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Colonoscopy with polypectomy reduces the incidence of and mortality from colorectal cancer (CRC).1,2 It is the cornerstone of effective prevention.3 The National Polyp Study showed that removal of adenomas during colonoscopy is associated with a reduction in CRC mortality by up to 50% relative to population controls.1,2 The lifetime risk to develop CRC in the United States is approximately 4.3%, with 90% of cases occurring after the age of 50 years.4 The recent reductions in CRC incidence and mortality have been largely attributed to the widespread uptake of CRC screening with polypectomy.5 The techniques and outcomes of polyp removal using colonoscopy, however, had historically remained understudied and thus, practice widely varied. A pooled analysis from 8 surveillance studies that followed participants with adenomas after a baseline colonoscopy suggested that although the majority (50%) of post-colonoscopy colon cancers were likely due to missed lesions, close to one-fifth of incident cancers were related to incomplete resection.7 Polypectomy techniques have expanded in parallel with advances in endoscopic imaging, technology, and tools. [...]the applications of cold snare polypectomy for small lesions, which can remove adenomatous tissue en bloc with surrounding normal mucosa, and endoscopic mucosal resection (EMR) for large and flat lesions, which utilizes submucosal injection to lift the lesion before snare resection, have evolved to improve complete and safer resection. Literature Review We performed a systematic review of the literature based on a defined search by a medical librarian of the Ovid Medline, Embase, and Cochrane databases from 1946 to December 2017, as well as reviews of manual references and scientific meeting abstracts of the American College of Gastroenterology, American Gastroenterology Association, American Society for Gastrointestinal Endoscopy, and United European Gastroenterology Week from 2014–2017.

Specifically, we will discuss 6 key questions that address the following 3 tasks: endoscopic recognition of colorectal polyps with deep submucosal invasion that should be referred directly to surgery; optimal endoscopic resection techniques and specimen handling when an increased risk of superficial submucosally invasive polyp is identified; and weighing the risks and benefits of surgery when an endoscopically removed polyp is found to have submucosal invasion. Grading of Evidence The US Multi-Society Task Force on Colorectal Cancer (USMSTF) consists of gastroenterologists with expertise in colorectal neoplasia (ie, CRC and precursor lesions, such as polyps). According to this classification, malignant polyps would fall under category 5.2 (submucosal carcinoma and beyond).Table 2. [...]the use of terms such as carcinoma or cancer in describing lesions confined to the mucosa may cause undue alarm to endoscopists, surgeons, patients, or primary care providers, and can lead to unnecessary surgery.

To evaluate limitations of common statistical modeling approaches in deriving clinical prediction models and explore alternative strategies. A previously published model predicted the likelihood of having a mutation in germline DNA mismatch repair genes at the time of diagnosis of colorectal cancer. This model was based on a cohort where 38 mutations were found among 870 participants, with validation in an independent cohort with 35 mutations. The modeling strategy included stepwise selection of predictors from a pool of over 37 candidate predictors and dichotomization of continuous predictors. We simulated this strategy in small subsets of a large contemporary cohort (2,051 mutations among 19,866 participants) and made comparisons to other modeling approaches. All models were evaluated according to bias and discriminative ability (concordance index, c) in independent data. We found over 50% bias for five of six originally selected predictors, unstable model specification, and poor performance at validation (median c = 0.74). A small validation sample hampered stable assessment of performance. Model prespecification based on external knowledge and using continuous predictors led to better performance (c = 0.836 and c = 0.852 with 38 and 2,051 events respectively). Prediction models perform poorly if based on small numbers of events and developed with common but suboptimal statistical approaches. Alternative modeling strategies to best exploit available predictive information need wider implementation, with collaborative research to increase sample sizes.

INTRODUCTION:Risk factors for serrated polyps (SPs) are not well understood.METHODS:Multivariable analyses of data from a multicenter colonoscopy-based study estimated odds ratios for having either a sessile serrated lesion or traditional serrated adenoma according to participant characteristics.RESULTS:Six thousand seventy-eighty participants were included in the analyses (565 with either a sessile serrated lesion or traditional serrated adenoma). White race was associated with a higher risk of SPs compared with Black race (adjusted odds ratio 4.64, 95% confidence interval 1.89-11.41). Obesity and current smoking were also associated with a higher risk of SPs.DISCUSSION:White race, smoking, and obesity are risk factors for precancerous SPs.

The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3,4,5,6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided.

Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression. We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5–13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30–0.99; P = 0.05). Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden’s syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome–hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden’s syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This US Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.

A correction to this paper has been published: https://doi.org/10.1007/s10689-021-00245-1