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Melanoma: HELP
Articles by Jean François Emile
Based on 16 articles published since 2009
(Why 16 articles?)
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Between 2009 and 2019, J. F. Emile wrote the following 16 articles about Melanoma.
 
+ Citations + Abstracts
1 Guideline French updated recommendations in Stage I to III melanoma treatment and management. 2017

Guillot, B / Dalac, S / Denis, M G / Dupuy, A / Emile, J F / De La Fouchardiere, A / Hindie, E / Jouary, T / Lassau, N / Mirabel, X / Piperno Neumann, S / De Raucourt, S / Vanwijck, R. ·Dermatology Department, CHU Montpellier. · Dermatology Department, CHU Dijon. · Laboratory of Biochemistry, CHU Nantes. · Dermatology Department, CHU Rennes. · Laboratory of Pathology, AP-HP Ambroise Paré Hospital, Boulogne, France. · Laboratory of Pathology, Centre Léon Bérard Lyon. · Department of Nuclear medicine, CHU Bordeaux. · Dermatology Department, CH Pau. · Department of Radiology, Institut Gustave Roussy Villejuif. · Department of Radiotherapy, Centre Oscar Lambret Lille. · Institut Curie, Paris, France. · 1 Avenue du 6 Juin, 1945, 14000 Caen, France. · Louvain Catholic University, Brussels, Belgium. ·J Eur Acad Dermatol Venereol · Pubmed #28120528.

ABSTRACT: As knowledge continues to develop, regular updates are necessary concerning recommendations for practice. The recommendations for the management of melanoma stages I to III were drawn up in 2005. At the request of the Société Française de Dermatologie, they have now been updated using the methodology for recommendations proposed by the Haute Autorité de Santé in France. In practice, the principal recommendations are as follows: for staging, it is recommended that the 7th edition of AJCC be used. The maximum excision margins have been reduced to 2 cm. Regarding adjuvant therapy, the place of interferon has been reduced and no validated emerging medication has yet been identified. Radiotherapy may be considered for patients in Stage III at high risk of relapse. The sentinel lymph node technique remains an option. Initial examination includes routine ultrasound as of Stage II, with other examinations being optional in stages IIC and III. A shorter strict follow-up period (3 years) is recommended for patients, but with greater emphasis on imaging.

2 Guideline [Update to the recommendations for management of melanoma stages I to III]. 2016

Guillot, B / Dalac, S / Denis, M G / Dupuy, A / Emile, J-F / De La Fouchardière, A / Hindie, E / Jouary, T / Lassau, N / Mirabel, X / Piperno Neumann, S / De Raucourt, S / Vanwijck, R. ·Département de dermatologie, hôpital Saint-Éloi, CHU de Montpellier, 34295 Montpellier cedex 5, France. Electronic address: b-guillot@chu-montpellier.fr. · Service de dermatologie, hôpital du Bocage sud, CHU de Dijon, BP 1542, 21079 Dijon cedex, France. · Laboratoire de biochimie, institut de biologie, 9, quai Moncousu, 44093 Nantes cedex, France. · Service de dermatologie, CHU de Rennes, Rennes, France. · Service d'anatomie pathologique, CHU Ambroise-Paré-Boulogne, 92104 Boulogne cedex, France. · Centre anticancéreux Léon-Bérard, 28, rue Laennec, 69008 Lyon, France. · Service de médecine nucléire Sud et Pellegrin, CHU de Bordeaux, Bordeaux, France. · Service de médecine, centre hospitalier de Pau, 64000 Pau, France. · Service d'imagerie médicale, institut Gustave-Roussy, 94800 Villejuif, France. · Centre Oscar-Lambret, 3, rue Fréderic-Combemale, 59000 Lille, France. · Institut Curie, 26, rue d'Ulm, 75005 Paris, France. · 1, avenue du 6-Juin, 14000 Caen, France. · Université catholique de Louvain, 10, avenue Hippocrate, 1200 Bruxelles, Belgique. ·Ann Dermatol Venereol · Pubmed #27527567.

ABSTRACT: As knowledge continues to develop, regular updates are necessary concerning recommendations for practice. The recommendations for the management of melanoma stages I to III were drawn up in 2005. At the request of the Société Française de Dermatologie, they have now been updated using the methodology for recommendations proposed by the Haute Autorité de Santé. In practice, the principal recommendations are as follows: for staging, it is recommended that the 7th edition of AJCC be used. The maximum excision margins have been reduced to 2cm. Regarding adjuvant therapy, the place of interferon has been reduced and no validated emerging medication has yet been identified. Radiotherapy may be considered for patients in stage III at high risk of relapse. The sentinel lymph node technique remains an option. Initial examination includes routine ultrasound as of stage II, with other examinations being optional in stages IIC and III. A shorter strict follow-up period (3years) is recommended for patients, but with greater emphasis on imaging.

3 Guideline [Guidelines for stage I to III melanoma]. 2016

Guillot, Bernard / Dalac, Sophie / Denis, Marc / Dupuy, Alain / Emile, Jean François / De La Fouchardiere, Arnaud / Hindie, Elif / Jouary, Thomas / Lassau, Nathalie / Mirabel, Xavier / Piperno Neumann, Sophie / De Raucourt, Sixtine / Vanwijck, Romain. ·Département de dermatologie, hôpital Saint-Eloi, CHU de Montpellier, 34295 Montpellier cedex 5, France. Electronic address: b-guillot@chu-montpellier.fr. · Service de dermatologie, hôpital du Bocage sud, CHU de Dijon, BP 1542, 21079 Dijon cedex, France. · Laboratoire de biochimie, institut de biologie, 9, quai Moncousu, 44093 Nantes cedex, France. · Service de dermatologie, CHU de Rennes, Rennes, France. · Service d'anatomie pathologique, CHU Ambroise-Paré Boulogne, 92104 Boulogne cedex, France. · Centre anticancéreux Léon-Bérard, 28, rue Laennec, 69008 Lyon, France. · Service de médecine nucléire sud et pellegrin, CHU de Bordeaux, Bordeaux, France. · Service de médecine, CH de Pau, 64000 Pau, France. · Service d'imagerie médicale, institut Gustave-Roussy, 94800 Villejuif, France. · Centre Oscar-Lambret, 3, rue Fréderic-Combemale, 59000 Lille, France. · Institut Curie, 26, rue d'Ulm, 75005 Paris, France. · Sixtine, 1, avenue du 6 juin, 14000 Caen, France. · Université catholique de Louvain, avenue Hippocrate, 10 B-1200 Bruxelles, Belgique. ·Bull Cancer · Pubmed #27456259.

ABSTRACT: -- No abstract --

4 Clinical Trial Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF(V600E)-mutated Erdheim-Chester disease. 2015

Haroche, Julien / Cohen-Aubart, Fleur / Emile, Jean-François / Maksud, Philippe / Drier, Aurélie / Tolédano, Dan / Barete, Stéphane / Charlotte, Frédéric / Cluzel, Philippe / Donadieu, Jean / Benameur, Neïla / Grenier, Philippe A / Besnard, Sophie / Ory, Jean-Paul / Lifermann, François / Idbaih, Ahmed / Granel, Brigitte / Graffin, Bruno / Hervier, Baptiste / Arnaud, Laurent / Amoura, Zahir. ·Julien Haroche, Fleur Cohen-Aubart, Philippe Maksud, Aurélie Drier, Dan Tolédano, Stéphane Barete, Frédéric Charlotte, Philippe Cluzel, Neïla Benameur, Philippe A. Grenier, Ahmed Idbaih, Baptiste Hervier, Laurent Arnaud, and Zahir Amoura, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière · Philippe Maksud, Stéphane Barete, Frédéric Charlotte, Philippe Cluzel, Philippe A. Grenier, Ahmed Idbaih, Julien Haroche, Fleur Cohen-Aubart, Baptiste Hervier, Laurent Arnaud, and Zahir Amoura, Paris VI University Pierre et Marie Curie · Jean Donadieu, AP-HP, Hôpital Trousseau, French National Center for Histiocytosis, Paris · Jean-François Emile, EA4340-BCOH, Versailles University, and AP-HP, Hôpital Ambroise Paré, Boulogne · Sophie Besnard, Centre Hospitalier Universitaire de Rennes, Pontchaillou University Hospital, Rennes Cedex · Jean-Paul Ory, Centre Hospitalier Régional de Vesoul, Vesoul · François Lifermann, Hôpital de Dax-Côte d'Argent, Dax · Brigitte Granel, Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Marseille · and Bruno Graffin, Hôpital d'Instruction des Armées Legouest, Metz, France. ·J Clin Oncol · Pubmed #25422482.

ABSTRACT: PURPOSE: Histiocytoses are rare disorders with heterogeneous prognosis. BRAF(V600E) mutations have been observed in half of patients with Langerhans cell histiocytosis (LCH) and in 50% to 100% of patients with Erdheim-Chester disease (ECD) patients. We recently reported short-term efficacy of a BRAF inhibitor (vemurafenib) in three patients with multisystemic ECD. PATIENTS AND METHODS: Vemurafenib was given to eight patients with multisystemic ECD with CNS and/or cardiac involvement. All patients were refractory to first-line treatment and harbored a BRAF(V600E) mutation. Four patients also had LCH lesions. Positron emission tomography (PET) scan response at month 6 was used as the main evaluation criterion. Secondary evaluation criteria were comparison at baseline and at last visit of PET and of cardiovascular and cerebral infiltrations (computed tomography scan and magnetic resonance imaging [MRI]). RESULTS: All patients were partial metabolic responders at 6 months of vemurafenib, and the median reduction in maximum standardized uptake value was 63.5% (range, 41.3% to 86.9%). Evaluation of cardiac and aortic infiltrations showed that seven patients had a partial response and one patient had stable disease according to surface measurements derived from RECIST criteria. The four patients with infratentorial CNS infiltration had an objective decrease of the lesions on MRI. All patients had an improvement of general symptoms and a persistent response to vemurafenib, with a median follow-up time of 10.5 months (range, 6 to 16 months). Skin adverse effects were frequent and severe. CONCLUSION: Vemurafenib has an objective and sustained efficacy in BRAF(V600E)-mutated ECD as second-line therapy. In contrast to melanoma, no resistance has emerged to date after 6 to 16 months.

5 Article Variation of mutant allele frequency in NRAS Q61 mutated melanomas. 2017

Hélias-Rodzewicz, Zofia / Funck-Brentano, Elisa / Terrones, Nathalie / Beauchet, Alain / Zimmermann, Ute / Marin, Cristi / Saiag, Philippe / Emile, Jean-François. ·Research Unit EA4340 Biomarkers in Cancerology and Hemato Oncology, Versailles SQY University, Paris-Saclay University, 9, Avenue Charles de Gaulle, 92104, Boulogne-Billancourt, France. zofia.helias-ext@aphp.fr. · Department of Pathology, Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, France. zofia.helias-ext@aphp.fr. · Research Unit EA4340 Biomarkers in Cancerology and Hemato Oncology, Versailles SQY University, Paris-Saclay University, 9, Avenue Charles de Gaulle, 92104, Boulogne-Billancourt, France. · Department of Dermatology, Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, France. · Department of Public Health, Ambroise Paré Hospital Ap-HP, Boulogne-Billancourt, France. · Department of Pathology, Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, France. · Research Unit EA4340 Biomarkers in Cancerology and Hemato Oncology, Versailles SQY University, Paris-Saclay University, 9, Avenue Charles de Gaulle, 92104, Boulogne-Billancourt, France. jean-francois.emile@uvsq.fr. · Department of Pathology, Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, France. jean-francois.emile@uvsq.fr. ·BMC Dermatol · Pubmed #28668077.

ABSTRACT: BACKGROUND: Somatic mutations of BRAF or NRAS activating the MAP kinase cell signaling pathway are present in 70% of cutaneous melanomas. The mutant allele frequency of BRAF V600E (M%BRAF) was recently shown to be highly heterogeneous in melanomas. The present study focuses on the NRAS Q61 mutant allele frequency (M%NRAS). METHODS: Retrospective quantitative analyze of 104 NRAS mutated melanomas was performed using pyrosequencing. Mechanisms of M%NRAS imbalance were studied by fluorescence in situ hybridization (FISH) and microsatellite analysis. RESULTS: M%NRAS was increased in 27.9% of cases. FISH revealed that chromosome 1 instability was the predominant mechanism of M%NRAS increase, with chromosome 1 polysomy observed in 28.6% of cases and intra-tumor cellular heterogeneity with copy number variations of chromosome 1/NRAS in 23.8%. Acquired copy-neutral loss of heterozygosity (LOH) was less frequent (19%). However, most samples with high M%NRAS had only one copy of NRAS locus surrounding regions suggesting a WT allele loss. Clinical characteristics and survival of patients with either <60% or ≥60% of M%NRAS were not different. CONCLUSION: As recently shown for M%BRAF, M%NRAS is highly heterogeneous. The clinical impacts of high M%NRAS should be investigated in a larger series of patients.

6 Article Reply to "Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma" by Mesbah Ardakani et al. 2017

Boespflug, Amélie / Funck-Brentano, Elisa / Hélias-Rodzewicz, Zofia / Maucort-Boulch, Delphine / Beauchet, Alain / Bringuier, Pierre-Paul / Dumontet, Charles / Emile, Jean-François / Saiag, Philippe / Dalle, Stéphane. ·Dermatology Unit, Hospices Civils de Lyon, Pierre-Bénite, France. · Cancer Research Center of Lyon, Claude Bernard Lyon-1 University, INSERM1052, CNRS 5286, Lyon,  France. · Pathology Department, Hospices Civiles de Lyon, Pierre-Bénite, France. · Department of Dermatology, Ambroise Paré Hospital (AP-HP), Boulogne-Billancourt, France. · Research Unit EA 4340 "Biomarkers in cancerology and in hemato-oncology, University of Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Boulogne-Billancourt, France. · Laboratoire de Biométrie et Biologie Evolutive, Biostatistique-Santé team, CNRS UMR 5558, Université Lyon 1, Villeurbanne, France. · Department of Pathology, Ambroise Paré Hospital (AP-HP), Boulogne-Billancourt, France. · Department of Public Health, Ambroise Paré Hospital (AP-HP), Boulogne-Billancourt, France. · Medical Oncology Department, Institut de Cancerologie des Hospices Civils de Lyon, Pierre-Bénite, France. ·Pigment Cell Melanoma Res · Pubmed #28627072.

ABSTRACT: -- No abstract --

7 Article Increase in NRAS mutant allele percentage during metastatic melanoma progression. 2016

Funck-Brentano, Elisa / Hélias-Rodzewicz, Zofia / Longvert, Christine / Mokhtari, Karima / Saiag, Philippe / Emile, Jean-François. ·Research Unit EA 4340 'Biomarkers in cancerology and in hemato-oncology', Université de Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Boulogne-Billancourt, France. · Department of Dermatology, AP-HP Ambroise Paré Hospital, Boulogne-Billancourt, France. · Department of Pathology, AP-HP Ambroise Paré Hospital, Boulogne-Billancourt, France. · Department of Neuropathology, AP-HP Pitié-Salpétrière Hospital, Paris, France. ·Exp Dermatol · Pubmed #26990546.

ABSTRACT: One-fifth of cutaneous melanomas have dominant gain-of-function mutations of the NRAS oncogene. We report the first two cases of increasing NRAS mutant allele frequency in melanoma metastases and show that the chromosomal mechanism of this homozygosity is an increased polysomy of chromosome 1. We observed an increase in NRAS mutant allele percentage (NRAS-MA%) in the metastatic melanoma progression from 2 patients with melanomas harbouring a NRAS mutation (p.Q61K in case 1 and p.Q61R in case 2). In case 1, we observed a NRAS-MA% increase from 18% within the first metastatic node to 81%, 92% and 85% respectively in the three subsequent metastases: lymph node, brain and subcutaneous metastases biopsied 1, 6 and 17 months, respectively, after the initial lymph node biopsy. In case 2, we observed an increase in NRAS-MA% from 40% within the primary melanoma to 63% within the metastatic lymph node. FISH analysis showed the same results in both cases: a frequent polysomy of chromosome 1 in metastasis samples with NRAS mutant allele percentage >60%, while most cells were disomic in the samples with well-balanced heterozygous mutations. The percentage of NRAS mutant allele may increase during metastatic progression and may be associated with chromosomal instability. Further studies are needed to evaluate the prognostic impact of the NRAS homozygous status and/or polyploidy in metastatic cutaneous melanomas.

8 Article Variations of BRAF mutant allele percentage in melanomas. 2015

Hélias-Rodzewicz, Zofia / Funck-Brentano, Elisa / Baudoux, Laure / Jung, Chan Kwon / Zimmermann, Ute / Marin, Cristi / Clerici, Thierry / Le Gall, Catherine / Peschaud, Frédérique / Taly, Valérie / Saiag, Philippe / Emile, Jean-François. ·EA4340, Versailles University, Boulogne-Billancourt, France. zofia.helias@aphp.fr. · Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France. zofia.helias@aphp.fr. · EA4340, Versailles University, Boulogne-Billancourt, France. elisa.funck-brentano@aphp.fr. · Department of Dermatology, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France. elisa.funck-brentano@aphp.fr. · EA4340, Versailles University, Boulogne-Billancourt, France. laure.baudoux@yahoo.fr. · Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea. ckjung@catholic.ac.kr. · EA4340, Versailles University, Boulogne-Billancourt, France. us.zimmermann@gmail.fr. · Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France. us.zimmermann@gmail.fr. · EA4340, Versailles University, Boulogne-Billancourt, France. cristi.marin@aphp.fr. · Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France. cristi.marin@aphp.fr. · EA4340, Versailles University, Boulogne-Billancourt, France. thierryclerici@noos.fr. · Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France. thierryclerici@noos.fr. · EA4340, Versailles University, Boulogne-Billancourt, France. legall.catherine@voila.fr. · Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France. legall.catherine@voila.fr. · EA4340, Versailles University, Boulogne-Billancourt, France. frederique.peschaud@aphp.fr. · Department of Surgery, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France. frederique.peschaud@aphp.fr. · INSERM UMR-S1147, University Paris Sorbonne Cite, Paris, France. valerie.taly@parisdescartes.fr. · EA4340, Versailles University, Boulogne-Billancourt, France. philippe.saiag@uvsq.fr. · Department of Dermatology, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France. philippe.saiag@uvsq.fr. · EA4340, Versailles University, Boulogne-Billancourt, France. jean-francois.emile@uvsq.fr. · Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France. jean-francois.emile@uvsq.fr. ·BMC Cancer · Pubmed #26141748.

ABSTRACT: BACKGROUND: BRAF mutations are present in 40% of human skin melanomas. Mutated tumors with an increased percentage of BRAF mutant alleles (BRAF-M%) may have a better response to RAF/MEK inhibitors. We evaluated the BRAF-M% in melanomas, and the genetic causes of its variation. METHODS: BRAF-M% was quantified by pyrosequencing, real-time PCR (rtPCR) and/or picoliter-droplet PCR (dPCR). BRAF mutant expression was detected by immunohistochemistry. Chromosomal alterations were analyzed with fluorescence in situ hybridization (FISH), and single nucleotide polymorphism (SNP) arrays. RESULTS: BRAF-M% quantification obtained with pyrosequencing was highly correlated (R = 0.94) with rtPCR, and with dPCR. BRAF-M% quantified from DNA and RNA were also highly correlated (R = 0.98). Among 368 samples with >80% tumor cells, 38.6% had a BRAF (V600E) mutation. Only 66.2% cases were heterozygous (BRAF-M% 30 to 60%). Increased BRAF-M% (>60%) was observed in 19% of cases. FISH showed a polysomy of chromosome 7 in 13.6%, 35.3% and 54.5% of BRAF wild-type, heterozygous and non-heterozygous BRAF-mutated samples, respectively (P < 0.005). Amplification (5.6%) and loss (3.2%) of BRAF locus were rare. By contrast, chromosome 7 was disomic in 27/27 BRAF-mutated nevi. CONCLUSIONS: BRAF-M% is heterogeneous and frequently increased in BRAF-mutant melanomas. Aneuploidy of chromosome 7 is more frequent in BRAF mutant melanomas, specifically in those with high BRAF-M%.

9 Article Detection of BRAF V600 mutations in melanoma: evaluation of concordance between the Cobas® 4800 BRAF V600 mutation test and the methods used in French National Cancer Institute (INCa) platforms in a real-life setting. 2015

Mourah, Samia / Denis, Marc G / Narducci, Fabienne Escande / Solassol, Jérôme / Merlin, Jean-Louis / Sabourin, Jean-Christophe / Scoazec, Jean-Yves / Ouafik, L'Houcine / Emile, Jean-François / Heller, Remy / Souvignet, Claude / Bergougnoux, Loïc / Merlio, Jean-Philippe. ·Department of Pharmacology-Genetics, AP-HP, Saint-Louis Hospital, Paris, France; INSERM UMRS 976 Paris, F-75010, France. · Department of Biochemistry, Nantes University Hospital, Nantes, France. · Department of Molecular Biology and Biochemistry, Lille Regional University Hospital, Lille, France. · Department of Biology-Pathology, Montpellier University Hospital, Montpellier, France. · Department of Tumor Biology, Alexis Vautrin Center, Vandoeuvre les Nancy, France. · Department of Pathology-Cytopathology, Rouen University Hospital, Rouen, France. · Laboratory of Pathology and Cytopathology, Edouard Herriot Hospital, Lyon, France; Department of Biology and Pathology, Gustave Roussy Hospital, Villejuif, France. · Department of Cancer Biology, Marseille Nord University Hospital, Marseille, France. · Department of Pathology, Ambroise Paré Hospital, Boulogne-Billancourt, France. · Department of Microbiology and Molecular Biology, Colmar hospital, Colmar, France. · Roche, Boulogne-Billancourt, France. · Department of Tumor Biology, Bordeaux University Hospital, Bordeaux, France. ·PLoS One · Pubmed #25789737.

ABSTRACT: Vemurafenib is approved for the treatment of metastatic melanoma in patients with BRAF V600 mutation. In pivotal clinical trials, BRAF testing has always been done with the approved cobas 4800 BRAF test. In routine practice, several methods are available and are used according to the laboratories usual procedures. A national, multicenter, non-interventional study was conducted with prospective and consecutive collection of tumor samples. A parallel evaluation was performed in routine practice between the cobas 4800 BRAF V600 mutation test and home brew methods (HBMs) of 12 national laboratories, labelled and funded by the French National Cancer Institute (INCa). For 420 melanoma samples tested, the cobas method versus HBM showed a high concordance (93.3%; kappa = 0.86) in BRAF V600 genotyping with similar mutation rates (34.0% versus 35.7%, respectively). Overall, 97.4% and 98.6% of samples gave valid results using the cobas and HBM, respectively. Of the 185 samples strictly fulfilling the cobas guidelines, the concordance rate was even higher (95.7%; kappa = 0.91; 95%CI [0.85; 0.97]). Out of the 420 samples tested, 28 (6.7%) showed discordance between HBM and cobas. This prospective study shows a high concordance rate between the cobas 4800 BRAF V600 test and home brew methods in the routine detection of BRAF V600E mutations.

10 Article Immunohistochemistry as a potential tool for routine detection of the NRAS Q61R mutation in patients with metastatic melanoma. 2015

Ilie, Marius / Long-Mira, Elodie / Funck-Brentano, Elisa / Lassalle, Sandra / Butori, Catherine / Lespinet-Fabre, Virginie / Bordone, Olivier / Gay, Alexandre / Zahaf, Katia / Poissonnet, Gilles / Lacour, Jean-Philippe / Bahadoran, Philippe / Ballotti, Robert / Gros, Audrey / Dutriaux, Caroline / Saiag, Philippe / Merlio, Jean-Philippe / Vergier, Béatrice / Emile, Jean François / Hofman, Véronique / Hofman, Paul. ·Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France; Human Biobank BB-0033-00025, Pasteur Hospital, Nice, France. · Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France. · EA4340-Biomarqueurs en Cancérologie et Onco-Hématologie (BCOH), University of Versailles Saint-Quentin-en-Yvelines (SQY), Boulogne, France; Department of General and Oncologic Dermatology, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Boulogne, France. · Human Biobank BB-0033-00025, Pasteur Hospital, Nice, France. · Surgery Department, Comprehensive Cancer Center Antoine Lacassagne, Nice, France. · Dermatology Department, Archet II Hospital, Nice, France. · Dermatology Department, Archet II Hospital, Nice, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Team 1, University of Nice Sophia Antipolis, Nice, France. · Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Team 1, University of Nice Sophia Antipolis, Nice, France. · Pathology and Molecular Biology Departments, Centre Hospitalier Universitaire (CHU) and EA2406 University of Bordeaux, Bordeaux, France. · Department of Oncologic Dermatology, CHU Bordeaux, Bordeaux, France. · EA4340-Biomarqueurs en Cancérologie et Onco-Hématologie (BCOH), University of Versailles Saint-Quentin-en-Yvelines (SQY), Boulogne, France; Department of Pathology, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Boulogne, France. · Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France; Human Biobank BB-0033-00025, Pasteur Hospital, Nice, France. Electronic address: hofman.p@chu-nice.fr. ·J Am Acad Dermatol · Pubmed #25659223.

ABSTRACT: BACKGROUND: It can be useful to assess the NRAS mutation status in patients with metastatic melanoma because NRAS-activating mutations confer resistance to RAF inhibitors, and NRAS-mutated patients appear to be sensitive to mitogen-activated protein kinase (MEK) inhibitors. OBJECTIVE: We aimed to assess the diagnostic accuracy of an immunohistochemistry (IHC) approach using a novel anti-NRAS (Q61R) monoclonal antibody on formalin-fixed paraffin-embedded tissue samples from patients with metastatic melanoma. METHODS: We conducted a retrospective multicenter cohort study on 170 patients with metastatic melanoma. The automated IHC assay was performed using the SP174 clone, and compared with results of the molecular testing. RESULTS: Evaluation of a test cohort with knowledge of the mutation status established a specific IHC pattern for the mutation. In the independent blinded analysis of the remaining cases, the anti-NRAS (Q61R) antibody accurately identified all NRAS Q61R-mutated tumors, and demonstrated 100% sensitivity and specificity. LIMITATIONS: Limitations include retrospective design and lack of multicenter interobserver reproducibility. CONCLUSION: The NRAS (Q61R) IHC assay is reliable and specific for the evaluation of the Q61R mutation status in metastatic melanoma and may be an alternative to molecular biology in evaluation of metastatic melanoma in routine practice.

11 Article Detection of BRAF p.V600E Mutations in Melanoma by Immunohistochemistry Has a Good Interobserver Reproducibility. 2014

Marin, Cristi / Beauchet, Alain / Capper, David / Zimmermann, Ute / Julié, Catherine / Ilie, Marius / Saiag, Philippe / von Deimling, Andreas / Hofman, Paul / Emile, Jean-François. ·From units EA4340 (Drs Marin, Julié, and Emile) and EA4339 (Drs Beauchet, Zimmermann, and Saiag), Versailles SQY University, Boulogne, France · the Departments of Pathology (Drs Marin, Zimmermann, Julié, and Emile), Public Health (Dr Beauchet), and General and Oncologic Dermatology (Dr Saiag), Ambroise Pare Hospital, APHP, Boulogne, France · the Department of Neuropathology, Ruprecht-Karls-University Heidelberg, and Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany (Drs Capper and Deimling) · and the Laboratory of Clinical and Experimental Pathology, Pasteur Hospital and Medical School, Nice Sophia University, Nice, France (Drs Ilie and Hofman). ·Arch Pathol Lab Med · Pubmed #23651150.

ABSTRACT: CONTEXT: Assessment of BRAF p.V600E mutational status has become necessary for treatment of patients with metastatic melanoma. Detection of p.V600E mutation by immunohistochemistry was recently reported in several tumor types. OBJECTIVE: To evaluate the interobserver reproducibility of BRAF p.V600E detection by immunohistochemistry in melanoma. DESIGN: Immunohistochemistry with VE1 antibody was performed on metastatic melanomas of 67 patients. Staining interpretation was performed on digital image virtual slides of tissue microarrays. The p.V600E status was determined by 7 pathologists from 3 European laboratories, blinded for other interpretations and for molecular biology results. RESULTS: Melanomas had p.V600E (n = 30), p.V600K (n = 4), p.K601E (n = 1), p.600-601delinsE (n = 1), or no p.V600 mutations (n = 31). Staining of p.V600E within mutated cells was cytoplasmic and diffuse, and for each case the staining on the 3 tissue microarray cores was similar. In 53 cases (79.1%) the 7 pathologists had perfect concordance. Agreement of interobserver reproducibility was almost perfect (κ = 0.81 [0.77-0.85]). Only 2 false-positive responses (0.9%) were obtained. The specificities reported were 100% for 5 pathologists (two of whom previously trained for p.V600E interpretation), and 97% for 2 untrained pathologists. CONCLUSIONS: Detection of BRAF p.V600E mutation by immunohistochemistry in melanomas has an excellent interobserver reproducibility. Our results suggest that immunohistochemistry could be used as a first step for detection of BRAF p.V600E mutation, to identify patients with melanoma as candidates for BRAF inhibitors.

12 Article Improvement of the quality of BRAF testing in melanomas with nationwide external quality assessment, for the BRAF EQA group. 2013

Emile, Jean-François / Tisserand, Julie / Bergougnoux, Loic / Nowak, Frédérique / Faucher, Gladwys / Surel, Sylvie / Lamy, Aude / Lecorre, Delphine / Helias-Rodzewicz, Zofia / Hofman, Paul / Sabourin, Jean-Christophe / Laurent-Puig, Pierre / Anonymous1200772. ·EA4340, Versailles SQY University, Boulogne, France. jean-francois.emile@uvsq.fr. ·BMC Cancer · Pubmed #24119386.

ABSTRACT: BACKGROUND: Knowledge about tumour gene mutation status is essential for the treatment of increasing numbers of cancer patients, and testing quality has a major impact on treatment response and cost. In 2012, 4,629 tests for BRAF p.V600 were performed in France, in patients with melanomas. METHODS: Two batches of unstained melanoma sections were sent, in May and November 2012, to the 46 laboratories supported by the French National Institute of Cancer (INCa). An external quality assessment (EQA) evaluated mutation status, response times and compliance with INCa recommendations. RESULTS: All the French laboratories involved in testing participated in the EQA. Fourteen different methods were used to detect BRAF mutations, most consisting of combinations of in-house techniques. False responses were noted in 25/520 cases (4.8%), 11 of which concerned confusion between p.V600E and p.V600K. Thus, 2.7% of responses would have led to inappropriate treatment. Within six months, mean response times decreased from 22 to 12 days (P<0.001), and the percentage of samples evaluated by a pathologist for tumour cell content increased, from 75.2% to 96.9% (P<0.001). CONCLUSION: Despite the use of non-certified methods, the false response rate was low. Nationwide EQA can improve the quality of molecular pathology tests on tumours.

13 Article Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. 2013

Haroche, Julien / Cohen-Aubart, Fleur / Emile, Jean-François / Arnaud, Laurent / Maksud, Philippe / Charlotte, Frédéric / Cluzel, Philippe / Drier, Aurélie / Hervier, Baptiste / Benameur, Neïla / Besnard, Sophie / Donadieu, Jean / Amoura, Zahir. ·Department of Internal Medicine and French Reference Center for Rare Auto-immune and Systemic Diseases, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Paris, France. julien.haroche@psl.aphp.fr ·Blood · Pubmed #23258922.

ABSTRACT: Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAFV600E gain-of-function mutations have been observed in 57% of cases of Langerhans cell histiocytosis (LCH) and 54% of cases of Erdheim-Chester disease (ECD), but not in other types of histiocytoses. Targeted therapy with an inhibitor of mutated BRAF (vemurafenib) improves survival of patients with melanoma. Here, we report vemurafenib treatment of 3 patients with multisystemic and refractory ECD carrying the BRAFV600E mutation; 2 also had skin or lymph node LCH involvement. The patients were assessed clinically, biologically (CRP values), histologically (skin biopsy), and morphologically (positron emission tomography [PET], computed tomography and magnetic resonance imaging). For all patients, vemurafenib treatment led to substantial and rapid clinical and biologic improvement, and the tumor response was confirmed by PET, computed tomography, and/or magnetic resonance imaging 1 month after treatment initiation. For the first patient treated, the PET response increased between months 1 and 4 of treatment. The treatment remained effective after 4 months of follow-up although persistent disease activity was still observed. Treatment with vemurafenib, a newly approved BRAF inhibitor, should be considered for patients with severe and refractory BRAFV600E histiocytoses, particularly when the disease is life-threatening.

14 Article Detection of BRAF p.V600E mutations in melanomas: comparison of four methods argues for sequential use of immunohistochemistry and pyrosequencing. 2013

Colomba, Emeline / Hélias-Rodzewicz, Zofia / Von Deimling, Andreas / Marin, Cristi / Terrones, Nathalie / Pechaud, Dominique / Surel, Sylvie / Côté, Jean-François / Peschaud, Frédérique / Capper, David / Blons, Hélène / Zimmermann, Ute / Clerici, Thierry / Saiag, Philippe / Emile, Jean-François. ·EA4340, University of Versailles, Boulogne, France. ·J Mol Diagn · Pubmed #23159108.

ABSTRACT: BRAF p.V600 mutation detection recently became necessary to treat metastatic melanoma patients with vemurafenib. This study compares different methods of detection of BRAF mutations. Melanoma samples from 111 patients were analyzed for BRAF mutations, and for 89 of them, results were obtained with the four following methods: Sanger sequencing, real-time PCR, immunohistochemistry, and pyrosequencing. All samples contained at least 60% of tumor cells. Directional Sanger sequencing of PCR products failed to detect 3 of 40 p.V600E-mutated cases (7.5%) (sensitivity, 92.5%; 95% CI, 78.5% to 98.0%). BRAF p.V600E-specific real-time PCR identified 39 of 40 p.V600E-mutated cases (97.6%) (sensitivity, 97.5%; 95% CI, 87.1% to 99.6%) and all 39 wild-type (WT) cases and surprisingly was also positive for 6/6 p.V600K (specificity, 87.8%; 95% CI, 75.8% to 94.3%). However, other mutations, p.V600R (n = 1), p.K601E (n = 2), and p.600_601delinsE (n = 1), were not detected. Immunohistochemistry with VE1, specific for p.V600E, identified all p.V600E and WT cases (sensitivity, 100%; 95% CI, 91.2% to 100%) but was negative for all other BRAF mutations. Pyrosequencing successfully identified all WT and mutated cases. Immunohistochemistry is highly specific for p.V600E, and could be used as a first-line method, as is currently performed for HER2 amplification detection. Pyrosequencing proved to be the most efficient method to detect BRAF mutations in melanomas and could be performed on VE1-negative or uninterpretable cases.

15 Article Prognostic value of BRAF(V⁶⁰⁰) mutations in melanoma patients after resection of metastatic lymph nodes. 2012

Moreau, Stéphanie / Saiag, Philippe / Aegerter, Philippe / Bosset, Daphné / Longvert, Christine / Hélias-Rodzewicz, Zofia / Marin, Cristi / Peschaud, Frédérique / Chagnon, Sophie / Zimmermann, Utte / Clerici, Thierry / Emile, Jean-François. ·Department of Pathology, Ambroise Paré Hospital, Boulogne, France. ·Ann Surg Oncol · Pubmed #22772867.

ABSTRACT: PURPOSE: BRAF (V600) mutations are frequent in melanomas, and BRAF(V600)-targeted therapy have dramatic, but often transitory, efficacy in stage IV patients. Prognosis of patients with American Joint Committee on Cancer (AJCC) stage III melanoma is heterogeneous. We aimed to determine the overall survival (OS) of stage III patients with a nodal deposit of ≥2 mm according to BRAF (V600) mutations and other previously reported prognostic criteria. METHODS: This retrospective study included 105 consecutive patients with stage III cutaneous melanomas. Most patients underwent a prospective follow-up. BRAF (V600) mutations were detected by sequencing and pyrosequencing of DNA in samples containing >60 % melanoma cells. RESULTS: BRAF mutations (p.V600E and p.V600K in 83 and 14 % of cases, respectively) were detected in 40 % of the patients. For patients with and without BRAF mutations, death occurred in 83.3 and 60.3 %, with a median OS of 1.4 and 2.8 years, respectively. Patient age, primary melanoma ulceration, number of invaded lymph nodes, AJCC staging at study entry, and BRAF status were linked to OS in the univariate analysis. The only characteristics associated with OS in the multivariate analysis were number of invaded lymph nodes (P = 0.005, hazard ratio 2.2, 95 % confidence interval 1.3-3.9) and BRAF status (P = 0.005, hazard ratio 1.9, 95 % confidence interval 1.2-3.1). CONCLUSIONS: BRAF (V600) status could be used to stage melanoma patients with nodal deposits. Our results may also help to plan adjuvant trials in these patients, for whom the low tumor load may induce longer efficacy of BRAF-targeted therapies.

16 Minor Usefulness of immunocytochemistry for the detection of the BRAF(V600E) mutation in circulating tumor cells from metastatic melanoma patients. 2013

Hofman, Véronique / Ilie, Marius / Long-Mira, Elodie / Giacchero, Damien / Butori, Catherine / Dadone, Bérengère / Selva, Eric / Tanga, Virginie / Passeron, Thierry / Poissonnet, Gilles / Emile, Jean-François / Lacour, Jean-Philippe / Bahadoran, Philippe / Hofman, Paul. · ·J Invest Dermatol · Pubmed #23303445.

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