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Background/Aims: Pancreatic cancer has the poorest survival rate among all cancer types. Therefore, it is essential to develop an effective treatment strategy for this cancer. Methods: We performed carbon ion radiotherapy (CIRT) in human pancreatic cancer cell lines and analyzed their survival, apoptosis, necrosis, and autophagy. To investigate the role of CIRT-induced autophagy, autophagy inhibitors were added to cells prior to CIRT. To evaluate tumor formation, we inoculated CIRT-treated murine pancreatic cancer cells on the flank of syngeneic mice and measured tumor weight. We immunohistochemically measured autophagy levels in surgical sections from patients with pancreatic cancer who received neoadjuvant chemotherapy (NAC) plus CIRT or NAC alone. Results: CIRT reduced the survival fraction of pancreatic cancer cells and induced apoptotic and necrotic alterations, along with autophagy. Preincubation with an autophagy inhibitor accelerated cell death. Mice inoculated with control pancreatic cancer cells developed tumors, while those inoculated with CIRT/autophagy inhibitor-treated cells showed significant evasion. Surgical specimens of NAC-treated patients expressed autophagy comparable to control patients, while those in the NAC plus CIRT group expressed little autophagy and nuclear staining. Conclusions: CIRT effectively killed the pancreatic cancer cells by inhibiting their autophagy-inducing abilities. [ABSTRACT FROM AUTHOR]

Background/Aims: Postoperative adhesions may induce adverse outcomes in patients. Adhesion formation is initiated by fibrin accumulation at the surgical site which is followed by local neutrophilia and the establishment of neutrophil extracellular traps (NET). Previous reports have suggested that the preventive efficacy of reagents designed to reduce postoperative adhesion is inversely correlated with neutrophilia and NET production. Antithrombin (AT) is a natural inhibitor of thrombin, a key factor in coagulation. Here, we evaluate whether treatment with AT and/or NET inhibitors prevent or reduce postoperative adhesion formation in mice. Methods: Mice were treated with AT and/or NET inhibitors before and/or after cecum cauterization and their adhesion scores were evaluated on day 7 post-operation. Immunochemistry/immunofluorescence analyses were also performed and we used GSK484, an inhibitor of peptidyl arginine deiminase 4 (PAD4), as the NET inhibitor. Results: AT or GSK484 partially rescued postoperative adhesion formation in mice. AT prevented thrombininduced plasminogen activator inhibitor 1 and interleukin-6 expression in mesothelial cells in vitro. However, AT could not prevent neutrophilia or NETs formation around the injured serosa. Finally, we investigated a combination of AT and a PAD4 inhibitor and found that this could inhibit almost all adhesion formation in these animals. Since AT-inactivating proteases are liberated following NET release, they might dampen the biological action of the AT treatment. This suggests that NET inhibitors might allow AT to exert its full action in the surgically injured serosa. Conclusion: Combined treatment with AT and GSK484 may effectively attenuate postoperative adhesion production in mice. [ABSTRACT FROM AUTHOR]

Background/Aims: Although adhesion formation is a frequent adverse event following intraperitoneal surgery, efficient prophylactic interventions have not yet been established. We recently reported that blockade of interleukin (IL)-6 prevented postoperative adhesion after cecum cauterization. Intriguingly, this intervention dampened tumor necrosis factor (TNF) induction in the injured serosa. Herein, we addressed whether TNF might be a key target and, if so, how TNF blockade rescued adhesion formation. Methods: Mice were administered an anti-TNF biologic (etanercept) on days -2 and -1 before and upon cecal cauterization. The adhesion scores were evaluated at day 7 postoperatively. Histological alterations were examined by immunochemistry/immunofluorescence studies. We incubated human neutrophils and mesothelial cell line cells with recombinant TNF in the presence of etanercept and measured transcript levels of cytokines and chemokines by quantitative reverse transcription- polymerase chain reaction (RT-qPCR). Results: Etanercept rescued mice from adhesion formation, accompanied by a robust reduction of neutrophilia in the injured serosa. Immunofluorescence revealed a substantial formation of neutrophil extracellular traps (NETs) with the potential to induce tissue damage and profibrotic responses. In contrast, the etanercepttreated mice lacked NET formation. In addition, etanercept inhibited TNF-induced IL-6, TNF, and neutrophil-recruiting chemokines in neutrophils and mesothelial cells, a major cellular source of myofibroblasts in the adhesion band. Conclusion: Prophylactic administration of etanercept might be a potential strategy for preventing postoperative adhesion formation. [ABSTRACT FROM AUTHOR]