The role of family history in predicting germline pathogenic variant carriers who develop pancreatic cancer: Results of a multicenter collaboration.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations. METHODS: Individuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first-degree relatives (FDRs) or second-degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed. RESULTS: The study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p = .004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p = .003) but there was no statistical difference when assessing only affected SDRs (p = .344). CONCLUSIONS: Most PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors.

Rising Rates of Severe Obesity in Adults Younger Than 50 Correspond to Rise in Hospitalizations for Non-malignant Gastrointestinal Disease.

BACKGROUND: Colorectal cancer incidence is rising in adults < 50 years old, possibly due to obesity. Non-malignant colorectal conditions are understudied in this population. We hypothesize that developing severe obesity in young adulthood also corresponds with increased hospitalization rates for non-malignant colorectal conditions. METHODS: We examined annual percent change (APC) in the prevalence of obesity in adults < 50 using the 2009-2014 National Health and Nutrition Examination Survey. Using the 2010-2014 Nationwide Readmission Database, we then compared yearly hospitalization trends for various gastrointestinal conditions and their outcomes in adults < 50 with severe obesity vs. no obesity. RESULTS: The prevalence of obesity increased in adults < 50 years in 2009-2014. This increase was most pronounced for severe obesity (APC of + 12.8%). The rate of patients with severe obesity < 50 who were admitted for gastrointestinal diseases has increased by 7.76% per year in 2010-2014 (p < 0.001). This increase was > 10% per year for colorectal conditions such Clostridium difficile infections (APC + 17.3%, p = 0.002), inflammatory bowel disease (APC + 13.1%, p = 0.001), and diverticulitis (APC + 12.7%, p = 0.002). The hospitalization rate for chronic liver diseases and acute pancreatitis also increased by 12.2% and 10.0% per year, respectively (p < 0.01). In contrast, young adults without obesity had lower hospitalization rate for most gastrointestinal diseases. Furthermore, adults with no obesity had lower mortality rates for appendicitis, diverticulitis, pancreatitis and chronic liver diseases than adults with severe obesity. CONCLUSION: Our data suggest that increased adiposity in young adults is associated with more hospitalization and worse outcomes for infectious/inflammatory gastrointestinal conditions. Future prevention strategies are warranted to ameliorate these trends.

Colorectal Neoplasia in CDH1 Pathogenic Variant Carriers: A Multicenter Analysis.

INTRODUCTION: Germline variants in CDH1 are associated with elevated risks of diffuse gastric cancer and lobular breast cancer. It is uncertain whether there is an increased risk of colorectal neoplasia. METHODS: This was a retrospective analysis of colonoscopy outcomes in patients with germline CDH1 pathogenic/likely pathogenic variants. RESULTS: Eighty-five patients were included with a mean age of 46.9 years. Initial colonoscopy found adenomatous polyps in 30 patients (35.3%), including advanced adenomas in 9 (10.6%). No colorectal cancers were identified on index or subsequent colonoscopies (when available). DISCUSSION: CDH1 carriers have colorectal neoplasia identified at similar rates as in the general population. Despite potential difficulties after gastrectomy, colorectal cancer screening remains important in this population.

International Delphi consensus guidelines for follow-up after prophylactic total gastrectomy: the Life after Prophylactic Total Gastrectomy (LAP-TG) study.

BACKGROUND: Prophylactic total gastrectomy (PTG) remains the only means of preventing gastric cancer for people with genetic mutations predisposing to Hereditary Diffuse Gastric Cancer (HDGC), mainly in the CDH1 gene. The small but growing cohort of people undergoing PTG at a young age are expected to have a life-expectancy close to the general population, however, knowledge of the long-term effects of, and monitoring requirements after, PTG is limited. This study aims to define the standard of care for follow-up after PTG. METHODS: Through a combination of literature review and two-round Delphi consensus of major HDGC/PTG units and physicians, and patient advocates, we produced a set of recommendations for follow-up after PTG. RESULTS: There were 42 first round, and 62 second round, responses from clinicians, allied health professionals and patient advocates. The guidelines include recommendations for timing of assessments and specialties involved in providing follow-up, micronutrient supplementation and monitoring, bone health and the provision of written information. CONCLUSION: While the evidence supporting the guidelines is limited, expert consensus provides a framework to best manage people following PTG, and could support the collection of information on the long-term effects of PTG.

Postoperative Hospital Outcomes of Elective Surgery for Nonmalignant Colorectal Polyps: Does the Burden Justify the Indication?

INTRODUCTION: Despite the increasing availability of advanced endoscopic resections and its favorable safety profile, surgery for nonmalignant colorectal polyps has continually increased. We sought to evaluate readmission rates and outcomes of elective surgery for nonmalignant colorectal polyps on a national level in the United States. METHODS: The Nationwide Readmissions Database (2010-2014 [International Classification of Diseases, Ninth Revision] and 2016-2018 [International Classification of Diseases, 10th Revision]) was used to identify all adult subjects (age ≥18 years) who underwent elective surgical resection of nonmalignant colorectal polyps. Multivariable analyses were performed for predictors of postoperative morbidity and 30-day readmission. RESULTS: Elective surgery for nonmalignant colorectal polyps was performed in 108,468 subjects from 2010 to 2014 and in 54,956 subjects from 2016 to 2018, most of whom were laparoscopic. Postoperative morbidity and 30-day readmission rates were 20.5% and 8.5% from 2010 to 2014, and 13.0% and 7.6% from 2016 to 2018, respectively. Index admission mortality rates were 0.3-0.4%; mortality rates were higher in those with postoperative morbidity. Multivariable analyses revealed that male sex, ≥3 comorbidities, insurance status, and open surgery predicted an increased risk of both postoperative morbidity and 30-day readmission. In addition, postoperative morbidity (2010-2014 [odds ratio 1.58; 95% confidence interval 1.44-1.74] and 2016-2018 [odds ratio 1.55; 95% confidence interval 1.37-1.75]) predicted early readmission. DISCUSSION: In this investigation of national practices, elective surgery for nonmalignant colorectal polyps remains common. There is considerable risk of adverse postoperative outcomes, which highlights the importance of increasing awareness of the range of endoscopic resections and referring subjects to expert endoscopy centers.

Cystic Fibrosis Transmembrane Conductance Regulator Modulator Use Is Associated With Reduced Pancreatitis Hospitalizations in Patients With Cystic Fibrosis.

INTRODUCTION: Acute pancreatitis (AP) occurs among patients with pancreas-sufficient cystic fibrosis (PS-CF) but is reportedly less common among patients with pancreas-insufficient cystic fibrosis (PI-CF). The incidence of AP may be influenced by cystic fibrosis transmembrane conductance regulator (CFTR) modulator use. We hypothesized that CFTR modulators would reduce AP hospitalizations, with the greatest benefit in PS-CF. METHODS: MarketScan (2012-2018) was queried for AP hospitalizations and CFTR modulator use among patients with CF. Multivariable Poisson models that enabled crossover between CFTR modulator treatment groups were used to analyze the rate of AP hospitalizations on and off therapy. Pancreas insufficiency was defined by the use of pancreas enzyme replacement therapy. RESULTS: A total of 10,417 patients with CF were identified, including 1,795 who received a CFTR modulator. AP was more common in PS-CF than PI-CF (2.9% vs 0.9%, P = 0.007). Overall, the observed rate ratio of AP during CFTR modulator use was 0.33 (95% confidence interval [CI] 0.10, 1.11, P = 0.07) for PS-CF and 0.38 (95% CI 0.16, 0.89, P = 0.03) for PI-CF, indicating a 67% and 62% relative reduction in AP hospitalizations, respectively. In a subset analysis of 1,795 patients who all had some CFTR modulator use, the rate ratio of AP during CFTR modulator use was 0.36 (95% CI 0.13, 1.01, P = 0.05) for PS-CF and 0.53 (95% CI 0.18, 1.58, P = 0.26) for PI-CF. DISCUSSION: CFTR modulator use is associated with a reduction in AP hospitalizations among patients with CF. These observational data support the prospective study of CFTR modulators to reduce AP hospitalizations among patients with CF.

Double somatic mismatch repair gene pathogenic variants as common as Lynch syndrome among endometrial cancer patients.

OBJECTIVE: Lynch syndrome is the most common cause of inherited endometrial cancer, attributable to germline pathogenic variants (PV) in mismatch repair (MMR) genes. Tumor microsatellite instability (MSI-high) and MMR IHC abnormalities are characteristics of Lynch syndrome. Double somatic MMR gene PV also cause MSI-high endometrial cancers. The aim of this study was to determine the relative frequency of Lynch syndrome and double somatic MMR PV. METHODS: 341 endometrial cancer patients enrolled in the Ohio Colorectal Cancer Prevention Initiative at The Ohio State University Comprehensive Cancer Center from 1/1/13-12/31/16. All tumors underwent immunohistochemical (IHC) staining for the four MMR proteins, MSI testing, and MLH1 methylation testing if the tumor was MMR-deficient (dMMR). Germline genetic testing for Lynch syndrome was undertaken for all cases with dMMR tumors lacking MLH1 methylation. Tumor sequencing followed if a germline MMR gene PV was not identified. RESULTS: Twenty-seven percent (91/341) of tumors were either MSI-high or had abnormal IHC indicating dMMR. As expected, most dMMR tumors had MLH1 methylation; (69, 75.8% of the dMMR cases; 20.2% of total). Among the 22 (6.5%) cases with dMMR not explained by methylation, 10 (2.9% of total) were found to have Lynch syndrome (6 MSH6, 3 MSH2, 1 PMS2). Double somatic MMR PV accounted for the remaining 12 dMMR cases (3.5% of total). CONCLUSIONS: Since double somatic MMR gene PV are as common as Lynch syndrome among endometrial cancer patients, paired tumor and germline testing for patients with non-methylated dMMR tumor may be the most efficient approach for LS screening.

EUS-guided confocal laser endomicroscopy: prediction of dysplasia in intraductal papillary mucinous neoplasms (with video).

BACKGROUND AND AIMS: Previous studies have validated EUS-guided needle-based confocal laser endomicroscopy (nCLE) diagnosis of intraductal papillary mucinous neoplasms (IPMNs). We sought to derive EUS-guided nCLE criteria for differentiating IPMNs with high-grade dysplasia/adenocarcinoma (HGD-Ca) from those with low/intermediate-grade dysplasia (LGD). METHODS: We performed a post hoc analysis of consecutive IPMNs with a definitive diagnosis from a prospective study evaluating EUS-guided nCLE in the diagnosis of pancreatic cysts. Three internal endosonographers reviewed all nCLE videos for the patients and identified potential discriminatory EUS-guided nCLE variables to differentiate HGD-Ca from LGD IPMNs (phase 1). Next, an interobserver agreement (IOA) analysis of variables from phase 1 was performed among 6 blinded external nCLE experts (phase 2). Last, 7 blinded nCLE-naïve observers underwent training and quantified variables with the highest IOA from phase 2 using dedicated software (phase 3). RESULTS: Among 26 IPMNs (HGD-Ca in 16), the reference standard was surgical histopathology in 24 and cytology confirmation of metastatic liver lesions in 2 patients. EUS-guided nCLE characteristics of increased papillary epithelial "width" and "darkness" were the most sensitive variables (90%; 95% confidence interval [CI], 84%-94% and 91%; 95% CI, 85%-95%, respectively) and accurate (85%; 95% CI, 78%-90% and 84%; 95% CI, 77%-89%, respectively) with substantial (κ = 0.61; 95% CI, 0.51-0.71) and moderate (κ = 0.55; 95% CI, 0.45-0.65) IOAs for detecting HGD-Ca, respectively (phase 2). Logistic regression models were fit for the outcome of HGD-Ca as predictor variables (phase 3). For papillary width (cut-off ≥50 µm), the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) for detection of HGD-Ca were 87.5% (95% CI, 62%-99%), 100% (95% CI, 69%-100%), and 0.95, respectively. For papillary darkness (cut-off ≤90 pixel intensity), the sensitivity, specificity, and AUC for detection of HGD-Ca were 87.5% (95% CI, 62%-99%), 100% (95% CI, 69%-100%), and 0.90, respectively. CONCLUSIONS: In this derivation study, quantification of papillary epithelial width and darkness identified HGD-Ca in IPMNs with high accuracy. These quantifiable variables can be used in multicenter studies for risk stratification of IPMNs. (Clinical trial registration number: NCT02516488.).

NCCN Guidelines Insights: Colorectal Cancer Screening, Version 2.2020.

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age to initiate screening in average risk individuals and follow-up for low-risk adenomas.

Diverticulitis in Morbidly Obese Adults: A Rise in Hospitalizations with Worse Outcomes According to National US Data.

BACKGROUND AND AIMS: Obesity is a known risk factor for diverticulitis. Our objective was to examine the less investigated impact of morbid obesity (MO) on admissions and clinical course of diverticulitis in a US representative database. METHODS: We retrospectively queried the 2010-2014 Nationwide Readmission Database to compare diverticulitis hospitalizations in 48,651 MO and 841,381 non-obese patients. Outcomes of mortality, clinical course, surgical events, and readmissions were compared using multivariable and propensity-score-matched analyses. RESULTS: The number of MO patients admitted with diverticulitis increased annually from 7570 in 2010 to 11,935 in 2014, while the total number of patients admitted with diverticulitis decreased (p = 0.003). Multivariable analysis demonstrates that MO was associated with increased mortality (adjusted odds ratio [aOR] 1.54; 95% confidence internal [CI]: 1.16, 2.05), intensive care admissions (aOR = 1.92; 95% CI: 1.61, 2.31), emergent surgery (aOR = 1.20; 95% CI: 1.11, 1.30), colectomy (aOR = 1.13; 95% CI: 1.08, 1.18), open laparotomy (aOR = 1.28; 95% CI: 1.21, 1.34), and colostomy (aOR = 1.34; 95% CI: 1.25, 1.43). Additionally, MO was associated with higher risk for multiple readmissions for diverticulitis within 30 days (aOR = 1.45; 95% CI: 1.08, 1.96) and 6 months (aOR = 1.21; 95% CI: 1.03, 1.42). A one-to-one matched propensity-score analysis confirmed our multivariable analysis findings. CONCLUSIONS: Analysis of national data demonstrates an increasing trend of MO patients' admissions for diverticulitis, with a presentation at a younger age. Furthermore, MO is associated with an increased risk of adverse outcomes and readmissions of diverticulitis. Future strategies are needed to ameliorate these outcomes.

Prevalence of Germline Mutations in Polyposis and Colorectal Cancer-Associated Genes in Patients With Multiple Colorectal Polyps.

BACKGROUND AND AIMS: Guidelines recommend genetic testing of patients with 10 or more cumulative adenomatous polyps. However, little is known about the utility of these tests-especially for older patients. We aimed to determine the prevalence of pathogenic mutations in patients with multiple colorectal polyps, stratified by age. METHODS: We performed a cross-sectional study of patients with 10 or more colorectal polyps who underwent multigene panel testing (MGPT) from March 2012 through December 2016 (n = 3789). Demographic, clinical and family history data were obtained from test requisition forms and accompanying clinic notes, pedigrees, and pathology reports. Subjects were stratified based on reported polyp histology. Primary outcomes of interest were gene mutations associated with adenomatous polyposis, hamartomatous polyposis, and non-polyposis colorectal cancer syndromes. RESULTS: Based on MGPT, the prevalence of mutations in adenomatous polyposis genes decreased with increasing age in all polyp count groups in the adenoma cohort (P < .001 for 10-19, 20-99, and 100 or more polyps). The prevalence of mutations in all genes of interest also decreased with increasing age but remained above 5% in all age and polyp cohorts. Increased age at testing was associated with a significantly lower risk of a mutation in any gene of interest with multivariate analysis. In the hamartoma cohort, the prevalence of mutations in hamartomatous polyposis genes was high regardless of polyp count (40% with 10-19 polyps, 72.1% with 20-99 polyps, and 50% with 100 or more polyps). CONCLUSION: Our findings support continued genetic testing of patients with 10 or more polyps including adenomas and/or hamartomas. MGPT that includes analysis of polyposis and non-polyposis colorectal cancer genes should be considered for these patients given the high proportion with mutations (above 5%) in all age groups.

Implementation of a Defecation Posture Modification Device: Impact on Bowel Movement Patterns in Healthy Subjects.

GOALS: The goal of this study was to evaluate the influence of defecation postural modification devices (DPMDs) on normal bowel patterns. BACKGROUND: The introduction of DPMDs has brought increased awareness to bowel habits in western populations. MATERIALS AND METHODS: A prospective crossover study of volunteers was performed that included real-time collection of data regarding bowel movements (BMs) for 4 weeks (first 2 wk without DPMD and subsequent 2 wk with DPMD). Primary outcomes of interest included BM duration, straining, and bowel emptiness with and without DPMD use. RESULTS: In total, 52 participants (mean age, 29 y and 40.1% female) were recruited for this study. At baseline 15 subjects (28.8%) reported incomplete emptying, 23 subjects (44.2%) had increased straining, and 29 subjects (55.8%) noticed blood on their toilet paper in the past year. A total of 1119 BMs were recorded (735 without DPMD and 384 with DPMD). Utilizing the DPMD resulted in increased bowel emptiness (odds ratio, 3.64; 95% confidence interval (CI), 2.78-4.77) and reduced straining patterns (odds ratio, 0.23; 95% CI, 0.18-0.30). Moreover, without the DPMD, participants had an increase in BM duration (fold increase, 1.25; 95% CI, 1.17-1.33). CONCLUSIONS: DPMDs positively influenced BM duration, straining patterns, and complete evacuation of bowels in this study.

Colonoscopy in Patients With Postmyocardial Infarction Gastrointestinal Bleeding: A Nationwide Analysis.

GOALS: The goal of this study was to evaluate outcomes of colonoscopy in the setting of post myocardial infarction (MI) gastrointestinal bleeding (GIB) in a large population-based data set. BACKGROUND: The literature to substantiate the proposed safety of colonoscopy following an acute MI is limited. STUDY: The Nationwide Inpatient Sample (2007 to 2013) was utilized to identify all adult patients (age, 18 y or above) hospitalized with a primary diagnosis of ST-elevation MI and receiving left heart catheterization (STEMI-C). The outcomes of patients with concomitant diagnosis of GIB receiving endoscopic intervention with esophagogastroduodenoscopy (EGD) or colonoscopy postcatheterization were compared with those who did not. Primary outcomes including mortality, length of stay, and hospital costs were evaluated with univariate and multivariate analysis. RESULTS: There were 131,752 patients with post-STEMI-C GIB (5.35% of all STEMI-C patients) and same admission colonoscopy was performed in 1599 patients (1.21%). Although the prevalence of post-STEMI-C GIB increased from 4.27% in 2007 to 5.87% in 2013 (P<0.001), patients receiving colonoscopy decreased from 1.42% to 1.09% (P<0.001) over the course of the study period. Multivariate analysis revealed that patients receiving no endoscopic intervention [odds ratio, 3.61; 95% confidence interval: 1.57, 8.31] or EGD alone (OR, 2.70; 95% confidence interval: 1.12, 6.49) have higher mortality compared with those receiving colonoscopy. CONCLUSIONS: Same admission colonoscopy performed for post-STEMI-C GIB was associated with lower mortality. However, despite increased incidence of GIB in these patients during the study period, a lower percentage of patients received colonoscopy. These results suggest that colonoscopy is safe but underutilized in this setting.

Cirrhosis Is Associated with Increased Mortality in Patients with Diverticulitis: A Nationwide Cross-Sectional Study.

BACKGROUND: Diverticulitis in patients with cirrhosis has been associated with higher surgical mortality, but no prior studies evaluate non-surgical treatment results. AIMS: Our aim was to compare the outcomes of hospitalization for diverticulitis in patients with and without cirrhosis. METHODS: We utilized the Nationwide Inpatient Sample (2007-2013) for patients with and without cirrhosis hospitalized for diverticulitis. Patients were further stratified by the presence of compensated versus decompensated cirrhosis. Validated ICD-9 codes captured patients and surgical procedures. Multivariate logistic regression models were fit. The primary outcomes of interest were mortality and surgical intervention rates. RESULTS: There were 1,555,469 patients hospitalized for diverticulitis without cirrhosis, and 7523 patients hospitalized for diverticulitis with cirrhosis. On multivariate analysis, patients with cirrhosis had an increased mortality rate (OR 2.28; 95% CI 1.48-3.5). There were no significant differences in surgical interventions. Subgroup multivariate analyses of compensated cirrhosis (n = 6170) and decompensated cirrhosis (n = 1353) revealed that decompensated cirrhosis had an increased mortality rate (OR 4.99; 95% CI 2.48-10.03) when compared to patients without cirrhosis, whereas those with compensated cirrhosis did not (OR 1.67; 95% CI 0.96-2.91). Those with compensated cirrhosis underwent less surgical interventions (OR 0.82; 95% CI 0.67-0.99) compared to those without cirrhosis. Patients with diverticulitis and cirrhosis had increased costs and lengths of hospitalization. CONCLUSION: Presence of cirrhosis in patients hospitalized for diverticulitis is associated with an increased mortality rate. These are novel findings, and future clinical studies should focus on improving diverticulitis outcomes in this group.