The benefit of pancreatic cancer surveillance in carriers of germline BRCA1/2 pathogenic variants.

BACKGROUND: Surveillance of high-risk individuals for pancreatic ductal adenocarcinoma (PDAC) is recommended. This study aimed to determine the prevalence and outcomes of PDAC and its precursor lesions in BRCA1/2 pathogenic variants (PVs) carriers undergoing pancreatic surveillance. METHODS: A retrospective multicenter cohort study of pancreatic surveillance outcomes in Israeli BRCA1/2 carriers preferably with a family history of PDAC. RESULTS: A total of 180 asymptomatic carriers participated in the screening programs, including 57 (31.7%) with BRCA1 PVs, 121 (67.2%) with BRCA2 PVs, and 12 (6.6%) with PVs in BRCA1/2 and other genes, for a median follow-up period of 4 years. Ninety-one individuals (50.5%) fulfilled the International Cancer of the Pancreas Screening (CAPS) criteria for surveillance whereas 116 (64.4%) fulfilled the American College of Gastroenterology (ACG) criteria. There were four cases of adenocarcinoma and four cases of grade 1-neuroendocrine tumor (G1-NET). All were BRCA2 carriers, and two had no family history of PDAC. Three cancer patients were at resectable stages (IA, IIA, IIB) whereas one had a stage IIIB tumor. Of the G1-NET cases, one had surgery and the others were only followed. Success rate for detection of confined pancreatic carcinoma was thus 1.6% (three of 180) in the whole cohort, 1.6% (two of 116) among individuals who fulfilled ACG criteria and 2.2% (two of 91) in those fulfilling CAPS criteria for surveillance. CONCLUSIONS: Despite the low detection rate of PDAC and its' high-risk neoplastic precursor lesions among BRCA1/2 carriers undergoing pancreatic surveillance, 75% of cancer cases were detected at a resectable stage.

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium.

OBJECTIVE: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. METHODS: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. RESULTS: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. CONCLUSIONS: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

The Cytotoxic Effect of Isolated Cannabinoid Extracts on Polypoid Colorectal Tissue.

Purified cannabinoids have been shown to prevent proliferation and induce apoptosis in colorectal carcinoma cell lines. To assess the cytotoxic effect of cannabinoid extracts and purified cannabinoids on both colorectal polyps and normal colonic cells, as well as their synergistic interaction. Various blends were tested to identify the optimal synergistic effect. Methods: Biopsies from polyps and healthy colonic tissue were obtained from 22 patients undergoing colonic polypectomies. The toxicity of a variety of cannabinoid extracts and purified cannabinoids at different concentrations was evaluated. The synergistic effect of cannabinoids was calculated based on the cells' survival. Isolated cannabinoids illustrated different toxic effects on the viability of cells derived from colorectal polyps. THC-d8 and THC-d9 were the most toxic and exhibited persistent toxicity in all the polyps tested. CBD was more toxic to polypoid cells in comparison to normal colonic cells at a concentration of 15 µM. The combinations of the cannabinoids CBDV, THCV, CBDVA, CBCA, and CBGA exhibited a synergistic inhibitory effect on the viability of cells derived from colon polyps of patients. Isolated cannabinoid compounds interacted synergistically against colonic polyps, and some also possessed a differential toxic effect on polyp and adjacent colonic tissue, suggesting possible future therapeutic value.

Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

PURPOSE: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants. METHODS: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. RESULTS: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. CONCLUSION: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Endoscopic treatment of early leaks and strictures after laparoscopic one anastomosis gastric bypass.

BACKGROUND: Laparoscopic one anastomosis gastric bypass has become a prominent bariatric procedure. Yet, early and late complications, primarily leaks and strictures, are not uncommon. This study summarizes our experience with endoscopic treatment of laparoscopic one anastomosis gastric bypass complications. METHODS: This is a retrospective study of consecutive patients referred to our hospital from 2015 to 2017 with post laparoscopic one anastomosis gastric bypass complications. Therapy was tailored to each case, including fully covered self-expandable metal stents, fibrin glue, septotomy, internal drainage with pigtail stents, through-the-scope and pneumatic dilation. Success was defined as resuming oral nutrition without enteral or parenteral support or further surgical intervention. RESULTS: Nine patients presented with acute or early leaks: 5 (56%) had staple-line leaks, 3 (33%) had anastomotic leaks and 1 (11%) had both. All were treated with stents. Adjunctive endoscopic drainage was applied in 4 patients (44%). Overall 5 patients (56%) with acute/ early leaks recovered completely, including all 3 patients with anastomotic leak and the patient with both leaks but only 1/5 with staple line leak (20%). Complication rate in the leak group reached 22%. Eight patients presented with strictures, 7 at the anastomosis and one due to remnant stomach misalignment. All anastomotic strictures were dilated successfully. However, the patient with the pouch stricture required conversion to Roux-en-Y gastric bypass after 3 failed attempts of dilation. CONCLUSION: Endoscopic treatments of laparoscopic one anastomosis gastric bypass complications are relatively effective and safe. Anastomosis-related complications are more amenable to endoscopic treatment compared to staple line leaks.

G-EYE colonoscopy is superior to standard colonoscopy for increasing adenoma detection rate: an international randomized controlled trial (with videos).

BACKGROUND AND AIMS: Colorectal cancer (CRC) is largely preventable with routine screening and surveillance colonoscopy; however, interval cancers arising from precancerous lesions missed by standard colonoscopy still occur. An increased adenoma detection rate (ADR) has been found to be inversely associated with interval cancers. The G-EYE device includes a reusable balloon integrated at the distal tip of a standard colonoscope, which flattens haustral folds, centralizes the colonoscope's optics, and reduces bowel slippage. The insufflated balloon also aims to enhance visualization of the colon during withdrawal, thereby increasing the ADR. METHODS: In this randomized, controlled, international, multicenter study (11 centers), patients (aged ≥50 years) referred to colonoscopy for screening, surveillance, or changes in bowel habits were randomized to undergo either balloon-assisted colonoscopy by using an insufflated balloon during withdrawal or standard high-definition colonoscopy. The primary endpoint was the ADR. RESULTS: One thousand patients were enrolled between May 2014 and September 2016 to undergo colonoscopy by experienced endoscopists; 803 were finally analyzed (standard colonoscopy n = 396; balloon-assisted colonoscopy n = 407). Baseline parameters were similar in both groups. Balloon-assisted colonoscopy provided a 48.0% ADR compared with 37.5% in the standard colonoscopy group (28% increase; P = .0027). Additionally, balloon-assisted colonoscopy provided for a significant increase in detection of advanced (P = .0033) flat adenomas (P < .0001) and sessile serrated adenomas/polyps (P = .0026). CONCLUSION: Balloon-assisted colonoscopy yielded a higher ADR and increased the detection of advanced, flat, and sessile serrated adenomas/polyps when compared with standard colonoscopy. Improved detection by the G-EYE device could impact the quality of CRC screening by reducing miss rates and consequently reducing interval cancer incidence. (Clinical trial registration number: NCT01917513.).

Genotype-Phenotype Associations of APC Mutations With Pouch Adenoma in Patients With Familial Adenomatous Polyposis.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) may carry various adenomatous polyposis coli (APC) mutations. However, genotype-phenotype correlation for APC mutations is still debated and is yet to be evaluated with regard to pouch polyp formation. OBJECTIVE: To evaluate the association between APC mutation type and exon location and the outcome of pouch adenoma. DESIGN SETTING AND PATIENTS: Forty-five FAP patients with defined pathogenic APC mutations, who underwent total proctocolectomy and ileal pouch anal anastomosis were classified by mutation type and location. Analysis was conducted for clinical and endoscopic parameters. RESULTS: Twenty patients had either indel/deletion mutations and 25 had nonsense/missense mutations. The indel/deletion group was associated with higher prevalence of preoperative hundreds of colonic adenomas (66.7% vs. 30%; P=0.030), lower rates of stapled versus sewn anastomosis (46.7% vs. 76%; P=0.060), of single stage surgery (13.3% vs. 44%; P=0.045) and with higher pouch adenoma formation rate (50% vs. 8%; P=0.002). Twenty-seven were carriers of exons 1 to 14 mutations and 18 were carriers of exon 15 mutations. Carriers of exon 15 mutations had higher prevalence of preoperative hundreds of colonic adenomas (55.6% vs. 22.2%; P=0.003) and a higher tendency for pouch and cuff adenoma formation rate. Adjusted odds ratio for pouch adenoma formation was 8.32 (1.42-48.80; P=0.019) for the indel/deletion group versus nonsense/missense, but no significant independent association was noted with mutation location. The mean number of pouch and cuff adenoma formation (per endoscopy) was higher among carriers of exon 15 mutations, but no significant independent association was noted the with mutation type. CONCLUSIONS: Type and location of APC mutation are associated with colonic polyp burden, surgical outcome and likelihood of developing pouch adenomas. These findings may contribute to surgical and endoscopic surveillance decisions for FAP patients.

Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report.

BACKGROUND: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. METHODS: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. RESULTS: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). CONCLUSIONS: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.

POLD1 and POLE Gene Mutations in Jewish Cohorts of Early-Onset Colorectal Cancer and of Multiple Colorectal Adenomas.

BACKGROUND: Germline mutations in the DNA polymerase genes POLD1 and POLE confer high risk for multiple colorectal adenomas and colorectal cancer. However, prevalence and the clinical phenotype of mutation carriers are still not fully characterized. OBJECTIVE: The purpose of this study was to assess the prevalence of germline mutations and to describe the genotype-phenotype correlation in POLD1 and POLE genes in Jewish subjects with multiple colorectal adenomas and/or early-onset mismatch repair proficient colorectal cancers. DESIGN: This study is a comparison of genetic and clinical data from affected and control groups. SETTINGS: The study was conducted at a high-volume tertiary referral center. PATIENTS: The study cohort included 132 subjects: 68 with multiple colorectal adenomas and 64 with early-onset mismatch repair proficient colorectal cancers. The control group included 5685 individuals having no colorectal cancer or colorectal adenomas. MAIN OUTCOME MEASURES: Study and control subjects were tested for POLD1 and POLE mutations and a clinical correlation was assessed. RESULTS: Eleven of the 132 study subjects (8.3%) carried either a POLD1 or a POLE mutation: 7 of 68 (10.3%) subjects with multiple colorectal adenomas and 4 of 64 (6.2%) subjects with early-onset mismatch repair proficient colorectal cancer. Three mutations were detected, showing statistical significance in frequency between study and control groups (p < 0.001). Eight of the 11 mutation carriers were Ashkenazi Jews carrying the same POLD1 mutation (V759I), implicating it as a possible low-to-moderate risk founder mutation. Phenotype of mutation carriers was notable for age under 50 at diagnosis, a propensity toward left-sided colorectal cancer, and extracolonic tumors (64%, 100%, and 27% of cases). LIMITATIONS: The study cohort was limited by its relatively small size. CONCLUSIONS: Germline mutations in POLD1 and POLE were found to be relatively frequent in our Jewish cohorts. Further studies are needed to clarify the importance of POLD1 and POLE mutations and to define the most suitable surveillance program for Jewish and other POLD1 and POLE mutation carriers. See Video Abstract at http://links.lww.com/DCR/A658.

Predicting Efficacy of Plastic Stents for Posttransplantation Biliary Strictures.

BACKGROUND: Biliary strictures (BS) are a common complication of liver transplantation. The standard treatment is sequential insertion of increasing numbers of plastic stents by endoscopic retrograde cholangiopancreatography (ERCP). Despite high success rates, some strictures fail to resolve and require surgery as definitive treatment. GOALS: To identify predictors of response or failure of standard endoscopic treatment, allowing earlier referral to alternative modalities when needed and avoiding unnecessary procedures. STUDY: Database of Gastroenterology Department at Tel Aviv Medical Center was retrospectively reviewed, and data regarding patients who underwent liver transplantation and developed BS were analyzed. RESULTS: Thirty-one patients met the study criteria. Twenty-four (77.4%) resolved with plastic stenting and 7 ultimately required surgery. There were no significant differences between stent responders and nonresponders regarding demographics, transplant and postoperative hospitalization data, time from transplantation to presentation with stricture, total number of ERCP sessions, or maximal number of stents.A trend toward difference was noted in the time elapsed between the first and the second ERCP, whereby ERCP nonresponders required a second procedure sooner than responders. Patients presenting to their second procedure as scheduled ultimately had a 95% endoscopic success rate, whereas those presenting urgently with acute cholangitis had a 55% failure rate (P=0.02). CONCLUSIONS: Urgent repeat ERCP is a harbinger of ultimate failure of plastic stent treatment for BS after liver transplant. This finding may assist earlier triage of these patients toward alternative treatment such as metal stents or surgery, thus sparing needless procedures and complications.

Use of endoscopic septotomy for the treatment of late staple-line leaks after laparoscopic sleeve gastrectomy.

Background Staple-line leak following laparoscopic sleeve gastrectomy is a dire adverse event. While the treatment of acute and early leaks is well established, there is still dispute regarding late and chronic leaks. We describe an endoscopic approach combining septotomy and sleeve stricture dilation for treating late/chronic leaks. Methods Ten consecutive patients with late/chronic proximal leaks were treated at our center. The septum separating the sleeve lumen from the perigastric cavity was progressively dissected over several sessions and the downstream stricture was pneumatically dilated. The technical and clinical success rates were evaluated. Results: All ten patients were treated successfully. Eight patients had sleeve strictures that were dilated in conjunction with septotomy. A mean of five sessions over the course of 43 days was needed to complete treatment. In two patients with a small perigastric cavity and no stricture, septotomy was achieved with through-the-scope balloon dilation of the fistula. No adverse events were encountered. Conclusions Septotomy accompanied by stricture dilation seems highly effective and safe in late and chronic leaks following sleeve gastrectomy.

GCN5 is a required cofactor for a ubiquitin ligase that targets NF-kappaB/RelA.

The transcription factor NF-kappaB is a critical regulator of inflammatory and cell survival signals. Proteasomal degradation of NF-kappaB subunits plays an important role in the termination of NF-kappaB activity, and at least one of the identified ubiquitin ligases is a multimeric complex containing Copper Metabolism Murr1 Domain 1 (COMMD1) and Cul2. We report here that GCN5, a histone acetyltransferase, associates with COMMD1 and other components of the ligase, promotes RelA ubiquitination, and represses kappaB-dependent transcription. In this role, the acetyltransferase activity of GCN5 is not required. Interestingly, GCN5 binds more avidly to RelA after phosphorylation on Ser 468, an event that is dependent on IKK activity. Consistent with this, we find that both GCN5 and the IkappaB Kinase (IKK) complex promote RelA degradation. Collectively, the data indicate that GCN5 participates in the ubiquitination process as an accessory factor for a ubiquitin ligase, where it provides a novel link between phosphorylation and ubiquitination.

A novel self-propelled disposable colonoscope is effective for colonoscopy in humans (with video).

BACKGROUND AND AIMS: The self-propelled disposable colonoscope (SPDC) with a 360° view is designed to enhance visualization, minimize risks of perforation and infection transmission, and shorten operator training time associated with conventional colonoscopy (CC). We evaluated SPDC efficacy for cecal intubation and safety. METHODS: Prospective patients presenting for colorectal cancer screening underwent SPDC immediately followed by CC. Initial patients necessary for SPDC operators to achieve proficiency comprised the training cohort. Subsequent enrolled patients comprised the study cohort. SPDC colonoscopy was performed up to the cecum, where anatomic landmarks were photographed and mucosal suction marks were placed. During SPDC withdrawal, polyps were recorded and similarly marked. On the second pass (by using CC), any potential mucosal damage and suction marks from the SPDC as well as polyps were recorded. Main endpoints included SPDC cecal intubation rates, confirmed by anatomic landmarks and residual marks seen on subsequent CC, and frequency and severity of adverse events and mucosal damage with SPDC. The secondary endpoint was subjective procedure proficiency, evaluated by the operator based on the training cohort. The tertiary endpoint was documenting pathologies visualized with SPDC. RESULTS: Fifty-six of 58 enrolled subjects completed the study. Proficiency with SPDC was attained after 8 to 10 procedures. Cecal intubation was successful in 98.2% (55/56 subjects; 95% confidence interval [CI], 90.4%-99.9%), including 100% (95% CI, 90.7%-100%) of the study cohort and 94.4% (95% CI, 72.7%-99.9%) of the training cohort. No mucosal damage or adverse events were reported. SPDC detected 87.5% of polyps seen in tandem CC, including all polyps larger than 5 mm. CONCLUSIONS: SPDC was highly successful, simple to use, and safe in achieving complete colonoscopy (cecal intubation). ( CLINICAL TRIAL REGISTRATION NUMBER: 0692-12-TLV.).

Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer.

BACKGROUND & AIMS: Activation of the transcription factor nuclear factor-κB (NF-κB) has been associated with the development of inflammatory bowel disease (IBD). Copper metabolism MURR1 domain containing 1 (COMMD1), a regulator of various transport pathways, has been shown to limit NF-κB activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in human beings. METHODS: We created mice with a specific disruption of Commd1 in myeloid cells (Mye-knockout [K/O] mice); we analyzed immune cell populations and functions and expression of genes regulated by NF-κB. Sepsis was induced in Mye-K/O and wild-type mice by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (LPS), colitis was induced by administration of dextran sodium sulfate, and colitis-associated cancer was induced by administration of dextran sodium sulfate and azoxymethane. We measured levels of COMMD1 messenger RNA in colon biopsy specimens from 29 patients with IBD and 16 patients without (controls), and validated findings in an independent cohort (17 patients with IBD and 22 controls). We searched for polymorphisms in or near COMMD1 that were associated with IBD using data from the International IBD Genetics Consortium and performed quantitative trait locus analysis. RESULTS: In comparing gene expression patterns between myeloid cells from Mye-K/O and wild-type mice, we found that COMMD1 represses expression of genes induced by LPS. Mye-K/O mice had more intense inflammatory responses to LPS and developed more severe sepsis and colitis, with greater mortality. More Mye-K/O mice with colitis developed colon dysplasia and tumors than wild-type mice. We observed a reduced expression of COMMD1 in colon biopsy specimens and circulating leukocytes from patients with IBD. We associated single-nucleotide variants near COMMD1 with reduced expression of the gene and linked them with increased risk for ulcerative colitis. CONCLUSIONS: Expression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD.

Endoscopy and EUS are key for effective surveillance and management of duodenal adenomas in familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) are prone to developing duodenal adenoma and cancer. Optimal surveillance and management of these adenomas are not well established. OBJECTIVE: We assessed the outcome of FAP patients undergoing intense multimodal surveillance and subsequent endoscopic resection of advanced lesions. PATIENTS: Eighty consecutive FAP patients enrolled during 2001 to 2011 from the Familial Cancer Clinic of a tertiary hospital as part of routine surveillance. DESIGN: Case series, prospective in years 2006 to 2011 and retrospective in years 2001 to 2006. SETTING AND INTERVENTION: Patients were followed by annual forward-view and/or side-view upper endoscopy. A biopsy sample was obtained from visible lesions and normal papillae. Ampullary adenomas were further assessed by EUS to determine dimensions and resectability. Advanced adenomas (size ≥ 10 mm, villous type, high-grade dysplasia) underwent endoscopic ampullectomy or polypectomy and continued surveillance. MAIN OUTCOME MEASUREMENTS: Detection of advanced adenomas by endoscopy and EUS, endoscopic maintenance of duodenum free of advanced adenoma and cancer. RESULTS: Patients (38 men and 42 women, mean age 32.68 ± 13.60) were followed 7.2 years and underwent 5.36 diagnostic studies on average. Thirty-eight patients had ampullary adenomas. Advanced adenoma was diagnosed by endoscopy in 10 patients. Importantly, EUS upstaged 9 additional patients to advanced adenoma and downstaged 1, thus altering the treatment course in 36% of patients performing EUS. Endoscopic ampullectomy was performed in 15 patients. Adenoma recurred in 10. Five remained nonadvanced and 5 in advanced stages: 3 were successfully retreated endoscopically and 2 ultimately required surgery for residual adenoma. Advanced nonampullary adenomas were successfully resected endoscopically in 23 patients. No patient had duodenal cancer during the study period. LIMITATIONS: Limited follow-up period, young age group, uncontrolled study. CONCLUSIONS: In an intense surveillance program for FAP patients, both endoscopy and EUS were key in accurate selection of advanced adenomas for endoscopic resection. During a 10-year period, only 2 patients required elective surgery and no cancer was observed.

Surveillance Outcome and Genetic Findings in Individuals at High Risk of Pancreatic Cancer.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate. PDAC surveillance is recommended in high-risk individuals (HRIs) with strong PDAC family history or a pathogenic germline variant (PGV) in a PDAC susceptibility gene. We aimed to explore a potential correlation between genetic status, extent of family history, pancreatic findings, and surveillance implications in heterogeneous PDAC HRIs. METHODS: A total of 239 HRIs from 202 families were tested genetically and underwent prospective pancreatic surveillance for 6 years. RESULTS: The cohort was divided into 3 groups: familial pancreatic cancer (FPC; 70 individuals, 54 families), familial non-FPC (81 individuals, 73 families), and hereditary pancreatic cancer (PC) (88 individuals, 75 families). PGVs were detected in 37.6% of all families, including 11.1% of FPC families and 9.6% of familial non-FPC families. The hereditary PC group had earlier onset of PDAC compared with the other 2 groups. BRCA2 PGV carriers showed earlier onset of PDAC and pancreatic cysts. Of the 239 HRIs, PDAC was detected in 11 individuals (4.6%), with 73% diagnosed at an early stage; 4 (1.67%) had pancreatic neuroendocrine tumor; 6 (2.5%) had main-duct intraductal papillary neoplasm (IPMN); and 41 (17.15%) had side-branch IPMN. Seventeen individuals were referred to surgery, and 12 were alive at the end of the study. DISCUSSION: The percentage of PDAC was similar in the 3 groups studied. The hereditary PC group, and particularly BRCA2 PGV carriers, had an earlier age of PDAC onset. PGVs were detected in a significant percentage of HRIs with PC. Surveillance seems effective for detection of early-stage PDAC and precursor lesions.

Data From a One-Stop-Shop Comprehensive Cancer Screening Center.

PURPOSE: Cancer is the second leading cause of death globally. However, by implementing evidence-based prevention strategies, 30%-50% of cancers can be detected early with improved outcomes. At the integrated cancer prevention center (ICPC), we aimed to increase early detection by screening for multiple cancers during one visit. METHODS: Self-referred asymptomatic individuals, age 20-80 years, were included prospectively. Clinical, laboratory, and epidemiological data were obtained by multiple specialists, and further testing was obtained based on symptoms, family history, individual risk factors, and abnormalities identified during the visit. Follow-up recommendations and diagnoses were given as appropriate. RESULTS: Between January 1, 2006, and December 31, 2019, 8,618 men and 8,486 women, average age 47.11 ± 11.71 years, were screened. Of 259 cancers detected through the ICPC, 49 (19.8%) were stage 0, 113 (45.6%) stage I, 30 (12.1%) stage II, 25 (10.1%) stage III, and 31(12.5%) stage IV. Seventeen cancers were missed, six of which were within the scope of the ICPC. Compared with the Israeli registry, at the ICPC, less cancers were diagnosed at a metastatic stage for breast (none v 3.7%), lung (6.7% v 11.4%), colon (20.0% v 46.2%), prostate (5.6% v 10.5%), and cervical/uterine (none v 8.5%) cancers. When compared with the average stage of detection in the United States, detection was earlier for breast, lung, prostate, and female reproductive cancers. Patient satisfaction rate was 8.35 ± 1.85 (scale 1-10). CONCLUSION: We present a proof of concept study for a one-stop-shop approach to cancer screening in a multidisciplinary outpatient clinic. We successfully detected cancers at an early stage, which has the potential to reduce morbidity and mortality as well as offer substantial cost savings.[Media: see text].