Faculty Bibliography

OBJECTIVE:Identify how surgical resection of pancreatic ductal adenocarcinoma (PDAC) affects systemic minimal residual disease (MRD). METHODS:Pancreatic tumors were generated by orthotopic implantation of tumor cells into the pancreas of immunocompetent mice. Tumor resection was carried out via distal pancreatectomy and splenectomy. Liver metastases and microenvironment immune changes were analyzed in resected vs. non-resected mice. RESULTS:Resection was accompanied by proliferative expansion of liver metastases and an increase in hepatic metastatic burden. Postoperative immune changes predominantly manifested as a time-dependent increase in eosinophils and decrease in neutrophils. The postoperative hepatic eosinophilia was protective of further metastatic progression. The parenchymal findings were detectable in the circulation, and the trends observed in the mouse model modeled those seen in PDAC patients postoperatively. CONCLUSION/CONCLUSIONS:Collectively, we describe a preclinical resection model that offers a means to investigate MRD. Using this model, we delineated effects of surgical resection on metastatic outgrowth and uncovered a protective link between the postoperative hepatic eosinophilia and further metastatic progression.

SUMMARY OF BACKGROUND DATA/BACKGROUND:Intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic cancer is typically managed like pancreatic intraepithelial neoplasia (PanIN)-derived pancreatic cancer. However, in IPMN-derived pancreatic cancer, the role of chemotherapy remains controversial, particularly in the neoadjuvant setting (NAT). OBJECTIVE:To evaluate the role of neoadjuvant chemotherapy in IPMN-derived pancreatic cancer. METHODS:Patients with IPMN-derived pancreatic cancer treated with either upfront surgery (US) or NAT were identified from eight international centers (2000-2023). Clinicopathologic data were compared. Date of first treatment was used for Kaplan-Meier and log-rank tests to compare overall (OS) and recurrence free survival (RFS). Multivariable Cox-regression was performed in patients that underwent NAT. RESULTS:In 1,019 patients, 76 (7%) underwent NAT. Patients who received NAT had higher baseline CA19-9 levels (P<0.001). Of these 76 patients, 27 (36%), 20 (26%), and 29 (38%) had resectable, borderline resectable, or locally advanced pancreatic cancer at diagnosis, respectively. Advanced resectability stage was significantly more common in the NAT patients as compared to those who underwent US (P<0.001). OS for US patients was 38.0 months (95%CI: 33.7.1-44.3), which was not statistically different than those that received NAT [27.5 mo (95%CI: 23.1-46.7), P=0.121]. This was also valid for patients with resectable disease [US: 38.1 mo vs. NAT: 35.6 mo, P=0.920)]. Complete or marked pathological treatment response (P=0.046) and serological CA19-9 normalization after NAT (P=0.017) were associated with improved survival. On Cox-regression for OS, N2 disease [HR: 4.15 (95%CI: 1.71-10.10)], elevated CA19-9 [HR: 2.02 (95%CI:1.06-3.85)] and R1 margin [HR: 2.36 (95%CI:1.20-4.61)] was independently associated with OS after NAT, while resectability status was not. CONCLUSION/CONCLUSIONS:After NAT and resection, advanced resectability stage was not associated with worse OS indicating the value of this approach for borderline resectable and locally advanced IPMN-derived pancreatic cancer. The benefit of NAT in resectable disease is unclear and may require an individualized approach. Biological treatment effect can be assessed with CA19-9 and confirmed by pathologic response.

BACKGROUND:The introduction of (m)FOLFIRINOX and gemcitabine-nab-paclitaxel has changed the perspective for patients with locally advanced pancreatic cancer (LAPC). Consequently, in experienced centres 23% of patients with LAPC undergo a resection with 5-year overall survival (OS) rates of up to 25%. In the Netherlands, the nationwide resection rate for LAPC remains low at 8%. The PREOPANC-4 program aims for a nationwide implementation of the international multidisciplinary best-practice to improve patient outcome. METHODS:Nationwide program implementing the international multidisciplinary best-practice for LAPC. In the training phase, multidisciplinary and surgical webinars are given by 4 international experts, leading to a clinical protocol, followed by surgical off-site and on-site proctoring sessions. In the implementation phase, the clinical protocol will be implemented in all centres, including a nationwide expert panel (2022-2024). Healthcare professionals will be trained in shared decision-making. Consecutive patients diagnosed with pathology-proven LAPC (i.e., arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion [DPCG criteria]) are eligible. Primary outcomes are median and 5-year OS from diagnosis, resection rate, in-hospital/30-day mortality and major morbidity (i.e., Clavien-Dindo grade ≥ IIIa), and radical resection (R0) rate. Secondary outcomes include quality of life, functioning, side effects, and patients' healthcare satisfaction in all included patients. Outcomes will be compared with patients with borderline resectable pancreatic cancer (BRPC) treated with neoadjuvant FOLFIRINOX in the PREOPANC-2 trial (EudraCT: 2017-002036-17) and a historical cohort of patients with LAPC from the PACAP registry (NCT03513705). The existing prospective LAPC Registry and PACAP PROMs (NCT03513705) will be used for data collection. In qualitative interviews, treatment preferences, values, and experiences of LAPC patients, their relatives, and healthcare professionals will be assessed for the development of shared decision-making supportive tools. It is hypothesized that the program will double the nationwide LAPC resection rate to 16% with major morbidity < 50% and mortality ≤ 5%, and OS following resection similar to that observed in patients with BRPC. DISCUSSION/CONCLUSIONS:The PREOPANC-4 program aims to safely implement the international multidisciplinary best-practice for LAPC leading to benchmark outcomes for both short-term morbidity, mortality, and OS. TRIAL REGISTRATION/BACKGROUND:PREOPANC-4 program was registered at ClinicalTrials.gov (NCT05524090) on September 1, 2022.

OBJECTIVE:To establish a novel method for evaluating carbohydrate antigen 19-9 (CA19-9) during neoadjuvant therapy (NAT) and assess its role in predicting overall (OS) and disease-free (DFS) survival in borderline resectable pancreatic adenocarcinoma (BR-PC). SUMMARY BACKGROUND DATA/BACKGROUND:Static CA19-9 values or percentage changes often fail to capture therapeutic responses in patients with BR-PC undergoing NAT. Improved evaluation methods are essential for guiding the treatment. METHODS:This was a retrospective multicenter study of patients who underwent BR-PC surgery. Two parameters were developed: slope coefficient (SC, change in CA19-9 divided by therapy duration) and mean δf (mδf, calculated as the sum of CA19-9 values over therapy intervals divided by the number of 15-day periods). The main objective was to correlate mδf with OS thresholds derived using a maximally selected log-rank statistic and validated in independent cohorts. RESULTS:Overall, 991 patients (median age 65 [59-71] years; 49% male) were included. The thresholds for mδf were defined as U.mL-1. month-1 (negative SC) and U.mL-1. month-1 (positive SC). Patients with mδf below these thresholds had significantly better prognoses, with hazard ratios (HR) for OS (95% CI) of 0.6 (0.4-0.8; P<0.01) and 0.4 (0.2-0.9; P=0.04) for negative and positive SC, respectively. Both thresholds were validated for mOS, with 29 vs 22 months (P=0.015) and 32 vs 16 months (P=0.0034) for negative and positive SC, respectively. Similarly, the mDFS was 13 vs 10 months (P=0.011) and 12 vs 7 months (P=0.0018), respectively. CONCLUSION/CONCLUSIONS:This CA19-9 evaluation approach accurately predicts survival outcomes, offering a valuable tool for optimizing treatment strategies. An mδf calculator is available at https://www.pancpals.com/tools.

BACKGROUND:Evidence regarding the optimal surgical approach for pancreatic neck/body cancer with portomesenteric vein (PV) involvement is scarce. We aimed to clarify the current practice using an international survey. METHODS:An online survey was distributed to members of nine international associations and study groups. Surgeons who performed pancreatectomy with PV resection (PVR) in the last 12 months were asked about three clinical scenarios with different PV involvement: scenarios A (<90°; length 1 cm), B (<90°; length 3 cm), and C (90-180°; length 3 cm), with or without common hepatic artery (CHA) involvement. PVR was defined according to the ISGPS definition. RESULTS:Overall, 222 surgeons from 49 countries in 6 continents completed the survey. The most selected procedures were left pancreatectomy with PVR ISGPS-type 1 for scenario A (52.3 %), PVR ISGPS-type 2 for B (28.8 %), and pancreatoduodenectomy with PVR ISGPS-type 3 for C (28.4 %). In patients with CHA involvement, the most selected procedures were left pancreatectomy without arterial reconstruction for A (57.7 %) and B (50.0 %), and total pancreatectomy for C (29.7 %). CONCLUSIONS:The survey illustrates the heterogeneity in surgical management of pancreatic neck/body cancer with PV involvement, indicating the need for prospective studies and guidelines.

BACKGROUND:Current guidelines recommend the resection of main duct- (MD) and mixed-type (MT) intraductal papillary mucinous neoplasms (IPMN) based on specific risk criteria to prevent or treat pancreatic cancer in selected patients. This paradigm follows high rates of malignancy observed in published surgical series. The aim of this systematic review and meta-analysis was to provide robust, pooled rates of invasive carcinoma (IC) and high-grade dysplasia (HGD) in resected MD- and MT-IPMNs of the pancreas. METHODS:The PubMed, Embase, Scopus, Web of Science, and Cochrane CENTRAL databases were systematically searched. Studies that reported rates of IC or HGD, diagnosed by histopathology of surgical specimens, in MD- or MT-IPMNs were included. Pooled prevalence with 95 % confidence interval (95 % CI) was calculated using a random effects model. Galbraith plots were used to evaluate heterogeneity. Risk of bias was assessed using the National Institutes of Health Quality Assessment Tool. RESULTS:Based on 51 studies, 59 % (95 % CI: 54 %, 64 %) of resected MD- and MT-IPMN had IC or HGD, with IC in up to 39 % (95 % CI: 33 %, 44 %) of lesions and HGD in 20 % (95 % CI: 16 %, 25 %). Most studies were deemed to be of good quality and Galbraith plots demonstrated high concordance. CONCLUSIONS:These results confirm the rates of IC and HGD in resected MD/MT-IPMNs. However, a significant proportion of patients have benign lesions, and future research is needed to develop precise diagnostics to distinguish between patients with and without high-risk or cancerous disease.

BACKGROUND:IPMN consensus guidelines make implicit judgments on what cancer risk level should prompt surgery. We used decision modeling to estimate this cancer risk threshold (CRT) for BD-IPMN patients. METHODS:We created a decision model to compare quality-adjusted life years (QALYs) following surgery or surveillance for BD-IPMNs. We simulated treatment decisions for hypothetical patients, varying age, comorbidities and lesion location (pancreatic head/tail). The base case was a 60-year-old patient with mild comorbidities and pancreatic head IPMN. Probabilities, life expectancies, and utilities were incorporated from literature/public datasets. CRT was defined as the level of cancer risk at which the expected value of QALYs for surgery first exceeded that of surveillance. RESULTS:In the base case, surgery was preferred over surveillance, yielding 21.90 vs. 21.88 QALYs. The optimal CRT for a BD-IPMN patient depended on age, comorbidities, and location. CRT in the base case was 20 % and 3 % for an IPMN in the head and tail of the pancreas, respectively. Other drivers of preferred treatment were age and likelihood of postoperative mortality. CONCLUSION/CONCLUSIONS:For BD-IPMNs, the optimal CRT varies depending on patient age and risk of surgical complications. Personalized risk threshold values could guide treatment decisions and inform future treatment consensus guidelines.