Early detection of pancreatic cancer by liquid biopsy "PANLIPSY": a french nation-wide study project.

BACKGROUND: Pancreatic cancer, predominantly characterized by ductal adenocarcinoma (PDAC) accounts for 90% of cases and is the fourth leading cause of cancer-related deaths globally. Its incidence is notably increasing. This poor prognosis is primarily due to late-stage diagnosis (approximately 70% to 80% of patients are diagnosed at an advanced stage), aggressive tumor biology, and low sensitivity to chemotherapy. Consequently, it is crucial to identify and develop a simple, feasible and reproducible blood-based signature (i.e., combination of biomarkers) for early detection of PDAC. METHODS: The PANLIPSY study is a multi-center, non-interventional prospective clinical trial designed to achieve early detection of PDAC with high specificity and sensitivity, using a combinatorial approach in blood samples. These samples are collected from patients with resectable, borderline or locally advanced, and metastatic stage PDAC within the framework of the French Biological and Clinical Database for PDAC cohort (BACAP 2). All partners of the BACAP consortium are eligible to participate. The study will include 215 PDAC patients, plus 25 patients with benign pancreatic conditions from the PAncreatic Disease Cohort of TOuLouse (PACTOL) cohort, and 115 healthy controls, totaling 355 individuals. Circulating biomarkers will be collected in a total volume of 50 mL of blood, divided into one CellSave tube (10 mL), two CELL-FREE DNA BCT® preservative tubes (18 mL), and five EDTA tubes (22 mL in total). Samples preparation will adhere to the guidelines of the European Liquid Biopsy Society (ELBS). A unique feature of the study is the AI-based comparison of these complementary liquid biopsy biomarkers. Main end-points: i) to define a liquid biopsy signature that includes the most relevant circulating biomarkers, ii) to validate the multi-marker panel in an independent cohort of healthy controls and patients, with resectable PDAC, and iii) to establish a unique liquid biopsy biobank for PDAC study. DISCUSSION: The PANLIPSY study is a unique prospective non-interventional clinical trial that brings together liquid biopsy experts. The aim is to develop a biological signature for the early detection of PDAC based on AI-assisted detection of circulating biomarkers in blood samples (CTCs, ctDNA, EVs, circulating immune system, circulating cell-free nucleosomes, proteins, and microbiota). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06128343 / NCT05824403. Registration dates: June 8,2023 and April 21, 2023.

Minimally invasive versus open distal pancreatectomy for resectable pancreatic neuroendocrine tumors: A propensity score matched multicentric comparative French study.

BACKGROUND: Minimally invasive surgery has gained momentum for left pancreatic resections. However, debate remains about whether it has any advantage over open surgery for distal pancreatectomy for pancreatic neuroendocrine tumors. METHODS: This retrospective review examined pancreatectomies performed for resectable pancreatic neuroendocrine tumors at 21 centers in France between January 2014 and December 2018. Short and long-term outcomes were compared before and after propensity score matching based on tumor size, sex, age, body mass index, center, and method of pancreatic transection. RESULTS: During the period study, 274 patients underwent left pancreatic resection for pancreatic neuroendocrine tumors [109 underwent distal splenopancreatectomy, and 165 underwent spleen-preserving distal pancreatectomy [(splenic vessel preservation (n = 97; 58.7%)/splenic vessel resection (n = 68; 41.3%)]. Before propensity score matching, minimally invasive surgery was associated with a lower rate of major morbidity (P = .004), lower rate of postoperative delayed gastric emptying (P = .04), and higher rate of "textbook" outcomes (P = .04). After propensity score matching, there were 2 groups of 54 patients (n = 30 distal splenopancreatectomy; n = 78 spleen-preserving distal pancreatectomy). Minimally invasive surgery was associated with less blood loss (P = .05), decreased rate of major morbidity (6% vs. 24%; P = .02), less delayed gastric emptying (P = .05) despite similar rates of postoperative fistula, hemorrhage, and reoperation (P > .05). The 5-year overall survival (79% vs. 75%; P = .74) and recurrence-free survival (10% vs 17%; P = .39) were similar. CONCLUSION: Minimally invasive surgery for left pancreatic resection can be safely proposed for patients with resectable left pancreatic neuroendocrine tumors. Minimally invasive surgery decreases the rate of major complications while providing comparable long-term oncologic outcomes.

Management of hepatocellular carcinoma recurrence after liver surgery and thermal ablations: state of the art and future perspectives.

Despite the improvements in surgical and medical therapy for hepatocellular carcinoma (HCC), recurrence still represents a major issue. Up to 70% of patients can experience HCC recurrence after liver resection (LR), as well as 20% of them even after liver transplantation (LT). The patterns of recurrence are different according to both the time and the location. Similarly, the risk factors and the management can change not only according to these patterns, but also according to the underlying liver condition and to the first treatment performed. Deep knowledge of such correlation is fundamental, since prevention and effective management of recurrence are undoubtedly the most important strategies to improve the outcomes of HCC treatment. Without adjuvant therapy, maintaining very close monitoring during the first 2 years in order to diagnose curable recurrence and continue this monitoring beyond 5 years because late recurrences exist, remains our only possibility today. Surgery represents the cornerstone treatment for HCC, including both LT and LR. However, new interesting therapeutic opportunities are coming from immunotherapy that has shown encouraging results also in the adjuvant setting. In such a complex and evolutionary scenario, the aim of this review is to summarize current strategies for the management of HCC recurrence, focusing on the different possible scenarios, as well as on future perspectives.

Effectiveness of endoscopic ultrasound (EUS)-guided choledochoduodenostomy vs. EUS-guided gallbladder drainage for jaundice in patients with malignant distal biliary obstruction after failed endoscopic retrograde cholangiopancreatography: Retrospective, multicenter study (GALLBLADEUS Study).

OBJECTIVES: The aim of this study was to compare endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) vs. EUS-gallbladder drainage (EUS-GBD) in cases of failed endoscopic retrograde cholangiopancreatography (ERCP) for jaundice resulting from malignant distal biliary obstruction (MDBO). METHODS: This multicenter retrospective study included patients with obstructive jaundice secondary to MDBO who underwent EUS-GBD or EUS-CDS with lumen-apposing metal stents after failed ERCP. The primary end-point was clinical success rate. Secondary end-points were technical success, periprocedural adverse events rate (<24 h), late adverse events rate (>24 h), overall survival, and time to recurrent biliary obstruction. RESULTS: A total of 78 patients were included: 41 underwent EUS-GBD and 37 underwent EUS-CDS. MDBO was mainly the result of pancreatic cancer (n = 63/78, 80.7%). Clinical success rate was similar for both procedures: 87.8% for EUS-GBD and 89.2% for EUS-CDS (P = 0.8). Technical success rate was 100% for EUS-GBD and 94.6% for EUS-CDS (P = 0.132). Periprocedural morbidity (<24 h) rates were similar between both groups: 4/41 (9.8%) for EUS-GBD and 5/37 (13.5%) for EUS-CDS (P = 0.368). There was a significantly higher rate of late morbidity (>24 h) among patients in the EUS-CDS group (8/37 [21.6%]) than in the EUS-GBD group (3/41 [7.3%]) (P = 0.042). The median follow-up duration was 4.7 months. Overall survival and time to recurrent biliary obstruction did not significantly differ between the groups. DISCUSSION: After failed ERCP for MDBO, EUS-GBD and EUS-CDS show comparable clinical success rates and technical success. EUS-GBD appears to be a promising alternative for MDBO, even as a second-line treatment after failed ERCP. Further studies are needed to validate these findings and compare the long-term outcomes of EUS-GBD and EUS-CDS.

Circulating Tumor DNA Clinical Applications in Hepatocellular Carcinoma: Current Trends and Future Perspectives.

BACKGROUND: Globally, liver cancers are the second most lethal malignancy after lung cancer (0.83 million deaths in 2020). Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer and is typically associated with liver fibrosis or cirrhosis. HCC diagnosis relies on histologic examination of surgical specimens or conventional tissue biopsy material. However, standard tissue biopsies are invasive and often do not accurately reflect the tumor heterogeneity. On the other hand, the use of liquid biopsies, represented mainly by circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), has greatly increased in the past 2 decades. Indeed, liquid biopsies are a noninvasive, repeatable, and sensitive approach to studying tumor biology. CONTENT: This review describes current clinical applications of ctDNA analysis in the management of patients with chronic liver disease, cirrhosis, and HCC. There is a substantial clinical potential of ctDNA, but interventional studies are still lacking for the moment. SUMMARY: Detection of ctDNA in both asymptomatic individuals and high-risk patients (with chronic liver disease or cirrhosis) contributes to the early diagnosis of HCC. ctDNA analysis also offer tremendous information on the tumor burden and on the risk of early recurrence. The implementation of ctDNA analysis, in association with classical tumor markers (e.g., alpha-fetoprotein), may improve (a) HCC screening in high-risk patients, (b) stratification of the recurrence risk after surgery, and (c) prognosis evaluation of patients with HCC.

First evidence of AXL expression on circulating tumor cells in metastatic breast cancer patients: A proof-of-concept study.

BACKGROUND: For several years, the AXL tyrosine kinase receptor, a member of the Tyro3-Axl-Mer (TAM) family, has been considered a new strategic target in oncology. AXL overexpression is common in solid tumors and is associated with poor prognosis. In this context, the detection of a subset of circulating tumor cells (CTCs) that express AXL (AXL+ CTCs) could be clinically relevant. METHODS: Immunostaining was performed to assess AXL expression in human breast cancer cell lines. The optimal conditions were established using flow cytometry. Spiking experiments were carried out to optimize the parameters of the CellSearch® system detection test. CTC enumeration and AXL expression were evaluated in patients with metastatic breast cancer (mBC) before treatment initiation. RESULTS: An innovative AXL+ CTC detection assay to be used with the CellSearch® system was developed. In a prospective longitudinal clinical trial, blood samples from 60 patients with untreated mBC were analyzed to detect AXL+ CTCs with this new assay. CTCs were detected in 35/60 patients (58.3%) and AXL+ CTCs were identified in 7 of these 35 patients (11.7% of all patients). CONCLUSION: This newly established AXL+ CTC assay is a promising tool that can be used for liquid biopsy in future clinical trials to stratify and monitor patients with cancer receiving anti-AXL therapies.

Defining Benchmark Outcomes for Distal Pancreatectomy: Results of a French Multicentric Study.

OBJECTIVE: Defining robust and standardized outcome references for distal pancreatectomy (DP) by using Benchmark analysis. BACKGROUND: Outcomes after DP are recorded in medium or small-sized studies without standardized analysis. Therefore, the best results remain uncertain. METHODS: This multicenter study included all patients undergoing DP for resectable benign or malignant tumors in 21 French expert centers in pancreas surgery from 2014 to 2018. A low-risk cohort defined by no significant comorbidities was analyzed to establish 18 outcome benchmarks for DP. These values were tested in high risk, minimally invasive and benign tumor cohorts. RESULTS: A total of 1188 patients were identified and 749 low-risk patients were screened to establish Benchmark cut-offs. Therefore, Benchmark rate for mini-invasive approach was ≥36.8%. Benchmark cut-offs for postoperative mortality, major morbidity grade ≥3a and clinically significant pancreatic fistula rates were 0%, ≤27%, and ≤28%, respectively. The benchmark rate for readmission was ≤16%. For patients with pancreatic adenocarcinoma, cut-offs were ≥75%, ≥69.5%, and ≥66% for free resection margins (R0), 1-year disease-free survival and 3-year overall survival, respectively. The rate of mini-invasive approach in high-risk cohort was lower than the Benchmark cut-off (34.1% vs ≥36.8%). All Benchmark cut-offs were respected for benign tumor group. The proportion of benchmark cases was correlated to outcomes of DP. Centers with a majority of low-risk patients had worse results than those operating complex cases. CONCLUSION: This large-scale study is the first benchmark analysis of DP outcomes and provides robust and standardized data. This may allow for comparisons between surgeons, centers, studies, and surgical techniques.

Survival after Multimodal Treatment Including Surgery for Metastatic Esophageal Cancer: A Systematic Review.

(1) Background: The management of metastatic esophageal cancer is more often limited to palliative chemotherapy. Limited data are available regarding the role of surgery that remains controversial. The aim of this systematic review is to assess the survival outcome of surgically treated metastatic esophageal cancer patients. (2) Methods: The present systematic review is designed using the PRISMA guidelines and has been registered with PROSPERO (CRD42019140306). Two reviewers independently searched and identified studies dealing with surgery for stage IV esophageal cancer in the Medline and Google Scholar databases between January 2008 and December 2019. (3) Results: Seven retrospective nonrandomized studies, totaling 1756 patients with stage IV esophageal cancer who underwent curative surgery, were included. Our analysis demonstrates a three-year overall survival rate of 23% (CI 95% 17-31) among patients undergoing surgery. Because only two comparative studies were identified, data compilation and relative risk evaluation through meta-analysis were not possible. (4) Conclusions: Multimodality treatment, including surgery in curative intent, seems associated with a significant chance of three-year overall survival. A prospective evaluation of this approach and validation of adequate selection criteria are needed.

Personalized pre-habilitation reduces anastomotic complications compared to up front surgery before ileocolic resection in high-risk patients with Crohn's disease: A single center retrospective study.

BACKGROUND: The aim of this study was to analyze the effect of a personalized prehabilitation (PP) before ileocolic resection (ICR) on the postoperative anastomotic complications in patients with Crohn's Disease (CD) with high risk of post-operative complications. MATERIALS AND METHODS: All high-risk patients who required ICR with primary anastomosis for CD between January 2010 and March 2020 were retrospectively analyzed. PP included nutritional support, antibiotic therapy or drainage of an abscess, stopping or decreasing corticosteroid treatments. Patients were considered as high risk for complications when they had at least one or more of these 3 risk factors (RF) (hypoalbuminemia <30 g/L or weight loss of >10% over the last 6 months, treatment with corticosteroids before surgery (within 4 weeks before surgery), or presence of preoperative intra-abdominal sepsis (abscess or enteral fistula)) according to ECCO guidelines 2020. RESULTS: Ninety high-risk patients were included in our cohort and the anastomotic complication rate was 11.1%. Sixty-four (71.1%) had preoperative prehabilitation (median duration of 37 days), and the mean albumin level (34 g/L vs 37 g/L; p < 0.001) and the number of RF (1.21 vs 1.06; p = 0.001) were improved by PP during the preoperative period. The rate of anastomotic complications at 90 days from surgery (6.25% vs 23.1%; p = 0.031) as well as the re-operation rate (3.1% vs 19.2%; p = 0.019) were lower after PP. No difference was found on the rate of readmission and the length of stay in this subgroup analysis. Biological treatment administration within 3 months before surgery was not a risk factor for postoperative complication. CONCLUSION: PP reduces the number of preoperative risk factors before ICR in high-risk patients with CD and allows primary anastomosis with a lower complication rate than in upfront operated patients.

A retropancreatic celio-mesenteric paraganglioma.

Paragangliomas are extra-adrenal pheochromocytomas that arise from chromaffin cells in the sympathetic or parasympathetic neural paraganglia. Surgery remains the only curative treatment, although prominent vascularity can make excision difficult. We have recently encountered a patient with a retropancreatic celio-mesenteric paraganglioma unusually located between celiac trunk (CT) and superior mesenteric artery.

Registrar performance in minimally invasive distal pancreatectomy and effects on postoperative outcomes.

BACKGROUND: Minimally invasive distal pancreatectomy (MIDP) is nowadays an established standard procedure for non-locally advanced pancreatic lesions without celio-mesenteric vascular invasion. However, little is known about how the involvement of junior surgeons in MIDP affects postoperative outcomes. We performed a retrospective case series study in order to determine whether registrar involvement in MIDP is associated with adverse outcomes. METHODS: Data were analyzed from a prospectively created database of consecutive patients undergoing MIDP. Only data from 91 patients who underwent MIDP for non-PDAC lesions were included. Patients were divided in 3 groups: Consultant P1 (first 20 MIDP, n=20), Consultant P2 (after 20 MIDP, n=44), and Registrar group (n=27). Conversion rates and 90-day postoperative outcomes were compared. RESULTS: Conversion rates were 5%, 0%, and 14% in Consultant P1 and P2 and Registrar groups, respectively (P1 vs. P2, p = 0.312 and P1 vs. Registrar, p=0.376). Only Comprehensive Complication Index was higher in Registrar group compared to Consultant P1 group (13 vs. 3.7; p = 0.041). Comparison between Consultant P2 and Registrar groups resulted in a significant higher conversion rate (0 vs. 14%, p = 0.029), increased blood loss (77 vs. 263 ml, p = 0.018), and longer surgery duration (156 vs. 212 min, p=0.001) for registrars MIDP. However, no differences were found in clinically relevant postoperative pancreatic fistula (CR-POPF) (16 vs. 7.5%, p=0.282), Clavien-Dindo severe complication ≥3 score (11 vs. 4%, p=0.396), or length of hospital stay (9 vs. 9 days; p=0.614) between the consultant and registrar cohorts. CONCLUSIONS: With all the limitations of a retrospective study with a small sample size, junior surgeons' involvement in MIDP for non-PDAC lesions resulted in higher conversion rate, blood loss and duration of surgery without statistically significant difference on clinical outcomes compared to a consultant.

Outcomes of elective left colectomy in renal-transplanted patients: a single-center case-control study (LECoRT study).

PURPOSE: Renal-transplanted patients are reported to have a high anastomotic leakage (AL) rate after colorectal surgery. We aimed to define AL-related morbidity and mortality rates after elective left colectomy in renal-transplanted patients. METHODS: Data were prospectively collected between 2010 and 2015 from patients who underwent elective left colectomy with supra-peritoneal anastomosis in a single French referral hospital. We compared AL rate, and morbidity and mortality rates between renal-transplanted patients and controls. RESULTS: We identified 120 patients who underwent elective left colectomy during the study period. We retrospectively divided this cohort into 20 (17%) kidney-transplanted recipients (KTR-group) and the remaining 100 patients comprised the control group (C-group). There were no significant differences in sex, age, ASA score, body mass index, history of abdominal surgery and benign/malignant disease ratio between the KTR-group and the C-group. The AL rate was approximately four times higher in the KTR-group versus the C-group (25% vs 7%, p = 0.028). Intra-abdominal septic complications (p = 0.0005) and reoperation rates (p = 0.025) were also higher in the KTR-group. The laparoscopic approach was performed less in the KTR-group (35% versus 93%, p < 0.0001). CONCLUSION: Renal transplantation was identified as a risk factor of AL following elective left colectomy, as well as increased intra-abdominal septic morbidity and higher reoperation rate. Further multicentric studies are required to identify potential independent risk factors of AL after colorectal surgery in these frail populations. TRIAL REGISTRATION: The present study was declared on ClinicalTrials.gov (ID: NCT04495023).

Neck transection level and postoperative pancreatic fistula after pancreaticoduodenectomy: A retrospective cohort study of 195 patients.

BACKGROUND: The aim of this study was to evaluate the impact of the level of neck transection on clinically relevant postoperative pancreatic fistula (CR-POPF) after standard pancreaticoduodenectomy (PD) with pancreaticojejunostomy. METHOD: A total of 195 patients with an early postoperative CT scan were retrospectively analyzed and divided into 2 groups (CR-POPF and No CR-POPF) in order to seek potential risk factors for CR-POPF. We focused our analysis on the relationship between CR-POPF and the level of neck transection, defined by measuring the distance between the left side of the portal vein and the remnant pancreatic stump on the postoperative CT scan. RESULT: CR-POPF occurred in 58 out of 195 PD (29.7%); grade B (17%) and grade C (12.7%). The Clavien-Dindo ≥ 3 morbidity rate was 33% (65/195) and the mortality rate was 2.5% (5/195). Multivariate analysis indicated that a 'right-sided' level of neck transection (P = 0.007), a firm pancreatic texture (P = 0.001), and a PD for non-pancreatic ductal adenocarcinoma histology (P = 0.032) were independent risk factors for CR-POPF. A full neck resection with systematic transection ≥7 mm at the left side of the portal vein seems to prevent CR-POPF harboring a protective effect (OR 0.056; 95% CI 0.003 to 0.978; P = 0.039). CONCLUSION: Here we further consolidate the concept describing the pancreatic neck as a vascular watershed, showing that a long remnant pancreatic neck could be an independent risk factor for CR-POPF after PD (NCT03850236). TRIAL REGISTRATION NUMBER AND AGENCY: The present study was approved by our local ethics committee and was declared on ClinicalTrials.gov (ID: NCT03850236).