasms ( IPMNs ) are poorly described subcentimeter pancreatic cysts with papillae and mucin similar to IPMNs .
2		They are larger than pancreatic intraepithelial neoplasia but do not meet the cutoff size for IPMNs ( >/= 1 cm ) .
3		GNAS codon 201 mutations are hallmark genetic alterations of IPMNs .
4		Hence , we sought to determine the GNAS status of incipient IPMNs to better classify these lesions .
5		Incipient IPMNs from 3 institutions were histologically reassessed , manually microdissected , and the genomic DNA was extracted .
6		Using a sensitive digital ligation technique , the mutational status of KRAS at codon 12 and GNAS at codon 201 was determined .
7		We included 21 incipient IPMNs from 7 male and 12 female patients with a median age of 63 years ( range , 40 to 76 y ) .
8		Most patients underwent surgery for pancreatic ductal adenocarcinoma ( N = 8 ) or ampullary adenocarcinoma ( N = 3 ) .
9		The median incipient IPMN size was 4 mm ( range , 2 to 7 mm ) , and a majority had gastric-foveolar ( N = 11 ) or intestinal ( N = 5 ) differentiation .
10		The maximum dysplasia observed was intermediate , and most of the lesions had intermediate-grade dysplasia .
11	Μ	Mutational analysis revealed KRAS codon 12 mutations in all 21 incipient IPMNs , whereas 7 lesions ( 33% ) in 7 individual patients harbored GNAS codon 201 mutations .
12		The presence of GNAS 201 mutations in incipient IPMNs suggests that a fraction of these cysts are in fact small IPMNs .
13		Morphologically , incipient IPMNs do not appear to be high-risk lesions .
14		Additional studies in a larger cohort are needed to define the relationship of incipient IPMNs to larger IPMNs and , more importantly , to determine their clinical significance .

PMID: 24186143 (Patient)   Terms:
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0		Epidermal growth factor receptor signaling pathway is frequently altered in ampullary carcinoma at protein and genetic levels .
1		Our objective was to explore alteration of the epidermal growth factor receptor ( EGFR ) signaling pathway in ampullary carcinoma .
2		Immunohistochemical studies were employed to evaluate expression of amphiregulin as well as expression and activation of EGFR .
3	Μ	A lab-developed assay was used to identify mutations in the EGFR pathway genes , including KRAS , BRAF , PIK3CA , PTEN , and AKT1 .
4		A total of 52 ampullary carcinomas were identified , including 25 intestinal-type and 24 pancreatobiliary-type tumors , with the intestinal type being associated with a younger age at diagnosis ( P = 003 ) and a better prognosis ( P<001 ) .
5	Μ	Expression of amphiregulin correlated with better differentiation ( P<001 ) , but no difference was observed between two major histologic types .
6		Expression and activation of EGFR was more commonly seen in the pancreatobiliary type ( P<001 ) .
7	Μ	Mutations were detected in 50% of the pancreatobiliary type and 60% of the intestinal type .
8		KRAS was the most common gene mutated in the pancreatobiliary type ( 42% ) as well as the intestinal type ( 52% ) .
9	Μ	Other mutations detected included PIK3CA , SMAD4 and BRAF .
10	✓	KRAS mutations at codons 12 and 13 did not adversely affect overall survival .	GM-INV-RO
11		In conclusion , EGFR expression and activation were different between intestinal - and pancreatobiliary-type ampullary carcinoma .
12		KRAS mutation was common in both histologic types ; however , the incidence appeared to be lower in the pancreatobiliary type compared with its pancreatic counterpart , pancreatic ductal adenocarcinoma .
13	Μ	Mutational analysis of the EGFR pathway genes may provide important insights into personalized treatment for patients with ampullary carcinoma .

PMID: 23316479 (None)   Terms:
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0		Tumor budding cells , cancer stem cells and epithelial-mesenchymal transition-type cells in pancreatic cancer .
1		TLN-4601 suppresses growth and induces apoptosis of pancreatic carcinoma cells through inhibition of Ras-ERK MAPK signaling .

PMID: 22699145 (None)   Terms:
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0		Frequencies and prognostic role of KRAS and BRAF mutations in patients with localized pancreatic and ampullary adenocarcinomas .
1		OBJECTIVES :
2		The frequencies and prognostic role of KRAS and BRAF mutations in patients operated on for pancreatic ductal adenocarcinomas ( PDACs ) and ampullary adenocarcinomas ( A-ACs ) are scantily studied .
3		METHODS :
4	Μ	KRAS and BRAF mutations were analyzed in formalin-fixed , paraffin-embedded tumor samples from primarily chemotherapy-naive patients operated on with radical intentions for PDAC ( n = 170 ) and A-AC ( n = 107 ) .
5		RESULTS :
6		Eighty percent of PDAC patients had KRAS mutations ( codon 12 mutations : 74% ) and 67% with A-AC ( codon 12 mutations : 54% ) .
7		BRAF mutations were less common , 16% in PDAC and 12% in A-AC , and no V600E mutations were found .
8		Fourteen percent with PDAC and 7% with A-AC had mutations in both KRAS and BRAF .
9	✓ Μ	Multivariate analysis , including KRAS status , stage , and American Society of Anesthesiologists physical status classification system score , demonstrated that KRAS mutations in patients with A-AC were associated with short recurrence-free survival ( RFS ) ( hazard ratio , 245 ; 95% confidence interval , 119-506 ; P = 0015 ) and overall survival ( OS ) ( 193 , 95% 112-331 ; P = 0018 ) .	GM-ASS-RO
10	✓	KRAS mutations in patients with PDAC were not associated with RFS and OS .	GM-ASS-RO
11	✓	BRAF mutations were not associated with RFS and OS .	GM-ASS-RO
12		CONCLUSIONS :
13		KRAS mutations frequencies were high in PDAC and A-AC .
14	✓	KRAS mutations were associated with poor prognosis in patients with A-AC , but not in patients with PDAC .	GM-ASS-RO

PMID: 19214369 (Patient)   Terms:
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0		Endocrine cells in ampullary carcinoma .
1		BACKGROUND/PURPOSE :
2		As ampullary carcinoma originates from four anatomical regions , it may have different behaviors depending on its origin .
3		We documented the presence of endocrine cells found in ampullary carcinoma , and we studied the clinicopathological implications of their presence .
4		METHODS :
5		We immunohistochemically examined the presence of an endocrine component in 62 surgically resected specimens of ampullary carcinoma , and we studied the clinicopathological differences between endocrine component-positive cases and endocrine component-negative cases .
6		RESULTS :
7		Endocrine cells were detected in 16 cases ( 26% ) ; 11 cases had many endocrine cells , and five cases had scattered endocrine cells .
8	Μ	Serotonin-positive cells were detected in all 16 cases , in which six cases had many positive cells .
9	Μ	Several somatostatin-positive cells were detected in three cases .
10		Endocrine cells were detected in ampulloduodenal polypoid lesions ( two cases ) and ampullopancreaticobiliary ducts ( 14 cases ) .
11		The histology of 15 of the 16 endocrine component-positive ampullary carcinomas was the intestinal type .
12	Μ	Pancreatic invasion and lymph node involvement were observed less frequently in endocrine component-positive cases ( P <001 ) .
13		There were no significant differences with respect to immunoreactivity for carbohydrate antigen ( CA ) 19.9 , carcinembryonic antigen ( CEA ) , and p53 overexpression , and K-ras mutations .
14		CONCLUSIONS :
15		Endocrine component-positive ampullary carcinoma seemed to be derived from the ampullopancreaticobiliary common duct or the ampulloduodenum , and to behave less aggressively than endocrine component-negative carcinoma .

PMID: 18677542 (None)   Terms:
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0		Loss of heterozygosity predicts poor survival after resection of pancreatic adenocarcinoma .
1		An expression signature of syndecan-1 ( CD138 ) , E-cadherin and c-met is associated with factors of angiogenesis and lymphangiogenesis in ductal breast carcinoma in situ .

PMID: 14677066 (Cell)   Terms: xenograft, in vitro, mice
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0		A novel cell line and xenograft model of ampulla of Vater adenocarcinoma .
1		Ampulla of Vater cancers ( AVC ) are of clinical relevance , as they represent more than one-third of patients undergoing surgery for pancreaticoduodenal malignancies and have a better prognosis than periampullary cancers of pancreaticobiliary origin .
2		The availability of cellular models is crucial to perform cell biology and pharmacological studies and clarify the relationship between AVC and pancreatic and biliary cancers .
3		Numerous cell lines are available for pancreatic and biliary adenocarcinomas , while only two have been reported recently for AVC .
4		These were derived from a poor and a well-differentiated AVC , and both had wild-type K - ras and mutated p53 .
5		We report the establishment of a novel AVC cell line ( AVC1 ) derived from a moderately differentiated cancer , having a mutated K - ras , wild-type p53 , and methylated p16 .
6		Thus , our cell line adds to the spectrum of available in vitro models representative of the different morphological and molecular presentations of primary AVC .
7		We further characterized AVC1 for the expression of relevant cell surface molecules and sensitivity to chemotherapeutic agents of common clinical use .
8		It expresses MHC-I and CD95/Fas , while HLA-DR , CD40 , CD80 , CD86 , MUC-1 , MUC-2 , and ICAM-1/CD54 are absent .
9		It has a low to moderate sensitivity to both 5-FU and gemcitabine , at variance with much higher sensitivity displayed by two pancreatic ductal carcinoma cell lines .
10		Lastly , AVC1 can be readily xenografted in immunodeficient mice , making it a suitable model for pre-clinical studies .

PMID: 12730870 (None)   Terms:
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0		Epigenetic and genetic alterations in duodenal carcinomas are distinct from biliary and ampullary carcinomas .
1		BACKGROUND & ; AIMS : Carcinomas of the extrahepatic bile ducts , ampulla of Vater , and duodenum are uncommon , and their epigenetic and genetic alterations are not well characterized .
2		METHODS :
3		We therefore compared the methylation profile and genetic alterations in 18 extrahepatic biliary , 9 ampullary , and 12 duodenal carcinomas .
4		We evaluated methylation at p16 , p14 , and human Mut L homologue ( hMLH1 ) by methylation - specific PCR ( MSP ) , and at cyclooxygenase 2 ( COX2 ) , O(6)- methyl-guanine methyltransferase ( MGMT ) , estrogen receptor ( ER ) , retinoic acid receptor beta 2 ( RAR beta ) , and T-type calcium channel ( CACNA1G ) genes , and methylated in tumor 1 ( MINT1 ) , MINT2 , MINT25 , MINT27 , and MINT31 loci by combined bisulfite restriction analysis ( COBRA ) ; mutation of K-ras , p53 , p16 , and p14 genes by sequencing ; loss of heterozygosity of chromosome 9p ; and microsatellite instability ( MSI ) .
5		RESULTS :
6		Duodenal carcinomas were methylated more frequently or had increased methylation densities than biliary carcinomas at p14 ( P = 004 ) , hMLH1 ( P = 004 ) , MGMT ( P = 001 ) , MINT1 ( P = 001 ) , MINT25 ( P = 001 ) , MINT27 ( P = 0001 ) , RAR beta ( P = 003 ) , and ER ( P = 0001 ) , and than ampullary carcinomas at RAR beta ( P = 002 ) and ER ( P = 003 ) .
7		In contrast , the methylation profiles of biliary and ampullary carcinomas were not statistically different .
8		Simultaneous methylation of 3 or more CpG islands (CpG island methylator phenotype-high) was more common in duodenal cancers ( P = 0004 ) .
9		MGMT methylation was associated with G-to-A mutation in K-ras ( P = 0006 ) , and hMLH1 methylation was associated with MSI-high ( P = 001 ) .
10		CONCLUSIONS :
11		Our findings indicate that the methylation profile and genetic alterations of duodenal carcinomas are distinct from biliary and ampullary carcinomas , and that tumor-specific methylation is associated with gene mutation and MSI .

PMID: 12640108 (Patient)   Terms:
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0		Role of the DPC4 tumor suppressor gene in adenocarcinoma of the ampulla of Vater : analysis of 140 cases .
1		The K-ras oncogene is activated in approximately 90% of pancreatic adenocarcinomas , and the DPC4 (MADH4/SMAD4) tumor suppressor gene is inactivated in approximately 55% of pancreatic adenocarcinomas .
2		The contributions of these genetic alterations to the development of adenocarcinoma of the ampulla of Vater have not been fully established .
3		One hundred forty surgically resected ampullary adenocarcinomas ( 76 with associated adenomas with high-grade dysplasia ) were immunohistochemically labeled for the DPC4 gene product , and in 85 cases the results were correlated with the status of the K-ras oncogene from previously reported data .
4		The results were correlated with clinical outcome and with other pathologic predictors of prognosis .
5		Complete loss of Dpc4 labeling was identified in 34% ( 95% confidence interval [CI] : 26% , 43% ) of the invasive carcinomas and in none ( upper 95% CI : 6% ) of the associated adenomas .
6		Focal loss of Dpc4 was seen in three ( 4% ; 95% CI : 1% , 14% ) of the areas of high-grade dysplasia .
7		Complete loss of Dpc4 expression was seen in 28/77 intestinal-type tumors , in 17/46 pancreaticobiliary-type tumors , and in 0/10 colloid carcinomas .
8	Μ	Activating point mutations in the K-ras gene were identified in 40% of the invasive cancers .
9	✓	There was no correlation between K-ras gene mutations and Dpc4 expression and no correlation between these variables and survival .	GM-ASS-RO
10		The overall 5-year survival rate was 38% .
11		Lymph node metastases were associated with shorter survival ( P =03 ) .
12		Loss of Dpc4 expression occurs in approximately one third of invasive ampullary cancers but is not seen in adenomas ; thus , loss of Dpc4 expression occurs late in ampullary carcinogenesis .
13		Although ampullary and pancreatic adenocarcinomas share histologic and molecular features , ampullary carcinomas are less likely to show loss of Dpc4 expression or K-ras gene mutations .

PMID: 12082617 (Patient)   Terms:
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0		Common occurrence of multiple K-RAS mutations in pancreatic cancers with associated precursor lesions and in biliary cancers .
1		Recent studies on small series of pancreatic cancer ( PC ) with foci of pancreatic intraepithelial neoplasia ( PanIN ) , a putative precursor lesion , have shown that multiple K-RAS mutations may coexist in the same neoplastic pancreas .
2		To see whether mutant-K-RAS polyclonality is a common and specific feature of pancreatic carcinogenesis , we investigated a unselected series of periampullary cancers ( 41 pancreatic , 13 biliary and two ampullary adenocarcinomas ) .
3	Μ	After hemi-nested polymerase chain reaction ( PCR ) , mutations identified with single strand conformation polymorphism ( SSCP ) were confirmed by allele -specific PCR and sequencing .
4		K-RAS codon 12 was mutated in 34 ( 83% ) pancreatic cancers and in 11 ( 85% ) biliary cancers .
5	Μ	Multiple distinct K-RAS mutations were found in 16 PC ( 39% of all cases , 47% of those with mutated K-RAS ) and in eight biliary cancers ( 62 and 72% , respectively ) .
6		In PC , multiple K-RAS mutations were more frequent ( P<0001 ) in cancers with ( nine of 12 , 75% ) than in those without detectable PanIN ( seven of 29 , 24% ) .
7	Μ	Individual precursor lesions of the same neoplastic pancreas were found to harbor distinct mutations .
8		Results show that multiple K-RAS mutations are frequent both in PC with associated PanIN and in biliary cancers , and indicate that clonally distinct precursor lesions of PC might variably contribute to tumor development .

PMID: 12051537 (Patient)   Terms:
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0		Duodenal cancer in a patient with Peutz-Jeghers syndrome : molecular analysis .
1		We experienced an unusual case of duodenal adenocarcinoma associated with Peutz-Jeghers syndrome ( PJS ) .
2		A 34-year-old woman was admitted to our hospital with abdominal pain .
3		She had been diagnosed as having PJS at 21 years of age , based on the presence of mucocutaneous pigmentation of the lip and fingertips , and colonic hamartomatous polyps .
4		Abdominal computed tomography revealed a tumor in the third portion of the duodenum extending into the pancreas head .
5		As the tumor was pathologically determined to be adenocarcinoma at the time of surgery , pylorus-preserving pancreaticoduodenectomy was performed .
6		We carried out molecular analyses of this patient to examine the pathway of carcinogenesis in PJS .
7		The tumor did not show somatic mutation of the APC and K-ras genes , which is a critical step for the adenoma-carcinoma sequence in colon cancer .
8	Μ	Importantly , a germline mutation of the STK11 gene was detected at codon 281 delC in exon 6 .
9	Μ	Moreover , the tumor showed loss of heterozygosity of the 19p marker near STK11 and somatic mutation of the p53 gene .
10		These findings suggest that STK11 is a tumor suppressor gene regulating the development of hamartomas , and that somatic mutation of p53 subsequently promotes gastrointestinal cancer at a later stage in PJS .

PMID: 11382316 (None)   Terms:
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0		Carcinogenesis of cancer of the papilla and ampulla : pathophysiological facts and molecular biological mechanisms .
1		BACKGROUND :
2		Ampullary cancer has one of the highest resectability rates and best prognoses among neoplasms arising in the periampullary region .
3		DISCUSSION : Early diagnosis due to early symptoms can partially explain the better prognosis as compared to other cancers of the periampullary region , but biologic factors should also be taken in account .
4		In the past few years , the molecular mechanisms underlying this disease have been investigated and alterations of genes that regulate different cell functions have been described .
5		Mutations of K-ras and of the tumor suppressor genes APC , p16 and p53 indicate a major disturbance in cell cycle regulation .
6		CONCLUSIONS :
7		If the molecular profile of ampullary cancer is examined in terms of rate and type of molecular changes , it seems to be more similar to intestinal than to pancreatic cancer .
8		Furthermore , the fact that many ampullary carcinomas arise from adenomas and the frequent finding of ampullary tumors in patients affected by polyposis syndromes also suggest that ampullary and colon cancers share common molecular mechanisms of carcinogenesis .

PMID: 11266517 (Patient)   Terms: case, control
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0		Neoplasms of the ampulla of vater with concurrent pancreatic intraductal neoplasia : a histological and molecular study .
1		Adenoma and adenocarcinoma of the ampulla of Vater are uncommon neoplasms of the gastrointestinal tract .
2		Only one report has analyzed the relationship between ampullary adenocarcinoma and pancreatic intraductal neoplasia ( PanIN ) , the precursor lesion of pancreatic adenocarcinoma .
3		An association between PanIN and ampullary adenoma has not been reported previously .
4		Case reports have documented the progression of PanIN to invasive pancreatic adenocarcinoma .
5		We reviewed five resected ampullary adenoma and 17 ampullary adenocarcinoma cases and evaluated the pancreas for PanIN .
6		Pancreatic sections from 35 autopsies were reviewed as a control group .
7		Immunohistochemistry for overexpression of p53 and COX-2 proteins was performed in selected cases , as was PCR analysis for K-ras mutations .
8		Follow-up clinical data were obtained .
9		All 22 ampullary neoplasms were associated with PanIN , which was high grade in two ( 40% ) adenoma cases and seven ( 41% ) adenocarcinoma cases .
10		In 16 ( 73% ) evaluable cases , PanIN extended to the pancreatic resection margin ; two of which had high grade PanIN .
11		Among the autopsy controls eight ( 23% ) had low-grade PanIN .
12		Seven of the 22 ampullary cases but none of the autopsy controls had coexistent pancreatitis .
13		A smoking history was present in two of four autopsy cases in which this history was available .
14		Overexpression of the p53 and COX-2 proteins was present in only one case of high-grade PanIN .
15		K-ras mutations were present in four of four of the PanIN lesions evaluated , including one autopsy case .
16		Clinical follow-up revealed no progression of PanIN to invasive carcinoma in the remnant pancreas , although the follow-up period was too short to adequately assess that risk ( an average of 38 y for adenoma cases and 25 y for adenocarcinoma cases ) .
17		We conclude that adenomas and carcinomas of the ampulla are associated with PanIN , and often high-grade PanIN .
18		Although its malignant potential has not been fully established , PanIN is underreported and often unrecognized .
19		PanIN may be analogous to colorectal adenoma in that both are prevalent in the older adult population , but few progress to carcinoma .

PMID: 10100716 (Patient)   Terms: prospective
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0		Clinical value of K-ras codon 12 analysis and endobiliary brush cytology for the diagnosis of malignant extrahepatic bile duct stenosis .
1		Extrahepatic biliary stenosis can be caused by benign and malignant disorders .
2		In most cases , a tissue diagnosis is needed for optimal management of patients , but the sensitivity of biliary cytology for the diagnosis of a malignancy is relatively low .
3	Μ	The additional diagnostic value of K-ras mutational analysis of endobiliary brush cytology was assessed .
4		Endobiliary brush cytology specimens obtained during endoscopic retrograde cholangiopancreaticography were prospectively collected from 312 consecutive patients with extrahepatic biliary stenosis .
5	Μ	The results of conventional light microscopic cytology and K-ras codon 12 mutational analysis were compared and evaluated in view of the final diagnosis made by histological examination of the stenotic lesion and/or patient follow-up.The sensitivities of cytology and mutational analysis to detect malignancy were 36 and 42% , respectively .
6		When both tests were combined , the sensitivity increased to 62% .
7	Μ	The specificity of cytology was 98% , and the specificity of the mutational analysis and of both tests combined was 89% .
8	Μ	Positive predictive values for cytology , mutational analysis , and both tests combined were 98 , 92 , and 94% , whereas the corresponding negative predictive values were 34 , 34 , and 44% , respectively .
9	Μ	The sensitivity of K-ras mutational analysis was 63% for pancreatic carcinomas compared to 27% for bile duct , gallbladder , and ampullary carcinomas .
10	Μ	K-ras mutational analysis can be considered supplementary to conventional light microscopy of endobiliary brush cytology to diagnose patients with malignant extrahepatic biliary stenosis , particularly in the case of pancreatic cancer .
11		The presence of a K-ras codon 12 mutation in endobiliary brush cytology per se supports a clinical suspicion of malignancy , even when the conventional cytology is negative or equivocal .

PMID: 9895049 (Patient)   Terms:
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0		Analysis of K-ras gene mutations in rare pancreatic and ampullary tumours .
1		OBJECTIVE :
2		Mutation of the K-ras oncogene is a frequent event in pancreatic ductal carcinogenesis and it is believed to occur at an early stage in the development of pancreatic cancer .
3		However , little is known of the role of K-ras mutations in rare pancreatic epithelial neoplasms , endocrine tumours or other non-epithelial tumours of the pancreas .
4		Furthermore , limited data are available regarding the role of K-ras mutations in the pathogenesis of ampullary tumours .
5		DESIGN AND METHODS :
6	Μ	Using single-strand conformation polymorphism ( SSCP ) and direct sequencing of polymerase chain reaction ( PCR )- amplified fragments , we analysed codons 12 and 13 for the presence of oncogenic mutations of the K-ras oncogene .
7		Tissues were obtained from patients undergoing tumour resection for various rare pancreatic or ampullary neoplasms ( number of cases in brackets ) : ampullary adenoma (1) , neuro-endocrine tumour (3) , malignant fibrous histiocytoma of the pancreas (1) , pancreatic cystadenocarcinoma (1) , serous cystadenoma (1) , and primary and metastatic adenocarcinoma of the ampulla (5) and pancreas (3) .
8		RESULTS :
9	Μ	K-ras gene mutations at codon 12 were detected in both pancreatic adenocarcinomas and in the metastatic lesion , whereas two ampullary cancers harboured a point mutation at codon 13 : GGC-->GGG and GGC-->GGT .
10		None of the other tumours exhibited a K-ras gene mutation at codons 12 or 13 .
11		CONCLUSION :
12		Pancreatic tumours other than ductal adenocarcinoma of the pancreas do not harbour mutations of the K-ras oncogene .
13		In addition , ampullary adenocarcinomas may present with codon 13 mutations ; however , these mutations were not associated with amino acid substitution .
14		Therefore , K-ras gene mutations seem to be a specific genetic alteration contributing to the pathogenesis of pancreatic ductal adenocarcinoma .

PMID: 9514055 (Patient)   Terms:
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0		Molecular pathogenesis of sporadic duodenal cancer .
1		Whether duodenal adenocarcinoma should be considered as a gastrointestinal or as a peripancreatic cancer is a matter of debate , as is the opportunity and type of treatment .
2		We investigated 12 such cancers for the genetic anomalies involved in the pathogenesis of gastrointestinal malignancies , including (a) those occurring in common-type cancers - allelic losses at chromosomes 3p , 5q , 17p and 18q , and Ki-ras and p53 alterations ; and (b) those characteristic of mutator-phenotype cancers - microsatellite instability and TGF-betaRII gene mutations .
3	Μ	We found Ki-ras and p53 mutations in five ( 42% ) and eight cancers ( 67% ) , respectively ; chromosome 3p , 5q , 17p and 18q allelic losses in two of nine ( 22% ) , six of ten ( 60% ) , six of nine ( 67% ) and three of ten ( 30% ) informative cancers , respectively .
4		Finally , three cancers ( 25% ) showed widespread microsatellite instability and two of them had a TGF-betaRII gene mutation .
5		Our data suggest that duodenal cancers may arise from either of the two known pathogenetic molecular pathways of gastric and colorectal cancers .
6	Μ	The majority of our cases were highly aggressive cancers with frequent chromosomal changes and p53 mutations as observed in the common-type gastrointestinal malignancies , while widespread subtle alterations characteristic of mutator-phenotype cancers occurred in a minority , which also showed a favourable long-term outcome .

PMID: 9369932 (Patient)   Terms:
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0		Frequent somatic mutations of the APC and p53 genes in sporadic ampullary carcinomas .
1		Although a close relation of somatic mutations of the adenomatous polyposis coli gene with ampullary carcinomas in familial adenomatous polyposis patients has been reported , the possible association with sporadic ampullary neoplasms has not been fully examined .
2		We have therefore investigated loss of heterozygosity at the adenomatous polyposis coli locus and the mutational status of a portion of the adenomatous polyposis coli gene , including the mutation cluster region , in 17 ampullary carcinomas of non-familial adenomatous polyposis patients .
3	Μ	Alteration of the adenomatous polyposis coli gene was found in 8 of 17 ( 471% ) cases , as missense or insertion mutations , with or without loss of heterozygosity .
4	Μ	Additional investigation of p53 ( exons 5-8 ) and K-ras ( codons 12 and 13 ) gene mutations revealed a striking mutational pattern of the p53 gene .
5	Μ	Nine of the 17 cases demonstrated a total of 12 mutations , 6 clustered at codon 189 and 3 at codon 166 .
6		Furthermore , 5 of the 12 mutations were nonsense mutations .
7		Regarding the K-ras gene , 4 of the 17 ( 235% ) cases had mutations in codon 12 , 3 of the 4 cases being derived from the intraduodenal bile duct .
8		The findings indicate that alterations of the adenomatous polyposis coli and the p53 genes are relatively frequent in sporadic ampullary carcinomas .
9		In particular , the clustering at specific p53 codons might offer an etiological clue to clarify ampullary carcinogenesis .
10		Mutations of the K-ras gene , on the other hand , might be characteristic of intraduodenal bile duct origin .

PMID: 9815548 (Patient)   Terms:
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0		K-ras mutation in adenomas and carcinomas of the ampulla of vater .
1		The role of K-ras mutations in the progression of tumors of the ampulla of Vater is not well understood .
2		To study the frequency and timing of K-ras mutations in ampullary tumors , areas of invasive carcinoma and adjacent adenomas were microdissected from paraffin blocks from 96 resected tumors .
3		DNA was extracted , PCR amplification of K-ras exon 1 was performed , and PCR products were sequenced .
4		Statistical analysis of K-ras mutations with respect to patient survival and clinicopathological factors was performed using the chi2 test , log-rank test , and Cox proportional hazard model .
5		Thirty-four of 92 ampullary carcinomas ( 370% ) and 25 of 46 adenomas ( 543% ) had mutations in K-ras exon 1 .
6		Twenty-two of 23 ( 957% ) adenomas adjacent to carcinomas with K-ras mutations also had K-ras mutations .
7		The only clinicopathological factor significantly associated with K-ras mutation was tumor size >2 cm ( P = = 0035 ) .
8	✓	Patient survival did not correlate with the K-ras mutation status ( P = 031 ) .	RO-ASS-GM
9		We conclude that K-ras mutations are frequent in both adenomas and carcinomas of the ampulla of Vater and appear to occur as an early genetic event .
10	Μ	The spectrum of mutations is similar to that observed in colorectal neoplasms , and these do not significantly correlate with patient survival .

PMID: 8541732 (Patient)   Terms:
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0		Analysis of K-ras gene mutations in periampullary cancers , gallbladder cancers and cholangiocarcinomas from paraffin-embedded tissue sections .
1	Μ	Point mutations of the K-ras gene were analyzed in 25 periampullary cancers ( 21 ampulla vater cancers , two common bile duct cancers and two duodenal cancers ) , two gallbladder cancers and six cholangiocarcinomas .
2		DNA extracted from the paraffin-embedded tissues was amplified with the polymerase chain reaction and subsequently analyzed by direct cycle sequencing at codons 12 , 13 and 18 of the K-ras gene .
3	Μ	Codon 61 was first screened with single strand conformation polymorphism and then sequenced by direct cycle sequencing .
4	Μ	No point mutation was found in any of the 25 periampullary cancers or the two gallbladder cancers .
5		These results are similar to previous reports .
6	✓	Mutation of the K-ras gene seems not to play an important role in tumorigenesis of periampullary cancer .	GM-INV-RO
7	Μ	In two of six ( 33% ) cholangiocarcinoma patients , point mutations were found .
8		Both mutations were transitions , GGT to GAT at codon 12 .
9		The incidence of mutation was greater than that in Thailand ( about 8% ) but less than that in Japan ( about 60% ) .
10		Mutation of the K-ras gene may play varied roles in the tumorigenesis of cholangiocarcinoma , depending on geographic area .

PMID: 7606737 (Patient)   Terms:
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0		Somatic mutations of the adenomatous polyposis coli gene in gastroduodenal tumors from patients with familial adenomatous polyposis .
1	Μ	We analyzed somatic mutations of the adenomatous polyposis coli ( APC ) , p53 , and K-ras genes in gastroduodenal polyps and normal gastroduodenal mucosa from 21 familial adenomatous polyposis patients , using PCR-single-strand conformation polymorphism and direct sequencing methods .
2	Μ	Seventy-five polyps were obtained from these patients endoscopically or surgically , and they were histopathologically diagnosed as mild adenoma , moderate adenoma , severe adenoma , adenocarcinoma , and fundic gland polyp.Examining the APC-coding region where somatic mutations in colorectal tumors are known to be clustered , we detected 47 somatic mutations .
3	Μ	The frequency of mutation detected was 6 of 9 ( 67% ) in ampullary adenomas , 1 of 2 ( 50% ) in ampullary adenocarcinoma , 11 of 24 ( 46% ) in non-ampullary adenomas , 26 of 29 ( 90% ) in gastric adenomas , and 3 of 11 ( 27% ) in gastric fundic gland polyps .
4	Μ	These mutations frequently occurred at codons 1450 , 1462-1465 , and 1554-1556 , the third being a newly found hot spot .
5		All mutations formed stop codons that resulted in truncated APC proteins .
6	Μ	K-ras mutation was detected only in an ampullary adenocarcinoma , and p53 mutation was not detected in any of the tumors analyzed .
7	Μ	There was no somatic mutation detected in samples of flat mucosa that were diagnosed as normal mucosa both endoscopically and histopathologically .
8		Frequent APC mutations in mild and small adenomas , similar to the findings in severe and large adenomas , suggested that the genetic change in the APC gene occurs in an early stage of forming gastroduodenal adenomas .
9		Moreover , the presence of somatic APC mutations in fundic gland polyps suggests that inactivation of the APC gene plays a role not only in forming adenomas but also in forming hyperplastic polyps in fundic gland mucosa , and there may be some additional steps to the adenoma-carcinoma sequence .

PMID: 7926462 (Patient)   Terms:
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0		Point mutation of K-ras gene codon 12 in biliary tract tumors .
1		BACKGROUND/AIMS :
2		Point mutations of the K-ras gene have been reported in a wide variety of human tumors .
3		However , there might be conflicting data about its presence or incidence in biliary tract tumors .
4		The aim of this study is to elucidate the presence and types of point mutation in biliary tract tumors , including gallbladder carcinoma and adenoma , extrahepatic bile duct carcinoma , and ampullary carcinoma .
5		METHODS :
6	Μ	Mutation bands detected in modified two-step polymerase chain reaction were eluted from agarose gel and analyzed by dideoxy sequencing method .
7		RESULTS :
8		Of 20 biliary tract tumors showing a mutation band , G to A single base substitutions were confirmed in 15 cases as the most frequent changes , which were divided into changes for aspartic acid ( GAT ) and ( 14 ) serine ( AGT ) (1) .
9		Changes for valine (GTT) were found in two cases .
10	Μ	In extrahepatic bile duct carcinoma , duplicate mutations ( GA/TT ) were found in two cases and triplicate mutation ( A/GA/TT ) in one case .
11		The adenoma portion of one "cancer in adenoma" case of gallbladder showed the single base transition ( GAT ) in the second position , same as in the carcinoma portion .
12		CONCLUSIONS :
13		Most of the biliary tract tumors comprised point mutation in K-ras gene codon 12 , and G to A transition was the most frequent .

PMID: 8249918 (Patient)   Terms:
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0		Mutation analysis of K-ras oncogenes in gastroenterologic cancers by the amplified created restriction sites method .
1		A rapid , simple , and nonradioactive method for diagnosing point mutations of c-K-ras oncogenes in gastroenterologic cancers is described .
2		This method involved the selective amplification of DNA fragments from cancer tissues of surgical specimens with specific oligonucleotide primers , followed by digestion with restriction enzymes that recognized artificially created or naturally occurring restriction sites .
3	Μ	To detect codon 12 mutations , an artificial Msp I site was created by introducing a single nucleotide mismatch into the 5' mutagenesis primer .
4	Μ	Using a similar approach , an Hae III site was created to detect codon 13 mutations .
5	Μ	Bal I and MBo II sites were used to detect codon 61 mutations .
6		A total of 61 gastroenterologic cancer cases were studied .
7	Μ	Of 35 cases of colorectal cancer , 7 showed mutations : 6 at codon 12 and 1 at codon 13 .
8	Μ	In 1 of 2 cases of cholangiocellular carcinoma , point mutation at codon 12 was found .
9	Μ	One case of duodenal cancer showed point mutation at codon 12 .
10	Μ	No mutations were found in the cases of hepatocellular carcinoma (4) , gastric cancer ( 12 ) , esophageal cancer (3) , or pancreatic cancer (2) .

PMID: 8283077 (Patient)   Terms:
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0		The point mutation of c-Ki-ras at codon 12 in carcinoma of the pancreatic head region and in intraductal mucin-hypersecreting neoplasm of the pancreas .
1		In order to clarify whether the detection of a point mutation in the c-Ki-ras gene at codon 12 in tumor tissues can assist in predicting the tumor's biological grade of malignancy , two types of tumors were investigated ; one was called "carcinoma in the pancreatic head region , " and the other was intraductal mucin-hypersecreting neoplasm of the pancreas ( IMHN ) .
2		Dot hybridization and a modified PCR technique developed by Haliassos et al .
3		were employed .
4	Μ	Among 16 cases of tumors in the pancreatic head region , the point mutation was detected with a high frequency only in pancreatic ductal cell carcinomas ( five out of six cases , 833% ) , but was not detected in extrahepatic bile duct carcinomas ( 0/5 ) or in ampullary carcinomas ( 0/5 ) .
5	Μ	In pancreatic ductal cell carcinomas , no relation was found between the occurrence of the point mutation and the histological type of the tumor .
6	Μ	Among 20 cases of IMHNs , the point mutation was found in 11 cases ( 55% ) .
7	Μ	No relation was found between the occurrence of the mutation and the size of IMHNs .
8		However , as the grade of cell atypia increased , the frequency of the mutation tended to become higher .
9		These results suggest that detection of this point mutation might be useful for distinguishing pancreatic ductal cell carcinoma from those of other origins in the pancreatic head region , and for the determination of the histopathological grade of malignancy in IMHNs .

PMID: 8492470 (Patient)   Terms:
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0		[ Detection of point mutation of K-ras gene codon 12 in biliary tract and ampullary carcinoma by modified two-step polymerase chain reaction ] .
1		The point mutation of K-ras gene at codon 12 was investigated in 11 cases of gall bladder carcinoma , 10 cases of extrahepatic bile duct carcinoma , 2 cases of intrahepatic bile duct carcinoma , and 4 cases of ampullary carcinoma by modified two-step polymerase chain reaction which employed paraffin embedded materials .
2	Μ	The results revealed that there were point mutations in 6/11 , 10/10 , 2/2 , and 4/4 , respectively .
3		Judging from the ratio of density of wild and mutant band , not all cancer cells in the tissue section contained the mutation .
4		So it was suggested that the normal cells were initiated for the malignant transformation by ras gene mutations and then , selection might occur against cells containing ras mutations during progression of the tumor .
5		Modified two-step polymerase chain reaction was markedly useful for detecting mutation even at low frequency among tumor cells .

PMID: 1741644 (Patient)   Terms: in vitro
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0		Distinguishing pancreatic carcinoma from other periampullary carcinomas by analysis of mutations in the Kirsten-ras oncogene .
1	Μ	The prevalence of Kirsten ( Ki ) -ras gene mutations was studied in 105 paraffin-embedded tissues obtained from 40 patients with pancreatic cancer , 48 with bile duct carcinoma ( 19 distal , 6 middle , and 23 proximal ) , 16 with ampullary carcinoma and 1 with duodenal cancer , by in vitro amplification of target sequences by the polymerase chain reaction ( PCR ) .
2		With regard to pancreatic cancers , the authors' data confirm the very high frequency ( 886% ) of Ki-ras gene mutations occurring at codon 12 .
3		Five pancreatic carcinomas did not contain the Ki-ras mutation and included rare types of histopathology .
4		By histologic review after the examination of Ki-ras mutations through PCR , the diagnosis of four patients could be legitimately revised from other periampullary carcinoma to pancreatic carcinoma .
5	Μ	In the ampullary carcinoma , the prevalence of mutations in Ki-ras codon 12 was 13.3% .
6	Μ	Although there was a large difference in incidence of mutations between distal and middle or proximal bile duct carcinoma , the prevalence of mutations in bile duct carcinoma was limited to 19.6% .
7		Unlike other approaches to diagnose periampullary carcinoma , detection of a mutation in Ki-ras codon 12 by PCR may distinguish pancreatic carcinoma from other periampullary carcinomas that have better prognoses .