Clinical and Financial Validation of the International Study Group for Pancreatic Surgery (ISGPS) Definition of Post-Pancreatectomy Acute Pancreatitis (PPAP): International Multicenter Prospective Study.

OBJECTIVE: To validate the ISGPS definition and grading system of PPAP after pancreatoduodenectomy (PD). SUMMARY BACKGROUND DATA: In 2022, the International Study Group for Pancreatic Surgery (ISGPS) defined post-pancreatectomy acute pancreatitis (PPAP) and recommended a prospective validation of its diagnostic criteria and grading system. METHODS: This was a prospective, international, multicenter study including patients undergoing PD at 17 referral pancreatic centers across Europe, Asia, Oceania, and the United States. PPAP diagnosis required the following three parameters: (1) postoperative serum hyperamylasemia /hyperlipasemia (POH) persisting on postoperative days 1 and 2, (2) radiologic alterations consistent with PPAP, and (3) a clinically relevant deterioration in the patient's condition. To validate the grading system, clinical and economic parameters were analyzed across all grades. RESULTS: Among 2902 patients undergoing PD, 7.5% (n=218) developed PPAP (6.3% grade B and 1.2% grade C). POH occurred in 24.1% of patients. Hospital stay was associated with PPAP grades (No POH/PPAP 10 days (IQR 7-17) days, grade B 22 days (IQR 15-34) days, and grade C 43 days (IQR 27-54) days; P<0.001), as well as intensive care unit admission (No POH/PPAP 5.4%, grade B 12.6%, grade C 82.9%; P<0.010), and hospital readmission rates (No POH/PPAP 7.3%, grade B 16.1%, grade C 18.5%; P<0.05). Costs of grade B and C PPAP were 2 and 11 times greater than uncomplicated clinical course, resp. (P<0.001). CONCLUSIONS: This first prospective, international validation study of the ISGPS definition and grading system for PPAP highlighted the relevant clinical and financial implications of this condition. These results stress the importance of routine screening for PPAP in patients undergoing PD.

REDISCOVER guidelines for borderline-resectable and locally advanced pancreatic cancer: management algorithm, unanswered questions, and future perspectives.

The REDISCOVER guidelines present 34 recommendations for the selection and perioperative care of borderline-resectable (BR-PDAC) and locally advanced ductal adenocarcinoma of the pancreas (LA-PDAC). These guidelines represent a significant shift from previous approaches, prioritizing tumor biology over anatomical features as the primary indication for resection. Condensed herein, they provide a practical management algorithm for clinical practice. However, the guidelines also highlight the need to redefine LA-PDAC to align with modern treatment strategies and to solve some contradictions within the current definition, such as grouping "difficult" and "impossible" to resect tumors together. Furthermore, the REDISCOVER guidelines highlight several areas requiring urgent research. These include the resection of the superior mesenteric artery, the management strategies for patients with LA-PDAC who are fit for surgery but unable to receive multi-agent neoadjuvant chemotherapy, the approach to patients with LA-PDAC who are fit for surgery but demonstrate high serum Ca 19.9 levels even after neoadjuvant treatment, and the optimal timing and number of chemotherapy cycles prior to surgery. Additionally, the role of primary chemoradiotherapy versus chemotherapy alone in LA-PDAC, the timing of surgical resection post-neoadjuvant/primary chemoradiotherapy, the efficacy of ablation therapies, and the management of oligometastasis in patients with LA-PDAC warrant investigation. Given the limited evidence for many issues, refining existing management strategies is imperative. The establishment of the REDISCOVER registry ( https://rediscover.unipi.it/ ) offers promise of a unified research platform to advance understanding and improve the management of BR-PDAC and LA-PDAC.

REDISCOVER International Guidelines on the Perioperative Care of Surgical Patients With Borderline-resectable and Locally Advanced Pancreatic Cancer.

OBJECTIVE: The REDISCOVER consensus conference aimed at developing and validating guidelines on the perioperative care of patients with borderline-resectable (BR-) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Coupled with improvements in chemotherapy and radiation, the contemporary approach to pancreatic surgery supports the resection of BR-PDAC and, to a lesser extent, LA-PDAC. Guidelines outlining the selection and perioperative care for these patients are lacking. METHODS: The Scottish Intercollegiate Guidelines Network (SIGN) methodology was used to develop the REDISCOVER guidelines and create recommendations. The Delphi approach was used to reach a consensus (agreement ≥80%) among experts. Recommendations were approved after a debate and vote among international experts in pancreatic surgery and pancreatic cancer management. A Validation Committee used the AGREE II-GRS tool to assess the methodological quality of the guidelines. Moreover, an independent multidisciplinary advisory group revised the statements to ensure adherence to nonsurgical guidelines. RESULTS: Overall, 34 recommendations were created targeting centralization, training, staging, patient selection for surgery, possibility of surgery in uncommon scenarios, timing of surgery, avoidance of vascular reconstruction, details of vascular resection/reconstruction, arterial divestment, frozen section histology of perivascular tissue, extent of lymphadenectomy, anticoagulation prophylaxis, and role of minimally invasive surgery. The level of evidence was however low for 29 of 34 clinical questions. Participants agreed that the most conducive means to promptly advance our understanding in this field is to establish an international registry addressing this patient population ( https://rediscover.unipi.it/ ). CONCLUSIONS: The REDISCOVER guidelines provide clinical recommendations pertaining to pancreatectomy with vascular resection for patients with BR-PDAC and LA-PDAC, and serve as the basis of a new international registry for this patient population.

Postoperative Hyperamylasemia (POH) is an Early Predictor of Pancreatic Fistula Occurrence and Severity after Distal Pancreatectomy: Results from a European Multicentric Study.

OBJECTIVES: The aim of this international multicentric study is to characterize postoperative hyperamylasemia (POH) after distal pancreatectomy (DP), with particular focus on its relationship with postoperative pancreatic fistula (POPF) occurrence and severity. BACKGROUND: The clinical relevance of POH after DP and its relationship with the occurrence and severity of POPF have not been explored yet. METHODS: All patients undergoing DP for any indication between 2015 and 2021 at three European referral Centers for pancreatic surgery were retrospectively analyzed. Drain fluid amylase (DFA), C-reactive protein (C-RP), and serum amylase were examined from postoperative-day (POD) 1 to 3. Biochemical leak (BL), POPF, POH, and post-pancreatectomy hemorrhage (PPH) were defined and graded according to ISGPS definitions. RESULTS: In total 1192 patients were included. Overall rates of POH and POPF were 18% (n= 210) and 29% (n= 344), respectively. The presence of DFA ≥2000 U/L on POD 1 (OR=2.11, 95% CI 1.68-2.86), C-RP ≥200 mg/L on POD 3 (OR=2.19, 95% CI 1.68-2.86), and POH (OR=1.58, 95% CI 1.14-2.19) were all independent early predictors of POPF (all P< 0.01). The presence of POH almost doubled the rate of POPF (43% vs. 26%, P<0.001), and higher POPF severity presented also higher POH rates (no POPF= 12%; BL= 19%; B POPF= 24%; C POPF= 52%). Among patients developing POPF, patients with POH had higher rates of PPH (22% vs 9%, P= 0.001), sepsis (24% vs 13%; P=0.011), re-operation (21% vs 8%; P< 0.01), and mortality (3% vs 0.3%; P= 0.025). CONCLUSIONS: The occurrence of POH is an early predictor of POPF and its severity after DP. The diagnosis of POH might define patients at higher risk for a complicated course, targeting them for prevention / mitigation strategies against pancreas specific complications.

Adjuvant Therapy After Upfront Resection of Resectable Pancreatic Cancer: Patterns of Omission and Use-A Prospective Real-Life Study.

BACKGROUND: Little is known about adjuvant therapy (AT) omission and use outside of randomized trials. We aimed to assess the patterns of AT omission and use in a cohort of upfront resected pancreatic cancer patients in a real-life scenario. METHODS: From January 2019 to July 2022, 317 patients with resected pancreatic cancer and operated upfront were prospectively enrolled in this prospective observational trial according to the previously calculated sample size. The association between perioperative variables and the risk of AT omission and AT delay was analyzed using multivariable logistic regression. RESULTS: Eighty patients (25.2%) did not receive AT. The main reasons for AT omission were postoperative complications (38.8%), oncologist's choice (21.2%), baseline comorbidities (20%), patient's choice (10%), and early recurrence (10%). At the multivariable analysis, the odds of not receiving AT increased significantly for older patients (odds ratio [OR] 1.1, p < 0.001), those having an American Society of Anesthesiologists score ≥II (OR 2.03, p = 0.015), or developing postoperative pancreatic fistula (OR 2.5, p = 0.019). The likelihood of not receiving FOLFIRINOX as AT increased for older patients (OR 1.1, p < 0.001), in the presence of early-stage disease (stage I-IIa vs. IIb-III, OR 2.82, p =0.031; N0 vs. N+, OR 3, p = 0.03), and for patients who experienced postoperative major complications (OR 4.7, p = 0.009). A twofold increased likelihood of delay in AT was found in patients experiencing postoperative complications (OR 3.86, p = 0.011). CONCLUSIONS: AT is not delivered in about one-quarter of upfront resected pancreatic cancer patients. Age, comorbidities, and postoperative complications are the main drivers of AT omission and mFOLFIRINOX non-use. CLINICALTRIALS REGISTRATION: NCT03788382.

No role for protease inhibitors as a mitigation strategy for postpancreatectomy acute pancreatitis (PPAP): Propensity score matching analysis.

BACKGROUND: While the use of protease inhibitor gabexate mesylate (GM) is still controversial in acute pancreatitis, it has never been tested for postpancreatectomy acute pancreatitis (PPAP). This study aims to assess the impact of GM on postoperative serum hyperamylasaemia (POH) or PPAP after pancreatoduodenectomy (PD). METHODS: Consecutive patients developing POH after PD between 2016 and 2021 were included. According to GM administration, patients were divided into GM-treated and control (CTR) groups. GM was administered from postoperative day 1-3 in POH patients who underwent surgery before 2017. A 2:1 propensity matching was used to minimize the risk of bias. RESULTS: Overall, 264 patients with POH were stratified in the GM (59 patients) and CTR (104 patients) cohorts, which showed balanced baseline characteristics after matching. No difference in postoperative complications was observed between the groups (all p > 0.05), except for PPAP occurrence, which was significantly higher in the GM group (37% vs. 22%, p = 0.037). A total of 45 patients (28%) evolved to PPAP. Comparing PPAP patients in the GM and CTR groups, no significant differences in POPF, relaparotomy, and mortality (all p > 0.09) were found. No difference in intravenous crystalloid administration was found in patients with PPAP, whether or not they developed major complications or pancreatic fistula (p > 0.05) CONCLUSION: Protease inhibitor seems ineffective in preventing a PPAP after PD once a POH has occurred. Further studies are needed to achieve benchmarks for treating PPAP and identify mitigation strategies to prevent the evolution of POH into additional morbidity.

Risk Models for Pancreatic Cyst Diagnosis.

The overall prevalence of pancreatic cysts (PCs) is high in the general population. In clinical practice PCs are often incidentally discovered and are classified into benign, premalignant, and malignant lesions according to the World Health Organization. For this reason, in the absence of reliable biomarkers, to date clinical decision-making relies mostly on risk models based on morphological features. The aim of this narrative review is to present the current knowledge regarding PC's morphologic features with related estimated risk of malignancy and discuss available diagnostic tools to minimize clinically relevant diagnostic errors.

Routes of nutrition for pancreatic fistula after pancreatoduodenectomy: a prospective snapshot study identifies the need for therapy standardization.

The aim of this study is to describe the current utilization of artificial nutrition [enteral (EN) or total parenteral (TPN)] for pancreatic fistula (POPF) after pancreatoduodenectomy (PD). Prospective data of 311 patients who consecutively underwent PD at a tertiary referral center for pancreatic surgery were collected. Data included the use of EN or TPN specifically for POPF treatment, including timing, outcomes, and adverse events related to their administration. POPF occurred in 66 (21%) patients and 52 (79%) of them were treated with artificial nutrition, for a median of 36 days. Forty (76%) patients were treated with a combination of TPN and EN. The median day of artificial nutrition start was postoperative day 7, with a median drain output of 180 cc/24 h. In 33 (63%) patients, artificial nutrition was started while only a biochemical leak was ongoing. Fungal infections and catheter-related bloodstream infection occurred in 13 (28%) and 15 (33%) TPN patients, respectively; among EN patients, 19 (41%) experienced diarrhea not responsive to pancreatic enzymes and 9 (20%) needed multiple endoscopic naso-jejunal tube positioning. The majority of the patients developing POPF after PD were treated with a combination of TPN and EN, with a clinically relevant rate of adverse events related to their administration. Standardization of nutrition routes in patients developing POPF is urgently needed.

Postoperative serum hyperamylasemia (POH) predicts additional morbidity after pancreatoduodenectomy: It is not all about pancreatic fistula.

BACKGROUND: The association between postoperative serum hyperamylasaemia (POH) and morbidity has been hypothesized but rarely explored once occurring with or without (POH-exclusive) a combined postoperative pancreatic fistula (POPF). METHODS: Analysis of patients who consecutively underwent pancreaticoduodenectomy from 2016 to 2020. POH was defined as serum amylase activity greater than the institutional upper limit of normal (52 U/L), persisting within the first 48 hours postoperatively (postoperative day [POD] 1 and 2). RESULTS: Among 852 patients, 15.8% developed POH-exclusive. Compared with patients without POH or POPF (64.3%), they showed a significantly higher postoperative burden (Clavien-Dindo ≥II: 52.6% vs 30.8%) with increased rates of bacteraemia (12.6% vs 6%), pleural effusion (13.3% vs 5.3%), postpancreatectomy haemorrhage (13.3% vs 7.5%), postpancreatectomy acute pancreatitis (PPAP) (10.3% vs 0%), and organ site infections (18.5% vs 10.9%; all P < .05). A total of 13.8% experienced POH with POPF leading to the worse outcome. The combined occurrence of POH with POPF led to a shorter median time to morbidity (3 PODs, 95% confidence interval [CI] 2.2-3.7 vs 6 PODs, 95% CI 4.2-8; P < .001) than patients experiencing POPF-exclusive (5.9%). In all, 46.6% of POH patients developed POPF. Body mass index (BMI) (odds ratio [OR] 1.1), male sex (OR 2.1), increased drain fluid amylase on POD 1 (OR 1.001), and increased C-reactive protein (OR 1.01) were independent risk factors for POPF once POH has occurred. CONCLUSION: POH has relevant postoperative clinical implications, independently from POPF occurrence. Developing POH with POPF leads to an earlier onset of higher postoperative burdens. Once POH is diagnosed, risk factors for additional POPF could identify patients who may benefit from additional surveillance, specific drains protocols, and preventive strategies.