The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. DESIGN: We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. RESULTS: Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNFα)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. CONCLUSIONS: This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.

Plastic pigtail vs lumen-apposing metal stents for drainage of walled-off necrosis (PROMETHEUS study): an open-label, multicenter randomized trial.

BACKGROUND: Lumen-apposing metal stents (LAMS) have displaced double-pigtail plastic stents (DPS) as the standard treatment for walled-off necrosis (WON),ß but evidence for exclusively using LAMS is limited. We aimed to assess whether the theoretical benefit of LAMS was superior to DPS. METHODS: This multicenter, open-label, randomized trial was carried out in 9 tertiary hospitals. Between June 2017, and Oct 2020, we screened 99 patients with symptomatic WON, of whom 64 were enrolled and randomly assigned to the DPS group (n = 31) or the LAMS group (n = 33). The primary outcome was short-term (4-weeks) clinical success determined by the reduction of collection. Secondary endpoints included long-term clinical success, hospitalization, procedure duration, recurrence, safety, and costs. Analyses were by intention-to-treat. CLINICALTRIALS: gov, NCT03100578. RESULTS: A similar clinical success rate in the short term (RR, 1.41; 95% CI 0.88-2.25; p = 0.218) and in the long term (RR, 1.2; 95% CI 0.92-1.58; p = 0.291) was observed between both groups. Procedure duration was significantly shorter in the LAMS group (35 vs. 45-min, p = 0.003). The hospital admission after the index procedure (median difference, - 10 [95% CI - 17.5, - 1]; p = 0.077) and global hospitalization (median difference - 4 [95% CI - 33, 25.51]; p = 0.82) were similar between both groups. Reported stent-related adverse events were similar for the two groups (36 vs.45% in LAMS vs. DPS), except for de novo fever, which was significantly 26% lower in LAMS (RR, 0.26 [0.08-0.83], p = 0.015). CONCLUSIONS: The clinical superiority of LAMS over DPS for WON therapy was not proved, with similar clinical success, hospital stay and similar safety profile between both groups, yet a significant reduction in procedure time was observed. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03100578.

Pancreatic cancer screening in high-risk individuals.

The incidence of pancreatic cancer is increasing, although globally it represents less than 3% of all cancers. Despite advances in medical and surgical management, survival rates have not significantly improved in recent years. Consequently, pancreatic cancer, though relatively uncommon, is the third leading cause of cancer-related deaths. This is primarily due to the disease´s late detection. Symptoms appear late and are nonspecific, and over 80% of cases are diagnosed at an advanced stage and unsuitable for curative surgery, resulting in a five-year survival rate below 10%. However, the exceptional cases that are diagnosed early show five-year survival rates exceeding 80%. Therefore, one of the keys to improving pancreatic cancer prognosis lies in early detection, making screening in high-risk individuals a potentially crucial strategy.

Symptomatic gallstone disease: Recurrence patterns and risk factors for relapse after first admission, the RELAPSTONE study.

BACKGROUND: Delayed cholecystectomy in patients with symptomatic gallstone disease is associated with recurrence. Limited data on the recurrence patterns and the factors that determine them are available. OBJECTIVE: We aimed to determine the pattern of relapse in each symptomatic gallstone disease (acute pancreatitis, cholecystitis, cholangitis, symptomatic choledocholithiasis, and biliary colic) and determine the associated factors. METHODS: RELAPSTONE was an international multicenter retrospective cohort study. Patients (n = 3016) from 18 tertiary centers who suffered a first episode of symptomatic gallstone disease from 2018 to 2020 and had not undergone cholecystectomy during admission were included. The main outcome was relapse-free survival. Kaplan-Meier curves were used in the bivariate analysis. Multivariable Cox regression models were used to identify prognostic factors associated with relapses. RESULTS: Mean age was 76.6 [IQR: 59.7-84.1], and 51% were male. The median follow-up was 5.3 months [IQR 2.1-12.4]. Relapse-free survival was 0.79 (95% CI: 0.77-0.80) at 3 months, 0.71 (95% CI: 0.69-0.73) at 6 months, and 0.63 (95% CI: 0.61-0.65) at 12 months. In multivariable analysis, older age (HR = 0.57; 95% CI: 0.49-0.66), sphincterotomy (HR = 0.58, 95% CI: 0.49-0.68) and higher leukocyte count (HR = 0.79; 95% CI: 0.70-0.90) were independently associated with lower risk of relapse, whereas higher levels of alanine aminotransferase (HR = 1.22; 95% CI: 1.02-1.46) and multiple cholelithiasis (HR = 1.19, 95% CI: 1.05-1.34) were associated with higher relapse rates. CONCLUSION: The relapse rate is high and different in each symptomatic gallstone disease. Our independent predictors could be useful for prioritizing patients on the waiting list for cholecystectomies.

Trasplante de microbiota fecal: indicaciones, metodología y perspectivas futuras / Faecal microbiota transplantation: indications, methodology and future prospects

La microbiota intestinal se define como el conjunto de microorganismos que habitan de forma natural en el tubo digestivo. Bacterias, hongos y virus se incluyen dentro de este ente fisiológico que va mucho más allá de ser un mero espectador pasivo de la mucosa intestinal. La microbiota interviene de forma activa en la homeostasis y su desregulación se ha relacionado con múltiples enfermedades de naturaleza infecciosa, metabólica y autoinmunitaria. El trasplante de microbiota fecal (TMF) consiste en la introducción de una solución de materia fecal debidamente procesada procedente de un donante sano en el tracto gastrointestinal de otro individuo con el fin de manipular las características de la microbiota del receptor. Aunque pueda parecer algo novedoso, los primeros casos se remontan a la época de la China Imperial; no obstante, no ha sido hasta los últimos 20 años cuando el interés y la actividad investigadora en este campo se han multiplicado de forma exponencial. Fruto de este trabajo el TMF constituye hoy en día una herramienta eficaz y validada en casos refractarios de diarrea por C. Difficile. Aunque la evidencia científica es menor, ya existen ensayos clínicos que evalúan su beneficio en la enfermedad inflamatoria intestinal y en el síndrome metabólico. Lo atractivo de su mecanismo fisiopatológico, la sencillez del procedimiento y su bajo coste lo sitúan como un tratamiento prometedor en múltiples enfermedades extradigestivas. El objetivo de esta revisión es resumir de una forma concisa, rigurosa y actualizada las indicaciones, metodología y seguridad del TMF.

The intestinal microbiota is defined as the set of organisms that live in the digestive tract. Bacteria, fungi and viruses are included in a physiological entity that goes far beyond being a passive spectator of the intestinal mucosa. The microbiota is actively involved in homeostasis and its imbalance has been linked to multiple infectious, metabolic and autoimmune diseases. Fecal microbiota transplantation (FMT) consists in the introduction of a solution made with processed stool from a healthy donor into the gastrointestinal tract of another individual in order to manipulate the characteristics of the receiver microbiota. Although it may seem new, the first cases date back to the days of Imperial China; however, it was not until the past 20 years when the interest and research in this field have grown exponentially. Nowadays, TMF is an effective and validated treatment in refractory cases of C.difficile diarrhea. Although the scientific evidence is less, there are clinical trials evaluating its benefit in inflammatory bowel disease and metabolic syndrome. The appeal of its pathophysiological mechanism, the simplicity of the procedure and its low cost place FMT as a promising treatment for multiple extraintestinal diseases. The objective of this review is to summarize in a concise, thorough and updated form its indications, methodology and safety.