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Melanoma: HELP
Articles by Sophie Piperno Neumann
Based on 36 articles published since 2010
(Why 36 articles?)
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Between 2010 and 2020, S. Piperno Neumann wrote the following 36 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. · ·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 Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT). 2018

Carvajal, Richard D / Piperno-Neumann, Sophie / Kapiteijn, Ellen / Chapman, Paul B / Frank, Stephen / Joshua, Anthony M / Piulats, Josep M / Wolter, Pascal / Cocquyt, Veronique / Chmielowski, Bartosz / Evans, T R Jeffry / Gastaud, Lauris / Linette, Gerald / Berking, Carola / Schachter, Jacob / Rodrigues, Manuel J / Shoushtari, Alexander N / Clemett, Delyth / Ghiorghiu, Dana / Mariani, Gabriella / Spratt, Shirley / Lovick, Susan / Barker, Peter / Kilgour, Elaine / Lai, Zhongwu / Schwartz, Gary K / Nathan, Paul. ·Richard D. Carvajal and Gary K. Schwartz, Columbia University Medical Center · Paul B. Chapman and Alexander N. Shoushtari, Memorial Sloan Kettering Cancer Center, New York, NY · Sophie Piperno-Neumann and Manuel J. Rodrigues, Institut Curie, Paris · Lauris Gastaud, Centre Antoine-Lacassagne, Nice, France · Ellen Kapiteijn, Leiden University Medical Center, Leiden, the Netherlands · Stephen Frank, Hebrew University Hadassah Medical School - The Sharett Institute of Oncology, Jerusalem · Jacob Schachter, Sheba Medical Center at Tel Hashomer, and Tel-Aviv University Medical School, Tel Aviv, Israel · Anthony M. Joshua, Princess Margaret Cancer Centre, Toronto, ON, Canada · Josep M. Piulats, Institut Catala d'Oncologia L'Hospitalet, L'Hospitalet de Llobregat, Barcelona, Spain · Pascal Wolter, University Hospitals Leuven, Leuven, Belgium · Veronique Cocquyt, Ghent University Hospital, Ghent, Belgium · Bartosz Chmielowski, University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA · T.R. Jeffry Evans, University of Glasgow, Glasgow · Delyth Clemett, Shirley Spratt, Susan Lovick, and Elaine Kilgour, AstraZeneca, Macclesfield · Dana Ghiorghiu and Gabriella Mariani, AstraZeneca, Cambridge · Paul Nathan, Mt Vernon Cancer Centre, Northwood, United Kingdom · Gerald Linette, Washington University School of Medicine, St Louis, MO · Carola Berking, University Hospital of Munich, Munich, Germany · Peter Barker, AstraZeneca, Gaithersburg, MD · and Zhongwu Lai, AstraZeneca, Waltham, MA. ·J Clin Oncol · Pubmed #29528792.

ABSTRACT: Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m

8 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.

9 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.

10 Article So Close, yet so Far: Discrepancies between Uveal and Other Melanomas. A Position Paper from UM Cure 2020. 2019

Rodrigues, Manuel / Koning, Leanne de / Coupland, Sarah E / Jochemsen, Aart G / Marais, Richard / Stern, Marc-Henri / Valente, André / Barnhill, Raymond / Cassoux, Nathalie / Evans, Andrew / Galloway, Iain / Jager, Martine J / Kapiteijn, Ellen / Romanowska-Dixon, Bozena / Ryll, Bettina / Roman-Roman, Sergio / Piperno-Neumann, Sophie / Anonymous4280998. ·Department of Medical Oncology and INSERM U830, Institut Curie, PSL Research University, 75005 Paris, France. manuel.rodrigues@curie.fr. · Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3BX, UK. · Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. · Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M13 9PL, UK. · Department of Genetics, Institut Curie, PSL Research University, 75005 Paris, France. · Champalimaud Foundation, 1400-038 Lisbon, Portugal. · Department of Biopathology, Institut Curie, PSL Research University, 75005 Paris, France. · Department of Ocular Oncology, Institut Curie, PSL Research University, 75005 Paris, France. · Melanoma Patient Network Europe, 75597 Uppsala, Sweden. · Department of Ophthalmology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. · Department of Medical Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. · Department of Ophthalmology and Ocular Oncology, Jagiellonian University Medical 31007 Krakow, Poland. · Department of Medical Oncology, Institut Curie, PSL Research University, 75005 Paris, France. · Department of Medical Oncology and INSERM U830, Institut Curie, PSL Research University, 75005 Paris, France. ·Cancers (Basel) · Pubmed #31336679.

ABSTRACT: Despite much progress in our understanding of uveal melanoma (UM) over the past decades, this rare tumour is still often misclassified. Although UM, like other melanomas, is very probably derived from melanocytes, it is drastically different from cutaneous melanoma and most other melanoma subtypes in terms of epidemiology, aetiology, biology and clinical features, including an intriguing metastatic hepatotropism. UM carries distinctive prognostic chromosome alterations, somatic mutations and gene expression profiles, allowing an active tailored surveillance strategy and dedicated adjuvant clinical trials. There is no standard systemic treatment for disseminated UM at present. In contrast to cutaneous melanoma, UMs are not

11 Article Development of a Prognostic Nomogram for Liver Metastasis of Uveal Melanoma Patients Selected by Liver MRI. 2019

Mariani, Pascale / Dureau, Sylvain / Savignoni, Alexia / Rouic, Livia Lumbroso-Le / Levy-Gabriel, Christine / Piperno-Neumann, Sophie / Rodrigues, Manuel J / Desjardins, Laurence / Cassoux, Nathalie / Servois, Vincent. ·Department of Surgical Oncology, Institut Curie, 26 rue d'Ulm, 75248 Cedex 05 Paris, France. pascale.mariani@curie.fr. · Department of Biostatistic, Institut Curie, 26 rue d'Ulm, 75248 Cedex 05 Paris, France. sylvain.dureau@curie.fr. · Department of Biostatistic, Institut Curie, 26 rue d'Ulm, 75248 Cedex 05 Paris, France. alexia.savignoni@curie.fr. · Department of Surgical Oncology, Institut Curie, 26 rue d'Ulm, 75248 Cedex 05 Paris, France. livia.lumbroso@curie.fr. · Department of Surgical Oncology, Institut Curie, 26 rue d'Ulm, 75248 Cedex 05 Paris, France. christine.levy@curie.fr. · Department of Medical Oncology, Institut Curie, 26 rue d'Ulm, 75248 Cedex 05 Paris, France. sophie.piperno-neumann@curie.fr. · Department of Medical Oncology, Institut Curie, 26 rue d'Ulm, 75248 Cedex 05 Paris, France. manuel.rodrigues@curie.fr. · Department of Surgical Oncology, Institut Curie, 26 rue d'Ulm, 75248 Cedex 05 Paris, France. laurence.desjardins@curie.fr. · Department of Surgical Oncology, Institut Curie, 26 rue d'Ulm, 75248 Cedex 05 Paris, France. nathalie.cassoux@curie.fr. · Department of Radiology, Institut Curie, 26 rue d'Ulm, 75248 Cedex 05 Paris, France. vincent.servois@curie.fr. ·Cancers (Basel) · Pubmed #31234340.

ABSTRACT: Patients with liver metastases of uveal melanoma (LMUM) die from their metastatic evolution within 2 years. We established a nomogram to choose a treatment adapted to life expectancy. From 2002 to 2013, we reviewed 224 patients with LMUM selected by liver MRI. A nomogram was developed based on a Cox model. The predictive performance of the model was assessed according to the C-statistic, Kaplan-Meier curve, and calibration plots. The median follow-up was 49.2 months (range, 0.6-70.9). The survival rates at 6, 12, and 24 months were 0.88 (0.95 CI [0.84-0.93]), 0.68 (0.95 CI [0.62-0.75]), and 0.26 (0.95 CI [0.21-0.33]), respectively. The four factors selected for the nomogram with a worse prognosis were: A disease-free interval between the UM and LMUM groups of less than 6 months (HR = 3.39; 0.95 CI [1.90-6.05]), more than 10 LMUM (HR = 3.95; 0.95 CI [1.97-4.43]), a maximum LMUM of more than 1200 mm2 (HR = 2.47; 0.95 CI [1.53-3.98]), and a lactate dehydrogenase (LDH) value greater than 1.5 (HR = 3.72; 0.95 CI [2.30-6.00]). The model achieved relatively good discrimination and calibration (C-statistic 0.71). This nomogram could be useful for decision-making and risk stratification for therapeutic options.

12 Article Uveal Melanoma: A European Network to Face the Many Challenges of a Rare Cancer. 2019

Piperno-Neumann, Sophie / Piulats, Jose Maria / Goebeler, Matthias / Galloway, Iain / Lugowska, Iwona / Becker, Jürgen C / Vihinen, Pia / Van Calster, Joachim / Hadjistilianou, Theodora / Proença, Rui / Caminal, Jose Maria / Rogasik, Muriel / Blay, Jean-Yves / Kapiteijn, Ellen. ·Department of Medical Oncology, Institut Curie, 75005 Paris, France. sophie.piperno-neumann@curie.fr. · Department of Medical Oncology, Catalan Cancer Institute, IDIBELL, CIBERONC, Hospitalet de Llobregat, 08908 Barcelona, Spain. jmpiulats@iconcologia.net. · Department of Dermatology, University Hospital Würzburg, 97080 Würzburg, Germany. Goebeler_M1@ukw.de. · European Patient Advocacy Group: Melanoma Patient Network Europe & OcuMel, Birmingham B13 8ET, UK. iain@idcapture.co.uk. · Department of Melanoma, Maria Skłodowska Curie Institute-Oncology Centre, 02-034 Warsaw, Poland. Iwona.Lugowska@coi.pl. · Translational Skin Cancer Research, University of Essen-Duisburg, German Cancer Consortium (DKTK), 47057 Duisburg, Germany. j.becker@dkfz.de. · Department of Oncology and FICAN West Cancer Center, Turku University Hospital, 20521 Turku, Finland. Pia.Vihinen@tyks.fi. · Department of Ophthalmology, UZ Leuven, 3000 Leuven, Belgium. joachim.vancalster@uzleuven.be. · Department of Ophthalmology, Università degli Studi di Siena UNISI, 53100 Siena, Italy. hadjistilian@unisi.it. · Onco-Ophthalmology National Reference Centre, CHUC, 3075 Coimbra, Portugal. rdproenca@gmail.com. · Department of Ophthalmololgy, Bellvitge University Hospital, L'Hospitalet de Llobregat, 08907 Barcelona, Spain. jmcaminal@bellvitgehospital.cat. · EURACAn coordination team, Centre Léon Bérard, 69008 Lyon, France. muriel.rogasik@lyon.unicancer.fr. · EURACAN network coordinator, Department of Medical Oncology, Centre Léon Bérard, Université Claude Bernard Lyon 1, 69100 Villeurbanne, France. jean-yves.blay@lyon.unicancer.fr. · Department of Medical Oncology, LUMC, 2333 ZA Leiden, the Netherlands. H.W.Kapiteijn@lumc.nl. ·Cancers (Basel) · Pubmed #31200439.

ABSTRACT: Uveal melanoma (UM) is the most frequent primary ocular cancer in adults, accounting for 5% of all melanomas. Despite effective treatments for the primary tumour, up to 50% of UM patients will develop metastasis, leading to a very poor prognosis and a median overall survival of 6 to 12 months, with no major improvements in the last 30 years. There is no standard oncological treatment available for metastatic UM patients, and BRAF/MEK and immune checkpoint inhibitors show disappointing results when compared to cutaneous melanoma (CM). Recent advances in biology, however, identified specific gene and chromosome alterations, potentially permitting an actively tailored surveillance strategy, and dedicated clinical studies. Being a rare cancer, UM patients have to overcome issues such as identifying referral centres, having access to information, and partnering with oncologists for specific management strategies and research priorities. Here, we describe how the EUropean Rare Adult solid CAacer Network (EURACAN) will help in addressing these challenges and accelerating international collaborations to enhance the development of innovative treatments in UM.

13 Article Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study. 2019

Khoja, L / Atenafu, E G / Suciu, S / Leyvraz, S / Sato, T / Marshall, E / Keilholz, U / Zimmer, L / Patel, S P / Piperno-Neumann, S / Piulats, J / Kivelä, T T / Pfoehler, C / Bhatia, S / Huppert, P / Van Iersel, L B J / De Vries, I J M / Penel, N / Vogl, T / Cheng, T / Fiorentini, G / Mouriaux, F / Tarhini, A / Patel, P M / Carvajal, R / Joshua, A M. ·Department of Medical Oncology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge. · AstraZeneca UK, Clinical Discovery Unit, Early Clinical Development, IMED Biotech Unit, Melbourn, UK. · Department of Biostatistics, University Health Network, Toronto, Canada. · EORTC Headquarters, Brussels, Belgium. · Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. · Department of Medical Oncology, Thomas Jefferson University, Philadelphia, USA. · Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK. · Charité-Universitätsmedizin, Berlin. · Department of Dermatology, University Hospital, University Duisburg-Essen, Germany & German Cancer Consortium (DKTK), Heidelberg, Germany. · Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Medical Oncology, Institut Curie, Paris, France. · Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), IDIBELL, Barcelona, Spain. · Ocular Oncology Service, Department of Ophthalmology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland. · Department of Dermatology, Saarland University Medical School, Hamburg, Germany. · Division of Medical Oncology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, USA. · Department of Diagnostic and Interventional Radiology, Darmstadt, Germany. · Department of Medical Oncology, Maastricht University Medical Centre, Maastricht. · Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands. · Centre Oscar Lambret, Lille, France. · Department of Diagnostic and Interventional Radiology, University Hospital Frankfurt, Johann Wolfgang Goethe-University, Frankfurt, Germany. · Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Canada. · Oncology Unit, Azienda Ospedaliera 'Ospedali Riuniti Marche Nord', Pesaro, Italy. · University of Rennes, INSERM, Department of Ophthalmology, CHU Rennes, Rennes, France. · UPMC Hillman Cancer Center, University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, USA. · Academic Unit of Oncology, Division of Cancer & Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK. · Division of Hematology/Oncology, Columbia University Medical Center, New York, USA. · Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. · Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney. · Melanoma Institute of Australia, Sydney, Australia. ·Ann Oncol · Pubmed #31150059.

ABSTRACT: BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data. METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated. RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus <3 cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5-11.0) and 1 year OS was 43% (95% CI 40-47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS. CONCLUSION: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.

14 Article Replacement and desmoplastic histopathological growth patterns: A pilot study of prediction of outcome in patients with uveal melanoma liver metastases. 2018

Barnhill, Raymond / Vermeulen, Peter / Daelemans, Sofie / van Dam, Pieter-Jan / Roman-Roman, Sergio / Servois, Vincent / Hurbain, Ilse / Gardrat, Sophie / Raposa, Graça / Nicolas, André / Dendale, Rémi / Pierron, Gaëlle / Desjardins, Laurence / Cassoux, Nathalie / Piperno-Neumann, Sophie / Mariani, Pascale / Lugassy, Claire. ·Department of Pathology, Institut Curie, Paris, France. · University of Paris Réné Descartes Faculty of Medicine, Paris, France. · HistoGeneX, Antwerpen, Belgium. · Faculty of Medicine and Health Sciences, University of Antwerp - MIPRO Center for Oncological Research (CORE) - TCRU, GZA Sint-Augustinus, Antwerpen, Belgium. · Department of Translational Research, Institut Curie, Paris, France. · Department of Radiology, Institut Curie, Paris, France. · Institut Curie, PSL Research University, CNRS, Paris, France. · Sorbonne Universités, UPMC Univ Paris 06, CNRS, Paris, France. · Cell and Tissue Imaging Core Facility PICT-IBiSA, Institut Curie, Paris, France. · Department of Radiotherapy, Institut Curie Orsay, Paris, France. · Department of Somatic Genetics, Institut Curie, Paris, France. · Department of Ophthalmology, Institut Curie, Paris, France. · Department of Medical Oncology, Institut Curie, Paris, France. · Department of Surgery, Institut Curie, Paris, France. ·J Pathol Clin Res · Pubmed #29917326.

ABSTRACT: Up to 50% of uveal melanomas (UM) metastasise to the liver within 10 years of diagnosis, and these almost always prove rapidly fatal. As histopathological growth patterns (HGPs) of liver metastases of the replacement and desmoplastic type, particularly from colon and breast carcinoma, may import valuable biological and prognostic information, we have studied HGP in a series of 41 UM liver metastases originating from 41 patients from the period 2006-2017. Twenty patients underwent enucleation while 21 had radiation therapy. Analysis of UM by array comparative genomic hybridisation revealed: 25 (64%) patients with high risk (monosomy3/8q gain); 13 (33%) intermediate risk (M3/8normal or disomy3/8q gain); and 1 low risk (disomy3/8normal). The principal HGP was replacement in 30 (73%) cases and desmoplastic in 11 (27%) cases. Cases with replacement demonstrated striking vascular co-option/angiotropism. With the development of liver metastasis, only the replacement pattern, largest primary tumour diameter, and R2 (incomplete resection) status predicted diminished overall survival (OS; p < 0.041, p < 0.017, p < 0.047, respectively). On multivariate analysis, only HGP (hazard ratio; HR = 6.51, p = 0.008) and resection status remained significant. The genomic high-risk variable had no prognostic value at this stage of liver metastasis. Chi-square test showed no association of HGP with monosomy 3 or 8q gain. Eighteen of 41 (44%) patients are alive with disease and 23 (56%) patients died with follow-up ranging from 12 to 318 months (mean: 70 months, median: 47 months). In conclusion, we report for the first time the frequency of the replacement and desmoplastic HGPs in liver UM metastases resected from living patients, and their potential important prognostic value for UM patients, as in other solid cancers. These results may potentially be utilised to develop radiological correlates and therapeutic targets for following and treating patients with UM metastases.

15 Article Selumetinib-based therapy in uveal melanoma patient-derived xenografts. 2018

Decaudin, Didier / El Botty, Rania / Diallo, Béré / Massonnet, Gerald / Fleury, Justine / Naguez, Adnan / Raymondie, Chloé / Davies, Emma / Smith, Aaron / Wilson, Joanne / Howes, Colin / Smith, Paul D / Cassoux, Nathalie / Piperno-Neumann, Sophie / Roman-Roman, Sergio / Némati, Fariba. ·Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University Paris, Paris, France. · Department of Medical Oncology, Institut Curie, Paris, France. · IMED Oncology, AstraZeneca, Cambridge, UK. · Department of Oncological Ophthalmology, Institut Curie, Paris, France. · Department of Translational Research, Institut Curie, PSL University Paris, Paris, France. ·Oncotarget · Pubmed #29774094.

ABSTRACT: The prognosis of metastatic uveal melanoma (UM) is among the worst of all human cancers. The identification of near-ubiquitous GNAQ/GNA11 mutations and the activation of MAPK signaling in UM have raised hopes of more effective, targeted therapies, based on MEK inhibition, for example. We evaluated the potential of drug combinations to increase the efficacy of the MEK inhibitor selumetinib (AZD6244, ARRY-142886), in UM cell lines and Patient-Derived Xenografts. We first evaluated the combination of selumetinib and DTIC. We found that DTIC did not improve the

16 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.

17 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.

18 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.

19 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.

20 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.

21 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.

22 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%.

23 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.

24 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.

25 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.

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