Clinical Case Summary

An 80-year-old woman with a history of right ovarian cancer, treated with total hysterectomy and bilateral salpingo-oophorectomy followed by adjuvant radiotherapy in 1984, presented with tenesmus and rectal bleeding. She had long-standing radiation-induced enteritis. Colonoscopy revealed a 50mm ulcerated neoplasm in the distal rectum. Histopathological analysis confirmed a low-grade rectal adenocarcinoma with loss of nuclear expression of the mismatch repair proteins MSH2 and MSH6. Staging with thoracoabdominal CT and pelvic MRI showed a distal rectal adenocarcinoma invading the vagina and levator ani muscle (cT4), cN0, with a suspicious left inguinal lymph node (possible cM1). Given her prior exposure to pelvic radiotherapy and the presence of chronic radiation-induced injury, a multidisciplinary team, after discussion with the patient and her family, decided to initiate off-label neoadjuvant treatment with dostarlimab for six months, completing a total of eight cycles. Six weeks after completion of immunotherapy, flexible sigmoidoscopy demonstrated a clinical near-complete response (near-cCR) and pelvic MRI showed radiologic complete response (rCR), with no evidence of residual tumor or lymphadenopathy. A new flexible sigmoidoscopy is scheduled in four weeks. If cCR is confirmed, the patient will enter a Watch and Wait surveillance program. Traditionally, rectal cancer treatment has relied on a combination of chemoradiotherapy and surgery, resulting in pathologic complete response in up to 25% of patients, but frequently associated with complications and treatment-related toxicity. Recent studies have demonstrated promising results with immune checkpoint inhibitors, particularly dostarlimab as single agent, an antiprogrammed cell death protein 1 monoclonal antibody. In recent studies so far, this agent was remarkably effective in mismatch repair–deficient, locally advanced rectal cancer, showing high rates of cCR and prolonged overall survival.

References

Andrea Cercek et al, A Phase Two, Single-Arm, Open-Label Study With Dostarlimab Monotherapy in Participants With Untreated Stage II/III dMMR/MSI-H Locally Advanced Rectal Cancer (AZUR-1), Clinical Colorectal Cancer

A. Cercek, M. Lumish, J. Sinopoli, J. Weiss, J. Shia, M. Lamendola-Essel, I.H. El Dika, N. Segal, M. Shcherba, R. Sugarman, Z. Stadler, R. Yaeger, J.J. Smith, B. Rousseau, G. Argiles, M. Patel, A. Desai, L.B. Saltz, M. Widmar, K. Iyer, J. Zhang, N. Gianino, C. Crane, P.B. Romesser, E.P. Pappou, P. Paty, J. Garcia-Aguilar, M. Gonen, M. Gollub, M.R. Weiser, K.A. Schalper, L.A. Diaz Jr. PD-1 BLockade in Mismatch Repair-deficient, Locally Advanced Rectal Cancer

Introduction

Gastric hyperplastic polyps (GHPs) carry a neoplastic transformation risk of up to 5%, with previous studies indicating an increased risk with larger polyp size. We aimed to evaluate the frequency and risk factors of its malignant transformation in a Portuguese cohort.

Aims & Methods

A multicenter retrospective cohort study was conducted including all patients undergoing endoscopic resection of GHPs ≥10mm from January 2013 to January 2024 in Portuguese tertiary reference centers. Patients with hereditary polyposis syndromes were excluded. Demographic, clinical, endoscopic, and histopathological data were collected.

Results

A total of 782 GHPs from eight centers were evaluated. The median age was 68 years (IQR 60-75), and 58.8% were female. Evidence of advanced gastritis stage (OLGIM≥3) and synchronous gastric neoplasia were present in 57 (10.2%) and 37 (4.7%) cases, respectively. The median lesion size was 15 mm (IQR 12-20), and most presented a polypoid morphology (96.8%). Most GHPs were removed by endoscopic mucosal resection (86.6%), followed by cold snare polypectomy (8.1%) endoscopic submucosal dissection (3.6%), and cold snare EMR (1.7%), achieving en-bloc resection in 677 cases (86.6%). Neoplastic transformation was observed in 33 polyps (4.2%) – 25 (3.2%) low/high-grade dysplasia and 8 (1.0%) adenocarcinoma; the resection was non-curative in 30.3% of cases.
In the multivariate analysis, OLGIM≥3 (OR 4.994, 95%CI 1.036-24.065), lesion size ≥25 mm (OR 7.973, 95%CI 7.973 (1.242-51.180), flat/depressed morphology (OR 9.57, 95%CI 1.096-83.712) and synchronous gastric neoplasia (OR 16.956, 95%CI 2.737-105.045) were independently associated with a higher risk of malignant transformation.

Conclusion

The risk of malignant transformation of GHPs in non-neglectable, with lesion size and morphology and concomitant precancerous gastric conditions/lesions being associated with a higher risk. Nevertheless, the rate of non-curative endoscopic resection is high. The identification of these features may help for optimizing and tailoring the selection of adequate endoscopic resection techniques and surveillance strategies in high-risk patients.

Introduction

Approximately 50% of patients with Ulcerative Colitis (UC) suffer from daily symptoms of faecal urgency, significantly impacting their quality of life¹. Treatment in quiescent disease is challenging and the first line treatment, loperamide, is often used with caution due to the side effect of constipation.
Enterosorbents such as Enterosgel provide a potential alternative treatment. Enterosgel is thought to work through the adsorption of small molecules in the gastrointestinal (GI) tract, with minimal or no systemic absorption and metabolism², without causing constipation. Enterosgel has shown clinical effectiveness in reducing urgency in patients with diarrhoea predominant irritable bowel syndrome (IBS-D), suggesting potential therapeutic value in patients with UC³, however the mechanism by which this may occur is unknown.

Aims & Methods

This study aimed to evaluate the in vitro adsorption capacity of Enterosgel for three key inflammatory mediators implicated in UC pathogenesis (IL-1β, MMP9 and TNF-α) to explore its potential as a therapeutic option in this patient group.
Three experimental paradigms were performed by diluting recombinant cytokines and enzymes in water-based Enterosgel solutions. After incubation, gel-free supernatants were harvested to analyse residual levels of metabolite via ELISA to identify the quantity of adsorption by Enterosgel. Conditions were conducted with different:

1. Incubation times (15,30,60,120 min)
2. Metabolite concentrations (5 concentrations ranging from 0 - 3000pg/mL)
3. Gel concentrations (0.056, 0.1125, 0.225g/mL)

Results

Enterosgel demonstrated measurable concentration-dependent adsorption of IL-1β, MMP9 and TNF-α with higher analyte input concentrations resulting in greater absolute adsorption. However for TNF-α adsorption saturated at 1000pg/mL, indicating that Enterosgel may not fully adsorb analytes at levels simulating extreme luminal inflammation. Charcoal consistently resulted in lower residual concentrations, although this did not reach statistical significance on permutation testing (p = 0.14).
In time dependent analysis, Enterosgel induced a rapid initial reduction in cytokine levels within 15 minutes, (IL-1β: 98.7%, MMP9: 99.4%, TNF-α: 95.8% adsorbed) with a plateau by 120 minutes (IL-1β: r²=0.74, MMP9: r²=0.64, TNF-α: r²=0.45). In contrast, charcoal demonstrated a near-linear monotonic decline with a slightly greater concentration adsorbed by 120 minutes (IL-1β: 99.9% vs. 99.8%; MMP9: 99.9% vs. 99.1%; TNF-α: 97.2 vs. 96.3%). Increasing gel concentrations improved adsorption efficiency; however, at the highest gel concentration small amounts of residual cytokines remained (IL-1β: 0.25%, MMP9: 0.28%, TNF-α: 3.5%). Doubling of gel concentration led to an average 30% decrease in residual cytokines.

Conclusion

Our findings suggest that Enterosgel demonstrates excellent adsorption of three key pro-inflammatory cytokines relevant to UC, with the greatest reduction at 1 hour and the highest gel concentration—though less than that achieved by charcoal. Evidence of saturation at high analyte levels suggests a limit to Enterosgel’s binding capacity under conditions simulating severe inflammation. These results highlight Enterosgel's clinical potential, however further validation with biological replicates and clinical studies assessing urgency in treated UC is required.

References

(1) Theresa Hunter Gibble, April N. Naegeli, Michael Grabner, Keith Isenberg, Mingyang Shan, et al. Identification of inadequate responders to advanced therapy among commercially-insured adult patients with Crohn’s disease and ulcerative colitis in the United States. 2023; 63 (23): 10.1186/s12876-023-02675-w.
(2) Howell CA, Mikhalovsky SV, Markaryan EN, Khovanov AV. Investigation of the adsorption capacity of the enterosorbent Enterosgel for a range of bacterial toxins, bile acids and pharmaceutical drugs. Scientific Reports. 2019; 9 (1): 10.1038/s41598-019-42176-z.
(3) Howell CA, Kemppinen A, Allgar V, Dodd M, Knowles CH, Mclaughlin J, et al. Double-blinded randomised placebo controlled trial of enterosgel (polymethylsiloxane polyhydrate) for the treatment of IBS with diarrhoea (IBS-D). BMJ; 2022.
(4) Shane O'Sullivan, John F Gilmer, Carols Medina. Matrix Metalloproteinases in Inflammatory Bowel Disease: An Update. Mediators of Inflammation. 2015; 2015 (1): 10.1155/2015/964131.
(5) Qingdong Guan JZ. Recent Advances: The Imbalance of Cytokines in the Pathogenesis of Inflammatory Bowel Disease. Mediators of Inflammation. 2017; 2017 (1): 10.1155/2017/4810258.

Introduction

The NLRP3 inflammasome is crucial in regulating innate immune responses, balancing inflammation and homeostasis. It acts as a sensor for danger signals, facilitates the release of pro-inflammatory cytokines and plays a role in TGFβ, NF-κB, and IL-6/JAK/STAT3 signaling. Although the NLRP3 inflammasome is well known for its role in inflammation, recent studies suggest that it may also influence liver regeneration by modulating hepatocyte proliferation and tissue remodeling. This study investigates the role of the NLRP3 inflammasome and its related pathways in liver regeneration over time.

Aims & Methods

Using a partial hepatectomy mouse model, this research examines mRNA expression dynamics of NLRP3 and associated components post-surgery through RNA sequencing (RNA-seq). Liver tissue was analyzed at different time points after partial hepatectomy. Pathway analysis investigated the regulation of related signaling pathways, such as TGFβ, NF-κB, IL-6/JAK/STAT3, and endoplasmic reticulum stress responses.

Results

NLRP3 and Caspase-1 mRNA levels remained unchanged during liver regeneration. In contrast, mRNA expression of NLRP3 inhibitors, including Hsp90 and Sugt1 were significantly upregulated. Pathway analysis revealed substantial upregulation of TGFβ pathway during early proliferation phase, increased NF-κB signaling throughout the process, and consistent activation of the IL-6/JAK/STAT3 signaling pathway and endoplasmic reticulum stress responses.

Conclusion

These findings indicate the complex regulatory mechanisms of the NLRP3 inflammasome in liver regeneration and the varying pathway activation at different stages. Understanding the role of the NLRP3 inflammasome in liver regeneration could offer new insights into potential therapeutic approaches for patients with chronic liver disease or impaired hepatic recovery after surgery.