Anne Demols

CD4+ T cells play an important role in acute experimental pancreatitis in mice ☆ ☆☆ ★

BACKGROUND & AIMS Few data are available on the potential role of T lymphocytes in experimental acute pancreatitis. The aim of this study was to characterize their role in the inflammatory cascade of acute pancreatitis. METHODS To type this issue, acute pancreatitis was induced by repeated injections of cerulein in nude mice and in vivo CD4(+) or CD8(+) T cell-depleted mice. The role of T lymphocyte-costimulatory pathways was evaluated using anti-CD40 ligand or anti-B7-1 and -B7-2 monoclonal blocking antibodies. The role of Fas-Fas ligand was explored using Fas ligand-targeted mutant (generalized lymphoproliferative disease) mice. Severity of acute pancreatitis was assessed by serum hydrolase levels and histology. Intrapancreatic interleukin 12, interferon gamma, Fas ligand, and CD40 ligand messenger RNA were detected by reverse-transcription polymerase chain reaction. Intrapancreatic T lymphocytes were identified by immunohistochemistry. RESULTS In control mice, T cells, most of them CD4(+) T cells, are present in the pancreas and are recruited during acute pancreatitis. In nude mice, histological lesions and serum hydrolase levels are significantly decreased. T-lymphocyte transfer into nude mice partially restores the severity of acute pancreatitis and intrapancreatic interferon gamma, interleukin 12, and Fas ligand gene transcription. The severity of pancreatitis is also reduced by in vivo CD4(+) (but not CD8(+)) T-cell depletion and in Fas ligand-targeted mutant mice. Blocking CD40-CD40 ligand or B7-CD28 costimulatory pathways has no effect on the severity of pancreatitis. CONCLUSIONS T lymphocytes, particularly CD4(+) T cells, play a pivotal role in the development of tissue injury during acute experimental pancreatitis in mice.

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.

n -acetylcysteine Decreases Severity of Acute Pancreatitis in Mice

Oxidative stress plays a major role in the early stage of acute pancreatitis. This study assessed the effects of N-acetylcysteine (NAC), a reduced glutathione (GSH) provider and a direct scavenger of reactive oxygen intermediates, in the course of acute pancreatitis in mice. Acute pancreatitis (AP) was induced by intraperitoneal (i.p.) injections of cerulein. Mice received NAC (1,000 mg/kg, i.p.) every 3 h, starting either 1 h before the first cerulein injection (prophylactic group) or 1 h after the first cerulein injection (therapeutic group), or i.p. saline injections for controls. Severity of AP was evaluated by histology, serum hydrolase levels, and serum and intrapancreatic levels of MCP-1 and interleukin 6 (IL-6). Pancreatic conjugated dienes and intrapancreatic and intrahepatic GSH levels were measured to assess the local and systemic oxidative processes. Acute pancreatitis was also induced with a CDE diet in controls and mice receiving either both NAC ad libidum in drinking water and 1,000 mg/kg i.p. injection once daily. The severity of pulmonary lesions was assessed by arterial blood gases (po2) and intrapulmonary myeloperoxidase (MPO content) measurements as well as the survival of mice. The severity of cerulein-induced AP was significantly decreased in the prophylactic group compared with the therapeutic and control groups. Prophylactic administration of NAC also decreased the intrapancreatic levels of conjugated dienes compared with controls. The intrapancreatic and systemic release of MCP-1 and IL-6 was also decreased in the prophylactic group 3 and 6 hours after AP induction. In addition, NAC pretreatment also reduced hepatic IL-6 production at 3 and 6 hours after starting cerulein challenge. In CDE-induced AP, the severity of lung injury (hypoxemia, MPO content) was decreased, and survival was improved by NAC. NAC administered in a prophylactic protocol limits the severity of experimental acute pancreatitis in mice, as well as its systemic complications and related mortality.

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.

Postoperative adjuvant gemcitabine and concurrent radiation after curative resection of pancreatic head carcinoma: a phase II study

PURPOSE The addition of radiation to adjuvant 5-fluorouracil for the treatment of pancreatic cancer has not yet shown any definite benefit. Gemcitabine (GEM) has potential activity in advanced pancreatic cancer and is a powerful radiosensitizer. We evaluated the feasibility of postoperative administration of GEM alone, followed by concurrent GEM and irradiation (RT) after curative resection for pancreatic adenocarcinoma. METHODS AND MATERIALS GEM 1000 mg/m(2) on Days 1 and 8 every 21 days for three courses was given within 8 weeks after surgery and was followed by GEM 300 mg/m(2) weekly +40 Gy in a split course. Twenty-two patients (median age 59 years, range 39-74, Performance Status 0-1) with Stage II and III curatively resected pancreatic head adenocarcinoma were included. RESULTS For GEM alone, all patients received the three planned courses, with dose reductions in 7 (32%) of 22 patients. All patients, except two, completed full chemoradiation; one received only 20 Gy because of both World Health Organization Grade 4 vomiting and thrombopenia and the other stopped RT after 32 Gy because of early disease progression. No reduction in GEM during RT was necessary; no toxic death was noted; and World Health Organization Grade 3-4 hematologic and nonhematologic toxicities occurred in 8 (36%) and 7 (nausea, vomiting) (32%) of 22 patients respectively. No late toxicity developed. After a median follow-up of 15 months, 11 patients were alive, and 2 patients had died of causes unrelated to their disease or toxicity, The median disease-free survival and overall survival was 6 and 15 months, respectively. CONCLUSION This adjuvant regimen was well tolerated and can be easily administered after curative surgery for pancreatic cancer. Its intensification with continuous RT is currently being investigated.

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.

Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study of the Belgian Group of Digestive Oncology

BACKGROUND Cholangiocarcinomas are uncommon tumours with a poor prognosis, that frequently present epidermal growth factor receptor overexpression. METHODS In a multi-centre phase II trial, patients with unresectable cholangiocarcinoma, naïve to chemotherapy, received Cetuximab (400 mg/m(2) at week 1, then 250 mg/m(2)/week) and Gemcitabine (1 g/m(2) on day 1, 8 and 15 every 4 weeks). Primary end point was progression-free survival (PFS) rate at 6 months, using a Simon 2-stage design. Moreover, we assessed the impact of KRAS status and skin toxic effect on efficacy. RESULTS Forty-four patients (41% locally advanced/59% metastatic) were enrolled. Median age was 61.5 years; ECOG PS was 0 (68%) or 1. Six months PFS reached 47%. Median OS was 13.5 months [95% confidence interval (CI) 9.8-31.8 months]. Nine patients (20.4%) had PR and disease-control rate was 79.5%. Grade 3/4-related toxic effects were haematological (52.2%), skin rash (13.6%) and fatigue (11.4%). KRAS mutations were found in 7 of 27 patients and had no influence on PFS. Skin toxic effect ≥grade 2 was associated with increased PFS (P = 0.05). CONCLUSION(S) Our study met its primary end point, suggesting that Gemcitabine-Cetuximab has activity in cholangiocarcinoma. KRAS status was not associated with PFS, unlike skin toxic effect, which could be used as a surrogate marker for efficacy. ClinicalTrials.gov Identifier: NCT00747097.

Feasibility of radiotherapy with concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma: a prospective dose finding phase I–II study

BACKGROUND The prognosis of pancreaticobiliary tumors is poor. The aim was to assess the feasibility of radiotherapy (RT) and concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma. PATIENTS AND METHODS Twenty-two patients with locally advanced pancreatic (n = 17) or biliary tract cancer (n = 5) were included. They received two cycles of gemcitabine/oxaliplatin followed by 5 weeks of RT in combination with a weekly fixed dose gemcitabine and an escalating dose of oxaliplatin from 40 up to 70 mg/m(2). National Cancer Institute-Common Toxicity Criteria 3.0 was used to score weekly the treatment-related toxicity. RESULTS The patients treated at a dose of 40 mg/m(2) of oxaliplatin had no dose-limiting toxicity. At 50 mg/m(2), two patients developed grade 4 thrombocytopenia. Nine patients received 60 mg/m(2), one developed grade 4 thrombocytopenia. Grade 4 thrombocytopenia in two patients and grade 3 diarrhea in one patient were observed with 70 mg/m(2). Median time to progression was 8 months and median overall survival was 17 months. CONCLUSIONS RT in combination with gemcitabine and oxaliplatin is feasible in patients with locally advanced pancreaticobiliary cancer. The reported time to progression underlines the potential activity of this regimen. The dose of 60 mg/m(2) of oxaliplatin can be considered as the recommended dose.

Raltitrexed plus gemcitabine (TOMGEM) in advanced pancreatic cancer. Results of a Belgian multicentre phase II study.

Objectives: This multicenter phase II study was designed to determine the activity and tolerance of gemcitabine and raltitrexed in advanced pancreatic adenocarcinoma. Patients andMethods: Thirty-three chemonaive patients with measurable disease received the TOMGEM regimen consisting of Raltitrexed 3 mg/m2 in 15 min followed by Gemcitabine 1,000 mg/m2 in 30 min on day 1, Gemcitabine alone 1,000 mg/m2 on day 8 and repeated on day 21. Results: Thirty-three patients (median age: 62; locally advanced/metastatic disease: 5/28) were enrolled; the total number of cycles administered was 173 (median: 4). There were 10 partial response (confirmed), 2 stable disease (SD) ≧24 weeks, 7 SD <24 weeks, and 14 progressive disease for a response rate of 30.3% (95% CI: 14–46%); a clinical benefit was observed in 8/30 patients assessed (30%); median duration of response was 9.1 months. National Cancer Institute Common Toxicity Criteria grade III or IV neutropenia/thrombocytopenia were observed in 42 and 12% of the patients, respectively. Relevant nonhematological toxicities (grade III–IV) were rare although one toxic death was observed. Median time to progression was 2.8 months; one-year survival was 21%; median survival was 4.7 months. Conclusion: Our data suggest that the combination of raltitrexed/gemcitabine is a very convenient regimen with an acceptable toxicity, and is active in advanced pancreatic cancer.