Simple Summary: Pancreatic cancer is one of the most lethal cancer types and its high refractoriness to therapies, including immunotherapy, has often been associated with the predominantly immune... Show moreSimple Summary: Pancreatic cancer is one of the most lethal cancer types and its high refractoriness to therapies, including immunotherapy, has often been associated with the predominantly immune suppressive tumor microenvironment that characterizes pancreatic tumors. Regulatory T cells (Tregs) are generally considered as drivers of immune suppression in cancers. However, an increasing number of reports suggest a paradoxical association between tumor infiltration by Tregs and improved patient prognosis, in particular in gastrointestinal cancers. Here we show that Treg infiltration in pancreatic ductal adenocarcinomas (PDAC) is associated with better overall survival of patients. Abstract: Pancreatic ductal adenocarcinoma (PDAC) is considered to be a poorly immunogenic cancer type that combines a low mutation burden with a strong immunosuppressive tumor microenvironment. Regulatory T cells (Tregs) are major drivers of immune suppression but their prognostic role, particularly in gastrointestinal malignancies, remains controversial. Lymphocytic infiltration in 122 PDAC samples was assessed by multispectral immunofluorescence with anti-Keratin, -CD3, -CD8, -FOXP3 and -CD163 antibodies. Differential infiltration by Tregs was analyzed in the context of transcriptomic profiles that were available for 65 tumors. High infiltration of CD3(+)CD8(-) (mainly CD4(+)) T cells and, especially, of the subset expressing FOXP3 (Tregs) was associated with improved patient survival, whilst cytotoxic CD3(+)CD8(+) T cell infiltration did not have an impact on overall survival. Transcriptomic analysis revealed three signatures in PDAC tumors comprising of epithelial-mesenchymal transition (EMT)/stromal, metabolic, and secretory/pancreatic signature. However, none of these signatures explained differences in Treg infiltration. We show that Tregs associate with improved overall survival in PDAC patients. This effect was independent of cytotoxic T cell infiltration and the transcriptomic profiles of their respective tumors. These findings provide a new layer of complexity in the study of PDAC tumor microenvironment that must be considered when developing immunotherapeutic interventions for this disease. Show less
Klompmaker, S.; Hilst, J. van; Wellner, U.F.; Busch, O.R.; Coratti, A.; D'Hondt, M.; ... ; European Consortium Minimally Inva 2020
Objective: To assess short-term outcomes after minimally invasive (laparoscopic, robot-assisted, and hybrid) pancreatoduodenectomy (MIPD) versus open pancreatoduodenectomy (OPD) among European... Show moreObjective: To assess short-term outcomes after minimally invasive (laparoscopic, robot-assisted, and hybrid) pancreatoduodenectomy (MIPD) versus open pancreatoduodenectomy (OPD) among European centers. Background: Current evidence on MIPD is based on national registries or single expert centers. International, matched studies comparing outcomes for MIPD and OPD are lacking. Methods: Retrospective propensity score matched study comparing MIPD in 14 centers (7 countries) performing >= 10 MIPDs annually (2012-2017) versus OPD in 53 German/Dutch surgical registry centers performing >= 10 OPDs annually (2014-2017). Primary outcome was 30-day major morbidity (Clavien-Dindo >= 3). Results: Of 4220 patients, 729/730 MIPDs (412 laparoscopic, 184 robot-assisted, and 130 hybrid) were matched to 729 OPDs. Median annual case-volume was 19 MIPDs (interquartile range, IQR 13-22), including the first MIPDs performed in 10/14 centers, and 31 OPDs (IQR 21-38). Major morbidity (28% vs 30%,P= 0.526), mortality (4.0% vs 3.3%,P= 0.576), percutaneous drainage (12% vs 12%,P= 0.809), reoperation (11% vs 13%,P= 0.329), and hospital stay (mean 17 vs 17 days,P> 0.99) were comparable between MIPD and OPD. Grade-B/C postoperative pancreatic fistula (POPF) (23% vs 13%,P< 0.001) occurred more frequently after MIPD. Single-row pancreatojejunostomy was associated with POPF in MIPD (odds ratio, OR 2.95,P< 0.001), but not in OPD. Laparoscopic, robot-assisted, and hybrid MIPD had comparable major morbidity (27% vs 27% vs 35%), POPF (24% vs 19% vs 25%), and mortality (2.9% vs 5.2% vs 5.4%), with a fewer conversions in robot-assisted- versus laparoscopic MIPD (5% vs 26%,P< 0.001). Conclusions: In the early experience of 14 European centers performing >= 10 MIPDs annually, no differences were found in major morbidity, mortality, and hospital stay between MIPD and OPD. The high rates of POPF and conversion, and the lack of superior outcomes (ie, hospital stay, morbidity) could indicate that more experience and higher annual MIPD volumes are needed. Show less
Goggins, M.; Overbeek, K.A.; Brand, R.; Syngal, S.; Chiaro, M. del; Bartsch, D.K.; ... ; Int Canc Pancreas Screening 2020
Objectives: A significant proportion of patients with pancreatic cancer are over the age of 70 years. The aim was to compare treatment and survival for older patients with pancreatic cancer treated... Show moreObjectives: A significant proportion of patients with pancreatic cancer are over the age of 70 years. The aim was to compare treatment and survival for older patients with pancreatic cancer treated throughout the Netherlands or Moffitt Cancer Center (Tampa, Florida).Methods: All age-eligible patients with pancreatic adenocarcinoma (2008-2012) were identified. Results were stratified by stage. Treatment (neoadjuvant, surgery, adjuvant and palliative treatment) and short-term survival were compared, and where appropriate adjusted (sex, age, grade, year) or stratified according to age or hospital (Netherlands-academic, teaching, non-teaching).Results: In total, 2728 patients were included. Neo-adjuvant chemoradiation was more often administered at Moffitt (non-metastatic stages), as was adjuvant chemoradiation and chemotherapy (p <.001). The proportion surgery was not significantly different. In patients with advanced disease, more patients at Moffitt underwent palliative chemotherapy (64.5% versus 17.4%; p < .001). Short-term survival was better among Moffitt patients (HR 0.30 (95%CI 0.11-0.82), HR 0.56 (0.41-0.72), HR 0.43 (0.36-0.52) for early, T3 or node positive and advanced). Differences were less pronounced comparing Dutch academic hospitals to Moffitt.Conclusion: In the present comparison, a treatment regimen as delivered at Moffitt was associated with prolonged short-term survival. Further detailed analyses of selection criteria for systemic treatment could lead to tailored treatment and improved outcomes. (C) 2019 Elsevier Ltd. All rights reserved. Show less
CDKN2A-p16-Leiden mutation carriers have a substantial risk of developing pancreatic ductal adenocarcinoma (PDAC). One of the main clinical features of hereditary cancer is the development of... Show moreCDKN2A-p16-Leiden mutation carriers have a substantial risk of developing pancreatic ductal adenocarcinoma (PDAC). One of the main clinical features of hereditary cancer is the development of multiple cancers. Since 2000, we have run a surveillance program for CDKN2A-p16-Leiden mutation carriers. The patients are offered a yearly MRI with optionally endoscopic ultrasound. In patients with a confirmed lesion, usually, a partial resection of the pancreas is recommended. A total of 18 PDAC (8.3%) were detected in 218 mutation carriers. In this report, we describe two CDKN2A-p16-Leiden patients with a synchronous and metachronous PDAC. Including two previously-reported cases, we identified four patients with multiple PDAC: two of 18 patients within the surveillance program (11%) and two patients with a proven CDKN2A-p16-Leiden mutation not participating in the surveillance program. In conclusion, this study demonstrated a high risk of developing multiple PDAC in CDKN2A-p16-Leiden mutation carriers. After detecting a primary tumor, it is very important to exclude the presence of a second synchronous tumor. Moreover, after a partial pancreatectomy for PDAC, close surveillance is necessary. In view of the current findings, offering a total pancreatectomy might be an appropriate option in patients with an early PDAC. Show less
