Latest Advances in Endoscopic Detection of Oesophageal and Gastric Neoplasia.

Endoscopy is the gold standard for the diagnosis of cancers and cancer precursors in the oesophagus and stomach. Early detection of upper GI cancers requires high-quality endoscopy and awareness of the subtle features these lesions carry. Endoscopists performing surveillance of high-risk patients including those with Barrett's oesophagus, previous squamous neoplasia or chronic atrophic gastritis should be familiar with endoscopic features, classification systems and sampling techniques to maximise the detection of early cancer. In this article, we review the current approach to diagnosis of these conditions and the latest advanced imaging and diagnostic techniques.

Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer.

Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.

Complications of diagnostic upper Gastrointestinal endoscopy: common and rare - recognition, assessment and management.

A clear understanding of the potential complications or adverse events (AEs) of diagnostic endoscopy is an essential component of being an endoscopist. Creating a culture of safety and prevention of AEs should be part of routine endoscopy practice. Appropriate patient selection for procedures, informed consent, periprocedure risk assessments and a team approach, all contribute to reducing AEs. Early recognition, prompt management and transparent communication with patients are essential for the holistic and optimal management of AEs. In this review, we discuss the complications of diagnostic upper gastrointestinal endoscopy, including their recognition, treatment and prevention.

A digital pathology workflow for the segmentation and classification of gastric glands: Study of gastric atrophy and intestinal metaplasia cases.

Gastric cancer is one of the most frequent causes of cancer-related deaths worldwide. Gastric atrophy (GA) and gastric intestinal metaplasia (IM) of the mucosa of the stomach have been found to increase the risk of gastric cancer and are considered precancerous lesions. Therefore, the early detection of GA and IM may have a valuable role in histopathological risk assessment. However, GA and IM are difficult to confirm endoscopically and, following the Sydney protocol, their diagnosis depends on the analysis of glandular morphology and on the identification of at least one well-defined goblet cell in a set of hematoxylin and eosin (H&E) -stained biopsy samples. To this end, the precise segmentation and classification of glands from the histological images plays an important role in the diagnostic confirmation of GA and IM. In this paper, we propose a digital pathology end-to-end workflow for gastric gland segmentation and classification for the analysis of gastric tissues. The proposed GAGL-VTNet, initially, extracts both global and local features combining multi-scale feature maps for the segmentation of glands and, subsequently, it adopts a vision transformer that exploits the visual dependences of the segmented glands towards their classification. For the analysis of gastric tissues, segmentation of mucosa is performed through an unsupervised model combining energy minimization and a U-Net model. Then, features of the segmented glands and mucosa are extracted and analyzed. To evaluate the efficiency of the proposed methodology we created the GAGL dataset consisting of 85 WSI, collected from 20 patients. The results demonstrate the existence of significant differences of the extracted features between normal, GA and IM cases. The proposed approach for gland and mucosa segmentation achieves an object dice score equal to 0.908 and 0.967 respectively, while for the classification of glands it achieves an F1 score equal to 0.94 showing great potential for the automated quantification and analysis of gastric biopsies.

Tertiary lymphoid structures (TLS) identification and density assessment on H&E-stained digital slides of lung cancer.

Tertiary lymphoid structures (TLS) are ectopic aggregates of lymphoid cells in inflamed, infected, or tumoral tissues that are easily recognized on an H&E histology slide as discrete entities, distinct from lymphocytes. TLS are associated with improved cancer prognosis but there is no standardised method available to quantify their presence. Previous studies have used immunohistochemistry to determine the presence of specific cells as a marker of the TLS. This has now been proven to be an underestimate of the true number of TLS. Thus, we propose a methodology for the automated identification and quantification of TLS, based on H&E slides. We subsequently determined the mathematical criteria defining a TLS. TLS regions were identified through a deep convolutional neural network and segmentation of lymphocytes was performed through an ellipsoidal model. This methodology had a 92.87% specificity at 95% sensitivity, 88.79% specificity at 98% sensitivity and 84.32% specificity at 99% sensitivity level based on 144 TLS annotated H&E slides implying that the automated approach was able to reproduce the histopathologists' assessment with great accuracy. We showed that the minimum number of lymphocytes within TLS is 45 and the minimum TLS area is 6,245µm2. Furthermore, we have shown that the density of the lymphocytes is more than 3 times those outside of the TLS. The mean density and standard deviation of lymphocytes within a TLS area are 0.0128/µm2 and 0.0026/µm2 respectively compared to 0.004/µm2 and 0.001/µm2 in non-TLS regions. The proposed methodology shows great potential for automated identification and quantification of the TLS density on digital H&E slides.

Recent advances in the detection and management of early gastric cancer and its precursors.

Despite declines in incidence, gastric cancer remains a disease with a poor prognosis and limited treatment options due to its often late stage of diagnosis. In contrast, early gastric cancer has a good to excellent prognosis, with 5-year survival rates as high as 92.6% after endoscopic resection. There remains an East-West divide for this disease, with high incidence countries such as Japan seeing earlier diagnoses and reduced mortality, in part thanks to the success of a national screening programme. With missed cancers still prevalent at upper endoscopy in the West, and variable approaches to assessment of the high-risk stomach, the quality of endoscopy we provide must be a focus for improvement, with particular attention paid to the minority of patients at increased cancer risk. High-definition endoscopy with virtual chromoendoscopy is superior to white light endoscopy alone. These enhanced imaging modalities allow the experienced endoscopist to accurately and robustly detect high-risk lesions in the stomach. An endoscopy-led staging strategy would mean biopsies could be targeted to histologically confirm the endoscopic impression of premalignant lesions including atrophic gastritis, gastric intestinal metaplasia, dysplasia and early cancer. This approach to quality improvement will reduce missed diagnoses and, combined with the latest endoscopic resection techniques performed at expert centres, will improve early detection and ultimately patient outcomes. In this review, we outline the latest evidence relating to diagnosis, staging and treatment of early gastric cancer and its precursor lesions.

Accuracy of endoscopic staging and targeted biopsies for routine gastric intestinal metaplasia and gastric atrophy evaluation study protocol of a prospective, cohort study: the estimate study.

INTRODUCTION: Patients with chronic atrophic gastritis (CAG) and intestinal metaplasia (IM) are at risk of developing gastric adenocarcinoma. Their diagnosis and management currently rely on histopathological guidance after random endoscopic biopsy sampling (Sydney biopsy strategy). This approach has significant flaws such as under-diagnosis, poor reproducibility and poor correlation between endoscopy and histology. This prospective, international multicentre study aims to establish whether endoscopy-led risk stratification accurately and reproducibly predicts CAG and IM extent and disease stage. METHODS AND ANALYSIS: Patients with CAG and/or IM on standard white light endoscopy (WLE) will be prospectively identified and invited to undergo a second endoscopy performed by an expert endoscopist using enhanced endoscopic imaging techniques with virtual chromoendoscopy. Extent of CAG/IM will be endoscopically staged with enhanced imaging and compared with standard WLE. Histopathological risk stratification through targeted biopsies will be compared with endoscopic disease staging and to random biopsy staging on WLE as a reference. At least 234 patients are required to show a 10 % difference in sensitivity and accuracy between enhanced imaging endoscopy-led staging and the current biopsy-led staging protocol of gastric atrophy with a power (beta) of 80 % and a 0.05 probability of a type I error (alpha). ETHICS AND DISSEMINATION: The study was approved by the respective Institutional Review Boards (Netherlands: MEC-2018-078; UK: 19/LO/0089). The findings will be published in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NTR7661; Pre-results.

The evolving role of endoscopy in the diagnosis of premalignant gastric lesions.

Gastric adenocarcinoma is a disease that is often detected late, at a stage when curative treatment is unachievable. This must be addressed through changes in our approach to the identification of patients at increased risk by improving the detection and risk assessment of premalignant changes in the stomach, including chronic atrophic gastritis and intestinal metaplasia. Current guidelines recommend utilising random biopsies in a pathology-led approach in order to stage the extent and severity of gastritis and intestinal metaplasia. This random method is poorly reproducible and prone to sampling error and fails to acknowledge recent advances in our understanding of the progression to gastric cancer as a non-linear, branching evolutionary model. Data suggest that recent advances in endoscopic imaging modalities, such as narrow band imaging, can achieve a high degree of accuracy in the stomach for the diagnosis of these premalignant changes. In this review, we outline recent data to support a paradigm shift towards an endoscopy-led approach to diagnosis and staging of premalignant changes in the stomach. High-quality endoscopic interrogation of the chronically inflamed stomach mucosa, supported by targeted biopsies, will lead to more accurate risk assessment, with reduced rates of under or missed diagnoses.

Risk of lymph node metastases in patients with T1b oesophageal adenocarcinoma: A retrospective single centre experience.

AIM: To assess clinical outcomes for submucosal (T1b) oesophageal adenocarcinoma (OAC) patients managed with either surgery or endoscopic eradication therapy. METHODS: Patients found to have T1b OAC following endoscopic resection between January 2008 to February 2016 at University College London Hospital were retrospectively analysed. Patients were split into low-risk and high-risk groups according to established histopathological criteria and were then further categorised according to whether they underwent surgical resection or conservative management. Study outcomes include the presence of lymph-node metastases, disease-specific mortality and overall survival. RESULTS: A total of 60 patients were included; 22 patients were surgically managed (1 low-risk and 21 high-risk patients) whilst 38 patients were treated conservatively (12 low-risk and 26 high-risk). Overall, lymph node metastases (LNM) were detected in 10 patients (17%); six of these patients had undergone conservative management and LNM were detected at a median of 4 mo after endoscopic mucosal resection (EMR). All LNM occurred in patients with high-risk lesions and this represented 21% of the total high-risk lesions. Importantly, there was no statistically significant difference in tumor-related deaths between those treated surgically or conservatively (P = 0.636) and disease-specific survival time was also comparable between the two treatment strategies (P = 0.376). CONCLUSION: T1b tumours without histopathological high-risk markers of LNM can be treated endoscopically with good out-comes. In selected patients, endoscopic therapy may be appropriate for high-risk lesions.