Introduction

Chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in hematological malignancies, but remain largely ineffective in solid tumors such as pancreatic ductal adenocarcinoma (PDAC). Major barriers include CAR-T cell dysfunction, poor infiltration, and limited persistence within the immunosuppressive tumor microenvironment. STING (stimulator of interferon genes) activation can remodel this environment by inducing inflammation and reversing cancer immune privilege. However, the use of STING agonists in combination with CAR-T cells is hampered by T cell-intrinsic STING signaling, which induces T cell dysfunction and apoptosis.

Aims & Methods

To overcome these limitations, we investigated the therapeutic potential of combining STING agonists with CAR-T cells genetically ablated for STING for the treatment of PDAC. Using CRISPR-Cas9-edited CAR-T cells and the STING agonist diABZI, we assessed antitumor activity in vitro using a CAR-T cell exhaustion model and in vivo using both a cell line-derived xenograft and a syngeneic mouse model.

Results

The combination of STING^KO CAR-T cells and diABZI substantially enhanced CAR-T cell function. In vitro, we observed improved tumor cell killing, increased CAR-T cell proliferation, reduced expression of exhaustion markers, and expansion of an effector-memory phenotype. These effects required genetic deletion of STING in CAR-T cells and were dependent on cancer cell-intrinsic STING signaling. Mechanistically, we identified a synergistic feedback loop, in which CAR-T cell-derived IFN-γ and TNF-α enhanced STING signaling in cancer cells, further promoting beneficial CAR-T cell states. In vivo, this combination achieved superior tumor control in both xenograft and syngeneic mouse models.

Conclusion

Our findings demonstrate that STING^KO CAR-T cells can be effectively combined with STING agonists to enhance therapeutic efficacy in immune-cold tumors such as PDAC. This strategy represents a promising approach to overcoming current barriers in CAR-T cell therapy for solid tumors.

Disclosure

I.P. reports reimbursement of travel expenses from Roche and received third-party funding for scientific research from Novartis. A.G. received research support from Tabby Therapeutics and from Nanogami for work unrelated to the paper. M.S. has received research funding from Amgen, BMS/Celgene, Gilead/Kite, Janssen, Miltenyi Biotech, Molecular Partners, Novartis, Roche, Seagen and Takeda, honoraria from AbbVie, Amgen, AvenCell, BMS, CanCell Therapeutics, Gilead, Janssen, Miltenyi Biomedicine, Molecular Partners, Pfizer and Roche and was invited as speaker by AstraZeneca, BMS, Gilead/Kite, GSK, Janssen, LAWG, Novartis, Pfizer, Roche and Springer Healthcare. S. K. has received honoraria from Cymab, Plectonic, TCR2 Inc., Miltenyi, Galapagos, Novartis, BMS and GSK. S. K. is an inventor of several patents in the field of immuno-oncology. S. K. received license fees from TCR2 Inc and Carina Biotech. S.K. received research support from TCR2 Inc., Tabby Therapeutics, Catalym GmBH, Plectonic GmBH and Arcus Bioscience for work unrelated to the manuscript. The other authors have no competing interests to declare.

Introduction

Endoscopic submucosal dissection (ESD) is a valuable technique for the en-bloc resection of superficial neoplasms in the anal canal. However, its safety and efficacy in patients who have previously undergone transanal endoscopic surgery (TES) —such as transanal minimally invasive surgery (TAMIS) and transanal endoscopic microsurgery (TEM)—remain unclear.

Aims & Methods

To assess the safety and outcomes of ESD in the anal canal for patients with a history of TES compared to naïve patients.
A retrospective analysis was conducted at our tertiary center on 51 patients who underwent ESD in the anal canal between March 2010 and November 2024. Patients with a history of transanal endoscopic surgery were compared to those undergoing ESD as their primary treatment. Key parameters, including resection speed, perforation rates, coagrasper usage, inpatient status, late hemorrhage, and recurrence, were evaluated. Statistical analysis was performed to determine significant differences between groups.

Results

Histological examination confirmed the following cases: 3 adenocarcinomas (including 1 non-curative ESD), 15 adenomas with high-grade dysplasia, 11 adenomas with low-grade dysplasia, 2 sessile serrated lesions, 15 sessile serrated lesions with dysplasia, 2 high-grade intraepithelial lesions, 2 low-grade intraepithelial lesions.
The median resection velocity was slightly lower in patients with recurrence (16.01 mm²/min) compared to those without recurrence (25.56 mm²/min), though this difference did not reach statistical significance (p = 0.062). Perforation occurred in 9.62% of cases, with similar rates between groups (p = 0.58), suggesting that prior TEM does not significantly increase the risk of this complication. Late hemorrhage was observed in 7.84% of patients, again without a significant difference between groups (p = 0.29).
The only statistically significant finding was the smaller lesion size in patients with recurrence (1,162 mm² vs. 2,250 mm², p = 0.045). This is likely due to intensive post-TEM surveillance, which allowed for early detection of recurrence before lesions could grow larger. Other factors, including sex, age, use of coagrasper during the procedure, en-bloc resection, R0 status, and inpatient admission rates, showed no significant differences between groups.

Conclusion

ESD in the anal canal after prior TES appears to be a safe and feasible procedure, with outcomes statistically comparable to those in naïve patients. Although absolute numbers suggest differences, particularly in lesion size, these findings may be influenced by the small sample size. Larger studies are needed to confirm these results and further evaluate long-term efficacy.

Introduction

Gastrointestinal endoscopy is considered a key examination in the setting of anemia workup. However, the yield of esophagogastroduodenoscopy (EGD) and colonoscopy varies depending on the patient's presentation and the type of anemia.

Aims & Methods

The aim of our study was to evaluate the efficiency of EGD and colonoscopy in adult patients with anemia. We retrospectively analysed patients who underwent EGD or colonoscopy for anemia workup in our department between 2018 and 2024. Patients with symptoms suggestive of another cause of anemia were excluded. Additionally, patients who presented with gastrointestinal symptoms and patients with a history of gastrointestinal disease or surgery that could be related to the occurrence of the anemia were also excluded.

Results

A total of 564 patients were included in the study, with a mean age of 72 ±12.8 years. The majority of patients were women (52.8%). 84.9% of the patients underwent EGD, and 49.8% underwent colonoscopy. Overall, 34.8% of patients underwent both examinations. Furthermore, an additional 17.5% were not required to undergo the second examination due to a concrete cause of anemia being found in the initial examination, raising the percentage of patients who completed evaluation to 295 (52.3%). Most of the patients had iron deficiency anemia (IDA) (68.7%). 163 (28.9%) patients had an endoscopic finding that was considered the cause of anemia. EGD yielded significant findings in 119 (24.8%) patients, and colonoscopy in 46 (16.4%) patients. The most prevalent finding of colonoscopy was colon cancer (27 patients), while the most prevalent findings of EGD were peptic ulcer disease (37 patients), stomach cancer (24 patients), and severe atrophic gastritis (18 patients). There was a significant association between the type of anemia and the diagnostic yield of endoscopy, with endoscopic findings being significantly more prevalent in patients with IDA (36.1%) compared to patients without (13.8%) (p < 0.001).

Conclusion

Gastrointestinal endoscopy is the cornerstone examination in patients with unexplained IDA. Conversely, in patients with non-IDA anemia, while endoscopy retains significant diagnostic value, a simultaneous workup for other causes outside the gastrointestinal system is also indicated.

Introduction

Functional bowel disorders are characterized by the presence of altered bowel habits with or without abdominal pain.¹ Irritable bowel syndrome (IBS) is diagnosed based on recurrent abdominal pain; however, distinctions in the clinical phenotypes of IBS subtypes and other functional bowel disorders (FBDs), such as functional diarrhea (FD) and functional constipation (FC), remain underexplored.^2,3

Aims & Methods

Aims: This study aimed to characterize the clinical presentation of IBS with predominant constipation (IBS-D) and IBS with predominant diarrhea (IBS-C), differentiating them from FD and FC, while recognizing the overlapping symptoms and the continuum between these conditions. Additionally, we examined the prevalence of psychological disorders and extra-intestinal comorbidities and identified potential mediators linking IBS to anxiety and depression.
Methods: Using data from the Rome Foundation Global Epidemiology Study, we analyzed 54,127 participants across 26 countries, including 2,195 patients with IBS. Clinical, dietary and psychological characteristics were assessed using validated questionnaires. Subgroup analyses compared IBS subtypes with FBDs, while mediation analyses (using the PROCESS macro and Baron and Kenny's method⁴) identified mediators of IBS-psychological distress relationship.

Results

As compared to patients with IBS-D, patients with IBS-C reported more severe pain characteristics, including prolonged pain episodes (50.7% vs. 47.0% of the time with pain lasting >30 minutes, p=0.030) and pain episodes that escalated to a sustained severe intensity (44.2% vs. 38.1%, p=0.026), frequently accompanied by back pain (36.7% vs. 30.9%, p<0.001). Regular use of prescribed pain medications was also more frequent in IBS-C (39.3%) than IBS-D (31.8%, p=0.004). In contrast, as compared to IBS-C, patients with IBS-D showed a stronger association of pain with changes in stool consistency (70% vs. 60% of time with pain, p<0.001) and frequency (mean 61.3% vs. 57.8% of time with pain, p=0.008). These associations remained significant in multiple regression models, which confirmed that IBS-C is more strongly linked to prolonged and escalating pain episodes, while IBS-D is more closely linked to pain associated with changes in stool frequency and consistency. As compared to FD, IBS-D patients reported greater dissatisfaction with bowel function (57.3±28.4 vs. 44.2±29.8, p<0.001), and more frequent loose stools (without constipation treatments) (60.0% vs. 50.0% of bowel movements, p<0.001), particularly after meals (60.0% vs. 40.0% of loose stools, p<0.001). IBS-C shows more severe constipation-related symptoms compared to FC (p<0.001). Mediation analyses revealed that concerns about bowel function, embarrassment discussing it, and work-related impairments partially mediated the relationship between IBS and psychological distress.

Conclusion

IBS-C is associated with more severe pain episodes, including prolonged and escalating pain, while in IBS-D pain is more strongly linked to bowel habit changes. These findings highlight the distinct clinical profiles of IBS subtypes and emphasize the need for personalized, multimodal management strategies. Identifying mediators of psychological distress in IBS can guide targeted interventions, improving patient outcomes.

References

1. Lacy, B. E. et al. Bowel Disorders. Gastroenterology (2016) doi:10.1053/j.gastro.2016.02.031.
2. Savarino, E. et al. Functional bowel disorders with diarrhoea: Clinical guidelines of the United European Gastroenterology and European Society for Neurogastroenterology and Motility. United European Gastroenterol J 10, 556–584 (2022).
3. Mearin, F. et al. Clinical Practice Guideline: Irritable bowel syndrome with constipation and functional constipation in the adult. Revista espanola de enfermedades digestivas 108, 332–63 (2016).
4. Baron, R. M. & Kenny, D. A. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol 51, 1173–82 (1986).