Introduction

Irritable Bowel Syndrome (IBS) is a Disorder of Gut-Brain Interaction (DGBI). The main IBS symptom is chronic abdominal pain. In some cases, this syndrome occurs following a gastrointestinal infection and is then referred to a post-infectious IBS (PI-IBS). The pathophysiological mechanisms remain unknown but could involve alterations in tryptophan metabolism. Its treatments are symptomatic. A mouse model of transient gastrointestinal infection with Citrobacter rodentium has been used to replicate the symptomatology of PI-IBS patients. It has been demonstrated colonic disturbances in tryptophan metabolism at four weeks post-infection (PI), including a decrease in tryptophol in fecal and cecal samples.

Aims & Methods

The aim of this study was to assess tryptophan metabolism alterations at the colonic level in a model of PI-IBS and to explore a therapeutic avenue to relieve intestinal symptoms in this model.
Following infection with C. rodentium (ATCC® 51459™ DBS100) in C57Bl6 mice, concentrations of tryptophan metabolites at the colonic level were analyzed by targeted metabolomic. Moreover, oral treatment with tryptophol (600 mg/kg) was administered twice a day for 8 days after the infectious phase to male and female mice. Colonic sensitivity was assessed using the colorectal distension (CRD) test, and the effect of tryptophol on neuronal activation was analyzed by calcium imaging in primary cultures of dorsal root ganglion (DRG) neurons. Moreover, RT-qPCR analysis were performed on colonic samples targeting the tryptophan metabolism pathways.

Results

Targeted metabolomic analyses revealed a decrease in tryptophol levels at four weeks PI in the colon of C. rodentium infected mice (p=0.036). Furthermore, daily administrations of tryptophol reversed the colonic hypersensitivity observed in infected animals (p=0.037) without sex-dependent differences at 4 weeks PI. In vitro mechanistic exploration revealed that tryptophol does not modify the number of neurons responding to an algogenic stimulation (Capsaicin), but their response intensity was significantly reduced after incubation with tryptophol at 100μM (p=0.018), indicating a neuroinhibitory effect of tryptophol on DRG neurons.

Conclusion

Tryptophol levels are reduced in colon, as in fecal and cecal samples, in a PI-IBS mouse model. Oral supplementation of tryptophol alleviates C. rodentium induced colonic hypersensitivity, likely by inhibiting sensory neurons, suggesting its therapeutic potential. Ongoing analysis should reveal more precisely the mechanisms of action of the tryptophol.

References

Meynier M, Baudu E, Rolhion N, Defaye M, Straube M, Daugey V, Modoux M, Wawrzyniak I, Delbac F, Villéger R, et al. 2022. AhR/IL-22 pathway as new target for the treatment of post-infectious irritable bowel syndrome symptoms. Gut Microbes 14: 2022997.

Introduction

Lynch syndrome (LS), the most common hereditary colorectal cancer (CRC) syndrome, is associated with an increased risk of small bowel malignancies. Given the feasibility of ileal intubation during colonoscopy, this study assesses the prevalence of ileal cancer in a large LS cohort and evaluates ileal intubation as a screening tool.

Aims & Methods

An analysis was performed on Lynch syndrome (LS) patients with ileal cancer enrolled in the prospectively maintained database of the German Consortium for Familial Intestinal Cancer (GCFIC). Demographic characteristics and cancer history were extracted. High-risk pathogenic germline variants (PGVs) were defined as MLH1, MSH2, and EPCAM, while MSH6 and PMS2 were considered low risk.
Additionally, data from 236 LS patients who underwent colonoscopy at a tertiary care center between 2018 and 2023 were retrospectively evaluated. A total of 596 complete colonoscopies were reviewed.

Results

Eight ileal cancers (0.28%) were identified, exclusively in high-risk PGV carriers (MLH1: 62.5%, MSH2: 37.5%), predominantly male (87.5%), with a median age of 56 years. Most cancers (75%) were symptom-detected; only one case was identified through screening. In the tertiary care cohort, ileal intubation was achieved in 96.6% of colonoscopies, leading to the identification of five ileal neoplasms (four adenomas, one carcinoma), all in patients with a history of right hemicolectomy or colectomy. The prevalence of ileal neoplasia in patients without an ileocecal valve was statistically significant at 7.7% (χ²(1, N = 236) = 11.8, p < .001).

Table 1: Cohort characteristics of the German Consortium for Familial Intestinal Cancer

Conclusion

Ileal intubation is a valuable extension of standard colonoscopy, especially for male high-risk PGV carriers with prior CRC and ileocecal valve removal. The strong link between ileal neoplasia and loss of the ileocecal valve suggests a role for colonic reflux, inflammation, and microbiome changes in ileal carcinogenesis.

Disclosure

Robert Hüneburg was funded by Deutsche Krebshilfe (DECADE), and Wilhelm-Sander-Stiftung.
Jacob Nattermann was funded by Wilhelm-Sander-Stiftung.

Introduction

Malignant biliary obstruction (MBO) caused by non-hepatobiliary-pancreatic (non-HBP) malignancies is a rare and underexplored indication for endoscopic retrograde cholangiopancreatography (ERCP). These cases often present a clinical dilemma: while ERCP offers a minimally invasive option, its utility remains uncertain in patients with poor prognosis and advanced disease.

Aims & Methods

We aimed to evaluate the effectiveness of ERCP-guided biliary drainage in this context and identify baseline predictors of clinical failure to help refine patient selection.
We conducted a retrospective analysis of all patients who underwent ERCP for malignant biliary obstruction of non-HBP origin between March 2018 and February 2025. Patients lacking essential clinical or follow-up data were excluded. Technical success was defined as adequate stent placement; clinical success as a ≥50% reduction in bilirubin or resolution of cholangitis within 2 weeks. The predictive role of bilirubin level, stricture location, serum albumin, and ECOG performance status was assessed. A ROC analysis evaluated the discriminative ability of pre-drainage bilirubin.

Results

Forty-eight patients were included (mean age: 55.6 years; 56% women). The most common primary cancers were colorectal (31%, n=15), gastric (18%, n=9), breast (14%, n=7), lung (10%, n=5), and ovarian (8%, n=4). Hilar strictures were observed in 54% (n=26) and mid-to-distal strictures in 46% (n=22). All procedures were performed using plastic stents. In most cases involving hilar strictures, long stents (e.g., 7 Fr / 12–15 cm) were used, and a single biliary sector—usually the most dilated or invaded—was preferentially drained. Technical success was achieved in 85.4% of cases. Clinical success occurred in 54.1% of patients, while early mortality (≤30 days) reached 10.4%, exclusively among individuals with ECOG status 4 and serum albumin <2.8 g/dL. Hilar strictures and total bilirubin levels >200 mg/L were significantly associated with lower clinical success rates (38% vs 65%, p=0.03 and 33% vs 62%, p=0.04, respectively). ROC analysis showed an AUC of 0.72 for bilirubin in predicting failure. Technical failures (14.6%) were mainly due to anatomical distortion or papillary inaccessibility.

Conclusion

Endoscopic biliary drainage in this population is technically achievable but offers limited clinical benefit, especially in cases with hilar involvement, severe hyperbilirubinemia, or poor overall condition. These findings emphasize the importance of using simple, baseline clinical indicators to guide treatment decisions, avoid unnecessary interventions, and adapt care strategies to the realities of resource-limited settings.

Disclosure

I have no conflict of interest.

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

Besides analgesia, opioids affect gastrointestinal (GI) motility, including decreased bowel peristalsis and delayed gastric emptying. Peripherally acting mu-opioid receptor antagonists, like naloxegol, are approved for treating opioid-induced constipation.

Aims & Methods

We aimed to evaluate the effects of naloxegol on opioid-induced lower GI tract dysfunction using magnetic resonance imaging (MRI) to assess changes in colonic volumes in healthy volunteers (HV).
In this double-blind, randomised, three-way crossover study, 15 HV complete three study visits, separated by ≥1 week washout, with administration of 25 mg naloxegol + 60 mg codeine, 60 mg codeine + placebo, or double placebo. During each visit, five abdominal MRI scans (each 20 min.) are obtained at 30 min intervals, at baseline, after drug intake, after a standardized 44 g oatmeal and 100 mL Nutridrink (313 kCal) meal, after a second drug dose, and after a bisacodyl 10 mg suppository administration. Colonic segmental volumes were quantified from all MRI scans using Entrolytics (Motilent, London, UK) in the ascending, transverse, descending, and rectosigmoid colon. We recorded the passage of stool during the study visit. Results are presented as medians with min. and max. P-values <0.05 are considered statistically significant. Adjusted p-values are used in case of post-hoc analysis.

Results

Interim analysis on 8 HVs (mean age 36±5y, 75% females) revealed that two subjects made stool on 2 mornings before the study visit. Four subjects passed stool in the double placebo group (2 postprandial, 2 post-bisacodyl), and 2 of them passed stool in the other 2 groups as well, around the same time. A significant scan x group effect was found for the whole colon volumes (p<0.05). More specifically, there was a significant difference in median ascending colon volumes between the scans (p=0.03), and especially in the double placebo group (Table). Although there was no significant difference in the median transverse colon volumes, bisacodyl led to a significant decrease in descending colon volume (p<0.0001), more specifically in the naloxegol+codein group and the double placebo group (ps<0.05), but not in the codein+placebo group. No significant differences in volumes of the rectosigmoid were detected.

Conclusion

Interim MRI analysis of 8 HVs suggests different colonic motility responses across groups and timepoints. Toilet visits were suppressed in both codeine groups. Different responses to drug and food intake were found in the ascending and descending colon between the naloxegol+codein and double placebo group on one hand compared to the codein+placebo group. Expansion and analysis of the full number of subjects will further clarify insights into the acute colonic responses to opioids and potential reversal by naloxegol.

Introduction

Gastric emptying is controlled by phasic gastric contractions which occur at a frequency of ~3 cycles per minute (cpm) in phase with gastric slow waves. Tests to measure slow waves cannot directly detect abnormal contractions. The Atmo Capsule possesses an accelerometer that measures changes in capsule orientation and can thus detect gastric contractions. We analyzed accelerometer data to define its capability to characterize gastric contraction frequency and amplitude in patients with suspected dysmotility, and to assess if frequency or amplitude vary in relation to transit delay.

Aims & Methods

Gut transit was measured by the Atmo Capsule in 209 subjects: 48 with predominant upper GI (UGI) symptoms alone (suspected gastroparesis), 21 with lower GI (LGI) symptoms (suspected slow colon transit) alone, and 140 with combined UGI+LGI symptoms. This analysis utilized data from subjects recording valid gastric emptying time (GET) measures and did not incur protocol deviations affecting gastric transit. Delays in GET were categorized as: normal, <5 h; delayed, 5-10 h; severely delayed, ≥10 h. Fast Fourier Transformation (FFT) of the accelerometer data allows for the identification and analysis of the dominant gastric frequency and amplitude using 10-minute windows and a cutoff frequency of 4.5 cpm. Variability of frequency and amplitude measures were estimated by calculating interquartile range (IQR) and range (max-min) values and were analyzed in relation to presenting symptoms and gastric emptying delays.

Results

Gastric data from 190 subjects were suitable for analysis: gastric contractions with dominant frequencies of 3.30 cpm (IQR 0.47, range 1.47) and amplitudes of 0.10 arbitrary units (au) (IQR 0.04, range 0.14) were detected in 185 (97%) of subjects. Mean contraction frequency tended to be higher in those with delayed GET compared with no delay (p=0.016) and severe delay (p=0.005) (Table 1). Frequency IQR (p=0.002) and range (p=0.002) were higher for GET delay vs. no delay, while range was higher in severe GET delay vs no delay (p<0.001). Mean amplitude was higher in subjects with severe GET delay compared with normal delay (p=0.008) and normal transit (p=0.001). Amplitude IQR and range were both higher in those with severe GET delay compared with normal delay (p=0.002; p=0.001) and no delay (p<0.001 for both). Frequency metrics were similar irrespective of predominant symptoms. Amplitude means (p=0.022), IQR (p=0.030) and range (p=0.0004) were higher for UGI vs. LGI symptoms.

Table 1. Dominant gastric frequencies and amplitudes in relation to gastric emptying delays. Data shown as median (interquartile range) and analyzed via Kruskal-Wallis test.

Conclusion

The Atmo Capsule accelerometer reliably characterizes 3 cpm gastric contraction frequency and amplitude in subjects with proposed delays in gut transit. Increased variabilities in contraction frequency and amplitude were defined in those with severely delayed gastric emptying and increased amplitude variability was found for predominant upper GI symptoms. We propose these higher variations identified by accelerometry may reflect hypomotility or contractile dropout, suggesting additional clinical utility of the Atmo Capsule in suspected gastroparesis.

Disclosure

These authors disclose the following: Braden Kuo, Anthony J. Lembo, Eammon M.M. Quigley, Satish S.C. Rao, and William D. Chey serve on the Medical Advisory Board of Atmo Biosciences. Michael Cline and Baharak Moshiree served on the Medical Advisory Board of Atmo Biosciences. Braden Kuo has received funding from NIH, Vanda, Atmo Biosciences, and Takeda and has consulted for Evoke, Takeda, Ironwood, Novo Nordisk, Cindome, and Neurogastrx. Thomas Abell has received funding from Gastric Dysrhythmias, Neurogastrx, NIH GpCRC, and Vanda and has consulted for Enterra Medical, Novo Nordisk, Nuvaira, and Vanda. Anthony J. Lembo has received funding from Ardelyx, Biomerica, GSK, Ironwood, Takeda, and Vibrant and holds stock with Allurion, Bristol Myer Squibb, and J&J. Abigail Stocker has received funding from Cindome, Enterra Medical, and Vanda. William D. Chey has received funding from Atmo Biosciences, Commonwealth Diagnostics Intl, QOL Medical, and Salix; has consulted for AbbVie, Ardelyx, Biomerica, Comvita, Gemelli, Ironwood, Nestle, QOL Medical, Phathom, Redhill, Salix, Vibrant, and Takeda; has filed patents with My Nutrition Health, Digital Manometry, and Rectal Expulsion Device; and holds stock options with Coprata, Evinature, Food Marble, Kiwi Bioscience, and Modify Health. The remaining authors disclose no conflicts.