Eric Deutsch

Institut de Cancérologie Gustave Roussy, Île-de-France, France

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Publications (147)686.01 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose/Objective(s) To describe a novel method to explore radiation dose-volume effects. Functional data analysis is used to investigate the information contained in differential dose-volume histograms. The method is applied to the normal tissue complication probability modeling of rectal bleeding (RB) for patients irradiated in the prostatic bed by 3-dimensional conformal radiation therapy. Methods and Materials Kernel density estimation was used to estimate the individual probability density functions from each of the 141 rectum differential dose-volume histograms. Functional principal component analysis was performed on the estimated probability density functions to explore the variation modes in the dose distribution. The functional principal components were then tested for association with RB using logistic regression adapted to functional covariates (FLR). For comparison, 3 other normal tissue complication probability models were considered: the Lyman-Kutcher-Burman model, logistic model based on standard dosimetric parameters (LM), and logistic model based on multivariate principal component analysis (PCA). Results The incidence rate of grade ≥2 RB was 14%. V65Gy was the most predictive factor for the LM (P=.058). The best fit for the Lyman-Kutcher-Burman model was obtained with n=0.12, m = 0.17, and TD50 = 72.6 Gy. In PCA and FLR, the components that describe the interdependence between the relative volumes exposed at intermediate and high doses were the most correlated to the complication. The FLR parameter function leads to a better understanding of the volume effect by including the treatment specificity in the delivered mechanistic information. For RB grade ≥2, patients with advanced age are significantly at risk (odds ratio, 1.123; 95% confidence interval, 1.03-1.22), and the fits of the LM, PCA, and functional principal component analysis models are significantly improved by including this clinical factor. Conclusion Functional data analysis provides an attractive method for flexibly estimating the dose-volume effect for normal tissues in external radiation therapy.
    International journal of radiation oncology, biology, physics 11/2014; 90(3):654–663. · 4.59 Impact Factor
  • E Deutsch, F Dhermain, C Chargari
    Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 10/2014;
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    ABSTRACT: Purpose To report the application of the Global Risk Analysis (GRA), an innovative proactive risk analysis method, to a radiotherapy department. Material and methods Analyses were conducted by a multidisciplinary working group with the support of a quality engineer. First, a mapping of hazardous situations was developed. For this, a double entry table was filled in, crossing the process of patient care divided into steps with a comprehensive list of pre-established hazards. The cells of the table represented interactions, which were, when relevant, considered as dangerous situations and then sorted by level of priority. For each high priority dangerous situation, scenarios were developed. Their criticality was assessed, using likelihood and severity scales, and a criticality matrix was used to allocate them into categories: acceptable (C1), tolerable (C2) and unacceptable (C3). Corrective actions were planned when relevant. Afterward, the criticality of the scenarios was reevaluated, leading to a residual risk mapping. Results The number of high priority dangerous situations to analyze was 78, for which 205 scenarios were generated: 95 C1, 98 C2, and 12 C3 scenarios. Twenty-two corrective actions were planned. Mapping of residual risk resulted in the disappearance of C3 risks, leaving 18 C2 scenarios, for which six monitoring indicators were implemented. Conclusion The implementation of the GRA appeared feasible and led to the implementation of 22 corrective actions based on scenarios, without the occurrence of any incidents.
    Radiotherapy and Oncology. 09/2014;
  • European journal of dermatology : EJD. 04/2014;
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    ABSTRACT: Cardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancer patients and in experimental models in order to identify novel therapeutic target. The size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes. In patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca(2+) transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals. Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart.
    Radiotherapy and Oncology 04/2014; · 4.52 Impact Factor
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    ABSTRACT: The goal of the present work was to compare outcomes of definitive concurrent cisplatin-based chemoradiotherapy (CRT) with cetuximab-based bioradiotherapy (BRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC). Between 2006 and 2012, 265 patients with locally advanced HNSCC were treated at our institution with CRT (n = 194; 73 %) with three cycles of cisplatin (100 mg/m(2), every 3 weeks) or BRT (n = 71; 27 %) with weekly cetuximab. Patients receiving BRT had more pre-existing conditions (Charlson index ≥ 2) than the CRT group (p = 0.005). Median follow-up was 29 months. In all, 56 % of patients treated with CRT received the planned three cycles (92 % at least two cycles) and 79 % patients treated with BRT received six cycles or more. The 2-year actuarial overall survival (OS) and progression-free survival (PFS) were 72 % and 61 %, respectively. In the multivariate analysis (MVA), T4 stage, N2-3 stage, smoking status (current smoker as compared with never smoker), and non-oropharyngeal locations predicted for OS, whereas BRT association with OS was of borderline significance (p = 0.054). The 2-year actuarial locoregional control (LRC) and distant control (DC) rates were 73 and 79 %, respectively. CRT was independently associated with an improved LRC (2-year LRC: 76 % for CRT vs. 61 % for BRT) and DC (2-year LRC: 81 % for CRT vs. 68 % for BRT) in comparison with BRT (p < 0.001 and p = 0.01 in the MVA). Subgroup analyses showed that T4 patients benefited significantly from CRT (vs. BRT) in LRC, while T1-3 did not. BRT patients had more G3-4 skin complications (p < 0.001) and CRT patients had higher rates of feeding tube placement (p = 0.006) and G3-4 gastrointestinal toxicities (p < 0.001). This retrospective analysis showed a better LRC in locally advanced HNSCC treated by cisplatin-based CRT than cetuximab-based BRT, and a nonsignificant trend towards an improved OS.
    Strahlentherapie und Onkologie 03/2014; · 4.16 Impact Factor
  • International journal of radiation oncology, biology, physics 03/2014; 88(3):755–756. · 4.59 Impact Factor
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    ABSTRACT: Cancer research has received a fresh impetus from the concept of cancer stem cell (CSC) which postulates the existence of a tumor cell population uniquely endowed with self-renewal capacity and therapy resistance. Despite recent progresses including targeted therapy, lung cancer treatment remains a challenge owing largely to disease recurrence. Providing a conceptual model of tumor resistance and disease relapse, the lung CSC has received extensive attention, leading to a flourishing literature and several ongoing clinical trials. In this study, we will discuss the data suggesting the existence of CSC in lung tumors and the potential clinical utility of CSCs as prognostic markers or cellular targets of new therapeutic strategies. We will also touch on the new fundamental developments of the CSC concept that ought to be considered if the integration of the CSC concept into clinical practice is to be successful and impact on lung cancer treatment.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 01/2014; 9(1):7-17. · 4.55 Impact Factor
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    ABSTRACT: Radiotherapy has a critical role in the treatment of small-cell lung cancer (SCLC). The effectiveness of radiation in SCLC remains limited as resistance results from defects in apoptosis. In the current study, we investigated whether using the Bcl-2/Bcl-XL inhibitor S44563 can enhance radiosensitivity of SCLC cells in vitro and in vivo. In vitro studies confirmed that S44563 caused SCLC cells to acquire hallmarks of apoptosis. S44563 markedly enhanced the sensitivity of SCLC cells to radiation, as determined by a clonogenic assay. The combination of S44563 and cisplatin-based chemo-radiation showed a significant tumor growth delay and increased overall survival in mouse xenograft models. This positive interaction was greater when S44563 was given after the completion of the radiation, which might be explained by the radiation-induced overexpression of anti-apoptotic proteins secondary to activation of the NF-κB pathway. These data underline the possibility of combining IR and Bcl-2/Bcl-XL inhibition in the treatment of SCLC as they underscore the importance of administering conventional and targeted therapies in an optimal sequence.
    Cell Death & Disease 01/2014; 5:e1423. · 6.04 Impact Factor
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    ABSTRACT: Background The kinesin spindle protein Eg5 is involved in mitosis, and its inhibition promotes mitotic arrest. EMD 534085, a potent, reversible Eg5 inhibitor, demonstrated significant preclinical antitumor activity. Methods This first-in-man, single-center, open-label, phase I dose-escalation study (3 + 3 design) investigated EMD 534085 safety, pharmacokinetics and antitumor activity in refractory solid tumors, Hodgkin's lymphoma, or non-Hodgkin's lymphoma. EMD 534085 (starting dose 2 mg/m(2)/day) was administered intravenously every 3 weeks. Doses were escalated in 100 % steps in successive cohorts of 3 patients until grade 2 toxicity occurred, followed by 50 % until the first dose-limiting toxicity (DLT) arose. If <2 of 6 patients experienced a DLT, doses were further increased by 25 %. Dose-escalation was stopped if a DLT occurred in ≥2 of 6 patients. Results Forty-four patients received EMD 534085. Median treatment duration was 43 days (range, 21-337). Thirty-eight patients (86 %) received ≥2 cycles. DLTs were grade 4 neutropenia (1 patient each at 108 and 135 mg/m(2)/day), and grade 3 acute coronary syndrome with troponin I elevation (1 patient at 135 mg/m(2)/day). The maximum tolerated dose (MTD) was 108 mg/m(2)/day. The most common treatment-related adverse events were asthenia (50 %) and neutropenia (32 %). EMD 534085 appeared to have linear pharmacokinetics. Increase in phospho-histone H3 positive cells in paired pre- and on-treatment biopsies showed evidence of target modulation. No complete or partial responses were observed. Best response was stable disease in 23 patients (52 %). Conclusions EMD 534085 appeared to be well tolerated; MTD was 108 mg/m(2)/day. Preliminary antitumor results suggested limited activity in monotherapy.
    Investigational New Drugs 09/2013; · 3.50 Impact Factor
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    ABSTRACT: Background / Purpose: Characterization of the genomic alterations (GA) that could drive tumor growth of an individual patient (pt) is now critical to better selecting targeted therapies in phase I trials. Main conclusion: High throughput molecular analysis is feasible in daily practice. It allows enrichment of phase I trials with specific GA, and leads to promising anti-tumor activity (20% PR as compared to the classical 7-10% PR obtained in all comers phase I trials).
    49th American Society of Clinical Oncology (ASCO) Annual Meeting 2013; 09/2013
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    ABSTRACT: Clinical oncology heavily relies on the use of radiotherapy, which often leads to merely transient responses that are followed by local or distant relapse. The molecular mechanisms explaining radioresistance are largely elusive. Here, we identified a dual role of autophagy in the response of cancer cells to ionizing radiation. On one hand, we observed that the depletion of essential autophagy-relevant gene products, such as ATG5 and Beclin 1, increased the sensitivity of human or mouse cancer cell lines to irradiation, both in vitro (where autophagy inhibition increased radiation-induced cell death and decreased clonogenic survival) and in vivo, after transplantation of the cell lines into immunodeficient mice (where autophagy inhibition potentiated the tumour growth-inhibitory effect of radiotherapy). On the other hand, when tumour proficient or deficient for autophagy were implanted in immunocompetent mice, it turned out that defective autophagy reduced the efficacy of radiotherapy. Indeed, radiotherapy elicited an anti-cancer immune response that was dependent on autophagy-induced ATP release from stressed or dying tumour cells and was characterized by dense lymphocyte infiltration of the tumour bed. Intratumoural injection of an ecto-ATPase inhibitor restored the immune infiltration of autophagy-deficient tumours post radiotherapy and improved the growth-inhibitory effect of ionizing irradiation. Altogether, our results reveal that beyond its cytoprotective function, autophagy confers immunogenic properties to tumours, hence amplifying the efficacy of radiotherapy in an immunocompetent context. This has far-reaching implications for the development of pharmacological radiosensitizers.Cell Death and Differentiation advance online publication, 13 September 2013; doi:10.1038/cdd.2013.124.
    Cell death and differentiation 09/2013; · 8.24 Impact Factor
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    ABSTRACT: The ACCORD 16 phase II trial aimed to evaluate the objective response rate after combination of conventional chemoradiotherapy (CRT) and cetuximab in locally advanced anal canal carcinoma (LAACC). Immunocompetent patients with histologically confirmed LAACC received CRT [45 gray (Gy)] in 25 fractions over 5 weeks, fluorouracil and cisplatin during weeks 1 and 5), in combination with weekly dose of cetuximab (250 mg/m(2) with a loading dose of 400 mg/m(2) 1 week before irradiation), and a standard dose boost (20 Gy). The trial was originally designed to include 81 patients to detect a 15% of objective response increase with the new combination in comparison with CRT. The trial was prematurely stopped after the declaration of 15 serious adverse events (SAEs) in 14 out of 16 patients. Five patients received the entire planned treatment, and the compliance was higher after amendments of the protocol. Among the 15 SAEs, 6 were unexpected. Grade (G) 3/4 acute toxic effects, observed in 88% patients, were general (n = 13, 81%), digestive (n = 9, 56%), dermatological (n = 5, 31%), infectious (n = 4, 25%), haematological (n = 3, 19%), and others (n = 9); and three patients suffered from six G3/4 late toxic effects. No treatment-related death was reported. All 11 assessable patients had an objective response consisting of six complete (55%) and five partial (45%) response 2 months after the end of the treatment. Thirteen patients were followed up with a median of 22 months [95% confidence interval (CI ): 18-27] and had a 1-year colostomy-free survival, progression-free and overall survival rate of 67% (95% CI: 40%-86%), 62% (95% CI: 36%-82%), and 92% (95% CI: 67%-99%), respectively. CRT plus cetuximab was unacceptably toxic in this population of patients. Results of others phase II trials evaluating this combination are awaited to confirm these findings. 2007-007029-38.
    Annals of Oncology 09/2013; · 7.38 Impact Factor
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    Journal of leukocyte biology 09/2013; 94(3):390-2. · 4.99 Impact Factor
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    ABSTRACT: Anthracyclines, discovered 50years ago, are antibiotics widely used as antineoplastic agents and are among the most successful anticancer therapies ever developed to treat a wide range of cancers, including hematological malignancies, soft tissue sarcomas and solid tumors. However, some anthracyclines, including doxorubicin, exhibit major signs of cardiotoxicity that may ultimately lead to heart failure (HF). Despite intensive research on doxorubicine-induced cardiotoxicity, the underlying mechanisms responsible for doxorubicin-induced cardiotoxicity have not been fully elucidated yet. Published literature so far has focused mostly on mitochondria dysfunction with consequent oxidative stress, Ca(2+) overload, and cardiomyocyte death as doxorubicin side effects, leading to heart dysfunction. This review focuses on the current understanding of the molecular mechanisms underlying doxorubicin-induced cardiomyocyte death (i.e.: cardiomyocyte death, mitochondria metabolism and bioenergetic alteration), but we will also point to new directions of possible mechanisms, suggesting potent prior or concomitant alterations of specific signaling pathways with molecular actors directly targeted by the anticancer drugs itself (i.e. calcium homeostasis or cAMP signaling cascade). The mechanisms of anticancer cardiac toxicity may be more complex than just mitochondria dysfunction. Partnership of both basic and clinical research is needed to promote new strategies in diagnosis, therapies with concomitant cardioprotection in order to achieve cancer treatment with acceptable cardiotoxicity along life span.
    La Presse Médicale 08/2013; · 0.87 Impact Factor
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    ABSTRACT: Cervical carcinoma remains a leading cause of female mortality worldwide and over 90% of these tumors contain the human papillomavirus (HPV) genome. Cross-talk between the epidermal growth factor receptor and HPV has been reported and is implicated in tumor progression. The combination of the antiviral compound cidofovir (Cd) with the monoclonal antibody antiepidermal growth factor receptor cetuximab (Cx) was evaluated. HPV-positive (HeLa and Me180) and HPV-negative (C33A, H460 and A549) human cancer cell lines were incubated with Cd (1-10 μg/ml) and/or Cx (10 or 50 μg/ml). The antitumor effect of the combination was assessed in vitro using a clonogenic survival assay, cell cycle analysis, and phospho-H2AX level. Tumor growth delay was assayed in vivo using xenograft models. A pan-genomic analysis was carried out to identify the genes expressed differentially in untreated HeLa HPV-positive cells versus cells treated by the Cd-Cx combination. The Cd-Cx combination inhibited proliferation in all the cell lines tested. The association of Cd and Cx exerted a synergistic activity on HPV-positive but not on HPV-negative cell lines. The combination delayed tumor growth of HPV-positive tumors in vivo; however, no efficacy was reported on HPV-negative C33A xenografts nor on cell lines treated by single-drug therapy. The combination induced an S-phase arrest associated with an enhanced level of the double-strand break in Me180 and HeLa cell lines. Gene profiling assays showed a significant differential modulation of genes in HeLa cell lines treated with the combination involving the EGR-1 transcription factor. The current data support a synergistic antiproliferative action of the Cd-Cx combination on HPV-related cervical tumors.
    Anti-cancer drugs 07/2013; 24(6):599-608. · 2.23 Impact Factor
  • R Mazeron, N Aguini, E Deutsch
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    ABSTRACT: Five radiotherapy accidents, from which two serial, occurred in France from 2003 to 2007, led the authorities to establish a roadmap for securing radiotherapy. By analogy with industrial processes, a technical decision form the French Nuclear Safety Authority in 2008 requires radiotherapy professionals to conduct analyzes of risks to patients. The process of risk analysis had been tested in three pilot centers, before the occurrence of accidents, with the creation of cells feedback. The regulation now requires all radiotherapy services to have similar structures to collect precursor events, incidents and accidents, to perform analyzes following rigorous methods and to initiate corrective actions. At the same time, it is also required to conduct analyzes a priori, less intuitive, and usually require the help of a quality engineer, with the aim of reducing risk. The progressive implementation of these devices is part of an overall policy to improve the quality of radiotherapy. Since 2007, no radiotherapy accident was reported.
    Cancer/Radiothérapie 06/2013; · 1.48 Impact Factor
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    ABSTRACT: IMPORTANCE The BRAF inhibitor, vemurafenib, was recently approved for the treatment of patients with BRAFV600 metastatic melanoma. Wider use of this drug and longer follow-up periods of treatment are resulting in the emergence of a growing number of reports detailing new adverse effects. Cutaneous adverse effects are preeminent with UV-A-dependent phototoxicity, hyperkeratotic folliculitis, hand-foot skin reaction, hair changes, verrucous papillomas, keratoacanthomas, and squamous cell carcinomas. OBSERVATIONS We report 2 cases of dermatitis occurring on a previously irradiated skin area in patients treated with vemurafenib for a BRAFV600-mutated metastatic melanoma. The first case occurred 10 days after a low dose of radiation was delivered that usually does not induce any radiodermatitis, suggesting radiosensitization by vemurafenib. The second case occurred 30 days after radiotherapy and was diagnosed as radiation recall dermatitis. CONCLUSIONS AND RELEVANCE Vemurafenib should be considered a potential cutaneous radiosensitizer and an inducer of radiation recall dermatitis. However, these adverse effects are easily managed with topical corticosteroids. Dose reduction or interruption of vemurafenib is not required. Further studies and reports will enlighten us as to whether this pharmacodynamic interaction between x-rays and vemurafenib is also seen with other BRAF or MEK inhibitors on the same mitogen-activated protein kinase pathway currently under development.
    JAMA dermatology (Chicago, Ill.). 05/2013;
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    ABSTRACT: Insulin-like growth factor receptor-1 (IGF-1R) inhibition could be a relevant therapeutic approach in small cell lung cancer (SCLC) given the importance of an IGF-1R autocrine loop and its role in DNA damage repair processes. We assessed IGF-1R and pAkt protein expression in 83 SCLC human specimens. The efficacy of R1507 (a monoclonal antibody directed against IGF-1R) alone or combined with cisplatin or ionizing radiation (IR) was evaluated in H69, H146 and H526 cells in vitro and in vivo. Innovative genomic and functional approaches were conducted to analyze the molecular behavior under the different treatment conditions. A total of 53% and 37% of human specimens expressed IGF-1R and pAkt, respectively. R1507 demonstrated single agent activity in H146 and H526 cells but not in H69 cells. R1507 exhibited synergistic effects with both Cisplatin and IR in vitro. The triple combination R1507-Cisplatin-IR led to a dramatic delay in tumor growth compared to Cisplatin-IR in H526 cells. Analyzing the apparent absence of antitumoral effect of R1507 alone in vivo, we observed a transient reduction of IGF-1R staining intensity in vivo, concomitant to the activation of multiple cell surface receptors and intracellular proteins involved in proliferation, angiogenesis and survival. Finally, we identified that the nucleotide excision repair pathway (NER) was mediated after exposure to R1507-CDDP and R1507-IR in vitro and in vivo. In conclusion, adding R1507 to the current standard Cisplatin-IR doublet reveals remarkable chemo- and radiosensitizing effects in selected SCLC models and warrants to be investigated in the clinical setting.
    Molecular Cancer Therapeutics 05/2013; · 5.60 Impact Factor
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    ABSTRACT: Radiosensitivity varies to a great extent across tumor types and also between patients bearing the same type of tumor. Radiation oncology pioneered the field of biomarkers with attempts to correlate tumor response to clonogenic survival, tumor potential doubling time (Tpot), and PaO2. Biomarkers predicting the clinical outcome after radiotherapy are already available, but their levels of evidence are heterogeneous. In light of these molecular factors, the issue of personalized radiation therapy in combination or as a standalone modality is addressed. Known molecular prognostic and predictive biomarkers and their present or potential respective therapeutic implications are described for six tumor types where radiotherapy is considered to be part of the mainstay: chemoradiation (e.g., gliomas, head and neck, cervical cancer), radiotherapy with or without androgen deprivation (e.g., prostate), neo-adjuvant chemoradiation (e.g., rectum), or adjuvant radiotherapy (e.g., breast).
    CANCER AND METASTASIS REVIEW 04/2013; · 9.35 Impact Factor

Publication Stats

2k Citations
686.01 Total Impact Points

Institutions

  • 2000–2014
    • Institut de Cancérologie Gustave Roussy
      • Department of Radiotherapy
      Île-de-France, France
  • 2011–2013
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2010
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2009
    • Institute of Cancer Research
      Londinium, England, United Kingdom
  • 2005
    • University of Pennsylvania
      • Department of Radiation Oncology
      Philadelphia, PA, United States