Mismatch repair protein status of non-neoplastic uterine and intestinal mucosa in patients with Lynch syndrome and double somatic mismatch repair protein mutations.

Mismatch repair (MMR) protein-deficient non-neoplastic colonic crypts and endometrial glands (dMMR crypts and glands) have been reported as a unique marker of underlying Lynch syndrome (LS). However, no large studies have directly compared the frequency of detection in cases with double somatic (DS) MMR mutations. We retrospectively analyzed 42 colonic resection specimens (24 LS and 18 DS) and 20 endometrial specimens (9 LS and 11 DS), including 19 hysterectomies and 1 biopsy for dMMR crypts and glands. All specimens were from patients with known primary cancers, including colonic adenocarcinomas and endometrial endometrioid carcinomas (including 2 mixed carcinomas). Four blocks of normal mucosa away from the tumor were selected from most cases, as available. MMR immunohistochemistry specific to the primary tumor mutations was analyzed. dMMR crypts were found in 65% of LS and 0% of DS MMR-mutated colonic adenocarcinomas (P < .001). Most dMMR crypts were detected in the colon (12 of 15) compared to the ileum (3 of 15). dMMR crypts showed single and grouped losses of MMR immunohistochemical expression. dMMR glands were found in 67% of LS and 9% (1 of 11) of DS endometrial cases (P = .017). Most dMMR glands were found in the uterine wall, with 1 LS and 1 DS case exhibiting dMMR glands in the lower uterine segment. Most cases exhibited multifocal and grouped dMMR glands. No morphologic atypia was identified in dMMR crypts or glands. Overall, we demonstrate that dMMR crypts and glands are highly associated with underlying LS, while being rarer in those with DS MMR mutations.

Universal tumor screening for lynch syndrome on colorectal cancer biopsies impacts surgical treatment decisions.

Universal tumor screening (UTS) for Lynch syndrome (LS) on colorectal cancer (CRC) can be performed on biopsies or resection specimens. The advantage of biopsies is the chance to provide preoperative genetic counseling/testing (GC/T) so patients diagnosed with LS can make informed decisions regarding resection extent. We evaluated utilization of UTS on biopsies, percentage of patients with deficient mismatch repair (dMMR) who underwent GC/T preoperatively, and whether surgical/treatment decisions were impacted. We performed a retrospective review of medical records to assess CRC cases with dMMR immunohistochemical staining from 1/1/2017 to 2/26/2021. 1144 CRC patients had UTS using MMR immunohistochemistry; 559 biopsies (48.9%) and 585 resections (51.1%). The main reason UTS was not performed on biopsy was it occurred outside our health system. 58 (5%) of CRCs were dMMR and did not have MLH1 promoter hypermethylation (if MLH1 and PMS2 absent). 28/58 (48.3%) of dMMR cases were diagnosed on biopsy. Of those 28, 14 (50%) eventually underwent GC/T, and 7 (25%) had GT results prior to surgery. One of the 7 had incomplete documentation of results affecting their treatment plan. Of the remaining 6 with complete documentation, 5 underwent surgery and one was treated with immunotherapy only. Three patients elected a more extensive surgery. 6/28 (21.4%) dMMR patients identified on biopsy made an informed surgical/treatment decision based on their dMMR status/LS diagnosis. When applied, UTS on biopsy followed by genetic counseling and testing informs surgical decision-making. Process and implementation strategies are in place to overcome challenges to more broadly optimize this approach.

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.

Mainstreaming germline genetic testing for patients with pancreatic cancer increases uptake.

Germline genetic testing is recommended for all patients with pancreatic cancer (PC) but uptake rates are low. We implemented a mainstreaming program in oncology clinics to increase testing for PC patients. Genetic counselors trained oncology providers to offer a standardized multigene panel and obtain informed consent using an educational video. Pre-test genetic counseling was available upon request. Otherwise, patients with identified pathogenic variants, strong family history, or questions regarding their results were referred for post-test genetic counseling. We measured rates of testing and genetic counseling visits. From September 2019 to April 2021, 245 patients with PC underwent genetic testing. This represents a 6.5-fold increase in germline testing volume (95% confidence interval 5.2-8.1) compared to previous years. At least one pathogenic or likely pathogenic variant (PV/LPV) was found in 34 (13.9%) patients, including 17 (6.9%) PV/LPVs in high or moderate risk genes and 18 (7.3%) in low risk or recessive genes. Five (2.0%) PVs had implications on treatment selection. 22 of the positive patients (64.7%) and an additional 8 PC patients (1 negative, 3 VUS, and 4 pre-test) underwent genetic counseling during the study period. Genetic counselors saw 2.0 PC patients/month prior to this project, 1.6 PC patients/month during this project, and would have seen 2.2 PC patients/month if all patients with pathogenic variants attended post-test counseling. Conclusions Mainstreaming genetic testing expands access for PC patients without overwhelming genetic counseling resources.

Endoscopic Surveillance in Patients with the Highest Risk of Gastric Cancer: Challenges and Solutions.

Gastric cancer is one of the most significant causes of cancer-related morbidity and mortality worldwide. Recognized modifiable risk factors include Helicobacter pylori infection, geographic location, select dietary factors, tobacco use and alcohol consumption. In addition, multiple hereditary cancer predisposition syndromes are associated with significantly elevated gastric cancer risk. Endoscopic surveillance in hereditary gastric cancer predisposition syndromes has the potential to identify gastric cancer at earlier and more treatable stages, as well as to prevent development of gastric cancer through identification of precancerous lesions. However, much uncertainty remains regarding use of endoscopic surveillance in hereditary gastric cancer predisposition syndromes, including whether or not it should be routinely performed, the surveillance interval and age of initiation, cost-effectiveness, and whether surveillance ultimately improves survival from gastric cancer for these high-risk individuals. In this review, we outline the hereditary gastric cancer predisposition syndromes associated with the highest gastric cancer risks. Additionally, we cover current evidence and guidelines addressing hereditary gastric cancer risk and surveillance in these syndromes, along with current challenges and limitations that emphasize a need for continued research in this field.

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.

Intraductal Papillary Mucinous Neoplasms in Hereditary Cancer Syndromes.

Hereditary pancreatic cancer, which includes patients with familial pancreatic cancer (FPC) and hereditary pancreatic cancer syndromes, accounts for about 10% of all pancreatic cancer diagnoses. The early detection of pre-cancerous pancreatic cysts has increasingly become a focus of interest in recent years as a potential avenue to lower pancreatic cancer incidence and mortality. Intraductal papillary mucinous cystic neoplasms (IPMNs) are recognized precursor lesions of pancreatic cancer. IPMNs have high prevalence in patients with hereditary pancreatic cancer and their relatives. While various somatic mutations have been identified in IPMNs, certain germline mutations associated with hereditary cancer syndromes have also been identified in IPMNs, suggesting a role in their formation. While the significance for the higher prevalence of IPMNs or similar germline mutations in these high-risk patients remain unclear, IPMNs do represent pre-malignant lesions that need close surveillance. This review summarizes the available literature on the incidence and prevalence of IPMNs in inherited genetic predisposition syndromes and FPC and speculates if IPMN and pancreatic cancer surveillance in these high-risk individuals needs to change.

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.

Hereditary Colorectal Cancer.

Around 10% to 16% of colorectal cancer patients have a pathogenic variant in a cancer susceptibility gene. Some of these variants are in cancer genes that are associated with colorectal cancer while others are not. The hereditary colorectal cancer syndromes can be divided into two major categories, the nonpolyposis and the polyposis conditions. The nonpolyposis conditions can be divided into those that lead to colorectal tumors with defective mismatch repair and those that do not. The polyposis conditions are further divided by predominant histology into the adenomatous, hamartomatous, serrated, and mixed polyposis conditions. All of these conditions are described in detail herein.

Yield of upper gastrointestinal screening in colonic adenomatous polyposis of unknown etiology: a multicenter study.

Background and study aims The majority of patients with 10 or more cumulative colorectal adenomas have uninformative genetic testing and meet criteria for colonic adenomatous polyposis of unknown etiology (CPUE). The yield of upper gastrointestinal screening in patients with CPUE after multi-gene panel testing is unknown and our objective was to characterize this. Patient and methods A multicenter, retrospective analysis of screening upper endoscopies in adults with CPUE after multi-gene panel testing was performed. Those with a history of gastroduodenal neoplasia prior to CPUE diagnosis were excluded. Demographic and clinical variables were collected and compared. Results One hundred and twenty-eight patients with CPUE were included from five participating centers. Nine (7.0 %) had gastroduodenal neoplasia on initial screening upper endoscopy. Those with over 100 colorectal adenomas had a significantly higher rate of gastroduodenal neoplasia than those with 20-99 or 10-19 colorectal adenomas (44.4 % vs 4.1 % vs 4.4 %, P  = 0.002). Similar results were seen when the analysis was restricted to only duodenal or ampullary adenomas. The only malignancy was a gastric cancer in a patient with 20 to 99 colorectal adenomas. When comparing patients with gastroduodenal neoplasia to those without, the only significantly different characteristic was the cumulative number of colorectal adenomas. Conclusions We found a 7 % rate of gastroduodenal neoplasia in patients with CPUE after multi-gene panel testing. Although patients with ≥ 100 colorectal adenomas had a significantly higher risk, over 4 % of patients with 10 to 99 colorectal adenomas had gastroduodenal neoplasia. Given this, we recommend a screening upper endoscopy at the time of a colonoscopy after CPUE diagnosis.

Endoscopic Management and Surgical Considerations for Familial Adenomatous Polyposis.

Familial adenomatous polyposis (FAP) is the development of many adenomatous colorectal polyps. Colonoscopy is recommended to start at age 10 to 12 years at intervals of 1 to 2 years. Colectomy is clearly indicated for malignancy or significant colorectal symptoms. After colectomy, endoscopic surveillance is still critical. Duodenal and gastric polyposis is also found in almost all patients with FAP. Screening with upper endoscopy and ampullary visualization is recommended, generally determined by age and staging of duodenal polyposis, but guidelines are increasingly factoring in ampullary and gastric manifestations. Surgical management of malignancy or advanced upper tract manifestations is needed.

Multiple colorectal adenomas in Lynch syndrome.

Background: Lynch syndrome has not traditionally been considered to have a high colorectal adenoma burden. However, with increasing adenoma detection rates in the general population, the incidence of adenoma detection in Lynch syndrome may also be increasing and leading to higher cumulative adenoma counts. Aim: To clarify the prevalence and clinical impact of multiple colorectal adenomas (MCRA) in Lynch syndrome. Methods: A retrospective review of patients with Lynch syndrome at our institution was performed to assess for MCRA (defined as ≥10 cumulative adenomas). Results: There were 222 patients with Lynch syndrome among whom 14 (6.3%) met MCRA criteria. These patients had increased incidence of advanced neoplasia (OR 10, 95% CI: 2.7-66.7). Conclusions: MCRA is not unusual in Lynch syndrome and is associated with a significantly increased likelihood of advanced colon neoplasia. Consideration should be given to differentiating colonoscopy intervals based on the presence of polyposis in Lynch syndrome.

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.

Outcomes of inpatient cholecystectomy among adults with cystic fibrosis in the United States.

BACKGROUND: Symptomatic biliary and gallbladder disorders are common in adults with cystic fibrosis (CF) and the prevalence may rise with increasing CF transmembrane conductance regulator modulator use. Cholecystectomy may be considered, but the outcomes of cholecystectomy are not well described among modern patients with CF. AIM: To determine the risk profile of inpatient cholecystectomy in patients with CF. METHODS: The Nationwide Inpatient Sample was queried from 2002 until 2014 to investigate outcomes of cholecystectomy among hospitalized adults with CF compared to controls without CF. A propensity weighted sample was selected that closely matched patient demographics, patient's individual comorbidities, and hospital characteristics. The propensity weighted sample was used to compare outcomes among patients who underwent laparoscopic cholecystectomy. Hospital outcomes of open and laparoscopic cholecystectomy were compared among adults with CF. RESULTS: A total of 1239 inpatient cholecystectomies were performed in patients with CF, of which 78.6% were performed laparoscopically. Mortality was < 0.81%, similar to those without CF (P = 0.719). In the propensity weighted analysis of laparoscopic cholecystectomy, there was no difference in mortality, or pulmonary or surgical complications between patients with CF and controls. After adjusting for significant covariates among patients with CF, open cholecystectomy was independently associated with a 4.8 d longer length of stay (P = 0.018) and an $18449 increase in hospital costs (P = 0.005) compared to laparoscopic cholecystectomy. CONCLUSION: Patients with CF have a very low mortality after cholecystectomy that is similar to the general population. Among patients with CF, laparoscopic approach reduces resource utilization and minimizes post-operative complications.

Prospective Statewide Study of Universal Screening for Hereditary Colorectal Cancer: The Ohio Colorectal Cancer Prevention Initiative.

Hereditary cancer syndromes infer high cancer risks and require intensive surveillance. Identification of high-risk individuals among patients with colorectal cancer (CRC) needs improvement. METHODS: Three thousand three hundred ten unselected adults who underwent surgical resection for primary invasive CRC were prospectively accrued from 51 hospitals across Ohio between January 1, 2013, and December 31, 2016. Universal Tumor screening (UTS) for mismatch repair (MMR) deficiency was performed for all, and pathogenic germline variants (PGVs) were identified using multigene panel testing (MGPT) in those who met at least one inclusion criterion: MMR deficiency, diagnosed < 50 years, multiple primary tumors (CRC or endometrial cancer), or with a first-degree relative with CRC or endometrial cancer. RESULTS: Five hundred twenty-five patients (15.9%) had MMR deficiency. Two hundred thirty-four of 3,310 (7.1%; 16% of the 1,462 who received MGPT) had 248 PGVs in cancer susceptibility genes. One hundred forty-two (4.3%) had a PGV in an MMR gene, and 101 (3.1%) had a PGV in a non-MMR gene. Ten with Lynch syndrome (LS) also had a non-MMR PGV and were included in both groups. Two (0.06%) had constitutional MLH1 hypermethylation. Of unexplained MMR-deficient patients, 88.4% (76 of 86) had double somatic MMR mutations. Testing for only MMR genes in MMR-deficient patients would have missed 18 non-MMR gene PGVs (7.3% of total PGVs identified). Had UTS been the only method used to screen for hereditary cancer syndromes, 38.6% (91 of 236) would have been missed, including 6.3% (9 of 144) of those with LS. These results have treatment implications as 5.3% (175 of 3,310) had PGVs in genes with therapeutic targets. CONCLUSION: UTS alone is insufficient for identifying a large proportion of CRC patients with hereditary syndromes, including some with LS. At a minimum, 7.1% of individuals with CRC have a PGV and pan-cancer MGPT should be considered for all patients with CRC.

Predictors of Early Readmissions in Hospitalized Patients With Gastroparesis: A Nationwide Analysis.

BACKGROUND/AIMS: Gastroparesis is a chronic gastrointestinal disorder that frequently presents with symptoms that are difficult to manage, necessitating frequent hospitalizations. We sought to determine the predictors of early readmission due to gastroparesis based on etiology. METHODS: We identified all adults discharged with a principal diagnosis of gastroparesis after hospitalization from the 2014 Nationwide Readmission Database. We compared etiology wise (diabetes, post-surgical, and idiopathic) early readmission. Multivariate regression analyses were performed to identify significant predictors of 30-day readmission. RESULTS: A total of 12 689 patients were identified, 30.7% diabetic, 2.6% post-surgical, and 66.7% were idiopathic. Patients with diabetic gastroparesis were more likely to be readmitted within 30 days than idiopathic (adjusted odds ratio [aOR], 0.81; 95% confidence interval [CI], 0.69-0.94) and post-surgical gastroparesis (aOR, 0.58; 95% CI, 0.34-0.98). Pyloroplasty was associated with less likelihood of 30-day readmission (aOR, 0.45; 95% CI, 0.20-0.97). In addition, male gender (aOR, 1.18; 95% CI, 1.02-1.37), modified Elixhauser comorbidity score ≥ 3 (aOR, 1.38; 95% CI, 1.18-1.61), chronic pain syndrome (aOR, 1.41; 95% CI, 1.11-1.78), younger (18-64 years) age (aOR, 1.64; 95% CI, 1.34-2.00), need for percutaneous endoscopic gastrostomy/jejunostomy tube (aOR, 2.06; 95% CI, 1.21-3.52), and need for total parenteral nutrition (aOR, 1.70; 95% CI, 1.24-2.35) were associated with increased risk of 30-day readmission. CONCLUSION: s One in 5 patients was readmitted with gastroparesis within 30 days. In the diabetic group, diabetes-related complications contributed to readmissions than gastroparesis. Pyloroplasty is associated with reduced early hospital readmission. Prospective studies are needed for validation of these results.

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.