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Background A significant proportion of upper gastrointestinal cancers (UGICs) remain undetected during esophagogastroduodenoscopy (EGD). We investigated the characteristics and risk factors of UGICs missed during endoscopy. Methods In this nationwide registry-based study, we analyzed two large Polish datasets (National Health Fund and National Cancer Registry) to identify individuals who underwent EGD and were subsequently diagnosed with UGIC. Cancers diagnosed Results We included 4 105 399 patients (mean age 56.0 years [SD 17.4]; 57.5 % female) who underwent 5 877 674 EGDs in 2012–2018. Within this cohort, 33 241 UGICs were diagnosed, of which 1993 (6.0 %) were missed. Within esophageal neoplasms, adenocarcinomas were more frequently missed than squamous cell cancers (6.1 % vs. 4.2 %), with a relative risk of 1.4 (95 % confidence interval [CI] 1.1–1.8, P = 0.01). Most gastric cancers were adenocarcinomas, of which 5.7 % were classified as missed. Overall, a higher proportion of missed UGICs than prevalent cancers presented at an advanced stage (42.2 % vs. 36.2 %, P Conclusions Among UGICs, esophageal adenocarcinomas were missed most frequently. Missed cancers occur more frequently within the primary care sector and are found more often in women and individuals with multiple comorbidities.

IntroductionCongenital hypogonadotropic hypogonadism results from a dysfunction of the hypothalamic-pituitary-gonadal axis, which is essential for the development and function of the reproductive system. It may be associated with anosmia, referred to as Kallmann syndrome, or a normal sense of smell. Numerous studies have proven that hypogonadotropic hypogonadism is not simply a monogenic Mendelian disease, but that more than one gene may be involved in its pathogenesis in a single patient. The oligogenic complex architecture underlying the disease is still largely unknown.Material and methodsTargeted next-generation sequencing (NGS) was used to screen for DNA variants in a cohort of 47 patients with congenital hypogonadotropic hypogonadism. The NGS panel consists of over 50 well-known and candidate genes, associated with hypogonadotropic state.ResultsHere we report the identification of new oligogenic variants in SPRY4/SEMA3A, SRA1/SEMA7A, CHD7/SEMA7A, CCDC141/POLR3B/POLR3B, and PROKR2/SPRY4/NSMF. These genes are known to contribute to the phenotype of hypogonadotropic hypogonadism, yet our results point to potential new “partners” underlying digenic and trigenic patterns.ConclusionsThe finding supports the importance of oligogenic inheritance and demonstrates the complexity of genetic architecture in hypogonadotropic hypogonadism. It also underlines the necessity for developing fine-tuned guidelines to provide a tool for adequate and precise sequence variant classification in non-Mendelian conditions.