Analysis of anti-tumor effect and mechanism of GLS1 inhibitor CB-839 in colorectal cancer using a stroma-abundant tumor model.

BACKGROUND: Glutaminase 1 (GLS1), a key enzyme in glutamine metabolism in cancer cells, acts as a tumor promoter and could be a potential therapeutic target. CB-839, a GLS1-specific inhibitor, was developed recently. Herein, we aimed to elucidate the anti-tumor effects and mechanism of action of CB-839 in colorectal cancer (CRC). METHODS: Using the UCSC Xena public database, we evaluated GLS1 expression in various cancers. Immunostaining for GLS1 was performed on 154 surgically resected human CRC specimens. Subsequently, we examined the GLS1 mRNA expression levels in eight CRC cell lines and evaluated the association between GLS1 expression and CB-839 efficacy. To create a reproducible CRC model with abundant stroma and an allogeneic immune response, we co-transplanted CT26 and stem cells into BALB/c mice and treated them with CB-839. Finally, RNA sequencing of mouse tumors was performed. RESULTS: Database analysis showed higher GLS1 expression in CRC tissues than in normal colon tissues. Clinical samples from 114 of the 154 patients with CRC showed positive GLS1 expression. GLS1 expression in clinical CRC tissues correlated with vascular invasion. CB-839 treatment inhibited cancer cell proliferation depending on GLS1 expression in vitro and inhibited tumor growth and metastasis in the CRC mouse model. RNA sequencing revealed that CB-839 treatment inhibited stromal activation, tumor growth, migration, and angiogenesis. These findings were validated through in vitro and in vivo experiments and clinical specimen analysis. CONCLUSIONS: GLS1 expression in CRC plays important roles in tumor progression. CB-839 has inhibitory effects on cancer proliferation and the tumor microenvironment.

Long-term prognosis after endoscopic submucosal dissection for esophageal cancer in older adult patients.

BACKGROUND: The validity of endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) in older individuals with comorbidities remains unclear. Therefore, this study evaluated the safety and efficacy of ESD and additional treatment for ESCC in older adult patients. METHODS: The clinicopathological characteristics and clinical outcomes of 398 consecutive older adult patients (≥ 65 years) with 505 lesions who underwent ESD for ESCC at the Hiroshima University Hospital between September 2007 and December 2019 were retrospectively evaluated. Additionally, the prognoses of 381 patients who were followed up for > 3 years were assessed. RESULTS: The mean patient age and procedure time were 73.1 ± 5.8 years and 77.1 ± 43.5 min, respectively. The histological en bloc resection rate was 98% (496/505). Postoperative stenosis, perforation, pneumonia, and delayed bleeding were conservatively treated in 82 (16%), 19 (4%), 15 (3%), and 5 (1%) patients, respectively. The 5-year overall and disease-specific survival rates were 78.9% and 98.0%, respectively (mean follow-up time: 71.1 ± 37.3 months). Multivariate analysis showed that age and the American Society of Anesthesiologists classification of physical status class ≥III (hazard ratio: 1.27; 95% confidence interval: 1.01-1.59, p = 0.0392) were independently associated with overall survival. A significantly lower overall survival rate was observed in the high-risk follow-up group than in the low-risk follow-up and high-risk additional treatment groups (p < 0.01). However, no significant difference in disease-specific survival was observed among the three groups. CONCLUSIONS: ESD is safe for ESCC treatment in patients aged ≥ 65 years. However, additional treatments should be considered based on the patient's general condition.

Predictive factors for esophageal stenosis in patients receiving prophylactic steroid therapy after endoscopic submucosal dissection for esophageal squamous cell carcinoma.

BACKGROUND: Methods to prevent esophageal stenosis (ES) after endoscopic submucosal dissection (ESD) for superficial esophageal squamous cell carcinoma (ESCC) have received increasing attention. Although steroid administration is a prophylactic treatment, the risk factors for ES during prophylactic steroid therapy remain unknown. Therefore, this study aimed to retrospectively evaluate the risk factors for refractory ES in patients administered prophylactic steroids after ESD for ESCC. METHODS: Among 795 patients with ESCC (854 lesions), 180 patients (211 lesions) administered local triamcinolone acetonide (TrA) and/or oral prednisolone were recruited for this study. We compared the total number of endoscopic balloon dilatation (EBD) procedures performed for post-ESD ES and clinical findings (tumor size, ESD history or chemoradiation therapy [CRT], entire circumferential resection, muscle layer damage, supplemental oral prednisolone administration, EBD with TrA injection, and additional CRT) between patients with refractory and non-refractory ES. EBD was continued until dysphagia resolved. We categorized cases requiring ≥ 8 EBD procedures as refractory postoperative stenosis and divided the lesions into two groups. RESULTS: Multivariate logistic regression analysis revealed that factors such as ESD history, CRT history, tumor size, and entire circumferential resection were independently associated with the development of refractory ES. The withdrawal rates of EBD at 3 years were 96.1% (52/53) and 58.5% (39/59) in the non-refractory and refractory groups, respectively. CONCLUSIONS: Our data suggest that entire circumferential resection and CRT history are risk factors for refractory post-ESD ES in ESCC, even with prophylactic steroid administration.

Long-term outcomes of patients with obscure gastrointestinal bleeding after negative capsule endoscopy.

BACKGROUND AND AIM: Although small-bowel capsule endoscopy (CE) is widely used for obscure gastrointestinal bleeding (OGIB), long-term outcomes for OGIB patients after negative CE remain unclear. Herein, we defined negative CE as P0 (no bleeding potential) or P1 (less likely to bleed), based on the P classification using CE. We aimed to clarify long-term outcomes of patients with OGIB after negative CE. METHODS: This single-center observational study enrolled 461 consecutive patients with OGIB who underwent CE from March 2014 to October 2021 and were followed up for >1 year. We examined rebleeding rates and predictive factors. RESULTS: Two hundred and twenty-four (49%) patients had P0, and 237 (51%) had P1 findings. Rebleeding occurred in 9% and 16% of patients in the P0 and P1 groups, respectively. Two patients in the P0 group and 15 in the P1 group showed rebleeding from the small bowel. The rate of small-bowel rebleeding was significantly lower in the P0 group than that in the P1 group (1% vs 6%, P = 0.002), as was the cumulative rebleeding rate (P = 0.004). In the multivariate analysis, history of endoscopic hemostasis (hazard ratio [HR] = 15.958, 95% confidence interval [CI]:4.950-51.447, P < 0.001) and P1 CE findings (HR = 9.989, 95% CI: 2.077-48.030, P = 0.004) were independently predicted small-bowel rebleeding. CONCLUSIONS: OGIB with P0 CE findings rarely showed rebleeding from the small bowel. Rebleeding may occur in patients with OGIB. Patients with history of endoscopic hemostasis for small-bowel lesions or P1 CE findings should be followed up intensively.

Comparison of clinical utility of deep learning-based systems for small-bowel capsule endoscopy reading.

BACKGROUND AND AIM: Convolutional neural network (CNN) systems that automatically detect abnormalities from small-bowel capsule endoscopy (SBCE) images are still experimental, and no studies have directly compared the clinical usefulness of different systems. We compared endoscopist readings using an existing and a novel CNN system in a real-world SBCE setting. METHODS: Thirty-six complete SBCE videos, including 43 abnormal lesions (18 mucosal breaks, 8 angioectasia, and 17 protruding lesions), were retrospectively prepared. Three reading processes were compared: (A) endoscopist readings without CNN screening, (B) endoscopist readings after an existing CNN screening, and (C) endoscopist readings after a novel CNN screening. RESULTS: The mean number of small-bowel images was 14 747 per patient. Among these images, existing and novel CNN systems automatically captured 24.3% and 9.4% of the images, respectively. In this process, both systems extracted all 43 abnormal lesions. Next, we focused on the clinical usefulness. The detection rates of abnormalities by trainee endoscopists were not significantly different across the three processes: A, 77%; B, 67%; and C, 79%. The mean reading time of the trainees was the shortest during process C (10.1 min per patient), followed by processes B (23.1 min per patient) and A (33.6 min per patient). The mean psychological stress score while reading videos (scale, 1-5) was the lowest in process C (1.8) but was not significantly different between processes B (2.8) and A (3.2). CONCLUSIONS: Our novel CNN system significantly reduced endoscopist reading time and psychological stress while maintaining the detectability of abnormalities. CNN performance directly affects clinical utility and should be carefully assessed.

Disease surveillance evaluation of primary small-bowel follicular lymphoma using capsule endoscopy images based on a deep convolutional neural network (with video).

BACKGROUND AND AIMS: Capsule endoscopy (CE) is useful in evaluating disease surveillance for primary small-bowel follicular lymphoma (FL), but some cases are difficult to evaluate objectively. This study evaluated the usefulness of a deep convolutional neural network (CNN) system using CE images for disease surveillance of primary small-bowel FL. METHODS: We enrolled 26 consecutive patients with primary small-bowel FL diagnosed between January 2011 and January 2021 who underwent CE before and after a watch-and-wait strategy or chemotherapy. Disease surveillance by the CNN system was evaluated by the percentage of FL-detected images among all CE images of the small-bowel mucosa. RESULTS: Eighteen cases (69%) were managed with a watch-and-wait approach, and 8 cases (31%) were treated with chemotherapy. Among the 18 cases managed with the watch-and-wait approach, the outcome of lesion evaluation by the CNN system was almost the same in 13 cases (72%), aggravation in 4 (22%), and improvement in 1 (6%). Among the 8 cases treated with chemotherapy, the outcome of lesion evaluation by the CNN system was improvement in 5 cases (63%), almost the same in 2 (25%), and aggravation in 1 (12%). The physician and CNN system reported similar results regarding disease surveillance evaluation in 23 of 26 cases (88%), whereas a discrepancy between the 2 was found in the remaining 3 cases (12%), attributed to poor small-bowel cleansing level. CONCLUSIONS: Disease surveillance evaluation of primary small-bowel FL using CE images by the developed CNN system was useful under the condition of excellent small-bowel cleansing level.

Endoscopic findings suggestive of a high risk of non-radical cure after definitive chemoradiotherapy for cT1bN0M0 esophageal squamous cell carcinoma.

BACKGROUND: Definitive chemoradiotherapy (DCRT) is a curative treatment option for cT1bN0M0 esophageal squamous cell carcinoma (ESCC); however, local residual disease and recurrence after complete remission may occur. We aimed to identify endoscopic findings associated with the risk of non-radical cure (local remnant or recurrence) after DCRT for cT1bN0M0 ESCC. METHODS: We retrospectively analyzed 40 consecutive patients with cT1bN0M0 ESCC who had undergone DCRT between January 2007 and December 2017. We examined the endoscopic findings in patients with residual or recurrent (RR) disease (RR group) and those without RR disease [non-RR (NRR) group] after DCRT. We also evaluated outcomes after DCRT for each endoscopic finding. RESULTS: There were 10 patients in the RR group and 30 patients in the NRR group. The RR group had a significantly larger tumor size and a higher proportion of lesions with type 0-I. The 5-year relapse-free survival rate was significantly lower in type 0-I and in the presence of B3 vessels. Endoscopic findings in 15 patients with cT1bN0M0 ESCC, type 0-I, who underwent DCRT revealed significantly more reddish lesions in the RR group compared to the NRR group. CONCLUSIONS: cT1bN0M0 ESCC large size, with B3 vessels, and type 0-I has a high risk of non-radical cure after DCRT, especially the reddish type 0-I, which may need to be considered for treatment similar to advanced cancer, including surgery with preoperative DCRT.

Automatic detection of various abnormalities in capsule endoscopy videos by a deep learning-based system: a multicenter study.

BACKGROUND AND AIMS: A deep convolutional neural network (CNN) system could be a high-level screening tool for capsule endoscopy (CE) reading but has not been established for targeting various abnormalities. We aimed to develop a CNN-based system and compare it with the existing QuickView mode in terms of their ability to detect various abnormalities. METHODS: We trained a CNN system using 66,028 CE images (44,684 images of abnormalities and 21,344 normal images). The detection rate of the CNN for various abnormalities was assessed per patient, using an independent test set of 379 consecutive small-bowel CE videos from 3 institutions. Mucosal breaks, angioectasia, protruding lesions, and blood content were present in 94, 29, 81, and 23 patients, respectively. The detection capability of the CNN was compared with that of QuickView mode. RESULTS: The CNN picked up 1,135,104 images (22.5%) from the 5,050,226 test images, and thus, the sampling rate of QuickView mode was set to 23% in this study. In total, the detection rate of the CNN for abnormalities per patient was significantly higher than that of QuickView mode (99% vs 89%, P < .001). The detection rates of the CNN for mucosal breaks, angioectasia, protruding lesions, and blood content were 100% (94 of 94), 97% (28 of 29), 99% (80 of 81), and 100% (23 of 23), respectively, and those of QuickView mode were 91%, 97%, 80%, and 96%, respectively. CONCLUSIONS: We developed and tested a CNN-based detection system for various abnormalities using multicenter CE videos. This system could serve as an alternative high-level screening tool to QuickView mode.

Exacerbation of Portal Hypertensive Enteropathy after Endoscopic Injection Sclerotherapy for Esophageal Varices.

INTRODUCTION: Portal hypertensive enteropathy (PHE) is a well-known small-bowel lesion that occurs with liver cirrhosis (LC) and is associated with increased hepatic venous pressure. However, it is unclear how esophageal varices (EV) treatment actually affects PHE. We aimed to analyze the effects of EV treatment on PHE. METHODS: Among LC patients who underwent capsule endoscopy (CE) more than twice to confirm PHE at our hospital from February 2009 to September 2018, we targeted those with no change in the Child-Pugh classification after EV treatment for the prevention of bleeding. Patients were assigned to groups based on the EV treatment method (endoscopic injection sclerotherapy [EIS] group or endoscopic variceal ligation [EVL] group). We analyzed the PHE findings before and after treatment, and we investigated changes in the collateral vein using computed tomography imaging. RESULTS: We analyzed 42 LC patients (27 men; mean age, 65.3 years); 20 were in the EIS group and 22 were in the EVL group. Exacerbation of PHE was significantly prevalent in the EIS group (90%) compared to that in the EVL group (50%). CE of PHE showed significantly prevalent exacerbation of villous edema in the EIS group (65%) compared to that in the EVL group (23%). Stenosis or disappearance of the feeding vessel (55%) and exacerbation of the hepatofugal collateral vein (35%) were significantly prevalent in the EIS group. CONCLUSIONS: EIS exacerbates PHE, especially villous edema, in LC patients with changes in collateral circulation.

Automatic detection and classification of protruding lesions in wireless capsule endoscopy images based on a deep convolutional neural network.

BACKGROUND AND AIMS: Protruding lesions of the small bowel vary in wireless capsule endoscopy (WCE) images, and their automatic detection may be difficult. We aimed to develop and test a deep learning-based system to automatically detect protruding lesions of various types in WCE images. METHODS: We trained a deep convolutional neural network (CNN), using 30,584 WCE images of protruding lesions from 292 patients. We evaluated CNN performance by calculating the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity, using an independent set of 17,507 test images from 93 patients, including 7507 images of protruding lesions from 73 patients. RESULTS: The developed CNN analyzed 17,507 images in 530.462 seconds. The AUC for detection of protruding lesions was 0.911 (95% confidence interval [Cl], 0.9069-0.9155). The sensitivity and specificity of the CNN were 90.7% (95% CI, 90.0%-91.4%) and 79.8% (95% CI, 79.0%-80.6%), respectively, at the optimal cut-off value of 0.317 for probability score. In a subgroup analysis of the category of protruding lesions, the sensitivities were 86.5%, 92.0%, 95.8%, 77.0%, and 94.4% for the detection of polyps, nodules, epithelial tumors, submucosal tumors, and venous structures, respectively. In individual patient analyses (n = 73), the detection rate of protruding lesions was 98.6%. CONCLUSION: We developed and tested a new computer-aided system based on a CNN to automatically detect various protruding lesions in WCE images. Patient-level analyses with larger cohorts and efforts to achieve better diagnostic performance are necessary in further studies.

Automatic detection of blood content in capsule endoscopy images based on a deep convolutional neural network.

BACKGROUND AND AIM: Detecting blood content in the gastrointestinal tract is one of the crucial applications of capsule endoscopy (CE). The suspected blood indicator (SBI) is a conventional tool used to automatically tag images depicting possible bleeding in the reading system. We aim to develop a deep learning-based system to detect blood content in images and compare its performance with that of the SBI. METHODS: We trained a deep convolutional neural network (CNN) system, using 27 847 CE images (6503 images depicting blood content from 29 patients and 21 344 images of normal mucosa from 12 patients). We assessed its performance by calculating the area under the receiver operating characteristic curve (ROC-AUC) and its sensitivity, specificity, and accuracy, using an independent test set of 10 208 small-bowel images (208 images depicting blood content and 10 000 images of normal mucosa). The performance of the CNN was compared with that of the SBI, in individual image analysis, using the same test set. RESULTS: The AUC for the detection of blood content was 0.9998. The sensitivity, specificity, and accuracy of the CNN were 96.63%, 99.96%, and 99.89%, respectively, at a cut-off value of 0.5 for the probability score, which were significantly higher than those of the SBI (76.92%, 99.82%, and 99.35%, respectively). The trained CNN required 250 s to evaluate 10 208 test images. CONCLUSIONS: We developed and tested the CNN-based detection system for blood content in CE images. This system has the potential to outperform the SBI system, and the patient-level analyses on larger studies are required.

Diagnostic Yield of Colon Capsule Endoscopy in Detection of Superficial Colorectal Lesions.

BACKGROUND: The efficacy of second-generation PillCam -COLON2 capsule endoscopy (CCE2) in detecting colorectal superficial lesions remains unclear. OBJECTIVE: We sought to determine the diagnostic yield of CCE2 in the detection of colorectal superficial lesions. METHODS: We performed CCE2 in 60 consecutive patients between April 2011 and -December 2017. Lesions ≥6 mm in size were detected in 34 patients (25 males, average age: 60.5 years). We performed endoscopic resection and histopathological analysis of all resected lesions within 3 months after CCE2. We considered the optical colonoscopy (OC) findings as the gold standard and evaluated CCE2 sensitivity. RESULTS: Sixty-seven lesions (≥6 mm) were detected via OC, with 27 colorectal superficial lesions and 40 protruded lesions. CCE2 sensitivity for ≥6-mm-sized, superficial, and protruded lesions was 84, 78, and 88%, respectively. No significant intergroup differences were observed. CCE2 false-negative colorectal superficial lesions accounted for 31% of right-sided colon lesions and 50% of sessile serrated adenomas/polyps (SSA/Ps). The CCE2 false-negative protruded lesions accounted for 17% of right-sided colon lesions. CONCLUSION: CCE2 sensitivities for colorectal superficial and protruded lesions were not significantly different. However, flat-type SSA/Ps in the right colon, especially when the transit time is fast, have a risk of demonstrating CCE2 false-negative results.

Artificial intelligence using a convolutional neural network for automatic detection of small-bowel angioectasia in capsule endoscopy images.

BACKGROUND AND AIM: Although small-bowel angioectasia is reported as the most common cause of bleeding in patients and frequently diagnosed by capsule endoscopy (CE) in patients with obscure gastrointestinal bleeding, a computer-aided detection method has not been established. We developed an artificial intelligence system with deep learning that can automatically detect small-bowel angioectasia in CE images. METHODS: We trained a deep convolutional neural network (CNN) system based on Single Shot Multibox Detector using 2237 CE images of angioectasia. We assessed its diagnostic accuracy by calculating the area under the receiver operating characteristic curve (ROC-AUC), sensitivity, specificity, positive predictive value, and negative predictive value using an independent test set of 10 488 small-bowel images, including 488 images of small-bowel angioectasia. RESULTS: The AUC to detect angioectasia was 0.998. Sensitivity, specificity, positive predictive value, and negative predictive value of CNN were 98.8%, 98.4%, 75.4%, and 99.9%, respectively, at a cut-off value of 0.36 for the probability score. CONCLUSIONS: We developed and validated a new system based on CNN to automatically detect angioectasia in CE images. This may be well applicable to daily clinical practice to reduce the burden of physicians as well as to reduce oversight.

Clinical usefulness of a deep learning-based system as the first screening on small-bowel capsule endoscopy reading.

BACKGROUND AND AIM: To examine whether our convolutional neural network (CNN) system based on deep learning can reduce the reading time of endoscopists without oversight of abnormalities in the capsule-endoscopy reading process. METHODS: Twenty videos of the entire small-bowel capsule endoscopy procedure were prepared, each of which included 0-5 lesions of small-bowel mucosal breaks (erosions or ulcerations). At another institute, two reading processes were compared: (A) endoscopist-alone readings and (B) endoscopist readings after the first screening by the proposed CNN. In process B, endoscopists read only images detected by CNN. Two experts and four trainees independently read 20 videos each (10 for process A and 10 for process B). Outcomes were reading time and detection rate of mucosal breaks by endoscopists. Gold standard was findings at the original institute by two experts. RESULTS: Mean reading time of small-bowel sections by endoscopists was significantly shorter during process B (expert, 3.1 min; trainee, 5.2 min) compared to process A (expert, 12.2 min; trainee, 20.7 min) (P < 0.001). For 37 mucosal breaks, detection rate by endoscopists did not significantly decrease in process B (expert, 87%; trainee, 55%) compared to process A (expert, 84%; trainee, 47%). Experts detected all eight large lesions (>5 mm), but trainees could not, even when supported by the CNN. CONCLUSIONS: Our CNN-based system for capsule endoscopy videos reduced the reading time of endoscopists without decreasing the detection rate of mucosal breaks. However, the reading level of endoscopists should be considered when using the system.

Automatic detection of erosions and ulcerations in wireless capsule endoscopy images based on a deep convolutional neural network.

BACKGROUND AND AIMS: Although erosions and ulcerations are the most common small-bowel abnormalities found on wireless capsule endoscopy (WCE), a computer-aided detection method has not been established. We aimed to develop an artificial intelligence system with deep learning to automatically detect erosions and ulcerations in WCE images. METHODS: We trained a deep convolutional neural network (CNN) system based on a Single Shot Multibox Detector, using 5360 WCE images of erosions and ulcerations. We assessed its performance by calculating the area under the receiver operating characteristic curve and its sensitivity, specificity, and accuracy using an independent test set of 10,440 small-bowel images including 440 images of erosions and ulcerations. RESULTS: The trained CNN required 233 seconds to evaluate 10,440 test images. The area under the curve for the detection of erosions and ulcerations was 0.958 (95% confidence interval [CI], 0.947-0.968). The sensitivity, specificity, and accuracy of the CNN were 88.2% (95% CI, 84.8%-91.0%), 90.9% (95% CI, 90.3%-91.4%), and 90.8% (95% CI, 90.2%-91.3%), respectively, at a cut-off value of 0.481 for the probability score. CONCLUSIONS: We developed and validated a new system based on CNN to automatically detect erosions and ulcerations in WCE images. This may be a crucial step in the development of daily-use diagnostic software for WCE images to help reduce oversights and the burden on physicians.

Clinical significance of small-bowel villous edema in patients with liver cirrhosis: A capsule endoscopy study.

BACKGROUND AND AIM: The relationship between the presence of villous edema (VE) in portal hypertensive enteropathy and clinical factors remains unclear. The aim of this study was to reveal the clinical factors related to VE in patients with liver cirrhosis (LC), and investigate the clinical significance of VE. METHODS: Between February 2009 and September 2016, 363 consecutive patients with LC underwent capsule endoscopy for diagnosing portal hypertensive enteropathy at Hiroshima University Hospital. We evaluated the relationship between the presence of VE and patients' clinical characteristics, findings of esophagogastroduodenoscopy and computed tomography, and survival time. RESULTS: Villous edema was observed in 131 patients (36%), and severe lesions were found in 71 (20%). The presence of VE was significantly greater in patients with Child-Pugh classification B or C, esophageal varices, portal hypertensive gastropathy (PHG), ascites, portal vein thrombosis (PVT), and splenomegaly. In multivariate analysis, Child-Pugh class B or C, esophageal varices, PVT, and splenomegaly were significant predictive factors for the presence of VE. Severe VE was significantly greater in patients with Child-Pugh class B or C, serum albumin level ≤ 3.2 mg/dL, PHG, and PVT. In multivariate analysis, PHG, Child-Pugh class B or C, PVT, were significant predictive factors for severe VE. CONCLUSIONS: Clinical factors related to portal hypertension were significantly correlated with VE. In particular PVT was correlated with the appearance and exacerbation of VE. Periodic capsule endoscopy in LC patients may lead to early detection of portal hypertension and PVT.

Gel immersion EMR of small-bowel inflammatory fibroid polyp using double-balloon endoscopy.

Video 1A case of an inflammatory fibroid polyp of the ileum that was safely resected using gel immersion EMR with double-balloon endoscopy.

Verrucous gastritis-like lesion in intramucosal Helicobacter pylori-uninfected signet ring cell carcinoma with poorly differentiated adenocarcinoma.

In Japan, accessible Helicobacter pylori (Hp) eradication therapy is associated with an increase in the prevalence of gastric cancers (GCs) in Hp uninfected stomachs. Signet ring cell carcinoma (SRCC) is the most common of these GCs. Intramucosal SRCC with poorly differentiated adenocarcinoma (PDA) occurring in Hp uninfected gastric mucosa is rare; furthermore, many Hp uninfected pure SRCCs exhibit discoloration and flat or slightly depressed lesions, and morphological elevation is relatively rare. We report a case of intramucosal SRCC with PDA with an elevated, verrucous gastritis-like lesion in a 57-year-old male patient. In the present case, the PDA area showed dense tumor cell growth and coexisting desmoplastic and fibrotic reactions. Histopathology and immunohistochemical staining identified extensive fibromuscular obliteration with smooth muscle bundles extending from the muscularis mucosa into the lamina propria. The patient underwent curative endoscopic submucosal dissection. The reporting and analysis of such rare cases may lead to a better understanding of the characteristics of advanced Hp uninfected GCs.

Severe Refractory Diarrhea Associated with COVID-19: A Case Report.

Introduction: Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is frequently associated with various gastrointestinal symptoms, including abdominal pain, vomiting, and diarrhea. Moreover, several cases of refractory diarrhea have been reported after COVID-19 recovery. Herein, we present a case of severe refractory diarrhea associated with COVID-19. Case Presentation: A 50-year-old man with no comorbidities was admitted to our hospital with SARS-CoV-2 pneumonia. His respiratory status deteriorated, and ventilatory management, including extracorporeal membrane oxygenation, was needed. The patient's respiratory condition improved, resulting in a transfer to another hospital for rehabilitation. However, the patient developed diarrhea that worsened to 6,000-7,000 mL/day, and he was transferred to our hospital. We diagnosed the patient with enterocolitis caused by cytomegalovirus infection and treated him with ganciclovir on day 5 after transfer to our hospital. The diarrhea did not improve. We suspected enterocolitis associated with COVID-19 and administered a methylprednisolone pulse (intravenous injection, 1,000 mg/day for 3 days) on day 10 after transfer, resulting in a marked improvement in his symptoms. The prednisolone dose was tapered, and no recurrence of diarrhea was observed thereafter. Conclusion: The prevalence of COVID-19-associated enterocolitis is low, and the pathogenesis of the disease remains unclear. Prednisolone administration should be considered in cases of post-COVID-19 symptoms of severe diarrhea due to a possible abnormal immune response related to COVID-19.

Clinicopathological and genomic features of superficial esophageal squamous cell carcinomas in nondrinker, nonsmoker females.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is sometimes detected in non-drinker and non-smoker females who are considered to have very low risk of ESCC development in daily practice. This study examined the clinicopathological and genomic characteristics of ESCCs in females with no history of drinking and smoking. METHODS: The sample comprised 118 ESCC lesions occurring in 95 female patients who underwent endoscopic submucosal dissection at our department between January 2008 and December 2019. The patients were categorized into two groups: 51 lesions in 49 patients with no history of drinking and smoking (nondrinker/nonsmoker [NDNS] group) and 69 lesions in 45 patients with a history of drinking or smoking (drinker/smoker [DS] group). We analyzed the differences in clinicopathological and cancerous genomic characteristics between the groups. Significant genomic alterations were validated using immunohistochemistry. RESULTS: Multiple logistic regression revealed that older age, fewer multiple Lugol-voiding lesions (LVLs), and reflux esophagitis (RE) were independently associated with the occurrence of ESCCs in the NDNS group. ESCC lesions in the NDNS group were predominantly located in the mid-thoracic esophagus, posterior wall side, with 0-IIa, the aspect ratio of the lesion >2 (vertical/horizontal), and endoscopic keratinization. Genetic analysis showed that CDKN2A driver alterations were significantly more frequent and KMT2D alterations were significantly less frequent in the NDNS group than in the DS group. KMT2D alterations were strongly correlated with immunostaining. CONCLUSION: Older nondrinker, nonsmoker females with RE and fewer multiple LVLs may develop longitudinal 0-IIa ESCC with keratinization of the posterior wall of the mid-thoracic esophagus. ESCCs in nondrinker, nonsmoker females had fewer KMT2D alterations and more CDKN2A alterations, which may be a biomarker for treatment.