Introduction

Ineffective esophageal motility (IEM) is a rare motility disorder characterized by weak or failed peristalsis at high-resolution manometry (HRM). There is an established association between IEM and gastroesophageal reflux-disease (GERD) symptoms. However, it is unclear why some patients present with dysphagia. In this study we aimed to investigated whether dysphagia in IEM is associated with specific HRM or pH-impedance monitoring (MII-pH) findings.

Aims & Methods

Adults (≥18 y) who underwent HRM for upper gastrointestinal symptoms who were diagnosed with IEM according to Chicago v4.0 between January 2021 and November 2024 were included. Patients’ gender, age, symptoms (dysphagia, chest pain, heartburn, regurgitation, belching), response to proton pump inhibitor (PPI) treatment and HRM data were recorded. All patients underwent MII-pH. Wilcoxon rank sum test, Pearson's chi-squared test and Fisher's exact test were used for comparisons. Significance was set at p<0.05.

Results

In the study period, 54 patients were diagnosed with IEM. Of them, 33 (61%) did not report dysphagia (IEM-GERD), while 21 (39%) had dysphagia (IEM-DYSPHAGIA). Of note, patients with or without dysphagia had a comparable prevalence of heartburn, chest pain, regurgitation, and erosive esophagitis. In addition, IEM-GERD and IEM-DYSPHAGIA were comparable in age and response to PPI treatment. IEM-GERD and IEM-DYSPHAGIA did not show significant differences in EGJ type, EGJ contractile integral (EGJ-CI), integrated relaxation pressure (IRP), percentage of ineffective or failed swallows, or the rapid drinking challenge (RDC) findings (p>0.05 for all), demonstrating an overall similar pathophysiology of peristalsis and EGJ opening. In terms of MII-pH, there was no statistical difference in GERD-related parameters between IEM-GERD and IEM-DYSPHAGIA, who showed comparable values of acid exposure time (AET), mean nocturnal baseline impedance (MNBI), symptoms association indexes (SI), and post-reflux swallow-induced peristatlic wave index (PSPW-I) (p>0.05 for all).

Conclusion

We showed that dysphagia in IEM is not explained by impaired EGJ outflow or worse peristalsis. IEM with and without dysphagia have a similar proportion of GERD symptoms, comparable MII-pH findings, and respond similarly to PPI treatment. Our findings suggest that dysphagia in IEM could be a symptomatic manifestation of GERD.
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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.

Introduction

Although traditionally regarded as a vestigial organ, the appendix is increasingly recognized for its potential role in modulating gut immunity and contributing to the development of significant inflammatory or neoplastic intestinal diseases [1]. However, the underlying mechanisms linking the appendix to these immune and pathological processes remain poorly understood. This study aimed to investigate the relationship between the local immune microenvironment and the mutational landscape of rectal carcinomas in the context of prior or progressive appendectomy status.

Aims & Methods

This study aimed to investigate the relationship between the local immune microenvironment and the mutational landscape of rectal carcinomas in the context of prior or progressive appendectomy status.
Patients enrolled in the IMMUNOREACT 1 and 2 studies (NCT04915326 and NCT04917263, respectively) were stratified according to appendectomy status. Immunohistochemical analysis was performed to assess a range of immune markers, including CD3, CD4, CD8, CD8β, Tbet, FoxP3, PD-L1, MSH6, PMS2, and CD80. Additionally, flow cytometry was employed to evaluate the percentage of epithelial cells expressing CD80, CD86, CD40, HLA-ABC, or HLA-DR, as well as to quantify activated CD8+ T cells, CD4+ Th1 cells, and regulatory T cells (Tregs). Non-parametric tests were used.

Results

In this cohort, 41 patients out of 163 underwent appendectomy for other causes (e.g. appendicitis) before having been diagnosed with a rectal cancer. When the two groups were compared for microenvironmental features, in the normal mucosa of patients who had a previous appendectomy there was a higher rate of epithelial cells expressing HLA-abc (p=0,04) and a higher expression of CTLA4 on CD3+ T cells (p=0,03) when compared to appendectomy-naive patients. Within the rectal cancer tissue, a higher expression of CD86 on epithelial (cancer) cells expression was found in patients who already had an appendectomy (p=0,03). In therapy naïve patients, previous appendectomy was associated to a higher activation of CD4+ T helpers (expression of CD25), (p=0.04), and to tendency of higher rate of epithelial cells expressing HLA-abc (p=0,06) and of T cells expressing CTLA-4 (p=0.08). In patients who had neoadjuvant therapy, lower level of PD-L1 on the leukocyte surface were observed in patients who had a previous appendectomy (p=0.039).

Conclusion

Our findings suggest that prior appendectomy may be associated with distinct alterations in the local immune microenvironment of rectal carcinomas, including increased expression of antigen-presenting and immune-regulatory molecules such as HLA-BC, CTLA4, and CD86. In therapy naïve patients, appendectomy seem to increase the activation of T helper cells counterbalanced by an increase of the number of T cells expressing CTLA-4. These immune shifts in both tumour tissue and adjacent healthy mucosa support the hypothesis that the appendectomy may in somehow alter the interaction between epithelia cells and intraepithelial T cells. Further trancriptomic ​analysis will shed light on the effect of appendectomy on mucosal microevironment of ​rectal cancer patients.

References

1. Collard MK, Tourneur-Marsille J, Uzzan M, Albuquerque M, Roy M, Dumay A, Freund JN, Hugot JP, Guedj N, Treton X, Panis Y, Ogier-Denis E. The Appendix Orchestrates T-Cell Mediated Immunosurveillance in Colitis-Associated Cancer. Cell Mol Gastroenterol Hepatol. 2023;15(3):665-687.