Introduction

The etiology of gastroesophageal reflux disease (GERD) is unknown but reflux-induced esophageal injury as a result of cytokine-mediated inflammation has been implicated (1). There is emerging evidence duodenal immune activation may be associated with an increased risk of GERD (2). Celiac disease is strongly associated with GERD which improves upon removal of gluten (3). The duodenum is the first major part of the gut to process food and swallowed aerosol antigens, and is a master controller of upper gut motility. The role of duodenal inflammation in GERD, if any, remains understudied. Assessing T-helper (Th) subsets using chemokine staining has been previously documented and allows the use of archived gut samples (4). We aimed to identify if there is a duodenal Th signal in GERD.

Aims & Methods

Two retrospective case control studies. Study 1; Duodenal biopsies of 3 groups: 1) GERD (n=22), defined as abnormal acid exposure time on 24-pH monitoring, with or without positive symptom association probability (GERD-SAP+ and GERD-SAP-). 2) Healthy controls (n=17): no symptoms, endoscopic or histological abnormalities. 3) Disease controls: Eosinophilic duodenitis (EoD): (n=8). Blinded histological review of duodenal samples to assess cellular and architectural changes. Dual Immunohistochemistry (IHC) was optimized to identify CD4-Th subsets using the chemokine staining patterns: Th1(CD4+CCR4-CCR5+CCR6-), Th2 (CD4+CCR4+CCR5-CCR6-) and Th17(CD4+CCR4+CCR5-CCR6+). Immunofluorescence confirmed co-staining. Dual IHC and blinded quantitative intensity measuring (H-score) were performed using HALO software. Clinical and histological data were collected. One-way Anova was used to compare signal intensity to controls. A positive signal is defined as a statistically significant higher co-staining of CD4-chemokine stain compared to controls. Study 2: Same methods used to assess esophageal T-helper signal in reflux esophagitis (LA Grade B and higher) (RE) (n=16) compared to eosinophilic esophagitis (EoE) (n=31), lymphocytic esophagitis (LE) (n=12) and healthy controls (n=11).

Results

Considering duodenal histopathology (study 1), no differences were found in any of the mean inflammatory cell counts and no architectural abnormalities comparing GERD to healthy controls. Considering duodenal IHC, the CD4 and CD8 intensities were not significantly higher in GERD compared to controls (p=0.96 and 0.96, respectively). GERD- SAP+ demonstrated a significantly higher Th2 intensity than controls (p=0.01), with no difference in Th1(p=0.55) and Th17 intensities (p= 0.27). A significantly higher Th17 intensity was found in EoD (p=0.006). Duodenal Th2 intensity was significantly higher in GERD with a history of atopy (p=0.035), upright reflux (p=0.037), low esophageal contraction amplitude (p=0.0025) and failed peristalsis (p=0.048). Th1 and Th17 intensities were not higher in any of the GERD subgroups compared to controls. Considering esophageal IHC (study 2), CD8 intensity was significantly elevated in RE (p=0.002), but the CD4 intensity was not (p=0.059). RE had a higher Th2 intensity with no difference in other Th markers (p<0.0001). Th-17 intensity was higher in EoE and LE (p=0.0017 and p<0.0001).

Conclusion

A significantly increased duodenal Th-2 signal is found in established GERD when present with a positive symptom association probability, while an increased esophageal Th-2 signal is found in documented reflux esophagitis. The role of immune activation in GERD deserves further investigation.

References

1. Souza RF, Huo X, Mittal V, et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury.
2. Ronkainen J, Aro P, Walker MM, et al.. Duodenal eosinophilia is associated with functional dyspepsia and new onset gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2019 Jul;50(1):24-32.
3. Irani MZ, Eslick GD, Burns GL, et al. Coeliac disease is a strong risk factor for Gastro-oesophageal reflux disease while a gluten free diet is protective: a systematic review and meta-analysis. EClinicalMedicine. 2024;71
4.Oki M, Ohtani H, Kinouchi Y, et al. Accumulation of CCR5+ T cells around RANTES+ granulomas in Crohn's disease: a pivotal site of Th1-shifted immune response? Laboratory investigation. 2005;85(1):137-45.

Disclosure

Nicholas J. Talley: Disclosures: GutSee Ltd (consulting microbiome, 2025), Brown University, Agency for Health Care Research and Quality (fiber and laxation) (2024), Rome Foundation (member gastroduodenal committee) (present) Biocodex (FD diagnostic tool) (present) Microba (consulting microbiome - commencing 2025) Comvita Manuka Honey (FD trial consulting) (2025), BluMaiden outside the submitted work. In addition, Dr. Talley has a patent Nepean Dyspepsia Index (NDI) 1998, a patent Licensing Questionnaires Talley Bowel Disease Questionnaire licensed to Mayo/Talley, “Diagnostic marker for functional gastrointestinal disorders” Australian Provisional Patent Application
2021901692, ”Methods and compositions for treating age-related neurodegenerative disease associated with dysbiosis” US Patent Application No. 63/537,725. Boards: The Gut Foundation Board (2025-present), Asia Pacific Association of Medical Editors (APAME) Board (President 2023-2025), Doctors for the Environment (Chair 2024-present), Luminal Faculty GESA (Chair) (2023-2025) Editorial: UptoDate (Section Editor), Mayo Clinic Proceeding Associate Editor (2023-present)
Financial support: Dr. Talley is supported by funding from the National Health and Medical Research Council (NHMRC) to the Centre for Research Excellence in Digestive Health and he holds an NHMRC Investigator grant.

Introduction

Currently, there is no established treatment strategy for obstructive unresectable colorectal cancer (OUCC). The European Society of Gastrointestinal Endoscopy guidelines suggest that colonic self-expandable metallic stent (SEMS) followed by chemotherapy can be safely performed, but Japanese guidelines suggested negative recommendation due to risk of SEMS-related complications. However, colonic SEMS has the advantage of early introduction of chemotherapy compared to other decompression methods, and avoidance of stoma creation, but its safety and efficacy are globally unknown.

Aims & Methods

Patients diagnosed with OUCC at initial presentation from April 2012 to December 2022, implanted with a SEMS, and introduced systemic chemotherapy within 3 months after implantation were included. The endpoints of this study were perforation during SEMS implantation and progression-free survival (PFS).

Results

A total of 302 patients were included from 26 centers, and 289 patients were included in the final analysis. The median age was 68 years, 59.2% were male, 10.7% had PS2-3, 11.1% had more than 3 metastatic organs, and 46.7% had RAS-mutated. Anti-EGFR antibody drugs were used in 30.8% and Bevacizumab in 19.0% of patients in 1^st line therapy. The time from implantation to the start of chemotherapy was 11 (IQR: 6-21days). The cumulative perforation rate was 8.7% and the median time of occurrence was 144 days. The perforation rate with Bevacizumab usage was higher, but the difference was not statistically significant (14.5% vs 7.3%, P=0.107). Anti-EGFR antibody usage was not statistically associated with SEMS-related complications. The response rate was 57.9%. Primary resection was performed in 34.9% of patients, and the time to resection was 129 days. Median PFS was 9.2 months. Univariate analysis showed significant differences in PFS for age, number of metastatic organs, perforation, Triplet regimen, anti-EGFR antibody, primary tumor resection, and colostomy, and independent prognostic factors in the Cox proportional hazards model were number of metastatic organs (≥3: HR 1.63, 95% CI 1.08-2.47), perforation (HR 1.72, 95% CI 1.10-2.69), and no primary resection (HR 4.22, 95% CI 2.88-6.20).

Conclusion

Obstruction itself is a poor prognostic factor, and patients with OUCC may tolerate treatment less well than non‑obstructed patients, particularly when angiogenesis inhibitors are difficult to use. Within this context, the efficacy of post‑SEMS chemotherapy in our cohort appears acceptable. However, given the relatively high perforation rate, early resection of the primary tumor should be considered in patients expected to continue and benefit from systemic therapy.

Introduction

The lymphocyte-to-monocyte ratio (LMR) is widely utilized as a surrogate marker of systemic inflammation and is increasingly recognized as an indicator of immune status within the tumor microenvironment, particularly in the setting of cancer immunotherapy.

Aims & Methods

^​​​​​This study aimed to evaluate the prognostic relevance of LMR in patients undergoing combination therapy with durvalumab (Dur) and tremelimumab (Tre) for unresectable hepatocellular carcinoma (uHCC). A total of 242 patients with uHCC who received Dur/Tre therapy at multiple institutions between February 2023 and March 2025 were retrospectively analyzed. Inclusion criteria encompassed available baseline LMR, Child-Pugh class A liver function, and complete clinical data. Patient characteristics were as follows: median age 74.0 years (IQR: 68.3–77.0); sex distribution, 202 males and 40 females; performance status (PS) 0/1/≥2: 201/32/9; underlying liver disease (HBV/HCV/HBV+HCV/NBNC): 37/72/1/132; BCLC stage (≤A/B/≥C): 19/68/155; Child-Pugh score (5/6): 125/117; alpha-fetoprotein (AFP) level: 57.6 ng/mL (IQR: 4.3–909.8); LMR: 3.14 (2.18–4.15); treatment line (first-/second-line): 94/148; and median observation period: 9.0 months (5.0–14.2).

Results

The median progression-free survival (PFS) and overall survival (OS) were 3.5 months (2.8–4.3) and 19.2 months (15.4–NA), respectively. Time-dependent ROC analysis identified 2.15 as the optimal LMR cutoff at 25% of the observation period (15.4 months). Objective response rates per RECIST version 1.1 were as follows: complete response (CR), 3.2%; partial response (PR), 15.5%; stable disease (SD), 32.4%; and progressive disease (PD), 48.9%. Disease control rate (DCR) was significantly higher in the LMR ≥2.15 group compared to the <2.15 group (55.4% vs. 37.3%, p = 0.026). Patients with LMR ≥2.15 demonstrated significantly longer PFS (3.8 months [95% CI: 3.8–4.6] vs. 2.7 months [95% CI: 2.00–4.00]; p= 0.005) and OS (NA months [95% CI NA: –17.9] vs. 13.2 months [95% CI: 8.5–17.1]; p = 0.005). In multivariate analysis using the Cox proportional hazards model, LMR ≥2.15 emerged as an independent predictor of both PFS (HR = 0.622; 95% CI: 0.438–0.884; p = 0.008) and OS (HR = 0.558; 95% CI: 0.328–0.949; p = 0.031). Hazard ratio approximation curves indicated that the range of LMR associated with significant prognostic impact on both PFS and OS was approximately 1.6 to 2.4. Subgroup analysis further demonstrated that in first-line treatment settings, patients with LMR ≥2.15 had superior PFS and OS outcomes compared to those with LMR <2.15 (PFS: p = 0.028; OS: p = 0.016).

Conclusion

​​​​LMR serves as a valuable prognostic biomarker in patients receiving Dur/Tre combination therapy for uHCC, with potential utility in guiding therapeutic decision-making.

Disclosure

Toshifumi Tada: lecture fees from AbbVie, Eisai, and Chugai
Atsushi Hiraoka: lecture fees from Eisai, Bayer, Eli Lilly, and Otsuka
Hidenori Toyoda: lecture fees from AbbVie, Eisai, Gilead, Terumo, and Bayer

Introduction

The management of malignant hilar biliary obstruction can be done by endoscopic biliary stenting, which is a well-established palliative treatment, improving the quality of life by relieving symptoms.

Aims & Methods

This systematic review and meta-analysis aimed to compare the use of stents placed above and across the sphincter of Oddi in patients with malignant hilar biliary obstruction. We performed a systematic search of the PubMed, Embase, and Cochrane Library databases in April 2025. Article screening was conducted independently by two authors using Rayyan software. Inclusion criteria were randomized controlled trials (RCTs) comparing stent placement above and across the sphincter of Oddi for malignant hilar biliary obstruction, evaluating at least one of the outcomes of interest. The outcomes were stent migration, stent patency, cholangitis, stent occlusion, and successful placement of the stent. RStudio software was used for statistical analysis, applying a random-effects model to calculate the risk ratio (RR) in binary outcomes and mean differences (MD) in continuous outcomes.

Results

We included three RCTs comprising 161 patients. There was no significant difference between the transpapillary and suprapapillary stents regarding the rates of stent migration (RR 2.03; 95% CI 0.41–10.16; p=0.39; I²=55%), cholangitis (RR 0.65; 95% CI 0.08–5.07; p=0.68; I²=0%), technical success (RR 0.99; 95% CI 0.95–1.04; p=0.80; I²=0%), and stent occlusion (MD 89.20; 95% CI 16.30–162.10; p=0.02; I²=78%). However, the mean number of patent stents was significantly lower in the suprapapillary stent group.

Conclusion

The two types of stent seem similar in terms of technique, efficacy, and safety, although the suprapapillary stent seems superior in terms of stent patency.

References

Ko SW, Joo HD, Song TJ, Kim S, Choi SJ, Oh CH, Oh D, Park JS, Yoon SB, Yoon JH, Seo DW, Lee SK. Impact of the suprapapillary method on patency in distal malignant biliary obstruction: a multicenter randomized controlled trial. Gastrointest Endosc. 2024 Oct;100(4):679-687.e1. doi: 10.1016/j.gie.2024.03.024. Epub 2024 Mar 21. PMID: 38521477.
Kurita A, Uza N, Asada M, Yoshimura K, Takemura T, Yazumi S, Kodama Y, Seno H. Stent placement above the sphincter of Oddi is a useful option for patients with inoperable malignant hilar biliary obstruction. Surg Endosc. 2022 May;36(5):2869-2878. doi: 10.1007/s00464-021-08576-x. Epub 2021 Jun 2. PMID: 34076770.
Finn Møller Pedersen, MD, Annmarie Touborg Lassen, Ove B. Schaffalitzky de Muckadell. Finn Møller Pedersen, MD, Annmarie Touborg Lassen, Ove B. Schaffalitzky de Muckadell. Gastroint Endosc. 1998;48(6):574-579.

Introduction

In the carcinogenic pathway of colorectal cancer, the first concept is the "adenoma-carcinoma sequence" and the second concept is the " serrated pathway ". In these concepts, adenomas and serrated lesions gradually progress to cancer. The third concept is the "de novo pathway," in which cancer develops without adenomas or serrated lesions and is also characterized by high malignancy and rapid progression. We have endoscopically characterized depressed colorectal cancers considered to be of the "de novo pathway" and validated the usefulness of pit pattern and EC classification.

Aims & Methods

A total of 54819 colorectal neoplasms were resected endoscopically or surgically in our institution from April 2001 to December 2024. They were subjects of this study. Advanced cancers were excluded. Of these, 1694 lesions were submucosally invasive (T1) carcinomas, 7330 lesions were classified as high-grade dysplasia and 39977 lesions as low-grade dysplasia. Morphologically, they were divided into 3 types: depressed, flat, and protruded type comprising 1.0 (%), 46.4 (%),and 52.6（%), respectively. Specifically, the distinctive features of depressed type neoplasms concerning their pit pattern and EC classification were examined. EC classification is a classification for an endocytoscopy that can evaluate pathology, such as nuclear atypia and glandular structure, by magnifying stained cells. EC1a is diagnosed as normal mucosa, EC1b is diagnosed as hyperplastic polyps, and if slit-like glandular ducts or spindle-shaped nuclei are present, it is classified as EC2 and diagnosed as an adenoma or intramucosal carcinoma. If irregularly shaped glandular ducts or nuclei with a high N/C ratio are found, it is classified as EC3a, and diagnosed as intramucosal carcinoma or SM lightly invasive carcinoma. If the glandular ducts are indistinct and the nucleus is irregularly shaped and darkly stained, it is classified as EC3b and diagnosed as SM highly invasive carcinoma.

Results

Most of the flat (91.5%) and protruded type (94.9%) lesions showed type IIIL or IV pit pattern, which are common findings in adenomas. On the other hand, most of the depressed type lesions (92.6%) classified as type IIIs, VI or VN pit patterns, are typically seen in carcinomas. As for endocytoscopy, most of flat and protruded type lesions were identified as EC2 corresponding to adenomas. In contrast, relatively high rates of depressed type lesions were categorized as EC3a (40.3%) and EC3b (52.4%), consistent with invasive carcinomas.
The proportion of T1 carcinomas in depressed type lesions was 58.7%, whereas in flat and protruded type lesions it was 2.5% and 2.5%, respectively. Additionally, 12.0% of depressed type lesions less than 5mm in diameter were T1 carcinomas, whereas flat and protruded type lesions were 0.01% and 0%, respectively.

Conclusion

This study revealed that depressed lesions were classified as type IIIs, VI or VN pit patterns on magnifying endoscopy and as type EC3a or EC3b on endocytoscopy. Lesions with these features or pit patterns tend to invade the submucosal layer even if they are small size. Despite their high potential for malignancy, depressed lesions are often ignored. However, it is critical to recognize their features and accurately diagnose lesions based on morphology, pit pattern, and EC classification.

Disclosure

Shin-ei Kudo and Masashi Misawa received speaking honoraria from Olympus Corporation and have an ownership interest of the products of Cybernet Systems. Tetsuo Nemoto received a research grant from Olympus Corporation for other studies. Other authors have nothing to declare.

Introduction

Gastroparesis is a disorder characterized by delayed gastric emptying without mechanical obstruction, leading to symptoms such as nausea, vomiting, abdominal pain, and bloating. Cannabis and its active compounds are thought to interact with the gastrointestinal system through cannabinoid receptors, influencing motility, sensation, and inflammation. Nevertheless, data pertaining to the interactions between cannabis use, gastric motility and gastrointestinal (GI) symptoms is still scant¹.

Aims & Methods

The aim of the current study was to compare GI symptoms and gastric motility in a cohort of patients referred for gastric emptying breath test (GEBT). In this prospective study, all consecutive patients referred for motility testing in a tertiary hospital were recruited. Following obtaining written informed consent, questionnaires, including ROME, SCL-90-R and SF36 were filled out by the patients. Carbon-13 spirulina GEBT was done performed according to protocol, following consumption of a standardized meal. Patients with ongoing (regular or occasional) cannabis use were compared with non-cannabis users for all symptoms, quality of life and GEBT testing results. An additional healthy cohort of volunteers was recruited for validation of GEBT cut-off values and comparison to the symptomatic cohort.

Results

A total of 88 patients and 14 healthy volunteers were included in the current study. Among patients, 15 (17%) were identified as cannabis users, and these were compared with 73 non-users. Mean age and gender did not differ between users and non-users (52.4 vs 43.0, and 21% vs 33% males, respectively, p=NS). Gastric emptying breath test results did not significantly differ between groups, both in terms of mean values (t^1/2 127.2 vs 129.2 minutes, users versus non-users, respectively; p=NS) and in the proportion of delayed gastric emptying (26.7% versus 32.9%, users versus non-users, respectively; p=NS). None of the healthy volunteers displayed delayed gastric emptying results. Cannabis users demonstrated a higher gastrointestinal symptom burden and a greater number of diagnosed disorders of gut-brain interaction (DGBI) compared to non-users.

Conclusion

In our cohort of patients referred for gastric emptying breath tests, gastric emptying was similar between cannabis users and non-users. This is in line with previous studies suggesting that cannabis does not improve delayed gastric emptying. Nevertheless, previous studies suggested that cannabis may alleviate gastroparesis-associated symptoms². In this context, our results show that cannabis use was rather associated a more severe and systemic symptomatic manifestation of gut-brain disorders, in contrast to a more localized upper gastrointestinal involvement seen in non-users. Although causality cannot be established, we do note that despite ongoing cannabis use, treatment response was sub-optimal in the user patient group. Factors contributing to these differences, such as physiological or psychological constructs, should be further explored.

References

¹Parkman HP et al. Marijuana Use in Patients with Symptoms of Gastroparesis: Prevalence, Patient Characteristics, and Perceived Benefit. Dig Dis Sci. 2020
²Barbash, B et al. Cannabinoids Lead to Significant Improvement in Gastroparesis—Related Abdominal Pain: 1204. American Journal of Gastroenterology 2018.

Clinical Case Summary

A 75-year-old male under follow-up for chronic anemia secondary to multiple gastrointestinal angiodysplasias. He required transfusions every two weeks and maintained a baseline hemoglobin level of around 7–8 g/dL despite repeated therapeutic endoscopy with argon plasma coagulation. In light of this, he began daily treatment with oral Thalidomide 50 mg, with a good response for three years. At that point, he developed persistent melena and also experienced a deep vein thrombosis attributed to the treatment, leading to its discontinuation. The regimen was then changed to subcutaneous Octreotide 10 mg monthly, later intensified to 30 mg per month. Despite this, he continued to have recurrent gastrointestinal bleeding and multiple hospital admissions due to anemia-related symptoms. With no other treatment options available, a weekly dose of 30 mg was prescribed, achieving a good response for two years. Eventually, due to loss of efficacy and refractoriness to other treatments, compassionate use of Bevacizumab was initiated at a dose of 7.5 mg/kg monthly. From the beginning and after three doses, the patient became asymptomatic and experienced no further bleeding episodes, maintaining hemoglobin levels around 12–13 g/dL.
Gastrointestinal angiodysplasias are a common and significant condition due to the increased demand they place on healthcare services. Their management is complex, and treatment options are limited, particularly in cases that are refractory to standardized therapies. In such patients, the use of Bevacizumab can be considered. Although evidence is limited, it shows promising results, as demonstrated in our case.

References

Figure 1. Enteroscopy image showing angiodysplasia in the small intestine
Figure 2. Therapeutic enteroscopy, image prior to argon plasma coagulation therapy
Figure 3. Capsule endoscopy image showing angiodysplasia in the small intestine
Figure 4. Another capsule endoscopy image showing active bleeding secondary to one of the angiodysplasias