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The intratumoral microenvironment, or stroma, is of major importance in the pathobiology of pancreatic ductal adenocarcinoma (PDA), and specific conditions in the stroma may promote increased cancer aggressiveness. We hypothesized that this heterogeneous and evolving compartment drastically influences tumor cell abilities, which in turn influences PDA aggressiveness through crosstalk that is mediated by extracellular vesicles (EVs). Here, we have analyzed the PDA proteomic stromal signature and identified a contribution of the annexin A6/LDL receptor-related protein 1/thrombospondin 1 (ANXA6/LRP1/TSP1) complex in tumor cell crosstalk. Formation of the ANXA6/LRP1/TSP1 complex was restricted to cancer-associated fibroblasts (CAFs) and required physiopathologic culture conditions that improved tumor cell survival and migration. Increased PDA aggressiveness was dependent on tumor cell-mediated uptake of CAF-derived ANXA6+ EVs carrying the ANXA6/LRP1/TSP1 complex. Depletion of ANXA6 in CAFs impaired complex formation and subsequently impaired PDA and metastasis occurrence, while injection of CAF-derived ANXA6+ EVs enhanced tumorigenesis. We found that the presence of ANXA6+ EVs in serum was restricted to PDA patients and represents a potential biomarker for PDA grade. These findings suggest that CAF-tumor cell crosstalk supported by ANXA6+ EVs is predictive of PDA aggressiveness, highlighting a therapeutic target and potential biomarker for PDA.

Background Patients with borderline (BR) or locally advanced (LA) pancreatic adenocarcinoma (PAC) are often treated with induction FOLFIRINOX (FLX). However, the role of additional preoperative chemoradiotherapy (CRT) is controversial. The aim of this study is to evaluate its impact in patients who underwent resection after induction FLX. Patients and Methods Retrospective analysis of prospective consecutive surgical BR or LA PAC patients after induction FLX in 23 French centers between November 2010 and December 2015, treated with or without preoperative additional CRT (FLX vs FLX + CRT groups). Results Two hundred three patients were included (106 BR, 97 LA PAC). Median number of FLX cycles was 6 (range 1–30); 50% ( n  = 102) of patients received additional CRT. Median duration between diagnosis and surgery was 5.4 and 8.7 months ( P  = 0.001) in the FLX and FLX + CRT group, respectively. The 90-day mortality, major complications, and pancreatic fistula rates were 4.4%, 17.7%, and 5.4%, respectively. After 45.1 months follow-up, overall survival (OS) and disease-free survival were 45.4 months and 16.2 months, respectively. Patients with additional CRT had higher R0 resection rate (89.2% vs 76.3%; P  = 0.017), ypN0 rate (76.2% vs 48.5%; P  < 0.001), and higher rate of pathologic major response (33.3% vs 12.9%; P  = 0.001). In the FLX + CRT group, patients had lower rate of locoregional relapse (28.3% vs 50.7%; P  = 0.004). Patients with additional CRT had longer OS than those receiving FLX alone (57.8 vs 35.5 months; P  = 0.007). Conclusions Pathological results and survival data argue for interest in additional CRT. Prospective studies on an intention-to-treat basis are needed to confirm these results.

Circulating tumor DNA (ctDNA) is a promising marker with a strong prognostic value in metastatic pancreatic ductal adenocarcinoma (mPDAC). However, ctDNA is not detected in about a third of patients with mPDAC. The objective of this study was to assess the correlation between ctDNA and tumor volume (TV). In this monocentric cohort of mPDAC patients naïve for chemotherapy, ctDNA quantity at baseline (before chemotherapy initiation) was assessed by droplet-based digital PCR targeting two methylated markers (HOXD8 and POU4F1). TV was measured in 3D, for the primary lesion and the metastatic sites, from baseline thoraco-abdomino-pelvic computed tomography (CT) scan. Among the 71 included patients, ctDNA was detected in 47 patients (66.2%). There was a significant correlation of total and liver TV with ctDNA quantity, with Spearman’s ρ of 0.353 ( p  = 0.01) and 0.500 ( p  < 0.001), respectively. Total and liver TV were higher in patients with detected ctDNA (129.5 vs. 31.8 mL, p  = 0.002 and 18 vs. 1 mL, p  < 0.001, respectively). Total and liver TV thresholds of 90.1 and 3.7 mL were associated with ctDNA detection, respectively. In conclusion, this study demonstrates, in patients with mPDAC, a moderate correlation between ctDNA and TV in mPDAC, especially for liver metastases TV.

Circulating tumor DNA (ctDNA) is a promising prognostic biomarker in various cancers. Due to the high recurrence rate of resectable pancreatic ductal adenocarcinoma (PDAC), effective strategies for prognostic stratification are necessary. Yet, for resectable PDAC, prognostic impact of ctDNA lacks systemic evidence. We sought to investigate the prognostic significance of baseline ctDNA and postoperative ctDNA in patients with resectable PDAC. PubMed, EMBASE, and the Cochrane library were searched up to March 2019. Five studies met the inclusion criteria, and 375 patients were pooled for the meta-analysis. Positive ctDNA significantly indicated poor overall survival (at baseline, hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.13–4.56; postoperative, HR 3.66, 95% CI 1.45–9.28). Patients with detectable ctDNA showed the trend to have higher risk for disease recurrence than those without detectable ctDNA (at baseline, HR 1.96, 95% CI 0.65–5.87; postoperative, HR 2.20, 95% CI 0.99–4.87). The results were consistent regardless of pre- or post-operative ctDNA. There was no significant heterogeneity among the included studies. In conclusion, our meta-analysis revealed that ctDNA, either at baseline or postoperative, might be a useful prognostic biomarker for stratifying risk of death and recurrence in resectable PDAC.

Background This trial wants to ascertain whether the RAPID procedure could improve graft availability and patient survival in hepatocellular carcinoma (HCC) setting. RAPID-HCC trial, which aims to decrease waiting times and mortality for patients on the transplant list by adopting a novel surgical approach, could be a major step forward in liver transplantation (LT). If successful, the RAPID procedure could become a new standard of care for LT, addressing the critical shortage of organs and improving outcomes for selected patients with early-stage HCC. We expected to provide critical evidence to support the wider adoption of this new approach. Methods The RAPID-HCC trial is a prospective, multicentre study conducted across five major university hospitals in France aiming to assess the feasibility, safety, tolerance, and efficacy of the RAPID procedure on HCC patients. A total of 50 adult HCC patients with preserved liver function (MELD score ≤ 15) will be enrolled and 34 of these will receive a split liver graft from a brain-dead donor (DBD). The RAPID procedure consists in splitting a deceased donor liver and transplanting it into two adult recipients. The operation consists of two phases: first, the donor’s left lateral lobe (G23) replaces the recipient’s left liver lobe (H1234), while the native right lobe stays to support hepatic function. The recipient’s right lobe (H5678) is removed four months later, leaving the graft fully functional. Primary outcomes will focus on the feasibility and safety of the procedure, assessed by successful completion of both surgical stages and monitoring for adverse events. Secondary outcomes will include graft and patient survival, incidence of rejection and HCC recurrence, waiting times and overall patient outcomes compared to conventional whole liver transplantation. Discussion Early insights from several studies hint that the RAPID method might improve graft availability and recipient survival. Still, further studies are needed to confirm these benefits, especially for HCC patients. RAPID HCC trial pushes forward liver transplants for HCC patients who still have good liver function. This method could reduce waiting times and mortality in transplant candidates. If successful, the RAPID procedure could be adopted as a new standard for LT. Trial registration {2a} {2b} ClinicalTrials.gov NCT05971628. Registered on August 2, 2023, before the start of inclusion. Project Code: APHP210351 / N° IDRCB: 2022-A02151-42. Grant support This study was supported by the French national PHRC-K Inca 2020.

Purpose In view of increased response rates and survivals in patients with metastatic pancreatic adenocarcinoma (PAC) with FOLFIRINOX, many centers proposed this regimen as induction chemotherapy for borderline (BR) or locally advanced (LA) PAC. The aim of this study was to assess surgical and oncological outcomes of patients who underwent resection after induction FOLFIRINOX therapy. Methods We prospectively identified surgical consecutive BR or LA PAC patients after induction FOLFIRINOX in 20 observational French centers between November 2010 and December 2013. Two independent experts retrospectively evaluated initial CT scan for central review. Results Eighty patients were included, 47 had BR and 33 had LA PAC. Median number of FOLFIRINOX cycles was 6 (range 1–30) and 65 % of patients received chemoradiation. The 30-day-mortality, major complications, and symptomatic pancreatic fistula rates were 2.5, 22.5, and 4 %, respectively. R0 resection was achieved in 84 %. After a median follow-up of 38.2 months since diagnosis, disease-free survival (DFS) was 17.16 months. The overall survival rates at 12 and 24 months were 92 and 81 %, respectively. A 26 % ( n  = 21) pathologic major response (pMR) rate was reached. In univariate and multivariate analysis, pMR was a prognostic factor for DFS (hazard ratio 0.33; P  = 0.01 and hazard ratio 0.38; P  = 0.035). Conclusions Resection after induction FOLFIRINOX is safe and associated with similar or better outcomes as upfront surgery in patients with PAC. A pMR was observed in 26 % of cases and was prognostic of DFS. This therapeutic design should be investigated in prospective studies.

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the third leading cause of cancer-related mortality within the next decade. Management of PDAC remains challenging with limited effective treatment options and a dismal long-term prognosis. Liquid biopsy and circulating biomarkers seem to be promising to improve the multidisciplinary approach in PDAC treatment. Circulating tumour DNA (ctDNA) is the most studied blood liquid biopsy analyte and can provide insight into the molecular profile and individual characteristics of the tumour in real-time and in advance of standard imaging modalities. This could pave the way for identifying new therapeutic targets and markers of tumour response to supplement diagnostic and provide enhanced stratified treatment. Although its specificity seems excellent, the current sensitivity of ctDNA remains a limitation for clinical use, especially in patients with a low tumour burden. Increasing evidence suggests that ctDNA is a pertinent candidate biomarker to assess minimal residual disease after surgery but also a strong independent prognostic biomarker. This review explores the current knowledge and recent developments in ctDNA as a screening, diagnostic, prognostic and predictive biomarker in the management of resectable PDAC but also technical and analytical challenges that must be overcome to move toward “precision onco-surgery.”

Aim To assess anatomic changes on computed tomography (CT) after neoadjuvant FOLFIRINOX (5-fluorouracil/leucovorin/irinotecan/oxaliplatin) chemotherapy for secondary resected borderline resectable (BR) and locally advanced (LA) pancreatic adenocarcinoma and their accuracy to predict resectability and pathological response. Methods Thirty-six patients with secondary resected BR/LA pancreatic adenocarcinoma after neoadjuvant FOLFIRINOX chemotherapy (± chemoradiotherapy) were retrospectively included. Two radiologists reviewed baseline and pre-surgical CTs in consensus. NCCN (National Comprehensive Cancer Network) classification, largest axis, product of the three axes (P3A), and arterial/venous involvement were studied and compared to pathological response and resection status and to disease-free survival (DFS). Results Thirty-one patients had R0 resection, including only six exhibiting a downstaging according to the NCCN classification. After treatment, the largest axis and P3A decreased ( P  < 0.0001). The pre-surgical largest axis and P3A were smaller in case of R0 resection ( P  = 0.019/ P  = 0.021). The largest axis/P3A variations were higher in case of complete pathological response ( P  = 0.011/P = 0.016). A decrease of the arterial/venous involvement was not able to predict R0 or ypT0N0 (P > 0.05). Progression of the vascular involvement was seen in two (5 %) patients and led to a shorter DFS. Conclusion In BR/LA pancreatic adenocarcinoma after the neoadjuvant FOLFIRINOX regimen (± chemoradiotherapy), significant tumour size decreases were observed on CT. However, CT staging was not predictive of resectability and pathological response. Key Points • Significant tumour size decreases were observed on CT after FOLFIRINOX (± chemoradiotherapy ). • CT is not able to predict R0 resection accurately after FOLFIRINOX (± chemoradiotherapy ). • CT is not able to predict complete response accurately after FOLFIRINOX (± chemoradiotherapy ). • Even with a stable NCCN classification , BR / LA pancreatic adenocarcinoma could have R0 resection .

ObjectiveThe prognostication of metastatic pancreatic adenocarcinoma (mPDAC) patients remains uncertain, mainly based on carbohydrate antigen 19-9 (CA19-9), with limited utility. Circulating tumour DNA (ctDNA) has been suggested as a prognostic factor, but its added value has been poorly explored. The objective was to determine whether ctDNA is an independent factor for the prognostication of mPDAC.DesignTranslational study based on two prospective collections of plasma samples of mPDAC patients naïve for chemotherapy. One used as a test series and the other as validation series coming from two randomised trials (Prodige 35 and Prodige 37). CtDNA was assessed by digital droplet PCR targeting two methylated markers (HOXD8 and POU4F1) according to a newly developed and validated method. Univariate and multivariate analyses were performed according to ctDNA status.ResultsOf 372 plasma samples available, 354 patients were analyzed for survival. In the validation series, 145 of 255 patients were found ctDNA positive (56.8%), Median PFS and OS were 5.3 and 8.2 months in ctDNA-positive and 6.2 and 12.6 months in ctDNA-negative patients, respectively. ctDNA positivity was more often associated with young age, high CA19-9 level and neutrophils lymphocytes ratio. In multivariate analysis including these previous markers, ctDNA was confirmed as an independent prognostic marker for PFS (adjusted hazard ratio (HR) 1.5, CI 95% [1.03–2.18], p = 0.034) and OS (HR 1.62, CI 95% [1.05–2.5], p = 0.029).ConclusionsIn this first ctDNA assessment in a large series of mPDAC derived from clinical trials, ctDNA was detectable in 56.8% of patients and confirmed as an independent prognostic marker.