Cell senescence constitutes a physiological process that serves as protection from malignant transformation of cells. However, recent scientific discoveries also identify cell senescence as pivotal in hepatocellular cancer (HCC) biology. The review herein aimed to accumulate evidence on senescence as a mediator of HCC occurrence in hepatitis B (HBV), C (HCV) virus infections, and non-alcoholic fatty liver disease (NAFLD). In HBV infection, the carcinogenic HBV X protein frequently mutates during chronic infection, and subsequently exhibits different effects on senescence. In HCV infection, senescent non-functional T-cells do not effectively clear pre-malignant hepatocytes. Furthermore, the HCV Core protein inhibits the occurrence of normal stress-induced hepatocyte senescence, allowing damaged cells to maintain their proliferative potential. In NAFLD-mediated HCC, current data point towards the gut microbiome and hepatic stellate cell senescence. Additionally, senescence contributes in the development of resistance in targeted therapies, such as sorafenib. Finally, the promising role of senotherapeutics in HCC was also explored. Overall, although we may still be at a primitive stage in fully unraveling the role of senescence in cancer, it seems that understanding and harnessing senescence may have the potential to revolutionize the way we treat hepatocellular cancer.

Due to abundant stroma and extracellular matrix, accompanied by lack of vascularization, pancreatic ductal adenocarcinoma (PDAC) is characterized by severe hypoxia. Epigenetic regulation is likely one of the mechanisms driving hypoxia-induced epithelial-to-mesenchymal transition (EMT), responsible for PDAC aggressiveness and dismal prognosis. To verify the role of DNA methylation in this process, we assessed gene expression and DNA methylation changes in four PDAC cell lines. BxPC-3, MIA PaCa-2, PANC-1, and SU.86.86 cells were exposed to conditioned media containing cytokines and inflammatory molecules in normoxic and hypoxic (1% O₂) conditions for 2 and 6 days. Cancer Inflammation and Immunity Crosstalk and Human Epithelial to Mesenchymal Transition RT² Profiler PCR Arrays were used to identify top deregulated inflammatory and EMT-related genes. Their mRNA expression and DNA methylation were quantified by qRT-PCR and pyrosequencing. BxPC-3 and SU.86.86 cell lines were the most sensitive to hypoxia and inflammation. Although the methylation of gene promoters correlated with gene expression negatively, it was not significantly influenced by experimental conditions. However, DNA methyltransferase inhibitor decitabine efficiently decreased DNA methylation up to 53% and reactivated all silenced genes. These results confirm the role of DNA methylation in EMT-related gene regulation and uncover possible new targets involved in PDAC progression.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by late detection and poor prognosis. Recent research highlights the pivotal role of epigenetic alter- ations in driving PDAC development and progression. These changes, in conjunction with genetic mutations, contribute to the intricate molecular landscape of the disease. Specific modifications in DNA methylation, histone marks, and non-coding RNAs are emerging as robust predictors of disease progression and patient survival, offering the potential for more precise prognostic tools compared to conventional clinical staging. Moreover, the detection of epigenetic alterations in blood and other non-invasive samples holds promise for earlier diagnosis and improved manage- ment of PDAC. This review comprehensively summarises current epigenetic research in PDAC and identifies persisting challenges. These include the complex nature of epigenetic profiles, tumour hetero- geneity, limited access to early-stage samples, and the need for highly sensitive liquid biopsy technologies. Addressing these challenges requires the standardisation of methodologies, integra- tion of multi-omics data, and leveraging advanced computational tools such as machine learning and artificial intelligence. While resource-intensive, these efforts are essential for unravelling the functional consequences of epigenetic changes and translating this knowledge into clinical appli- cations. By overcoming these hurdles, epigenetic research has the potential to revolutionise the management of PDAC and improve patient outcomes.

Background: Congenital abnormalities are not very common and are even rarer when two or more are combined. Congenital malformation of the superior mesenteric vein may not affect normal development, or it may lead to moderate or even severe symptoms. In combination with intestinal malrotation, however, it may lead to the need for surgical intervention in the early years of life. Case presentation: We present the case of a 22-year-old patient who had been diagnosed with iron deficiency anaemia at the age of two months. As a result of the absence of the proximal section of the superior mesenteric vein, the patient has always needed iron supplements and an occasional erythrocyte transfusion. This has resulted from the formation of collaterals throughout the small bowel, causing chronic blood loss with its clinical manifestation. Although, there are some congenital abnormalities of the superior mesenteric vein, the absence of the superior mesenteric vein is rare, and in this case the clinical course was quite severe. Therefore, we planned bypass surgery for this patient to reduce the duodenal collaterals and resolve the persistent anaemia caused by chronic blood loss from the duodenum. We successfully performed the surgery consisting of the formation of anastomosis between the large collateral vein from the distal end of the superior mesenteric vein and the anterior inferior pancreaticoduodenal vein. Conclusion: The purpose of this case report is to describe the rare anatomical malformation of the superior mesenteric vein accompanied by intestinal malrotation, with its potential clinical implications regarding symptoms, clinical presentation, and the impact on potential surgery planning.

The extreme lethality and limited treatment options for pancreatic ductal adenocarcinoma (PDAC) underscore the urgent need for innovative therapeutic strategies. This study presents the first preclinical investigation of a cell-free gene-directed enzyme prodrug therapy (GDEPT) based on conditioned medium (CM) from placenta-derived mesenchymal stem cells (PlacMSCs) engineered to express the yeast cytosine deaminase::uracil phosphoribosyltransferase (yCD::UPRT) fusion enzyme. The CM was concentrated tenfold (cCM) and characterized by proteomics, transmission electron microscopy, and Western blotting, confirming extracellular vesicle (EV) enrichment and UPRT expression. Therapeutic efficacy was evaluated in coculture models comprising PDAC cell lines (BxPC-3, MIA PaCa-2, SU.86.86), patient-derived xenograft organoids (PDXOs), and cancer-associated fibroblasts (PCAFs). Immunocytochemistry and Western blot analyses revealed a predominant myofibroblastic CAF phenotype, characterized by strong alpha-smooth muscle actin (αSMA) expression and low interleukin-6 levels. Treatment with yCD::UPRT-PlacMSC-cCM in the presence of 5-fluorocytosine (5-FC) enabled efficient enzymatic conversion to 5-fluorouracil (5-FU), yielding 10 μg/mL from an initial 100 μg/mL of 5-FC. This resulted in robust, dose-dependent cytotoxicity (50 % to 80 % reduction in viability) across monocultures and stromal-rich cocultures, effectively overcoming PCAF-mediated drug resistance. Therapeutic response was governed primarily by tumor cell characteristics rather than PCAF heterogeneity. In PDXOs derived from two early-stage (IA, IIB) primary tumors and one metastatic lesion, 100 µL of yCD::UPRT-PlacMSC-cCM induced cytotoxicity comparable to 1 μg/mL of 5-FU, while 25 µL was insufficient to significantly reduce viability. Collectively, these findings demonstrate that yCD::UPRT-PlacMSC-cCM delivers potent, stromal-bypassing cytotoxicity in PDAC models and represents a promising cell-free therapeutic approach for this treatment-refractory cancer.

To achieve an R0 resection margin in patients with locally advanced pancreatic ductal adenocarcinoma, high-volume pancreatic centers standardly incorporate portal vein or superior mesenteric vein resection. However, there is currently no consensus on the optimal reconstructive approach. Postoperative venous thrombosis or stenosis can significantly increase patient morbidity or mortality. The objective of this study was to report the long-term patency rate of portal/superior mesenteric vein reconstruction, as well as to identify potential predictors of postoperative venous thrombosis/stenosis. A single-center retrospective cohort analysis was conducted on patients undergoing pancreatic resection due to pancreatic tumor. The patency of the vascular reconstruction was assessed by routine surveillance using computed tomographic imaging at 3, 6, 9, and 12 months after surgery. A total of 297 pancreatic resections were performed with 53 patients undergoing concomitant venous resection. Among these, 26.4% (N = 14) had primary closure, 22.7% (N = 12) underwent an end-to-end anastomosis, and 50.9% (N = 27) received an interposition graft reconstruction. At the 1-year follow up, 90.2% (N = 37) of patients with venous reconstruction had a fully patent vein. The analysis did not reveal any statistically significant perioperative or postoperative factors associated with an increased risk of reconstruction thrombosis. While our study confirms a high long-term patency rate of 90.2% at 1 year, it underscores the necessity for a randomized controlled trial to determine the optimal method of venous reconstruction in pancreatic surgery.