The prediction, prevention, and mitigation of pancreatic fistula: Recent advancements in the era of risk stratification and personalized management.

This doctoral thesis is a collection of original papers sharing the theme of pancreatic fistula after pancreatic surgery. The common thread is the surgeon's will to address proactively this potentially catastrophic event during all perioperative phases, following a risk-based, dynamic, and personalized management. It therefore starts with a proposal for preoperative fistula risk stratification, tailored to the individual patient, aimed at improving preoperative counseling & decision-making, but also influencing actionable factors (e.g., BMI). It continues with an attempt to renovate current intraoperative risk scores, generally based on macroscopic features of the pancreatic gland, proposing a microscopic quantification of the acinar cell content in the residual parenchyma, ultimately responsible for the secretion of the dangerous enzymes that characterize postoperative fistula. This novel tool, developed in collaboration with San Raffaele Hospital, seems capable of dichotomizing the fistula risk in either high or low, finally getting rid of ‘grey areas’ where the preferable strategy is unknown. Moreover, a multicentric collaboration with Karolinska Institute and Oslo University Hospital demonstrates how early postoperative predictors, such as serum amylase values, can be used during the first two postoperative days to drive a fast-track surgical management after distal pancreatectomy. For patients in the high-risk categories after pancreatoduodenectomy, trans-anastomotic stents result as the optimal mitigation strategies to avoid severe morbidity. While in patients without a stent an early drain removal policy is recommended, in patients with stents drain removal should be postponed until a later postoperative period, when postoperative fistula predictors reach acceptable diagnostic accuracy. Finally, in selected case with extremely high fistula risk, total pancreatectomy seems a valuable option to prevent pancreatic fistula, given better surgical outcomes and comparable quality of life, only in few selected cases and after adequate counselling due to life-long exocrine and endocrine insufficiency.