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Introduction: Esophageal cancer-associated fistula is strongly linked to elevated mortality. This study aims to investigate the impact of endoscopic closure on outcomes in patients with esophageal cancer-related fistula.

Methods: We retrospectively analyzed the clinical data of patients with esophageal cancer-related fistula. These patients were categorized into endoscopic closure group and conservative treatment group. The Clinical Pulmonary Infection Score (CPIS) gap, duration of hospitalization, ICU admission rates, in-hospital mortality rates, and hospitalization costs were compared between endoscopic group and conservative group. Additionally, factors associated with post-fistula survival and healing were assessed.

Results: Univariate and multivariate COX regression analyses revealed that endoscopic closure could significantly improve short-term pulmonary infections based on CPIS gap (3 vs. 2; p = 0.004) but did not influence survival or fistula healing outcomes, and the hospitalization costs were elevated (USD 6,653 vs. USD 3,350; p = 0.005). Subgroup analysis focusing on esophagotracheal fistulas was also consistent with these results. Protective factors associated with improved survival prognosis included higher albumin levels (HR = 0.928, 95% CI: 0.875-0.984, p = 0.012), absence of bloodstream infections (positive blood culture [HR = 23.055, 95% CI: 5.193-102.357, p < 0.001]), non-T4 stage (T4 stage [HR = 1.792, 95% CI: 1.052-3.052, p = 0.032]), and no distant metastasis (distant metastasis [HR = 2.122, 95% CI: 1.127-3.996, p = 0.020]). Cervical esophageal fistula (upper [HR = 0.154, 95% CI: 0.041-0.570, p = 0.005]; middle [HR = 0.128, 95% CI: 0.027-0.609, p = 0.010]; lower [HR = 0.218, 95% CI: 0.052-0.902, p = 0.036]) was significantly associated with improved fistula healing outcomes, while a history of radiotherapy (HR = 0.265, 95% CI: 0.089-0.788, p = 0.017) was a risk factor for esophageal fistula healing.

Conclusion: Our study indicates that multiple factors are significantly associated with the prognosis of patients with esophageal fistula. Endoscopic closure treatment effectively manages short-term infections, but it associates with higher hospitalization costs and does not significantly enhance long-term healing or survival prognosis.

Background: Superficial non-ampullary duodenal epithelial tumors (SNADETs) were previously considered rare. However, the widespread use of health checkup endoscopy, improvements in endoscopic imaging and heightened awareness of SNADETs among endoscopists have recently led to an increase in their detection rate. Particularly for large SNADETs, the possibility of including cancer must be considered, and thus, complete and reliable resection is essential. Although surgical resection has traditionally been the standard treatment, its high invasiveness has led to increased interest in less invasive endoscopic treatments. Nevertheless, due to the unique anatomical and physiological features of the duodenum, endoscopic treatment in the duodenum remains highly challenging and presents many technical difficulties.

Summary: This review provides a comprehensive overview of current endoscopic treatment options for large SNADETs, including conventional endoscopic mucosal resection (C-EMR), underwater endoscopic mucosal resection (U-EMR), cold snare endoscopic mucosal resection (CS-EMR), endoscopic submucosal dissection (ESD), and laparoscopic-endoscopic cooperative surgery, incorporating the latest clinical findings. While C-EMR, U-EMR, and CS-EMR are associated with lower technical difficulty and favorable safety, they tend to show lower en bloc resection rates and higher recurrence rates for large SNADETs when compared to ESD. In contrast, ESD offers higher en bloc resection rates but carries a greater risk of complications due to its technical complexity. To overcome these limitations, several techniques have been developed, such as the pocket-creation method, water pressure method, improved closure strategies for mucosal defects, and drainage with endoscopic nasobiliary and pancreatic drainage to prevent exposure to pancreatic juice and bile.

Key messages: Multiple endoscopic strategies are available for the treatment of large SNADETs. However, due to the rarity of the disease and variation in institutional expertise, a standardized treatment strategy has not yet been established. Endoscopic treatment for large SNADETs is technically very challenging and carries a high risk. Therefore, careful consideration of the indication for each treatment method, along with a full understanding of their respective advantages and disadvantages, is essential. In recent years, the safety of endoscopic resection has been gradually improving due to various technical innovations and better management of adverse events, making ESD, which offers a high en bloc resection rate, an increasingly reasonable treatment option.

Background: Achalasia is a rare primary esophageal motility disorder of the esophageal smooth muscle, characterized by abnormal relaxation of the lower esophageal sphincter and associated with abnormal, spastic, or absent esophageal body peristalsis.

Summary: The primary pathophysiological defect is abnormal esophageal inhibitory nerve function from neuronal death in the esophageal neuronal plexuses and ganglia that control esophageal smooth muscle peristalsis. This is a consequence of an autoimmune cytotoxic insult from molecular mimicry following an intercurrent viral infection, typically herpes simplex virus, varicella zoster virus, human papillomavirus, measles virus, and even the COVID-19 virus. Neuronal inflammation rather than death can lead to an imbalance between excitatory and inhibitory forces, and varying degrees of retained spastic, premature or even normal peristalsis in the smooth muscle esophageal body. Chagas disease caused by Trypanosoma cruzi, eosinophilic inflammation, direct infiltration with neoplastic cells from adjacent cancers, or humoral autoimmune destruction from distant cancers can also result in an achalasia-like syndrome. Mechanical obstruction from tight strictures, anti-reflux or bariatric surgery, and extrinsic compression can mimic the manometric features of achalasia. Chronic opioid medication usage can result in a clinical and pathophysiological syndrome identical to spastic achalasia.

Key messages: Careful clinical evaluation and judicious interpretation of esophageal function tests following pathophysiological principles can lead to an accurate diagnosis of achalasia, opening the door to durable permanent disruption of the malfunctioning esophageal smooth muscle and resulting in symptom relief.

Introduction: Ulcerative colitis (UC) increases the risk of colorectal cancer (CRC). Although 5-aminosalicylic acid (5-ASA) has long been regarded as chemopreventive, it remains unclear whether 5-ASA therapy still confers this benefit when used concomitantly with tumour necrosis factor (TNF) inhibitors.

Methods: We performed a retrospective cohort study using the nationwide Japanese Medical Data Vision database. Patients with UC who initiated TNF inhibitors were followed from the first TNF inhibitor prescription until CRC diagnosis or disenrollment. Concomitant 5-ASA use was defined as prescription within 90 days before or after TNF initiation. Cumulative incidence was compared with Kaplan-Meier curves and the log-rank test; hazard ratios (HRs) were estimated with multivariable Cox regression and inverse probability of treatment weighting (IPTW), adjusting for age, sex, primary sclerosing cholangitis (PSC), diabetes, obesity, immunomodulator use, type of TNF agent, and prior advanced therapy exposure.

Results: Among 9,919 eligible patients, 8,387 (84.6%) received concomitant 5-ASA. During follow-up (median 3.14 years), 161 CRC events occurred: crude incidence 3.67/1,000 person-years (with 5-ASA use) versus 4.58/1,000 person-years (without 5-ASA use) (p = 0.421). Concomitant 5-ASA was not associated with CRC risk (adjusted HR 1.25, 95% CI 0.76-2.04; IPTW-adjusted HR: 1.28, 95% CI: 0.78-2.11). Independent risk factors were older age, male sex, and PSC.

Conclusions: We found no measurable chemopreventive benefit of concomitant 5-ASA in UC patients receiving TNF inhibitors during this treatment phase. Accordingly, 5-ASA need not be prioritised for CRC prevention at this stage. Longer observation is required to clarify any benefit beyond the early years of TNF inhibitors.

Background: Endoscopic resection (ER) is a minimally invasive alternative to surgical resection for superficial non-ampullary duodenal epithelial tumors (SNADETs); however, it carries a high risk of adverse events (AEs) due to the thin duodenal wall and the technical challenges of endoscopic maneuverability. This review discusses the management of intraoperative and delayed postoperative AEs associated with duodenal ER.

Summary: Various ER techniques for SNADETs, including cold snare polypectomy (CSP), endoscopic mucosal resection (EMR), underwater EMR (UEMR), and endoscopic submucosal dissection (ESD), present different risk profiles. CSP has a very low risk of AEs, while EMR and UEMR exhibit moderate AE risks (up to 18.7%) and high recurrence rates, particularly in cases of piecemeal resections. ESD enables high en bloc resection rates but is associated with a considerable risk of AEs (up to 45.5%). Intraoperative AEs can be managed endoscopically using various closure techniques. To prevent intraoperative AEs during ESD, the use of scissor-type knives and specialized methods such as the pocket-creation method and water pressure method may be employed. Delayed AEs require effective closure of mucosal defects to prevent delayed perforation, which poses a high risk of conversion to surgical intervention.

Key messages: Careful patient selection and implementation of preventive strategies are essential to minimize AEs and optimize the safety of duodenal ER. A comprehensive understanding of the risk profiles of different ER techniques, along with appropriate preventive measures, is critical for safe and effective treatment. A multidisciplinary approach involving experienced endoscopists, surgeons, and radiologists is crucial to optimizing patient outcomes.

Background: The recognition of superficial non-ampullary duodenal epithelial tumors (SNADETs) has increased with advancements in endoscopic technology and increased awareness among clinicians. White light imaging (WLI) remains the primary diagnostic modality for SNADETs. However, data for standardized endoscopic diagnostic approaches are lacking.

Summary: SNADETs are typically identified by their whitish, flat-elevated appearance and are predominantly located in the descending duodenum. The whitish mucosa is referred to as milk white mucosa (MWM). Although biopsies are traditionally performed for the diagnosis, biopsies have limited sensitivity for histological grading and may cause submucosal fibrosis, which complicates subsequent endoscopic resection. SNADETs are classified as gastric, gastrointestinal, or intestinal mucin phenotypes. Gastric SNADETs are usually found in the pre-ampullary region and are typically lacking MWM, whereas intestinal-type SNADETs often exhibit MWM. Several endoscopic features under WLI, such as lesion color, size, surface depression, and morphology, are useful for predicting the grade of dysplasia. Features such as a submucosal tumor-like appearance, deep depression, and oral side location are important for assessing submucosal invasion.

Key messages: WLI plays an important role in the detection and initial assessment of SNADETs. Although differentiating SNADETs from other duodenal lesions using WLI alone remains challenging, understanding the endoscopic features associated with each mucin phenotype aids in accurate distinction of high-grade dysplasia from low-grade dysplasia. Future studies are warranted to establish a comprehensive endoscopic diagnostic system for SNADETs.

Introduction: Multichannel intraluminal impedance and pH monitoring (MII-pH) is the gold standard for diagnosing gastroesophageal reflux disease (GERD). However, the clinical value of the symptom-reflux association (SRA) obtained using MII-pH remains unknown. The current study aimed to investigate the effect of SRA on the efficacy of secondary treatment in refractory true GERD.

Methods: This study included patients who underwent MII-pH monitoring for evaluating proton pump inhibitor (PPI)- or potassium-competitive acid blocker (P-CAB)-refractory GERD symptoms and who were diagnosed with abnormal acid reflux (acid exposure time >6%). Patients with a positive symptom index (SI) and symptom association probability on the MII-pH monitoring were included in the SRA-positive group and the remaining ones in the SRA-negative group. The differences in the subsequent treatment efficacy between the two groups were retrospectively analyzed. Treatment efficacy was evaluated using the Frequency Scale for the Symptoms of GERD (FSSG) questionnaire.

Results: Of the 192 patients with PPI-/P-CAB-refractory GERD, 41 (21.4%) were diagnosed with abnormal acid reflux. Among them, 30 (7 in the SRA-positive group and 23 in the SRA-negative group) underwent symptom assessments before and after treatment. The SRA-positive group had a significantly greater symptom improvement after treatment compared with the SRA-negative group (FSSG score changes: -13.0 ± 6.5 vs. -5.4 ± 8.2, p = 0.016).

Conclusions: SRA evaluation is effective in predicting secondary treatment outcomes in patients with abnormal acid reflux.

Background: Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disorder caused by the retrograde flow of gastric contents into the esophagus, leading to bothersome symptoms and complications. Its pathophysiology is complex and multifactorial, and recent research has aimed to explain the heterogeneity of GERD phenotypes, each influenced by different underlying mechanisms that contribute to symptom presentation and disease progression.

Summary: GERD arises from an imbalance between defensive mechanisms and disruptive factors. Key pathophysiological contributors include esophageal gastric junction dysfunction, transient lower esophageal sphincter relaxations, esophageal motility abnormalities, delayed gastric emptying, and thoracoabdominal pressure gradients. Mucosal damage is exacerbated by prolonged exposure to acid and bile, pepsin activity, and impaired esophageal volume and chemical clearance. Additionally, central and peripheral neural modulation influences symptom perception, with heightened visceral sensitivity and esophageal hypervigilance playing significant roles in symptom severity and treatment response. Emerging diagnostic techniques such as high-resolution manometry, impedance-pH monitoring, and EndoFLIP® are improving our ability to identify specific pathophysiological abnormalities, leading to more personalized approaches to GERD management.

Key messages: (i) GERD results from a multifactorial interplay between anatomical, functional, and neurophysiological mechanisms. (ii) Esophageal clearance, EGJ structure and function, acid exposure, mucosal resistance, and neural modulation are crucial determinants of symptom severity and disease progression. (iii) The presence of different phenotypes of the reflux disease (e.g., GERD, functional heartburn, and reflux hypersensitivity) underscores the need for individualized diagnostic and therapeutic strategies. (iv) Advances in diagnostic technologies enhance our understanding of GERD pathophysiology, facilitating tailored management approaches beyond acid suppression therapies. Future research should focus on refining GERD phenotyping and integrating mechanistic insights into personalized treatment paradigms.

Introduction: Non-ampullary duodenal epithelial tumors with a gastrointestinal mixed phenotype (mixed-type NADETs) have not been thoroughly analyzed. We aimed to elucidate the clinicopathological and endoscopic characteristics of mixed-type NADETs.

Methods: A total of 229 NADETs from 218 patients collected from February 2010 to December 2023 were analyzed. Based on immunohistochemistry for MUC5AC, MUC6, MUC2, and CD10, the NADETs were classified into gastric phenotype (GP), gastric predominant mixed phenotype (GPP), intestinal predominant mixed phenotype (IPP), and intestinal phenotype (IP).

Results: Among the 229 NADETs, there were 20, 22, 69, and 118 lesions classified as GP, GPP, IPP, and IP, respectively. Tumor location (first/second/third) was GP = 13/7/0, GPP = 12/8/2, IPP = 13/52/4, and IP = 16/94/8 (p < 0.01). Mean tumor sizes of GP, GPP, IPP, and IP were 14.7/18.5/10.9/10.3 mm (p < 0.01), respectively. The ratio of category 4/5 by Vienna classification was 50.0, 68.2, 13.0, and 2.5% (p < 0.01), respectively. In the comparisons between GP vs. GPP and IP vs. IPP, white opaque substance was significantly less frequently observed in GP than in GPP (p < 0.05), the ratio of category 4/5 was significantly higher in IPP than in IP (p < 0.01), but no significant differences were observed in tumor location, coloration, macroscopic type, and endoscopic findings including magnifying endoscopy with narrow-band imaging.

Conclusion: Mixed-type NADETs (GPP and IPP) exhibited similar endoscopic and clinicopathological characteristics to their predominant phenotypes, and may have a higher malignant potential than the pure phenotypes.

Introduction: We investigated the importance of skin microbiota in functional dyspepsia (FD) based on the skin-gut axis theory and revealed potential mechanisms. This study also validates recent popular FD treatments.

Methods: We used mendelian randomization (MR) to analyze 418 gut bacteria and 145 skin bacteria, identifying key symbionts in FD development. Bibliometric keyword analysis was conducted on current FD therapies. Finally, we used a mouse model of FD to assess body weight, food intake, gastric residue rate, small intestine transit rate, and fecal water content after interventions with skin-gut symbionts and treatment methods. Hematoxylin-eosin staining observed gastric antrum tissue morphology. RhoA and ROCK1 protein and mRNA levels in gastric antrum tissue were detected by western blot and real-time PCR. Fluorescence immunoassay observed ROCK1 and vesicular acetylcholine transporter (VAChT) protein expression.

Results: Streptococcus has a causal relationship with FD. Bibliometric analysis highlighted electroacupuncture as a research hotspot. Skin Streptococcus colonization reduced food intake, body weight, small intestine transit rate, and increased gastric residue rate in FD mice, decreasing RhoA, ROCK1, and VAChT protein and mRNA levels. Antibiotics reversed these effects. Electroacupuncture improved weight, appetite, gastrointestinal motility, and RhoA, ROCK1, and VAChT protein, and mRNA levels in FD mice.

Conclusion: The study confirmed the pathogenic role of skin Streptococcus in FD and the therapeutic value of electroacupuncture at Tianshu acupoint, potentially via RhoA/ROCK1 signaling pathway regulation.