Pancreatectomy Induces Cancer-Promoting Neutrophil Extracellular Traps.

BACKGROUND: Neutrophil extracellular traps (NETs) occur when neutrophil chromatin is decondensed and extruded into the extracellular space in a web-like structure. Originally described as an anti-microbial function, this process has been implicated in the pathogenesis of pancreatic disease. In addition, NETs are upregulated during physiologic wound-healing and coagulation. This study evaluated how the inflammatory response to pancreatic surgery influences NET formation. METHODS: For this study, 126 patients undergoing pancreatectomy gave consent before participation. Plasma was collected at several time points (preoperatively and through the postoperative outpatient visit). Plasma levels of NET markers, including cell-free DNA (cfDNA), citrullinated histone H3 (CitH3), interleukin (IL)-8, IL-6, and granulocyte colony-stimulating factor (G-CSF) were measured using enzyme-linked immunosorbent assay (ELISA). Patient clinical data were retrospectively collected from a prospectively maintained database. RESULTS: After pancreatic resection, NET markers (cfDNA and CitH3) were elevated, peaking on postoperative days 3 and 4. This increase in NETs was due to an inherent change in neutrophil biology. Postoperatively, NET-inducing cytokines (IL-8, IL-6, and G-CSF) were increased, peaking early in the postoperative course. The patients undergoing the robotic approach had a reduction in NETs during the postoperative period compared with those who underwent the open approach. The patients who experienced a pancreatic leak had an increase in NET markers during the postoperative period. CONCLUSIONS: Pancreatectomy induces cancer-promoting NET formation. The minimally invasive robotic approach may induce fewer NETs, although the current analysis was limited by selection bias. Pancreatic leak resulted in increased NETs. Further study into the potential for NET inhibition during the perioperative period is warranted.

Biologic Functions of Hydroxychloroquine in Disease: From COVID-19 to Cancer.

Chloroquine (CQ) and Hydroxychloroquine (HCQ), initially utilized in the treatment of malaria, have now developed a long list of applications. Despite their clinical relevance, their mechanisms of action are not clearly defined. Major pathways by which these agents are proposed to function include alkalinization of lysosomes and endosomes, downregulation of C-X-C chemokine receptor type 4 (CXCR4) expression, high-mobility group box 1 protein (HMGB1) inhibition, alteration of intracellular calcium, and prevention of thrombus formation. However, there is conflicting data present in the literature. This is likely the result of the complex overlapping pathways between these mechanisms of action that have not previously been highlighted. In fact, prior research has focused on very specific portions of particular pathways without describing these in the context of the extensive CQ/HCQ literature. This review summarizes the detailed data regarding CQ/HCQ's mechanisms of action while also providing insight into the overarching themes. Furthermore, this review provides clinical context to the application of these diverse drugs including their role in malaria, autoimmune disorders, cardiovascular disease, thrombus formation, malignancies, and viral infections.

Defining the Optimal Duration of Neoadjuvant Therapy for Pancreatic Ductal Adenocarcinoma: Time for a Personalized Approach?

ABSTRACT: Despite recent advances, pancreatic ductal adenocarcinoma (PDAC) continues to be associated with dismal outcomes, with a cure evading most patients. While historic treatment for PDAC has been surgical resection followed by 6 months of adjuvant therapy, there has been a recent shift toward neoadjuvant treatment (NAT). Several considerations support this approach, including the characteristic early systemic spread of PDAC, and the morbidity often surrounding pancreatic resection, which can delay recovery and preclude patients from starting adjuvant treatment. The addition of NAT has been suggested to improve margin-negative resection rates, decrease lymph node positivity, and potentially translate to improved survival. Conversely, complications and disease progression can occur during preoperative treatment, potentially eliminating the chance of curative resection. As NAT utilization has increased, treatment durations have been found to vary widely between institutions with an optimal duration remaining undefined. In this review, we assess the existing literature on NAT for PDAC, reviewing treatment durations reported across retrospective case series and prospective clinical trials to establish currently used approaches and seek the optimal duration. We also analyze markers of treatment response and review the potential for personalized approaches that may help clarify this important treatment question and move NAT toward a more standardized approach.