Raphaël Maréchal

The interleukin‐17 pathway is involved in human alcoholic liver disease

Immune dysregulations in alcoholic liver diseases are still unclear, especially regarding alcoholic hepatitis inflammatory burst. Interleukin‐17 (IL‐17) is known to enhance neutrophil recruitment. We studied the IL‐17 pathway in alcoholic cirrhosis and alcoholic hepatitis. Patients with alcoholic liver disease were compared with patients with chronic hepatitis C virus (HCV) infection or autoimmune liver disease and with healthy controls. IL‐17 plasma levels and peripheral blood mononuclear cell secretion were assessed by enzyme‐linked immunosorbent assay (ELISA) and T cell phenotype by flow cytometry. IL‐17 staining and co‐staining with CD3 and myeloperoxidase were performed on liver biopsy specimens. IL‐17 receptor expression was studied on liver biopsies and in human hepatic stellate cells as well as their response to recombinant IL‐17 by chemotaxis assays. IL‐17 plasma levels were dramatically increased in alcoholic liver disease patients. Peripheral blood mononuclear cells of patients with alcoholic liver disease produced higher amounts of IL‐17, and their CD4+ T lymphocytes disclosed an IL‐17–secreting phenotype. In the liver, IL‐17–secreting cells contributed to inflammatory infiltrates in alcoholic cirrhosis, and alcoholic hepatitis foci disclosed many IL‐17+ cells, including T lymphocytes and neutrophils. In alcoholic liver disease, liver IL‐17+ cells infiltrates correlated to model for end‐stage liver disease score, and in alcoholic hepatitis to modified discriminant function. IL‐17 receptor was expressed in alcoholic liver disease by hepatic stellate cells, and these cells recruited neutrophils after IL‐17 stimulation in a dose‐dependent manner through IL‐8 and growth related oncogen α (GRO‐α) secretion in vitro. Conclusion: Human alcoholic liver disease is characterized by the activation of the IL‐17 pathway. In alcoholic hepatitis, liver infiltration with IL‐17–secreting cell infiltrates is a key feature that might contribute to liver neutrophil recruitment. (Clinical trials number NCT00610597). (HEPATOLOGY 2009;49:646–657.)

Gemcitabine and oxaliplatin (GEMOX) in gemcitabine refractory advanced pancreatic adenocarcinoma: a phase II study

Gemcitabine and oxaliplatin (GEMOX) are active as first-line therapy against advanced pancreatic cancer. This study aims to evaluate the activity and tolerability of this combination in patients refractory to standard gemcitabine (GEM). A total of 33 patients (median age of 57) were included with locally advanced and metastatic evaluable diseases, who had progressed during or following GEM therapy. The GEMOX regimen consisted of 1000 mg m−2 of GEM at a 100-min infusion on day 1, followed on day 2 by 100 mg m−2 of oxaliplatin at a 2-h infusion; a cycle that was given every 2 weeks. All patients received at least one cycle of GEMOX (median 5; range 1–29). Response by 31 evaluable patients was as follows: PR: 7/31(22.6%), s.d. ⩾8 weeks: 11/31(35.5%), s.d. <8 weeks: 1/31(3.2%), PD: 12/31(38.7%). Median duration of response and TTP were 4.5 and 4.2 months, respectively. Median survival was 6 months (range 0.5–21). Clinical benefit response was observed in 17/31 patients (54.8%). Grade III/IV non-neurologic toxicities occurred in 12/33 patients (36.3%), and grade I, II, and III neuropathy in 17(51%), 3(9%), and 4(12%) patients, respectively. GEMOX is a well-tolerated, active regimen that may provide a benefit to patients with advanced pancreatic cancer after progression following standard gemcitabine treatment.

Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study

BACKGROUND Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in locally advanced rectal cancer (LARC). To evaluate in LARC patients, the feasibility and efficacy of a short intense course of induction oxaliplatin before preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS Patients with T2-T4/N+ rectal adenocarcinoma were randomly assigned to arm A-preoperative CRT with 5-fluorouracil (5-FU) continuous infusion followed by surgery-or arm B-induction oxaliplatin, folinic acid and 5-FU followed by CRT and surgery. The primary end point was the rate of ypT0-1N0 stage achievement. RESULTS Fifty seven patients were randomly assigned (arm A/B: 29/28) and evaluated for planned interim analysis. On an intention-to-treat basis, the ypT0-1N0 rate for arms A and B were 34.5% (95% CI: 17.2% to 51.8%) and 32.1% (95% CI: 14.8% to 49.4%), respectively, and the study therefore was closed prematurely for futility. There were no statistically significant differences in other end points including pathological complete response, tumor regression and sphincter preservation. Completion of the preoperative CRT sequence was similar in both groups. Grade 3/4 toxicity was significantly higher in arm B. CONCLUSIONS Short intense induction oxaliplatin is feasible in LARC patients without compromising the preoperative CRT completion, although the current analysis does not indicate increased locoregional impact on standard therapy.

New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel

Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.

Deoxycitidine kinase is associated with prolonged survival after adjuvant gemcitabine for resected pancreatic adenocarcinoma

Gemcitabine (2′,2′‐difluorodeoxycytidine) administration after resection of pancreatic cancer improves both disease‐free survival (DFS) and overall survival (OS). Deoxycytidine kinase (dCK) mediates the rate‐limiting catabolic step in the activation of gemcitabine. The authors of this report studied patient outcomes according to the expression of dCK after a postoperative gemcitabine‐based chemoradiation regimen.

Current standards and new innovative approaches for treatment of pancreatic cancer

Pancreatic adenocarcinoma remains a devastating disease with a 5-year survival rate not exceeding 6%. Treatment of this disease remains a major challenge. This article reviews the state-of-the-art in the management of this disease and the new innovative approaches that may help to accelerate progress in treating its victims. After careful pre-therapeutic evaluation, only 15-20% of patients diagnosed with a pancreatic cancer (PC) are eligible for upfront radical surgery. After R0 or R1 resection in such patients, evidence suggests a significantly positive impact on survival of adjuvant chemotherapy comprising 6 months of gemcitabine or fluorouracil/folinic acid. Delayed adjuvant chemoradiation is considered as an option in cases of positive margins. Borderline resectable pancreatic cancer (BRPC) is defined as a tumour involving the mesenteric vasculature to a limited extend. Resection of these tumours is technically feasible, yet runs the high risk of a R1 resection. Neoadjuvant treatment probably offers the best chance of achieving successful R0 resection and long-term survival, but the best treatment options should be determined in prospective randomised studies. Gemcitabine has for 15 years been the only validated therapy for advanced PC. Following decades of negative phase III studies, increasing evidence now suggests that further significant improvements to overall survival can be achieved via either Folfirinox or gemcitabine + nab-paclitaxel regimens. Progress in systemic therapy may improve the chances of resection in borderline resectable pancreatic cancer (BRPC) or locally advanced PC. This requires first enhancing knowledge of the genetic events driving carcinogenesis, which may then be translated into clinical studies.

Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma

BACKGROUND Prognosis of patients with pancreatic adenocarcinoma is poor. Many prognostic biomarkers have been tested, but most studies included heterogeneous patients. We aimed to investigate the prognostic and/or predictive values of four relevant biomarkers in a multicentric cohort of patients. PATIENTS AND METHODS A total of 471 patients who had resected pancreatic adenocarcinoma were included. Using tissue microarray, we assessed the relationship of biomarker expressions with the overall survival: Smad4, type II TGF-β receptor, CXCR4, and LKB1. RESULTS High CXCR4 expression was found to be the only independent negative prognostic biomarker [hazard ratio (HR)=1.74; P<0.0001]. In addition, it was significantly associated with a distant relapse pattern (HR=2.19; P<0.0001) and was the strongest prognostic factor compared with clinicopathological factors. In patients who did not received adjuvant treatment, there was a trend toward decrease in the overall survival for negative Smad4 expression. Loss of Smad4 expression was not correlated with recurrence pattern but was shown to be predictive for adjuvant chemotherapy (CT) benefit (HR=0.59; P=0.002). CONCLUSIONS CXCR4 is a strong independent prognostic biomarker associated with distant metastatic recurrence and appears as an attractive target to be evaluated in pancreatic adenocarcinoma. Negative SMAD4 expression should be considered as a potential predictor of adjuvant CT benefit.BACKGROUND Prognosis of patients with pancreatic adenocarcinoma is poor. Many prognostic biomarkers have been tested, but most studies included heterogeneous patients. We aimed to investigate the prognostic and/or predictive values of four relevant biomarkers in a multicentric cohort of patients. PATIENTS AND METHODS A total of 471 patients who had resected pancreatic adenocarcinoma were included. Using tissue microarray, we assessed the relationship of biomarker expressions with the overall survival: Smad4, type II TGF-β receptor, CXCR4, and LKB1. RESULTS High CXCR4 expression was found to be the only independent negative prognostic biomarker [hazard ratio (HR) = 1.74; P < 0.0001]. In addition, it was significantly associated with a distant relapse pattern (HR = 2.19; P < 0.0001) and was the strongest prognostic factor compared with clinicopathological factors. In patients who did not received adjuvant treatment, there was a trend toward decrease in the overall survival for negative Smad4 expression. Loss of Smad4 expression was not correlated with recurrence pattern but was shown to be predictive for adjuvant chemotherapy (CT) benefit (HR = 0.59; P = 0.002). CONCLUSIONS CXCR4 is a strong independent prognostic biomarker associated with distant metastatic recurrence and appears as an attractive target to be evaluated in pancreatic adenocarcinoma. Negative SMAD4 expression should be considered as a potential predictor of adjuvant CT benefit.

Putative contribution of CD56 positive cells in cetuximab treatment efficacy in first-line metastatic colorectal cancer patients

BackgroundActivity of cetuximab, a chimeric monoclonal antibody targeting the epidermal growth factor receptor, is largely attributed to its direct antiproliferative and proapoptotic effects. Antibody-dependent cell-mediated cytotoxicity (ADCC) could be another possible mechanism of cetuximab antitumor effects and its specific contribution on the clinical activity of cetuximab is unknown.MethodsWe assessed immune cells infiltrate (CD56, CD68, CD3, CD4, CD8, Foxp3) in the primary tumor of metastatic colorectal cancer (mCRC) patients treated with a first-line cetuximab-based chemotherapy in the framework of prospective trials (treatment group) and in a matched group of mCRC patients who received the same chemotherapy regimen without cetuximab (control group). The relationship between intra-tumoral immune effector cells, the K-ras status and the efficacy of the treatment were investigated. We also evaluated in vitro, the ADCC activity in healthy donors and chemonaive mCRC patients and the specific contribution of CD56+ cells.ResultsADCC activity against DLD1 CRC cell line is maintained in cancer patients and significantly declined after CD56+ cells depletion. In multivariate analysis, K-ras wild-type (HR: 4.7 (95% CI 1.8-12.3), p = 0.001) and tumor infiltrating CD56+ cells (HR: 2.6, (95%CI:1.14-6.0), p = 0.019) were independent favourable prognostic factors for PFS and response only in the cetuximab treatment group. By contrast CD56+ cells failed to predict PFS and response in the control group.ConclusionsCD56+ cells, mainly NK cells, may be the major effector of ADCC related-cetuximab activity. Assessment of CD56+ cells infiltrate in primary colorectal adenocarcinoma may provide additional information to K-ras status in predicting response and PFS in mCRC patients treated with first-line cetuximab-based chemotherapy.

Tolerance and efficacy of gemcitabine and gemcitabine-based regimens in elderly patients with advanced pancreatic cancer.

Objectives: Gemcitabine is the backbone therapy of patients with advanced pancreatic cancer. Its tolerability and efficacy remain poorly studied in elderly. Methods: We selected patients coming from phase 2 and 3 studies, conducted between January 2001 and December 2004 in our department, evaluating gemcitabine-based first-line chemotherapy. We evaluated the treatment efficacy, tolerability, and compared patients younger than 70 years (group A) and aged 70 years and older (group B). We assessed the contribution of patient-, tumor- and treatment-related variables on the prognostic of patients aged 70 years and older. Results: Ninety-nine patients were studied: groups A (n = 57) and B (n = 42) treated by gemcitabine alone (n = 61) and gemcitabine-based combination (n = 38). Tumor growth control (66.6% vs 59.6%), time to progression (119 vs 104 days), and overall survival (240 vs 220 days) were comparable for groups A and B, respectively. For patients (n = 47) receiving a second-line chemotherapy (group A, n = 33; group B, n = 14), the efficacy and toxicity were similar in both group. Baseline alanine aminotransferase and Karnofski performance status were independent negative prognostic factors for elderly patients. Conclusions: Our study suggests that elderly patients undergoing gemcitabine do as well than younger patients.

Prognostic Factors and Prognostic Index for Chemonaïve and Gemcitabine-Refractory Patients with Advanced Pancreatic Cancer

Background: Gemcitabine monotherapy is the cornerstone of the treatment of patients suffering from advanced pancreatic cancer (PC). For a few years, new chemotherapeutic agents and combinations have been under validation. The use of such treatment makes it necessary to determine factors that could predict survival time. Patients and Methods: To identify factors that predict survival time in chemonaïve patients with advanced PC and after gemcitabine failure, a retrospective analysis was performed on patients with advanced PC coming from phase II and III studies and treated with gemcitabine-based first-line chemotherapy. Results: Ninety-nine patients (median age 66 years, range 27–87) suffering from pathologically proven unresectable or metastatic adenocarcinoma of the pancreas were reviewed. Median overall survival time for the whole population was 251 days and progression-free survival in first- and second-line treatment was 108 and 67 days, respectively. The Cox regression analysis identified aspartate transaminase >53 IU/l, weight loss ≧10% and Karnofsky performance status <90 as significant independent negative prognostic factors in first-line and CA 19-9 >400 IU/ml and albumin ≤3.5 mg/dl in second-line chemotherapy. A prognostic index was calculated from the regression coefficients for each independent prognostic factor and used to classify the patients in 3 different groups with good, intermediate and poor prognosis. The prognosis index in chemonaïve and gemcitabine-refractory patients was (Karnofsy performance status × 0.52) + (weight loss × 1.10) + (aspartate transaminase × 0.82) and (albumin × 1.40) + (CA 19-9 × 0.74), respectively. Conclusions: Predictive factors could be identified in first- and second-line treatments, although they require prospective validation before they could be used in the design and analysis of future clinical trials.