Eve Maubec

Assistance Publique – Hôpitaux de Paris, Lutetia Parisorum, Île-de-France, France

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Publications (81)218.25 Total impact

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    ABSTRACT: IMPORTANCE Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), occurs in elderly patients and has been considered as a lymphoma with a poor prognosis, with estimated 5-year specific survival rates of approximately 50%. The hypothesis of an improvement in prognosis over time has not been studied. OBJECTIVES To evaluate this hypothesis in a large series of patients and investigate factors associated with prognosis as well as improvement in the prognosis. DESIGN, SETTING, AND PARTICIPANTS A retrospective multicenter study was conducted including dermatology departments belonging to the French Study Group on Cutaneous Lymphoma. Participants were 115 patients with PCDLBCL-LT diagnosed between 1988 and 2003 (period 1) or between 2004 and 2010 (period 2). MAIN OUTCOMES AND MEASURES Age, sex, period of diagnosis, number of skin lesions, tumor stage, tumor location (leg vs nonleg), lactate dehydrogenase level, type of therapy (with or without a combination of rituximab and polychemotherapy [PCT]), and outcome were recorded. Baseline characteristics and outcome were compared according to period of diagnosis and type of therapy. Prognosis factors were identified by univariate and multivariate survival analyses. RESULTS The mean age of the patients was 76.9 years, and 47% of the patients were older than 80 years. The 3- and 5-year specific survival rates improved between period 1 and period 2, from 55% to 74% and from 46% to 66%, respectively (P = .01). Patients had similar baseline characteristics during both periods, but rituximab-PCT regimens were administered to 88.5% of the patients in period 2 vs 16.7% in period 1 (P < .001). The 3- and 5-year specific survival rates were 80% and 74%, respectively, in patients who received a rituximab-PCT regimen compared with 48% and 38% in those who received less-intensive therapies. No significant difference was observed between both groups in age and baseline prognostic factors. In multivariate analysis, treatment without rituximab-PCT was the only adverse prognostic factor (odds ratio, 4.6 [95% CI, 2.4-9.1]; P < .001), whereas the number of skin lesions (P = .06) and location on the leg (P = .07) had only borderline significance. CONCLUSIONS AND RELEVANCE A major improvement in the survival of patients with PCDLBCL-LT has occurred over time in France, mainly as a result of the use of intensive rituximab-PCT regimens in most patients, including very elderly ones. Until further prospective clinical trials are conducted, such regimens should be considered as the standard of care in these patients.
    JAMA dermatology. 03/2014;
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    ABSTRACT: Objectives The French ENT Society (SFORL) created a workgroup to draw up guidelines for the management of immunodeficient patients with head and neck cancer of cutaneous origin. The present guidelines cover diagnostic and therapeutic management and prevention of head and neck cancer of cutaneous origin in immunodeficient patients, and in particular in transplant patients and those with HIV infection. Materials and methods The present guidelines were based on a critical multidisciplinary reading of the literature. Immunosuppression and its varieties are defined. The usual risk factors for skin cancer and those specific to immunodeficiency are presented. The prevention, assessment and management of cutaneous carcinoma, melanoma, Kaposi's sarcoma and lymphoma are dealt with. The level of evidence of the source studies was assessed so as to grade the various guidelines. When need be, expert opinions are put forward. Results Immunodeficient patients are at higher risk of head and neck skin tumors. The level of risk depends on the type of deficiency; there is an especially high risk of squamous cell carcinoma in transplant patients and of Kaposi's sarcoma in HIV-positive subjects. Various viruses are associated with skin cancers. Skin tumors are often evolutive in case of immunodeficiency, requiring rapid treatment. Management is generally the same as in immunocompetent subjects and should be discussed in a multidisciplinary team meeting. Immunosuppression may need to be modulated. In organ transplant patients, the only class of immunosuppressants with proven antitumoral efficacy are mTOR inhibitors, particularly in cutaneous squamous cell carcinoma. The rhythm of clinical surveillance should be adapted according to the risk of recurrence. Preventive measures should be undertaken. Conclusion Skin cancers in immunodeficiency are highly evolutive, requiring the earliest possible treatment. Immunosuppression may need modulating. As the risk of recurrence may be elevated, careful surveillance should be implemented. Preventive measures should also be undertaken.
    European Annals of Otorhinolaryngology, Head and Neck Diseases 01/2014;
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    ABSTRACT: Objectifs La Société française d’otorhinolaryngologie (SFORL) a organisé un groupe de travail chargé de la rédaction de recommandations pour la prise en charge des patients immunodéprimés atteints de tumeurs de la tête et du cou de point de départ cutané. Ces recommandations abordent la prise en charge diagnostique et thérapeutique ainsi que les mesures de prévention des tumeurs de la tête et du cou à point de départ cutané survenant chez les immunodéprimés, en particulier les transplantés et les patients infectés par le VIH. Matériels et méthodes L’élaboration de ces recommandations repose sur une lecture critique multidisciplinaire de la littérature. L’immunosuppression et les différents types d’immunosuppression ont été définis. Les facteurs de risque habituels des tumeurs cutanées et ceux spécifiques à l’immunodéprimé sont présentés. La prévention, le bilan et la prise en charge des carcinomes cutanés, du mélanome, de la maladie de Kaposi et des lymphomes sont traités. Le niveau de preuve des études a été estimé, permettant de grader le niveau des recommandations. Le cas échéant, des avis d’experts ont été proposés. Résultats Les immunodéprimés ont un risque accru de développer des tumeurs cutanées de l’extrémité cervico-céphalique. Le risque de développer ces tumeurs varie en fonction du type d’immunosuppression ; il existe un risque particulièrement élevé de carcinomes épidermoïdes chez les transplantés et de maladie de Kaposi chez les patients séropositifs pour le VIH. Différents virus sont associés à ces cancers cutanés. Les tumeurs cutanées de l’immunodéprimé sont souvent caractérisées par leur évolutivité justifiant une prise en charge thérapeutique rapide. La prise en charge spécifique, en général similaire à celle du sujet immunocompétent, doit être discutée en RCP. La modulation de l’immunosuppression doit être envisagée. Chez le transplanté d’organe, la seule classe d’immunosuppresseurs ayant un effet anti-tumoral documenté est celle des inhibiteurs de mTOR en particulier pour les carcinomes épidermoïdes cutanés. La fréquence de la surveillance clinique doit être adaptée au risque de récidive. Des mesures de prévention doivent être proposées. Conclusion Les tumeurs cutanées de l’immunodéprimé sont souvent caractérisées par leur évolutivité justifiant une prise en charge thérapeutique la plus précoce possible. Une modulation de l’immunosuppression doit être discutée. En raison d’un risque souvent élevé de récidive, une surveillance attentive doit être proposée. Les mesures de prévention doivent également être respectées.
    Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale. 01/2014; 131(2):107–116.
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    ABSTRACT: Melanomas are characterized by high metastatic potential, with regional lymph node (LN) representing the most frequent site of early dissemination in this disease. These regional LN also represent the primary site for differentiation of natural killer cells (NK cells). While blood-derived NK cells can efficiently lyse melanoma cells isolated from metastatic LN (M-LN), there has been no study of the properties of the most disease-relevant NK cells isolated from M-LN in melanoma patients. Here we report that M-LN contain 0.5-11% of CD56bright NK cells among CD45+ hematopoietic cells present and that this cell population surrounded tumor cell clusters in M-MN. This NK cell population was characterized by expression of CD62L, chemokine receptors and high levels of natural cytotoxicity receptors (NCRs), NKG2D and DNAM-1. Expression of NCR-NKp30 and NKG2D correlated negatively with percentages of tumor cells in M-LN. Interestingly, M-LN contained a unique subset of mature CD56brightCD16+ NK cells displaying co-regulated expression of NCR and NKG2D activating receptors. Ex vivo analyses suggested that M-LN-derived NK cells were inactive but could be activated by appropriate cytokine signals (IL-2 or IL-15), could lyse metastatic melanoma cells in a highly efficient manner compared to blood-derived NK cells. Taken together, the results offer evidence that adjuvant immunotherapy that targets NK cells in M-LN for activation may improve treatment of sentinel LN-positive melanoma patients.
    Cancer Research 11/2013; · 8.65 Impact Factor
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    ABSTRACT: IMPORTANCE Curative treatment of aggressive Kaposi sarcoma (KS) with conventional chemotherapy in human immunodeficiency virus (HIV)-infected patients remains difficult. The administration of thalidomide, an immunomodulatory drug with antiangiogenic effects, is limited by its toxicity. This engenders interest in evaluating thalidomide analogues such as lenalidomide with better toxicity profiles. To our knowledge, we describe for the first time a patient with visceral KS successfully treated with lenalidomide. OBSERVATIONS A man with advanced visceral HIV-related KS progressing after 11 months of highly active antiretroviral therapy (HAART) and 2 lines of conventional chemotherapy (pegylated liposomal doxorubicin and docetaxel) was treated with lenalidomide on a compassionate use basis. He showed a rapid partial response without any substantial adverse effect but experienced relapse after 5 months of treatment, in a context of virologic failure. CONCLUSIONS AND RELEVANCE Similar to our observation, good partial response without toxic effects has been reported in 3 patients with only skin involvement. Because immune reconstitution syndrome may occur in HIV-infected patients with KS undergoing HAART, KS improvement may be partly explained by immune recovery. An ongoing US phase 1/2 trial will better evaluate the efficacy and tolerance of lenalidomide in patients with HIV-related KS with and without visceral involvement.
    JAMA dermatology (Chicago, Ill.). 10/2013;
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    ABSTRACT: BACKGROUND: Genital and anorectal mucosal melanomas (GAMM) are rare, compared to cutaneous melanoma (CM). Many epidemiological and genetic studies have been carried out in CM. In contrast, the genetic and environmental risk factors for GAMM have been poorly documented up to now. OBJECTIVE: The aim of the study was to compare the distribution of pigmentation and nevus phenotypes, sun exposure and family history of melanoma between GAMM and CM patients. METHODS: For that purpose, we compared two series of 81 GAMM and 293 CM patients. RESULTS: GAMM and CM patients did not show significant differences for phenotypic risk factors. However, GAMM patients tend to display red hair (10.8% vs 5.5%, P = 0.08) and a poor tanning ability (22.2% vs 13.3%, P = 0.06) at a higher frequency than CM patients.A family history of melanoma was significantly more frequent in the GAMM than in the CM series (18.2% vs 7.5%, P = 0.005). Apart from the GAMM index case, affected relatives had CM except in one family. The frequency of multiple primary melanomas (MPM) was similar in GAMM and CM series (6.5% vs 5.3%, P=0.43). All GAMM patients with MPM had only one GAMM primary while the other primary was cutanaeous. No CDKN2A germline mutation was detected in GAMM patients. CONCLUSIONS: This study shows that GAMM and CM may occur in the same patient and GAMM may develop in a familial setting. The association of both GAMM and CM in patients and families suggests shared genetic factors by these two types of melanoma. This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 05/2013; · 3.76 Impact Factor
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    ABSTRACT: INTRODUCTION: Blastic plasmacytoid Dentritic Cell Neoplasm (BPDCN) is, as defined in the new 2008 World health Organized (WHO) classification of tumors of hematopoietic and lymphoid tissue, a rare disease characterized by malignant proliferation of a contingent blastic plasmacytoid dendritic cell. This rare entity is mostly revealed and diagnosed on cutaneous spreading associated d'emblée or not with a leukaemic component .The prognosis is very poor. We herein studied a large cohort of 90 patients with BPDCN and try to define additional clues to coin earlier the correct diagnosis and manage such patients accordingly. MATERIALS AND METHOD: We retrospectively reviewed BPDCN cases registered in the French Study Group on Cutaneous Lymphoma (GFELC) database from November 1995 to January 2012. Ninety patients were studied. Demographic data, clinical presentation, initial staging, and outcome were recorded. RESULTS: The studied group contained 62 male and 28 female patients (sex ratio 2.2). Age ranged from 8 to 103 years at the time of diagnosis (mean age: 67.2 years).Three major different clinical presentations were identified: Sixty six patients (73.2%) presented with nodular lesions only, 11 patients with "bruise-like» patches (12.2%).The remaining 13 ones showed disseminated lesions (patches and nodules). Mucosal lesions were seen in five patients (5.6%) The median survival in patients with BPDCN was at 12 months . CONCLUSIONS: We here distinct three different clinical presentation of BPDCN. Nodular pattern is actually a more common feature than the originally reported "bruise-like" pattern. Despite the fact that BPDCN may initially appear as a localized skin tumor an aggressive management including allogenic bone marrow transplantation should be considered d'emblée since it is so far the only one option associated with long term survival. This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 05/2013; · 3.76 Impact Factor
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    ABSTRACT: BACKGROUND: Merkel cell polyomavirus has been recognized to be associated with Merkel cell carcinoma (MCC), but the evolution of this cancer probably depends on various factors. Vitamin D deficiency, defined by serum 25-hydroxyvitamin D levels <50 nmol/L, seems to influence cancer behavior and progression, but has never been assessed in MCC patients. OBJECTIVES: First, to evaluate whether vitamin D deficiency was associated with tumor characteristics and prognosis in a cohort of MCC patients. Second, to assess expression of the vitamin D receptor (VDR) in MCC tumors. METHODS: Clinical findings, Merkel cell polyomavirus markers and vitamin D status were assessed in a cohort of French MCC patients. The study was limited to the 89 patients for whom the serum sample had been collected within 3 years after the diagnosis of MCC. Correlation between vitamin D deficiency and MCC characteristics and outcome were determined in regression analyses. VDR expression in MCC tumours was assessed by immunohistochemistry. RESULTS: Vitamin D deficiency was noted in 65.1% of the patients and was independently associated with greater tumor size at diagnosis (P = 0.006) and with metastasis recurrence (HR, 2.89; 95% CI, 1.03 to 8.13; P = 0.043), but not with death from MCC, although there was a trend (HR, 5.28; 95% CI, 0.75 to 36.96; P = 0.093). VDR was found to be strongly expressed in all 28 MCC tumor specimens investigated. CONCLUSION: The association between vitamin D deficiency and MCC characteristics and outcome, together with detection of the VDR in MCC cells, suggest that vitamin D could influence the biology of MCC.
    Journal of the European Academy of Dermatology and Venereology 02/2013; · 2.69 Impact Factor
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    ABSTRACT: Melanomas are aggressive skin tumors characterized by high metastatic potential. Immunotherapy is a valuable alternative for metastatic melanoma patients resistant to chemotherapy. Natural Killer (NK) cells are efficient anti-tumor cytotoxic effectors. We previously showed that blood NK cells from stage IV metastatic melanoma patients display decreased NK receptors and that chemotherapy modifies the functional status of blood NK cells. To investigate the role of NK cells along melanoma progression, we have here studied NK cells from patients at different stages of the disease. First, we showed that ex vivo NK cells from certain stage III-IV patients displayed low degranulation potential. Using a dynamic label-free assay, we found that immunoselected IL-2 activated blood NK cells from patients efficiently lysed melanoma cells through NKp46 and NKG2D receptors, independently to the clinical stage. Moreover, the ex vivo phenotype of circulating NK cells from 33 patients (stage I to IV) was extensively analyzed. NK cells from patients displayed higher variability in the percentages of Natural Cytotoxicity Receptors (NCR) and Natural Killer Group 2D (NKG2D) receptor expression compared to donor NK cells. The main defect was the decreased expression of NCR1 (NKp46) by NK cells from metastatic patients. Interestingly, we found a positive correlation between the NK cell percentages of NKp46 and the duration of stage IV in melanoma patients. Finally, we showed that NK cells infiltrated primary melanomas and displayed a predominant peritumoral distribution. These results are new arguments for the development of NK-based therapies in melanoma patients.
    PLoS ONE 01/2013; 8(10):e76928. · 3.73 Impact Factor
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    ABSTRACT: BACKGROUND: Features associated with an increased frequency of cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations have been identified in families with 3 or more patients with cutaneous melanoma (CM). However, in families with 2 patients with CM, which represent the majority of familial melanoma, these factors have been rarely studied. OBJECTIVE: We investigated association of 3 clinical features with the presence of a CDKN2A mutation in a family by extent of CM family clustering (2 vs ≥3 patients with CM among first-degree relatives in a family). METHODS: We included 483 French families that comprised 387 families with 2 patients with CM (F2 families) and 96 families with 3 or more patients with CM (F3+ families). Three clinical factors were examined individually and in a joint analysis: median age at diagnosis younger than 50 years, and 1 or more patient in a family with multiple primary melanoma or with pancreatic cancer. RESULTS: The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). Although early age at melanoma diagnosis and occurrence of multiple primary melanoma in 1 or more patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families. LIMITATIONS: The study was not population based. CONCLUSIONS: This study shows that factors associated with CDKN2A mutations differ by extent of CM family clustering. It indicates that, in France, families with 2 patients with CM are eligible for genetic testing especially when there is an early age at CM diagnosis and/or 1 or more patients with multiple primary melanoma.
    Journal of the American Academy of Dermatology 07/2012; · 4.91 Impact Factor
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    ABSTRACT: So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (ΨKXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K-occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.
    Nature 12/2011; 480(7375):94-8. · 38.60 Impact Factor
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    ABSTRACT: To evaluate the efficacy and safety of cetuximab, a monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR), as a first-line monotherapy in patients with unresectable squamous cell carcinoma of the skin (SCCS). Thirty-six patients received cetuximab (initial dose of 400 mg/m(2) followed by subsequent weekly doses of 250 mg/m(2)) for at least 6 weeks with a 48-week follow-up. The primary end point was the disease control rate (DCR) at 6 weeks (according to Response Evaluation Criteria in Solid Tumors [RECIST] criteria). Secondary end points included best response rate, overall survival, progression-free survival (PFS), and toxicity assessment. Association of treatment efficacy with RAS mutations or FcγR genotypes was investigated. Median age of the study population was 79 years. DCR at 6 weeks was obtained in 25 of 36 patients (69%; 95% CI, 52% to 84%) of the intention-to-treat population. The best responses were eight partial responses and two complete responses. There were no cetuximab-related deaths. There were three related serious adverse events: two grade 4 infusion reactions and one grade 3 interstitial pneumopathy. Grade 1 to 2 acne-like rash occurred in 78% of patients and was associated with prolonged PFS. One HRAS mutation was identified. Combined FcγRIIa-131H/H and/or FcγRIIIa-158V/V polymorphisms were not associated with the clinical outcomes. As a first-line treatment in patients with unresectable SCCS, cetuximab achieved 69% DCR. A randomized phase III trial is warranted to confirm that cetuximab may be considered as a therapeutic option especially in elderly patients. The low frequency of RAS mutations in SCCS makes SCCS tumors attractive for EGFR inhibition.
    Journal of Clinical Oncology 08/2011; 29(25):3419-26. · 18.04 Impact Factor
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    ABSTRACT: The relationships of pregnancy and melanoma have been debatable. Our aim was to assess the influence of gestation on the course of melanoma in a classic murine model of tumor progression and in women. B16 mouse melanoma cells were injected in nonpregnant or pregnant mice on day 5 of gestation. Animals were evaluated for tumor progression, metastases, and survival. Tumor sections were analyzed for lymphatic and blood vessel number and relative surface and expression of angiogenic growth factors. Finally, primary melanomas from pregnant and nonpregnant women, matched for age and tumor thickness, were also considered. Tumor growth, metastasis, and mortality were increased in B16-injected pregnant mice. Tumors displayed an increase in intratumoral lymphangiogenesis during gestation. This increased lymphatic angiogenesis was not observed in normal skin during gestation, showing its specificity to the tumor. An analysis of melanoma from pregnant and matched nonpregnant women showed a similar increase in lymphatic vessels. Tumors from pregnant mice had increased expression of vascular endothelial growth factor A at the RNA and protein levels. The increased vascular endothelial growth factor A production by melanoma cells could be reproduced in culture using pregnant mouse serum. In conclusion, pregnancy results in increased lymphangiogenesis and subsequent metastasis. Caution should be applied in the management of patients with advanced-stage melanoma during gestation.
    American Journal Of Pathology 04/2011; 178(4):1870-80. · 4.52 Impact Factor
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    ABSTRACT: A new human polyomavirus, Merkel cell polyomavirus (MCV), was identified in 2008 in tumor tissue of patients with Merkel cell carcinoma (MCC), a relatively rare human skin cancer. In this study, we investigated patients with MCC and controls for the presence of antibodies against MCV and their association with clinical characteristics. Antibodies against MCV were investigated by enzyme-linked immunosorbent assay in 68 patients with MCC and 82 controls using VP1 virus-like particles produced in insect cells. Antibodies against MCV were detected in all patients with MCC and in 85% of controls. However, high antibody titers (> 10,000) were rarely observed in controls (7.3%) and they were detected in 64.7% of patients with MCC (P < .001) in contrast to the absence of VP1 expression in tumor samples. In addition, the geometric mean titer of anti-MCV in patients with MCC was around 14 times higher than that observed in MCV-positive controls (P < .001) and was not correlated with tumor viral load. High antibody titers were not found to be associated with any subject or tumor characteristics, but better progression-free survival was observed in patients with high antibody titers (hazard ratio, 4.6; 95% CI, 1.7 to 12.2; P = .002). High titers of MCV antibodies in a much higher proportion of patients with MCC than in controls confirmed the association between MCV infection and MCC. The findings also indicated that a better progression-free survival occurred in patients with high MCV antibody titers and suggested that there are at least two distinct etiologic causes of MCC.
    Journal of Clinical Oncology 03/2011; 29(12):1612-9. · 18.04 Impact Factor
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    ABSTRACT: There is no consensus regarding the therapeutic utility of sentinel lymph node biopsy (SLNB) versus that of nodal observation (NO) in melanoma. To prospectively evaluate a standardized counseling procedure and its effect on patient choices to undergo SLNB or NO. In four centers, patients with melanoma eligible for SLNB or NO received a complete counseling procedure that included verbal information from dermatologists and surgeons, a detailed information sheet, and a written consent form. Data collected included patient and tumor characteristics, counseling conditions, and specialties of informing doctors. Factors influencing patients' choices were studied using multivariate analysis. Of 343 consecutive patients, 309 were offered SLNB and NO and received complete verbal and written information from a dermatologist alone (62%) or in association with a surgeon (38%). Approximately half took advice from trusted persons, and half asked for additional time before making a decision; 268 (86.7%) ultimately decided to undergo SLNB. Multivariate analysis showed that older patients, those with a head and neck melanoma, and those informed without a surgeon present were more likely to prefer NO. This counseling procedure was easily implemented in clinical practice. Patients favored SLNB but were able to understand uncertainties and express preferences.
    Dermatologic Surgery 02/2011; 37(2):199-206. · 1.87 Impact Factor
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    ABSTRACT: Programmed death-1 (PD-1) is involved in T-cell tolerance to self-antigens. For some cancers, it has been suggested that the expression of a ligand of PD-1, namely PD-L1, could contribute to tumor escape from immune destruction. Nevertheless, the relationship between PD-1 expression on tumor-infiltrating T lymphocytes (TILs), disease stage, and TIL responsiveness is still poorly documented. In this study, we show that freshly isolated CD4(+) and CD8(+) TILs express substantial levels of PD-1 in primary melanomas. The expression of PD-1 was further increased at later stages in distant cutaneous metastases, especially on CD8(+) TILs. The expression of PD-1 ligands was frequent only in metastases, on both tumor cells and tumor-derived myeloid cells. TILs isolated from these cutaneous tumors are poorly reactive ex vivo, with blunted calcium response and IFN-γ production after TCR stimulation. Surprisingly, in distinct parts of a primary melanoma, either invasive or regressing, we show that TILs similarly express PD-1 and remain dysfunctional. The expressions of PD-1 and PD-L1 in metastatic melanoma lesions could be considered as witnesses of an unsuccessful anti-tumoral immune response, but the direct involvement of PD-1 in the severity of the disease, and the importance of TILs in tumor regression, remain to be established.
    Journal of Investigative Dermatology 02/2011; 131(6):1300-7. · 6.19 Impact Factor
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    ABSTRACT: To improve cancer immunotherapy, a better understanding of the weak efficiency of tumor-infiltrating T lymphocytes (TIL) is necessary. We have analyzed the functional state of human TIL immediately after resection of three types of tumors (NSCLC, melanoma and RCC). Several signalling pathways (calcium, phosphorylation of ERK and Akt) and cytokine secretion are affected to different extents in TIL, and show a partial spontaneous recovery within a few hours in culture. The global result is an anergy that is quite distinct from clonal anergy induced in vitro, and closer to adaptive tolerance in mice. PD-1 (programmed death -1) is systematically expressed by TIL and may contribute to their anergy by its mere expression, and not only when it interacts with its ligands PD-L1 or PD-L2, which are not expressed by every tumor. Indeed, the TCR-induced calcium and ERK responses were reduced in peripheral blood T cells transfected with PD-1. Inhibition by sodium stibogluconate of the SHP-1 and SHP-2 phosphatases that associate with several inhibitory receptors including PD-1, relieves part of the anergy apparent in TIL or in PD-1-transfected T cells. This work highlights some of the molecular modifications contributing to functional defects of human TIL.
    PLoS ONE 01/2011; 6(3):e17621. · 3.73 Impact Factor
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    ABSTRACT: Patients with melanoma (MM) have an increased risk of kidney cancer, and there is an excess risk of MM among patients with renal cell carcinoma (RCC). The objective of the current study was to analyze a series of 42 patients with both MM and RCC to identify clinical and pathologic features as well as risk factors of this association. Clinical and pathologic characteristics of 42 patients who developed both MM and RCC (the MM + RCC series) were compared with 2 published series in each cancer alone: a series of 293 patients with MM (MM series) and a series of 1527 patients with RCC (RCC series). RCC was diagnosed concomitantly or after MM in 83% of patients in the MM + RCC series. Those patients displayed a high proportion of asymptomatic RCC at diagnosis (70%) and a higher frequency of stage I tumors (61%) than patients in the RCC series. Compared with the MM series, patients in the MM + RCC series more often were men, had a higher frequency of blond/red hair, had poor tanning ability, and had a higher number of nevi. In addition, patients in the MM + RCC series had a high aggregation of other malignancies (mainly skin cancers) and a significantly higher frequency of family history of MM (P = .005). Only 2 cyclin-dependent kinase 2A gene (CDKN2A) germline mutations were identified among patients in the MM + RCC series who also were members of MM-prone families. The high aggregation of cancers among patients in the MM + RCC series and the familial clustering of MM argued for a genetic predisposition that may be partly independent of CDKN2A.
    Cancer 12/2010; 116(24):5716-24. · 5.20 Impact Factor
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    ABSTRACT: a clinical study of 14 patients presenting both malignant melanoma and HIV infection, and analysis of the literature to determine the frequency and specific features of this association. ten men and four women of median age 43 years were included. In 50% of cases, the primary melanoma consisted of spreading superficial melanoma with a mean Breslow thickness of 2.83 mm. In two cases, regional lymph node metastasis was discovered but with no primary melanoma being identified. HIV infection was already documented on diagnosis of melanoma in 11 cases, and it was discovered in three cases at the time of surgery for melanoma (treatment of the primary melanoma in two cases, and in one case, regional lymph node dissection two years after the initial diagnosis). Eight patients died within a mean period of 39 months, with melanoma being the cause of death in six cases. Following relapse of melanoma, the course of the disease was severe, with mean stage IV survival of 3.6 months. No response to chemotherapy was observed where such treatment was feasible. the presence of HIV appears to be an aggravating factor for the outcome of metastatic melanoma. our study suggests the importance of clinical examination of pigmented lesions in HIV patients in order to ensure early identification of melanoma.
    Annales de Dermatologie et de Vénéréologie 12/2010; 137(12):769-74. · 0.60 Impact Factor

Publication Stats

494 Citations
218.25 Total Impact Points

Institutions

  • 2008–2013
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2007–2012
    • Paris Diderot University
      Lutetia Parisorum, Île-de-France, France
    • Institut de Cancérologie Gustave Roussy
      • Department of Radiotherapy
      Île-de-France, France
  • 2006–2011
    • Hôpital Bichat - Claude-Bernard (Hôpitaux Universitaires Paris Nord Val de Seine)
      • Service de Dermatologie
      Paris, Ile-de-France, France
  • 2010
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2001–2004
    • Hôpital Henri Mondor (Hôpitaux Universitaires Henri Mondor)
      • Service de Dermatologie
      Créteil, Île-de-France, France