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Melanoma: HELP
Articles by Sophie Piperno Neumann
Based on 31 articles published since 2008
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Between 2008 and 2019, S. Piperno Neumann wrote the following 31 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
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 Review Upcoming translational challenges for uveal melanoma. 2015

Amirouchene-Angelozzi, Nabil / Schoumacher, Marie / Stern, Marc-Henri / Cassoux, Nathalie / Desjardins, Laurence / Piperno-Neumann, Sophie / Lantz, Olivier / Roman-Roman, Sergio. ·Candiolo Cancer Institute - Fondazione Piemontese per la Ricerca sul Cancro (FPRC), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino 10060, Italy. · Department of Translational Research, Institut Curie, 26 rue d'Ulm, Paris 75005, France. · INSERM U830, Institut Curie, 26 rue d'Ulm, Paris 75005, France. · Department of Ophthalmological Oncology, Institut Curie, 26 rue d'Ulm, Paris 75005, France. · Department of Medical Oncology, Institut Curie, 26 rue d'Ulm, Paris 75005, France. · INSERM U932, Institut Curie, 26 rue d'Ulm, Paris 75005, France. ·Br J Cancer · Pubmed #26505679.

ABSTRACT: The past few years have witnessed major advances in the understanding of the molecular landscape of uveal melanoma (UM). The discovery of a mutational background that is completely different from the one of skin melanoma has granted to UM a stand-alone status. The absence of effective therapy for metastatic disease offers now a chessboard for targeted therapy but at the same time urges preclinical science to develop accordingly, to guide the use of economical resources to the best profit of patients. This review describes the current knowledge on the biology of this disease and discusses the challenges that must be undertaken to translate this knowledge into real benefit for patients.

5 Review [Advances in uveal melanoma]. 2014

Piperno-Neumann, Sophie / Desjardins, Laurence. · ·Rev Prat · Pubmed #24649554.

ABSTRACT: -- No abstract --

6 Review Therapeutic options in metastatic uveal melanoma. 2012

Mariani, Pascale / Servois, Vincent / Piperno-Neumann, Sophie. ·Department of Surgery, Institut Curie, Paris, France. pascale.mariani@curie.net ·Dev Ophthalmol · Pubmed #22042020.

ABSTRACT: Systemic treatments for metastatic uveal melanoma patients give poor results. R0 resection of liver metastases showed a real benefit in survival in a very highly selected population. Based on our multivariate analysis, we propose surgical treatment to metastatic patients with time from diagnosis of uveal melanoma to liver metastases > 24 months, number of liver metastases ≤4 lesions, and absence of detectable miliary disease. Liver MRI is currently the best imaging method in this context even if miliary disease is still difficult to diagnose. Molecular and chromosomal classification strongly predicting metastatic death has to be used to identify genetic profiles and pathways involved in the pathogenesis of uveal melanoma leading to new targeted therapeutic strategies.

7 Clinical Trial Sorafenib in metastatic uveal melanoma: efficacy, toxicity and health-related quality of life in a multicentre phase II study. 2016

Mouriaux, F / Servois, V / Parienti, J J / Lesimple, T / Thyss, A / Dutriaux, C / Neidhart-Berard, E M / Penel, N / Delcambre, C / Peyro Saint Paul, L / Pham, A D / Heutte, N / Piperno-Neumann, S / Joly, F. ·Service d'ophtalmologie (Department of Ophthalmology), CHU Rennes, 35033 Rennes, France. · Faculté de Médecine (Faculty of Medicine), Université de Rennes 1, F35043 Rennes, France. · Centre universitaire d'ophtalmologie-Recherche (Ophthalmology-Research University Centre), Hôpital du Saint-Sacrement, Centre de Recherche du CHU de Québec (CHU Quebec Research Centre), G1S 4L8 Québec, Canada. · CHU Caen, F-14033 Caen France. · Institut Curie, Département d'Imagerie Médicale (Curie Institute, Department of Medical Imaging), F-75005 Paris, France. · Centre Eugène Marquis, F-35000 Rennes, France. · Centre Antoine Lacassagne, F-06000 Nice, France. · Service Dermatologie (Dermatology Department), CHU de Bordeaux, F-33000 Bordeaux, France. · Centre Léon Bérard, F-69000 Lyon, France. · Centre Oscar Lambret, F-59000 Lille, France. · Centre François Baclesse, F-14000 Caen France. · Département d'Oncologie Médicale, Institut Curie, (Department of Medical Oncology, Curie Institute), 75005 Paris, France. ·Br J Cancer · Pubmed #27253171.

ABSTRACT: BACKGROUND: The aim of the study was to analyse efficacy, safety, and health-related quality of life (HRQoL) for sorafenib treatment in patients with metastatic uveal melanoma. METHODS: A multicentre, single-arm phase II trial was conducted. The primary objective was to determine the non-progression rate (RECIST) at 24 weeks for patients receiving sorafenib at a dose of 800 mg per day. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and HRQoL. RESULTS: Thirty-two patients were included. Ten patients showed non-progression at 24 weeks (31.2%) without objective tumour responses. The estimated 24-week PFS was 31.2% (95% CI: 14.8%-47.6%) and the estimated 24-week OS was 62.5% (95% CI: 45.4%-79.6%). Ten patients (34.3%) had at least one grade 3 or 4 adverse reaction and 12 patients (41.4%) required dose modifications due to toxicity. At 24 weeks, no patient had an improvement in global HRQoL and 87.5% experienced a permanent increase in physical fatigue. CONCLUSIONS: Sorafenib demonstrated non-progression at 24 weeks in 31.2% of patients. However, 41.4% of patients required dose modifications due to toxicity and no improvement in HRQoL was demonstrated.

8 Clinical Trial Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial. 2014

Leyvraz, S / Piperno-Neumann, S / Suciu, S / Baurain, J F / Zdzienicki, M / Testori, A / Marshall, E / Scheulen, M / Jouary, T / Negrier, S / Vermorken, J B / Kaempgen, E / Durando, X / Schadendorf, D / Gurunath, R Karra / Keilholz, U. ·Oncology Department, University Hospital, Lausanne, Switzerland. ·Ann Oncol · Pubmed #24510314.

ABSTRACT: BACKGROUND: In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM. PATIENTS AND METHODS: Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m(2) on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points. RESULTS: Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths. CONCLUSION: HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. EUDRACT NUMBER AND CLINICALTRIALSGOV IDENTIFIER: 2004-002245-12 and NCT00110123.

9 Article Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors. 2018

Rodrigues, Manuel / Mobuchon, Lenha / Houy, Alexandre / Fiévet, Alice / Gardrat, Sophie / Barnhill, Raymond L / Popova, Tatiana / Servois, Vincent / Rampanou, Aurore / Mouton, Aurore / Dayot, Stéphane / Raynal, Virginie / Galut, Michèle / Putterman, Marc / Tick, Sarah / Cassoux, Nathalie / Roman-Roman, Sergio / Bidard, François-Clément / Lantz, Olivier / Mariani, Pascale / Piperno-Neumann, Sophie / Stern, Marc-Henri. ·Institut Curie, PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, 75248, France. · Department of Medical Oncology, Institut Curie, PSL Research University, Paris, 75248, France. · Department of Genetics, Institut Curie, PSL Research University, Paris, 75248, France. · Department of Biopathology, Institut Curie, PSL Research University, Paris, 75248, France. · Faculty of Medicine, University of Paris Descartes, Paris, 75006, France. · Department of Medical Imaging, Institut Curie, PSL Research University, Paris, 75248, France. · Institut Curie, PSL Research University, Laboratory of Circulating Tumor Biomarkers, SiRIC, Paris, 75248, France. · Institut Curie, PSL Research University, INSERM CIC-BT 1428, Paris, 75248, France. · Institut Curie, PSL Research University, INSERM U830 and Institut Curie Genomics of Excellence (ICGex) Platform, Paris, 75248, France. · Institut Curie, PSL Research University, Biological Resource Center, Paris, 75248, France. · Department of Pathology, Quinze-Vingts National Ophthalmology Hospital, Paris, 75012, France. · Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital, Paris, 75012, France. · Department of Ocular Oncology, Institut Curie, PSL Research University, Paris, 75248, France. · Department of Translational Research, Institut Curie, PSL Research University, Paris, 75248, France. · UVSQ, Paris Saclay University, Saint-Quentin, 78035, France. · Department of Surgical Oncology, Institut Curie, PSL Research University, Paris, 75248, France. · Institut Curie, PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, 75248, France. marc-henri.stern@curie.fr. · Department of Genetics, Institut Curie, PSL Research University, Paris, 75248, France. marc-henri.stern@curie.fr. ·Nat Commun · Pubmed #29760383.

ABSTRACT: Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity. This MBD4-related hypermutator phenotype may explain unexpected responses to immune checkpoint inhibitors.

10 Article Nanobodies against surface biomarkers enable the analysis of tumor genetic heterogeneity in uveal melanoma patient-derived xenografts. 2017

Crépin, Ronan / Gentien, David / Duché, Angeline / Rapinat, Audrey / Reyes, Cecile / Némati, Fariba / Massonnet, Gérald / Decaudin, Didier / Djender, Selma / Moutel, Sandrine / Desrumeaux, Klervi / Cassoux, Nathalie / Piperno-Neumann, Sophie / Amigorena, Sebastian / Perez, Franck / Roman-Roman, Sergio / de Marco, Ario. ·Tumor Target and Therapeutic Antibody - Identification Platform (TAb-IP), Paris Cedex 05, France. · Translational Research Department, Institut Curie, PSL Research University, Paris, France. · Medical Oncology Department, Institut Curie, Paris Cedex 05, France. · Institut Curie, PSL Research University, Paris Cedex 05, France. · UMR144, Institut Curie, Paris, France. · Department of Surgical Oncology, Institut Curie, Paris, France. · Department of Medical Oncology, Institut Curie, Paris, France. · INSERM Unit 932, Paris cedex 05, France. · SIRIC INCa-DGOS-4654, Paris, France. · CIC IGR Curie 1428, Paris, France. · Department of Biomedical Sciences and Engineering, University of Nova Gorica (UNG), Vipava, Slovenia. ·Pigment Cell Melanoma Res · Pubmed #28140525.

ABSTRACT: Monoclonal antibodies specific for biomarkers expressed on the surface of uveal melanoma (UM) cells would simplify the immune capture and genomic characterization of heterogeneous tumor cells originated from patient-derived xenografts (PDXs). Antibodies against four independent tumor antigens were isolated by panning a nanobody synthetic library. Such antibodies enabled flow cytometry-based sorting of distinct cell subpopulations from UM PDXs and to analyze their genomic features. The complexity and specificity of the biochemical and genomic biomarker combinations mirrored the UM tumor polyclonality. The data showed that MUC18 is highly and universally displayed on the surface of UM cells with different genetic background and consequently represents a reliable pan-biomarker for their identification and purification. In contrast, the other three biomarkers were detected in very variable combinations in UM PDX cells. The availability of the identified nanobodies will be instrumental in developing clone-specific drug evaluation and rational clinical strategies based on accurate genomic profiling.

11 Article Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma. 2016

Carita, Guillaume / Frisch-Dit-Leitz, Estelle / Dahmani, Ahmed / Raymondie, Chloé / Cassoux, Nathalie / Piperno-Neumann, Sophie / Némati, Fariba / Laurent, Cécile / De Koning, Leanne / Halilovic, Ensar / Jeay, Sebastien / Wylie, Andrew / Emery, Caroline / Roman-Roman, Sergio / Schoumacher, Marie / Decaudin, Didier. ·Laboratory of Preclinical Investigation, Department of Translational Research, PSL University, Institut Curie, Paris, France. · Department of Translational Research, Institut Curie, PSL University, Paris, France. · Department of Ophthalmological Oncology, Institut Curie, Paris, France. · Department of Medical Oncology, Institut Curie, Paris, France. · Residual Tumor & Response to Treatment Laboratory, Department of Translational Research, Institut Curie, PSL University, Paris, Paris, France. · RPPA Platform, Department of Translational Research, Institut Curie, PSL University, Paris, France. · Novartis Institutes for Biomedical Research, Cambridge, MA, USA. ·Oncotarget · Pubmed #27507190.

ABSTRACT: Uveal melanoma (UM) is the most common cancer of the eye in adults. Many UM patients develop metastases for which no curative treatment has been identified. Novel therapeutic approaches are therefore urgently needed. UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway, leading to the use of PKC inhibitors as a rational strategy to treat UM tumors. Encouraging clinical activity has been noted in UM patients treated with PKC inhibitors. However, it is likely that curative treatment regimens will require a combination of targeted therapeutic agents. Employing a large panel of UM patient-derived xenograft models (PDXs), several PKC inhibitor-based combinations were tested in vivo using the PKC inhibitor AEB071. The most promising approaches were further investigated in vitro using our unique panel of UM cell lines. When combined with AEB071, the two agents CGM097 (p53-MDM2 inhibitor) and RAD001 (mTORC1 inhibitor) demonstrated greater activity than single agents, with tumor regression observed in several UM PDXs. Follow-up studies in UM cell lines on these two drug associations confirmed their combination activity and ability to induce cell death. While no effective treatment currently exists for metastatic uveal melanoma, we have discovered using our unique panel of preclinical models that combinations between PKC/mTOR inhibitors and PKC/p53-MDM2 inhibitors are two novel and very effective therapeutic approaches for this disease. Together, our study reveals that combining PKC and p53-MDM2 or mTORC1 inhibitors may provide significant clinical benefit for UM patients.

12 Article Validation of a Prognostic Staging for Metastatic Uveal Melanoma: A Collaborative Study of the European Ophthalmic Oncology Group. 2016

Kivelä, Tero T / Piperno-Neumann, Sophie / Desjardins, Laurence / Schmittel, Alexander / Bechrakis, Nikolaos / Midena, Edoardo / Leyvraz, Serge / Zografos, Leonidas / Grange, Jean-Daniel / Ract-Madoux, Guillaume / Marshall, Ernest / Damato, Bertil / Eskelin, Sebastian. ·Ocular Oncology Service, Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Electronic address: tero.kivela@helsinki.fi. · Department of Medical Oncology, Institut Curie, Paris, France. · Department of Ocular Oncology, Institut Curie, Paris, France. · Department of Hematology and Medical Oncology, Charité, Berlin, Germany. · Department of Ophthalmology, Charité, Berlin, Germany. · Department of Ophthalmology, University of Padova, Padova, Italy. · Department of Oncology, University Hospital, Lausanne, Switzerland. · Hopital Jules Gonin, University Hospital, Lausanne, Switzerland. · Department of Ophthalmology, Croix-Rousse Hospital and Centre Léon Bérard, Lyon, France. · Clatterbridge Centre for Oncology, Bebington, Wirral, Merseyside, United Kingdom. · St Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom. · Ocular Oncology Service, Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. ·Am J Ophthalmol · Pubmed #27296487.

ABSTRACT: PURPOSE: To validate a staging system for metastatic uveal melanoma that will facilitate planning, reporting, and interpreting the results of clinical trials. DESIGN: Reliability and validity study. METHODS: The performance index, the largest diameter of the largest metastasis and alkaline phosphatase level at the time of diagnosis of metastases, and overall survival of 249 patients from 7 ocular oncology centers who died of dissemination were analyzed. Predicted median survival time calculated according to the Helsinki University Hospital Working Formulation was used to assign patients to stages IVa, IVb, and IVc, which correspond to predicted survival times of ≥12, <12-6, and <6 months, respectively. The predictions were compared against observed survival. RESULTS: The 3 variables used to assign stage were independent predictors of survival in the validation dataset. Of the 249 patients, 110 (44%), 109 (44%), and 30 (12%) were classified to Working Formulation stages IVa, IVb, and IVc, respectively. Corresponding median observed survival times were 18.6, 10.7, and 4.6 months and worsened by increasing stage (P < .001). Of 201 patients managed without surgical resection of metastases, 83 (41%), 89 (44%), and 29 (15%) were classified to stages IVa, IVb, and IVc, respectively, and their median observed survival times were 17.2, 10.0, and 4.6 months (P < .001). Survival of 47 patients who underwent resection did not differ by working formulation stage (P = .69). CONCLUSIONS: This multicenter study confirms that the Working Formulation is a reliable and valid, repeatable system for dividing metastatic uveal melanoma into distinct prognostic subgroups, especially for stage-specific reporting of survival in prospective clinical trials.

13 Article Protein Tyrosine Phosphatase 4A3 (PTP4A3) Promotes Human Uveal Melanoma Aggressiveness Through Membrane Accumulation of Matrix Metalloproteinase 14 (MMP14). 2016

Maacha, Selma / Anezo, Océane / Foy, Malika / Liot, Géraldine / Mery, Laurence / Laurent, Cécile / Sastre-Garau, Xavier / Piperno-Neumann, Sophie / Cassoux, Nathalie / Planque, Nathalie / Saule, Simon. ·Institut Curie, PSL Research University, Centre National de La Recherche Scientifique (CNRS), Institut National de la Santé Et de la Recherche Médicale (INSERM), Unité Mixte de Recherche 3347 (UMR), Unité 1021 Orsay, France 2Université Paris Sud, Universi. · Residual Tumor & Response to Treatment Lab, Institut Curie - Translational Research Department, Paris, France. · Tumor Biology Department, Institut Curie, Paris, France. · Department of Medical Oncology, Institut Curie, Paris, France. · Department of Surgical Oncology, Institut Curie, Paris, France. · Institut Curie, PSL Research University, Centre National de La Recherche Scientifique (CNRS), Institut National de la Santé Et de la Recherche Médicale (INSERM), Unité Mixte de Recherche 3347 (UMR), Unité 1021 Orsay, France 7Université Paris Diderot, Sorb. ·Invest Ophthalmol Vis Sci · Pubmed #27096756.

ABSTRACT: PURPOSE: To study PTP4A3 phosphatase and MMP14 metalloprotease synergy in uveal melanoma aggressiveness. METHODS: Cell membrane localization of matrix metalloprotease 14 (MMP14) in uveal melanoma cells expressing protein tyrosine phosphatase A3 (PTP4A3) was assessed by flow cytometry or immunohistochemistry. The vesicular trafficking of MMP14 in the presence of PTP4A3 was evaluated in OCM-1 cells expressing either the wild-type or mutated phosphatase. Finally, MMP14 localization at the cell membrane of OCM-1 cells was impaired using RNA interference, and the PTP4A3-related migration in vitro and invasiveness in vivo of the treated cells were evaluated. RESULTS: We found that the membrane-anchored MMP14 is enriched at the cell surface of OCM-1 cells, patient-derived xenograft cells, and human primary uveal melanoma tumors expressing PTP4A3. Moreover, we show that PTP4A3 and MMP14 colocalize and that the vesicular trafficking of MMP14 is faster in the presence of active PTP4A3. Finally, we demonstrate that inhibition of MMP14 expression in uveal melanoma cells expressing PTP4A3 impairs their migration in vitro and invasiveness in vivo. CONCLUSIONS: Our observations indicate that PTP4A3 increases cell membrane accumulation of MMP14 as a result of increased cellular trafficking of the metalloprotease. We also show that downregulation of MMP14 expression reduced PTP4A3-induced cell migration and invasiveness. Taken together, our findings suggest that PTP4A3-related subcellular localization of MMP14 is an important event in metastasis induction.

14 Article Radiofrequency ablation and surgical resection of liver metastases from uveal melanoma. 2016

Mariani, P / Almubarak, M M / Kollen, M / Wagner, M / Plancher, C / Audollent, R / Piperno-Neumann, S / Cassoux, N / Servois, V. ·Department of Surgical Oncology, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France. Electronic address: pascale.mariani@curie.net. · Department of Surgical Oncology, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France. · Department of Radiology, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France. · Department of Biostatistics, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France. · Department of Medical Oncology, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France. ·Eur J Surg Oncol · Pubmed #26968227.

ABSTRACT: BACKGROUND: The resection of liver metastasis from uveal melanoma (LMUM) remains controversial. In this study, we evaluated treatment with radiofrequency ablation (RFA) for liver metastases alone or in combination with surgical liver resection. METHODS: A total of 72 patients with LMUM were evaluated in this study. Of these, 57 patients underwent surgical resection (S) while 15 patients had RFA ± S. Clinicopathologic factors were evaluated in terms of recurrence and survival using Chi-square and log-rank tests, respectively. RESULTS: We studied 22 metastases treated by RFA. There were no statistically significant differences between the groups in terms of median age of onset, synchronous nature of the metastases, time from primary tumour treatment to liver metastasis, diameter of the largest metastasis, presence of liver miliary disease, and the type of liver resection. There was a statistically lower number of liver metastases and more bilobar metastases in the RFA group than in the S group. The median overall survival after liver surgery was 27 months in group S and 28 months in the RFA group ± S. The median disease-free survival was 10 months in group S and 7 months in the RFA group ± S. There were no statistically significant differences in the median overall survival and disease-free survival between groups. CONCLUSIONS: The results of this retrospective analysis show that RFA can be used to treat liver metastases to spare the hepatic parenchyma. RFA ± liver surgery and liver surgery alone demonstrate similar survival times.

15 Article Phase II Trial of Bevacizumab in Combination With Temozolomide as First-Line Treatment in Patients With Metastatic Uveal Melanoma. 2016

Piperno-Neumann, Sophie / Diallo, Alhassane / Etienne-Grimaldi, Marie-Christine / Bidard, François-Clément / Rodrigues, Manuel / Plancher, Corine / Mariani, Pascale / Cassoux, Nathalie / Decaudin, Didier / Asselain, Bernard / Servois, Vincent. ·Department of Medical Oncology, Institut Curie, Paris, France sophie.piperno-neumann@curie.fr. · Department of Biostatistics, Institut Curie, Paris, France. · Onco-Pharmacology Laboratory, Centre Antoine Lacassagne, Nice, France. · Department of Medical Oncology, Institut Curie, Paris, France. · Department of Surgical Oncology, Institut Curie, Paris, France. · Preclinical Investigation Laboratory, Institut Curie, Paris, France. · Department of Radiology and Nuclear Medicine, Institut Curie, Paris, France. ·Oncologist · Pubmed #26911405.

ABSTRACT: BACKGROUND: In experimental models, bevacizumab suppressed in vitro growth and in vivo hepatic metastasis of ocular melanoma cells. Additional preclinical data suggested a potential benefit when combining bevacizumab with dacarbazine. METHODS: This noncomparative phase II study evaluated a combination of bevacizumab (10 mg/kg on days 8 and 22) with temozolomide (150 mg/m(2) on days 1-7 and 15-21) in 36 patients with metastatic uveal melanoma (MUM). The primary endpoint was the progression-free rate (PFR) at 6 months. Using a modified 2-step Fleming plan, at least 10 of 35 patients were required to support a predefined PFR at 6 months of 40%. Secondary objectives were progression-free survival (PFS), overall survival (OS), and safety; liver perfusion computed tomography (CT) for response imaging; and impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics. RESULTS: First- and second-step analyses revealed nonprogression at 6 months in 3 of 17 and 8 of 35 patients, respectively. Finally, the 6-month PFR was 23% (95% confidence interval [CI]: 10-39), with long-lasting stable disease in 5 patients (14%). Median PFS and OS were 12 weeks and 10 months, respectively. No unexpected toxicity occurred. Liver perfusion CT imaging was not useful in assessing tumor response, and VEGF-A gene polymorphisms were not correlated with toxicity or survival. CONCLUSION: In patients with MUM, a combination of bevacizumab plus temozolomide achieved a 6-month PFR of 23%.

16 Article Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. 2016

Alsafadi, Samar / Houy, Alexandre / Battistella, Aude / Popova, Tatiana / Wassef, Michel / Henry, Emilie / Tirode, Franck / Constantinou, Angelos / Piperno-Neumann, Sophie / Roman-Roman, Sergio / Dutertre, Martin / Stern, Marc-Henri. ·Department of Genetics and Biology of Cancers, INSERM U830, Institut Curie, PSL Research University, Paris 75248, France. · Depatment of Developmental Biology and Genetics, CNRS UMR 3215/INSERM U934, Institut Curie, PSL Research University, Paris 75248, France. · Translational Research Department, Institut Curie, PSL Research University, Paris 75248, France. · Department of Molecular Bases of Human Diseases, CNRS UPR 1142, IGH-Institute of Human Genetics, Montpellier 34090, France. · Department of Medical Oncology, Institut Curie, Paris 75248, France. · Department of Genotoxic stress and Cancer, CNRS UMR 3348, Institut Curie, PSL Research University, Orsay 91400, France. ·Nat Commun · Pubmed #26842708.

ABSTRACT: Hotspot mutations in the spliceosome gene SF3B1 are reported in ∼20% of uveal melanomas. SF3B1 is involved in 3'-splice site (3'ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear. Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1(R625/K666) mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3'ss. Modelling the differential junctions in SF3B1(WT) and SF3B1(R625/K666) cell lines demonstrates that the deregulated splice pattern strictly depends on SF3B1 status and on the 3'ss-sequence context. SF3B1(WT) knockdown or overexpression do not reproduce the SF3B1(R625/K666) splice pattern, qualifying SF3B1(R625/K666) as change-of-function mutants. Mutagenesis of predicted branchpoints reveals that the SF3B1(R625/K666)-promoted splice pattern is a direct result of alternative branchpoint usage. Altogether, this study provides a better understanding of the mechanisms underlying splicing alterations induced by mutant SF3B1 in cancer, and reveals a role for alternative branchpoints in disease.

17 Article Prospective study of surveillance testing for metastasis in 100 high-risk uveal melanoma patients. 2015

Piperno-Neumann, S / Servois, V / Mariani, P / Plancher, C / Lévy-Gabriel, C / Lumbroso-Le Rouic, L / Couturier, J / Asselain, B / Desjardins, L / Cassoux, N. ·Department of medical oncology, institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: sophie.piperno-neumann@curie.fr. · Department of radiology and nuclear medicine, institut Curie, 26, rue d'Ulm, 75005 Paris, France. · Department of surgical oncology, institut Curie, 26, rue d'Ulm, 75005 Paris, France. · Department of biostatistics, institut Curie, 26, rue d'Ulm, 75005 Paris, France. · Department of genetics, institut Curie, 26, rue d'Ulm, 75005 Paris, France. ·J Fr Ophtalmol · Pubmed #25978872.

ABSTRACT: Despite advances in the local treatment of UM, half of patients develop metastases typically to the liver with poor survival. Microscopic complete surgical resection (R0) of liver metastases improves survival in high selected patients. Early identification of high-risk patients might allow detection of asymptomatic metastases, and increase R0 liver surgery rate. From October 2006 to December 2009, we conducted a prospective study to detect early minimal lesions with 6-monthly liver function tests (LFTs) and liver MRI in 100 high-risk patients. High risk was defined by primary tumor clinical or genomic criteria: thickness>8mm or diameter>15 mm, or extra-scleral extension, or monosomy 3 by FISH or aCGH. With a median follow-up of 49 months, the 5-year metastasis-free survival and overall survival were 47 and 33%, respectively. Of the 60 patients who became metastatic, 50 (83%) had exclusive liver metastasis. LFTs screening had no sufficient accurary, but biannual MRI showed high predictive value to detect metastasis and select patients eligible for curative surgery: 25/50 underwent laparotomy and among them, 8/25 (32%) had a R0 surgery. Median survival after metastasis was 14 months, mean survival reached 40 months in the R0 resected population. Six-monthly liver MRI screening is recommended in patients with large tumors or genomic high risk in order to detect early patient candidates to complete resection of liver metastases.

18 Article Diffusion-weighted MRI for uveal melanoma liver metastasis detection. 2015

Wagner, Mathilde / Mariani, Pascale / Bidard, François Clément / Rodrigues, Manuel Jorge / Farkhondeh, Fereshteh / Cassoux, Nathalie / Piperno-Neumann, Sophie / Petras, Slavomir / Servois, Vincent. ·Department of Radiology and Nuclear Medicine, Institut Curie, 26 rue d'Ulm, 75005, Paris, France. ·Eur Radiol · Pubmed #25712144.

ABSTRACT: OBJECTIVES: We aimed to assess the sensitivity of diffusion-weighted (DW) magnetic resonance (MR) imaging for the detection of pathologically confirmed uveal melanoma liver metastases (UMLM). METHODS: Twenty patients who underwent complete surgical resection of their UMLM (N = 83) were included. Pre-surgery liver MR imaging included T2-weighted, T1-weighted, DW and dynamic-gadolinium-enhanced MR sequences. Two radiologists independently reviewed three sets of images (DW / morphologic-dynamic / combined) for each patient using intraoperative and pathological findings as a standard of reference. RESULTS: The sensitivities of the morphologic-dynamic and DW images for UMLM detection were 63 % and 59 %, respectively, for reader #1 (R1) and 64 % and 53 %, for reader #2 (R2). Sensitivity of the combined set was higher than sensitivity in the two other sets (R1:69 %, R2:67 %), but was only significantly different than the sensitivity of the DW images (McNemar test). For the three sets and the two readers, the sensitivity for UMLM smaller than 5 mm (37-46 %) was significantly lower than that for UMLM larger than 5 mm (67-90 %). The sensitivity for UMLM located in the subcapsular area (41-54 %) was significantly lower than that for intraparenchymal UMLM (68-86 %) (Chi-square test). CONCLUSION: Our study shows that the addition of DW imaging to morphologic-dynamic images does not significantly increase MR sensitivities for UMLM detection. KEY POINTS: • The MR imaging sensitivity for uveal melanoma liver metastases (UMLM) was 69 %. • Addition of DW imaging to morphologic-dynamic images does not increase sensitivity significantly. • Sensitivity for subcapsular UMLM was significantly lower than sensitivity for intraparenchymal UMLM. • The T2 shortening effect does not appear to influence lesion detection in DWI.

19 Article Establishment of novel cell lines recapitulating the genetic landscape of uveal melanoma and preclinical validation of mTOR as a therapeutic target. 2014

Amirouchene-Angelozzi, Nabil / Nemati, Fariba / Gentien, David / Nicolas, André / Dumont, Amaury / Carita, Guillaume / Camonis, Jacques / Desjardins, Laurence / Cassoux, Nathalie / Piperno-Neumann, Sophie / Mariani, Pascale / Sastre, Xavier / Decaudin, Didier / Roman-Roman, Sergio. ·Biophenics Laboratory, Translational Research Department, Institut Curie, 26 rue d'Ulm, 75005 Paris, France. Electronic address: Nabil.Amirouchene-Angelozzi@curie.fr. · Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Fariba.Nemati@curie.fr. · Genomics Platform, Translational Research Department, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: David.Gentien@curie.fr. · Department of Tumor Biology, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Andre.Nicolas@curie.fr. · Institut Curie, INSERM U830, France. Electronic address: Amaury.Dumont@curie.fr. · Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Guillaume.Carita@curie.fr. · Institut Curie, INSERM U830, France. Electronic address: Jacques.Camonis@curie.fr. · Department of Ophthalmological Oncology, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Laurance.Desjardins@curie.net. · Department of Ophthalmological Oncology, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Nathalie.Cassoux@curie.net. · Department of Medical Oncology, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Sophie.Piperno-Neumann@curie.net. · Department of Surgery, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Pascale.Mariani@curie.net. · Department of Tumor Biology, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Xavier.Sastre@curie.net. · Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Didier.Decaudin@curie.net. · Translational Research Department, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Sergio.Roman-Roman@curie.fr. ·Mol Oncol · Pubmed #24994677.

ABSTRACT: Uveal melanoma (UM) is the most common primary tumor of the eye in adults. There is no standard adjuvant treatment to prevent metastasis and no effective therapy in the metastatic setting. We have established a unique panel of 7 UM cell lines from either patient's tumors or patient-derived tumor xenografts (PDXs). This panel recapitulates the molecular landscape of the disease in terms of genetic alterations and mutations. All the cell lines display GNAQ or GNA11 activating mutations, and importantly four of them display BAP1 (BRCA1 associated protein-1) deficiency, a hallmark of aggressive disease. The mTOR pathway was shown to be activated in most of the cell lines independent of AKT signaling. mTOR inhibitor Everolimus reduced the viability of UM cell lines and significantly delayed tumor growth in 4 PDXs. Our data suggest that mTOR inhibition with Everolimus, possibly in combination with other agents, may be considered as a therapeutic option for the management of uveal melanoma.

20 Article High numbers of differentiated effector CD4 T cells are found in patients with cancer and correlate with clinical response after neoadjuvant therapy of breast cancer. 2014

Péguillet, Isabelle / Milder, Maud / Louis, Delphine / Vincent-Salomon, Anne / Dorval, Thierry / Piperno-Neumann, Sophie / Scholl, Suzy M / Lantz, Olivier. ·Authors' Affiliations: Clinical immunology Laboratory; Center of Clinical Investigations CICBT507 IGR/Curie; Departments of Pathology, and Medical Oncology; and Inserm U932, Institut Curie, Paris, France. ·Cancer Res · Pubmed #24535711.

ABSTRACT: CD4(+) T cells influence tumor immunity in complex ways that are not fully understood. In this study, we characterized a population of human differentiated effector CD4(+) T cells that is defined by low levels of the interleukin (IL)-2 and IL-7 receptors (CD25(-)CD127(-)). We found that this cell population expands in patients with various types of cancer, including breast cancer, to represent 2% to 20% of total CD4(+) blood T lymphocytes as compared with only 0.2% to 2% in healthy individuals. Notably, these CD25(-)CD127(-)CD4 T cells expressed effector markers such as CD244 and CD11b with low levels of CD27, contrasting with the memory phenotype dominating this population in healthy individuals. These cells did not cycle in patients, nor did they secrete IL-10 or IL-17, but instead displayed cytotoxic features. Moreover, they encompassed oligoclonal expansions paralleling an expansion of effector CD8(+) T cells that included tumor antigen-specific T cells. During neoadjuvant chemotherapy in patients with breast cancer, we found that the increase in CD25(-)CD127(-) CD4(+) T cells correlated with tumor regression. This observation suggested that CD4(+) T cells included tumor antigen-specific cells, which may be generated by or participate in tumor regressions during chemotherapy. In summary, our results lend support to the hypothesis that CD4(+) T cells are involved in human antitumor responses.

21 Article Targeting Bcl-2/Bcl-XL induces antitumor activity in uveal melanoma patient-derived xenografts. 2014

Némati, Fariba / de Montrion, Catherine / Lang, Guillaume / Kraus-Berthier, Laurence / Carita, Guillaume / Sastre-Garau, Xavier / Berniard, Aurélie / Vallerand, David / Geneste, Olivier / de Plater, Ludmilla / Pierré, Alain / Lockhart, Brian / Desjardins, Laurence / Piperno-Neumann, Sophie / Depil, Stéphane / Decaudin, Didier. ·Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, Paris, France. · I.D.R.S., Institut de Recherches Servier, Croissy, France. · I.R.I.S., Institut de Recherches International Servier, Suresnes, France. · Department of Tumor Biology, Institut Curie, Paris, France. · Department of Ophthalmological Oncology, Institut Curie, Paris, France. · Department of Medical Oncology, Institut Curie, Paris, France. · I.D.R.S., Institut de Recherches Servier, Croissy, France ; I.R.I.S., Institut de Recherches International Servier, Suresnes, France. · Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, Paris, France ; Department of Medical Oncology, Institut Curie, Paris, France. ·PLoS One · Pubmed #24454684.

ABSTRACT: PURPOSE: Uveal melanoma (UM) is associated with a high risk of metastases and lack of efficient therapies. Reduced capacity for apoptosis induction by chemotherapies is one obstacle to efficient treatments. Human UM is characterized by high expression of the anti-apoptotic protein Bcl-2. Consequently, regulators of apoptosis such as Bcl-2 family inhibitors may constitute an attractive approach to UM therapeutics. In this aim, we have investigated the efficacy of the Bcl-2/Bcl-XL inhibitor S44563 on 4 UM Patient-Derived Xenografts (PDXs) and derived-cell lines. EXPERIMENTAL DESIGN: Four well characterized UM PDXs were used for in vivo experiments. S44563 was administered alone or combined with fotemustine either concomitantly or after the alkylating agent. Bcl-2, Bcl-XL, and Mcl-1 expressions after S44563 administration were evaluated by immunohistochemistry (IHC). RESULTS: S44563 administered alone by at 50 and 100 mg/kg i.p. induced a significant tumour growth inhibition in only one xenograft model with a clear dose effect. However, when S44563 was concomitantly administered with fotemustine, we observed a synergistic activity in 3 out of the 4 tested models. In addition, S44563 administered after fotemustine induced a tumour growth delay in 2 out of 3 tested xenografts. Finally, IHC analyses showed that Bcl-2, Bcl-XL, and Mcl-1 expression were not modified after S44563 administration. CONCLUSION: The novel anti-apoptotic experimental compound S44563, despite a relative low efficacy when administered alone, increased the efficacy of fotemustine in either concomitant or sequential combinations or indeed subsequent to fotemustine. These data support further exploration of potential therapeutic effect of Bcl-2/Bcl-xl inhibition in human UM.

22 Article Genome-wide profiling is a clinically relevant and affordable prognostic test in posterior uveal melanoma. 2014

Cassoux, Nathalie / Rodrigues, Manuel Jorge / Plancher, Corine / Asselain, Bernard / Levy-Gabriel, Christine / Lumbroso-Le Rouic, Livia / Piperno-Neumann, Sophie / Dendale, Rémi / Sastre, Xavier / Desjardins, Laurence / Couturier, Jérôme. ·Department of Surgical Oncology, Institut Curie 26 rue d'Ulm, Paris, France. · Department of Medical Oncology, Institut Curie 26 rue d'Ulm, Paris, France. · Department of Biostatistics, Institut Curie 25 rue d'Ulm, Paris, France. · Department of Radiotherapy Orsay Proton therapy, Center Institut Curie Orsay, Paris, France. · Department of Pathology, Institut Curie 25 rue d'Ulm, Paris, France. · Department of Genetics, Institut Curie 25 rue d'Ulm, Paris, France. ·Br J Ophthalmol · Pubmed #24169649.

ABSTRACT: OBJECTIVE: This study investigated the capacity of genetic analysis of uveal melanoma samples to identify high-risk patients and discusses its clinical implications. METHODS: Patients with posterior uveal melanoma were prospectively enrolled. Tumour samples were derived from enucleated globe, fine-needle aspirates or endoresection. Chromosome 3 and 8 status was determined by array comparative genomic hybridisation (array-CGH). Patients were followed after treatment to detect metastasis. RESULTS: Four groups were classified by array-CGH. Patients were divided into disomy 3 and normal chromosome 8 (D3/8nl), disomy 3 and 8q gain (D3/8g), monosomy 3 and normal chromosome 8 (M3/8nl) and monosomy 3 and 8 or 8q gain (M3/8g). Median follow-up was 28 months (range: 1-147 months). At the end of the study, 128 patients (33.7%) had developed metastasis and 96 patients had died. Univariate Cox proportional hazard analysis showed that factors associated with metastasis included basal tumour diameter p=0.0007, tumour thickness p=0.01, mixed/epithelioid cell type p=0.0009 and genomic data p<0.0001. High-risk profile was more strongly associated with metastasis than the other prognostic factors p<0.001. Multivariate Cox modelling analysis showed that the status of chromosomes 3 and 8 were the only two variables that independently contributed to prognosis: monosomy 3 alone p=0.001 and monosomy 3 and 8q gain p<0.0001. CONCLUSIONS: Array-CGH allowed identification of three prognostic groups with low, intermediate and high risk of developing metastasis. Array-CGH is a reliable and inexpensive method for uveal melanoma prognosis. This method is now currently used in France.

23 Article Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma. 2014

Bidard, François-Clément / Madic, Jordan / Mariani, Pascale / Piperno-Neumann, Sophie / Rampanou, Aurore / Servois, Vincent / Cassoux, Nathalie / Desjardins, Laurence / Milder, Maud / Vaucher, Isabelle / Pierga, Jean-Yves / Lebofsky, Ronald / Stern, Marc-Henri / Lantz, Olivier. ·Department of Medical Oncology, Institut Curie, Paris, France; Laboratory of Circulating Tumor Biomarkers, Institut Curie, Paris, France. ·Int J Cancer · Pubmed #23934701.

ABSTRACT: Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been recently investigated in several cancer types, but their respective clinical significance remains to be determined. In our prospective study, we compared the detection rate and the prognostic value of these two circulating biomarkers in patients with metastatic uveal melanoma. GNAQ/GNA11 mutations were characterized in archived tumor tissue. Using a highly sensitive and mutation-specific bidirectional pyrophosphorolysis-activated polymerization (bi-PAP) technique, GNAQ c.626A>T, GNAQ c.626A>C and GNA11 c.626A>T copy numbers were quantified in plasma from 12 mL of blood. CTCs were detected at the same time in 7.5 mL of blood by the CellSearch technique. Patient characteristics and outcome were prospectively collected. CTCs (≥1) were detected in 12 of the 40 included patients (30%, range 1-20). Among the 26 patients with known detectable mutations, ctDNA was detected and quantified in 22 (84%, range 4-11,421 copies/mL). CTC count and ctDNA levels were associated with the presence of miliary hepatic metastasis (p = 0.004 and 0.03, respectively), with metastasis volume (p = 0.005 and 0.004) and with each other (p < 0.0001). CTC count and ctDNA levels were both strongly associated with progression-free survival (p = 0.003 and 0.001) and overall survival (p = 0.0009 and <0.0001). In multivariate analyses, ctDNA appeared to be a better prognostic marker than CTC. In conclusion, ctDNA and CTC are correlated and both have poor prognostic significance. CTC detection can be performed in every patient but, in patients with detectable mutations, ctDNA was more frequently detected than CTC and has possibly more prognostic value.

24 Article SF3B1 mutations are associated with alternative splicing in uveal melanoma. 2013

Furney, Simon J / Pedersen, Malin / Gentien, David / Dumont, Amaury G / Rapinat, Audrey / Desjardins, Laurence / Turajlic, Samra / Piperno-Neumann, Sophie / de la Grange, Pierre / Roman-Roman, Sergio / Stern, Marc-Henri / Marais, Richard. ·The Cancer Research UK Manchester Institute, Wilmslow Road, Manchester M20 4BX, UK. · The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. · Institut Curie, Paris, 75248 France. · Platform of Molecular Biology facilities, Translational Research Department, Institut Curie, Paris, 75248 France. · INSERM U830, Paris, 75248 France. · Department of Ophthalmological Surgery, Institut Curie, Paris, 75248 France. · Department of Medical Oncology, Institut Curie, Paris, 75248 France. · GenoSplice, Hopital Saint-Louis, Paris, 75010 France. ·Cancer Discov · Pubmed #23861464.

ABSTRACT: SIGNIFICANCE: Our data show that despite its dismal prognosis, uveal melanoma is a relatively simple genetic disease characterized by recurrent chromosomal losses and gains and a low mutational burden. We show that SF3B1 is recurrently mutated in uveal melanoma, and the mutations are associated with aberrant alternative splicing.

25 Article Choroidal melanoma: does endoresection prevent neovascular glaucoma in patient treated with proton beam irradiation? 2013

Cassoux, Nathalie / Cayette, Sylvia / Plancher, Corine / Lumbroso-Le Rouic, Livia / Levy-Gabriel, Christine / Asselain, Bernard / Sastre, Xavier / Couturier, Jérôme / Arrufat, Sandrine / Piperno-Neumann, Sophie / Dendale, Remi / Lehoang, Phuc / Desjardins, Laurence. ·Department of Ocular Oncology, Institut Curie, Paris, France. ·Retina · Pubmed #23514798.

ABSTRACT: PURPOSE: To evaluate the efficacy of endoresection after proton beam radiotherapy to prevent neovascular glaucoma (NVG) in patients treated for choroidal melanoma. METHODS: From a series of 4,867 patients treated for choroidal melanoma were prospectively recorded in the database (Macro Infermed 3.075). One hundred and seventy-one patients presenting a tumor diameter >10 mm and thickness >5 mm treated with proton beam (PB) radiotherapy were selected. One group of 63 patients was treated with PB therapy followed by endoresection (PE) of the scar. This group was compared with 2 historical matched controlled groups: 57 patients treated with PB therapy alone (P) and 51 patients treated with PB therapy followed by transpupillary thermotherapy of the scar (PTTT). Main outcome measures are as follows: age, gender, tumor diameter, tumor thickness, pre- and posttreatment visual acuity, NVG rate, secondary enucleation rate, and 5-year survival. Statistical analysis was performed using R version 2.5.1 software. RESULTS: Correlations between the 3 groups were P = 0.29 for age, P = 4.7×10 for tumor diameter, and P = 6.44×10 for tumor thickness. Comparison between the 3 groups showed that 2-year survival without secondary enucleation was 96.2% for PE, 88.8% for P, and 98% for PTTT (P = 0.203) (95% confidence interval). Two-year survival without NVG (95% confidence interval) was 92.7% (85.1-1.00) for PE, 54.6% for P, and 62.1% for PTTT (P = 0.0001). The difference between the endoresection (PE) group and the PB radiotherapy (P) and PB radiotherapy + TTT (PTTT) groups in terms of reduction of the NVG rate was statistically significant. Relative risk of developing NVG was calculated with the P group as reference, relative risk = 1. The relative risk of the PTTT group was 0.79 (20% reduction of the risk), and the relative risk of the PE group was 0.18 (82% reduction of the risk of developing NVG). CONCLUSION: This study shows that endoresection of the necrotic scar after PB radiotherapy reduces the risk of NVG and secondary enucleation for selected choroidal melanoma patients.

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