Stylianos Elemes

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis and limited therapeutic options, particularly in advanced disease. Although immune checkpoint inhibitors (ICIs) have transformed the treatment of several solid tumors, their activity in unselected PDAC remains minimal. We conducted a narrative review of the literature using predefined search terms related to PDAC, immune checkpoint inhibition, tumor microenvironment, and predictive biomarkers. Candidate biomarkers were classified into three categories according to their biological origin and clinical assessment: tumor-intrinsic genomic and molecular biomarkers, tissue-based immune and microenvironmental biomarkers, and circulating biomarkers. Among available biomarkers, mismatch repair deficiency/microsatellite instability-high (dMMR/MSI-H) status has the strongest evidence supporting ICI selection in PDAC and is incorporated into current treatment guidelines. High tumor mutational burden (TMB-H) represents a complementary tumor-agnostic biomarker, although PDAC-specific evidence remains limited. DNA damage response (DDR) alterations, particularly those affecting core homologous recombination repair (HRR) genes and resulting in homologous recombination deficiency (HRD), are more relevant to platinum- and PARP inhibitor-based strategies, while their role in immunotherapy remains investigational and may be most applicable to combination approaches. Other proposed biomarkers, including Programmed Death-Ligand 1 (PD-L1) expression, tumor-infiltrating lymphocytes, systemic inflammatory indices, circulating tumor DNA, and spatial or multiomic signatures, currently provide mainly prognostic, monitoring, or exploratory information. In conclusion, dMMR/MSI-H remains the most robustly established biomarker for ICI selection in PDAC, while TMB-H provides a complementary but less well-validated option and all other candidate biomarkers remain primarily tools for prognostic assessment, disease monitoring, or investigation requiring further prospective validation.

Background/Objectives: Lynch syndrome is an inherited autosomal dominant disease that predisposes to a broad spectrum of malignancies. This condition is driven by a germline pathogenic variant in one or more of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2, EPCAM) that results in genomic microsatellite instability (MSI-high). However, microsatellite-stable (MSS) tumors in Lynch syndrome patients may occur, but the relevant literature is scant. Our aim is to systematically identify, organize, and characterize the comprehensive available literature for Lynch syndrome-associated gynecological cancers (vulvar, vaginal, cervical, ovarian, endometrial) exhibiting a dMMR/MSS phenotype. Methods: Systematic review of the literature. Three medical databases, major related conferences and relevant oncology journals were scrutinized for relative evidence. Results: Eleven reports were identified comprising 2351 patients, 774 had confirmed Lynch syndrome (LS), of whom MSI results were available for 299 patients. In total, 130 patients developed LS-associated gynecological cancers, for whom MSI results were available. Among them, 36 tumors (27.7%) exhibited a dMMR/MSS molecular phenotype (23 endometrial, 12 ovarian, one synchronous endometrial–ovarian). No data for vulvar, vaginal, or cervical cancers were found. For dMMR/MSS endometrial cancers, the mean age at diagnosis was 50.5 years (range 36–62). dMMR/MSS tumors arose predominantly in MSH6 and, to a lesser extent, PMS2 carriers. No data on selective response to immune checkpoint inhibitors treatment were available. Conclusions: Lynch syndrome-associated gynecological cancers with dMMR/MSS phenotype are strongly underrepresented in the literature. Endometrial and ovarian cancers with dMMR/MSS phenotype are early onset and arise in a small proportion of patients. Better characterization is demanding to unearth whether response to immunotherapy treatment vary across Lynch dMMR/MSS and dMMR/MSI-High phenotypes.

Introduction: Clostridioides difficile (C. difficile) is primarily associated with colonic disease, including pseudomembranous colitis. However, in rare instances, it may cause extraintestinal infectious and non-infectious manifestations, particularly in immunocompromised patients or those with significant underlying conditions. Search Methods: A literature review was performed using PubMed, Embase, and Researchgate databases up to 15 February 2025. The following search strings were used: “extraintestinal manifestations”, “extracolonic manifestations”, “extraintestinal infections”, “extracolonic infections”, “Clostridium difficile”, and “Clostridioides difficile”. Results: Extraintestinal manifestations of C. difficile appear to represent fewer than 1% of all reported infections. The most frequently reported infectious complications include bacteremia and abdominopelvic infections and abscesses, often involving polymicrobial cultures, with the isolation of C. difficile alongside microorganisms typically found in the normal intestinal microbiota. Rare non-infectious cases, such as reactive arthritis, have also been described. The underlying pathogenetic mechanism is believed to involve disruption of the intestinal barrier and translocation of bacteria or toxins to sterile sites. Conclusions: Though rare, extraintestinal C. difficile manifestations pose important clinical challenges. Better understanding of their mechanisms is essential for early recognition and appropriate management. Further research is warranted to define potential mechanisms and therapeutic approaches.