Small Bowel Carcinomas Associated with Immune-Mediated Intestinal Disorders: The Current Knowledge. Giuffrida Paolo,Vanoli Alessandro,Arpa Giovanni,Bonometti Arturo,Luinetti Ombretta,Solcia Enrico,Corazza Gino Roberto,Paulli Marco,Di Sabatino Antonio Cancers Small bowel carcinomas (SBC) are uncommon neoplasms, whose predisposing conditions include hereditary syndromes and immune-mediated intestinal disorders including coeliac disease (CD) and Crohn's disease (CrD). Although both CD-associated SBC (CD-SBC) and CrD-associated SBC (CrD-SBC) arise from an inflammatory background, they differ substantially in tumour cell phenotype, frequency of microsatellite instability and nuclear β-catenin expression, as well as in prognosis. For these patients, high tumour-infiltrating lymphocyte density and glandular/medullary histotype represent independent positive prognostic factors. Dysplasia adjacent to SBC is rare and characterized by intestinal phenotype and nuclear β-catenin in CD, while it is frequent and typified by gastro-pancreatobiliary marker expression and preserved membranous β-catenin in CrD. Recent evidence suggests that Epstein-Barr virus-positive dysplasia and SBC, albeit exceptional, do exist and are associated with CrD. In this review, we summarize the novel pathological and molecular insights of clinical and therapeutic interest to guide the care of CD-SBC and CrD-SBC. 10.3390/cancers11010031
    Small bowel carcinomas in celiac or Crohn's disease: distinctive histophenotypic, molecular and histogenetic patterns. Vanoli Alessandro,Di Sabatino Antonio,Martino Michele,Klersy Catherine,Grillo Federica,Mescoli Claudia,Nesi Gabriella,Volta Umberto,Fornino Daniele,Luinetti Ombretta,Fociani Paolo,Villanacci Vincenzo,D'Armiento Francesco P,Cannizzaro Renato,Latella Giovanni,Ciacci Carolina,Biancone Livia,Paulli Marco,Sessa Fausto,Rugge Massimo,Fiocca Roberto,Corazza Gino R,Solcia Enrico Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Non-familial small bowel carcinomas are relatively rare and have a poor prognosis. Two small bowel carcinoma subsets may arise in distinct immune-inflammatory diseases (celiac disease and Crohn's disease) and have been recently suggested to differ in prognosis, celiac disease-associated carcinoma cases showing a better outcome, possibly due to their higher DNA microsatellite instability and tumor-infiltrating T lymphocytes. In this study, we investigated the histological structure (glandular vs diffuse/poorly cohesive, mixed or solid), cell phenotype (intestinal vs gastric/pancreatobiliary duct type) and Wnt signaling activation (β-catenin and/or SOX-9 nuclear expression) in a series of 26 celiac disease-associated small bowel carcinoma, 25 Crohn's disease-associated small bowel carcinoma and 25 sporadic small bowel carcinoma cases, searching for new prognostic parameters. In addition, non-tumor mucosa of celiac and Crohn's disease patients was investigated for epithelial precursor changes (hyperplastic, metaplastic or dysplastic) to help clarify carcinoma histogenesis. When compared with non-glandular structure and non-intestinal phenotype, both glandular structure and intestinal phenotype were associated with a more favorable outcome at univariable or stage- and microsatellite instability/tumor-infiltrating lymphocyte-inclusive multivariable analysis. The prognostic power of histological structure was independent of the clinical groups while the non-intestinal phenotype, associated with poor outcome, was dominant among Crohn's disease-associated carcinoma. Both nuclear β-catenin and SOX-9 were preferably expressed among celiac disease-associated carcinomas; however, they were devoid, per se, of prognostic value. We obtained findings supporting an origin of celiac disease-associated carcinoma in SOX-9-positive immature hyperplastic crypts, partly through flat β-catenin-positive dysplasia, and of Crohn's disease-associated carcinoma in a metaplastic (gastric and/or pancreatobiliary-type) mucosa, often through dysplastic polypoid growths of metaplastic phenotype. In conclusion, despite their common origin in a chronically inflamed mucosa, celiac disease-associated and Crohn's disease-associated small bowel carcinomas differ substantially in histological structure, phenotype, microsatellite instability/tumor-infiltrating lymphocyte status, Wnt pathway activation, mucosal precursor lesions and prognosis. 10.1038/modpathol.2017.40
    Dynamics of occurrence of refractory coeliac disease and associated complications over 25 years. Eigner W,Bashir K,Primas C,Kazemi-Shirazi L,Wrba F,Trauner M,Vogelsang H Alimentary pharmacology & therapeutics BACKGROUND:Refractory coeliac disease, enteropathy associated T-cell lymphoma and small bowel adenocarcinoma are rare but prognostically important complications in coeliac disease. AIM:To analyse potential changes in occurrence of complicated coeliac disease over the last 25 years. METHODS:One thousand one hundred and thirty eight patients were included and evaluated based on their time of first presentation at the Medical University of Vienna, Austria. Occurrences of refractory coeliac disease and associated malignancies were evaluated for 5-year intervals from January 1990 until December 2014 and were compared over time. RESULTS:2.6% (n = 29) were diagnosed with refractory coeliac disease (females 65.6%, mean age at diagnosis 62.8 years). The proportion of those patients was 2.6%, 3.1%, 3.3%, 2.7% and 0.5% for the 5 year intervals from 1990 onwards. Thus, the number of refractory cases has been decreasing since 2000 (P = 0.024). The number of patients presenting with lymphoma (n = 7) was 0.6%, 0.4%, 1.1%, 0.8% and 0% from 1990 to 2014. Similarly the number of patients with adenocarcinoma (n = 4) decreased to 0% until 2014. Overall mortality in patients suffering from refractory disease was 48%. Of all patients diagnosed with lymphoma 71.4% died with a 5-year survival rate of 28.6%. CONCLUSIONS:Over the past 15 years the occurrence of complicated coeliac disease has been decreasing. This possibly reflects a higher awareness of coeliac disease and optimised diagnosis and treatment with avoidance of long-term immunological disease activity. Symptomatic disease and a delay in diagnosis are risk factors for refractory coeliac disease and related cancer. 10.1111/apt.13867
    Coeliac disease: review of diagnosis and management. Walker Marjorie M,Ludvigsson Jonas F,Sanders David S The Medical journal of Australia Coeliac disease is an immune-mediated systemic disease triggered by exposure to gluten, and manifested by small intestinal enteropathy and gastrointestinal and extra-intestinal symptoms. Recent guidelines recommend a concerted use of clear definitions of the disease. In Australia, the most recent estimated prevalence is 1.2% in adult men (1:86) and 1.9% in adult women (1:52). Active case finding is appropriate to diagnose coeliac disease in high risk groups. Diagnosis of coeliac disease is important to prevent nutritional deficiency and long term risk of gastrointestinal malignancy. The diagnosis of coeliac disease depends on clinico-pathological correlation: history, presence of antitransglutaminase antibodies, and characteristic histological features on duodenal biopsy (when the patient is on a gluten-containing diet). Human leucocyte antigen class II haplotypes DQ2 or DQ8 are found in nearly all patients with coeliac disease, but are highly prevalent in the general population at large (56% in Australia) and testing can only exclude coeliac disease for individuals with non-permissive haplotypes. Adhering to a gluten free diet allows duodenal mucosal healing and alleviates symptoms. Patients should be followed up with a yearly review of dietary adherence and a health check. Non-coeliac gluten or wheat protein sensitivity is a syndrome characterised by both gastrointestinal and extra-intestinal symptoms related to the ingestion of gluten and possibly other wheat proteins in people who do not have coeliac disease or wheat allergy recognised by diagnostic tests.
    Small bowel adenocarcinoma as a complication of celiac disease: clinical and diagnostic features. Caio Giacomo,Volta Umberto,Ursini Francesco,Manfredini Roberto,De Giorgio Roberto BMC gastroenterology BACKGROUND:Small bowel adenocarcinoma (SBA) is a rare neoplasm, which can occur in a sporadic form or can be associated with a number of predisposing conditions such as hereditary syndromes and immune-mediated intestinal disorders, e.g. celiac disease (CD). However, the features of SBA in the context of CD remain only partly understood. This study was aimed to show the main clinical features, diagnostic procedures and management options of SBA cases detected in a large cohort of celiac patients diagnosed in a single tertiary care center. METHODS:We retrospectively reviewed all the SBA cases detected in a cohort of 770 CD patients (599 females; F / M ratio: 3.5:1; median age at diagnosis 36 years, range 18-80 years), diagnosed at the Celiac Disease Referral Center of our University Hospital (Bologna, Italy) from January 1995 to December 2014. RESULTS:Five (0.65%) out of our 770 CD patients developed SBA. All of them were female with a mean age of 53 years (range 38-72 years). SBA, diagnosed at the same time of the CD diagnosis in three cases, was localized in the jejunum in four cases and in the duodenum in one case. The clinical presentation of SBA was characterized by intestinal sub-occlusion in two cases, while the predominant manifestation of the remaining three cases was iron deficiency anaemia, abdominal pain and acute intestinal obstruction, respectively. All the patients were referred to surgery, and three cases with advanced stage neoplasia were also treated with chemotherapy. The overall survival rate at 5 years was 80%. CONCLUSIONS:Although in a limited series, herein presented CD-related SBA cases were characterized by a younger age of onset, a higher prevalence in female gender and a better overall survival compared to sporadic, Crohn- and hereditary syndrome-related SBA. 10.1186/s12876-019-0964-6
    Small bowel adenocarcinoma complicating Crohn's disease: a single-centre experience emphasizing the importance of screening for dysplasia. Grolleau Chloé,Pote Nicolas M,Guedj Nathalie S,Zappa Magaly,Theou-Anton Nathalie,Bouhnik Yoram,Panis Yves,Cazals-Hatem Dominique L Virchows Archiv : an international journal of pathology Small bowel adenocarcinoma (SBA) complicating Crohn's disease (CD) is rare and generally found incidentally on surgical specimens. We report our experience in CD-associated SBA observed this last decade in a tertiary referral centre in order to update its incidence, clinical presentation and pathological features. All SBAs diagnosed in patients who underwent surgery for CD between 2006 and 2016 were retrospectively included. Clinico-pathological characteristics were reviewed, and follow-up was updated. SBA was diagnosed in 9 (1.7%) of 522 patients who underwent SB resection(s) after a median CD duration of 15 years [0-32]. The median age at diagnosis was 46 years. Seven (78%) patients had obstructive symptoms refractory to medical treatment. Pre-operative biopsy revealed neoplasia in five (56%) patients (dysplasia in three and SBA in two) justifying the surgery. Two (29%) of the seven patients with imaging had features suggestive of cancer. In all specimens, SBA developed in active ileitis with adjacent dysplasia. Stage I low-grade tubulo-glandular adenocarcinoma was observed in 33% of patients. Stage IV high-grade adenocarcinoma was observed in 56% of patients, and mucinous/signet ring cell differentiation predominated in 44% of patients. Molecular analysis showed no BRAF mutation, a KRAS mutation in one case and a microsatellite instability phenotype suggestive of Lynch syndrome in one case. After a median follow-up of 24 months [7-82], four (44%) patients died with advanced stage IV SBA. This surgical series confirms that CD-associated SBA is rare with an incidence of 1.7%. Adjacent dysplasia was present in all specimens and was identified before surgery in all patients who benefit from ileal biopsies. This strengthens the importance of screening all longstanding CD by endoscopy if surgery is not considered. 10.1007/s00428-017-2125-z
    Systematic review with meta-analysis: use of 5-aminosalicylates and risk of colorectal neoplasia in patients with inflammatory bowel disease. Bonovas S,Fiorino G,Lytras T,Nikolopoulos G,Peyrin-Biroulet L,Danese S Alimentary pharmacology & therapeutics BACKGROUND:The relationship of 5-aminosalicylates' use with the risk of colorectal neoplasia in patients with inflammatory bowel disease (IBD) has been the focus of a growing body of research. AIM:To investigate this association through an updated meta-analysis of observational studies. METHODS:PubMed, Scopus and major conference proceedings were searched up to December 2016. The identified studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates were calculated using random-effect models. Detailed subgroup analyses were performed. The GRADE approach was used to assess the quality of evidence. RESULTS:Thirty-one independent observational studies including 2137 cases of colorectal neoplasia (of which 76% were cancers) were incorporated. Between-study heterogeneity was moderate, while strong suspicion of small-study effects was raised. The overall analysis revealed a protective association between 5-aminosalicylates' use and colorectal neoplasia (RR = 0.57, 95% CI: 0.45-0.71). When the analysis was stratified according to study design and setting, the association was significant in cohort (RR = 0.65, 95% CI: 0.43-0.99; n = 10) and case-control studies (RR = 0.53, 95% CI: 0.40-0.70; n = 21), population-based (RR = 0.70, 95% CI: 0.52-0.94; n = 12) and hospital-based studies (RR = 0.46, 95% CI: 0.34-0.61; n = 19). Exposure to 5-aminosalicylates was protective against cancer (RR = 0.58, 95% CI: 0.45-0.74) and dysplasia (RR = 0.54, 95% CI: 0.35-0.84). The reduction in colorectal neoplasia risk was strong in ulcerative colitis (RR = 0.50, 95% CI: 0.38-0.64), but nonsignificant in Crohn's disease (RR = 0.76, 95% CI: 0.43-1.33). Mesalazine (mesalamine) use was protective (RR = 0.70, 95% CI: 0.51-0.94) with evidence of a dose-effect. The effect of sulfasalazine was marginally nonsignificant (RR = 0.72, 95% CI: 0.51-1.01). CONCLUSIONS:Our findings support a potential chemopreventive role of 5-aminosalicylates in IBD. Further, high-quality prospective research is warranted. 10.1111/apt.14023
    Mucinous phenotype and CD10 expression of primary adenocarcinoma of the small intestine. Kumagai Reiko,Kohashi Kenichi,Takahashi Shunsuke,Yamamoto Hidetaka,Hirahashi Minako,Taguchi Kenichi,Nishiyama Kenichi,Oda Yoshinao World journal of gastroenterology AIM:To clarify the correlation with phenotypic expression, clinicopathological features, genetic alteration and microsatellite-instability status in small intestinal adenocarcinoma (SIA). METHODS:The cases of 47 patients diagnosed with primary SIAs that were surgically resected at our institution in 1975-2005 were studied. We reviewed clinicopathological findings (age, gender, tumor size, gross appearance, histological morphologic type, invasion depth, lymphatic permeation, venous invasion, and lymph node metastasis), and the immunohistochemical expression of MUC5AC, MUC6, MUC2, CD10, and mismatch-repair (MMR) proteins (MLH1 and MSH2). We analyzed KRAS and BRAF gene mutations, and the microsatellite instability (MSI) status. The immunohistochemical staining of CD10, MUC2, MUC5AC and MUC6 was considered positive when distinct staining in > 5% of the adenocarcinoma cells was recorded. To evaluate of MMR protein expression, we used adjacent normal tissue including lymphoid follicles, inflammatory cells, and stromal cells as an internal positive control. Sections without nuclear staining in the tumor cells were considered to have lost the expression of the respective MMR protein. RESULTS:There were 29 males and 18 females patients (mean age 59.9 years, range: 23-87 years). Tumors were located in the duodenum in 14 cases (30%), the jejunum in 21 cases (45%), and the ileum in 12 cases (25%). A phenotypic expression analysis revealed 20 MUC2-positive tumors (42.6%), 11 MUC5AC-positive (23.4%), 4 MUC6-positive (8.5%), and 7 CD10-positive (14.9%). The tumor sizes of the MUC2(+) tumors were significantly larger than those of the MUC2(-) tumors (mean, 5.7 ± 1.4 cm vs 4.7 ± 2.1 cm, P < 0.05). All three tumors with adenomatous component were positive for MUC2 (P < 0.05). Polypoid appearance was seen significantly more frequently in the CD10(+) group than in the CD10(-) group (P < 0.05). The tumor size was significantly larger in the CD10 (+) group than in the CD10(-) group (mean, 5.9 ± 1.4 cm vs 5.0 ± 2.1 cm, P < 0.05). Of 34 SIAs with successfully obtained MSI data, 4 were MSI-high. Of the 4 SIAs positive for both MUC5AC and MUC2, 3 showed MSI-H (75%) and 3 were mucinous adenocarcinoma (75%). KRAS mutations were detected in 4 SIAs. SIAs had KRAS mutation expressed only MUC2, but were negative for MUC5AC, MUC6 and CD10. CONCLUSION:These findings suggest that the phenotypic expression of SIAs is correlated with their biological behavior, genetic alteration, and MSI status. 10.3748/wjg.v21.i9.2700
    Loss of ARID1A expression is associated with poor prognosis in small intestinal carcinoma. Kim Min Jong,Gu Mi Jin,Chang Hee-Kyung,Yu Eunsil Histopathology AIMS:To investigate AT-rich interactive domain-containing protein 1A (ARID1A) and p53 expression in small intestinal carcinoma (SIC) and to determine its prognostic significance. METHODS AND RESULTS:Immunohistochemical staining for ARID1A and p53 was performed in 178 SICs using a tissue microarray (TMA). Loss of or low ARID1A expression was observed in 36 (20.2%) and 60 (33.7%) of cases, respectively. Aberrant p53 expression was observed in 99 (55.6%) cases. Loss of or low ARID1A expression was found to be associated with signet ring cell carcinoma and undifferentiated carcinoma, a high-grade tumour, and a higher T stage. No relationship was found between aberrant p53 expression and clinicopathological factors or overall survival. Patients with loss of ARID1A expression, irrespective of p53 expressional status, showed significantly poorer overall survival than those expressing ARID1A. Multiple regression analysis revealed that grade and pT stage were associated significantly with ARID1A loss, and multivariate analysis showed that patients with high ARID1A expression had a lower risk of death than those with loss of ARID1A expression. CONCLUSIONS:Low or loss of ARID1A expression is correlated significantly with a high-grade tumour, higher T stage, and poorer overall survival. These findings suggest that ARID1A expression could be used as a prognostic marker in SIC. 10.1111/his.12566
    Alterations in ERBB2 and BRCA and microsatellite instability as new personalized treatment options in small bowel carcinoma. Quaas Alexander,Heydt Carina,Waldschmidt Dirk,Alakus Hakan,Zander Thomas,Goeser Tobias,Kasper Philipp,Bruns Christiane,Brunn Anna,Roth Wilfried,Hartmann Nils,Bunck Anne,Schmidt Matthias,Buettner Reinhard,Merkelbach-Bruse Sabine BMC gastroenterology BACKGROUND:Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma. METHODS:We performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2). RESULTS:In five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations - one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation. Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions. CONCLUSION:Our results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas. 10.1186/s12876-019-0942-z
    Genetics of adenocarcinomas of the small intestine: frequent deletions at chromosome 18q and mutations of the SMAD4 gene. Bläker Hendrik,von Herbay Axel,Penzel Roland,Gross Stefanie,Otto Herwart F Oncogene The small intestinal mucosa makes up about 90% of the total surface of the gastrointestinal tract. However, adenocarcinomas arise rarely in this location. To elucidate genetic alterations underlying tumour development in the small intestine we investigated 17 sporadic adenocarcinomas. By comparative genomic hybridization recurrent gains of chromosomal material were found at chromosomes 7, 8, 13q, and 20 (5/17, each), while non-random losses were seen at 8p, 17p (4/17, each), and 18 (8/17 cases). Deletions at 5q, the location of the APC tumour suppressor gene, were seen in three cases. Microsatellite analysis with markers on chromosomal arms 1p, 5q, 8p, 17p, 18q, 19p, and 22q revealed a microsatellite instable phenotype in two cases and a high frequency of loss at 18q21-q22 (80%). Given the high incidence of 18q21-q22 deletions, we performed sequencing analysis of SMAD4, a downstream component of the TGFbeta-pathway, located at 18q21. Four tumours displayed mutations in highly conserved domains of the gene indicating disruption of TGFbeta-signalling. Our data reveal complex genetic alterations in sporadic small intestinal carcinomas. However, most tumours share deletions of 18q21-q22, which frequently target SMAD4. This indicates that disruption of TGFbeta-signalling plays a critical role in small intestinal tumorigenesis. 10.1038/sj.onc.1205041
    Occupation and small bowel adenocarcinoma: a European case-control study. Kaerlev L,Teglbjaerg P S,Sabroe S,Kolstad H A,Ahrens W,Eriksson M,González A L,Guénel P,Hardell L,Launoy G,Merler E,Merletti F,Suárez-Varela M M,Stang A Occupational and environmental medicine OBJECTIVES:Because of the rarity of small bowel adenocarcinoma (SBA), little is known about the aetiology of this disease. This study aimed to identify occupational clustering of cases SBA as a systematic approach to new hypotheses on the aetiology of this disease. METHODS:A European multicentre case-control study was conducted in 1995-7, inclusive. Incident cases aged 35-69 years with SBA (n=168) were recruited before acceptance by a pathologist. Altogether 107 cases and 3915 controls were accepted, of which 79 cases, 579 colon cancer controls, and 2070 population controls were interviewed. RESULTS:The strongest industrial risk factors for SBA taking account of 10 years' exposure lag were dry cleaning, manufacture of workwear, mixed farming (women), and manufacture of motor vehicles (men). A significantly increased risk of SBA (odds ratio (OR) and 95% confidence interval (95% CI)) was found among men employed as building caretakers, OR 6.7 (1.7 to 26.0) and women employed as housekeepers, OR 2.2 (1.1 to 4.9); general farm labourers, OR 4.7 (1.8 to 12.2); dockers, OR 2.9 (1.0 to 8.2); dry cleaners or launderers, OR 4.1 (1.2 to 13.6); and textile workers (sewers or embroiderers), OR 2.6 (1.0 to 6.8). For the last four groups, together with welders OR 2.7 (1.1 to 6.6) (men) an exposure-response pattern was found when calculating the ORs for jobs held 1-5 years and >5 years, with never having held the job as reference. The ORs (95% CIs) for 1-5 years and >5 years were 4.3 (0.4 to 44.0) and 3.5 (0.9 to 13.7), 3.0 (0.3 to 26.2) and 4.3 (0.9 to 21.2), 4.6 (0.4 to 48.1) and 11.0 (2.0 to 60.4), 1.3 (0.2 to 11.0) and 5.8 (2.0 to 17.2), and 2.8 (0.3 to 23.8) and 4.6 (1.3 to 16.6), respectively, for each of these occupations. Among welders, people performing semiautomatic arc welding (MIG/MAG) were identified as a high risk group (OR 5.0 (1.3 to 19.6)). CONCLUSIONS:This explorative study suggests an increased occurrence of SBA in certain occupations, which needs further evaluation. 10.1136/oem.57.11.760
    Occupation and cancer - follow-up of 15 million people in five Nordic countries. Pukkala Eero,Martinsen Jan Ivar,Lynge Elsebeth,Gunnarsdottir Holmfridur Kolbrun,Sparén Pär,Tryggvadottir Laufey,Weiderpass Elisabete,Kjaerheim Kristina Acta oncologica (Stockholm, Sweden) We present up to 45 years of cancer incidence data by occupational category for the Nordic populations. The study covers the 15 million people aged 30-64 years in the 1960, 1970, 1980/1981 and/or 1990 censuses in Denmark, Finland, Iceland, Norway and Sweden, and the 2.8 million incident cancer cases diagnosed in these people in a follow-up until about 2005. The study was undertaken as a cohort study with linkage of individual records based on the personal identity codes used in all the Nordic countries. In the censuses, information on occupation for each person was provided through free text in self-administered questionnaires. The data were centrally coded and computerised in the statistical offices. For the present study, the original occupational codes were reclassified into 53 occupational categories and one group of economically inactive persons. All Nordic countries have a nation-wide registration of incident cancer cases during the entire study period. For the present study the incident cancer cases were classified into 49 primary diagnostic categories. Some categories have been further divided according to sub-site or morphological type. The observed number of cancer cases in each group of persons defined by country, sex, age, period and occupation was compared with the expected number calculated from the stratum specific person years and the incidence rates for the national population. The result was presented as a standardised incidence ratio, SIR, defined as the observed number of cases divided by the expected number. For all cancers combined (excluding non-melanoma skin cancer), the study showed a wide variation among men from an SIR of 0.79 (95% confidence interval 0.66-0.95) in domestic assistants to 1.48 (1.43-1.54) in waiters. The occupations with the highest SIRs also included workers producing beverage and tobacco, seamen and chimney sweeps. Among women, the SIRs varied from 0.58 (0.37-0.87) in seafarers to 1.27 (1.19-1.35) in tobacco workers. Low SIRs were found for farmers, gardeners and teachers. Our study was able to repeat most of the confirmed associations between occupations and cancers. It is known that almost all mesotheliomas are associated with asbestos exposure. Accordingly, plumbers, seamen and mechanics were the occupations with the highest risk in the present study. Mesothelioma was the cancer type showing the largest relative differences between the occupations. Outdoor workers such as fishermen, gardeners and farmers had the highest risk of lip cancer, while the lowest risk was found among indoor workers such as physicians and artistic workers. Studies of nasal cancer have shown increased risks associated with exposure to wood dust, both for those in furniture making and for those exposed exclusively to soft wood like the majority of Nordic woodworkers. We observed an SIR of 1.84 (1.66-2.04) in male and 1.88 (0.90-3.46) in female woodworkers. For nasal adenocarcinoma, the SIR in males was as high as 5.50 (4.60-6.56). Male waiters and tobacco workers had the highest risk of lung cancer, probably attributable to active and passive smoking. Miners and quarry workers also had a high risk, which might be related to their exposure to silica dust and radon daughters. Among women, tobacco workers and engine operators had a more than fourfold risk as compared with the lung cancer risk among farmers, gardeners and teachers. The occupational risk patterns were quite similar in all main histological subtypes of lung cancer. Bladder cancer is considered as one of the cancer types most likely to be related to occupational carcinogens. Waiters had the highest risk of bladder cancer in men and tobacco workers in women, and the low-risk categories were the same ones as for lung cancer. All this can be accounted for by smoking. The second-highest SIRs were among chimney sweeps and hairdressers. Chimney sweeps are exposed to carcinogens such as polycyclic aromatic hydrocarbons from the chimney soot, and hairdressers' work environment is also rich in chemical agents. Exposure to the known hepatocarcinogens, the Hepatitis B virus and aflatoxin, is rare in the Nordic countries, and a large proportion of primary liver cancers can therefore be attributed to alcohol consumption. The highest risks of liver cancer were seen in occupational categories with easy access to alcohol at the work place or with cultural traditions of high alcohol consumption, such as waiters, cooks, beverage workers, journalists and seamen. The risk of colon cancer has been related to sedentary work. The findings in the present study did not strongly indicate any protective role of physical activity. Colon cancer was one of the cancer types showing the smallest relative variation in incidence between occupational categories. The occupational variation in the risk of female breast cancer (the most common cancer type in the present series, 373 361 cases) was larger, and there was a tendency of physically demanding occupations to show SIRs below unity. Women in occupations which require a high level of education have, on average, a higher age at first child-birth and elevated breast cancer incidence. Women in occupational categories with the highest average number of children had markedly lower incidence. In male breast cancer (2 336 cases), which is not affected by the dominating reproductive factors, there was a suggestion of an increase in risk in occupations characterised by shift work. Night-shift work was recently classified as probably carcinogenic, with human evidence based on breast cancer research. The most common cancer among men in the present cohort was prostate cancer (339 973 cases). Despite the huge number of cases, we were unable to demonstrate any occupation-related risks. The observed small occupational variation could be easily explained by varying PSA test frequency. The Nordic countries are known for equity and free and equal access to health care for all citizens. The present study shows that the risk of cancer, even under these circumstances, is highly dependent on the person's position in the society. Direct occupational hazards seem to explain only a small percentage of the observed variation - but still a large number of cases - while indirect factors such as life style changes related to longer education and decreasing physical activity become more important. This publication is the first one from the extensive Nordic Occupational Cancer (NOCCA) project. Subsequent studies will focus on associations between specific work-related factors and cancer diseases with the aim to identify exposure-response patterns. In addition to the cancer data demonstrated in the present publication, the NOCCA project produced Nordic Job Exposure Matrix (described in separate articles in this issue of Acta Oncologica) that transforms information about occupational title histories to quantitative estimates of specific exposures. The third essential component is methodological development related to analysis and interpretation of results based on averaged information of exposures and co-factors in the occupational categories. 10.1080/02841860902913546
    S100A4 expression is a prognostic indicator in small intestine adenocarcinoma. Roh Jin,Knight Spencer,Chung Joon-Yong,Eo Soo-Heang,Goggins Michael,Kim Jihoon,Cho Hyungjun,Yu Eunsil,Hong Seung-Mo Journal of clinical pathology AIMS:Due to the rarity of small intestine adenocarcinoma (SIAC), estimating the prognosis for patients with surgically resected SIAC is difficult. Overexpression of S100A4 has been linked to worse patient survival in several malignant neoplasms, but its significance in SIAC has not been determined. METHODS:S100A4 protein expression was assessed in 197 surgically resected SIAC cases and compared with clinicopathological factors, including patient survival. RESULTS:A progressive increase in S100A4 labelling was observed in normal intestinal epithelium, adenoma and adenocarcinoma (p<0.001), and 50 SIAC cases (26.2%) showed strong S100A4 expression. Patients with SIAC with strong S100A4 expression had a higher pT classification (p=0.05), as well as increased lymph node metastasis (p=0.009) and perineural invasion (p=0.002). Patients with SIAC with strong S100A4 expression had significantly worse survival (median survival, 21 months) than those with weak/no S100A4 expression (42.5 months) by univariable (p=0.04) and multivariable (p=0.01) analyses. CONCLUSIONS:S100A4 overexpression is observed in a subset of SIACs, is associated with advanced disease and can be used as a prognostic indicator of poor prognosis in patients with SIAC. 10.1136/jclinpath-2013-201883
    Lifestyle factors and small intestine adenocarcinoma risk: A systematic review and meta-analysis. Bennett Caoimhe M,Coleman Helen G,Veal Philip G,Cantwell Marie M,Lau Charlotte C L,Murray Liam J Cancer epidemiology BACKGROUND:Although the incidence of small intestinal adenocarcinoma (SIA) is low, rates are increasing and little information regarding modifiable lifestyle risk factors is available. AIM:To provide a systematic review of lifestyle factors and SIA risk. METHODS:Ovid MEDLINE, EMBASE and Web of science were searched from inception to week 1 October 2013. Nine publications that reported on SIA risk in relation to alcohol intake (n=6), tobacco smoking (n=6), diet (n=5), body mass (n=3), physical activity (n=1), hormone use (n=1) and/or socio-economic status (n=3) were retrieved. Results for alcohol, smoking and SIA risk were pooled using random-effects meta-analyses to produce relative risks (RR) and 95% confidence intervals (CI). RESULTS:The summary RR for individuals consuming the highest versus lowest category of alcohol intake was 1.51 (95% CI 0.83-2.75; n=5 studies) with significant increased risks emerging in sensitivity analysis with reduced heterogeneity (RR: 1.82, 95% CI: 1.05-3.15; n=4 studies). The pooled SIA RR for individuals in the highest versus lowest category of smoking was 1.24 (95% CI 0.71-2.17; n=5 studies). In relation to dietary factors, high fibre intakes and normal body weight may be protective, while high intakes of red/processed meat and sugary drinks may increase SIA risk. Evidence on socio-economic status and SIA risk was equivocal. Data on other factors were too sparse to draw any conclusions. CONCLUSIONS:Alcohol may be associated with an increased risk of SIA. Further investigation of lifestyle factors, particularly alcohol, smoking and diet, in the aetiology of this cancer is warranted in large consortial studies. 10.1016/j.canep.2015.02.001
    Small bowel adenocarcinoma in patients with Crohn's disease compared with small bowel adenocarcinoma de novo. Palascak-Juif Vanessa,Bouvier Anne Marie,Cosnes Jacques,Flourié Bernard,Bouché Olivier,Cadiot Guillaume,Lémann Marc,Bonaz Bruno,Denet Christine,Marteau Philippe,Gambiez Luc,Beaugerie Laurent,Faivre Jean,Carbonnel Franck Inflammatory bowel diseases BACKGROUND:Data concerning small bowel adenocarcinoma (SBA) in Crohn's disease (CD) come from case reports and small retrospective series. The aim of this study was to further describe SBA in patients with CD and compare it with SBA de novo. METHODS:Twenty patients with CD with SBA recruited in French university hospitals were studied and compared with 40 patients with SBA de novo recruited from a population-based registry. SBA occurred after a median time of 15 years of CD and was located within the inflamed areas of the ileum (n=19) or jejunum (n=1), whereas in patients with SBA de novo, it was distributed all along the small intestine. Median age at diagnosis of SBA was 47 years (range, 33-72 yr) in patients with CD and 68 years (range, 41-95 yr) in those with SBA de novo. RESULTS:The cumulative risk of SBA, assessed in a subgroup of patients, was 0.2% and 2.2% after 10 and 25 years of ileal CD, respectively. SBA accounted for 25% and 45% of the risk of gastrointestinal carcinoma after 10 and 25 years of CD, respectively. Diagnosis was made preoperatively in 1/20 patients with CD and 22/40 patients with SBA de novo. Signet ring cells were found in 35% of patients with CD but not in patients with SBA de novo. Relative survival was not significantly different in these 2 categories of patients (54 versus 37% and 35 versus 30% in patients with and without CD at 2 and 5 yr, respectively). CONCLUSIONS:SBA in CD is different from SBA de novo. It arises from longstanding ileal inflammation and is difficult to diagnose. SBA cumulative risk increases after 10 years of CD and is likely to cause premature mortality in patients with early-onset CD. 10.1097/01.mib.0000179211.03650.b6
    Risk factors associated with small bowel adenocarcinoma in Crohn's disease: a case-control study. Piton Gaël,Cosnes Jacques,Monnet Elisabeth,Beaugerie Laurent,Seksik Philippe,Savoye Guillaume,Cadiot Guillaume,Flourie Bernard,Capelle Philippe,Marteau Philippe,Lemann Marc,Colombel Jean Frédéric,Khouri Elie,Bonaz Bruno,Carbonnel Franck The American journal of gastroenterology BACKGROUND AND AIMS:It is well established that Crohn's disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). The data concerning SBA risk factors in CD are scanty. The aim of this study was to identify them. METHODS:In 11 French centers affiliated with the GETAID (Groupe d'Etude Thérapeutique des Affections Inflammatoires du Tube Digestif), we identified 29 patients with CD and SBA. Eighty-seven CD controls without SBA recruited in a single center were matched to the cases for sex, age, duration, and CD site. A conditional logistic regression, taking into account the matching between cases and controls, was performed. RESULTS:In univariate analysis, the cases had had significantly less small bowel resection and received prolonged treatment with salicylates (more than 2 yr), less often than the controls (odds ratio, OR [95% confidence interval, CI] 0.07 [0.01-0.32] and 0.29 [0.10-0.82], respectively). In multivariate analysis, both associations remained significant (OR 0.04 [0.01-0.28], P= 0.001; OR 0.16 [0.03-0.79], P= 0.02, respectively). CONCLUSION:This study suggests that small bowel resection and prolonged salicylates use may protect against SBA in CD patients. 10.1111/j.1572-0241.2008.01847.x
    Small bowel adenocarcinoma: Results from a nationwide prospective ARCAD-NADEGE cohort study of 347 patients. Aparicio Thomas,Henriques Julie,Manfredi Sylvain,Tougeron David,Bouché Olivier,Pezet Denis,Piessen Guillaume,Coriat Romain,Zaanan Aziz,Legoux Jean-Louis,Terrebone Eric,Pocard Marc,Gornet Jean-Marc,Lecomte Thierry,Lombard-Bohas Catherine,Perrier Hervé,Lecaille Cédric,Lavau-Denes Sandrine,Vernerey Dewi,Afchain Pauline, International journal of cancer Small bowel adenocarcinoma (SBA) is a rare tumour. We conducted a prospective cohort to describe the prevalence, survival and prognostic factors in unselected SBA patients. The study enrolled patients with all stages of newly diagnosed or recurrent SBA at 74 French centres between January 2009 and December 2012. In total, 347 patients were analysed; the median age was 63 years (range 23-90). The primary tumour was in the duodenum (60.6%), jejunum (20.7%) and ileum (18.7%). The prevalence of predisposing disease was 8.7%, 6.9%, 1.7%, 1.7% and 0.6% for Crohn disease, Lynch syndrome, familial adenomatous polyposis, celiac disease and Peutz-Jeghers syndrome, respectively. At diagnosis, 58.9%, 5.5% and 35.6% of patients had localised and resectable, locally advanced unresectable and metastatic disease, respectively. Crohn disease was significantly associated with younger age, poor differentiation and ileum location, whereas Lynch syndrome with younger age, poor differentiation, early stage and duodenum location. Adjuvant chemotherapy (oxaliplatin-based in 89.9%) was performed in 61.5% of patients with locally resected tumours. With a 54-months median follow-up, the 5-year overall survival (OS) was 87.9%, 78.2% and 55.5% in Stages I, II and III, respectively. The median OS of patients with Stage IV was 12.7 months. In patients with resected tumours, poor differentiation (p = 0.047) and T4 stage (p = 0.001) were associated with a higher risk of death. In conclusion, our study showed that the prognosis of advanced SBA remains poor. Tumour characteristics differed according to predisposing disease. In SBA-resected tumours, the prognostic factors for OS were grade and T stage. 10.1002/ijc.32860
    Whole-exome sequencing of duodenal adenocarcinoma identifies recurrent Wnt/β-catenin signaling pathway mutations. Yuan Wei,Zhang Zhou,Dai Binghua,Wei Qing,Liu Jinjin,Liu Yuzhen,Liu Yun,He Lin,Zhou Daizhan Cancer BACKGROUND:Genomic alterations of small bowel cancers remain poorly understood due to the rarity of these diseases. In the current study, the authors report the identification of somatic mutations from patients with duodenal adenocarcinoma by whole-exome sequencing. METHODS:Whole-exome sequencing and follow-up analysis were conducted in 12 matched tumor-normal tissue duodenal adenocarcinoma tissue pairs to examine the genetic characteristics of this disease. Somatic mutations (single-nucleotide variants and short insertion/deletions) were obtained and filtered and then searched for recurrently mutated genes and pathways. RESULTS:An excess of C-to-T transitions at the CpG dinucleotide was observed in the substitution of bases. The authors identified recurrent mutations in tumor protein p53 (TP53), KRAS, catenin (cadherin-associated protein) β-1 (CTNNB1), AT-rich interactive domain 2 (ARID2), adenomatous polyposis coli (APC), erb-b2 receptor tyrosine kinase 2 (ERBB2), ARID1A, cadherin-related family member 1 (CDHR1), NRAS, Bcl-2-related ovarian killer (BOK), radial spoke head 14 homolog (chlamydomonas) (RTDR1), cell division cycle 27 (CDC27), catalytic subunit of phosphoinositide-3-kinase (PIK3CA), and SMAD family member 4 (SMAD4). Pathway scan indicated that the Wnt signaling pathway, regulation of the actin cytoskeleton pathway, ErbB signaling pathway, and the pathway of focal adhesion were the most extensively affected pathways. CONCLUSIONS:This genomic characterization of duodenal adenocarcinoma provides researchers with insight into its somatic landscape and highlights the vital role of the Wnt/β-catenin signaling pathway. The study data also indicate that duodenal adenocarcinomas have a genetic resemblance to gastric and colorectal cancers. These discoveries may benefit the future development of molecular diagnosis and personalized therapies. Cancer 2016;122:1689-96. © 2016 American Cancer Society. 10.1002/cncr.29974
    Prognostic Role of Body Mass Index in Advanced Small Bowel Adenocarcinoma Patients Receiving Palliative Chemotherapy. Lee Dae-Won,Lee Kyung-Hun,Kim Tae-Yong,Han Sae-Won,Oh Do-Youn,Im Seock-Ah,Kim Tae-You,Bang Yung-Jue Nutrition and cancer As small bowel adenocarcinoma (SBA) is a rare cancer worldwide, prognostic factors have not been clearly defined. The purpose of this study is to assess the prognostic role of clinicopathologic features, including body mass index (BMI), in patients with advanced SBA. A total of 28 consecutive patients with advanced SBA treated with palliative chemotherapy were retrospectively enrolled and analyzed. Clinicopathologic features, progression-free survival (PFS), and overall survival (OS) were compared according to BMI level. Eighteen patients had BMI < 25 kg/m(2) (overweight/normal/underweight in Asian) and ten patients had BMI ≥ 25 kg/m(2) (obese in Asian). Baseline characteristics were similar regardless of patient's BMI. Compared to patients with BMI < 25 kg/m(2), patients with BMI ≥ 25 kg/m(2) had higher response rate to chemotherapy (40.0% vs. 0%, P = 0.010), longer OS (11.2 vs. 7.0 months, P = 0.018) and a tendency toward prolonged PFS (2.1 vs. 1.9 months, P = 0.085). Multivariate analysis revealed that BMI ≥ 25 kg/m(2) is an independent positive prognostic factor of OS (adjusted hazard ratio 0.35, P = 0.024). In conclusion, baseline BMI ≥ 25 kg/m(2) has a positive prognostic role in patients with advanced SBA. 10.1080/01635581.2016.1180413
    Effect and mechanism of vitamin D on the development of colorectal cancer based on intestinal flora disorder. Zhou Xueyan,Chen Chunxia,Zhong Ya' Nan,Zhao Feng,Hao Zhixiang,Xu Yinxue,Lai Ran,Shen Guifang,Yin Xiaoxing Journal of gastroenterology and hepatology BACKGROUND:To investigate the correlation between the level of circulating vitamin D and the development of colorectal cancer (CRC) and to clarify the effect and mechanism of vitamin D on the development of CRC. METHODS:Serum samples from 63 patients with CRC (CRC group) and 61 healthy volunteers (normal group) were collected. Azoxymethane + dextran sodium sulfate-induced CRC mouse model and dietary models with different doses of vitamin D were established to verify whether vitamin D supplementation could reverse the occurrence and development of CRC at the overall animal level. Intestinal barrier integrity and microbial defense response were evaluated by detection of intestinal flora and expression of related genes. RESULTS:In the clinical serum samples, compared with the normal group, the level of 25 (OH) D3 in the CRC group was relatively low (P < 0.01), which was consistent with the clinical situation in mice. Vitamin D deficiency aggravated the deterioration of enteritis and intestinal cancer in CRC mice, whereas the overall condition of CRC mice improved after vitamin D supplementation. Vitamin D has a significant regulatory effect on the homeostasis of the intestinal flora, particularly in the regulation of intestinal probiotics, Akkermansia muciniphila-mediated colon barrier integrity. CONCLUSIONS:Vitamin D deficiency is closely related to the high incidence of CRC, and vitamin D supplementation can inhibit the occurrence and development of CRC. Vitamin D plays a role in the reversal of CRC mainly through the regulation of intestinal flora, especially the regulation of A. muciniphila-mediated colon barrier integrity. 10.1111/jgh.14949
    Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma. Jun Sun-Young,Kim Misung,Jin Gu Mi,Kyung Bae Young,Chang Hee-Kyung,Sun Jung Eun,Jang Kee-Taek,Kim Jihun,Yu Eunsil,Woon Eom Dae,Hong Seung-Mo Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) chemotherapy in colorectal cancer. But the status of KRAS and BRAF mutations and their clinicopathologic and prognostic significance has not been extensively evaluated in small intestinal adenocarcinomas. In this work, the KRAS and BRAF genes in 190 surgically resected small intestinal adenocarcinoma cases were sequenced and their association with various clinicopathologic variables, including survival of the patients, was analyzed. KRAS or BRAF mutations were observed in 63 (33%) cases. Sixty-one cases had KRAS mutations and 2 had BRAF mutations and the two types of mutation were mutually exclusive. The majority of KRAS mutations were G>A transition (43/61 cases, 71%) or p.G12D (31/61 cases, 51%). The patients with mutant KRAS tended to have higher pT classifications (P=0.034) and more frequent pancreatic invasion (P=0.020) than those with wild-type KRAS. Multivariate logistic regression analysis showed that certain mutated KRAS subtypes (G>A transitions and G12D mutations) were significantly correlated with higher pT classification (P=0.015 and 0.004, respectively) than wild-type KRAS and other KRAS mutations. The patients with KRAS or BRAF mutation had a tendency to shorter overall survival than those with wild-type KRAS and BRAF (P=0.148), but subgroup analysis demonstrated the patients with KRAS mutations showed worse survival (median, 46.0 months; P=0.046) than those with wild-type KRAS (85.4 months) in lower pT classification (pT1-pT3) group. In summary, KRAS and, infrequently, BRAF mutations are observed in a subset of small intestinal adenocarcinomas, and are associated with higher pT classification and more frequent pancreatic invasion. KRAS mutation is a poor prognostic predictor in patients with lower pT classification tumors. Anti-EGFR targeted therapy could be applied to about two-thirds of small intestinal adenocarcinoma patients, namely those with wild-type KRAS and BRAF if they have metastatic disease, similar to colorectal cancer patients. 10.1038/modpathol.2016.40
    Endoscopic Detection of Small Bowel Dysplasia and Adenocarcinoma in Crohn's Disease: A Prospective Cohort-Study in High-Risk Patients. Simon M,Cosnes J,Gornet J M,Seksik P,Stefanescu C,Blain A,Pariente B,Nancey S,Vuitton L,Nachury M,D'Haens G,Filippi J,Chevret S,Laharie D, Journal of Crohn's & colitis BACKGROUND AND AIMS:Crohn's disease [CD] is associated with an increased risk of small bowel adenocarcinoma [SBA]. There are no recommendations on endoscopic screening of SBA in CD patients. The aim of this study was to evaluate the feasibility and value of endoscopic screening for SBA in CD patients at high-risk of SBA. METHODS:We performed an exploratory multi-centre study in a prospective cohort of CD patients at high-risk of SBA defined as long-term small bowel disease without bowel resection for the past 10 years. Depending on the location of the disease, baseline upper and/or lower enteroscopies were performed. Random and targeted biopsies using chromoendoscopy were taken. Patients were followed-up for at least 1 year after inclusion. RESULTS:In total, 101 patients [62 men; median age: 48 years; median duration of disease: 19 years] were recruited in ten centres. The endoscopic procedure was incomplete in 47 cases because of impassable strictures and dilation was performed in four patients. Indeterminate small bowel dysplasia was identified in two patients at endoscopic screening; SBA was confirmed in one after surgical resection. With an at least 1-year follow-up duration, two additional cases of SBA were identified in patients who underwent surgery for obstruction, resulting in a 33% sensitivity rate for SBA endoscopic screening. CONCLUSION:In a cohort of high-risk patients, the prevalence of dysplasia and SBA on CD was 4%. Because of its low sensitivity, endoscopic screening cannot be recommended for surveillance in CD patients at high-risk of SBA. 10.1093/ecco-jcc/jjw123
    Interplay between bile acids and the gut microbiota promotes intestinal carcinogenesis. Wang Sinan,Dong Wenxiao,Liu Li,Xu Mengque,Wang Yu,Liu Tianyu,Zhang Yujie,Wang Bangmao,Cao Hailong Molecular carcinogenesis The gut microbiota and the bile acid pool play pivotal roles in maintaining intestinal homeostasis. Bile acids are produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. Gut dysbiosis has been reported to be associated with colorectal cancer. However, the interplay between bile acid metabolism and the gut microbiota during intestinal carcinogenesis remains unclear. In the present study, we investigated the potential roles of bile acids and the gut microbiota in the cholic acid (CA; a primary bile acid)-induced intestinal adenoma-adenocarcinoma sequence. Apc mice, which spontaneously develop intestinal adenomas, were fed a diet supplemented with 0.4% CA for 12 weeks. Mice that were fed a normal diet were regarded as untreated controls. In CA-treated Apc mice, the composition of the gut microbiota was significantly altered, and CA was efficiently transformed into deoxycholic acid (a secondary bile acid) by the bacterial 7α-dehydroxylation reaction. The intestinal adenoma-adenocarcinoma sequence was observed in CA-treated Apc mice and was accompanied by an impaired intestinal barrier function and IL-6/STAT3-related low-grade inflammation. More importantly, microbiota depletion using an antibiotic cocktail globally compromised CA-induced intestinal carcinogenesis, suggesting a leading role for the microbiota during this process. Overall, our data suggested that the crosstalk between bile acids and the gut microbiota mediated intestinal carcinogenesis, which might provide novel therapeutic strategies against intestinal tumor development. 10.1002/mc.22999
    Identification of marker genes and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas. Sakaguchi Yoshiki,Yamamichi Nobutake,Tomida Shuta,Takeuchi Chihiro,Kageyama-Yahara Natsuko,Takahashi Yu,Shiogama Kazuya,Inada Ken-Ichi,Ichinose Masao,Fujishiro Mitsuhiro,Koike Kazuhiko Journal of gastroenterology BACKGROUND:The mechanism behind the pathogenesis and carcinogenesis of these neoplasms is not fully understood. The objective of this study was to identify genetic markers and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas through gene expression analysis. METHODS:Gene expression profiling was performed in 4 pairs of duodenal adenoma/adenocarcinomas and corresponding matched normal tissue. Genes with consistent expression differences were identified and confirmed in 7 independent pairs. Gene set enrichment analysis (GSEA) was performed to characterize gene expression profiles of duodenal adenoma/adenocarcinomas, together with immunohistochemical staining of candidate oncogenic genes. RESULTS:626 probes consistently demonstrated over a twofold expression difference between tumor-normal pairs. Reverse transcriptase polymerase chain reaction of genes with the most prominent difference in expression between tumors and normal mucosa (KLK7, KLK6, CEMIP, MMP7, KRT17, LGR5, G6PC, S100G, APOA1) validated the results of gene expression analysis. GSEA demonstrated a strong association between duodenal adenoma/adenocarcinomas with colorectal adenomas (p < 10) and gene expression patterns seen after APC gene knockout (p < 10), suggesting that the Wnt/β-catenin pathway plays a crucial role in the carcinogenesis of these neoplasms. Immunohistochemical staining of an independent group of duodenal adenomas confirmed over-accumulation of β-catenin in 80.0% (16/20). CONCLUSIONS:Precancerous duodenal adenomas and early stage adenocarcinomas demonstrate gene expression characteristics with a strong resemblance to colorectal adenomas. The results of this study strongly suggest that upregulation of the Wnt/β-catenin pathway is the major factor involved in the initial stages of the carcinogenesis of duodenal adenocarcinomas. 10.1007/s00535-018-1489-4
    DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway. Adam Liana,San Lucas F Anthony,Fowler Richard,Yu Yao,Wu Wenhui,Liu Yulun,Wang Huamin,Menter David,Tetzlaff Michael T,Ensor Joe,Manyam Ganiraju,Arold Stefan T,Huff Chad,Kopetz Scott,Scheet Paul,Overman Michael J Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease. Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations. Two SBA models with kinase activating mutations were tested for sensitivity to anti-ERBB2 agents and . Biochemical changes were measured by reverse-phase protein arrays. RESULTS:WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. Although mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%. mutations and amplifications were present in 23% of samples. Patients with alterations in the ERBB2 signaling cascade (64%) demonstrated worse clinical outcomes (median survival 70.3 months vs. 109 months; log-rank HR = 2.4, = 0.03). Two ERBB2-mutated (V842I and Y803H) cell lines were generated from SBA patient samples. Both demonstrated high sensitivity to ERBB2 inhibitor dacomitinib (IC < 2.5 nmol/L). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, whereas it had no effect in an SBA wild-type model. CONCLUSIONS:The and models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating mutations in patients with SBA that harbor these alterations. 10.1158/1078-0432.CCR-18-1480
    Impact of tumor site on the prognosis of small bowel adenocarcinoma. Falcone Rosa,Romiti Adriana,Filetti Marco,Roberto Michela,Righini Riccardo,Botticelli Andrea,Pilozzi Emanuela,Ghidini Michele,Pizzo Claudio,Mazzuca Federica,Marchetti Paolo Tumori BACKGROUND:Because of a lack of large-scale prospective studies there is no clear indication about the management of patients with small bowel adenocarcinoma (SBA). This study evaluated clinical outcome of patients diagnosed with SBA at our institution. METHODS:Clinicopathologic features, treatments, and clinical outcome of patients diagnosed with SBA between 2006 and 2017 were retrospectively analyzed. Median time of survival was calculated and compared using the log-rank test. Multivariate Cox regression was used to test independence of significant factors in univariate analysis. RESULTS:Forty patients were included in the study; the majority (82.5%) had a tumor in the duodenum (including ampulla of Vater) and an early stage disease at the diagnosis. Median overall survival (OS) in the whole study population was 26.5 months. Patients with a tumor of the lower part of the small intestine (jejunum, ileum, and appendix) showed a better OS compared with that of patients with upper SBA (40 months vs 26 months, respectively; =0.09). Primary tumor site and stage were independent predictors of OS. CONCLUSIONS:Our results suggest a prognostic role for the primary tumor site. This finding deserves to be further investigated to ensure better classification as well as more effective management strategies for SBA. 10.1177/0300891619839297
    Microbiome Dysbiosis and Predominant Bacterial Species as Human Cancer Biomarkers. Shirazi Mohsen Sagheb R,Al-Alo K Z K,Al-Yasiri Mohammed Hashim,Lateef Zainab M,Ghasemian Abdolmajid Journal of gastrointestinal cancer PURPOSE:To evaluate bacterial agents as cancer biomarkers. METHODS AND RESULTS:Various bacterial species have been demonstrated to involve in human cancers. However, the data is not enough for better understanding of predominant specific species. Application of a rapid and early-diagnostic, cost-effective, non-invasive, and inclusive method is a crucial approach for obtaining valid results. The role of Helicobacter pylori (H. pylori) in gastric and duodenal cancer has been confirmed. From investigation among previous publications, we attempted to make it clear which bacterial species significantly and specifically increase in various cancer types. It was unraveled that there is significant change in Granulicatella adiacens (G. adiacens) in lung cancer (LC), Fusobacterium nucleatum (F. nucleatum) in colorectal cancer (CRC), H. pylori and Porphyromonas gingivalis (P. gingivalis) in pancreatic cancer, and Streptococcus spp. in oral cancer. CONCLUSION:Alteration in the cell cycle by means of different mechanisms such as inflammation, alteration in cell signaling, invasion and immune evasion, specific niche colonization, induction of DNA damage and mutation, expression of some microRNAs, and enhancing epigenetic effects are the most common mechanisms employed by bacterial species. 10.1007/s12029-019-00311-z
    Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy. Parikh Aparna R,He Yuting,Hong Ted S,Corcoran Ryan B,Clark Jeff W,Ryan David P,Zou Lee,Ting David T,Catenacci Daniel V,Chao Joseph,Fakih Marwan,Klempner Samuel J,Ross Jeffrey S,Frampton Garrett M,Miller Vincent A,Ali Siraj M,Schrock Alexa B The oncologist BACKGROUND:Alterations in the DNA damage response (DDR) pathway confer sensitivity to certain chemotherapies, radiation, and other DNA damage repair targeted therapies. are the most well-studied DDR genes, but recurrent alterations are described in other DDR pathway members across cancers. Deleterious DDR alterations may sensitize tumor cells to poly (ADP-ribose) polymerase inhibition, but there are also increasing data suggesting that there may also be synergy with immune checkpoint inhibitors. The relevance of DDR defects in gastrointestinal (GI) cancers is understudied. We sought to characterize DDR-defective GI malignancies and to explore genomic context and tumor mutational burden (TMB) to provide a platform for future rational investigations. MATERIALS AND METHODS:Tumor samples from 17,486 unique patients with advanced colorectal, gastroesophageal, or small bowel carcinomas were assayed using hybrid-capture-based comprehensive genomic profiling including sequencing of 10 predefined DDR genes: , , , , , , , and . TMB (mutations per megabase [mut/Mb]) was calculated from up to 1.14 Mb of sequenced DNA. Clinicopathologic features were extracted and descriptive statistics were used to explore genomic relationships among identified subgroups. RESULTS:DDR alterations were found in 17% of cases: gastric adenocarcinoma 475/1,750 (27%), small bowel adenocarcinoma 148/666 (22%), esophageal adenocarcinoma 467/2,501 (19%), and colorectal cancer 1,824/12,569 (15%). (9.2%) and (4.7%) were the most commonly altered DDR genes in this series, followed by (2.3%), (1.1%), (1.0%), (0.8%), (0.7%), (0.6%), (0.1%) and (0.1%). More than one DDR gene alteration was found in 24% of cases. High microsatellite instability (MSI-H) and high TMB (TMB-H, ≥20 mut/Mb) were found in 19% and 21% of DDR-altered cases, respectively. Of DDR-altered/TMB-H cases, 87% were also MSI-H. However, even in the microsatellite stable (MSS)/DDR-wild-type (WT) versus MSS/DDR-altered, TMB-high was seen more frequently (0.4% vs. 3.3%, < .00001.) Median TMB was 5.4 mut/Mb in the MSS/DDR-altered subset versus 3.8 mut/Mb in the MSS/DDR-WT subset ( ≤ .00001), and alterations were enriched in the MSS/TMB-high cases. CONCLUSION:This is the largest study to examine selected DDR defects in tubular GI cancers and confirms that DDR defects are relatively common and that there is an association between the selected DDR defects and a high TMB in more than 20% of cases. Microsatellite stable DDR-defective tumors with elevated TMB warrant further exploration. IMPLICATIONS FOR PRACTICE:Deleterious DNA damage response (DDR) alterations may sensitize tumor cells to poly (ADP-ribose) polymerase inhibition, but also potentially to immune checkpoint inhibitors, owing to accumulation of mutations in DDR-defective tumors. The relevance of DDR defects in gastrointestinal (GI) cancers is understudied. This article characterizes DDR-defective GI malignancies and explores genomic context and tumor mutational burden to provide a platform for future rational investigations. 10.1634/theoncologist.2019-0034
    Molecular alterations and PD-L1 expression in non-ampullary duodenal adenocarcinoma: Associations among clinicopathological, immunophenotypic and molecular features. Watari Jiro,Mitani Seiichiro,Ito Chiyomi,Tozawa Katsuyuki,Tomita Toshihiko,Oshima Tadayuki,Fukui Hirokazu,Kadowaki Shigenori,Natsume Seiji,Senda Yoshiki,Tajika Masahiro,Hara Kazuo,Yatabe Yasushi,Shimizu Yasuhiro,Muro Kei,Morimoto Takeshi,Hirota Seiichi,Das Kiron M,Miwa Hiroto Scientific reports Non-ampullary duodenal adenocarcinoma (NADC) is extremely rare. Little is known about its clinicopathological and molecular features or its management. Herein we retrospectively analyzed the cases of 32 NADC patients, focusing on microsatellite instability (MSI), genetic mutations, CpG island methylator phenotype (CIMP), and immunostaining including mucin phenotype and PD-L1 expression. The incidence of MSI, KRAS/BRAF/GNAS mutations and CIMP was 51.6%, 34.4%/3.1%/6.5% and 28.1%, respectively. PD-L1 expression was seen in 34.4% of patients. No significant associations between clinicopathological features and KRAS/BRAF/GNAS genetic mutations or CIMP were found. Histologically non-well-differentiated-type NADCs and those in the 1st portion of the duodenum were significantly associated with later stages (stages III-IV) (P = 0.006 and P = 0.003, respectively). Gastric-phenotype NADCs were frequently observed in the 1st portion and in late-stage patients; their cancer cells more frequently expressed PD-L1. Histologically, the non-well-differentiated type was an independent predictor of PD-L1 expression in cancer cells (OR 25.05, P = 0.04) and immune cells (OR 44.14, P = 0.02). Only late-stage disease (HR 12.23, P = 0.01) was a prognostic factor for worse overall survival in a Cox proportional hazards regression model. Our observation of high proportions of MSI and PD-L1 expression may prompt the consideration of immune checkpoint inhibitors as a new treatment option for NADCs. 10.1038/s41598-019-46167-y
    Effect of marital status on duodenal adenocarcinoma survival: A Surveillance Epidemiology and End Results population analysis. Wang Na,Bu Qingting,Liu Qingqing,Yang Jin,He Hairong,Liu Jie,Ren Xuequn,Lyu Jun Oncology letters Numerous studies have shown that marital status may be a prognostic factor in various malignancies, but little is known about its effect on duodenal adenocarcinoma. The aim of the present study was to determine the association between marital status and survival in patients with duodenal adenocarcinoma. The Surveillance, Epidemiology and End Results database was utilized to analyze 2,018 patients who had been diagnosed with duodenal adenocarcinoma between January 2004 and December 2015. Kaplan-Meier and Cox regression analyses were also used to determine the impact of marital status on overall survival (OS) and cause-specific survival (CSS). The 5-year OS rate was higher in married patients (32.6%) compared with unmarried (26.8%) patients (P<0.001), as was the 5-year CSS rate (38.8 vs. 33.7%; P<0.001). Multivariate analysis demonstrated that marital status was an independent prognostic factor for duodenal adenocarcinoma, with married patients having improved OS (P<0.001) and CSS (P=0.001) compared with unmarried patients. Subgroup analysis showed that marital status played a role in the survival of patients at American Joint Committee on Cancer Tumor-Node-Metastasis stage I, but not of patients at stages II, III or IV. The survival outcomes for duodenal adenocarcinoma are improved in married patients compared with those in unmarried patients. Therefore, attention should be paid to the impact of social factors and socio-economic factors on unmarried patients, in order to improve their survival outcomes. 10.3892/ol.2019.10475
    Laparoscopic pancreaticoduodenectomy for periampullary tumors: lessons learned from 500 consecutive patients in a single center. Song Ki Byung,Kim Song Cheol,Lee Woohyung,Hwang Dae Wook,Lee Jae Hoon,Kwon Jaewoo,Park Yejong,Lee Seung Jae,Park Guisuk Surgical endoscopy BACKGROUND:Laparoscopic pancreaticoduodenectomy (LPD) is a feasible option in selected patients. However, its use has not yet been generalized since it is time-consuming, physically demanding, and technically challenging. It might be essential to share the experience of high-volume centers to understand its use. METHODS:We retrospectively reviewed the data of 500 consecutive patients who underwent LPD at a single institution between January 2007 and December 2017. RESULTS:The patients included 272 women and 228 men (mean age, 57.1 years). The most common indication for LPD was intraductal papillary neoplasm (n = 104, 20.8%). Overall and major (Clavien-Dindo grades III-V) complication rates were 37.2% and 4.8%, respectively. Fifty-four patients (10.8%) had clinically relevant (grade B/C) pancreatic fistulas. There were 3 (0.6%) 90-day mortalities. The most common late complication was bilioenteric stricture (25, 5%). Two hundred thirty patients were diagnosed with periampullary cancer. The 5-year overall survival rates of pancreatic cancer, common bile duct cancer, ampulla of Vater cancer, and duodenal cancer were 37.4, 63.2, 78, and 88.9%, respectively. We analyzed learning curves of first-generation and second-generation surgeons. A risk-adjusted cumulative sum analysis demonstrated a learning curve of 55 cases for LPD with the first-generation surgeon and earlier competency with the second-generation surgeon. CONCLUSIONS:LPD has the potential to become an alternative surgery to open pancreaticoduodenectomy for periampullary tumors with acceptable outcomes. We could reduce the steep learning curve with structured training, close supervision, and well-trained operation teams. Perioperative and oncologic outcomes of LPD will be optimized after overcoming the learning curve. 10.1007/s00464-019-06913-9
    Clinical significance of cancer specific methylation of the CDO1 gene in small bowel cancer. Kojima Keita,Nakamura Takatoshi,Ooizumi Yosuke,Igarashi Kazuharu,Tanaka Toshimichi,Yokoi Keigo,Ishii Satoru,Nishizawa Nobuyuki,Katoh Hiroshi,Kosaka Yoshimasa,Sato Takeo,Watanabe Masahiko,Yamashita Keishi PloS one Although small bowel cancer (SBC) is extremely rare, its prognosis is poor, and molecular mechanism of the SBC development remains unclear. The aim of our study is to elucidate whether DNA methylation of the promoter region of the cancer-specific methylation gene, cysteine dioxygenase 1 (CDO1), contributes to the carcinogenic process in SBC. The study group comprised patients with 53 patients with SBC, 107 colorectal cancer (CRC), and other rare tumors of the small intestine such as 4 malignant lymphomas, 2 leiomyosarcomas, and 9 gastrointestinal stromal tumors. We analyzed the extent of methylation in each tissue using quantitative TaqMan methylation-specific PCR for CDO1. Significantly higher CDO1 methylation was observed in cancer tissues compared with non-cancerous mucosa of the small intestine (ROC = 0.96). Among the various clinicopathological factors, positive correlation of CDO1 methylation with tumor diameter was observed (R = 0.31, p = 0.03), and the CDO1 methylation level was a possible prognostic factor for relapse-free survival (p = 0.09). Compared with CRC, SBC had a significantly poorer prognosis (p = 0.007) and displayed a significantly higher CDO1 methylation level (p < 0.0001). Intriguingly, especially in pStage I/II, there were robust prognostic difference between SBC and CRC (p = 0.08 / p < 0.0001), which may reflect CDO1 methylation status (p = 0.02 / p = 0.001). Among small bowel tumors, CDO1 methylation in SBC was higher in order of malignant lymphoma, cancer, and leiomyosarcoma/GIST (p = 0.002) by ANOVA. The CDO1 gene shows extremely cancer-specific hypermethylation, and it can be a prognostic marker in SBC. 10.1371/journal.pone.0211108
    Duodenal tumor risk in Lynch syndrome. Hammoudi Nassim,Dhooge Marion,Coriat Romain,Leblanc Sarah,Barret Maximilien,Bordacahar Benoit,Beuvon Frederic,Prat Frederic,Maksimovic Fanny,Chaussade Stanislas Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver BACKGROUND AND AIMS:Lynch syndrome (LS) is associated with an increased risk of small bowel tumors but routine screening is not recommended in international guidelines. The aim of our study was to determinate the prevalence of duodenal tumors in a French cohort of LS patients. METHODS:Patients carrying a germline pathogenic variant in a MMR gene, supported by our local network, in which at least one upper endoscopy had been performed, were included. We registered the occurrence of duodenal lesions in those patients. RESULTS:154 LS patients were identified including respectively 85 MSH2 and 41 MLH1 mutated patients respectively. Seven out of 154 (4.5%) had at least one duodenal lesion. Median age at diagnosis was 58 years (range: 49-73). The twelve lesions locations were: descending duodenum (n = 7), genu inferius (n = 2), duodenal bulb (n = 1), ampulla (n = 1), fourth duodenum (n = 1). Three lesions were invasive adenocarcinomas. The incidence rate of duodenal lesions in patients with MSH2 or MLH1 pathogenic variants was respectively 7.1% (6 out of 85) and 2.4% (1 out of 41) emphasizing a trend toward increased risk of developing duodenal lesion in MSH2 mutated patients: OR: 5.17, IC95% (0.8-60.07), p = 0.1307. CONCLUSION:Regarding this high prevalence rate, especially in MSH2 patients, regular duodenal screening during upper endoscopy should be considered in routine in LS patients. 10.1016/j.dld.2018.10.005
    Prognostic implications of immune classification in a multicentre cohort of patients with small intestinal adenocarcinoma. Noh Byeong-Joo,Hong Seung-Mo,Jun Sun-Young,Eom Dae-Woon Pathology The diagnosis of small intestinal adenocarcinoma (SIAC) is usually determined at an advanced stage due to non-specific symptoms and the difficulty of exploring the small intestine. Therefore, the majority of SIAC patients have limited chemotherapeutic options. Until recently, the development of novel and effective therapies for SIAC have been limited owing to the low number of samples that have been collected and the low incidence of SIAC. Immunotherapies are becoming a focus. However, in SIAC, only a few studies to identify immunotherapy-responsive subgroups and their prognostic indicators have been reported. In the present study, we categorise primary SIAC into four types of tumour immune microenvironments and propose a strategy for identifying patient subgroups that are most likely to be immunotherapy-responsive. Formalin-fixed, paraffin-embedded tissue samples of a multicentre cohort of patients with SIAC (n=195) were collected using tissue microarrays. Immunohistochemical (IHC) stains for PD-L1, PD-1, and CD8 were performed, and microsatellite instability was evaluated using an IHC stain. Tumour microenvironment immune type (TMIT) I [PD-L1-positive tumour cells and CD8-high tumour-infiltrating lymphocytes (TILs)] and TMIT III (PD-L1-positive tumour cells and CD8-low TILs) show the best and worse prognoses, respectively. PD-L1 expression was significantly associated with high microsatellite instability (MSI) status. CD8-high TILs were positively correlated with PD-1-high TILs and high MSI. The TMIT I subgroup demonstrated a more patent CD8/PD-L1/PD-1 signalling pathway compared to other TMITs. Therefore, the TMIT I subgroup can be expected to have an effective response to immune checkpoint inhibitor therapies in SIAC. Such classification of SIACs into four immune types can be useful in predicting the prognosis of patients and the identification of immunotherapy-responsive subgroups. 10.1016/j.pathol.2019.09.004
    Small-bowel carcinomas associated with celiac disease: transcriptomic profiling shows predominance of microsatellite instability-immune and mesenchymal subtypes. Rizzo Francesca,Vanoli Alessandro,Sahnane Nora,Cerutti Roberta,Trapani Davide,Rinaldi Antonio,Sellitto Assunta,Ciacci Carolina,Volta Umberto,Villanacci Vincenzo,Calabrò Antonio,Arpa Giovanni,Luinetti Ombretta,Paulli Marco,Solcia Enrico,Di Sabatino Antonio,Sessa Fausto,Weisz Alessandro,Furlan Daniela Virchows Archiv : an international journal of pathology 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. 10.1007/s00428-019-02675-w
    Genetic risks and familial associations of small bowel carcinoma. Shenoy Santosh World journal of gastrointestinal oncology Adenocarcinoma of small intestines (SBA) is a relatively rare malignancy with poor outcomes due to delayed diagnosis. Fifty percent of patients have metastases on presentation and therefore early detection and treatment offers the best long term outcomes. Certain genetic polyposis syndromes and familial diseases are associated with increased risks for SBA. These include familial adenomatous polyposis (FAP), Lynch syndromes (LS), Juvenile polyposis syndrome, Peutz-Jeghers syndrome, Crohn's disease (CD) and celiac disease. Mutations in APC gene, Mismatch repair genes, STK11 gene, and SMAD4 gene have been implicated for the genetic diseases respectively. While there are no specific inherited genetic mutations for CD, genome-wide association studies have established over 140 loci associated with CD. CpG island mutations with defects in mismatch repair genes have been identified in celiac disease. Significant diagnostic advances have occurred in the past decade and intuitively, it would seem beneficial to use these advanced modalities for surveillance of these patients. At present it is debatable and no clear data exists to support this approach except for established guidelines to diagnose duodenal polyps in FAP, and LS. Here we discuss the genetic alterations, cancer risks, signaling mechanisms and briefly touch the surveillance modalities available for these genetic and clinical syndromes. English language articles from PubMed/Medline and Embase was searched were collected using the phrases "small-bowel adenocarcinoma, genetics, surveillance, familial adenomatous polyposis, lynch syndromes, Peutz-Jeghers syndrome, juvenile polyposis syndrome, CD and celiac disease". Figures, tables and schematic diagram to illustrate pathways are included in the review. 10.4251/wjgo.v8.i6.509
    DNA mismatch repair deficiency but not ARID1A loss is associated with prognosis in small intestinal adenocarcinoma. González Iván,Goyal Bella,Xia Michelle D,Pai Reetesh K,Ma Changqing Human pathology Small intestinal adenocarcinoma is an uncommon neoplasm with poor prognosis. It is clinically approached similarly to colorectal carcinoma (CRC). The prognostic value of DNA mismatch repair protein deficiency (dMMR) in CRC is well established, but its role in small intestinal adenocarcinoma remains inconclusive. Recently, loss of expression of ARID1A, a tumor suppressor gene product, by immunohistochemistry (IHC) was linked to dMMR and poor outcome in small intestinal adenocarcinoma, suggesting that it may be an emerging prognostic biomarker. We hypothesized that dMMR and/or ARID1A loss may be associated with clinical outcome in small intestinal adenocarcinoma. We examined dMMR and ARID1A loss by IHC in 120 surgically resected, nonampullary small intestinal adenocarcinomas collected from 2 tertiary centers. ARID1A loss was detected in 6 (7%) of 92 ARID1A-stained adenocarcinomas, whereas 21 (18%) of 120 adenocarcinomas demonstrated dMMR. ARID1A loss was not associated with survival or dMMR. dMMR adenocarcinomas had no distant metastasis, whereas 22 (22%) of 99 MMR-proficient adenocarcinomas had (P = .01). dMMR was an independent, positive predictor of disease-free survival (P = .035, hazard ratio: 0.2). Compared with dMMR CRC, dMMR small intestinal adenocarcinomas more frequently demonstrated loss of MSH2 and MSH6 and less often showed loss of MLH1 and PMS2 (both P < .001). In summary, ARID1A loss by IHC is uncommon in small intestinal adenocarcinomas. dMMR small intestinal adenocarcinomas are nonmetastatic tumors, frequently demonstrate loss of MSH2 and MSH6, and have superior disease-free survival. Our results suggest that all small intestinal adenocarcinomas should be tested for MMR protein deficiency. 10.1016/j.humpath.2018.10.013
    Functional Expression of Mucin1 in Human Duodenal Adenocarcinoma. Shiba Satomi,Miki Atsushi,Ohzawa Hideyuki,Teratani Takumi,Sakuma Yasunaru,Lefor Alan Kawarai,Kitayama Joji,Sata Naohiro The Journal of surgical research OBJECTIVE:Mucin1 (MUC1), a member of the mucin family, is a glycoprotein which is often expressed in malignant cells. However, the expression and function of MUC1 in human duodenal adenocarcinoma (DAC) has not yet been characterized because of its low frequency. Here, we examined the functional roles of core protein (MUC1-C) in DAC. MATERIALS AND METHODS:Using a human duodenal cancer cell line, HuTu80, proliferation, migration, invasion, ALDH activity was assessed by cell counting kit-8, scratch wound healing, matrigel invasion, and ALDEFUOR assays, respectively. The function of MUC1 protein was evaluated with knockdown using specific siRNA as well as anti-MUC1-C peptide, GO203. MUC1 expression in human DAC was evaluated immunohistochemically in surgically resected tumors. RESULTS:The positive expression of MUC1 in HuTu80 was confirmed by RT-PCR and flow cytometry. In vitro cell growth was inhibited by the addition of 50-100 μM GO203 as well as treatment with siRNA for MUC1-C. Silencing of MUC1-C also significantly reduced migration, invasion, ALDH activity. Local injection of GO-203 (14 mg/kg) significantly suppressed the growth of subcutaneous HuTu80 tumors in nude mice. Immunohistochemically, MUC1 was strongly detected in seven DAC cases, but not in 11 others. The outcome of patients with high MUC1 expression was significantly worse than those without MUC1 expression. CONCLUSIONS:These results suggest that MUC1 is functionally associated with the malignant potential of DAC and could be a novel therapeutic target for this rare tumor. 10.1016/j.jss.2019.01.006
    Clinical Outcomes of Small Bowel Adenocarcinoma. Akce Mehmet,Jiang Renjian,Zakka Katerina,Wu Christina,Alese Olatunji B,Shaib Walid L,Behera Madhusmita,El-Rayes Bassel F Clinical colorectal cancer BACKGROUND:Small bowel adenocarcinomas (SBAs) are rare tumors. Management of SBA is extrapolated from colorectal cancer treatments. Recent evidence suggests that the biology and molecular features of SBA differ from colorectal cancer. The aim of this study was to evaluate the management and outcome of SBA patients. PATIENTS AND METHODS: The National Cancer Data Base (NCDB) was queried for patients with SBA between 2004 and 2013 using ICD-O-3 histology code 8140/3 and topography codes C17.0, C17.1, C17.2, C17.8, and C17.9. Univariate and multivariate survival analyses were conducted to analyze the association between SBA location and overall survival (OS) stratified by stage. Treatment outcomes of surgery, radiation, and systemic therapy were compared. RESULTS:A total of 7954 SBA patients were identified; duodenum (D) 4607 (57.9%), jejunum (J) 1241 (15.6%), ileum (I) 857 (10.8%), and unspecified 1249 (15.7%). A total of 53.6% patients were male, and 76.6% white. Median age was 66 years. D mostly presented as stage IV disease (37.6%), J as stage II (34.5%) and IV disease (33.8%), and I as stage II (32.2%) and III (30.3%) disease (P < .001). Grade distribution was similar among D, J, and I; the majority were moderately differentiated (40.8%-55.0%), followed by poorly differentiated (30.9%-35.8%) and well differentiated (6.0%-12.4%) (P < .001). D underwent surgery (50.2%) less often than J (90.8%) and I (94.5%) (P < .001). Adjuvant radiation was provided in 8.5% of D, 2.6% of J, and 2.1% of I (P < .001). Adjuvant chemotherapy was provided in 21.9% of D, 50.2% of J, and 42.0% of I (P < .001). The rate of adjuvant chemotherapy was the highest in patients with stage III SBA, and was as follows: D (43.4%), J (65.4%), and I (63.6%) (P < .001). In univariate and multivariate analyses of all patients, adjuvant chemotherapy was associated with improved OS in stage II-III SBA patients. J had the best 5-year OS rate (42.0%; 95% confidence interval, 38.8-45.1, P < .001), and D had the worst (23.0%; 95% confidence interval, 21.6-24.2, P < .001). In multivariate analysis stratified by stage, chemotherapy was associated with improved OS in patients with stage II-IV SBA. CONCLUSION:Most SBA patients present with stage IV disease. D underwent surgery less often than J and I. Stage II and III D received adjuvant chemotherapy less often compared to stage II and III J and I. Adjuvant chemotherapy was associated with improved OS in patients with stage II-III disease. J had the best 5-year OS rate, and D had the worst. 10.1016/j.clcc.2019.08.002
    Therapeutic potential of the antidiabetic drug metformin in small bowel adenocarcinoma. Chiyo Taiga,Kato Kiyohito,Iwama Hisakazu,Fujihara Shintaro,Fujita Koji,Tadokoro Tomoko,Ohura Kyoko,Samukawa Eri,Yamana Yoshimi,Kobayashi Nobuya,Matsunaga Tae,Nishiyama Noriko,Ayaki Maki,Yachida Tatsuo,Morishita Asahiro,Kobara Hideki,Mori Hirohito,Masaki Tsutomu International journal of oncology Small bowel adenocarcinoma (SBAC) accounts for 3% of all gastrointestinal tract tumors and approximately 0.5% of all cancer cases. Recent studies have indicated that the use of metformin, one of the most commonly prescribed antidiabetic drugs, is associated with a better prognosis for certain malignant diseases. However, there have been no reports on the effect of metformin in SBAC. In the present study, we evaluated the effect of metformin on human SBAC cell proliferation in vitro and in vivo and identified the microRNAs (miRNAs) associated with its antitumor effects. Metformin inhibited the proliferation of HuTu80 cells in a time- and dose-dependent manner. Importantly, metformin reduced the expression of cyclin D1, cyclin E, cyclin-dependent kinase 4, and phosphorylated retinoblastoma protein, which resulted in cell cycle arrest at the G0/G1 phase. This arrest was accompanied by activation of AMPKα and inhibition of mammalian target of rapamycin and p70s6k. Additionally, metformin reduced the levels of phosphorylated epidermal growth factor receptor and ROR2 as well as markedly altered miRNA expression in HuTu80 cells. Metformin also inhibited tumor growth in vivo in a xenograft mouse model. Our data suggest that metformin might have therapeutic potential in SBAC. 10.3892/ijo.2017.3971
    Comparison of abdominal adiposity and overall obesity in relation to risk of small intestinal cancer in a European Prospective Cohort. Lu Yunxia,Cross Amanda J,Murphy Neil,Freisling Heinz,Travis Ruth C,Ferrari Pietro,Katzke Verena A,Kaaks Rudolf,Olsson Åsa,Johansson Ingegerd,Renström Frida,Panico Salvatore,Pala Valeria,Palli Domenico,Tumino Rosario,Peeters Petra H,Siersema Peter D,Bueno-de-Mesquita H B,Trichopoulou Antonia,Klinaki Eleni,Tsironis Christos,Agudo Antonio,Navarro Carmen,Sánchez María-José,Barricarte Aurelio,Boutron-Ruault Marie-Christine,Fagherazzi Guy,Racine Antoine,Weiderpass Elisabete,Gunter Marc J,Riboli Elio Cancer causes & control : CCC BACKGROUND:The etiology of small intestinal cancer (SIC) is largely unknown, and there are very few epidemiological studies published to date. No studies have investigated abdominal adiposity in relation to SIC. METHODS:We investigated overall obesity and abdominal adiposity in relation to SIC in the European Prospective Investigation into Cancer and Nutrition (EPIC), a large prospective cohort of approximately half a million men and women from ten European countries. Overall obesity and abdominal obesity were assessed by body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Multivariate Cox proportional hazards regression modeling was performed to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). Stratified analyses were conducted by sex, BMI, and smoking status. RESULTS:During an average of 13.9 years of follow-up, 131 incident cases of SIC (including 41 adenocarcinomas, 44 malignant carcinoid tumors, 15 sarcomas and 10 lymphomas, and 21 unknown histology) were identified. WC was positively associated with SIC in a crude model that also included BMI (HR per 5-cm increase = 1.20, 95 % CI 1.04, 1.39), but this association attenuated in the multivariable model (HR 1.18, 95 % CI 0.98, 1.42). However, the association between WC and SIC was strengthened when the analysis was restricted to adenocarcinoma of the small intestine (multivariable HR adjusted for BMI = 1.56, 95 % CI 1.11, 2.17). There were no other significant associations. CONCLUSION:WC, rather than BMI, may be positively associated with adenocarcinomas but not carcinoid tumors of the small intestine. IMPACT:Abdominal obesity is a potential risk factor for adenocarcinoma in the small intestine. 10.1007/s10552-016-0772-z
    Comparison of associations of body mass index, abdominal adiposity, and risk of colorectal cancer in a large prospective cohort study. Keimling Marlen,Renehan Andrew G,Behrens Gundula,Fischer Beate,Hollenbeck Albert R,Cross Amanda J,Leitzmann Michael F Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology BACKGROUND:Increased body mass index (BMI) is an established colorectal cancer risk factor. High waist circumference or waist-hip-ratio (WHR) may better reflect an abnormal metabolic state and be more predictive of colorectal cancer risk than BMI. METHODS:We examined BMI, waist circumference, WHR, and hip circumference in relation to colorectal cancer risk among 203,177 participants followed for 10 years. We derived standardized colorectal cancer risk estimates for each anthropometric parameter and compared predictive characteristics (Harrell's C-index). In women, we examined whether hormone replacement therapy (HRT) use modified the associations between anthropometric measures and colorectal cancer. RESULTS:We ascertained 2,869 colorectal cancers. In men, increased colon cancer risks were associated with BMI [HR per SD, 1.14; 95% confidence interval (CI), 1.08-1.20], waist circumference (HR per SD, 1.17; 95% CI, 1.08-1.27), and WHR (HR per SD, 1.09; 95% CI, 1.04-1.14). In women, anthropometric variables were unrelated to colon cancer. For men and women, anthropometric variables were unrelated to rectal cancer. Compared with BMI, waist circumference and WHR did not materially influence colon cancer prediction models [C-index changes: -0.0041 and 0.0046 (men); 0.0004 and 0.0005 (women)]. In current HRT users, colon cancer was inversely or suggestively inversely associated with waist circumference (HR per SD, 0.78; 95% CI, 0.63-0.97) and WHR (HR per SD, 0.88; 95% CI, 0.76-1.01), but positively related to hip circumference (HR per SD, 1.39; 95% CI, 1.13-1.71). CONCLUSION:BMI, waist circumference, and WHR show comparable positive associations with colon cancer in men. Associations between anthropometric measures and colon cancer are weak or null in women, but there is some evidence for effect modification by HRT. IMPACT:These findings may improve our understanding of the relation of adiposity to colorectal cancer. 10.1158/1055-9965.EPI-13-0353
    Body weight, fat distribution and colorectal cancer risk: a report from cohort studies of 134255 Chinese men and women. Li H,Yang G,Xiang Y-B,Zhang X,Zheng W,Gao Y-T,Shu X-O International journal of obesity (2005) OBJECTIVE:The objective was to evaluate the association of body size and fat distribution with the risk of colorectal cancer (CRC) in Chinese men and women. DESIGN:This was a population-based, prospective cohort study. SUBJECTS:The analysis included 134,255 Chinese adults enrolled in the Shanghai Women's Health Study and the Shanghai Men's Health Study, with an average follow-up of 11.0 and 5.5 years, respectively. MEASUREMENTS:Waist circumference (WC), body mass index (BMI) and waist-to-hip ratio (WHR) were measured by trained interviewers at baseline. Multivariable Cox models were used to calculate adjusted hazard ratios (HRs) for incident CRC. RESULTS:A total of 935 incident CRC cases were identified. Both measures of general adiposity (measured by BMI) and central adiposity (measured by WHR and WC) were significantly associated with an increased risk of colon cancer in men but not in women. Multivariable-adjusted HRs for colon cancer in men in the highest compared with the lowest quintiles were 2.15 (95% confidence interval (CI): 1.35-3.43; P for trend=0.0006) for BMI, 1.97 (95% CI: 1.19-3.24; P for trend=0.0004) for WHR and 2.00 (95% CI: 1.21-3.29; P for trend=0.0002) for WC. The BMI-associated risk was attenuated in analyses stratified by WHR, whereas the WHR-associated risk remained significant in the high BMI stratum (HR for comparison of extreme tertiles of WHR: 3.38, 95% CI: 1.47-7.75; P for trend =0.0002). None of these anthropometric measures were significantly associated with rectal cancer. CONCLUSION:Obesity, particularly central obesity, was associated with an increased risk of colon cancer in men. 10.1038/ijo.2012.152
    Adiposity and risks of colorectal and small intestine cancer in Chinese adults: a prospective study of 0.5 million people. Pang Yuanjie,Kartsonaki Christiana,Guo Yu,Chen Yiping,Yang Ling,Bian Zheng,Bragg Fiona,Millwood Iona Y,Mao Enke,Li Yilei,Shi Liya,Chen Junshi,Li Liming,Holmes Michael V,Chen Zhengming British journal of cancer BACKGROUND:Uncertainty remains about the associations of adiposity with intestinal cancer in China and by its anatomical subtype. METHODS:The prospective China Kadoorie Biobank recorded 3024 incident cases of colorectal (CRC) and 143 cases of small intestine (SIC) cancer during a 10-year follow-up among 509 568 participants without prior cancer at baseline. Cox regression was used to estimate adjusted hazard ratios (HRs) for specific cancers associated with adiposity. RESULTS:Overall mean body mass index (BMI) was 23.7  kg/m. BMI was positively associated with CRC (HR per SD 1.10 [95% CI 1.06-1.14]), colon (1.13 [1.07-1.18]), and rectal (1.07 [1.02-1.13]) cancer. For waist circumference, the corresponding HRs per SD were 1.14 (1.10-1.18), 1.18 (1.13-1.24), and 1.11 (1.05-1.16), respectively. The adjusted HRs were somewhat greater in men than women. Adiposity was positively, but non-significantly, associated with SIC risk. CONCLUSIONS:Among relatively lean Chinese adults, adiposity was associated with risks of colon and rectal cancer, with the associations somewhat stronger in men than women. 10.1038/s41416-018-0124-8
    Duodenal Adenomas in Patients With Multiple Colorectal Adenomas Without Germline APC or MUTYH Mutations. Kallenberg Frank G J,Latchford Andrew,Lips Nikki C,Aalfs Cora M,Bastiaansen Barbara A J,Clark Susan K,Dekker Evelien Diseases of the colon and rectum BACKGROUND:Patients with genetic adenomatous polyposis syndromes have an increased risk for duodenal cancer, and clear surveillance recommendations exist for this group. However, limited data are available on the duodenal phenotype of patients with multiple colorectal adenomas (10-99) without a germline APC or MUTYH mutation. OBJECTIVE:We aimed to assess the frequency, extent, and progression of duodenal adenomas in patients with multiple colorectal adenomas without a germline APC or MUTYH mutation. DESIGN:This was an historical cohort study. SETTINGS:This study was undertaken at 2 polyposis registries: the Academic Medical Center in the Netherlands, and St. Mark's Hospital in the United Kingdom. PATIENTS:We collected data on all patients with 10 to 99 colorectal adenomas and absent APC and MUTYH mutations, who underwent ≥1 esophagogastroduodenoscopy. MAIN OUTCOME MEASURES:The frequency, extent, and progression of duodenal adenomas were measured. Demographic and endoscopic data were collected, described, and compared between patients with and without duodenal adenomas. RESULTS:Eighty-three patients were identified, of which 8 (9.6%) had duodenal adenomas, detected at a median of 58 years (range, 45-75 y). Duodenal adenomas were detected in 6 of 8 patients at first esophagogastroduodenoscopy. At diagnosis, all 8 patients had Spigelman stage I or II disease. Two of 5 patients with duodenal adenomas who underwent follow-up esophagogastroduodenoscopies increased to stage III disease. The other 3 remained stable. No one developed duodenal cancer. No differences in demographic and endoscopic data were found between patients with and without duodenal adenomas. LIMITATIONS:This study was limited by its retrospective design, selection bias, and small sample size. CONCLUSIONS:Duodenal adenomas are found in a minority of patients with multiple colorectal adenomas without a germline APC or MUTYH mutation, at an average age of 58 years, and, at diagnosis, disease severity is mild. These results are a first step in unraveling the duodenal phenotype of these patients, which is needed to provide appropriate upper GI screening and surveillance recommendations. See Video Abstract at http://links.lww.com/DCR/A357. 10.1097/DCR.0000000000000868
    Cancer Risk in the Early Stages of Inflammatory Bowel Disease in Korean Patients: A Nationwide Population-based Study. Jung Yoon Suk,Han Minkyung,Park Sohee,Kim Won Ho,Cheon Jae Hee Journal of Crohn's & colitis Background and Aims:The association between inflammatory bowel disease [IBD] and cancer remains poorly defined in Asian populations. Therefore, we conducted a nationwide population-based study to determine the cancer risk in Korean patients with IBD. Methods:Using the National Health Insurance claims data, we collected data on patients diagnosed with IBD (5595 Crohn's disease [CD] and 10 049 ulcerative colitis [UC]) from 2011 to 2014. Standardized incidence ratios [SIRs] of overall and site-specific cancers in IBD patients in comparison with the general population were calculated. Results:The overall cancer risk was higher in CD patients [SIR, 2.2; 95% confidence interval, 1.5-3.0 in men and 3.3; 2.4-4.5 in women] and UC patients [1.9; 1.6-2.3 in men and 1.9; 1.5-2.4 in women]. There were significantly increased risks for the following cancers: small bowel cancer [31.2; 3.8-112.8], colorectal cancer [CRC] [3.7; 1.6-7.2] and haematological cancer [4.0; 1.1-10.3] in men with CD; small bowel cancer [61.1; 7.4-220.6], CRC [4.7; 1.5-10.9], liver cancer [15.3; 5.6-33.2], pancreatic cancer [8.6; 1.0-31.0] and haematological cancer [11.0; 3.6-25.7] in women with CD; CRC [2.1; 1.3-3.3] and cancer of the prostate [3.5; 2.1-5.5], brain/central nervous system [6.1; 1.3-17.9] and thyroid [2.2; 1.1-3.9] in men with UC; and CRC [3.0; 1.5-5.3], cancer of the liver [4.4; 1.6-9.7] and cervix uteri [5.7; 2.4-11.1], and haematological cancer [3.5; 1.1-8.1] in women with UC. Women with CD had an increased risk of non-Hodgkin lymphoma [NHL] and leukaemia. Women with UC had an increased risk of NHL. Conclusions:Korean patients with IBD are at increased risk for overall, intestinal and haematological cancer. 10.1093/ecco-jcc/jjx040
    Clinicopathologic features, surgical treatments, and outcomes of small bowel tumors: A retrospective study in China. Zhang Shuisheng,Zheng Cuiling,Chen Yingtai,Xu Quan,Ma Jie,Yuan Wei,Jiang Qinglong,Zhao Yajie,Zhang Jianwei,Che Xu,Wang Chengfeng,Huang Xiaozhun,Chen Fang,Wang Nianchang,Ma Xiao,Lan Zhongmin International journal of surgery (London, England) BACKGROUND:Small bowel tumors are relatively rare. Accumulation of data regarding their clinical presentation, pathologic features, prognostic factors, treatment modalities, and outcome has been an issue. We summarize the clinicopathologic features and evaluate the long-term outcome of patients with small bowel tumors who underwent surgery. METHODS:This is a retrospective study of medical records of 456 patients with small bowel tumors treated surgically at a Cancer Hospital between 1999 and 2016. RESULTS:The study included 275 males (60.3%) and 181 females (39.7%). Small bowel tumors were difficult to diagnose because of non-specific symptoms. The most common symptoms were alimentary symptoms (56.8%) and abdominal pain (37.3%). Final histopathology revealed 241 adenocarcinomas (52.9%), 153 gastrointestinal stromal tumors (GISTs; 33.6%), 16 neuroendocrine tumors (NETs; 3.5%), and 46 other types of tumors (10.1%). The 456 surgeries performed included 153 pancreaticoduodenectomies, 241 limited duodenum resections, 60 palliative bypass surgeries, and 2 abdominal explorations. The 5-year overall survival and progression-free survival rates for patients with small bowel tumor were 57.2% and 44.6%, respectively. Adenocarcinomas resulted in the worst overall survival compared to GISTs or NETs, and tumors with duodenal location resulted in a worse survival compared to those with non-duodenal location. CONCLUSION:Surgery is the mainstay of treatment for small bowel tumors. Adenocarcinomas and duodenal involvement seem to contribute to poor outcomes. 10.1016/j.ijsu.2017.05.076
    Small Bowel Carcinomas in Coeliac or Crohn's Disease: Clinico-pathological, Molecular, and Prognostic Features. A Study From the Small Bowel Cancer Italian Consortium. Vanoli Alessandro,Di Sabatino Antonio,Furlan Daniela,Klersy Catherine,Grillo Federica,Fiocca Roberto,Mescoli Claudia,Rugge Massimo,Nesi Gabriella,Fociani Paolo,Sampietro Gianluca,Ardizzone Sandro,Luinetti Ombretta,Calabrò Antonio,Tonelli Francesco,Volta Umberto,Santini Donatella,Caio Giacomo,Giuffrida Paolo,Elli Luca,Ferrero Stefano,Latella Giovanni,Ciardi Antonio,Caronna Roberto,Solina Gaspare,Rizzo Aroldo,Ciacci Carolina,D'Armiento Francesco P,Salemme Marianna,Villanacci Vincenzo,Cannizzaro Renato,Canzonieri Vincenzo,Reggiani Bonetti Luca,Biancone Livia,Monteleone Giovanni,Orlandi Augusto,Santeusanio Giuseppe,Macciomei Maria C,D'Incà Renata,Perfetti Vittorio,Sandri Giancarlo,Silano Marco,Florena Ada M,Giannone Antonino G,Papi Claudio,Coppola Luigi,Usai Paolo,Maccioni Antonio,Astegiano Marco,Migliora Paola,Manca Rachele,Martino Michele,Trapani Davide,Cerutti Roberta,Alberizzi Paola,Riboni Roberta,Sessa Fausto,Paulli Marco,Solcia Enrico,Corazza Gino R Journal of Crohn's & colitis Background and Aims:An increased risk of small bowel carcinoma [SBC] has been reported in coeliac disease [CD] and Crohn's disease [CrD]. We explored clinico-pathological, molecular, and prognostic features of CD-associated SBC [CD-SBC] and CrD-associated SBC [CrD-SBC] in comparison with sporadic SBC [spo-SBC]. Methods:A total of 76 patients undergoing surgical resection for non-familial SBC [26 CD-SBC, 25 CrD-SBC, 25 spo-SBC] were retrospectively enrolled to investigate patients' survival and histological and molecular features including microsatellite instability [MSI] and KRAS/NRAS, BRAF, PIK3CA, TP53, HER2 gene alterations. Results:CD-SBC showed a significantly better sex-, age-, and stage-adjusted overall and cancer-specific survival than CrD-SBC, whereas no significant difference was found between spo-SBC and either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly higher rate of MSI and median tumour-infiltrating lymphocytes [TIL] than CrD-SBC and spo-SBC. Among the whole SBC series, both MSI─which was the result of MLH1 promoter methylation in all but one cases─and high TIL density were associated with improved survival at univariable and stage-inclusive multivariable analysis. However, only TILs retained prognostic power when clinical subgroups were added to the multivariable model. KRAS mutation and HER2 amplification were detected in 30% and 7% of cases, respectively, without prognostic implications. Conclusions:In comparison with CrD-SBC, CD-SBC patients harbour MSI and high TILs more frequently and show better outcome. This seems mainly due to their higher TIL density, which at multivariable analysis showed an independent prognostic value. MSI/TIL status, KRAS mutations and HER2 amplification might help in stratifying patients for targeted anti-cancer therapy. 10.1093/ecco-jcc/jjx031
    Small bowel endoscopy in familial adenomatous polyposis and Lynch syndrome. Koornstra Jan Jacob Best practice & research. Clinical gastroenterology Patients with familial adenomatous polyposis (FAP) and patients with Lynch syndrome have an increased risk of developing small intestinal neoplasia. In both conditions, the lifetime risk to develop small bowel cancer is estimated to be around 5%. In FAP, this risk is associated with the degree of duodenal polyposis, classically assessed by the Spigelman classification. For this reason, gastroduodenal surveillance with forward-viewing and side-viewing endoscopy is generally recommended. Studies using video capsule endoscopy and balloon-assisted enteroscopy in FAP patients have revealed that jejunal and ileal polyps occur frequently in FAP, especially in those with extensive duodenal polyposis. Nevertheless, the clinical relevance of small bowel polyps beyond the duodenum appears to be limited. Compared to FAP, little is known about the prevalence and natural history of small bowel neoplasia in Lynch syndrome. Surveillance of the small bowel is not recommended in Lynch syndrome, although recent data using capsule endoscopy provided promising results. 10.1016/j.bpg.2012.01.022
    Frequency and Features of Duodenal Adenomas in Patients With MUTYH-Associated Polyposis. Walton Sarah-Jane,Kallenberg Frank G J,Clark Susan K,Dekker Evelien,Latchford Andrew Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association BACKGROUND & AIMS:MUTYH-associated polyposis (MAP) is similar to familial adenomatous polyposis (FAP), in that it increases the risk for duodenal adenomas and cancer. Almost all patients with FAP develop duodenal adenomas and 5% develop duodenal cancer. Little is known about the prevalence of duodenal adenomas and cancer in patients with MAP, but current surveillance recommendations are the same for patients with FAP-they should begin surveillance when they are 25 years old. We aimed to assess the prevalence, extent, and progression of duodenal adenomas in patients with MAP and evaluate upper gastrointestinal tract surveillance recommendations. METHODS:In a retrospective study, we collected data on all patients (n = 92) with MAP undergoing surveillance esophagogastroduodenoscopy from registries at St Mark's Hospital (London, UK) and the Academic Medical Center (Amsterdam, The Netherlands) from 2002 through 2014. We collected information on adenoma development, age at adenoma detection, interventions, and disease progression. RESULTS:Duodenal adenomas were detected in 31 patients (34%), at a median age of 50 years. When duodenal polyposis first was detected, it was Spigelman stages I or II in 84% of patients; most had few small polyps, without high-grade dysplasia or villous features. Subsequent esophagogastroduodenoscopy evaluation of 18 of these patients found that 14 (78%) had Spigelman stages 0 to II disease (median follow-up period, 7.8 y). Disease progressed in stage in 6 patients, over 9.5 years, because of lesion size or villous features (2 reached stage IV disease). Adenomas were down-staged in 8 patients after biopsy or polypectomy analyses, and were unchanged for 3 patients. CONCLUSIONS:In a data analysis from 92 patients with MAP, duodenal polyposis seemed to develop less frequently than in patients with FAP, and developed at a later age. Increasing lesion size and villous change appear to promote adenoma progression, rather than polyp number or dysplasia. It may be time to consider a new staging system for patients with MAP, to better determine disease severity and surveillance strategies. 10.1016/j.cgh.2016.02.020
    The impact of chromoendoscopy for surveillance of the duodenum in patients with MUTYH-associated polyposis and familial adenomatous polyposis. Hurley Joanna J,Thomas Laura E,Walton Sarah-Jane,Thomas-Gibson Siwan,Haycock Adam,Suzuki Noriko,Mort Matthew,Williams Geraint,Morgan Meleri,Clark Susan K,Sampson Julian R,Dolwani Sunil Gastrointestinal endoscopy BACKGROUND AND AIMS:Duodenal polyposis and cancer have become a key issue for patients with familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). Almost all patients with FAP will develop duodenal adenomas, and 5% will develop cancer. The incidence of duodenal adenomas in MAP appears to be lower than in FAP, but the limited available data suggest a comparable increase in the relative risk and lifetime risk of duodenal cancer. Current surveillance recommendations, however, are the same for FAP and MAP, using the Spigelman score (incorporating polyp number, size, dysplasia, and histology) for risk stratification and determination of surveillance intervals. Previous studies have demonstrated a benefit of enhanced detection rates of adenomas by use of chromoendoscopy both in sporadic colorectal disease and in groups at high risk of colorectal cancer. We aimed to assess the effect of chromoendoscopy on duodenal adenoma detection, to determine the impact on Spigelman stage and to compare this in individuals with known pathogenic mutations in order to determine the difference in duodenal involvement between MAP and FAP. METHODS:A prospective study examined the impact of chromoendoscopy on the assessment of the duodenum in 51 consecutive patients with MAP and FAP in 2 academic centers in the United Kingdom (University Hospital Llandough, Cardiff, and St Mark's Hospital, London) from 2011 to 2014. RESULTS:Enhanced adenoma detection of 3 times the number of adenomas after chromoendoscopy was demonstrated in both MAP (P = .013) and FAP (P = .002), but did not affect adenoma size. In both conditions, there was a significant increase in Spigelman stage after chromoendoscopy compared with endoscopy without dye spray. Spigelman scores and overall adenoma detection was significantly lower in MAP compared with FAP. CONCLUSIONS:Chromoendoscopy improved the diagnostic yield of anomas in MAP and FAP 3-fold, and in both MAP and FAP this resulted in a clinically significant upstaging in Spigelman score. Further studies are required to determine the impact of improved adenoma detection on the management and outcome of duodenal polyposis. 10.1016/j.gie.2018.04.2347
    Risks for lymphoma and gastrointestinal carcinoma in patients with newly diagnosed adult-onset celiac disease: Consequences for follow-up: Celiac disease, lymphoma and GI carcinoma. van Gils Tom,Nijeboer Petula,Overbeek Lucy Ih,Hauptmann Michael,Castelijn Daan Ar,Bouma Gerd,Mulder Chris Jj,van Leeuwen Flora E,de Jong Daphne United European gastroenterology journal Background:The association between celiac disease (CD) and the development of lymphoid and gastrointestinal (GI) malignancies have been reported. However, data are scarce yet needed to develop evidence-based follow-up programs. Objective:The objective of this article is to assess relative (RR) and absolute risks of lymphoma and GI carcinoma for newly diagnosed patients. Methods:A case-control design to determine RR was performed with cases (lymphoma or GI carcinoma) and controls (melanoma or basal cell carcinoma) diagnosed 1994-2014, retrieved from the Dutch nationwide population-based pathology database (PALGA). Within this population, individuals with histologically proven CD before or simultaneously diagnosed with the malignancy were identified. Results:A total of 349/301,425 cases (0.1%) and 282/576,971 (0.05%) controls were diagnosed with CD. Risk of T-cell lymphoma, predominantly enteropathy-associated T-cell lymphoma (EATL), was strongly associated with CD diagnosis (RR = 35.8 (95% CI 27.1-47.4)). Although most often synchronously diagnosed, T-cell lymphoma RR ≥ 1 year after CD diagnosis was still elevated (RR = 12.7 (95% CI 7.6-21.3)). Other CD-associated malignancies were small bowel adenocarcinoma (RR = 11.9 (95% CI 8.2-17.2)) and esophageal squamous cell carcinoma (RR = 3.5 (95% CI 2.1-5.8)). Absolute risks were relatively low. Other types of lymphomas and GI carcinomas were not associated with CD. Conclusion:Increased risk for specific malignancies in CD should alert physicians for EATL (both intestinal and extraintestinal) and small bowel adenocarcinoma in patients with CD diagnosed at age ≥ 50 years. 10.1177/2050640618800540
    Influence of marital status on small intestinal adenocarcinoma survival: an analysis of the Surveillance, Epidemiology, and End Results (SEER) database. Chen Zhihui,Cui Ji,Dai Weigang,Yang Hong,He Yulong,Song Xinming Cancer management and research Aim:No studies have been published on the relationship between marital status and outcomes in small intestinal cancers. The present study was conducted to explore the influence of marital status on small intestinal adenocarcinoma survival based on the Surveillance, Epidemiology, and End Results (SEER) database. Methods:Data from eligible patients diagnosed with small intestinal adenocarcinoma between 2004 and 2015 were extracted from the SEER database. Patients were categorized into married group (including common law) and unmarried group (including single [never married], widowed, divorced, separated, and unmarried or domestic partner). The primary endpoints were 5-year overall survival (OS) and 5-year cancer-specific survival (CSS). A survival curve was generated by the Kaplan-Meier method, and the survival rate differences were estimated by a log-rank test. A multivariate Cox proportional hazard model was used to evaluate the independent risk factors for survival. Results:A total of 6,747 small intestinal adenocarcinoma patients were enrolled, including 3,862 married and 2,885 unmarried patients. The 5-year OS and 5-year CSS were significantly greater in married patients than in unmarried patients (27.1 vs 18.8% for OS and 45.7 vs 39.3% for CSS, both <0.001). After adjusting for age, insurance status, tumor primary site, TNM stage, tumor grade, tumor histology, and surgery, the multivariate Cox proportional hazards model showed that marriage is an independent protective factor for OS (HR =0.789, 95% CI: 0.745-0.836, <0.001) and CSS (HR =0.794, 95% CI: 0.736-0.857, <0.001). Conclusion:Married small intestinal adenocarcinoma patients have better OS and CSS than unmarried patients. Psychological and economic supports from the spouses of married patients may contribute to improvements in survival. 10.2147/CMAR.S177430
    Intestinal cancer stem cells marked by Bmi1 or Lgr5 expression contribute to tumor propagation via clonal expansion. Yanai Hirotsugu,Atsumi Naho,Tanaka Toshihiro,Nakamura Naohiro,Komai Yoshihiro,Omachi Taichi,Tanaka Kiyomichi,Ishigaki Kazuhiko,Saiga Kazuho,Ohsugi Haruyuki,Tokuyama Yoko,Imahashi Yuki,Ohe Shuichi,Hisha Hiroko,Yoshida Naoko,Kumano Keiki,Kon Masanori,Ueno Hiroo Scientific reports Although the existence of cancer stem cells in intestine tumors has been suggested, direct evidence has not been yet provided. Here, we showed, using the multicolor lineage-tracing method and mouse models of intestinal adenocarcinoma and adenoma that Bmi1- or Lgr5- positive tumorigenic cells clonally expanded in proliferating tumors. At tumor initiation and during tumor propagation in the colon, the descendants of Lgr5-positive cells clonally proliferated to form clusters. Clonal analysis using ubiquitous multicolor lineage tracing revealed that colon tumors derived from Lgr5-positive cells were monoclonal in origin but eventually merged with neighboring tumors, producing polyclonal tumors at the later stage. In contrast, the origin of small intestine tumors was likely polyclonal, and during cancer progression some clones were eliminated, resulting in the formation of monoclonal tumors, which could merge similar to colon tumors. These results suggest that in proliferating intestinal neoplasms, Bmi1- or Lgr5-positive cells represent a population of cancer stem cells, whereas Lgr5-positive cells also function as cells-of-origin for intestinal tumors. 10.1038/srep41838
    Clinicopathological features, surgical treatments, and survival outcomes of patients with small bowel adenocarcinoma. Zhang Shuisheng,Yuan Wei,Zhang Jianwei,Chen Yingtai,Zheng Cuiling,Ma Jie,Jiang Qinglong,Zhao Yajie,Xu Quan,Wang Chengfeng Medicine To date, because of their rarity, the clinicopathological features and surgical outcomes of small bowel adenocarcinomas (SBAs) have been insufficiently explored. We evaluated the clinicopathological features and long-term outcomes of patients who underwent surgery for SBA.This retrospective study (from 1999 to 2016) examined patients with SBA treated surgically at the China National Cancer Center/Cancer Hospital. Clinicopathological features, preoperative evaluation, surgical treatment, and outcome parameters were reviewed and analyzed.Among the 241 patients studied, pancreaticoduodenectomies were performed in 51.0%, partial resection in 24.5%, palliative bypass surgery in 23.7%, and abdominal exploration in 0.8% of the patients. Majority of the patients were diagnosed at an advanced disease stage, and the duodenum was the most common tumor site. Postoperative complications occurred in 44.4% of the patients. Median overall and progression-free survival rates were 22.0 and 13.0 months, respectively. The 5-year overall and progression-free survival rates for patients with duodenal adenocarcinoma were 30.2% and 21.7%, respectively. Duodenal adenocarcinomas, lymph node metastases, distant metastases, poor differentiation, and lymphovascular invasion were associated with poor overall survival outcomes. The 3 factors associated with progression-free survival were the degree of differentiation, lymph node metastases, and distant metastases.Surgery remains the mainstay of treatment for SBA. A poor prognosis could be owing to the site, metastasis, differentiation, and lymphovascular invasion; however, the prognosis may improve through early diagnosis and operation. 10.1097/MD.0000000000007713
    Meta-analysis of postoperative adjuvant therapy for small bowel adenocarcinoma. Ye Xiaojian,Zhang Guoqiang,Chen Haibin,Li Yong PloS one OBJECTIVE:The role of adjuvant therapy in small bowel adenocarcinoma (SBA), a rare malignancy with a poor prognosis, is controversial. The purpose of this article is to investigate the impact of adjuvant therapy on the survival of patients with SBA in a meta-analysis. METHODS:We performed a comprehensive search of PubMed, EMBASE and the Cochrane Library database between 2010 and 2017. Hazard ratios (HR) with 95% confidence intervals (95%CI) were used to assess the effect of adjuvant chemotherapy and/or radiation treatment after curative surgery in patients with SBA. Moreover, impact of age, sex, stage, differentiation, lymph node involvement, and margin status was also evaluated. RESULTS:We included 15 studies to evaluate the effect of adjuvant therapy on the survival of patients with SBA. The pooled HR of overall survival (OS) involving 5986 patients showed that adjuvant therapy did not have a statistically significant effect on the survival of patients with SBA (pooled HR = 0.89, 95% CI = 0.73-1.09, p = 0.25). Further, 607 patients with duodenal adenocarcinoma (DA) had similar results (pooled HR = 0.96, 95% CI = 0.75-1.23, p = 0.77). Similarly, adjuvant treatment vs. non-adjuvant treatment in terms of disease-free survival (DFS) or relapse-free survival (RFS) showed the same results (pooled HR = 0.89, 95% CI = 0.64-1.23, p = 0.48). However, we found that adjuvant therapy resulted in favorable postoperative survival in Europe according to the subgroup analysis (pooled HR = 0.63, 95% CI = 0.5-0.8, p = 0.0002). In addition, the pooled HR shows that stage, differentiation, lymph node involvement, and margin status were related to the OS of patients with SBA. CONCLUSION:Patients with SBA who received adjuvant therapy after surgery did not receive a significant survival benefit. Adjuvant therapy may be more useful in advanced cancer or metastatic patients. 10.1371/journal.pone.0200204
    ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma. Laforest Anais,Aparicio Thomas,Zaanan Aziz,Silva Fabio Pittella,Didelot Audrey,Desbeaux Aurélien,Le Corre Delphine,Benhaim Leonor,Pallier Karine,Aust Daniela,Pistorius Steffen,Blons Hélène,Svrcek Magali,Laurent-Puig Pierre European journal of cancer (Oxford, England : 1990) AIM OF THE STUDY:Small bowel adenocarcinoma (SBA) is a rare and aggressive tumour with poor outcomes. Because of its low incidence, the number prospective studies remains insufficient leading to poor knowledge and absence of standard of care. Aiming to better understand small bowel carcinogenesis we investigated the frequency of somatic mutations in a large data set of patients in more than 740 mutational hotspots among 46 genes. METHODS:In total, 83 SBA cases were selected from two European databases. The sequencing was performed using the Ion 316 Chip. Additionally we looked into ERBB2 expression and microsatellite instability (MSI) status. RESULTS:The tumours most frequently were duodenal (47%) and stage ⩾3 (63%). Eight genes were mutated with a frequency >5%: KRAS, TP53, APC, SMAD4, PIK3CA, ERBB2, BRAF and FBXW7. ERBB2 alterations are present in 10 patients (12%) through mutations (7 cases) or amplifications (3 cases). ERBB2 mutations were significantly associated with duodenal tumour location (P=0.04). In this group, there was a positive association with dMMR status (P=0.006) and APC mutation (P=0.02) but negative association with p53 mutations (P=0.038). CONCLUSIONS:This study describes the first large screening of somatic mutations in SBA using next generation sequencing. The ERBB2 mutation was revealed to be one of the most frequent alterations in SBA with a distribution dependent on tumour location. In most cases ERBB2 mutation was identical (p.L755S). In clinical practice, this may suggest that more than 10% of the patients with SBA could be treated using an anti-ERBB2-targeted agent. 10.1016/j.ejca.2014.04.007
    Genomic Profiling of Small-Bowel Adenocarcinoma. Schrock Alexa B,Devoe Craig E,McWilliams Robert,Sun James,Aparicio Thomas,Stephens Philip J,Ross Jeffrey S,Wilson Richard,Miller Vincent A,Ali Siraj M,Overman Michael J JAMA oncology Importance:Small-bowel adenocarcinomas (SBAs) are rare cancers with a significantly lower incidence, later stage at diagnosis, and worse overall survival than other intestinal-derived cancers. To date, comprehensive genomic analysis of SBA is lacking. Objective:To perform in-depth genomic characterization of a large series of SBAs and other gastrointestinal tumors to draw comparisons and identify potentially clinically actionable alterations. Design, Setting, and Participants:Prospective analysis was performed of clinical samples from patients with SBA (n = 317), colorectal cancer (n = 6353), and gastric carcinoma (n = 889) collected between August 24, 2012, and February 3, 2016, using hybrid-capture-based genomic profiling, at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions. Results:Of the 7559 patients included in analysis, 4138 (54.7%) were male; the median age was 56 (range, 12-101) years. The frequency of genomic alterations seen in SBA demonstrated distinct differences in comparison with either colorectal cancer (APC: 26.8% [85 of 317] vs 75.9% [4823 of 6353], P < .001; and CDKN2A: 14.5% [46 of 317] vs 2.6% [165 of 6353], P < .001) or gastric carcinoma (KRAS: 53.6% [170 of 317] vs 14.2% [126 of 889], P < .001; APC: 26.8% [85 of 317] vs 7.8% [69 of 889], P < .001; and SMAD4: 17.4% [55 of 317] vs 5.2% [46 of 889], P < .001). BRAF was mutated in 7.6% (484 of 6353) of colorectal cancer and 9.1% (29 of 317) of SBA samples, but V600E mutations were much less common in SBA, representing only 10.3% (3 of 29) of BRAF-mutated cases. The ERBB2/HER2 point mutations (8.2% [26 of 317]), microsatellite instability (7.6% [13 of 170]), and high tumor mutational burden (9.5% [30 of 317]) were all enriched in SBA. Significant differences were noted in the molecular profile of unspecified SBA compared with duodenal adenocarcinoma, as well as in inflammatory bowel disease-associated SBAs. Targetable alterations in several additional genes, including PIK3CA and MEK1, and receptor tyrosine kinase fusions, were also identified in all 3 series. Conclusions and Relevance:This study presents to our knowledge the first large-scale genomic comparison of SBA with colorectal cancer and gastric carcinoma. The distinct genomic differences establish SBA as a molecularly unique intestinal cancer. In addition, genomic profiling can identify potentially targetable genomic alterations in the majority of SBA cases (91%), and the higher incidence of microsatellite instability and tumor mutational burden in SBA suggests a potential role for immunotherapy. 10.1001/jamaoncol.2017.1051
    Inflammatory Bowel Disease and Small Bowel Cancer Risk, Clinical Characteristics, and Histopathology: A Population-Based Study. Bojesen Rasmus Dahlin,Riis Lene Buhl,Høgdall Estrid,Nielsen Ole Haagen,Jess Tine Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association BACKGROUND & AIMS:Inflammatory bowel disease (IBD) may increase risk of small bowel cancer (SBC). However, little is known of the characteristics and features of IBD-SBC, due to a low number of cases worldwide. We performed a population-based study of IBD and SBC to calculate risk and increase our understanding of clinical characteristics and histopathological and molecular features. METHODS:The study population consisted of all individuals aged 16 years or older living in Denmark during 1978-2010. Through linkage between national registers and subsequent scrutiny of medical records and pathology descriptions, we identified 40 cases of IBD-SBC. Risk was calculated by standardized incidence ratio (SIR) (observed/expected); patient characteristics were derived from medical files, and surgery specimens were obtained from hospitals nationwide for histopathological and molecular analyses. RESULTS:During 241,620 person-years of follow-up, 23 patients with Crohn's disease developed small bowel adenocarcinoma (SIR, 14.38; 95% confidence interval, 8.78-22.20) and 9 developed neuroendocrine tumors (SIR, 6.83; 95% confidence interval, 3.13-12.97). No significantly increased risk of SBC was found among patients with ulcerative colitis. Most patients with SBC had moderate-to-severe Crohn's disease with small bowel and upper gastrointestinal involvement. Assessment of surgical specimens of small bowel adenocarcinomas revealed a clear transition from inflammation to dysplasia and cancer, whereas no tumors had evidence of microsatellite instability. CONCLUSIONS:In a population-based study of patients in Denmark with IBD and SBC, we found risk of adenocarcinomas and neuroendocrine tumors to be increased among persons with Crohn's disease. Most patients with IBD-SBC had extensive IBD of moderate-to-severe activity. Adenocarcinomas appeared to develop via an inflammation-dysplasia-carcinoma pathway, but differed from IBD-related colorectal adenocarcinomas in their molecular features. 10.1016/j.cgh.2017.06.051
    APC:T1556fs and STK11 mutations in duodenal adenomas and adenocarcinomas. Kojima Yohei,Ohtsuka Kouki,Ohnishi Hiroaki,Abe Nobutsugu,Furuse Junji,Watanabe Takashi,Sugiyama Masanori Surgery today PURPOSE:Duodenal adenoma and adenocarcinoma (AC) are rare tumors, and few studies have examined their genetic features. We aimed to determine the key genetic changes in duodenal adenoma and AC, and to clarify the possible involvement of the adenoma-carcinoma sequence in duodenal tumor carcinogenesis. METHODS:Nineteen duodenal tumors collected by endoscopic mucosal resection or surgical resection were classified as AC, adenoma with high-grade dysplasia (HGD), or adenoma with low-grade dysplasia (LGD) per the World Health Organization tumor classification. When a tumor contained two or more components with different dysplasia grades, the highest grade was assigned as the tumor grade. Representative areas of these components with different grades were microdissected and evaluated by a genomic analysis. Mutational hotspots involving 50 oncogenes and tumor suppressor genes were analyzed by next-generation sequencing, and their association with the dysplasia grade was investigated. RESULTS:We analyzed 27 tumor components of AC or adenoma, with 11 normal mucosal samples obtained from 19 patients with duodenal tumors. The most prevalent abnormality among 50 genes tested was the KRAS mutation, which was detected in 12/19 (63.2%) patients, followed by APC and TP53 mutations (47.4 and 36.8%, respectively). According to the tumor dysplasia grading of each component, KRAS mutations were found in 5/8 (62.5%) tumors with AC components, 6/9 (66.7%) tumors with HGD components, and 3/10 (30.0%) tumors with LGD components. TP53 mutations were found in 4/8 (50.0%) tumors with AC components, 3/9 (33.3%) tumors with HGD components, and 1/10 (10.0%) tumors with LGD components. APC mutations were found in 2/8 (25.0%) tumors with AC components, 6/9 (66.7%) tumors with HGD components, and 5/10 (50.0%) tumors with LGD components. Notably, an APC:T1556fs mutation was detected in six cases (31.6%), five of which were adenoma cases. Furthermore, STK11 mutations were confirmed in 2/8 (25.0%) AC cases and in 1/11 (9.1%) adenoma cases. CONCLUSION:APC:T1556fs and STK11 mutations found in duodenal adenomas/ACs highlight the importance of proteins encoded by these genes in tumor development. APC mutations were identified in duodenal adenomas more frequently than in duodenal ACs, which differed from the observations of typical adenoma-carcinoma sequences seen in colorectal cancer, suggesting the limited involvement of this mechanism in duodenal cancer development. 10.1007/s00595-018-1649-4
    Extracolonic cancer risk in Dutch patients with APC (adenomatous polyposis coli)-associated polyposis. Ghorbanoghli Zeinab,Bastiaansen Barbara Aj,Langers Alexandra Mj,Nagengast Fokko M,Poley Jan-Werner,Hardwick James Ch,Koornstra Jan J,Sanduleanu Silvia,de Vos Tot Nederveen Cappel Wouter H,Witteman Ben Jm,Morreau H,Dekker Evelien,Vasen Hans Fa Journal of medical genetics BACKGROUND:Screening of patients with familial adenomatous polyposis (FAP) have led to a substantial reduction in mortality due to colorectal cancer (CRC). Recent guidelines suggest that surveillance of non-intestinal malignancies should also be considered in those patients. However, the value of these surveillance programmes is unknown. The aims of this study were (1) to assess the occurrence of extracolonic malignancies in a large series of adenomatous polyposis coli (APC) mutation carriers and (2) to evaluate the causes of death. METHODS:All APC mutation carriers were selected from the Dutch polyposis registry. Data on causes of death were collected. Pathology reports were retrieved from the Dutch Pathology Registry. RESULTS:A total of 85 extracolonic malignancies were diagnosed in 74 of 582 APC mutation carriers. Duodenal and skin cancers were the most prevalent cancers. Thyroid cancer was observed in only 1.5% of the cases. The main cause of death was cancer (59% of all deaths), with 42% due to CRC and 21% due to duodenal cancer. One patient died from thyroid cancer. The second and third most common causes of death were cardiovascular disease (13% of all deaths) and desmoid tumours (11% of all deaths), respectively. CONCLUSION:Extending surveillance programmes to other cancers will not contribute significantly to the survival of patients with FAP. 10.1136/jmedgenet-2017-104545
    Duodenal localization is a negative predictor of survival after small bowel adenocarcinoma resection: A population-based, propensity score-matched analysis. Wilhelm Alexander,Galata Christian,Beutner Ulrich,Schmied Bruno M,Warschkow Rene,Steffen Thomas,Brunner Walter,Post Stefan,Marti Lukas Journal of surgical oncology BACKGROUND AND OBJECTIVES:This study assessed the influence of tumor localization of small bowel adenocarcinoma on survival after surgical resection. METHODS:Patients with resected small bowel adenocarcinoma, ACJJ stage I-III, were identified from the Surveillance, Epidemiology, and End Results database from 2004 to 2013. The impact of tumor localization on overall and cancer-specific survival was assessed using Cox proportional hazard regression models with and without risk-adjustment and propensity score methods. RESULTS:Adenocarcinoma was localized to the duodenum in 549 of 1025 patients (53.6%). There was no time trend for duodenal localization (P = 0.514). The 5-year cancer-specific survival rate was 48.2% (95%CI: 43.3-53.7%) for patients with duodenal carcinoma and 66.6% (95%CI: 61.6-72.1%) for patients with cancer located in the jejunum or ileum. Duodenal localization was associated with worse overall and cancer-specific survival in univariable (HR = 1.73; HR = 1.81, respectively; both P < 0.001), multivariable (HR = 1.52; HR = 1.65; both P < 0.001), and propensity score-adjusted analyses (HR = 1.33, P = 0.012; HR = 1.50, P = 0.002). Furthermore, young age, retrieval of more than 12 regional lymph nodes, less advanced stage, and married matrimonial status were positive, independent prognostic factors. CONCLUSIONS:Duodenal localization is an independent risk factor for poor survival after resection of adenocarcinoma. 10.1002/jso.24877
    Reproductive history and risk of small bowel cancer by histologic type: a population-based study. Lu Yunxia,Lambe Mats,Martling Anna,Lagergren Jesper Cancer causes & control : CCC PURPOSE:The male predominance of the two main histologic malignancies of the small bowel cancer may reflect a role of sex hormones which will be examined in this study. METHODS:This was a nationwide population-based nested case-control study, based on a cohort of subjects born between 1932 and 2008, as identified in the Swedish Multi-Generation Register. For each case of small bowel cancer, 10 age- and sex-matched controls were randomly selected. Number of children and age at having the first child were analyzed in relation to the risk of small bowel cancer using conditional logistic regression, providing odds ratios (ORs) and 95 % confidence intervals (CIs). RESULTS:A total of 632 female cases and 894 male cases of small bowel cancer were included. No overall increased risk of small bowel cancer was found in parous compared to non-parous women (OR = 1.02, 95 % CI 0.67-1.54). There was no association between age at first birth and small bowel cancer (>30 years of age vs <20 years; OR = 1.04, 95 % CI 0.72-1.50). No associations were detected in separate analyses of adenocarcinoma or carcinoid of the small bowel. No distinct risk patterns were discerned in men compared to women. CONCLUSIONS:Reproductive history does not seem to be associated with the risk of small bowel cancer, independent of histologic type. 10.1007/s10552-012-0080-1
    A potential association between exposure to hepatitis B virus and small bowel adenocarcinoma. DeFilippis Ersilia M,Mehta Mamta,Ludwig Emmy Journal of gastrointestinal oncology Chronic infection with hepatitis B virus (HBV) has never been described as a risk factor for small bowel adenocarcinoma, although infection is a known risk factor for hepatocellular carcinoma. From May 2009 to December 2014, we implemented an institution-wide screening program for hepatitis B viral serologies prior to starting chemotherapy. Evidence of exposure [hepatitis B core antibody (anti-HBc) positivity in the absence of hepatitis B surface antigen (HBsAg) positivity] was highest in patients with hepatocellular carcinoma (21.1%), followed by small bowel cancer (12.5%). The small bowel adenocarcinoma cases with anti-HBc positivity were reviewed. Special attention was paid to known risk factors for small bowel cancers. One patient had a diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC). However, the other patients had no genetic syndromes, history of inflammatory bowel disease or other chronic inflammation to explain their risk. We postulate exposure to bile acids, tumorigenesis of hepatocytes and cholangiocytes, and/or damage to the intestinal mucosa secondary to HBV exposure/infection as potential mechanisms for development of small bowel adenocarcinoma. More research is warranted to further elucidate this association. 10.21037/jgo.2015.10.05
    Separation of Low- Versus High-grade Crohn's Disease-associated Small Bowel Carcinomas is Improved by Invasive Front Prognostic Marker Analysis. Arpa Giovanni,Grillo Federica,Giuffrida Paolo,Nesi Gabriella,Klersy Catherine,Mescoli Claudia,Lenti Marco Vincenzo,Lobascio Gessica,Martino Michele,Latella Giovanni,Malvi Deborah,Macciomei Maria Cristina,Fociani Paolo,Villanacci Vincenzo,Rizzo Aroldo,Ferrero Stefano,Sessa Fausto,Orlandi Augusto,Monteleone Giovanni,Biancone Livia,Cantoro Laura,Tonelli Francesco,Ciardi Antonio,Poggioli Gilberto,Rizzello Fernando,Ardizzone Sandro,Sampietro Gianluca,Solina Gaspare,Oreggia Barbara,Papi Claudio,D'Incà Renata,Vecchi Maurizio,Caprioli Flavio,Caronna Roberto,D'Errico Antonietta,Fiocca Roberto,Rugge Massimo,Corazza Gino Roberto,Luinetti Ombretta,Paulli Marco,Solcia Enrico,Di Sabatino Antonio,Vanoli Alessandro Journal of Crohn's & colitis BACKGROUND AND AIMS:Crohn's disease-associated small bowel carcinoma is a rare event, usually reported to have a severe prognosis. However, in previous investigations we have found a minority of cases displaying a relatively favourable behaviour, thus outlining the need to improve the histopathological prediction of Crohn's disease-associated small bowel carcinoma prognosis. METHODS:As in recent studies on colorectal cancer, a substantial improvement in prognostic evaluations has been provided by the histological analysis of the tumour invasive front; we therefore systematically analysed the tumour budding and poorly differentiated clusters in the invasive front of 47 Crohn's disease-associated small bowel carcinomas collected through the Small Bowel Cancer Italian Consortium. RESULTS:Both tumour budding and poorly differentiated cluster analyses proved highly effective in prognostic evaluation of Crohn's disease-associated small bowel carcinomas. In addition, they retained prognostic value when combined with two other parameters, i.e. glandular histology and stage I/II, both known to predict a relatively favourable small bowel carcinoma behaviour. In particular, association of tumour budding and poorly differentiated clusters in a combined invasive front score allowed identification of a minor subset of cancers [12/47, 25%] characterised by combined invasive front low grade coupled with a glandular histology and a low stage [I or II] and showing no cancer-related death during a median follow-up of 73.5 months. CONCLUSIONS:The improved distinction of lower- from higher-grade Crohn's disease-associated small bowel carcinomas provided by invasive front analysis should be of potential help in choosing appropriate therapy for these rare and frequently ominous neoplasms. 10.1093/ecco-jcc/jjz140
    Small Bowel Adenocarcinoma: Is There a Difference in Survival for Crohn's Versus Sporadic Cases? Fields Adam C,Hu Frances Y,Lu Pamela,Irani Jennifer,Bleday Ronald,Goldberg Joel E,Melnitchouk Nelya Journal of Crohn's & colitis BACKGROUND AND AIMS:It is well known that Crohn's disease is a risk factor for the development of small bowel adenocarcinoma. However, the association between Crohn's disease-associated small bowel adenocarcinoma and survival is less understood. The goal of this study was to determine the impact of Crohn's disease on survival in small bowel adenocarcinoma. METHODS:Patients with small bowel adenocarcinoma, either associated with Crohn's disease or diagnosed sporadic, were identified in the National Cancer Database from 2004-2016. The primary outcome was overall survival. RESULTS:Of 2668 patients, 493 had Crohn's disease-associated small bowel adenocarcinoma and 2175 had sporadic small bowel adenocarcinoma. Crohn's disease patients were more likely to present at a younger age [62 vs 65, p < 0.001], have tumours located in the ileum [62.7% vs 25.0%, p < 0.001], and have poorly differentiated tumours [47.0% vs 31.7%, p < 0.001] compared with sporadic small bowel adenocarcinoma. Factors associated with significantly decreased survival included older age (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.02-1.03, p < 0.00)], higher Charlson score [HR: 1.39, 95% CI: 1.13-1.72, p = 0.002], higher tumour grade [HR: 1.09, 95% CI: 1.04-1.14, p < 0.001], positive surgical margins [HR: 1.60, 95% CI: 1.39-1.84, p < 0.001], and higher stage of disease [HR: 1.90, 3.75, 8.13, 95% CI: 1.37-2.64, 2.68-5.24, 5.77-11.47, for II, III, IV, respectively, compared with I, all p < 0.001]. Receipt of chemotherapy was associated with significantly improved survival [HR: 0.61, 95% CI: 0.53-0.70, p < 0.001]. Crohn's disease [HR: 1.01, 95% CI: 0.99-1.02, p = 0.39], was not significantly associated with survival. CONCLUSION:Compared with sporadic patients, Crohn's disease patients have similar overall survival, and Crohn's disease is not an independent risk factor for mortality. 10.1093/ecco-jcc/jjz157
    Epidemiology of Cancers of the Small Intestine: Trends, Risk Factors, and Prevention. Barsouk Adam,Rawla Prashanth,Barsouk Alexander,Thandra Krishna Chaitanya Medical sciences (Basel, Switzerland) The latest data from the United States and Europe reveal that rare small intestine cancer is on the rise, with the number of cases having more than doubled over the past 40 years in the developed world. Mortality has grown at a slower pace, thanks to improvements in early diagnosis and treatment, as well as a shift in the etiology of neoplasms affecting the small intestine. Nevertheless, 5-year survival for small intestine adenocarcinomas has lingered at only 35%. Lifestyle in developed nations, including the rise in obesity and physical inactivity, consumption of alcohol, tobacco, and red and processed meats, and occupational exposures may be to blame for the proliferation of this rare cancer. Identification of hereditary and predisposing conditions, likely to blame for some 20% of cases, may help prevent and treat cancers of the small intestine. Studies of the neoplasm have been limited by small sample sizes due to the rarity of the disease, leaving many questions about prevention and treatment yet to be answered. 10.3390/medsci7030046