Diagnostic performance of linked color imaging for gastric cancer by Helicobacter pylori infection status: A subanalysis of the large-scale, multicenter randomized controlled trial LCI-FIND.

BACKGROUND: Linked color imaging (LCI) is a new image enhancement technology that facilitates the recognition of subtle differences in mucosal color. In the large-scale, multicenter randomized controlled trial LCI-FIND, LCI demonstrated good diagnostic performance for the detection of tumor lesions in the upper gastrointestinal tract. The aim of the present study was to exploratively evaluate the diagnostic performance of LCI according to H. pylori infection status as a subanalysis of LCI-FIND trial. METHODS: The patients were randomly allocated to receive white light imaging (WLI) first, followed by LCI (WLI group), or vice versa (LCI group), and the two groups were compared for the detection of tumors. Data from this trial were analyzed by the presence/absence of H. pylori infection and further analyzed by successful or unsuccessful eradication in the H. pylori infection group. RESULTS: The 752 patients in the WLI group and 750 patients in the LCI group who had participated in the LCI-FIND trial were included. In the successful eradication group, more gastric lesions were detected by primary mode in the LCI group than in the WLI group, indicating that more lesions were missed by WLI. Fisher's exact probability test for the comparison of the WLI and LCI groups yielded a p-value of 0.0068, with missed gastric lesions being detected 0.136 times (95% confidence interval: 0.020-0.923), significantly less with LCI than with WLI. CONCLUSION: The current study suggests that LCI should be used for gastric cancer screening, particularly in patients with successful H. pylori eradication.

Endoscopic and histological risk stratification for gastric cancer using gastric intestinal metaplasia.

BACKGROUND AND AIM: Intestinal metaplasia (IM) of the gastric mucosa is strongly associated with the risk of gastric cancer (GC). This study was performed to investigate the usefulness of endoscopic and histological risk stratification for GC using IM. METHODS: This was a post-hoc analysis of a multicenter prospective study involving 10 Japanese facilities (UMINCTR000027023). The ridge/tubulovillous pattern, light blue crest (LBC), white opaque substance (WOS), endoscopic grading of gastric IM (EGGIM) score using non-magnifying image-enhanced endoscopy, and operative link on gastric IM assessment (OLGIM) were evaluated for their associations with GC risk in all patients. RESULTS: In total, 380 patients (115 with GC and 265 without GC) were analyzed. The presence of an LBC (limited to antrum: odds ratio [OR] 2.4 [95% confidence interval 1.1-5.0], extended to corpus: OR 3.6 [2.1-6.3]), the presence of WOS (limited to antrum: OR 3.0 [1.7-5.3], extended to corpus: OR 4.2 [2.1-8.2]), and histological IM (limited to antrum: OR 3.2 [1.4-7.4], extended to corpus: OR 8.5 [4.5-16.0]) were significantly associated with GC risk. Additionally, the EGGIM score (5-8 points: OR 8.8 [4.4-16.0]) and OLGIM (stage III/IV: OR 12.5 [6.1-25.8]) were useful for stratification of GC risk. The area under the receiver operating characteristic curve value for GC risk was 0.740 for OLGIM and 0.706 for EGGIM. CONCLUSIONS: The LBC, WOS, EGGIM, and OLGIM were strongly associated with GC risk in Japanese patients. This finding can be useful for GC risk assessment in daily clinical practice.

Risk stratification of synchronous gastric cancers including alcohol-related genetic polymorphisms.

BACKGROUND AND AIM: We previously identified that ever-smoking and severe gastric atrophy in pepsinogen are risk factors for synchronous gastric cancers (SGCs). This study aimed to determine the association of alcohol drinking status or alcohol-related genetic polymorphism with SGCs and also stratify their risk. METHODS: This multi-center prospective cohort study included patients who underwent endoscopic submucosal dissection for the initial early gastric cancers at 22 institutions in Japan. We evaluated the association of alcohol drinking status or alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase 2 (ALDH2) genotypes with SGCs. We then stratified the risk of SGCs by combining prespecified two factors and risk factors identified in this study. RESULTS: Among 802 patients, 130 had SGCs. Both the ADH1B Arg and ALDH2 Lys alleles demonstrated a significant association with SGCs on multivariate analysis (odds ratio, 1.77), although alcohol drinking status showed no association. The rates of SGCs in 0-3 risk factors in the combined evaluation of three risk factors (ever-smoking, severe gastric atrophy in pepsinogen, and both the ADH1B Arg and ALDH2 Lys alleles) were 7.6%, 15.0%, 22.0%, and 32.1%, respectively. The risk significantly increased from 0 to 3 risk factors on multivariate analysis (P for trend <0.001). CONCLUSIONS: Both the ADH1B Arg and ALDH2 Lys alleles were at high risk for SGCs. The risk stratification by these three factors may be a less invasive and promising tool for predicting their risk.

A Novel Dry Simulator Model for Learning Comprehensive Endoscopic Retrograde Cholangiopancreatography/Endoscopic Sphincterotomy Procedures while Minimizing Adverse Bleeding Events (with Video).

INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy (EST) are essential skills for performing endoscopic cholangiopancreatic procedures. However, these procedures have a high incidence of adverse events, and current training predominantly relies on patient-based approaches. Herein, we aimed to develop an ERCP/EST simulator model to address the need for safer training alternatives, especially for learners with limited ERCP experience. METHODS: The model was designed to facilitate the use of actual endoscopic devices, supporting learning objectives that align with the components of the validated Bethesda ERCP Skill Assessment Tool (BESAT). BESAT focuses on skills, such as papillary alignment, maintenance of duodenoscope position, gentle and efficient cannulation, controlled sphincterotomy in the correct trajectory, and guidewire manipulation. Thirty gastroenterology trainees used the simulator between May 2022 and March 2023, and their satisfaction was assessed using a visual analog scale (VAS) and pre- and post-training questionnaires. RESULTS: The novel simulator model comprised a disposable duodenal papillary section, suitable for incision with an electrosurgical knife, alongside washable upper gastrointestinal tract and bile duct sections for repeated use. The duodenal papillary section enabled reproduction of a realistic endoscope position and the adverse bleeding events due to improper incisions. The bile duct section allowed for the reproduction of fluoroscopic-like images, enabling learners to practice guidewire guidance and insertion of other devices. Following training, the median VAS score reflecting the expectation for model learning significantly increased from 69.5 (interquartile range [IQR]: 55.5-76.5) to 85.5 (IQR: 78.0-92.0) (p < 0.01). All participants expressed a desire for repeated simulator training sessions. CONCLUSIONS: This innovative simulator could serve as a practical educational tool, particularly beneficial for novices in ERCP. It could facilitate hands-on practice with actual devices, enhancing procedural fluency and understanding of precise incisions to minimize the risk of bleeding complications during EST.

Porphyromonas gingivalis Lipopolysaccharide Damages Mucosal Barrier to Promote Gastritis-Associated Carcinogenesis.

BACKGROUND: Recent epidemiological studies suggested correlation between gastric cancer (GC) and periodontal disease. AIMS: We aim to clarify involvement of lipopolysaccharide of Porphyromonas gingivalis (Pg.), one of the red complex periodontal pathogens, in the GC development. METHODS: To evaluate barrier function of background mucosa against the stimulations, we applied biopsy samples from 76 patients with GC using a Ussing chamber system (UCs). K19-Wnt1/C2mE transgenic (Gan) mice and human GC cell-lines ± THP1-derived macrophage was applied to investigate the role of Pg. lipopolysaccharide in inflammation-associated carcinogenesis. RESULTS: In the UCs, Pg. lipopolysaccharide reduced the impedance of metaplastic and inflamed mucosa with increases in mRNA expression of toll-like receptor (TLR) 2, tumor necrosis factor (TNF) α, and apoptotic markers. In vitro, Pg. lipopolysaccharide promoted reactive oxidative stress (ROS)-related apoptosis as well as activated TLR2-ß-catenin-signaling on MKN7, and it increased the TNFα production on macrophages, respectively. TNFα alone activated TLR2-ß-catenin-signaling in MKN7, while it further increased ROS and TNFα in macrophages. Under coculture with macrophages isolated after stimulation with Pg. lipopolysaccharide, ß-catenin-signaling in MKN7 was activated with an increase in supernatant TNFα concentration, both of which were decreased by adding a TNFα neutralization antibody into the supernatant. In Gan mice with 15-week oral administration of Pg. lipopolysaccharide, tumor enlargement with ß-catenin-signaling activation were observed with an increase in TNFα with macrophage infiltration. CONCLUSIONS: Local exposure of Pg. lipopolysaccharide may increase ROS on premalignant gastric mucosa to induce apoptosis-associated barrier dysfunction and to secrete TNFα from activated macrophages, and both stimulation of Pg. lipopolysaccharide and TNFα might activate TLR2-ß-catenin-signaling in GC.

Risk factors and pattern of metastatic recurrence after endoscopic resection with additional treatment for esophageal cancer.

Although esophageal cancers invading the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic resection (ER) are associated with a risk of lymph node metastasis, details of metastatic recurrence after additional treatment remain unknown. We aimed to identify the risk factors for metastatic recurrence and recurrence patterns in patients receiving additional treatment after ER for esophageal cancer. Between 2006 and 2017, patients with pT1a-MM/pT1b-SM esophageal cancer who underwent ER with additional treatment (esophagectomy, chemoradiotherapy [CRT], and radiation therapy) at 21 institutions in Japan were enrolled. We evaluated the risk factors for metastatic recurrence after ER with additional treatment. Subsequently, the rate and pattern (locoregional or distant) of metastatic recurrence were investigated for each additional treatment. Of the 220 patients who received additional treatment, 57, 125, and 38 underwent esophagectomy, CRT, and radiation therapy, respectively. In the multivariate analysis, lymphatic invasion was the sole risk factor for metastatic recurrence after additional treatment (hazard ratio, 3.50; P = 0.029). Although the risk of metastatic recurrence with additional esophagectomy was similar to that with CRT (hazard ratio, 1.01; P = 0.986), the rate of locoregional recurrence tended to be higher with additional esophagectomy (80.0% (4/5) vs. 36.4% (4/11)), leading to a better prognosis in patients with metastatic recurrence after additional esophagectomy than CRT (survival rate, 80.0% (4/5) vs. 9.1% (1/11)). Patients with lymphatic invasion have a high risk of metastatic recurrence after ER with additional treatment for pT1a-MM/pT1b-SM esophageal cancer. Additional esophagectomy may result in a better prognosis after metastatic recurrence.

Clinical outcomes of endoscopic submucosal dissection for esophageal squamous cell carcinoma with esophageal varices: Multicenter retrospective study.

OBJECTIVES: Clinical outcomes of endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) with esophageal varices (EVs) are obscure. We aimed to elucidate the clinical outcomes of ESD for ESCC with EVs in a multicenter, retrospective study. METHODS: We established a retrospective cohort of 30 patients with ESCC complicating EVs, who underwent ESD at 11 Japanese institutions. Rates of en bloc resection and R0 resection, procedure time, and adverse events were evaluated as indicators of the feasibility and safety of ESD. Additional treatment, recurrence, and metastasis of the lesions were evaluated as indicators of the long-term efficacy of ESD. RESULTS: Portal hypertension was caused by cirrhosis, of which alcohol was the most common cause. En bloc resection was achieved in 93.3% and R0 resection in 80.0% of the patients. The median procedure time was 92 min. Adverse events included a case of uncontrolled intraoperative bleeding leading to discontinuation of ESD and a case of esophageal stricture due to extensive resection. During the follow-up period of a median for 42 months, a patient with local recurrence and another patient with liver metastasis were observed. One patient died of liver failure after receiving chemoradiotherapy as an additional treatment after ESD. No patient died of ESCC. CONCLUSION: This multicenter, retrospective cohort study demonstrated the safety and efficacy of ESD for ESCC with EVs. Further studies are needed to establish appropriate treatment methods for EVs before ESD and additional treatments for patients with insufficient ESD.

Is blue light imaging without magnification satisfactory as screening for esophageal squamous cell carcinoma? Post-hoc analysis of multicenter randomized controlled trial.

OBJECTIVES: Narrow light observation is currently recommended as an alternative to Lugol chromoendoscopy (LCE) to detect esophageal squamous cell carcinoma (ESCC). Studies revealed little difference in sensitivity between the two modalities in expert settings; however, these included small numbers of cases. We aimed to determine whether blue light imaging (BLI) without magnification is satisfactory for preventing misses of ESCC. METHODS: This was a post-hoc analysis of a multicenter randomized controlled trial targeting patients at high risk of ESCC in expert settings. In this study, BLI without magnification followed by LCE was performed. The evaluation parameters included: (i) the diagnostic abilities of ESCC; (ii) the endoscopic characteristics of lesions with diagnostic differences between the two modalities; and (iii) the color difference between cancerous and noncancerous areas in BLI and LCE. RESULTS: This study identified ESCC in 49 of 699 cases. Of these cases, nine (18.4%) were missed by BLI but detected by LCE. In per-patient analysis, the sensitivity of BLI was lower than that of LCE following BLI (83.7% vs. 100.0%; P = 0.013), whereas the specificity and accuracy of BLI were higher (88.2% vs. 81.2%; P < 0.001 and 87.8% vs. 82.5%; P < 0.001, respectively). No significant endoscopic characteristics were identified, but the color difference was lower in BLI than in LCE (21.4 vs. 25.1; P = 0.003). CONCLUSION: LCE following BLI outperformed BLI in terms of sensitivity in patients with high-risk ESCC. Therefore, LCE, in addition to BLI, would still be required in screening esophagogastroduodenoscopy even by expert endoscopists.

Association between continuous cessation or reduction of drinking alcohol and improvement of multiple dysplastic lesions in patients with esophageal squamous cell carcinoma after endoscopic resection.

BACKGROUND: Multiple development of squamous cell carcinoma (SCC) in the upper aerodigestive tract has been explained by the 'field cancerization phenomenon' associated with alcohol drinking. Squamous dysplastic lesion is clinically visualised as a Lugol-voiding lesion (LVL) by chromoendoscopy. Whether cessation or reduction of alcohol drinking improves multiple LVL and reduces the risk of field cancerization has not been elucidated. METHODS: We analysed 330 patients with newly diagnosed superficial esophageal SCC (ESCC) enrolled in the cohort study. The grade of LVL was assessed in all patients every 6 months. We instructed the patients to stop smoking and drinking and recorded their drinking and smoking status every 6 months. RESULTS: Among 330 patients, we excluded 98 with no LVL or no drinking habit. Of the remaining 232 patients, 158 continuously ceased or reduced their drinking habit. Patients who ceased or reduced their drinking habit significantly showed improvement in the grade of LVL. Multivariate analysis showed that continuous cessation or reduction of drinking habit improved the grade of LVL (hazard ratio [HR] = 8.5, 95% confidence interval [CI] 1.7-153.8, p = 0.0053). Higher grade of LVL carried a high risk of multiple ESCC and head and neck SCC (HNSCC) (HR = 3.7, 95% CI 2.2-6.4, p < 0.0001). Improvement in LVL significantly decreased the risk of multiple ESCC and HNSCC (HR = 0.2, 95% CI 0.04-0.7, p = 0.009). CONCLUSIONS: This is the first report indicating that field cancerization was reversible and cessation or reduction of drinking alcohol could prevent multiple squamous dysplastic lesion and multiple ESCC and HNSCC development. CLINICAL TRIALS REGISTRY NUMBER: UMIN000001676.

Metachronous primary gastric cancer after endoscopic resection in patients with esophageal squamous cell carcinoma.

BACKGROUND: This study aimed to evaluate the risk factors for developing metachronous primary Gastric Cancer (GC) after Endoscopic Resection (ER) for esophageal Squamous Cell Carcinoma (SCC). METHODS: We studied 283 patients with esophageal SCC who underwent ER. The study outcomes were as follows: (1) incidence of metachronous primary GC after ER; and (2) predictors for the development of metachronous primary GC after ER by the Cox proportional hazards model. RESULTS: The median follow-up was 43.1 months (1.81-79.1), and the 3-year cumulative incidence of metachronous primary GC was 6.5% (95%CI: 4.1-10.4). The incidence of metachronous primary GC during the follow-up period was 2.31 per 100 person-years. The frequencies of severe gastric atrophy and macrocytosis at the timing of ER were significantly higher in patients with than without metachronous primary GC (91.7% vs. 73.2%, p = 0.0422, 20.8% vs. 5.2%, p = 0.0046, respectively). Severe gastric atrophy was associated with the development of metachronous primary GC (sex-and-age adjusted hazard ratio (HR) [95%CI] = 4.12 [0.95-27.78], p = 0.0093). Macrocytosis was associated with the development of metachronous primary GC (sex-and-age adjusted HR = 4.76 [1.75-13.0], p = 0.0012) and found to be an independent predictor for metachronous primary GC by multivariate Cox proportional hazards analysis (HR [95%CI] = 4.35 [1.60-11.84], p = 0.004). CONCLUSIONS: Severe gastric atrophy and macrocytosis should be noted in the development of metachronous primary GC after ER for esophageal SCC. In particular, macrocytosis at the timing of ER was considered an important predictor. CLINICAL TRIALS REGISTRY NUMBER: UMIN000001676.

Risk factors for the development of second primary esophageal squamous-cell carcinoma after endoscopic resection for esophageal squamous-cell carcinoma according to genetic polymorphisms related to alcohol and nicotine metabolism.

BACKGROUND: Multiple development of esophageal squamous-cell carcinoma is explained by field cancerization and is associated with alcohol consumption and smoking. We investigated the association between the development of second primary esophageal squamous-cell carcinoma after endoscopic resection for esophageal squamous-cell carcinoma and genetic polymorphisms related to alcohol and nicotine metabolism. METHODS: The study group comprised 56 patients with esophageal squamous-cell carcinoma after endoscopic resection. The main variables were the following: (i) cumulative incidence and total number of second primary esophageal squamous-cell carcinoma according to genetic polymorphisms in alcohol dehydrogenase 1B, aldehyde dehydrogenase 2 and cytochrome P450 2A6; and (ii) risk factors of second primary esophageal squamous-cell carcinoma identified using a multivariate Cox proportional-hazards model. The frequencies of alcohol dehydrogenase 1B, aldehyde dehydrogenase 2 and cytochrome P450 2A6 genetic polymorphisms in the buccal mucosa were analyzed. RESULTS: The median follow-up was 92.8 months (range: 2.7-134.2). Slow-metabolizing alcohol dehydrogenase 1B was associated with a higher 7-year cumulative incidence of second primary esophageal squamous-cell carcinoma (fast-metabolizing alcohol dehydrogenase 1B vs slow-metabolizing alcohol dehydrogenase 1B: 20.5% vs 71.4%, P = 0.006). Slow-metabolizing alcohol dehydrogenase 1B (relative risk [95% confidence interval]: 3.17 [1.49-6.73]), inactive aldehyde dehydrogenase 2 (2.17 [1.01-4.63]) and poorly-metabolizing cytochrome P450 2A6 (4.63 [1.74-12.33]) had a significantly higher total number of second primary esophageal squamous-cell carcinoma per 100 person-years. In the multivariate Cox proportional-hazards model, slow-metabolizing alcohol dehydrogenase 1B was a significant risk factor of the development of second primary esophageal squamous-cell carcinoma (hazard ratio 9.92, 95% confidence interval: 2.35-41.98, P = 0.0018). CONCLUSIONS: Slow-metabolizing alcohol dehydrogenase 1B may be a significant risk factor for the development of second primary esophageal squamous-cell carcinoma. In addition, inactive aldehyde dehydrogenase 2 and poorly-metabolizing cytochrome P450 2A6 may be important factors.

Prognostic Benefit of Additional Treatment After Endoscopic Submucosal Dissection for Esophageal Squamous Cell Carcinoma.

BACKGROUND: Although additional treatment is considered for patients with esophageal squamous cell carcinoma (ESCC) invading into the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic submucosal dissection (ESD), the actual benefits of this method remain to be elucidated. AIMS: We aimed to evaluate the prognostic benefits of additional treatment in such patients. METHODS: Between 2006 and 2017, we enrolled patients with pT1a-MM/pT1b-SM ESCC after ESD at 21 institutions in Japan. Overall survival (OS) and disease-specific survival (DSS) were compared between the additional treatment and follow-up groups after propensity score matching, to reduce the bias of baseline characteristics. A subgroup analysis was performed according to the pathological findings: category A, pT1a-MM but negative for lymphovascular invasion (LVI) and vertical margin (VM); category B, tumor invasion into the submucosa ≤ 200 µm but negative for LVI and VM; category C, others. RESULTS: Of 593 patients with pT1a-MM/pT1b-SM ESCC after ESD, 101 matched pairs were extracted after propensity score matching. The OSs were similar between the additional treatment and follow-up groups (80.6% vs. 78.6% in 5 years; P = 0.972). In a subgroup analysis, the OS in the additional treatment group was significantly lower than that in the follow-up group (65.7% vs. 95.2% in 5 years; P = 0.037) in category A, whereas OS did not significantly differ in category C (76.8% vs. 69.5% in 5 years; P = 0.360). CONCLUSIONS: Additional treatment after ESD in patients with pT1a-MM/pT1b-SM ESCC was not associated with an improved prognosis.

Blue light imaging and linked color imaging as a screening mode for esophageal squamous cell carcinoma in high-risk patients: Multicenter randomized trial.

OBJECTIVES: Blue light imaging (BLI) and linked color imaging (LCI) are superior to conventional white light imaging for detecting esophageal squamous cell carcinoma (ESCC). Hence, we compared their diagnostic performances in ESCC screening. METHODS: This open-labeled, randomized controlled trial was performed at seven hospitals. Patients with a high risk of ESCC were randomly assigned to the BLI group (BLI followed by LCI) and LCI group (LCI followed by BLI). The primary end-point was the detection rate of ESCC in the primary mode. The main secondary end-point was its miss rate in the primary mode. RESULTS: In total, 699 patients were enrolled. The detection rate of ESCC did not significantly differ between the BLI and LCI groups (4.0% [14/351] vs. 4.9% [17/348]; P = 0.565); however, the number of patients with ESCC tended to be smaller in the BLI group (19 vs. 30). Notably, the miss rate of ESCC was lower in the BLI group (26.3% [5/19] vs. 63.3% [19/30]; P = 0.012) and LCI detected no ESCCs missed by BLI. The sensitivity was higher in BLI (75.0% vs. 47.6%; P = 0.042); on the other hand, the positive predictive value in BLI tended to be lower (28.8% vs. 45.5%; P = 0.092). CONCLUSIONS: The detection rates of ESCC did not significantly differ between BLI and LCI. Although BLI may have the potential to be advantageous over LCI for the diagnosis of ESCC, it is still unclear whether BLI is superior to LCI, and a further large-scale study is needed. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT1022190018-1).

Nitric oxide could promote development of Barrett's esophagus by S-nitrosylation-induced inhibition of Rho-ROCK signaling in esophageal fibroblasts.

Barrett's esophagus arises in the process of wound healing in distal esophageal epithelium damaged by gastroesophageal reflux disease. Differentiation of fibroblast into myofibroblasts, a smooth muscle cell-like phenotype and tissue contraction are crucial processes in wound healing. No study has evaluated mechanism by which luminal esophageal nitric oxide (NO) affect Rho-associated coiled coil-forming protein kinase (Rho-ROCK) signaling pathway, a key factor of tissue contraction, in stromal fibroblasts to develop Barrett's esophagus. Using esophageal fibroblasts, we performed collagen-based cell contraction assays and evaluated influence of Rho-ROCK signaling in the exposure to acidic bile salts and NOC-9, which is an NO donor. We found that enhanced cell contraction induced by acidic bile salts was inhibited by NO, accompanied by decrease in phosphorylated myosin light chain expression and stress fiber formation. NO directly S-nitrosylated GTP-RhoA and consequently blocked Rho-ROCK signaling. Moreover, exposure to NO and Y27632, a Rho-ROCK signaling inhibitor, decreased α-SMA expression and increased bone morphogenetic protein-4 (BMP4) expression and secretion. These findings could account for the increased expression of BMP4 in the columnar epithelial cells and stromal fibroblasts in human Barrett's esophagus. NO could impair wound contraction by blocking the Rho-ROCK signaling pathway and promote the development of Barrett's esophagus.NEW & NOTEWORTHY Barrett's esophagus is the condition where esophageal epithelium damaged by gastroesophageal reflux disease (GERD) is abnormally healed via replacing of metaplastic columnar epithelium, but very few studies have conducted focusing wound healing in the development of Barrett's esophagus. Esophageal luminal nitric oxide inhibits Rho-ROCK signaling pathway in esophageal fibroblasts, which leads to delay tissue contraction, a pivotal step in proper wound healing. Moreover, this inhibition increases tissue BMP4 expression. Impaired wound healing could be related to Barrett's esophagus.

Effectiveness of second-look endoscopy after gastric endoscopic submucosal dissection in patients taking antithrombotic agents: a multicenter propensity score matching analysis.

BACKGROUND: The risk of bleeding after gastric endoscopic submucosal dissection (ESD) in antithrombotic agent users has increased, and its management remains a problem. Second-look endoscopy (SLE) following gastric ESD in antithrombotic agent users may be effective in preventing delayed bleeding, but this requires elucidation. Therefore, this study aimed to investigate the efficacy of SLE in reducing bleeding after gastric ESD in patients receiving antithrombotic agents. METHODS: This retrospective cohort study was conducted at 19 referral hospitals in Japan. A total of 1,245 patients who were receiving antithrombotic agents underwent gastric ESD between January 2013 and July 2018. The incidence of delayed bleeding was compared between SLE and non-SLE groups using propensity score matching analysis. RESULTS: Overall, 858 patients (SLE group, 657 patients; non-SLE group, 201 patients) were analyzed. After matching, 198 pairs were created. Delayed bleeding occurred in 10 patients (5.1%) in the SLE group and 16 patients (8.1%) in the non-SLE group [odds ratio (OR) 0.605, 95% confidence interval (CI) 0.23-1.46, p = 0.310]. In the subgroup analysis, SLE reduced the incidence of delayed bleeding in patients receiving heparin bridging therapy (6.3% and 40.0%, respectively; p = 0.004). In the SLE group, prophylactic coagulation did not significantly reduce delayed bleeding compared to the no treatment group (14.6% and 8.6%, respectively; p = 0.140). CONCLUSIONS: SLE was ineffective in reducing bleeding after gastric ESD in antithrombotic agent users, overall. A prospective comparative study is warranted to definitively evaluate the effectiveness of SLE in reducing bleeding in high-risk patients.

Is Additional Gastrectomy Required for Elderly Patients after Endoscopic Submucosal Dissection with Endoscopic Curability C-2 for Early Gastric Cancer?

BACKGROUND: With the ongoing growth of the aged population, the number of elderly patients suffering from gastric cancer has increased in Japan. Since the frequency of lymph node metastasis (LNM) in patients after endoscopic submucosal dissection (ESD) with endoscopic curability (eCura) C-2 for early gastric cancer (EGC) is relative low, the following question can be raised: "Is additional gastrectomy required for elderly patients with such criteria for ESD?" SUMMARY: For therapeutic decision-making after ESD with eCura C-2, the risk of all-cause mortality and impaired quality of life (QoL) should thus be evaluated. Risk stratification of LNM and gastric cancer-specific mortality was established by the eCura system; however, it remains unclear how much these categories and treatment selection affect all-cause mortality. The contribution of prognostic tools for predicting all-cause mortality was noted to vary across the studies of patients with EGC; thus, further studies that investigate comprehensive geriatric assessment (CGA) may be required. Regarding the QoL, studies on elderly patients remain to be lacking. Furthermore, one of the issues with CGA and QoL tools is that they are time consuming. Key Messages: Combined evaluation of risk stratification of gastric cancer-specific mortality by the eCura system and risk of nongastric cancer-related mortality and impaired QoL may be the current optimal method to decide treatment strategy after ESD with eCura C-2 for EGC among elderly patients. A large-scale prospective study that investigates CGA domains is required to identify predictors of all-cause mortality and impaired QoL, and a more easily usable tool should be developed.

Clinical Outcomes of Small Infantile Hemangiomas Treated With Pulsed Dye Laser.

BACKGROUND: Infantile hemangioma (IH) often causes cosmetic disfigurement. Early intervention with propranolol for large, high-risk lesions is recommended in the American Academy of Pediatrics' Clinical Practice Guideline. Conversely, strategies for the management of small, low-risk lesions have not been established; however, pulsed dye laser (PDL) is often used to treat these lesions. OBJECTIVE: To investigate clinical outcomes of PDL in small IH lesions. PATIENTS AND METHODS: Fifty-three cases with 58 small IHs which did not meet the criteria for high-risk lesions in the guideline and were treated only with PDL were retrospectively reviewed. The characteristics of IHs and residual skin changes after treatment were evaluated. RESULTS: Forty-seven lesions (81.0%) were superficial hemangiomas, whereas 11 (19.0%) were combined-type. The median maximum diameter was 10.0 mm. Forty-five lesions (77.6%) exhibited various residual skin changes after PDL treatment, including anetoderma (53.5%), telangiectasia and erythema (43.1%), hyperpigmentation (34.5%), redundant skin (3.4%), and fibrofatty tissue (3.4%). Of these, the incidence of anetoderma and fibrofatty tissue were significantly higher in the combined group than in the superficial group ( p = .036 and .033, respectively). CONCLUSION: Even small lesions, especially combined-type, often result in cosmetic problems after PDL treatment.

Linked Color Imaging Focused on Neoplasm Detection in the Upper Gastrointestinal Tract : A Randomized Trial.

BACKGROUND: Linked color imaging (LCI) is a new image-enhanced endoscopy technique that allows users to recognize slight differences in mucosal color. OBJECTIVE: To compare the performance of LCI with white light imaging (WLI) in detecting neoplastic lesions in the upper gastrointestinal tract. DESIGN: A controlled, multicenter trial with randomization using minimization. (University Hospital Medical Information Network Clinical Trials Registry: UMIN000023863). SETTING: 16 university hospitals and 3 tertiary care hospitals in Japan. PATIENTS: 1502 patients with known previous or current cancer of the gastrointestinal tract and undergoing surveillance for gastrointestinal cancer. INTERVENTION: WLI followed by LCI examination (WLI group) or LCI followed by WLI examination (LCI group). MEASUREMENTS: Diagnosis of 1 or more neoplastic lesions in the pharynx, esophagus, or stomach in the first examination (primary outcome) and 1 or more neoplastic lesions overlooked in the first examination (secondary outcome). RESULTS: 752 patients were assigned to the WLI group and 750 to the LCI group. The percentage of patients with 1 or more neoplastic lesions diagnosed in the first examination was higher with LCI than with WLI (60 of 750 patients or 8.0% [95% CI, 6.2% to 10.2%] vs. 36 of 752 patients or 4.8% [CI, 3.4% to 6.6%]; risk ratio, 1.67 [CI, 1.12 to 2.50; P = 0.011]). The proportion with overlooked neoplasms was lower in the LCI group than in the WLI group (5 of 750 patients or 0.67% [CI, 0.2% to 1.6%] vs. 26 of 752 patients or 3.5% [CI, 2.3% to 5.0%]; risk ratio, 0.19 [CI, 0.07 to 0.50]). LIMITATION: Endoscopists were not blinded. CONCLUSION: LCI is more effective than WLI for detecting neoplastic lesions in the pharynx, esophagus, and stomach. PRIMARY FUNDING SOURCE: Fujifilm Corporation.

Decreased Expression of NRF2 Target Genes after Alcohol Exposure in the Background Esophageal Mucosa of Patients with Esophageal Squamous Cell Carcinoma.

Patients with esophageal squamous cell carcinoma (ESCC) might have a specific mechanism for the carcinogenesis by alcohol consumption in the background esophageal mucosa, and nuclear factor erythroid 2-related factor 2 (NRF2), which plays a protective role against esophageal carcinogenesis, and barrier dysfunction might be associated with this phenomenon. This study aimed to confirm this hypothesis. Twenty patients with superficial ESCCs (ESCC patients) and 20 age- and sex-matched patients without ESCC (non-ESCC patients) were enrolled. Biopsy samples were obtained from non-neoplastic esophageal mucosa: one for histological evaluation, one for quantitative real-time polymerase chain reaction (PCR), and two for the mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) and, thereafter, for PCR. The TEER after acetaldehyde or both acetaldehyde and ethanol exposure did not differ significantly between ESCC and non-ESCC patients. Unlike non-ESCC patients, mRNA levels of NRF2 target genes and claudin4 in ESCC patients tended to decrease after the exposure, with a significant difference between no exposure and both acetaldehyde and ethanol exposure in NRF2 target genes (p < 0.05). Furthermore, in ESCC patients, the decreased tendency of mRNA levels of NRF2 target genes after the exposure was more pronounced in high-risk states, such as aldehyde dehydrogenase 2 (ALDH2) Lys alleles (Glu/Lys + Lys/Lys), Lugol-voiding lesion grade C, and drinking history. In conclusion, the protective role of NRF2 against carcinogenesis from alcohol exposure might be disrupted in the background esophageal mucosa of ESCC patients, which might lead to a high incidence of metachronous ESCC.

Kyoto classification risk scoring system and endoscopic grading of gastric intestinal metaplasia for gastric cancer: Multicenter observation study in Japan.

OBJECTIVES: The usefulness of endoscopic and histological risk assessment for gastric cancer (GC) has not been fully investigated in Japanese clinical practice. METHODS: In this multicenter observation study, GC and non-GC patients were prospectively enrolled in 10 Japanese facilities. The Kyoto classification risk scoring system, the Kimura-Takemoto endoscopic atrophy classification, the endoscopic grading of gastric intestinal metaplasia (EGGIM), the operative link on gastritis assessment (OLGA) and the operative link on gastric intestinal metaplasia assessment (OLGIM) were applied to all patients. The strength of an association with GC risk was compared. In addition, important endoscopic findings in the Kyoto classification were identified. RESULTS: Overall, 115 GC and 265 non-GC patients were analyzed. Each risk stratification method had a significant association with GC risk in univariate analysis. In multivariate analysis, OLGIM stage III/IV (odds ratio [OR] 2.8 [95% CI 1.5-5.3]), high EGGIM score (OR 1.8 [1.0-3.1]) and opened-type Kimura-Takemoto (OR 2.5 [1.4-4.5]) had significant associations with GC risk. In the Kyoto classification, opened-type endoscopic atrophy, invisible regular arrangement of collecting venules (RAC), extensive (>30%) intestinal metaplasia in the corpus in image-enhanced endoscopy, and map-like redness in the corpus were independent high-risk endoscopic findings. The modified Kyoto classification risk scoring system using these four findings demonstrated a better area under the receiver operating characteristic curve value (0.750, P = 0.052) than that of the original Kyoto classification (0.706). CONCLUSIONS: The OLGIM stage III/IV, high EGGIM score and open-typed Kimura-Takemoto had strong association with GC risk in Japanese patients. The modified Kyoto classification risk scoring system may be useful for GC risk assessment, which warrants further validation. (UMIN000027023).