Markus W. Buechler

Objective: To evaluate the presence of pancreatic cancer cells within the TRIANGLE compartment (area between mesenteric-portal axis, celiac trunk, and superior mesenteric artery) and to determine its potential role for locoregional recurrence. Background: Approximately 30% of patients develop locoregional recurrence after resection of pancreatic ductal adenocarcinoma (PDAC), most of them within the TRIANGLE compartment. The surgical approach to oncologically clean this compartment aims to improve local control by resecting the perineural, lymphatic and soft tissue around and in-between the celiac trunk, superior mesenteric artery, and mesenteric-portal axis, a region not typically addressed in standard pancreatic resections. Methods: Prospective study of patients who underwent a TRIANGLE compartment resection for PDAC between January 2023 and December 2024. Histopathological analyses were performed to assess cancer involvement in lymph nodes, perineural, adipose, and lymphovascular tissue. Cancer-positive (Tr+) and cancer-negative (Tr−) TRIANGLE patients were compared. Results: A total of 131 patients received a resection of the TRIANGLE compartment, 56 (43%) after neoadjuvant chemotherapy. The TRIANGLE compartment contained malignant cells in 41 patients (31%) with different tissue types affected. Stratified by tumor stage, 56% with locally advanced (n = 14/25), 40% with borderline resectable (n = 8/20), and 21% with resectable tumors (n = 15/72) harbored cancer cells within the TRIANGLE compartment. Conclusion: This study is the first to demonstrate that in 1 out of 3 patients with PDAC, the TRIANGLE compartment harbors cancer cells. This might explain the high rates of locoregional recurrence observed after standard pancreatic resection. By incorporating the TRIANGLE compartment into the standard surgical management of PDAC, surgeons might be able to improve local disease control.

Background: Multimodal treatment with preoperative chemotherapy is increasingly used for locally advanced pancreatic cancer (LAPC) to enable surgical resection. However, the optimal time between the last cycle of preoperative chemotherapy and surgery remains unclear. This study aimed to evaluate the association between timing of surgery after preoperative chemotherapy and overall survival of patients with LAPC. Methods: Patients with LAPC who underwent pancreatic resection after preoperative chemotherapy between 2018 and 2023 were enrolled from a prospectively maintained database. The cohort was stratified by a predefined interval between the last cycle of chemotherapy and surgery (short interval: < 4 weeks vs long interval: ≥ 4 weeks). Results: After preoperative chemotherapy, 169 patients underwent surgery, including 56 (33.1%) patients in the short-interval group and 113 (66.9%) patients in the long-interval group. Baseline characteristics, surgical procedures, and postoperative morbidity were comparable between the two groups. Most patients received FOLFIRINOX (85.5 %) with a median of nine cycles. Patients with the long interval showed significantly improved overall survival from the time of LAPC diagnosis (20.7 vs 29.5 months; p  = 0.019) as well as from surgery (16.1 vs 23.1 months; p  = 0.024). In multivariable analysis, the interval of 4 weeks or longer was an independent predictor of improved survival. Further analysis suggested an optimal time window of 4–8 weeks between the last chemotherapy cycle and surgery. Conclusion: An interval of at least 4 weeks between the last cycle of preoperative chemotherapy and surgery for LAPC was associated with significantly improved overall survival, with an optimal window of 4–8 weeks.

Objective: To compare outcomes of patients with or without PPH and to identify risk factors associated with postoperative mortality. Background: Postpancreatectomy hemorrhage (PPH) remains one of the most harmful events after pancreatic resection. Methods: This analysis was conducted from a prospectively maintained database on patients who underwent elective pancreatic resection from 2001 to 2022. PPH rates and determinants were compared across resection types and mortality risk factors in PPH patients were identified through uni- and multivariable analyses. Results: Of 10,467 patients, 5,711 were men (54.6%); median age was 63 years (IQR, 54-71 y). The overall major morbidity rate was 22.7% with an in-hospital mortality of 3.2%. PPH occurred in 610 patients (5.9%). CR-POPF strongly predicted PPH (OR 5.93, 95% CI, 4.80–7.34; P P P< 0.001). Independent risk factors for mortality in the PPH group after pancreatic head or distal resections were higher age (OR; 2.79, P= 0.001), relaparotomy for bleeding (OR, 6.35, 95% CI, 3.04-14.0; P< 0.001), bleeding from the SMA (OR, 3.92; P= 0.07) or the hepatic artery (OR, 3.05; P= 0.02), sepsis (OR, 4.10; P< 0.001) and very late (POD ≥16) bleeding (OR, 3.95; P= 0.03). After total pancreatectomy, only recurrent bleeding (OR, 2.36; P= 0.07) and intraabdominal infection (OR, 3.10; P= 0.22) were identified as independent predictors for mortality. Conclusions: The occurrence of PPH represents the most severe complication after pancreatic resection and is associated with an almost 10-fold increase in mortality. This effect is even more pronounced in patients undergoing more complex resections.

Background: Chyle leak is a relevant complication after surgery for pancreatic ductal adenocarcinoma (PDAC). Increasing use of multimodal neoadjuvant therapy (NAT) and extended resections may contribute to a higher incidence. This study aimed to describe the incidence of clinically relevant chyle leak and identify its risk factors in patients with PDAC treated with NAT and surgery versus upfront surgery. Patients and Methods: Patients undergoing PDAC resection between 2014 and 2019 were identified from a prospective institutional database. Clinicopathologic and demographic data were extracted. The primary outcome was clinically relevant chyle leak according to the International Study Group of Pancreatic Surgery (ISGPS). Univariable and multivariable logistic regression were performed to identify associated factors. Results: A total of 1402 patients were included: 1090 (77.7%) underwent upfront surgery, and 312 (22.3%) received NAT. Pancreatic head resections were performed in 718 (51.2%), distal pancreatectomies in 317 (22.6%), and total pancreatectomies in 367 (26.2%) individuals. Overall, 108 (7.7%) developed clinically relevant chyle leak: 88 (6.3%) grade B and 20 (1.4%) grade C. NAT (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.10–1.91), T stage (pT2/3/4 versus pT0/1, OR 1.53, 95% CI 1.03–2.34), and total pancreatectomy (OR 2.29, 95% CI 1.78–2.96) were associated with any chyle leak. For grade B/C, only NAT was an independent risk factor (OR 2.63, 95% CI 1.74–3.94). Age, resection type, and nodal status were not independent risk factors. Conclusions: NAT is an independent risk factor for clinically relevant chyle leak following PDAC resection. These findings highlight the need for risk-adapted postoperative management and warrant prospective validation.

Pancreatic ductal adenocarcinoma (PDAC) is associated with intratumoral microbiota changes. However, defining the normal pancreatic microbial composition remains a challenge. Herein, we tested the hypothesis that the microbial profiling of normal pancreatic tissue from healthy organ donors (HC) could help in determining the signature of microbiota in PDAC. Matched pairs of tumor and normal tissues from PDAC patients (n = 32) and normal pancreatic tissues from HC (n = 17) were analyzed by 16S rRNA gene sequencing. Dissimilarities in all the beta metrics emerged in both normal samples and tumor samples, compared to HC (Bray–Curtis dissimilarity and Jaccard distance: p = 0.002; weighted UniFrac distances: p = 0.42 and p = 0.012, respectively; unweighted UniFrac distance: p = 0.009); a trend toward a lower Faith’s phylogenetic distance was found at the tumor level vs. HC (p = 0.08). Within PDAC, a lower Faith’s phylogenetic distance (p = 0.003) and a significant unweighted UniFrac distance (p = 0.024) were observed in tumor samples vs. normal samples. We noted the presence of a decreased abundance of bacteria with potential beneficial effects (Jeotgalicoccus) and anticancer activity (Acinetobacter_guillouiae) in PDAC vs. HC; bacteria involved in immune homeostasis and suppression of tumor progression (Streptococcus_salivarius, Sphingomonas) were reduced, and those implicated in tumor initiation and development (Methylobacterium-Methylorubrum, g_Delftia) were enhanced in tumor samples vs. normal samples. Metagenomic functions involved in fatty acid synthesis were reduced in normal samples compared to HC, while peptidoglycan biosynthesis IV and L-rhamnose degradation were more abundant in tumor samples vs. normal samples. Future prospective studies on larger populations, also including patients in advanced tumor stages and considering all potential existing confounding factors, as well as further functional investigations, are needed to prove the role of microbiota-mediated pathogenicity in PDAC.

Objective: To assess the prognostic impact of margin status in patients with resected intraductal papillary mucinous neoplasms (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) and to inform future intraoperative decision-making on handling differing degrees of dysplasia on frozen section. Background: The ideal oncologic surgical outcome is a negative transection margin with normal pancreatic epithelium left behind. However, the prognostic significance of reresecting certain degrees of dysplasia or invasive cancer at the pancreatic neck margin during pancreatectomy for IPMN-derived PDAC is debatable. Methods: Consecutive patients with resected and histologically confirmed IPMN-derived PDAC (2002–2022) from 6 international high-volume centers were included. The prognostic relevance of a positive resection margin (R1) and degrees of dysplasia at the pancreatic neck margin were assessed by log-rank test and multivariable Cox-regression for overall survival (OS) and recurrence-free survival. Results: Overall, 832 patients with IPMN-derived PDAC were included, with 322 patients (39%) having an R1-resection on final pathology. Median OS (mOS) was significantly longer in patients with an R0 status compared with those with an R1 status (65.8 vs 26.3 mo P P =0.344). However, high-grade dysplasia (mOS: 26.1 mo, P =0.001) and invasive cancer (mOS: 25.0 mo, P P <0.001). Conclusions: In IPMN-derived PDAC, normal epithelium or low-grade dysplasia at the neck have similar outcomes, while pancreatic neck margins with high-grade dysplasia or invasive cancer are associated with poorer outcomes. Conversion of a high-risk to low-risk margin after intraoperative frozen section is associated with survival benefit and should be performed when feasible.

Objective: Our investigation on in-hospital mortality after 4474 pancreatoduodenectomies aimed to identify time-dependent risks as well as windows of opportunity to rescue patients from complications. Background: Pancreatoduodenectomy is generally considered a safe procedure with a 1% to 10% perioperative mortality based on complexity and surgical volume. Yet, patients are susceptible to life-threatening complications particularly with extended resections. Recognition of distinct vulnerabilities over time while patients recover is required to permit focused monitoring, sophisticated resource allocation, and the greatest surgical safety. Methods: Patients who deceased in-hospital after pancreatoduodenectomy between 2003 and 2021 were retrieved from the institutional pancreatectomy registry and analyzed in detail with respect to their postoperative course. Results: Among 4474 pancreatoduodenectomies, 156 patients deceased in-hospital (3.5%). When assessing root causes of mortality, we observed 3 different clusters of complications, which were postpancreatectomy-specific (51.9%), visceral vasculature–associated (25.6%), or cardiopulmonary in origin (17.9%). The median times of root cause onset in the 3 categories were postoperative day (POD) 9, POD 4.5 ( P =0.008), and POD 3 ( P P =0.009), and POD 8 ( P P =0.017), and 1 day ( P <0.001). The 3 categories were similarly distributed between different types of surgical complexity. Conclusions: Postpancreatectomy-specific complications prompt almost half of the in-hospital mortalities after pancreatoduodenectomy, with rather long intervals for interventions to prevent failure to rescue. In contrast, visceral vasculature-related events and cardiopulmonary complications dominate early in-hospital mortalities with short intervals until mortality, demanding rigorous management of such events or preoperative conditioning. These data externally validate a previous high-volume initiative and highlight distinct windows of opportunity to optimize perioperative safety.