QUAIDE - Quality assessment of AI preclinical studies in diagnostic endoscopy.

Artificial intelligence (AI) holds significant potential for enhancing quality of gastrointestinal (GI) endoscopy, but the adoption of AI in clinical practice is hampered by the lack of rigorous standardisation and development methodology ensuring generalisability. The aim of the Quality Assessment of pre-clinical AI studies in Diagnostic Endoscopy (QUAIDE) Explanation and Checklist was to develop recommendations for standardised design and reporting of preclinical AI studies in GI endoscopy.The recommendations were developed based on a formal consensus approach with an international multidisciplinary panel of 32 experts among endoscopists and computer scientists. The Delphi methodology was employed to achieve consensus on statements, with a predetermined threshold of 80% agreement. A maximum three rounds of voting were permitted.Consensus was reached on 18 key recommendations, covering 6 key domains: data acquisition and annotation (6 statements), outcome reporting (3 statements), experimental setup and algorithm architecture (4 statements) and result presentation and interpretation (5 statements). QUAIDE provides recommendations on how to properly design (1. Methods, statements 1-14), present results (2. Results, statements 15-16) and integrate and interpret the obtained results (3. Discussion, statements 17-18).The QUAIDE framework offers practical guidance for authors, readers, editors and reviewers involved in AI preclinical studies in GI endoscopy, aiming at improving design and reporting, thereby promoting research standardisation and accelerating the translation of AI innovations into clinical practice.

Risk of stricture after endoscopic submucosal dissection in the cervical esophagus and efficacy of local steroid injection for stricture prevention (with video).

BACKGROUND AND AIMS: There is a high incidence of stricture after endoscopic submucosal dissection (ESD) for cervical esophageal cancer. We aimed to elucidate the risk factors for stricture and to evaluate the efficacy of steroid injection for stricture prevention in the cervical esophagus. METHODS: We retrospectively analyzed 100 patients who underwent ESD for cervical esophageal cancer to (1) identify the factors associated with stricture among patients who did not receive steroid injection, and (2) compare the incidence of stricture between patients with and without steroid injection. RESULTS: Among 48 patients who did not receive steroid injection, there were significant differences in tumor size (P = .026), resection time (P = .028), and circumferential extent of the mucosal defect (P = .005) between patients with stricture (n = 5) and without stricture (n = 43). Compared with patients without steroid injection, patients with steroid injection had a significantly lower incidence of stricture when the post-ESD mucosal defect was <3/4 and ≥1/2 (40% versus 8%; P = .039). For the patients with a post-ESD mucosal defect of ≥3/4 (n = 13), local steroid injection was performed for all of them, and 6 (46%) developed stricture. CONCLUSIONS: Patients who underwent ≥1/2 circumferential resection were at high risk of cervical esophageal stricture. Steroid injection had a stricture prevention effect in patients with <3/4 and ≥1/2 circumferential resection, but seemed to be insufficient in preventing stricture in patients with ≥3/4 circumferential resection.

Randomized controlled trial of artificial intelligence diagnostic system in clinical practice to detect esophageal squamous cell carcinoma.

Background Artificial intelligence (AI) has made remarkable progress in image recognition using deep learning systems and has been used to detect esophageal squamous cell carcinoma (ESCC). However, all previous reports were not investigated in clinical settings, but in a retrospective design. Therefore, we conducted this trial to determine how AI can help endoscopists detect ESCC in clinical settings. Methods This was a prospective, single-center, exploratory, and randomized controlled trial. High-risk patients with ESCC undergoing screening or surveillance esophagogastroduodenoscopy were enrolled and randomly assigned to either the AI or control group. In the AI group, the endoscopists watched both the AI monitor detecting ESCC with annotation and the normal monitor simultaneously, whereas in the control group, the endoscopists watched only the normal monitor. In both groups, the endoscopists observed the esophagus using white-light imaging (WLI), followed by narrow-band imaging (NBI) and iodine staining. The primary endpoint was the enhanced detection rate of ESCC by non-experts using AI. The detection rate was defined as the ratio of WLI/NBI-detected ESCCs to all ESCCs detected by iodine staining. Results A total of 320 patients were included in this analysis. The detection rate of ESCC in non-experts was 47% in the AI group and 45% in the control group (p=0.93), with no significant difference, was similar to that in experts (87% vs. 57%, p=0.20) and all endoscopists (57% vs. 50%, p=0.70). Conclusions This study could not demonstrate an improvement in the esophageal cancer detection rate using the AI diagnostic support system for ESCC.

Evaluating the usefulness of considering the size and morphological type of type B2 vessel area based on Japan Esophageal Society classification in estimating tumor invasion depth in superficial esophageal squamous cell carcinomas: study protocol for a prospective observational study (Japan BEES study).

BACKGROUND: Accurate evaluation of tumor invasion depth is essential to determine the appropriate treatment strategy for patients with superficial esophageal cancer. The pretreatment tumor depth diagnosis currently relies on the magnifying endoscopic classification established by the Japan Esophageal Society (JES). However, the diagnostic accuracy of tumors involving the muscularis mucosa (MM) or those invading the upper third of the submucosal layer (SM1), which correspond to Type B2 vessels in the JES classification, remains insufficient. Previous retrospective studies have reported improved accuracy by considering additional findings, such as the size and macroscopic type of the Type B2 vessel area, in evaluating tumor invasion depth. Therefore, this study aimed to investigate whether incorporating the size and/or macroscopic type of the Type B2 vessel area improves the diagnostic accuracy of preoperative tumor invasion depth prediction based on the JES classification. METHODS: This multicenter prospective observational study will include patients diagnosed with MM/SM1 esophageal squamous cell carcinoma based on the Type B2 vessels of the JES classification. The tumor invasion depth will be evaluated using both the standard JES classification (standard-depth evaluation) and the JES classification with additional findings (hypothetical-depth evaluation) for the same set of patients. Data from both endoscopic depth evaluations will be electronically collected and stored in a cloud-based database before endoscopic resection or esophagectomy. This study's primary endpoint is accuracy, defined as the proportion of cases in which the preoperative depth diagnosis matched the histological depth diagnosis after resection. Outcomes of standard- and hypothetical-depth evaluation will be compared. DISCUSSION: Collecting reliable prospective data on the JES classification, explicitly concerning the B2 vessel category, has the potential to provide valuable insights. Incorporating additional findings into the in-depth evaluation process may guide clinical decision-making and promote evidence-based medicine practices in managing superficial esophageal cancer. TRIAL REGISTRATION: This trial was registered in the Clinical Trials Registry of the University Hospital Medical Information Network (UMIN-CTR) under the identifier UMIN000051145, registered on 23/5/2023.

Classification of fundic gland polyps for predicting gastric neoplasms in Helicobacter pylori-negative patients with familial adenomatous polyposis.

BACKGROUND: In familial adenomatous polyposis (FAP) patients, fundic gland polyps (FGPs) have been considered a risk factor for gastric neoplasms. We speculated that FGPs in FAP patients spread directionally from the greater to the lesser curvature of the gastric body and investigated the relationship between the distribution of FGPs and gastric neoplasm development. METHODS: We extracted 195 FAP patients from two institutions and reviewed their medical records. Gastric polyposis was classified based on the FGP distribution (P0, no FGPs; P1, localized in the fundus or greater curvature of the gastric body; P2, spreading to the anterior or posterior wall; P3, involving the proximal half of the lesser curvature; and P4, spreading from P3 to the anal side of the lesser curvature). RESULTS: The 195 eligible patients were divided into the neoplasm group (n = 54, 28%) and the non-neoplasm group (n = 141, 72%). Overall, 24% of the patients were Helicobacter pylori (H. pylori)-positive. In the FGP distribution, the rate of patients with gastric neoplasm tended to increase significantly with each step towards an increasingly wide distribution from P0 to P4 in H. pylori-negative patients, but not in H. pylori-positive ones. In addition, in H. pylori-negative patients, the likelihood of neoplasm increased consistently from P0 to P4, with the highest odds ratio (95% confidence interval) at P4 of 14.1 (2.5-154.4). Furthermore, multivariate analysis showed P4 and Spigelman stage ≥III were significantly associated with gastric neoplasm development. CONCLUSION: FGP distribution was correlated with gastric neoplasm development in FAP patients.

Endoscopic submucosal dissection for lesions developing in the irradiated area of head and neck cancer.

BACKGROUND AND AIM: Effective treatment of lesions that develop in the irradiated area of head and neck squamous cell carcinoma is a major concern. This study aimed to clarify the efficacy and safety of endoscopic resection for such lesions. METHODS: Among consecutive patients who underwent endoscopic resection for histologically proven head and neck squamous cell carcinoma between January 2014 and December 2021, those who received definitive radiotherapy/chemoradiotherapy before endoscopic resection were included in this single-center, retrospective study. Short- and long-term outcomes were evaluated. RESULTS: Among 422 patients who underwent endoscopic resection for 615 lesions, 43 patients with 57 lesions were eligible. All 57 lesions were treated with endoscopic submucosal dissection and en bloc resection was achieved in all lesions. Grade 3 of Common Toxicity Criteria for Adverse Events v5.0 occurred in eight (19%) patients (dysphagia, seven; stricture, three; aspiration pneumonia, two; and pharyngeal necrosis, one [some cases overlapped]), but no grade ≥ 4 events occurred. Enteral nutrition by gastrostomy was temporarily required in two patients owing to dysphagia and laryngeal necrosis. During the median follow-up of 40 (interquartile range, 29.5-61) months after endoscopic submucosal dissection for the lesions developed in the irradiated area, local recurrence and metachronous lesions developed in two (5%) and nine (21%) patients, respectively. However, total laryngectomies and tracheostomies were avoided in all patients. The 3-year overall and disease-specific survivals were 81% (95% confidence interval, 64%-91%) and 94% (95% confidence interval, 79%-99%), respectively. CONCLUSIONS: Favorable local control and safety of endoscopic submucosal dissection were demonstrated.

Gastro-esophageal diagnostic workup before bariatric surgery or endoscopic treatment for obesity: position statement of the International Society of Diseases of the Esophagus.

Obesity is a chronic and multifactorial condition characterized by abnormal weight gain due to excessive adipose tissue accumulation that represents a growing worldwide challenge for public health. In addition, obese patients have an increased risk of hiatal hernia, esophageal, and gastric dysfunction, as well as gastroesophageal reflux disease, which has a prevalence over 40% in those seeking endoscopic or surgical intervention. Surgery has been demonstrated to be the most effective treatment for severe obesity in terms of long-term weight loss, comorbidities, and quality of life improvements and overall mortality decrease. The recent emergence of bariatric endoscopic techniques promises less invasive, more cost-effective, and reproducible approaches to the treatment of obesity. With the endorsement of the International Society for Diseases of the Esophagus, we started a Delphi process to develop consensus statements on the most appropriate diagnostic workup to preoperatively assess gastroesophageal function before bariatric surgical or endoscopic interventions. The Consensus Working Group comprised 11 international experts from five countries. The group consisted of gastroenterologists and surgeons with a large expertise with regard to gastroesophageal reflux disease, bariatric surgery and endoscopy, and physiology. Ten statements were selected, on the basis of the agreement level and clinical relevance, which represent an evidence and experience-based consensus of the International Society for Diseases of the Esophagus.

Multiple foci of dilated vessels as a new predictor of metachronous esophageal cancer.

OBJECTIVES: Prediction of the risk of esophageal squamous cell carcinoma (SCC) by endoscopic findings without iodine staining, which is irritating to the esophagus, would be beneficial. In a previous retrospective study, we found that multiple foci of dilated vascular areas (MDV) of the esophageal mucosa, seen in narrow-band imaging (NBI)/blue laser imaging (BLI), are associated with iodine-unstained lesions and, thus, may be a predictor of esophageal SCC. This prospective study aimed to investigate the association between MDV and metachronous esophageal SCC. METHODS: Patients with a history of endoscopic resection for esophageal SCC were included in the study. First, evaluation of the MDV using NBI or BLI was conducted during the initial endoscopy. The patients were then monitored for metachronous esophageal SCC by endoscopic surveillance. The association between the number of MDV and incidence of metachronous esophageal SCC was investigated. RESULTS: From February 2018 to May 2019, 206 patients were enrolled and 201 patients were included in the analysis. Patients were followed up until October 2022. The median (interquartile range) endoscopic follow-up period was 1260 (1105-1348) days. The incidence of metachronous esophageal SCC at 2 years was 7.1% in patients with MDV ≤4 and 13.9% in patients with MDV ≥5 (P < 0.01). In the multivariate analysis, MDV was an independent predictor of metachronous esophageal SCC, with an odds ratio (95% confidence interval) of 2.37 (1.06-5.31). CONCLUSION: Multiple foci of dilated vascular area is a useful predictor for stratifying the risk of metachronous esophageal SCC.

First-line pembrolizumab plus chemotherapy for advanced/metastatic esophageal cancer: 1-year extended follow-up in the Japanese subgroup of the phase 3 KEYNOTE-590 study.

BACKGROUND: First-line pembrolizumab plus chemotherapy (pembrolizumab-chemotherapy) demonstrated improved efficacy and a manageable safety profile versus placebo plus chemotherapy (placebo-chemotherapy) in the subgroup analysis of Japanese patients with advanced/metastatic esophageal cancer in KEYNOTE-590 at a median follow-up of 24.4 months. Longer-term data from the Japanese subgroup analysis of KEYNOTE-590 are reported. METHODS: Patients were randomly assigned 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for ≤ 35 cycles plus chemotherapy (cisplatin 80 mg/m2 and 5-fluorouracil 800 mg/m2/day). Endpoints included overall survival (OS) and progression-free survival (PFS; investigator-assessed per RECIST v1.1; dual primary) and safety (secondary). Early tumor shrinkage (ETS) and depth of response (DpR) were assessed post hoc. RESULTS: Overall, 141 patients were enrolled in Japan. As of July 9, 2021, median follow-up was 36.6 months (range, 29.8-45.7). Pembrolizumab-chemotherapy showed a trend toward favorable OS (hazard ratio [HR], 0.70; 95% confidence interval [CI] 0.47-1.03) and PFS (0.57; 0.39-0.83) versus placebo-chemotherapy. In the pembrolizumab-chemotherapy group, patients with ETS ≥ 20% (55/74; 74.3%) versus < 20% (19/74; 25.7%) had favorable OS (HR, 0.23; 95% CI 0.12-0.42) and PFS (0.24; 0.13-0.43). Patients with DpR ≥ 60% (31/74; 41.9%) versus < 60% (43/74; 58.1%) had favorable OS (HR, 0.37; 95% CI 0.20-0.68) and PFS (0.24; 0.13-0.43). Grade 3-5 treatment-related adverse events occurred in 55/74 patients (74.3%) with pembrolizumab-chemotherapy and 41/67 patients (61.2%) with placebo-chemotherapy. CONCLUSIONS: With longer-term follow-up of Japanese patients with advanced/metastatic esophageal cancer, efficacy continued to favor pembrolizumab-chemotherapy compared with placebo-chemotherapy, with no new safety signals observed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03189719.

Evaluating the discrepancies between evidence-based and community standard practices in the endoscopic diagnosis of esophageal squamous cell carcinoma: a survey study.

BACKGROUND: The practice of endoscopic diagnosis of esophageal squamous cell carcinoma (ESCC) often diverges from evidence-based standards due to various factors, including inadequate dissemination of evidence or a mismatch between evidence and real-world contexts. This survey aimed to identify discrepancies between evidence-based standard practices and community standard practices for ESCC among endoscopists. METHODS: An online survey targeting endoscopists who perform upper gastrointestinal endoscopy at least weekly was conducted to collect data on clinical practices related to ESCC diagnosis. The survey, comprising 20 questions, was disseminated through multiple professional networks. Descriptive statistical analysis and logistic regression were performed to analyze the data. RESULTS: Data from 819 endoscopists were included in the analyses. Notably, a significant proportion employed narrow-band imaging/blue-laser imaging over iodine staining, and preferences varied based on risk assessment for ESCC. In total, 64.0% of endoscopists primarily used iodine solution at a concentration of 1% or less, while 96.5% of endoscopists performed an observation of the oral cavity and the pharynx when conducting upper gastrointestinal endoscopies on individuals at high risk of ESCC. The surveillance interval for metachronous multiple ESCCs was most commonly every 6 months, followed by every 12 months. In addition, most physicians conducted surveillance of metastatic recurrence at 6-month intervals. CONCLUSIONS: This survey highlights significant gaps between evidence-based and community standard practices in the endoscopic diagnosis of ESCC. These findings underscore the need for enhanced dissemination of evidence-based guidelines and consideration of real-world clinical contexts to bridge these gaps and optimize patient care.

Multicenter retrospective analysis of complications and risk factors in endoscopic resection for esophageal cancer across Japan.

BACKGROUND: Endoscopic resection (ER) is a minimally invasive treatment for esophageal cancer that sometimes causes complications. To understand the real-world incidence and risk factors for these complications, a nationwide survey was conducted across Japan. METHODS: This retrospective multicenter study included patients who underwent ER for esophageal cancer from April 2017 to March 2018 (2017 complication analysis) and April 2021 to March 2022 (2021 complication analysis). The study assessed the complication rates and conducted risk factor analyses for endoscopic submucosal dissection (ESD) using data for these patients, with exclusions based on specific criteria to ensure data accuracy. RESULTS: In the 2021 complication analysis, there were two mortalities highly likely attributable (0.03%) to ER and one mortality possibly attributable (0.01%) to ER. Intraoperative perforation, delayed bleeding, and pneumonia occurred in 137 cases (1.8%), 44 cases (0.6%), and 130 cases (1.7%), respectively. In the multivariate analysis for complications after ESD, low ER volume of the facility was an independent risk factor for perforation, while lesion location in the cervical or upper thoracic esophagus was an independent factor for reduced risk of perforation. Age ≥ 80 years was a risk factor for pneumonia, while use of traction techniques was a factor for reduced risk of pneumonia. Lesions located in the middle thoracic esophagus had a lower risk of stricture, and the risk of stricture increased as the circumferential extent of the lesion increased. CONCLUSIONS: This large-scale study provided detailed insights into the complications associated with esophageal ER and identified significant risk factors.

A simpler diagnostic algorithm of the Japan Esophageal Society classification for Barrett's esophagus-related superficial neoplasia.

BACKGROUND: We previously developed a Japan Esophageal Society Barrett's Esophagus (JES-BE) magnifying endoscopic classification for superficial BE-related neoplasms (BERN) and validated it in a nationwide multicenter study that followed a diagnostic flow chart based on mucosal and vascular patterns (MP, VP) with nine diagnostic criteria. Our present post hoc analysis aims to further simplify the diagnostic criteria for superficial BERN. METHODS: We used data from our previous study, including 10 reviewers' assessments for 156 images of high-magnifying narrow-band imaging (HM-NBI) (67 dysplastic and 89 non-dysplastic histology). We statistically analyzed the diagnostic performance of each diagnostic criterion of MP (form, size, arrangement, density, and white zone), VP (form, caliber change, location, and greenish thick vessels [GTV]), and all their combinations to achieve a simpler diagnostic algorithm to detect superficial BERN. RESULTS: Diagnostic accuracy values based on the MP of each single criterion or combined criteria showed a marked trend of being higher than those based on VP. In reviewers' assessments of visible MPs, the combination of irregularity for form, size, or white zone had the highest diagnostic performance, with a sensitivity of 87% and a specificity of 91% for dysplastic histology; in the assessments of invisible MPs, GTV had the highest diagnostic performance among the VP of each single criterion and all combinations of two or more criteria (sensitivity, 93%; specificity, 92%). CONCLUSION: The present post hoc analysis suggests the feasibility of further simplifying the diagnostic algorithm of the JES-BE classification. Further studies in a practical setting are required to validate these results.

Predictors of technical difficulty for trainees in esophageal endoscopic submucosal dissection.

BACKGROUND: Esophageal endoscopic submucosal dissection (ESD) is technically challenging, especially for trainees, and requires a safe training system. This study aimed to identify predictors of technical difficulty facing trainees performing esophageal ESD to establish such system. METHODS: This was a single-center retrospective study of patients with esophageal cancer who underwent ESD performed by trainees between January 2010 and August 2022. Technical difficulties were defined as muscularis propria exposure and long procedure time (≥ 90 min). Factors associated with these technical difficulties were investigated. RESULTS: A total of 798 lesions in 721 patients were evaluated. Muscularis propria exposure occurred in 298 lesions (37.3%), including 10 perforations (1.3%). The procedure time was ≥ 90 min in 134 lesions (16.8%). In the multivariate analysis, tumor size ≥ 20 mm, tumors ≥ 1/2 of the circumference, and those close to previous treatment scars significantly increased the incidence of both difficulties, whereas tumors in the upper esophagus significantly decreased this incidence. Furthermore, female sex and tumors in the left wall were independent predictors of muscularis propria exposure, and elevated morphology was an independent predictor of long procedure time. Muscularis propria exposure and long procedure time occurred in more than half of the cases with three or more predictors of each difficulty. CONCLUSIONS: Large tumors and tumors close to previous treatment scars increase technical difficulties for trainees in esophageal ESD. Conversely, tumors in the upper esophagus reduce these difficulties. These results enable us to predict the difficulty level preoperatively and select appropriate cases in stepwise training.

Remarkable response as a new indicator for endoscopic evaluation of local efficacy of non-surgical treatments for esophageal cancer.

In Japan, standard of care of the patients with resectable esophageal cancer is neoadjuvant chemotherapy (NAC) followed by esophagectomy. Patients unfitted for surgery or with unresectable locally advanced esophageal cancer are generally indicated with definitive chemoradiotherapy (CRT). Local disease control is undoubtful important for the management of patients with esophageal cancer, therefore endoscopic evaluation of local efficacy after non-surgical treatments must be essential. The significant shrink of primary site after NAC has been reported as a good indicator of pathological good response as well as favorable survival outcome after esophagectomy. And patients who could achieve remarkable shrink to T1 level after CRT had favorable outcomes with salvage surgery and could be good candidates for salvage endoscopic treatments. Based on these data, "Japanese Classification of Esophageal Cancer, 12th edition" defined the new endoscopic criteria "remarkable response (RR)", that means significant volume reduction after treatment, with the subjective endoscopic evaluation are proposed. In addition, the finding of local recurrence (LR) at primary site after achieving a CR was also proposed in the latest edition of Japanese Classification of Esophageal Cancer. The findings of LR are also important for detecting candidates for salvage endoscopic treatments at an early timing during surveillance after CRT. The endoscopic evaluation would encourage us to make concrete decisions for further treatment indications, therefore physicians treating patients with esophageal cancer should be well-acquainted with each finding.

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study.

BACKGROUND: The options for first-line treatment of advanced oesophageal squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1 antibody, tislelizumab, has shown antitumour activity in previously treated patients with advanced oesophageal squamous cell carcinoma. We report interim analysis results from the RATIONALE-306 study, which aimed to assess tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma. METHODS: This global, randomised, double-blind, parallel-arm, placebo-controlled, phase 3 study was conducted at 162 medical centres across Asia, Europe, Oceania, and North America. Patients (aged ≥18 years) with unresectable, locally advanced, recurrent or metastatic oesophageal squamous cell carcinoma (regardless of PD-L1 expression), Eastern Cooperative Oncology Group performance status of 0-1, and measurable or evaluable disease per Response Evaluation Criteria in Solid Tumours (version 1.1) were recruited. Patients were randomly assigned (1:1), using permuted block randomisation (block size of four) and stratified by investigator-chosen chemotherapy, region, and previous definitive therapy, to tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet, comprising a platinum agent (cisplatin 60-80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1) plus a fluoropyrimidine (fluorouracil [750-800 mg/m2 intravenously on days 1-5] or capecitabine [1000 mg/m2 orally twice daily on days 1-14]) or paclitaxel (175 mg/m2 intravenously on day 1). Treatment was continued until disease progression or unacceptable toxicity. Investigators, patients, and sponsor staff or designees were masked to treatment. The primary endpoint was overall survival. The efficacy analysis was done in the intention-to-treat population (ie, all randomly assigned patients) and safety was assessed in all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03783442. FINDINGS: Between Dec 12, 2018, and Nov 24, 2020, 869 patients were screened, of whom 649 were randomly assigned to tislelizumab plus chemotherapy (n=326) or placebo plus chemotherapy (n=323). Median age was 64·0 years (IQR 59·0-69·0), 563 (87%) of 649 participants were male, 86 (13%) were female, 486 (75%) were Asian, and 155 (24%) were White. 324 (99%) of 326 patients in the tislelizumab group and 321 (99%) of 323 in the placebo group received at least one dose of the study drug. As of data cutoff (Feb 28, 2022), median follow-up was 16·3 months (IQR 8·6-21·8) in the tislelizumab group and 9·8 months (IQR 5·8-19·0) in the placebo group, and 196 (60%) of 326 patients in the tislelizumab group versus 226 (70%) of 323 in the placebo group had died. Median overall survival in the tislelizumab group was 17·2 months (95% CI 15·8-20·1) and in the placebo group was 10·6 months (9·3-12·1; stratified hazard ratio 0·66 [95% CI 0·54-0·80]; one-sided p<0·0001). 313 (97%) of 324 patients in the tislelizumab group and 309 (96%) of 321 in the placebo group had treatment-related treatment-emergent adverse events. The most common grade 3 or 4 treatment-related treatment-emergent adverse events were decreased neutrophil count (99 [31%] in the tislelizumab group vs 105 [33%] in the placebo group), decreased white blood cell count (35 [11%] vs 50 [16%]), and anaemia (47 [15%] vs 41 [13%]). Six deaths in the tislelizumab group (gastrointestinal and upper gastrointestinal haemorrhage [n=2], myocarditis [n=1], pulmonary tuberculosis [n=1], electrolyte imbalance [n=1], and respiratory failure [n=1]) and four deaths in the placebo group (pneumonia [n=1], septic shock [n=1], and unspecified death [n=2]) were determined to be treatment-related. INTERPRETATION: Tislelizumab plus chemotherapy as a first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy. Given that the interim analysis met its superiority boundary for the primary endpoint, as confirmed by the independent data monitoring committee, this Article represents the primary study analysis. FUNDING: BeiGene.

Genotype-phenotype correlation for extracolonic aggressive phenotypes in patients with familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) patients develop various life-threatening extracolonic comorbidities that appear individually or within a family. This diversity can be explained by the localization of the adenomatous polyposis coli (APC) variant, but few reports provide definitive findings about genotype-phenotype correlations. Therefore, we investigated FAP patients and the association between the severe phenotypes and APC variants. Of 247 FAP patients, 126 patients from 85 families identified to have APC germline variant sites were extracted. These sites were divided into six groups (Regions A to F), and the frequency of severe comorbidities was compared among the patient phenotypes. Of the 126 patients, the proportions of patients with desmoid tumor stage ≥III, number of FGPs ≥1000, multiple gastric neoplasms, gastric neoplasm with high-grade dysplasia, and Spigelman stage ≥III were 3%, 16%, 21%, 12%, and 41%, respectively, while the corresponding rates were 30%, 50%, 70%, 50%, and 80% in patients with Region E (codons 1398-1580) variants. These latter rates were significantly higher than those for patients with variants in other regions. Moreover, the proportion of patients with all three indicators (desmoid tumor stage ≥III, number of FGPs ≥1000, and Spigelman stage ≥III) was 20% for those with variants in Region E and 0% for those with variants in other regions. Variants in Region E indicate aggressive phenotypes, and more intensive management is required.

Predictors of stricture after non-circumferential endoscopic submucosal dissection of the esophagus and single-dose triamcinolone injection immediately after the procedure.

BACKGROUND AND AIMS: Local triamcinolone (TA) injection is widely used to prevent stricture formation after endoscopic submucosal dissection (ESD). However, stricture develops in up to 45% of patients despite this prophylactic measure. We therefore conducted a single-center prospective study to identify predictors of stricture after esophageal ESD and local TA injection. METHODS: Patients who underwent esophageal ESD and local TA injection and who were comprehensively assessed for lesion- and ESD-related factors were included in the study. Multivariate analyses were conducted to identify the predictors of stricture. RESULTS: A total of 203 patients were included in the analysis. Multivariate analysis identified residual mucosal width ≤5 mm (odds ratio [OR], 29.0; P < .0001) or 6 to 10 mm (OR, 3.7; P = .04), history of chemoradiotherapy (OR, 5.1; P = .045), and tumor in the cervical or upper thoracic esophagus (OR, 3.8; P = .018) as independent predictors of stricture. Based on the ORs of the predictors, patients were stratified into 2 groups according to stricture risk: patients in the high-risk group (residual mucosal width ≤5 mm or 6-10 mm with another predictor) had a stricture rate of 52.5% (31 of 59 cases), and patients in the low-risk group (residual mucosal width ≥11 mm or 6-10 mm without other predictors) had a stricture rate of 6.3% (9 of 144 cases). CONCLUSIONS: We identified predictors of stricture after ESD and local TA injection. Local TA injection prevented stricture formation after ESD in low-risk patients but was not sufficient to prevent stricture in high-risk patients. Additional interventions should thus be considered in high-risk patients. (University Hospital Medical Network Clinical Trials Registry number: UMIN 000028894.).

Efficacy and safety of intensive downstaging polypectomy (IDP) for multiple duodenal adenomas in patients with familial adenomatous polyposis: a prospective cohort study.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) risk developing multiple duodenal adenomas (MDAs), leading to duodenal cancer and death. We investigated the efficacy and safety of intensive downstaging polypectomy (IDP) for MDAs integrated with new-generation procedures. METHODS: This prospective phase II study, conducted at a tertiary cancer center, enrolled patients with FAP who had MDAs. We performed IDP including cold snare/forceps polypectomy (CSP/CFP) and underwater endoscopic mucosal resection (UEMR). The primary end point was the downstaging of Spigelman stage at 1-year follow-up. RESULTS: 2424 duodenal polyps in 58 patients with FAP underwent IDP, including 2413 CSPs in 57 patients, seven CFPs in one patient, and four UEMRs in four patients. Only one major adverse event was observed (grade 3 hyperamylasemia) without clinical manifestations. We performed additional UEMR, CSP, and CFP for one, 12, and 22 patients, respectively, during initial follow-up. Overall, 55 patients completed protocol examination; the Spigelman stage was significantly reduced at the 1-year follow-up endoscopy (P < 0.001), with downstaging observed in 39 patients (71 %). Among the 26 patients with Spigelman stage IV at initial examination and protocol completion, 23 (88 %) showed downstaging. There was no major change in Spigelman stages from 1-year follow-up esophagogastroduodenoscopy to a median of 37 months (range 3-56). CONCLUSIONS: IDP, including new-generation procedures, showed significant downstaging with acceptable adverse events for MDA in patients with FAP, even those with advanced-stage disease. Lesion selection for different resection techniques may be important for suitable and sustainable management of MDA in patients with FAP.

A single-center prospective study evaluating the usefulness of artificial intelligence for the diagnosis of esophageal squamous cell carcinoma in a real-time setting.

BACKGROUND: Several pre-clinical studies have reported the usefulness of artificial intelligence (AI) systems in the diagnosis of esophageal squamous cell carcinoma (ESCC). We conducted this study to evaluate the usefulness of an AI system for real-time diagnosis of ESCC in a clinical setting. METHODS: This study followed a single-center prospective single-arm non-inferiority design. Patients at high risk for ESCC were recruited and real-time diagnosis by the AI system was compared with that of endoscopists for lesions suspected to be ESCC. The primary outcomes were the diagnostic accuracy of the AI system and endoscopists. The secondary outcomes were sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and adverse events. RESULTS: A total of 237 lesions were evaluated. The accuracy, sensitivity, and specificity of the AI system were 80.6%, 68.2%, and 83.4%, respectively. The accuracy, sensitivity, and specificity of endoscopists were 85.7%, 61.4%, and 91.2%, respectively. The difference between the accuracy of the AI system and that of the endoscopists was - 5.1%, and the lower limit of the 90% confidence interval was less than the non-inferiority margin. CONCLUSIONS: The non-inferiority of the AI system in comparison with endoscopists in the real-time diagnosis of ESCC in a clinical setting was not proven. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs052200015, 18/05/2020).

Endoscopic features of gastric neuroendocrine carcinoma.

BACKGROUND AND AIM: The endoscopic features of gastric neuroendocrine carcinoma (G-NEC) have not been clarified; therefore, they were investigated in relation to clinicopathological findings. METHODS: Consecutive patients with G-NECs who had undergone endoscopic or surgical resection at our institution between January 2005 and March 2022 were included in this retrospective study. The endoscopic and clinicopathological findings of the lesions were analyzed to provide information of diagnostic value. In addition, cases of gastric neuroendocrine tumor (G-NET) and common-type gastric adenocarcinoma treated in the same study period were identified to compare the endoscopic findings between each G-NEC versus G-NET, and G-NEC versus common-type gastric adenocarcinoma. Patients with common-type gastric adenocarcinoma were matched for age, sex, tumor size, and depth of tumor invasion in 1:3 ratio. RESULTS: Among 15 patients with 15 G-NECs, submucosal tumor-like marginal elevation (87%), adherent white coat (67%), and ulceration with a distinct border (60%) were characteristic endoscopic findings in white-light images. Magnifying narrow-band imaging endoscopy revealed an absent microsurface (MS) pattern plus disrupted irregular microvessel (MV) in five (71%) of seven cases with evaluable MS and MV patterns. The area with an absent MS pattern plus disrupted irregular MV corresponded to the histological finding of NEC component in all five cases. These endoscopic features were all significantly more frequent in G-NECs than G-NETs (n = 22) or common-type gastric adenocarcinomas (n = 45). CONCLUSIONS: These endoscopic features should be taken into consideration to increase the index of suspicion and to improve the accuracy of target biopsies for G-NEC.