Kohei Funasaka

Abstract Background and study aims Esophageal endoscopic submucosal dissection (ESD) has a higher complication rate than gastric ESD. Scissor-type devices, including the stag beetle (SB) knife, are reportedly safer and have shorter procedure times than tip devices. To clarify the characteristics of the SB knife, we compared the treatment outcomes of esophageal ESD with a tip-type knife to those with an SB knife combination. Patients and methods Between January 2016 and March 2023, clinical data from 197 lesions in 178 patients who underwent esophageal ESD were analyzed retrospectively. Every lesion was assigned to either the tip-type group or the SB group based on the devices with which the submucosa was initially dissected. We compared procedure time and complications and analyzed the risk of muscular exposure using multivariate analysis. Results Procedure time was not significantly different between the tip-type and SB groups (60.3±42.2 min vs. 58.8±29.1 min). The variation in procedure time was significant according to F test P=0.002). Incidence of muscular exposure was significantly lower in the SB group than in the tip-type group (24.5% vs. 11.1%, P=0.016). These differences were significant in resected specimens larger than 21 mm. Procedure time over 60 minutes (odds ratio [OR] 2.5, 95% confidence interval [CI]: 1.15–5.42, P=0.02) was a risk factor for muscular exposure, and submucosal dissection with an SB knife was a safety factor (OR 0.4, 95% CI: 0.18–0.89, P=0.02). Conclusions Performing esophageal ESD with an SB knife is a safe procedure with less variation in procedure time and less muscule exposure.

BACKGROUND: Rebleeding after hemostasis of the gastroduodenal ulcer (GDU) is one of the indicators associated with death among GDU patients. However, there are few studies on risk score that contribute to rebleeding after endoscopic hemostasis of bleeding peptic ulcers. AIMS: The aim of this study was to identify factors associated with rebleeding, including patient factors, after endoscopic hemostasis of bleeding gastroduodenal ulcers and to stratify the risk of rebleeding. METHODS: We retrospectively enrolled 587 consecutive patients who were treated for Forrest Ia to IIa bleeding gastroduodenal ulcers with endoscopic hemostasis at three institutions. Risk factors associated with rebleeding were assessed using univariate and multivariate logistic regression analyses. The Rebleeding Nagoya University (Rebleeding-N) scoring system was developed based on the extracted factors. The Rebleeding-N score was internally validated using bootstrap resampling methods. RESULTS: Sixty-four patients (11%) had rebleeding after hemostasis of gastroduodenal ulcers. Multivariate logistic regression analysis revealed four independent rebleeding risk factors: blood transfusion, albumin <2.5, duodenal ulcer, and diameter of the exposed vessel ≧2 mm. Patients with 4 risk factors in the Rebleeding-N score had a 54% rebleeding rate, and patients with 3 risk factors had 44% and 25% rebleeding rates. In the internal validation, the mean area under the curve of the Rebleeding-N score was 0.830 (95% CI = 0.786-0.870). CONCLUSIONS: Rebleeding after clip hemostasis of bleeding gastroduodenal ulcers was associated with blood transfusion, albumin <2.5, diameter of the exposed vessel ≧2 mm, and duodenal ulcer. The Rebleeding-N score was able to stratify the risk of rebleeding.

Inflammatory myofibroblastic tumor (IMT) is a rare tumor composed of myofibroblasts with inflammatory blood cell infiltration. It commonly occurs in the lungs and rarely in the esophagus. We herein report a valuable case of IMT originating in the esophagus. A 60-year-old Japanese woman with dysphagia had a large subepithelial lesion (SEL) in the cervical esophagus, which was 15 cm in length. Surgical resection was performed to confirm the pathological diagnosis and improve the symptoms. The postoperative diagnosis was IMT composed of multiple nodules. There was no recurrence or metastasis within one year after surgery.

BACKGROUND AND AIM: In colorectal endoscopic submucosal dissection (ESD), post-ESD electrocoagulation syndrome (PECS) has been recognized as one of the major complications. There are no reports on the relationships between ESD findings and PECS. This study aims to evaluate the risk factors for PECS, including ESD findings such as muscularis propria exposure. METHODS: We performed a retrospective cohort study of patients who underwent colorectal ESD between January 2017 and December 2021 in Japan. The grade of injury to the muscle layer caused by ESD was categorized as follows: Grade 0, no exposure of muscularis propria; Grade 1, muscularis propria exposure; Grade 2, torn muscularis propria; and Grade 3, colon perforation. The risk factors for PECS, including injury to the muscle layer, were analyzed by univariate and multivariate analyses. RESULTS: Out of 314 patients who underwent colorectal ESD, PECS occurred in 28 patients (8.9%). The multivariate analysis showed that female sex (odds ratio [OR] 3.233; 95% confidence interval [95% CI]: 1.264-8.265, P = 0.014), large specimen size (≥ 40 mm) (OR 6.138; 95% CI: 1.317-28.596, P = 0.021), long procedure time (≥ 90 min) (OR 2.664; 95% CI: 1.053-6.742, P = 0.039), and Grade 1 or 2 injury to the muscle layer (OR 3.850; 95% CI: 1.090-13.61, P = 0.036) were independent risk factors for PECS. CONCLUSIONS: Injury to the muscle layer, such as exposure or tear, was identified as a novel independent risk factor for PECS. We should perform colorectal ESD carefully to avoid injuring the muscle layers.

OBJECTIVES: Comprehensive assessments of the long-term outcomes of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in the elderly are unavailable. We aimed to create a scoring system to predict the long-term prognosis after ESD for EGC among patients aged ≥75 years. METHODS: We conducted retrospective studies of two cohorts: a single-center cohort (2006-2011) for developing the scoring system, and a multicenter cohort for validating the developed system (2012-2016). In the development cohort, factors related to death after ESD were identified using multivariable Cox regression analysis, and a predictive scoring system was developed. In the validation cohort, the scoring system was validated in 295 patients. RESULTS: In the development cohort, Charlson comorbidity index (CCI) ≥3 (hazard ratio [HR] 3.017), high psoas muscle index (PMI) (HR 2.206), and age ≥80 years (HR 1.978) were significantly related to overall survival after ESD. Therefore, high CCI, low PMI, and age ≥80 years were assigned 1 point each. The patients were categorized into low (≤1 point) and high (≥2 points) score groups based on their total scores. In the validation cohort, 184 and 111 patients were assigned to the low- and high-score groups, respectively. In comparisons based on Kaplan-Meier curves, the 5-year survival rate was 91.5% in the low-score group and 57.8% in the high-score group (log-rank test; P < 0.001). CONCLUSION: Our scoring system including high CCI, low PMI, and age ≥80 years could stratify the long-term prognosis of elderly patients aged ≥75 years after ESD for EGC.

BACKGROUND: The management of bleeding during endoscopic submucosal dissection (ESD) is critical and related to the procedure time. We collaborated on a new image enhancement algorithm with parameter optimization for clinical use being developed by FUJIFILM Co. and processed white light image data offline to evaluate the effectiveness of this technology. This study aims to evaluate the clinical usefulness of this technology. METHODS: Eighteen video scenes of bleeding points from 5 gastric ESDs were selected and processed by the new image enhancement algorithm. The time until a bleeding point was found, visibility of a bleeding point and color abnormality of the submucosal layer were evaluated by ESD experts, ESD trainees, and endoscopy trainees. The color differences between the bleeding point and the surroundings in CIE- L*a*b* color space were calculated in the original and enhanced images. RESULTS: The time until a bleeding point was found in the enhanced videos was significantly shorter than that in the original videos (11.10 seconds vs. 13.85 seconds) (P=0.017). On a 5-point (-2 to +2) Likert scale of visibility, the enhanced image was slightly superior to the original (+0.45), and the appearance of the submucosa was comparable between images (+0.14). The color difference among the bleeding areas on the enhanced images were significantly larger than that on the original images (10.93 vs. 8.36). CONCLUSION: This novel image enhancement algorithm emphasizes the color difference between a bleeding point and the surrounding area, which would help find bleeding points faster during ESD for the less experienced endoscopists.

Gastric endoscopic submucosal dissection (ESD) is increasingly performed in patients receiving antithrombotic therapy. Second-look endoscopy (SLE) has been performed empirically in several clinical settings. We investigated whether SLE omission was associated with an increased risk of postESD bleeding in all patients, including those administered antithrombotic agents. Between July 2016 and June 2018, 229 patients were treated with a clinical pathway for gastric ESD that involved SLE on the day after ESD (SLE group). Between September 2018 and May 2020, 215 patients were treated using a clinical pathway that did not include SLE (nonSLE group). We retrospectively compared the incidence of postESD bleeding among the propensity score-matched cohorts and determined the risk factors for postESD bleeding using multivariate analysis. The propensity score-matched cohorts showed no significant differences in the incidence of postESD bleeding between the SLE (3.2%) and nonSLE (5.1%) groups. Multivariate analysis revealed that the presence of lesions in the lower gastric body (adjusted odds ratio [OR] 2.17, 95% confidence interval [CI] 1.06-4.35, P.03) was a significant risk factor for postESD bleeding during admission, whereas resected specimen size ≥ 40 mm (adjusted OR 3.21, 95% CI 1.19-8.19, P.02) and antiplatelet therapy (adjusted OR 4.16, 95% CI 1.47-11.80, P.007) were significant risk factors after discharge. Complete omission of SLE after gastric ESD does not increase postESD bleeding in clinical practice.

OBJECTIVES: Although black stools are one of the signs of upper gastrointestinal bleeding, not all patients without hematemesis need endoscopic intervention. There is no apparent indicator to select who needs treatment thus far. The aim of this study was to establish a novel score that predicts the need for endoscopic intervention in patients with black stools without hematemesis. METHODS: We retrospectively enrolled 721 consecutive patients with black stools without hematemesis who underwent emergency endoscopy from two facilities. In the development stage (from January 2016 to December 2018), risk factors that predict the need for endoscopic intervention were determined from the data of 422 patients by multivariate logistic regression analysis, and a novel scoring system, named the modified Nagoya University score (modified N score), was developed. In the validation stage (from January 2019 to September 2020), we evaluated the diagnostic value of the modified N score for 299 patients. RESULTS: Multivariate logistic regression analysis revealed four predictive factors for endoscopic intervention: syncope, the blood urea nitrogen (BUN) level, and the BUN/creatinine ratio as positive indicators and anticoagulant drug use as a negative indicator. In the validation stage, the area under the curve of the modified N score was 0.731, and the modified N score showed a sensitivity of 82.0% and a specificity of 58.8%. CONCLUSIONS: Our modified N score, which consists of only four factors, can identify patients who need endoscopic intervention among those with black stools without hematemesis.

BACKGROUND: In Japan, endoscopic submucosal dissection (ESD) has been widely performed for ESD-adapted gastric cancer, but little is known about the prognostic factors after ESD for gastric cancer in older patients. The psoas muscle index (PMI) is an indicator of sarcopenia calculated from computed tomography images and reportedly related to the prognosis of some diseases. This study aimed to explore factors related to long-term survival after ESD for gastric cancer in patients aged ≥ 80 years. METHODS: We retrospectively reviewed 88 patients (63 men, 25 women) with early gastric cancer who underwent ESD at ≥ 80 years. Possible factors related to death after gastric ESD were analyzed by univariate and multivariate analyses using a Cox proportional hazards model. The estimated overall survival (OS) was compared between the groups stratified by significant factors. RESULTS: The 5-year OS rate was 73.9% (median follow-up period, 5.4 years). In the multivariate analysis, a low PMI (< 6.36 in men, < 3.92 in women) (hazard ratio [HR] 2.89, 95% confidence interval [CI] 1.11-7.54) and high Charlson comorbidity index (CCI) (≥ 3) (HR 1.87, 95% CI 1.14-3.09) were independently related to death after ESD. The 5-year OS rates were significantly higher in the high PMI group (82.3% vs. 70.7%, P = 0.026) and the low CCI group (76.0% vs. 37.9%, P = 0.002). CONCLUSION: In addition to low CCI, high PMI is a predictor of long-term survival after ESD for gastric cancer in patients aged ≥ 80 years.

Various scoring systems have been developed to predict the need for endoscopic treatment in patients with non-variceal upper gastrointestinal bleeding (NVUGIB). However, they have rarely been applied in clinical practice because the processes are complicated. The aim of this study was to establish a simple scoring system that predicts the need for endoscopic intervention in patients with NVUGIB. We retrospectively enrolled 509 consecutive patients with suspected NVUGIB who underwent emergency endoscopy. In the development cohort (from January 2016 to December 2018), risk factors that predict the need for endoscopic intervention were determined from 349 patients' data by multivariate logistic regression analysis. This led to the development of a novel scoring system named the Nagoya University score (N score). In the validation cohort (from January 2019 to September 2020), we evaluated the diagnostic value of the N score, the Hirosaki score, and the Glasgow-Blatchford scores (GBS) by receiver operating characteristic (ROC) curves using another 160 patients' data. Multivariate logistic regression analysis revealed syncope, hematemesis, blood urea nitrogen (BUN), and BUN/Cr as significant predictive factors for endoscopic intervention. In the validation study, the N score was superior to the GBS and equal to the Hirosaki score in predicting the endoscopic intervention (AUC, N score 0.776 [95% CI 0.702-0.851] vs. GBS 0.615 [0.523-0.708], Hirosaki 0.719 [0.636-0.803]). The N score revealed a sensitivity of 84.5% and a specificity of 61.8%. Our N score, which is consisted of only four factors, would select patients who require endoscopic intervention with high probability.

Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) is useful for pathologically diagnosing gastrointestinal stromal tumor (GIST) before surgery. However, its role in mutation analysis remains unclear. To examine the feasibility of analyzing GIST mutations using mRNA obtained with EUS-FNA, we prospectively enrolled 41 patients with subepithelial lesion from which EUS-FNA was successfully acquired tissue sample. Thirty-two, 5, and 4 subepithelial lesions were diagnosed as GISTs, schwannomas, and leiomyomas, respectively. After RNA was extracted from FNA sample, RNA was converted to cDNA. Full-length sequence of the KIT cDNA amplified via the polymerase chain reaction (PCR) was successful in 31 (96.9%) out of 32 GIST and three out of 9 non-GIST (33.3%). The KIT mutation statuses of 31 GISTs in which KIT cDNA was amplified were successfully determined through directional sequencing. Furthermore, 15 of 16 surgically excised GISTs exhibited the same mutation status in both the EUS-FNA and resected samples. In vitro experiment, the minimum number of cells required to amplify full-length of KIT cDNA from RNA was one-tenth of that required to amplify KIT exon11 gene from DNA. This study clarifies that mutation analysis using RNA obtained with EUS-FNA is feasible and reliable. Moreover, our data would support that RNA-based mutation is superior to DNA-based mutation analysis in GIST.

Although the majority of gastrointestinal stromal tumors (GISTs) possess KIT mutations that induce constitutive signal transduction, the clinical outcomes are variable. The ETS translocation variant 1 (ETV1) gene encodes a transcription factor that is reported to cooperate with KIT in GISTs. However, the clinical role of ETV1 is largely unknown. The aim of this study was to examine ETV1 expression and its associations with clinical features in GISTs. We conducted a cohort study involving 64 patients with GISTs who underwent surgical resection between October 2008 and February 2015. ETV1 mRNA expression was compared with that in non-GISTs and was analyzed among risk classifications or clinical outcomes. The GIST samples exhibited significantly higher ETV1 mRNA expression than the non-GIST samples (P < 0.0001). Sixty-four GISTs were stratified into high or low ETV1 mRNA expression groups based on the median relative abundance of ETV1 mRNA. The multivariate analysis showed that low ETV1 expression, as well as tumor size and mitotic index, was an independent factor of recurrence (hazard ratio: 8.1). Patients with high ETV1 expression achieved significantly longer recurrence-free survival (RFS) times than those with low ETV1 expression (P = 0.025). Our study revealed that low ETV1 expression is an independent factor of recurrence after surgery in patients with GISTs, and thus, low ETV1 expression might be a marker of more aggressive malignant GISTs.

BACKGROUND AND AIM: Magnifying endoscopy is useful for diagnosis of early gastrointestinal neoplasms by visualizing microvascular (MV) and microsurface (MS) structures of the mucosa when combined with image-enhanced endoscopy. However, precise control of the endoscope is needed because the depth of focus is narrow and the target may move. These problems may be overcome by the all-in-focus (AIF) technique, which was developed in the engineering field. The aim of the study was to evaluate magnifying endoscopic image with AIF algorithm. METHODS: Twenty gastric neoplasms were examined. Images were acquired at 80× magnification and converted to endoscopic images with an AIF algorithm (EI-AIF). The focus area and MV and MS patterns in the original image and the EI-AIF were compared on a 5-point Likert scale, where 5 indicates that the EI-AIF was superior. Intraclass correlation coefficients (ICCs) were used to assess the inter-evaluator reliability. An image quality measurement value was calculated for each image as an indicator of the degree of focus. RESULTS: The scores for focus area, MV, and MS were 4.78 ± 0.45 (ICC = 0.63), 4.12 ± 0.76 (ICC = 0.70), and 4.72 ± 0.52 (ICC = 0.45), respectively, with the EI-AIF significantly superior for all three items (P < 0.05 by Student's t-test). ICCs for the focus area and MV were > 0.60, indicating strong inter-evaluator reliability. Image quality measurement was higher for the EI-AIF compared with the original image in every case. CONCLUSIONS: Endoscopic observation with AIF algorithm gives a better image quality that allows easier evaluation of MV and MS patterns. This technique may resolve the difficulties with magnifying endoscopic observation.

Plummer-Vinson syndrome is a rare entity, characterized by dysphagia, esophageal web formation, and iron deficiency anemia. The patient was a 63-year-old woman with a clinical history of iron deficiency anemia and glossitis in her 20s to 40s and who had experienced swallowing difficulties for the past 20 years. A membranous stricture was found in the cervical esophagus during a fluoroscopic examination. An endoscopic examination conducted under general anesthesia revealed an oblique linear scar on the proximal surface of the stricture. Sequential balloon dilation was performed successfully. We suggest that the esophageal web formation might have been related to the healing of an esophageal ulcer.

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract. It is well known that activating mutations in the receptor tyrosine kinases KIT and platelet-derived growth factor receptor-α have essential roles in the pathogenesis of GISTs. The activation of these receptor protein kinases triggers multiple signaling pathways that promote cell proliferation and survival; however, the exact mechanism by which the activation of these kinases promotes the progression of GISTs remains uncertain. The aim of the present was to search for genes that are associated with the progression of GIST. The present study used reverse transcription-quantitative polymerase chain reaction to demonstrate that adenosine monophosphate deaminase 3 (AMPD3) was highly expressed in GISTs. Furthermore, transfection of GIST-T1 cells with KIT-specific small interfering RNA (siRNA) demonstrated that the expression of AMPD3 was dependent on KIT expression, while the depletion of AMPD3 in human GIST-T1 cells using AMPD3-specific siRNA resulted in the suppression of cell migration and invasion. In addition, AMPD3 depletion sensitized GIST-T1 cells to the tyrosine kinase inhibitor imatinib. The results of the present suggested that the combined inhibition of tyrosine kinases and AMPD3 may be effective for the treatment of GISTs.

Integrin-mediated activation of Cdc42 is essential for cell polarization, whereas the integrin adaptor protein Cas is required for cell migration during wound healing. After phosphorylation on tyrosine residues, Cas recruits the adaptor proteins Crk and Nck to execute integrin-mediated signals. However, the mechanisms leading to Cdc42 activation and its relationship with Cas, Crk and Nck have not been elucidated clearly. In the present study, we demonstrate that Cas utilizes Nck2 to activate Cdc42 and induce cell polarization in response to wounding. By contrast, Cas recruits CrkII to activate Rac1 and promote the extension of cell protrusions needed for cell motility. These results indicate that Cas utilizes Nck2 and CrkII in a coordinated set of distinct pathways leading to cell migration.