Evolution of Systemic Treatment for Hepatocellular Carcinoma: Changing Treatment Strategies and Concepts.

Systemic therapy for hepatocellular carcinoma (HCC) has undergone substantial advancements. With the advent of atezolizumab plus bevacizumab (ATZ/BEV) combination therapy, followed by durvalumab plus tremelimumab, the era of immunotherapy for HCC has commenced. The emergence of systemic treatment with high response rates has led to improvements in overall survival while enabling conversion to radical surgical resection in some patients with HCC. In patients with intermediate-stage HCC, new treatment strategies combining systemic treatment and transcatheter arterial chemoembolization (TACE) are under development in clinical trials. Moreover, the addition of local therapies, such as TACE, to systemic treatment according to the treatment effect could achieve a certain percentage of complete response. In the IMbrave050 trial, the efficacy of ATZ/BEV combination therapy was validated in patients predicted to have a high risk of recurrence, especially in those who had undergone radical surgery or radiofrequency ablation for HCC. Therefore, systemic treatment for HCC is entering a new phase for all disease stages. The objective of this review is to organize the current position of systemic therapy for each HCC stage and discuss the development of new treatment methods and strategies, with a focus on regimens incorporating immune checkpoint inhibitors, along with future prospects.

Efficacy of Two Kinds of Scissor-Type Knives for Colorectal Endoscopic Submucosal Dissection: A Retrospective Comparative Study.

INTRODUCTION: Scissor-type knives are spreading as safe devises in endoscopic submucosal dissection (ESD). We evaluated the efficacy of two kinds of scissor-type knives (Clutch Cutter: CC, Fujifilm Co. and SB Knife Jr2: SB, SB-KAWASUMI Laboratories. Inc.) in colorectal ESD. METHODS: This single-center retrospective study analyzed 178 ESD cases treated with CC from January 2020 to August 2021 and 91 cases with SB from September 2021 to December 2023. The two groups were compared through propensity score matching. Therapeutic results, such as ESD procedure time, en bloc resection rate, perioperative bleeding frequency, and complications, were analyzed in each group. Risk factors for long ESD procedure time (≥ 90 min) were also examined. RESULTS: After matching, 87 cases in each group were analyzed. There was no significant difference in the ESD procedure time (min, median [interquartile range]) between the CC and SB groups (54.0 [36.0-72.0] vs. 53.0 [39.0-72.0], p = 0.99). Additionally, there were no differences in the en bloc resection (100% vs. 100%, p = 1.00), perioperative perforation (1.1% vs. 1.1%, p = 1.00), or delayed bleeding (1.1% vs. 0.0%, p = 1.00). There was a significant difference in perioperative bleeding frequency (mean ± standard deviation: 1.8 ± 2.6 vs. 3.0 ± 3.5, p < 0.01). The significant risk factors (odds ratio [95% confidence interval]) for long ESD procedure time in patients treated with CC or SB were antiplatelet (7.51 [1.82-31.00]), large lesion size (1.08 [1.05-1.12]), severe fibrosis (24.30 [7.60-77.90]), and perioperative bleeding frequency (1.34 [1.14-1.56]). CONCLUSIONS: CC and SB in colorectal ESD enabled high en bloc resection and low complication rates. CC showed significantly less perioperative bleeding than SB.

Urolithin A-mediated augmentation of intestinal barrier function through elevated secretory mucin synthesis.

Maintaining the mucus layer is crucial for the innate immune system. Urolithin A (Uro A) is a gut microbiota-derived metabolite; however, its effect on mucin production as a physical barrier remains unclear. This study aimed to elucidate the protective effects of Uro A on mucin production in the colon. In vivo experiments employing wild-type mice, NF-E2-related factor 2 (Nrf2)-deficient mice, and wild-type mice treated with an aryl hydrocarbon receptor (AhR) antagonist were conducted to investigate the physiological role of Uro A. Additionally, in vitro assays using mucin-producing cells (LS174T) were conducted to assess mucus production following Uro A treatment. We found that Uro A thickened murine colonic mucus via enhanced mucin 2 expression facilitated by Nrf2 and AhR signaling without altering tight junctions. Uro A reduced mucosal permeability in fluorescein isothiocyanate-dextran experiments and alleviated dextran sulfate sodium-induced colitis. Uro A treatment increased short-chain fatty acid-producing bacteria and propionic acid concentration. LS174T cell studies confirmed that Uro A promotes mucus production through the AhR and Nrf2 pathways. In conclusion, the enhanced intestinal mucus secretion induced by Uro A is mediated through the actions of Nrf-2 and AhR, which help maintain intestinal barrier function.

Development of high-quality artificial intelligence for computer-aided diagnosis in determining subtypes of colorectal cancer.

BACKGROUND AND AIM: There are no previous studies in which computer-aided diagnosis (CAD) diagnosed colorectal cancer (CRC) subtypes correctly. In this study, we developed an original CAD for the diagnosis of CRC subtypes. METHODS: Pretraining for the CAD based on ResNet was performed using ImageNet and five open histopathological pretraining image datasets (HiPreD) containing 3 million images. In addition, sparse attention was introduced to improve the CAD compared to other attention networks. One thousand and seventy-two histopathological images from 29 early CRC cases at Kyoto Prefectural University of Medicine from 2019 to 2022 were collected (857 images for training and validation, 215 images for test). All images were annotated by a qualified histopathologist for segmentation of normal mucosa, adenoma, pure well-differentiated adenocarcinoma (PWDA), and moderately/poorly differentiated adenocarcinoma (MPDA). Diagnostic ability including dice sufficient coefficient (DSC) and diagnostic accuracy were evaluated. RESULTS: Our original CAD, named Colon-seg, with the pretraining of both HiPreD and ImageNET showed a better DSC (88.4%) compared to CAD without both pretraining (76.8%). Regarding the attentional mechanism, Colon-seg with sparse attention showed a better DSC (88.4%) compared to other attentional mechanisms (dual: 79.7%, ECA: 80.7%, shuffle: 84.7%, SK: 86.9%). In addition, the DSC of Colon-seg (88.4%) was better than other types of CADs (TransUNet: 84.7%, MultiResUnet: 86.1%, Unet++: 86.7%). The diagnostic accuracy of Colon-seg for each histopathological type was 94.3% for adenoma, 91.8% for PWDA, and 92.8% for MPDA. CONCLUSION: A deep learning-based CAD for CRC subtype differentiation was developed with pretraining and fine-tuning of abundant histopathological images.

Safety/efficacy of atezolizumab + bevacizumab during anti-platelet/anticoagulation therapy in unresectable hepatocellular carcinoma.

BACKGROUND AND AIMS: This study aimed to determine the safety and efficacy of atezolizumab + bevacizumab therapy in hepatocellular carcinoma patients receiving anti-platelet agents or anticoagulants. METHODS: Patients were divided into those using (IM out) and those not using (IM in) anti-platelet agents or anticoagulants, who violated the exclusion criteria of the IMbrave150 trial, and were retrospectively examined. RESULTS: The study included 185 patients (IM in: 157; IM out: 28). For first-line treatment, progression-free survival was 184 days for IM in and 266 days for IM out (p = .136). Overall survival was 603 days for IM in and not reached for IM out (p = .265), with no significant between-group difference. Similarly, there were no significant between-group differences in progression-free survival or overall survival for later-line treatment. Haemorrhagic adverse events of ≥grade 3 were observed in 11 IM in patients and 3 IM out patients. No significant factors associated with haemorrhagic adverse events of ≥grade 3 were identified in the multivariate analysis including IM out classification, whose p value was .547. Regarding thrombotic/embolic adverse events in the IM out group, one case of exacerbation of portal vein thrombosis was observed. No deaths were directly attributable to bleeding events or exacerbations of thrombosis. CONCLUSION: Atezolizumab + bevacizumab therapy shows similar safety and efficacy in patients receiving and those not receiving anti-platelet agents or anticoagulants; therefore, it can be considered for patients with hepatocellular carcinoma receiving anti-platelet agents or anticoagulants.

The Comparison of Diagnostic Ability between Blue Laser/Light Imaging and Narrowband Imaging for Sessile Serrated Lesions with or without Dysplasia.

Objectives: Diagnostic ability of sessile serrated lesions (SSL) and SSL with dysplasia (SSLD) using blue laser/light imaging (BLI) has not been well examined. We analyzed the diagnostic accuracy of BLI for SSL and SSLD using several endoscopic findings compared to those of narrow band imaging (NBI). Materials and Methods: This was a subgroup analysis of prospective studies. 476 suspiciously serrated lesions of ≥2 mm on the proximal colon showing serrated change with magnified NBI or BLI in our institution between 2014 and 2021 were examined histopathologically. After propensity score matching, we evaluated the diagnostic ability of SSL and SSLD of the NBI and BLI groups regarding various endoscopic findings. For WLI findings, granule, depression, and reddish were examined for diagnosing SSLD. For NBI/BLI findings, expanded crypt opening (ECO) or thick and branched vessels (TBV) were examined for diagnosing SSL. Network vessels (NV) and white dendritic change (WDC) defined originally were examined for diagnosing SSLD. Results: Among matched 176 lesions, the sensitivity of lesions with either ECO or TBV for SSL in the NBI/BLI group was 97.5%/98.5% (p = 0.668). Those with either WDC or NV for diagnosing SSLD in the groups were 81.0%/88.9% (p = 0.667). Regarding the rates of endoscopic findings among 30 SSLD and 290 SSL, there were significant differences in WDC (66.4% vs. 8.6%, p < 0.001), NV (55.3% vs. 1.4%, p < 0.001), and either WDC or NV (86.8% vs. 9.0%, p < 0.001). Conclusions: The diagnostic ability of BLI for SSL and SSLD was not different from NBI. NV and WDC were useful for diagnosing SSLD.

Ramucirumab for advanced hepatocellular carcinoma in the current real world: a Japanese single-arm study post-REACH-2 (The R-evolution study).

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.

Pathophysiological Implications of Protein Lactylation in Pancreatic Epithelial Tumors.

Protein lactylation is a post-translational modification associated with glycolysis. Although recent evidence indicates that protein lactylation is involved in epigenetic gene regulation, its pathophysiological significance remains unclear, particularly in neoplasms. Herein, we investigated the potential involvement of protein lactylation in the molecular mechanisms underlying benign and malignant pancreatic epithelial tumors, as well as its role in the response of pancreatic cancer (PC) cells to gemcitabine. Increased lactylation was observed in the nuclei of intraductal papillary mucinous adenoma, non-invasive intraductal papillary mucinous carcinoma, and invasive carcinoma, in parallel to the upregulation of hypoxia-inducible factor-1α. This observation indicated that a hypoxia-associated increase in nuclear protein lactylation could be a biochemical hallmark in pancreatic epithelial tumors. The standard PC chemotherapy drug gemcitabine suppressed histone lactylation in vitro, suggesting that histone lactylation might be relevant to its mechanism of action. Taken together, our findings suggest that protein lactylation may be involved in the development of pancreatic epithelial tumors and could represent a potential therapeutic target for PC.

Detailed Superiority of the CAD EYE Artificial Intelligence System over Endoscopists for Lesion Detection and Characterization Using Unique Movie Sets.

Objectives: Detailed superiority of CAD EYE (Fujifilm, Tokyo, Japan), an artificial intelligence for polyp detection/diagnosis, compared to endoscopists is not well examined. We examined endoscopist's ability using movie sets of colorectal lesions which were detected and diagnosed by CAD EYE accurately. Methods: Consecutive lesions of ≤10 mm were examined live by CAD EYE from March-June 2022 in our institution. Short unique movie sets of each lesion with and without CAD EYE were recorded simultaneously using two recorders for detection under white light imaging (WLI) and linked color imaging (LCI) and diagnosis under blue laser/light imaging (BLI). Excluding inappropriate movies, 100 lesions detected and diagnosed with CAD EYE accurately were evaluated. Movies without CAD EYE were evaluated first by three trainees and three experts. Subsequently, movies with CAD EYE were examined. The rates of accurate detection and diagnosis were evaluated for both movie sets. Results: Among 100 lesions (mean size: 4.7±2.6 mm; 67 neoplastic/33 hyperplastic), mean accurate detection rates of movies without or with CAD EYE were 78.7%/96.7% under WLI (p<0.01) and 91.3%/97.3% under LCI (p<0.01) for trainees and 85.3%/99.0% under WLI (p<0.01) and 92.6%/99.3% under LCI (p<0.01) for experts. Mean accurate diagnosis rates of movies without or with CAD EYE for BLI were 85.3%/100% for trainees (p<0.01) and 92.3%/100% for experts (p<0.01), respectively. The significant risk factors of not-detected lesions for trainees were right-sided, hyperplastic, not-reddish, in the corner, halation, and inadequate bowel preparation. Conclusions: Unique movie sets with and without CAD EYE could suggest it's efficacy for lesion detection/diagnosis.

Deep learning and digital pathology powers prediction of HCC development in steatotic liver disease.

BACKGROUND AND AIMS: Identifying patients with steatotic liver disease who are at a high risk of developing HCC remains challenging. We present a deep learning (DL) model to predict HCC development using hematoxylin and eosin-stained whole-slide images of biopsy-proven steatotic liver disease. APPROACH AND RESULTS: We included 639 patients who did not develop HCC for ≥7 years after biopsy (non-HCC class) and 46 patients who developed HCC <7 years after biopsy (HCC class). Paired cases of the HCC and non-HCC classes matched by biopsy date and institution were used for training, and the remaining nonpaired cases were used for validation. The DL model was trained using deep convolutional neural networks with 28,000 image tiles cropped from whole-slide images of the paired cases, with an accuracy of 81.0% and an AUC of 0.80 for predicting HCC development. Validation using the nonpaired cases also demonstrated a good accuracy of 82.3% and an AUC of 0.84. These results were comparable to the predictive ability of logistic regression model using fibrosis stage. Notably, the DL model also detected the cases of HCC development in patients with mild fibrosis. The saliency maps generated by the DL model highlighted various pathological features associated with HCC development, including nuclear atypia, hepatocytes with a high nuclear-cytoplasmic ratio, immune cell infiltration, fibrosis, and a lack of large fat droplets. CONCLUSIONS: The ability of the DL model to capture subtle pathological features beyond fibrosis suggests its potential for identifying early signs of hepatocarcinogenesis in patients with steatotic liver disease.

Differential Effects of Genetic Polymorphism on Comorbid Disease in Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND & AIMS: PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567 have been associated with an increased risk of liver-related events (LREs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we investigated the combined effects of these variants on LREs. METHODS: The longitudinal multicenter cohort study enrolled 1178 patients with biopsy-proven MASLD. We calculated the genetic risk of hepatic fibrosis and LRE according to the impact of these variants. RESULTS: Patients with genetic fibrosis scores of 2, 3, and 4 or 5 were at greater risk than patients with scores of 0 or 1, with odds ratios of 2.45 (95% CI, 1.27-4.74), 2.14 (95% CI, 1.17-3.94), and 2.54 (95% CI, 1.35-4.77), respectively. Multivariate analysis revealed that PNPLA3 and TM6SF2, but not HSD17B13, were associated significantly with LRE development. The hazard ratio of the genetic high-risk group for LRE was 1.91 (95% CI, 1.20-3.04). The higher risk of LRE development in the genetic high-risk group also was seen in patients with F ≥ 3 or Fibrosis-4 index > 2.67. The hazard ratios of the genetic high-risk group for LRE were greater in patients without obesity, without diabetes, and of younger age compared with patients with obesity, with diabetes, or of older age, respectively. CONCLUSIONS: This combination of MASLD-related genetic variants is useful for predicting LREs in Japanese patients with MASLD. The genetic risk according to these variants is useful for LRE risk assessment, especially in patients without metabolic risk factors or in younger patients in Japan.

Prevalence of colonoscopy in Japan using a large-scale health claims data compared to esophagogastroduodenoscopy.

OBJECTIVE: Prevalence of colonoscopy (CS) is an important countermeasure against colorectal cancer (CRC). In this study, we used large-scale data for a comparison of CS with esophagogastroduodenoscopy (EGD) in Japan. METHODS: This was a retrospective descriptive study. Commercially anonymized patient data were collected from various health insurance societies (JMDC, Inc. Tokyo, Japan) generated from the insurance registry, receipts (inpatient, outpatient, and prescription), and health checkup data. The data also included healthy subjects who had never been examined in a hospital. The data of 2,760,048 persons who were 50-75 years old during January 2012-December 2019 were extracted from the original data source. The annual rate, the prevalence rate (frequency of those undergoing at least one endoscopy during the period), and the percentage of repeaters (undergoing endoscopy at least twice during the period) of CS were calculated and compared to those of EGD. RESULTS: The annual rates in 2012/2015/2019 were 3.4%/4.5%/5.3% for CS, respectively, and increased gradually from 2012 to 2019. Those rates were 7.0%/7.9%/7.4% for EGD, respectively, and did not increase. The prevalence rates of CS and EGD were 25.3% and 36.2%, respectively, among the 137,246 participants over 8 years. The prevalence rates of individuals in their 50 s/60 s/70 s were 23.0%/25.9%/31.4% for CS and 33.0%/37.6%/40.7% for EGD, respectively. The proportions of males/females were 27.9%/20.7% for CS, and 36.4%/35.8% for EGD, respectively. The repeat rates of CS and EGD were 40.3% and 44.8%, respectively, over 8 years. CONCLUSIONS: Using large-scale data, we determined the status of CS and EGD in Japan.

Effects of mouthwash on periodontal pathogens and glycemic control in patients with type 2 diabetes mellitus.

Periodontitis is known to be associated with type 2 diabetes mellitus (T2DM), and gargling with mouthwash is known to reduce the incidence of periodontitis by inhibiting periodontal pathogens. However, the effects of mouthwash on oral and systemic conditions in patients with T2DM remain unknown. In this study, we investigated the effects of gargling with mouthwash on the number of red complex species, including Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, and HbA1c levels in patients with T2DM. Patients were instructed to gargle with water for 6 months, followed by gargling with mouthwash containing chlorhexidine gluconate for the subsequent 6 months. At each clinic visit, saliva was collected and bacterial DNA was extracted to detect red complex species using the polymerase chain reaction technique. The HbA1c level was determined using a blood sample. The number of red complex species significantly decreased in younger or male patients who gargled with mouthwash. Furthermore, HbA1c levels significantly decreased in younger patients or patients with higher HbA1c levels who gargled with mouthwash. These results suggest that gargling with mouthwash reduces the number of red complex species and improves the hyperglycemic status in patients with T2DM, especially younger patients.

Prognostic value of moderate or massive ascites in patients with advanced gastric cancer.

Advanced gastric cancer is a highly aggressive malignancy. The available literature does not provide the prognostic value of ascites based on their degree, because most clinical trials exclude patients who present with massive ascites. Therefore, this study examined whether the presence or degree of ascites has a prognostic value in 124 patients with advanced gastric cancer. The degree of ascites was assessed using computed tomography and classified as none, small, moderate or massive. The overall survival (OS) was compared based on the presence or degree of ascites. Furthermore, a Cox proportional hazards analysis was performed to ascertain the predictors of OS. The cumulative 1-year and 2-year OS rates in patients without ascites were 43.5 and 20.2%, respectively, whereas those in patients with ascites were 29.1 and 13.6%, respectively (P=0.116). The cumulative 1-year and 2-year OS rates in patients without moderate or massive ascites were 39.5 and 20.9%, respectively; however, those in patients with moderate or massive ascites were 28.0 and 4.0%, respectively (P=0.027). Multivariate analysis showed that diffuse-type [hazard ratio (HR), 1.532; 95% confidence interval (CI), 1.002-2.343; P=0.049], moderate or massive ascites (HR, 2.153; 95% CI, 1.301-3.564; P=0.003) and chemotherapy (HR, 0.189; 95% CI, 0.101-0.352; P<0.001) were significant predictive factors of OS. In conclusion, the present study indicated that moderate or massive ascites may influence the OS of patients with advanced gastric cancer.

Efficacy of Glycicumarin and Isoliquiritigenin in Suppressing Colonic Peristalsis in Both an Animal Model and a Clinical Trial.

Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) show excessive peristalsis, and antispasmodic agents may be useful therapeutic agents. There are few reports on the use of Kampo medicines for the treatment of IBS-D. Shakuyakukanzoto (SKT) is a Kampo medicine that is effective against abdominal pain. We examined the relationship between SKT and intestinal peristalsis in an animal model and a prospective study. In the animal model, SKT and its components were administered from the serosal side of the colon and colonic peristalsis was evaluated using intraluminal pressure and spatiotemporal mapping before and after the administration of SKT and its components. In this clinical trial, we used abdominal ultrasonography (US) to obtain long-axis images of the sigmoid colon of 11 patients. The frequency of intestinal peristalsis was measured using US in five patients with SKT and six patients without medication after the ingestion of a test meal. The primary outcome was the frequency of peristalsis. The Clinical Trial Registry Website (Trial No. UMIN-CTR; UMIN000051547). In the animal model, peony did not suppress peristalsis frequency, but SKT (p = 0.005) and glycyrrhiza (p = 0.001) significantly suppressed peristalsis frequency compared with saline and peony. Among the glycyrrhiza components, glycycoumarin and isoliquiritigenin suppressed the peristalsis frequency compared to dimethyl sulfoxide (control) (p = 0.001, 0.01, respectively). In a clinical trial, peristalsis was significantly suppressed after oral administration in patients taking SKT (p = 0.03). Administration of SKT was found to inhibit colonic peristalsis, with glycicumarin and isoliquiritigenin being particularly relevant among its components.

Multiple duodenal epithelial tumors in a patient with polymerase proofreading-associated polyposis in POLE variant.

Polymerase proofreading-associated polyposis (PPAP) is a rare disease with autosomal-dominant inheritance caused by germline variants in the POLE and POLD1 genes. PPAP has been reported to increase the risk of multiple cancers, including colon, duodenal, and endometrial cancers. Herein, we report a case in which multiple duodenal tumors led to the detection of a POLE mutation. A 43-year-old woman underwent esophagogastroduodenoscopy (EGD). Multiple duodenal tumors were detected, and all lesions were treated endoscopically. The patient had a history of multiple colorectal cancers and endometrial cancer along with a family history of cancer; hence, genetic testing was performed, and POLE variant, c.1270C > G (p.Leu424Val) was detected. Hereditary colorectal cancer syndromes should be considered in patients with colorectal cancer who have multiple cancers or a family history of cancer, and multigene panel sequencing is useful in confirming the diagnosis. In addition, duodenal tumors frequently coexist in patients with PPAP-carrying POLE variants, while the endoscopic treatment for duodenal tumors becomes safe and useful with several new approaches. Therefore, surveillance EGD is necessary in such patients for the early detection and treatment of duodenal tumors.

Clinical outcomes of the over-the-scope clip closure after duodenal endoscopic submucosal dissection: A multicenter retrospective study.

BACKGROUND AND AIM: Prophylactic closure with the over-the-scope clip (OTSC) after endoscopic submucosal dissection (ESD) of superficial non-ampullary duodenal epithelial tumors (SNADETs) has been reported to reduce postoperative adverse events (AEs). However, there are few evidences regarding AEs-associated factors and long-term outcomes of OTSCs. METHODS: From January 2011 to December 2020, 139 consecutive patients with SNADETs who underwent ESD followed by OTSC closure in five institutions were extracted in this retrospective study. The primary endpoint was the rate of postoperative AEs after prophylactic OTSC closure. The secondary endpoints were the complete closure rate, residual rate, and long-term AEs associated with residual OTSCs. RESULTS: The rate of complete closure of the mucosal defect was 97.3% (142) in 146 SNADETs, which were completely resected by ESD. Postoperative AEs, including delayed bleeding, delayed perforation, and localized peritonitis, occurred in 6.2%, 3.4%, and 2.1% of patients, respectively; however, all of the cases improved without surgical treatment. In the multivariate logistic regression analysis, the use of two or more OTSCs was a significant independent risk factor for postoperative AEs (odds ratio, 2.94; 95% confidence interval, 1.02-8.46; P = 0.046). The residual OTSC rate was 46.4% at 1 year postoperatively, and long-term AEs included duodenal erosions and ulcers associated with residual OTSCs. CONCLUSIONS: Prophylactic closure with OTSCs after duodenal ESD can provide acceptable short-and long-term outcomes for preventing postoperative AEs. However, multiple OTSCs were the independent risk factors of postoperative AEs due to the gaps between and near the OTSCs.

Underwater endoscopic papillectomy for a small neuroendocrine tumor of the ampulla of Vater.

Neuroendocrine tumors (NETs) of the ampulla of Vater are rare. Therefore, there is a lack of comprehensive information regarding their pathogenesis. We herein present the case of a patient with a 5-mm ampullary NET who demonstrated the presence of lymphatic invasion after undergoing endoscopic papillectomy. A 44-year-old woman was referred to our hospital for treatment of a grade 1 NET in the ampulla of Vater. Endoscopic ultrasonography revealed a hypoechoic mass within the submucosal layer without obvious infiltration into the common bile duct or the main pancreatic duct. We performed underwater endoscopic papillectomy (UEP) to remove the tumor with a negative margin. Pathological evaluation of the resected specimen showed a grade 1 NET with a negative margin. However, pancreaticoduodenectomy was subsequently performed because of the risk of lymph node metastasis, which was expected due to the significant number of NET cells infiltrating the endothelium of the lymphatic vessels. No lymph node metastasis or recurrence was observed during the 26-month follow-up period. UEP is a useful method to achieve complete resection for diagnostic and therapeutic purposes. UEP may be a novel option for endoscopic treatment of ampullary NET.