Bruno Chauffert

Université de Picardie Jules Verne, Amiens, Picardie, France

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Publications (290)962.95 Total impact

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    ABSTRACT: Improving the pre-clinical characterization of therapeutic approaches and developing new biological assays that will enable treatment personalization for individual patients are promising developments in oncology. Here we describe a new approach consisting of culturing human tumour explants. This approach involves the preparation of slices from freshly-obtained, surgically-resected material that can be maintained ex vivo for several days. Recent studies have provided proof of principle that this approach can be easily implemented in order to explore the mode of action of various anticancer drugs and the responses of 'real' tumours at the individual patient level. We present the practical aspects and highlight the versatility of this approach, which allows for the analysis of the susceptibility of any individual tumour to multiple anticancer drugs in parallel. We discuss its potential as a companion assay in the design of optimal clinical trials and as a guide for the prescription of medical treatment. We discuss which future clinical and biological studies are needed to validate the information gathered from cultured tumour explants, and to integrate this information with that gathered from other assays in order to optimize the medical treatment of cancer.
    No preview · Article · Jan 2016 · International Journal of Oncology
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    ABSTRACT: Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC). A decrease in the serum levels of Alpha-fetoprotein (AFP) is reported to be the biological parameter that is best associated with disease control by sorafenib. In order to provide a biological rationale for the variations of AFP, we analyzed the various steps of AFP production in human HCC cell lines exposed to sorafenib. Sorafenib dramatically reduced the levels of AFP produced by HCC cells independently of its effect on cell viability. The mRNA levels of AFP decreased upon sorafenib treatment, while the AFP protein remained localized in the Golgi apparatus. Sorafenib activated the Regulated Inositol-Requiring Enzyme-1α (IRE-1α) and the PKR-like ER Kinase (PERK)-dependent arms of the Unfolded Protein Response (UPR). The inhibition of IRE-1α partially restored the mRNA levels of AFP upon treatment with sorafenib. The inhibition of both pathways partially prevented the drop in the production of AFP induced by sorafenib. The findings provide new insights on the regulation of AFP, and identify it as a biomarker suitable for the exploration of HCC cell proteostasis in the context of therapeutic targeting.
    No preview · Article · Nov 2015 · Cancer letters

  • No preview · Article · Oct 2015 · Quality of Life Research
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    ABSTRACT: Aims Two clinical trials investigating the addition of bevacizumab (BEV) to TMZ treatment (Chinot et al., NEJM 2014; Gilbert et al., NEJM 2014) for unresectable glioblastoma (UGB) highlighted an improvement of progression-free survival (PFS) but no effect on overall survival. Health-related quality of life (HRQoL) results were divergent and compromised the conclusion about clinical benefit of BEV. A phase II clinical trial evaluating BEV and irinotecan (IRI) in addition to TMZ-based chemoradiation for UGB was conducted (Chauffert et al., Annals of Oncology 2014). The primary objective 6-month PFS rate from 50% to 66% was not reached. This present study focuses on the HRQoL analysis (secondary endpoint). Methods EORTC QLQ-C30 and its BN20 brain cancer module were used at baseline, during treatment and every 4 weeks until progression. Time until definitive HRQoL score deterioration (TUDD) was used as a modality of longitudinal HRQoL analysis, with a 10-point Minimal Clinically Important Difference, including or not death as an event. TUDD was estimated with the Kaplan-Meier method. Cox model was used to estimate Hazard Ratios (HR) and its 95% confidence interval (CI). Multivariate Cox model investigated factors associated with TUDD. Results Among the 120 patients included from 2009 to 2011, 90 patients (75%) filled the baseline HRQoL questionnaires (45 in each treatment arm). For TUDD, patients in BEV/IRI arm presented a longer TUDD than those of TMZ arm for 9/15 dimensions of the QLQ-C30 and 10/11 dimensions of the BN20. As an example, patients in BEV/IRI arm presented a longer TUDD of cognitive functioning than those of TMZ arm (Median 3.8 months (95%CI 2.5-NA) for BEV/IRI vs. 5.0 (95%CI 3.0-NA) for TMZ, HR=0.80 (0.41-1.57)). Conclusions Patients in BEV/IRI arm presented a longer TUDD than those of the TMZ arm. These HRQoL results are consistent to those obtained with AVAGLIO trial suggesting HRQoL benefit for patients with BEV.
    No preview · Conference Paper · Oct 2015
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    ABSTRACT: s: In rectal cancer, the incidence of synchronous liver metastases (SLM) ranges from 14% to 30%. The treatment of SLM combines neo-adjuvant chemo- and/or radiotherapy with of one three surgical resection strategies (rectal resection first, liver resection first or simultaneous resection). The present study evaluated the success rate for each resection strategy. From January 2005 to December 2013, we retrospectively included all patients with distal (middle and low) rectal cancer (MLRC) and SLM and who had been operated on with curative intent. The primary study endpoint was the proportion of complete resections at both tumour sites. The secondary endpoints were postoperative morbidity, the long-term outcome and risk factors for incomplete resection. 52 patients were included. There were no significant intergroup differences in the incidence of complete resection (respectively 74%, 66% and 50% in the rectum-first (n=20), simultaneous (n=10) and liver-first groups (n=5); p=0.3), the overall complication rate or mortality rate after rectal resection (p=0.5) or liver resection (p=0.8), overall survival (60, 47 and 38 months, respectively; p=0.4) or disease-free survival (31, 32 and 7.8 months, respectively; p=0.1). Emergency surgery was the only risk factor for treatment failure (p=0.01). There were no differences in short and long-term outcomes between the three strategies. No one oncological strategy should be favoured for all cases of MLRC with SLM. The strategy should be choosen, based on the oncological emergency (rectum-first or liver-first), predictive factors for morbidity in rectal surgery and MDT discussion. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Aug 2015 · International Journal of Surgery (London, England)
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    ABSTRACT: The incidence of cirrhosis is increasing in parallel with that of hepatitis C and non-alcoholic steatohepatitis. Patients with colon cancer and liver cirrhosis constitute an important at-risk group. Many colorectal surgeons and oncologists are not familiar with the management of colon cancer in patients with cirrhosis. Here, we review the literature on the management and prognosis of patients with both colon cancer and cirrhosis. The MEDLINE, PubMed and the Cochrane Library electronic databases were systematically searched with appropriate keywords. Only publications in French or English were selected. For most studies, the level of evidence is weak. Child A patients should probably be managed in the same way as general population, although they have an elevated risk of morbidity and a five-year survival rate of just 70%. Child B and C patients should be managed more cautiously, although no specific recommendations can be made at present. For colon surgery, laparotomy should be preferred in patients with cirrhosis. The role of adjuvant chemotherapy is unclear, since survival is strongly associated with the improvements in liver function. Oxaliplatin appears to be associated with an elevated post-chemotherapy morbidity rate in patients with portal hypertension. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Jun 2015 · Surgical Oncology
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    Full-text · Article · Jun 2015 · Annals of Oncology
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    ABSTRACT: Cetuximab is a targeted therapy with demonstrated efficacy in the management of head and neck squamous cell carcinoma (HNSCC). However, no laboratory assay is available to predict its efficacy in an individual patient. Short-term cultures of tumor slices were performed on nine tumor samples obtained after surgical resection in patients. Cancer cell proliferation was evaluated by immunohistochemistry and the impact of cetuximab on cell proliferation was examined. Tumor architecture and the heterogeneous composition of HNSCC were preserved for at least 48 hours during short-term culture of tumor slices. HNSCC cells demonstrated a heterogeneous individual response to cetuximab. Short-term culture of tumor slices is a strategy to estimate the clinical activity of cetuximab in individual HNSCC patients. Further studies are required to correlate the results obtained with the clinical response of individual patients to cetuximab. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    No preview · Article · May 2015 · Head & Neck

  • No preview · Article · May 2015 · Revue d Épidémiologie et de Santé Publique
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    Full-text · Article · Apr 2015 · Annals of Oncology
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    ABSTRACT: Chordoma is a rare malignant axial tumour that develops from embryonic remnants of the notochord. Surgery and irradiation are the standard initial treatment. However, local recurrence is frequent and cytotoxic chemotherapy is inefficient. Transient activity of imatinib, a platelet-derived growth factor receptor inhibitor, was described in a phase II study. Activity of epidermal growth factor receptor (EGFR) inhibitors (erlotinib, gefitinib) has also been shown in a few recent case reports. We describe a 68-year-old female in whom clivus chordoma recurred after surgery and radiotherapy. The tumour progressed despite imatinib treatment. A partial and sustained response (28+ months) was obtained using erlotinib, an EGFR inhibitor. Erlotinib should be evaluated in a prospective trial investigating new potential therapies against recurrent chordoma.
    Preview · Article · Mar 2015 · Case Reports in Oncology
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    ABSTRACT: Sorafenib is the medical reference for treatment of hepatocellular carcinoma (HCC). Multiple forms of cytotoxicity are induced by sorafenib in HCC cells in vitro but it is unclear what extent of apoptosis and necrosis is induced in HCC patients receiving sorafenib. The M30 and M65 biomarkers, which reflect the release of cytokeratin-18 and its apoptotic cleavage fragments, were measured in patients with HCC (n=36) and matched patients with cirrhosis (n=47). A serum sample was collected from 20 patients with HCC four weeks after the onset of treatment with sorafenib. Basal serum levels of M30 and M65 were increased in patients with HCC compared to those with uncomplicated cirrhosis. No statistically significant increase in the level of M30 or M65 was found in the sera of patients with HCC after sorafenib. The findings indicate that sorafenib is not a potent inducer of HCC cell death in most patients. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
    No preview · Article · Mar 2015 · Anticancer research
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    ABSTRACT: Chordomas, derived from undifferentiated notochordal remnants, represent less than 4% of bone primary tumors. Despite surgery followed by radiotherapy, local and metastatic relapses are frequent. In case of locally advanced or metastatic chordomas, medical treatment is frequently discussed. While chemotherapy is ineffective, it would appear that some molecular targeted therapies, in particular imatinib, could slow down the tumor growth in case-reports, retrospective series, and phase I or II trials. Nineteen publications, between January 1990 and September 2014, have been found describing the activity of these targeted therapies. A systematic analysis of these publications shows that the best objective response with targeted therapies was stabilization in 52 to 69% of chordomas. Given the indolent course of advanced chordoma and because of the absence of randomized trial, the level of evidence to treat chordomas with molecular therapy is low (level III), whatever the drug. Furthermore, we could not draw firm conclusion on the activity of imatinib. Other putative targets have also been described. Therefore, further clinical trials are expected, especially with these targets. Nevertheless, it seems essential, in those future studies, to consider the naturally slow course of the disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    No preview · Article · Jan 2015 · Critical Reviews in Oncology/Hematology
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    ABSTRACT: Background: A randomized phase III trial demonstrated that vandetanib treatment is effective in patients with metastatic medullary thyroid cancer (MTC), leading to regulatory approval, but its use may be associated with toxicities that require specific monitoring and management. The objective of the present study performed in France was to describe the toxicity profile and efficacy of vandetanib treatment when given outside any trial. Methods: Sixty-eight patients were treated with vandetanib in the frame of a temporary use authorization (ATU) in France from August 2010 to February 2012, when the drug was available on request for patients with locally advanced or metastatic MTC. Patients were registered by the French health authorities, and characteristics, treatment parameters, toxicity profile, and efficacy were retrospectively reviewed. Eight patients were excluded from the analysis because vandetanib treatment was not administered (n=3), had been given in a trial before ATU (n=3), or was given for a non-MTC cancer (n=2). Results: Data from the 60 MTC patients were analyzed. Mean age was 58 years (range 11-83 years), 39 patients were male, and six had hereditary MTC. Fifty-six (93%) had metastatic disease in the mediastinum (82%), bones (65%), liver (53%), or lung (53%), and four had only locally advanced disease. At the time of study evaluation, with a median follow-up of 20 months and a median duration of treatment of 9.7 months (range 0.3-36 months), 15 patients were continuing vandetanib treatment (range 18-36 months). Median progression-free survival was 16.1 months. Twenty-five patients discontinued treatment for disease progression (range 0.3-29 months). Best tumor response was a complete response in one patient, a partial response in 12 (20%), stable disease in 33 (55%), and progression in seven patients (12%). All patients had at least one adverse event (AE) during treatment. The main AEs were skin toxicity, diarrhea, and asthenia. Sixteen patients (27%) discontinued treatment for toxicity, and one patient died from vandetanib-induced cardiac toxicity. Conclusions: Vandetanib is an effective option for patients with advanced MTC. AEs should be monitored carefully and should be minimized by educating both patients and care providers and by applying symptomatic treatment and dose reduction.
    Preview · Article · Jan 2015 · Thyroid: official journal of the American Thyroid Association
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    ABSTRACT: Background: Heated intraperitoneal chemotherapy (HIPEC) treats residual microscopic disease after cytoreductive surgery. In experimental models, the open HIPEC technique has shown a higher and more homogenous concentration of platinum in the peritoneum than achieved using the closed technique. A 25-cm H2O pressure enhances the penetration of oxaliplatin. Because pressure is easier to set up with the closed technique, high pressure may counterbalance the drawbacks of this technique versus open HIPEC, and a higher pressure may induce a higher penetration. Because higher concentration does not mean deeper penetration, a study of tissues beneath the peritoneum is required. Finally, achieving a deeper penetration (and a higher concentration) raises the question of the passage of drugs through the surgical glove and the surgeon's safety. Methods: Four groups of pigs underwent HIPEC with oxaliplatin (150 mg/L) for 30 minutes in open isobaric pressure and pressure at 25 cm H2O, and closed pressure at 25 and 40 cm H2O. Systemic absorption and peritoneal mapping of the concentration of platinum were analyzed, as well as in the retroperitoneal tissue and the surgical gloves. Results: Blood concentrations were higher in open groups. In the parietal surfaces, the concentrations were not different between the isobaric and the closed groups (47.08, 56.39, and 48.57 mg/kg, respectively), but were higher in the open high-pressure group (85.93 mg/kg). In the visceral surfaces, they were lower in the closed groups (3.2 and 3.05 mg/kg) than in the open groups (7.03 and 9.56 mg/kg). Platinum concentrations were similar in the deep retroperitoneal tissue when compared between isobaric and high-pressure procedures. No platin was detected in the internal aspect of the gloves. Conclusion: The use of high pressure during HIPEC does not counterbalance the drawbacks of closed techniques. The tissue concentration of oxaliplatin achieved with the open techniques is higher, even if high pressure is applied during a closed technique. Open 25 cm H2O HIPEC achieved the highest tissue penetration of oxaliplatin, but did not enhance the depth of oxaliplatin penetration. High pressure did not enhance the risk of HIPEC.
    No preview · Article · Dec 2014 · Surgery
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    ABSTRACT: In spite of the novel strategies to treat colon cancer, mortality rates associated with this disease remain consistently high. Tumour recurrence has been linked to the induction of resistance towards chemotherapy that involves cellular events that enable cancer cells to escape cell death. Treatment of colon cancer mainly implicates direct or indirect DNA-damaging agents and increased repair or tolerances towards subsequent lesions contribute to generate resistant populations. Resveratrol (RSV), a potent chemosensitising polyphenol, might share common properties with chemotherapeutic drugs through its indirect DNA-damaging effects reported in vitro. In this study, we investigated how RSV exerts its anticancer effects in models of colon cancer with a particular emphasis on the DNA-damage response (DDR; PIKKs-Chks-p53 signalling cascade) and its cellular consequences. We showed in vitro and in vivo that colon cancer models could progressively escape the repeated pharmacological treatments with RSV. We observed for the first time that this response was correlated with transient activation of the DDR, of apoptosis and senescence. In vitro, a single treatment with RSV induced a DDR correlated with S-phase delay and apoptosis, but prolonged treatments led to transient micronucleations and senescence phenotypes associated with polyploidisation. Ultimately, stable resistant populations towards RSV displaying higher degrees of ploidy and macronucleation as compared to parental cells emerged. We linked these transient effects and resistance emergence to the abilities of these cells to progressively escape RSV-induced DNA damage. Finally, we demonstrated that this DNA damage was triggered by an overproduction of reactive oxygen species (ROS) against which cancer cells could adapt under prolonged exposure to RSV. This study provides a pre-clinical analysis of the long-term effects of RSV and highlights ROS as main agents in RSV's indirect DNA-damaging properties and consequences in terms of anticancer response and potent resistance emergence.
    Full-text · Article · Nov 2014 · Cell Death & Disease
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    ABSTRACT: Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour. The loss of function of the retinoblastoma (Rb) protein is an important event during liver carcinogenesis, but it is unclear whether the Rb status modulates the response of HCC cells to sorafenib. Here, we examined this question in HCC cells with reduced levels of Rb achieved through stable RNA interference. We show that HCC cells with reduced levels of Rb exhibit a two- to threefold increase in cell death induction upon exposure to sorafenib compared with controls. Sorafenib treatment of Balb/c nude mice that received tumour xenografts derived from HCC cells with reduced Rb levels resulted in complete tumour regression in 50% of the animals treated, compared with tumour stabilization in mice that received control cells. We show that, upon exposure to sorafenib, the Rb-negative status of HCC cells promotes the occurrence of ferroptosis, a form of oxidative necrosis. The findings highlight the role of Rb in the response of HCC cells to sorafenib and the regulation of ferroptosis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    No preview · Article · Nov 2014 · Cancer Letters
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    ABSTRACT: Background/aim: Ferroptosis is a recently identified form of regulated necrosis that can be experimentally induced in cancer cells with the chemical inducer erastin. Recently, we identified sorafenib, an inhibitor of oncogenic kinases, as an inducer of ferroptosis in hepatocellular carcinoma cells. Whether sorafenib is able to exert its ferroptotic activity in cancer cells originating from other tissues is presently unclear. Materials and methods: We compared the levels of ferroptosis induced by sorafenib with those induced by the reference compound erastin in a panel of ten human cell lines originating from various tissues. Results: Sorafenib induced ferroptosis in different cancer cell lines. We found a positive correlation between the ferroptotic potency of sorafenib and erastin. Compared to other kinase inhibitors, sorafenib is the only drug that displays ferroptotic efficacy. Conclusion: The findings establish sorafenib as the first clinically-approved anticancer drug that can induce ferroptosis.
    No preview · Article · Nov 2014 · Anticancer research
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    Full-text · Dataset · Oct 2014
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    ABSTRACT: Ifosfamide is used in the treatment of sarcomas and other tumors. It sometimes provokes encephalopathy, which is a serious complication even if it is usually reversible within 48-72 h after drug cessation. Ifosfamide is required to be activated by hepatic cytochrome P450 (CYP), especially the 3A4 subtype, leading to 4-hydroxy-ifosfamide. Ifosfamide is also converted by CYP3A4 to inactive but neurotoxic metabolites. Aprepitant is a neurokinin-1 receptor antagonist that is a potent antiemetic used in combination with 5-HT3 antagonists and corticosteroids. Aprepitant has an inhibitory effect, as well as a possible inductive effect, on CYP3A4. Since ifosfamide and aprepitant are both substrates of CYP3A4, a pharmacokinetic interaction could result in secondary effects such as the potentialization of neurological side effects. In this report, we describe 2 cases of fatal encephalopathy in patients who have received both ifosfamide and aprepitant, and we discuss the mechanisms that could be involved. Our observations draw attention to the fact that aprepitant must be avoided, or at least used with caution, in patients who are receiving ifosfamide due to the risk of severe neurological side effects.
    Full-text · Article · Sep 2014 · Case Reports in Oncology

Publication Stats

6k Citations
962.95 Total Impact Points


  • 2012-2015
    • Université de Picardie Jules Verne
      • LNPC - Lymphocyte normal et pathologique et cancers
      Amiens, Picardie, France
  • 1997-2014
    • University of Burgundy
      Dijon, Bourgogne, France
  • 1989-2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2002-2013
    • Centre Georges-François Leclerc
      Dijon, Bourgogne, France
  • 1990-2013
    • Centre Hospitalier Universitaire de Dijon
      • • Service of Digestive and Oncological Surgery - Visceral Surgery and Emergency
      • • Laboratory of Pharmacology and Toxicology
      Dijon, Bourgogne, France
  • 1984-2012
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2007
    • Agence française de lutte contre le dopage
      Saint-Germain, Pays de la Loire, France
  • 1999
    • Centre Hospitalier Lyon Sud
      Lyons, Rhône-Alpes, France
  • 1995
    • CHRU de Strasbourg
      Strasburg, Alsace, France