Introduction

Lynch syndrome (LS) is a heritable autosomal dominant genetic condition caused by mutations in several DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6, PMS2 and EPCAM. Affected individuals have an increased life-long risk of developing cancers especially colorectal cancer (CRC) and endometrial cancer (EC). LS accounts for approximately up to 3% of all CRC. Traditionally, diagnosis was based on clinical criteria (Amsterdam II, Bethesda and revised Bethesda), which have proven to be of limited applicability in clinical practice. In recent years tumor testing via immunohistochemistry (IHC) of all CRCs for the expression of MMR proteins has successfully integrated into clinical care. Universal screening through IHC of CRC tumor samples is cost-effective and recommended by major guidelines, which also recommend its application to endometrial cancers.

Aims & Methods

Our aim was to assess the main differences between LS families where the first individual received a genetic diagnosis after IHC on tumor sample and LS families where the first individual received a genetic diagnosis due to meeting the Amsterdam II or revised Bethesda criteria. We obtained data (year of genetic test confirmation, first tumor diagnosis, family tree) of all our single center’s LS patients who undergo surveillance in our Institute (n = 101 patients). Accordingly, we grouped patients by family and identified each family’s index case-defined as the first individual to receive a genetic diagnosis - and relatives of index cases. Therefore, we divided the cohort into two groups: families whose the index case was identified after IHC on tumor sample and families whose the index case was identified due to meeting the Amsterdam II or revised Bethesda criteria. We subsequently evaluatedwhether patients identified through IHC would have also met the revised Bethesda or Amsterdam II criteria for genetic testing.

Results

We found that index cases identified through IHC (n =16; of which 8 on CRC tissue, 7 on EC tissue and 1 on lung cancer tissue) had a mean age of 57.93 years at the time of genetic diagnosis, whereas those identified through clinical criteria (n = 20) had a mean age of 46.35 years. As for the relatives, those whose index case was identified via IHC (n = 11) had a mean age of 45.72 years, while relatives of individuals diagnosed based on clinical criteria (n= 54) had a mean age of 37.96 years. Patients carrying pathogenic variants in MSH6 and PMS2 (leading to lower penetrance and a late onset of LS related cancers) were 8 out of 16 (50 %) in the IHC group and 1 out of 20 (5 %) in the clinical criteria group. Furthermore 8 out of 16 (50%) index patients diagnosed through IHC did not meet the Amsterdam II criteria.

Conclusion

The mean age of index cases diagnosed due to clinical criteria is lower than that of cases identified through IHC, probably because of the early onset of LS related cancers in these patients and since the clinical criteria require at least one case to be diagnosed at a young age (<50 years old). In contrast, universal immunohistochemistry (IHC) screening enables the detection of all patients with mismatch repair-deficient tumors, including those diagnosed later in life and those without an evident family history of cancer or carrying pathogenic variants in genes such as MSH6 and PMS2 with a lower penetrance. Our data strengthen the important role of IHC screening for MMR proteins loss of expression both in CRC and EC to find LS families that would not be possible to identify with clinical criteria only.

Introduction

Recent research from the Netherlands, the United States, and Korea suggests that individuals who receive a positive result on the fecal immunochemical test (FIT) may be at a higher risk of developing gastroesophageal cancer (GEC) within the following 36 months. However, the associations reported in these studies may be biased due to differences in age and sex between the FIT-positive and FIT-negative groups and other confounding factors.

Aims & Methods

We aimed to evaluate the association between FIT results and the risk of GEC in a matched cohort by age and sex. Additionally, we assessed the cost-effectiveness of a one-time Esophago-Gastro-Duodenoscopy (EGD) for individuals with positive FIT results.. We created a matched cohort of individuals aged 50 to 75 who underwent FIT testing at Clalit Health in Israel between June 2016 and June 2019. For each FIT-positive individual, we matched three FIT-negative individuals based on age, sex, and H. pylori status. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were utilized to evaluate the association between a positive FIT result and the risk of GEC within 36 months. We calculated the incremental cost-effectiveness ratio (ICER) for a one-time EGD at $400 in individuals who tested positive for FIT. Screening is considered cost-effective if the ICER is below $50,000.

Results

The primary cohort included 483,710 individuals, while the matched cohort comprised 151,500 individuals (47.6% female, median age 62.5 years). During the follow-up period, 202 cases of GEC occurred: 0.2% (64/38,575) among FIT-positive individuals and 0.1% (138/112,925) among FIT-negative individuals, adjusted HR 1.39 (95% CI 1.03-1.87). Age, male sex, H. pylori exposure, country of birth, proton-pump inhibitor usage, smoking status, and anemia were all significantly associated with an increased risk of gastric cancer. A one-time EGD has been determined to be a cost-effective option in a range of ages and rates of localized disease at the time of EGD.

Conclusion

This matched cohort study suggests that individuals with a positive FIT may have an increased risk of GEC, which occurs at an overall rate of 0.2% within 36 months. A one-time EGD priced at $400 can be cost-effective in many scenarios.

Disclosure

NONE

Introduction

Individuals with Lynch syndrome (LS) are predisposed to different tumors, including gastric (GC) and duodenal (DC) cancer, especially those with specific mutations or familial aggregation. However, the role of esophagogastroduodenoscopy (EGD) in these patients is still uncertain, with heterogeneous recommendations among different guidelines.

Aims & Methods

To estimate the overall incidence of GC and DC in individuals with LS, to determine the incidence of GC and DC in higher-risk subgroups within these patients, as well as to clarify the usefulness of screening or surveillance by EGD.

Systematic search of Pubmed and Embase for cohort studies and clinical trials from inception to April 2024. Incidences of GC and DC were calculated, as well as the relative risk (RR) and their respective 95% confidence intervals in those studies comparing patients under surveillance with EGD vs without. A meta-analysis was performed using a random-effects model. Heterogeneity was assessed with the I² statistic.

Results

A total of 584 studies were obtained, of which 30 were finally included, with a total of 31264 patients with LS. The overall incidence of GC was 2.04% (95%CI 1.63-2.45). The incidence of GC was 2.60% (95%CI 1.61-3.60) in MLH1 carriers and 2.91% (95%CI 1.63-2.45) in MSH2 carriers. In those with LS and family history, the incidence of GC was 25.94% (95%CI 15.01-36.87). The incidence of DC was 1.61% (95%CI 1.21-2.00).
Only 3 studies compared patients with LS in follow-up with EGD vs those without follow-up, evidencing a protective effect of EGD for GC [RR 0.31 (95%CI 0.14-0.69)], but not for DC [RR 0.65 (95%CI 0.22-1.32)].

Conclusion

The incidence of GC and DC in patients with LS is higher than that of the general population, especially in those patients with MLH1, MSH2 mutations or family aggregation. Surveillance with EGD could help to reduce this incidence through the diagnosis of premalignant lesions.

Introduction

In recent years, artificial intelligence (AI) has been widely explored to enhance capsule endoscopy (CE), with the goal of improving the efficiency of the reading process. While most AI models have been developed for small bowel and colon analysis, the development of esophagogastric (E-G) models has been limited due to the scarcity of frames captured during the procedure, making it challenging to develop a robust model. This study aims to develop an interoperable ubiquitous model capable detecting pleomorphic lesions in the E-G tract.

Aims & Methods

We included 59,482 E-G frames, from 774 CE procedures of 5 centers, to develop a Convolutional Neural Network (CNN). The dataset was divided following an exam-based split, with 90% allocated for training – including a 5-fold cross validation – while the remaining was used for testing. The primary outcomes were: sensitivity, specificity, accuracy and area under the curve (AUC).

Results

During training, the CNN achieved mean sensitivity of 85.0% (IC95% 76.5–93.5), specificity of 96.3% (IC95% 93.9–98.7), accuracy of 93.6% (IC95% 91.7–95.4), and AUC-ROC of 0.98 (IC95% 0.97–0.98). During testing, the sensitivity, specificity and accuracy of CNN were 92.2%, 95.1% and 94.6%, respectively.

Conclusion

CE-AI models capable of assessing E-G are crucial step toward developing a truly robust panendoscopic model. This ubiquitous and interoperable model capable of lesion detection in both esophagus and stomach, achieved good overall accuracy. However, prospective real-world studies comparing its performance with standard upper endoscopy are still needed to validate its clinical applicability.

Introduction

Prophylactic total gastrectomy (PTG) is the definitive treatment for hereditary diffuse gastric cancer syndrome (HDGC). Endoscopic surveillance informs the requirement and optimal timing to surgery. However, endoscopic recognition of early signet ring cell carcinoma (SRCC) remains challenging. In this study, we aimed to develop and prospectively validate a user-friendly diagnostic framework with machine-learning to support endoscopists in accurate identification of early SRCC during surveillance in HDGC individuals.

Aims & Methods

We retrospectively analysed 147 HDGC individuals undergoing endoscopic surveillance to evaluate the diagnostic accuracy of endoscopic criteria (Cambridge criteria), develop a clinical decision tree (cDT) to better apply the criteria based on machine leaning, and investigate its clinical significance. We then prospectively validated cDT in 66 CDH1 pathogenic-variant carriers. The inter-observer agreement and diagnostic accuracy of Cambridge criteria and cDT were assessed through multi-reader multi-case study.

Results

Retrospective analysis of 537 endoscopies showed Cambridge criteria achieved 82.8% (48/58) sensitivity and 78.2% (140/179) specificity for SRCC diagnosis. The presence and number of neoplastic pale areas are independent predictors of higher cancer burden in HDGC individuals. In prospective study, cDT had 77.8% (21/27) sensitivity and 90.7% (49/54) specificity. The cDT significantly improved average sensitivity among non-experts from 66.7% to 72.5% and 87.5%, and among experts from 74.1% to 80.0% and 91.7% (P = 0.03).

Conclusion

We developed and validated a practical endoscopic framework to enhance SRCC assessment during HDGC endoscopic surveillance.