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Brodowicz T.,Medical University of Vienna | Liegl-Atzwager B.,Medical University of Graz | Tresch E.,Biostatistics Unit | Taieb S.,Center Oscar Lambret | And 9 more authors.
BMC Cancer

Background: Angiogenesis, among other signaling pathways, plays a key-role in sarcoma biology. Regorafenib (RE) has recently been shown to be effective in imatinib and sunitinib-refractory GIST in a phase III trial. Methods/design: We are conducting an international trial (France, Austria and Germany) consisting in 4 parallel double-blind placebo-controlled randomized (1/1) phase II trials to assess the activity and safety of RE in doxorubicin-refractory STS (ClinicalTrials.gov: NCT01900743). Each phase II trial is dedicated to one of the 4 following histological subgroups: liposarcoma, leiomyosarcoma, synovial sarcoma and other sarcoma. Within each randomized trial the following stratification factors will be applied: countries and prior exposure to pazopanib. Key-eligibility criteria are: measurable disease, age ≥18, not>3 previous systemic treatment lines for metastatic disease, metastatic disease not amenable to surgical resection. The primary endpoint is progression-free survival (PFS) according to central radiological review. Secondary endpoints are: Toxicity (NCI-CTC AE V4.0); time to progression; Growth modulation index in pts receiving RE after randomization; 3 and 6months PFS-Rates, best response rate and overall survival. Each phase II trial will be separately analyzed. In 3 trials, statistical assumptions are: PFS0=1.6 & PFS1=4.6months; 1-sided α=0.1; β=0.05 with a total sample size of 192 pts. To take into account the rarity of synovial sarcoma, the statistical assumptions are: PFS0=1.6 & PFS1=4.6months; 1-sided α=0.1; β=0.2 Tumor assessment is done monthly during the 4 first months, and every 3months thereafter. After central radiological confirmation of tumor progression, an optional open-label option is offered to eligible patients. Discussion: The design of this trial allows an assessment of regorafenib activity over placebo in four sarcoma strata and might provide evidence for launching a phase III trial. This study includes both integrative and exploratory translational research program. The study is enrolling since June 2013 (Trial Registration Number: EudraCT N°: 2012-005743-24, on the 15th February 2012). © Brodowicz et al. Source

Mariette C.,Lille University Hospital Center | Mariette C.,North of France University | Mariette C.,French Institute of Health and Medical Research | Gronnier C.,Lille University Hospital Center | And 64 more authors.
Journal of the American College of Surgeons

Background: Self-expanding metallic stents (SEMSs) have been used as a bridge to surgery, relieving dysphagia and maintaining nutrition, in patients with operable but obstructive esophageal cancer (EC). However, the impact of SEMSs on oncologic outcomes is unknown. The aim of this study was to evaluate the impact of SEMS insertion before EC surgery on oncologic outcomes. STUDY DESIGN: From 2000 to 2010, two thousand nine hundred and forty-four patients who underwent an operation for EC with a curative intent were included in a multicenter European cohort. Through propensity score analysis, patients who underwent SEMS insertion (SEMS group, n = 38) were matched 1:4 to control patients who did not undergo SEMS insertion (control group, n = 152). RESULTS: The SEMS and control groups were comparable according to age, sex, tumor location, clinical stage, American Society of Anesthesiologists score, dysphagia, malnutrition, neoadjuvant treatment administration, histology, and surgical procedure. Self-expanding metallic stent insertion was complicated by tumoral perforation in 2 patients. The in-hospital postoperative mortality and morbidity rates for the SEMS vs control groups were 13.2% vs 8.6% (p = 0.370) and 63.2% vs 59.2% (p = 0.658), respectively. The R0 resection rate (71.0% vs 85.5%; p = 0.041), median time to recurrence (6.5 vs 9.0 months; p = 0.040), and 3-year overall survival (25% vs 44%; p = 0.023) were significantly reduced in the SEMS group, and the 3-year locoregional recurrence rate was increased (62% vs 34%; p = 0.049). The results remained significant after excluding SEMS-related esophageal perforations. After adjusting for confounding factors, SEMS insertion was a predictor of poor prognosis (hazard ratio = 1.6; p = 0.038). CONCLUSIONS: Self-expanding metallic stent insertion, as a bridge to surgery, has a negative impact on oncologic outcomes in EC. © 2015 by the American College of Surgeons Source

Markar S.R.,Imperial College London | Gronnier C.,Lille University Hospital Center | Gronnier C.,North of France University | Gronnier C.,French Institute of Health and Medical Research | And 11 more authors.
Annals of Surgery

Objective: The objectives of this study were to establish if R1 resection margin after esophagectomy was (i) a poor prognostic factor independent of patient and tumor characteristics, (ii) a marker of tumor aggressiveness and (iii) to look at the impact of adjuvant treatment in this subpopulation. Methods: Data were collected from 30 European centers from 2000 to 2010. Patients with an R1 resection margin (n = 242) were compared with those with an R0 margin (n = 2573) in terms of short-and long-term outcomes. Propensity score matching and multivariable analyses were used to compensate for differences in baseline characteristics. Results: Independent factors significantly associated with an R1 resection margin included an upper third esophageal tumor location, preoperative malnutrition, and pathological stage III. There were significant differences between the groups in postoperative histology, with an increase in pathological stage III and TRG 4-5 in the R1 group. Total average lymph node harvests were similar between the groups; however, there was an increase in the number of positive lymph nodes seen in the R1 group. Propensity matched analysis confirmed that R1 resection margin was significantly associated with reduced overall survival and increased overall, locoregional, and mixed tumor recurrence. Similar observations were seen in the subgroup that received neoadjuvant chemoradiation. In R1 patients adjuvant therapy improved survival and reduced distant recurrence however failed to affect locoregional recurrence. Conclusions: This large multicenter European study provides evidence to support the notion that R1 resection margin is a prognostic indication of aggressive tumor biology with a poor long-term prognosis. © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Markar S.,Imperial College London | Gronnier C.,Lille University Hospital Center | Gronnier C.,North of France University | Gronnier C.,French Institute of Health and Medical Research | And 48 more authors.
Annals of Surgery

Objective: The aim of this study was to the determine impact of severe esophageal anastomotic leak (SEAL) upon long-term survival and locoregional cancer recurrence. Background: The impact of SEAL upon long-term survival after esophageal resection remains inconclusive with a number of studies demonstrating conflicting results. Methods: A multicenter database for the surgical treatment of esophageal cancer collected data from 30 university hospitals (2000-2010). SEAL was defined as a Clavien-Dindo III or IV leak. Patients with SEAL were compared with those without in terms of demographics, tumor characteristics, surgical technique, morbidity, survival, and recurrence. Results: From a database of 2944 operated on for esophageal cancer between 2000 and 2010, 209 patients who died within 90 days of surgery and 296 patients with a R1/R2 resection were excluded, leaving 2439 included in the final analysis; 208 (8.5%) developed a SEAL and significant independent association was observed with low hospital procedural volume, cervical anastomosis, tumoral stage III/IV, and pulmonary and cardiovascular complications. SEAL was associated with a significant reduction in median overall (35.8 vs 54.8 months; P=0.002) and disease-free (34 vs 47.9 months; P=0.005) survivals. After adjustment of confounding factors, SEAL was associated with a 28% greater likelihood of death [hazard ratio=1.28; 95% confidence interval (CI): 1.04-1.59; P=0.022], as well as greater overall (OR=1.35; 95% CI: 1.15-1.73; P=0.011), locoregional (OR=1.56; 95% CI: 1.05-2.24; P=0.030), and mixed (OR=1.81; 95% CI: 1.20-2.71; P=0.014) recurrences. Conclusions: This large multicenter study provides strong evidence that SEAL adversely impacts cancer prognosis. The mechanism through which SEAL increases local recurrence is an important area for future research. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Simonneau C.,Lille University of Science and Technology | Leclercq B.,Lille University of Science and Technology | Mougel A.,Lille University of Science and Technology | Adriaenssens E.,Lille University of Science and Technology | And 10 more authors.
Chemical Science

The development of MET receptor agonists is an important goal in regenerative medicine, but is limited by the complexity and incomplete understanding of its interaction with HGF/SF (Hepatocyte Growth Factor/Scatter Factor). NK1 is a natural occurring agonist comprising the N-terminal (N) and the first kringle (K1) domains of HGF/SF. In the presence of heparin, NK1 can self-associate into a "head to tail" dimer which is considered as the minimal structural module able to trigger MET dimerization and activation whereas isolated K1 and N domains showed a weak or a complete lack of agonistic activity respectively. Starting from these structural and biological observations, we investigated whether it was possible to recapitulate the biological properties of NK1 using a new molecular architecture of isolated N or K1 domains. Therefore, we engineered multivalent N or K1 scaffolds by combining synthetic and homogeneous site-specifically biotinylated N and K1 domains (NB and K1B) and streptavidin (S). NB alone or in complex failed to activate MET signaling and to trigger cellular phenotypes. Importantly and to the contrary of K1B alone, the semi-synthetic K1B/S complex mimicked NK1 MET agonist activity in cell scattering, morphogenesis and survival phenotypic assays. Impressively, K1B/S complex stimulated in vivo angiogenesis and, when injected in mice, protected the liver against fulminant hepatitis in a MET dependent manner whereas NK1 and HGF were substantially less potent. These data reveal that without N domain, proper multimerization of K1 domain is a promising strategy for the rational design of powerful MET agonists. © The Royal Society of Chemistry 2015. Source

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