Samadder, Niloy J

Purpose: Neuroendocrine neoplasms (NENs) are increasingly recognized to have a hereditary predilection, yet the prevalence and clinical relevance of pathogenic germline variants (PGVs) in unselected patients with NEN remain poorly defined. This prospective, multicenter study aimed to evaluate the prevalence and clinical utility of PGVs through universal multigene panel testing in a diverse cohort of patients with NENs. Patients and Methods: Between 2018 and 2024, we enrolled unselected patients with NENs from 3 Mayo Clinic Cancer Centers. Germline genetic testing was performed using a next-generation sequencing panel of up to 84 cancer predisposition genes. Patients were not selected based on age, disease stage, ethnicity, or family history. Variants were classified as PGVs, variants of uncertain significance (VUS), or negative. Clinical and demographic data were analyzed descriptively. Results: Among 88 patients, PGVs were identified in 15.9% (n=14), most frequently in high- or moderate-penetrance genes including MEN1 , CHEK2 , MITF , and MUTYH . PGVs were most commonly found in pancreatic NENs [n=12/55 (21.8%)], followed by small bowel NENs [n=2/20 (10%)], with no PGVs detected in lung NENs. Mismatch repair (MMR) gene alterations were identified in 5.7% of patients, including 1 MLH1 PGV and 4 MSH2/MSH6 VUS, 2 of which demonstrated MMR deficiency by protein testing. VUS were reported in 34.1% of patients. Notably, 35.7% of PGV-positive patients did not meet current NCCN or ACMG testing criteria, and 53.9% had PGVs in genes outside of cancer-specific guideline recommendations. Conclusions: Universal germline testing in unselected patients with NEN identified clinically relevant PGVs in over 15% of cases. These findings support broader genetic testing approaches to guide treatment, enhance familial risk assessment, and inform cascade testing—regardless of traditional clinical selection criteria.

SummaryIntroductionPost‐colonoscopy colorectal cancers (PCCRCs) have been proposed as a performance metric for colonoscopy quality assurance programs. Previously, there was no standardised terminology or reporting methods. In 2018, the World Endoscopy Organization (WEO) advised standardised definitions and prevalence calculation methodology.AimsTo assess PCCRC burden using WEO standardised methods, to explore causes of heterogeneity, and to review changes in prevalence over timeMethodsWe updated a prior systematic review by searching Ovid MEDLINE and EMBASE databases from 1 January 2013 to 31 January 2021 to identify population‐based studies (or multicentre studies representative of the local population) reporting PCCRC prevalence (PROSPERO [CRD42020183796]). Two authors independently determined study eligibility, assessed quality, and extracted data. We estimated the PCCRC 3‐year prevalence using WEO‐recommended methodologies and investigated between‐study sources of heterogeneity. We examined changes in prevalence over time.ResultsFifteen studies reporting on 25 872 PCCRC cases met eligibility criteria. Pooled PCCRC 3 year prevalence was 8.2% (95% CI = 6.9%‐9.4%, I2 = 98.2%) across four European studies using WEO precise methodology. Proximal PCCRC prevalence was greater than distal (9.7% [95% CI = 7.0%‐12.4%] vs 5.4% [95% CI = 2.9%‐7.8%], I2 = 99.2%). Seven studies reporting PCCRC rates over time showed no consistent trend: four showed a decrease, one an increase and two were unchanged. Between‐study heterogeneity was high.ConclusionsPooled 3‐year PCCRC prevalence was 8.2% (95% CI = 6.9%‐9.4%). Despite WEO standardised methodology to define and calculate PCCRC rates, there was significant heterogeneity among studies. Comparing rates between populations remains challenging and additional studies are needed to better understand the global PCCRC burden to inform quality assurance programs.

Objectives: To determine the risk and risk factors for mental illness among colorectal cancer (CRC) survivors across short-term and long-term follow-up periods. Methods: We used the Utah Cancer Registry to identify CRC survivors diagnosed between 1997 and 2013. Mental health diagnoses were available in electronic medical records and statewide facilities data that were linked by the Utah Population Database. CRC survivors were matched to individuals from a general population cohort. The risk of developing a mental illness was compared between cohorts. The association between mental illness and mortality was also analyzed. Results: In total, 8961 CRC survivors and 35,897 individuals in a general population cohort were identified. CRC survivors were at increased risk for any mental health diagnosis at 0 to 2 years (hazard ratio [HR], 3.70; 95% confidence interval [CI], 3.47-3.95), >2 to 5 years (HR, 1.23; 95% CI, 1.09-1.38), and >5 years (HR, 1.20; 95% CI, 1.07-1.36) after cancer diagnosis. CRC survivors were also at increased risk of depressive disorders specifically during the same time periods. At >5 years, CRC survivors still had an increased risk of developing many mental health diagnoses. Factors associated with increased risk of any mental health disorder among CRC survivors included colostomy and Charlson Comorbidity Index of 1+. There was an increased risk of death for CRC survivors diagnosed with any mental health disorder (HR, 2.18; 95% CI, 2.02-2.35) and depression (HR, 2.10; 95% CI, 1.92-2.28). Conclusions: CRC survivors are at increased risk for mental health disorders in the short-term and long-term. Survivors who develop mental health disorders also experience decreased survival.