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Melanoma: HELP
Articles by Enrique Espinosa
Based on 21 articles published since 2008
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Between 2008 and 2019, E. Espinosa wrote the following 21 articles about Melanoma.
 
+ Citations + Abstracts
1 Guideline SEOM clinical guideline for the management of malignant melanoma (2017). 2018

Berrocal, A / Arance, A / Castellon, V E / de la Cruz, L / Espinosa, E / Cao, M G / Larriba, J L G / Márquez-Rodas, I / Soria, A / Algarra, S M. ·Servicio de Oncología Médica, Consorcio Hospital General Universitario de Valencia, Avda. Tres Cruces 2, 46014, Valencia, Spain. berrocal.alf@gmail.com. · Hospital Clinic I Provincial de Barcelona, Barcelona, Spain. · Hospital Torrecárdenas, Almería, Spain. · Complejo Hospitalario Regional Virgen Macaren, Seville, Spain. · Hospital Universitario la Paz, Madrid, Spain. · Hospital Universitario Quirón Dexeus, Barcelona, Spain. · Hospital Universitario Clínico San Carlos, Madrid, Spain. · Hospital General Universitario Gregorio Marañón, Madrid, Spain. · Hospital Universitario Ramón y Cajal, Madrid, Spain. · Clínica Universitaria de Navarra, Pamplona, Spain. ·Clin Transl Oncol · Pubmed #29116432.

ABSTRACT: All melanoma suspected patients must be confirmed histologically and resected. Sentinel node biopsy must be done when tumor is over 1 mm or if less with high-risk factors. Adjuvant therapy with interferon could be offered for patients with high-risk melanoma and in selected cases radiotherapy can be added. Metastatic melanoma treatment is guided by mutational BRAF status. BRAF wild type patients must receive anti-PD1 containing therapy and BRAF mutated patients BRAF/MEK inhibitors or anti-PD1 containing therapy. Up to 10 years follow up is reasonable for melanoma patients with dermatologic examinations and physical exams.

2 Guideline Guidelines for biomarker testing in metastatic melanoma: a National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology. 2014

Martín-Algarra, S / Fernández-Figueras, M T / López-Martín, J A / Santos-Briz, A / Arance, A / Lozano, M D / Berrocal, A / Ríos-Martín, J J / Espinosa, E / Rodríguez-Peralto, J L / Anonymous3550772 / Anonymous3560772. ·Medical Oncology Department, Clínica Universidad de Navarra, Avenida de Pio XII, 36, 31008, Pamplona, Spain, smalgarra@unav.es. ·Clin Transl Oncol · Pubmed #24129426.

ABSTRACT: This consensus statement, conceived as a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM), makes diagnostic and treatment recommendations for the management of patients with advanced or metastatic melanoma based on the current scientific evidence on biomarker use. This document thus provides an opportunity to improve healthcare efficiency and resource use, which will benefit these patients. Based on the data available so far, this expert group recommends routinely testing patients with metastatic melanoma for BRAF mutation status, as the result affects the subsequent therapeutic management of these patients. The analysis of genetic alterations in KIT may be reasonable in patients with primary tumours in acral or mucosal sites or on chronically sun-exposed skin, in an advanced condition, but not in patients with other types of melanomas. This panel believes that testing for other genetic alterations, such as NRAS mutation status in patients not carrying BRAF mutations, GNAQ/GNA11 mutational analysis or genetic alterations in PTEN, is not currently indicated as routine clinical practice, because the results do not influence treatment planning in these patients at the present time. Other important issues addressed in this document are the organisational requirements and quality controls needed for proper testing of these biomarkers, and the legal implications to be borne in mind.

3 Review Spanish Multidisciplinary Melanoma Group (GEM) guidelines for the management of patients with advanced melanoma. 2015

Berrocal, Alfonso / Espinosa, Enrique / Marín, Severiano / Malvehy, Josep / Moreno, David / Lozano, Maria Dolores / Martin-Algarra, Salvador / Lopez, Jose Antonio / Conill, Carlos / Rodriguez-Peralto, Jose Luis. ·Department of Oncology. · Service of Oncology, Hospital La Paz, Madrid, Spain. · Plastic Surgery, Consorcio Hospital General Universitario, Avda, Tres Cruces, 2, 46014 Valencia, Spain. · Dermatology Department, Melanoma Unit, Hospital Clinic, Barcelona, Spain. · Dermatology Unit, Hospital Universitario Virgen Macarena, Seville, Spain. · Department of Pathology. · Department of Oncology, Clinica Universitaria de Navarra, Pamplona, Spain. · Department of Radiation Oncology, Hospital Clinic, Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain. · Department of Pathology, Hospital 12 de Octubre, Madrid, Spain. ·Eur J Dermatol · Pubmed #26693633.

ABSTRACT: Advanced melanoma is a relatively uncommon condition whose therapeutic management has undergone major changes over the past four years. The present article aims to establish recommendations for the management of these patients based on the best available evidence reached by consensus of a group of professionals familiar in the treatment of these patients. These professionals, belonging to Spanish Multidisciplinary Melanoma Group, reviewed the diagnostic process and the incorporation of new techniques of molecular diagnosis of advanced disease; treatment and monitoring of stage III both as adjuvant locoregional treatments have been addressed, as well as new therapies for stage IV. We have reviewed the palliative treatment alternatives for disseminated disease, such as surgery, radiotherapy or non-cytotoxic systemic treatments. Finally, we have also reviewed the most relevant toxicities of new drugs and their management in clinical practice.

4 Review Treatment algorithms in stage IV melanoma. 2015

Espinosa, Enrique / Grob, Jean-Jacques / Dummer, Reinhard / Rutkowski, Piotr / Robert, Caroline / Gogas, Helen / Kefford, Richard / Eggermont, Alexander M M / Martin Algarra, Salvador / Hauschild, Axel / Schadendorf, Dirk. ·1Service of Oncology, Hospital La Paz, Madrid, Spain · 2Department of Dermatology, Hopital Ste Marguerite, Marseille, France · 3Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland · 4Department of Sarcoma and Melanoma, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland · 5Department of Dermatology (CR), and General Director (AE), Institute Gustave Roussy, Villejuif Cedex, France · 6First Department of Medicine, University of Athens Medical School, Athens, Greece · 7Department of Oncology, Westmead Hospital and Melanoma Institute Australia, University of Sydney, Sydney, Australia · 8Service of Oncology, Clinica Universitaria de Navarra, Pamplona, Spain · 9Department of Dermatology, University of Kiel, Kiel, Germany · and 10Department of Dermatology, University Hospital Essen, Essen, Germany. ·Am J Ther · Pubmed #24413374.

ABSTRACT: The molecular classification of melanoma and the advent of new drugs are changing the paradigm of therapy for advanced melanoma. A review of the recent key studies was performed, followed by a discussion in an expert forum. The aim of this review was to generate a therapeutic algorithm for stage IV melanoma. Tumor genotyping for BRAF and/or KIT should be performed before selection of therapy. For most BRAF-mutated melanoma patients and particularly those with a high tumor load, vemurafenib or other BRAF inhibitors such as dabrafenib are the treatment of choice. KIT inhibitors can be effective in KIT-mutant tumors, especially in those patients with mutations at exons 11 and 13. Ipilimumab is a good option for patients with nontargetable or nondetected mutations and those who progress under therapy with vemurafenib or a KIT inhibitor. There is still a role for conventional chemotherapy either as first-line treatment in BRAF wild-type patients or as salvage therapy in second or third line, or after other treatment modalities. Participation in clinical trials is strongly encouraged, either in first or in subsequent lines. New therapeutic options for advanced melanoma are guided by tumor genotyping. The current therapeutic algorithm includes kinase inhibitors, anti-CTLA4 therapy, immunotherapy, and chemotherapy, depending on the tumor genotype and response to previous treatments. Participation in clinical trials should always be encouraged because the treatment goal is long-term survival and potential cure in a subset of patients.

5 Review Side effects and toxicities of targeted therapies in stage IV melanoma. 2015

Ascierto, Paolo A / Bastholt, Lars / Hersey, Peter / Cinat, Gabriela / Eggermont, Alexander M M / Hauschild, Axel / Espinosa, Enrique / Robert, Caroline. ·1Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori-Fondazione G. Pascale, Naples, Italy; 2Odense University Hospital, Odense, Denmark; 3Newcastle University, Newcastle, Australia; 4Instituto de Oncologia Angel Rolfo, Buenos Aires, Argentina; 5Institut Gustave Roussy, Villejuif, France; 6University of Kiel, Kiel, Germany; 7Hospital La Paz, Madrid, Spain; and 8Institut Gustave Roussy, Villejuif, France. ·Am J Ther · Pubmed #24185314.

ABSTRACT: As the incidence of melanoma continues to increase worldwide, the search for new therapies for advanced (stage IV) melanoma brings with it new patterns of toxicity to contend with. This review covers the toxicity profiles of new treatments for advanced melanoma currently in development. Therefore, the latest literature on melanoma treatment was surveyed for data on reported toxicities. The new types of treatments can be roughly divided into targeted tyrosine kinase inhibitors and immunomodulating agents. Each has its own set of toxicities particular to type and to individual drug. Targeted tyrosine kinase inhibitors generally cause fatigue, whereas immunomodulatory agents induce a specific set of adverse events known as immune-related adverse events (irAEs). Despite the incidence of adverse events, these agents hold promise for the treatment of stage IV melanoma. With new treatment opportunities come increased chance of toxic reactions. The key to successful melanoma treatment in the future is likely to be novel combinations of new therapeutic agents.

6 Review Who benefits most from adjuvant interferon treatment for melanoma? 2015

Gogas, Helen / Abali, Huseyin / Ascierto, Paolo A / Demidov, Lev / Pehamberger, Hubert / Robert, Caroline / Schachter, Jacob / Eggermont, Alexander M M / Hauschild, Axel / Espinosa, Enrique. ·1First Department of Medicine, Athens University Medical School, Athens, Greece; 2Division of Medical Oncology, Baskent University School of Medicine, Adana, Turkey; 3Unit of Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori Fondazione "G. Pascale," Naples, Italy; 4Department of Biotherapy, Blokhin Cancer Center, Moscow, Russia; 5Department of Dermatology, Medical University of Vienna, Vienna, Austria; 6Department of Dermatology, Institute Gustave Roussy, Villejuif Cedex, France; 7Department of Oncology, Sheba Medical Center, Tel Hashomer, Israel; 8Department of Dermatologie, University of Kiel, Kiel, Germany; and 9Oncology Service, Hospital La Paz, Madrid, Spain. ·Am J Ther · Pubmed #24176884.

ABSTRACT: Metastatic melanoma has a poor prognosis; the median survival for patients with stage IV melanoma ranges from 8 to 18 months after diagnosis. Interferon-α provides significant improvement in disease-free survival at the cost of poor tolerability. Identifying patients who benefit the most may improve the cost:benefit ratio. In addition, no data exist for the role of adjuvant therapy in noncutaneous melanoma. Molecular profiles may help to identify patients who benefit the most from adjuvant interferon therapy. In this review, the American Joint Commission on Cancer 2009 staging criteria and emerging biomarker data to guide adjuvant treatment decisions will be discussed. Several criteria to guide selection of patients are discussed in detail. These include Breslow thickness, number of positive lymph nodes, whether or not the primary lesion has ulcerated, immunologic markers, and cytokine profiles. Substantial progress has been made in deciding which patients benefit from interferon-α adjuvant therapy. Interferon-α is the only agent currently approved for the adjuvant treatment of this deadly disease, despite its side effect profile. More effective drugs with better tolerability are needed.

7 Review Melanoma: diagnosis, staging, and treatment. Consensus group recommendations. 2014

Berrocal, Alfonso / Cabañas, Luis / Espinosa, Enrique / Fernández-de-Misa, Ricardo / Martín-Algarra, Salvador / Martínez-Cedres, José Carlos / Ríos-Buceta, Luis / Rodríguez-Peralto, José Luis. ·Department of Oncology, Hospital General Universitario, Valencia, Spain. ·Adv Ther · Pubmed #25145549.

ABSTRACT: The incidence of malignant melanoma is increasing worldwide. In Spain, its incidence is increasing faster than any other cancer type, with a 5-year survival rate of about 85%. The impact and characteristics of malignant melanoma in the Spanish population can be ascertained from the national melanoma registry of the Academia Española de Dermatología y Venereología. This review presents consensus group recommendations for the diagnosis, staging and treatment of malignant melanoma in Spain. Incidence and mortality are discussed, as well as evaluation of various prevention and treatment strategies. Prognostic factors, such as BRAF and C-KIT mutations, which are expected to become routine staging procedures over the next few years, are outlined, especially in relation to treatment options. The use of recently approved targeted agents such as ipilimumab, a cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitor, and vemurafenib, a BRAF inhibitor, in metastatic disease are also discussed.

8 Review Advances in cutaneous melanoma. 2012

Espinosa, Enrique / Berrocal, Alfonso / López Martín, José Antonio / González Cao, María / Cerezuela, Pablo / Mayordomo, José Ignacio / Martín Algarra, Salvador / Anonymous790725. ·Service of Oncology, Hospital La Paz, Madrid, Spain. eespinosa00@hotmail.com ·Clin Transl Oncol · Pubmed #22551537.

ABSTRACT: After several decades of slow progress in the field of melanoma, significant advances have been reported in recent years. These include a better understanding of the molecular biology of the tumour, a new staging classification system, insights into the patterns of relapse in early stage, and new drugs for the treatment of advanced disease. Ipilimumab and vemurafenib have just been approved and provide a survival benefit in stage IV. Both compounds are under evaluation in the adjuvant setting, where interferon remains the only drug with proven efficacy. Further investigation is required to treat patients with primary or secondary resistance to new drugs.

9 Review Immunotherapy of distant metastatic disease. 2009

Schadendorf, D / Algarra, S M / Bastholt, L / Cinat, G / Dreno, B / Eggermont, A M M / Espinosa, E / Guo, J / Hauschild, A / Petrella, T / Schachter, J / Hersey, P. ·Department of Dermatology, University Hospital Essen, Essen, Germany. dirk.schadendorf@uk-essen.de ·Ann Oncol · Pubmed #19617297.

ABSTRACT: Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon alpha, and/or with various chemotherapeutic agents (biochemotherapy) is associated with significant toxicity and poor efficacy that does not improve overall survival of 96% of patients. Many studies with allogeneic and autologous vaccines have demonstrated no clinical benefit, and some randomised trials even showed a detrimental effect in the vaccine arm. The ongoing effort to develop melanoma vaccines based on dendritic cells and peptides is driven by advances in understanding antigen presentation and processing, and by new techniques of vaccine preparation, stabilisation and delivery. Several agents that have shown promising activity in metastatic melanoma including IL-21 and monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) or CD137 are discussed. Recent advances of intratumour gene transfer technologies and adoptive immunotherapy, which represents a promising although technically challenging direction, are also discussed.

10 Review Small molecules and targeted therapies in distant metastatic disease. 2009

Hersey, P / Bastholt, L / Chiarion-Sileni, V / Cinat, G / Dummer, R / Eggermont, A M M / Espinosa, E / Hauschild, A / Quirt, I / Robert, C / Schadendorf, D. ·Immunology and Oncology Unit, Calvary Mater Newcastle Hospital, New South Wales, Australia. Peter.Hersey@newcastle.edu.au ·Ann Oncol · Pubmed #19617296.

ABSTRACT: Chemotherapy, biological agents or combinations of both have had little impact on survival of patients with metastatic melanoma. Advances in understanding the genetic changes associated with the development of melanoma resulted in availability of promising new agents that inhibit specific proteins up-regulated in signal cell pathways or inhibit anti-apoptotic proteins. Sorafenib, a multikinase inhibitor of the RAF/RAS/MEK pathway, elesclomol (STA-4783) and oblimersen (G3139), an antisense oligonucleotide targeting anti-apoptotic BCl-2, are in phase III clinical studies in combination with chemotherapy. Agents targeting mutant B-Raf (RAF265 and PLX4032), MEK (PD0325901, AZD6244), heat-shock protein 90 (tanespimycin), mTOR (everolimus, deforolimus, temsirolimus) and VEGFR (axitinib) showed some promise in earlier stages of clinical development. Receptor tyrosine-kinase inhibitors (imatinib, dasatinib, sunitinib) may have a role in treatment of patients with melanoma harbouring c-Kit mutations. Although often studied as single agents with disappointing results, new targeted drugs should be more thoroughly evaluated in combination therapies. The future of rational use of new targeted agents also depends on successful application of analytical techniques enabling molecular profiling of patients and leading to selection of likely therapy responders.

11 Clinical Trial Open-label, multicentre safety study of vemurafenib in 3219 patients with BRAF 2017

Blank, Christian U / Larkin, James / Arance, Ana M / Hauschild, Axel / Queirolo, Paola / Del Vecchio, Michele / Ascierto, Paolo A / Krajsova, Ivana / Schachter, Jacob / Neyns, Bart / Garbe, Claus / Chiarion Sileni, Vanna / Mandalà, Mario / Gogas, Helen / Espinosa, Enrique / Hospers, Geke A P / Miller, Wilson H / Robson, Susan / Makrutzki, Martina / Antic, Vladan / Brown, Michael P. ·The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, The Netherlands. Electronic address: c.blank@nki.nl. · The Royal Marsden NHS Foundation Trust, London, UK. Electronic address: James.Larkin@rmh.nhs.uk. · Department of Medical Oncology, Hospital Clínic Barcelona, Barcelona, Spain. Electronic address: AMARANCE@clinic.ub.es. · Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany. Electronic address: ahauschild@dermatology.uni-kiel.de. · IRCCS San Martino-IST, Genova, Italy. Electronic address: paola.queirolo@hsanmartino.it. · Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Michele.delvecchio@istitutotumori.mi.it. · Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. Electronic address: paolo.ascierto@gmail.com. · General University Hospital, Dermatooncology U, Prague, Czech Republic. Electronic address: Ivana.Krajsova@vfn.cz. · Chaim Sheba Medical Centre, Oncology Institute, Ramat-Gan, Israel. Electronic address: Jacob.schachter@sheba.health.gov.il. · Afdelingshoofd, Medische Oncologie, Brussels, Belgium. Electronic address: bart.neyns@uzbrussel.be. · Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany. Electronic address: claus.garbe@med.uni-tuebingen.de. · Oncology Institute of Veneto-IRCCS, Padova, Italy. Electronic address: vanna.chiarion@ioveneto.it. · Papa Giovanni XIII Hospital, Bergamo, Italy. Electronic address: mariomandala@tin.it. · University of Athens, Athens, Greece. Electronic address: hgogas@hol.gr. · Hospital La Paz, Madrid, Spain. Electronic address: eespinosa00@hotmail.com. · University Medical Centre Groningen, Groningen, The Netherlands. Electronic address: g.a.p.hospers@umcg.nl. · McGill University, Segal Cancer Centre, Montreal, Quebec, Canada. Electronic address: wilsonmiller@gmail.com. · F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: susan.robson@roche.com. · F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: martina.makrutzki@roche.com. · F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: vladan.antic@roche.com. · Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia; Discipline of Medicine, University of Adelaide, Adelaide, Australia. Electronic address: MichaelP.brown@sa.gov.au. ·Eur J Cancer · Pubmed #28501764.

ABSTRACT: BACKGROUND: The orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAF METHODS: This was an open-label, multicentre study of vemurafenib (960 mg bid) in patients with previously treated or untreated BRAF mutation-positive metastatic melanoma (cobas RESULTS: After a median follow-up of 32.2 months (95% CI, 31.1-33.2 months), 3079/3219 patients (96%) had discontinued treatment. Adverse events (AEs) were largely consistent with previous reports; the most common all-grade treatment-related AEs were arthralgia (37%), alopecia (25%) and hyperkeratosis (23%); the most common grade 3/4 treatment-related AEs were squamous cell carcinoma of the skin (8%) and keratoacanthoma (8%). In the exploratory analysis, patients with DOR ≥12 months (n = 287) or ≥24 months (n = 133) were more likely to experience grade 3/4 AEs than the overall population. No new specific safety signals were observed with longer vemurafenib exposure. CONCLUSIONS: After 2 years' follow-up, safety was maintained in this large group of patients with BRAF

12 Clinical Trial Safety of vemurafenib in patients with BRAF 2016

Arance, A M / Berrocal, A / Lopez-Martin, J A / de la Cruz-Merino, L / Soriano, V / Martín Algarra, S / Alonso, L / Cerezuela, P / La Orden, B / Espinosa, E. ·Hospital Clínic and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AMARANCE@clinic.ub.es. · Hospital General Universitario de Valencia, Valencia, Spain. · Hospital Universitario 12 de Octubre, Madrid, Spain. · Hospital Univ. Virgen de la Macarena de Sevilla, Seville, Spain. · Instituto Valenciano de Oncología, Valencia, Spain. · Clínica Universidad de Navarra, Navarra, Spain. · Hospital Clínico de Málaga, Malaga, Spain. · Hospital Universitario Santa Lucía de Cartagena, Cartagena, Spain. · Roche Farma, Madrid, Spain. · Hospital Universitario La Paz, Madrid, Spain. ·Clin Transl Oncol · Pubmed #26983408.

ABSTRACT: OBJECTIVES: Vemurafenib tolerability was assessed in a large, open-label, multicentre study in patients with BRAF METHODS: Patients with previously treated or treatment-naive, unresectable stage IIIC or stage IV, BRAF RESULTS: 301 Spanish patients were included, 70 % with M1c disease, 22 % with brain metastases and 51 % with prior systemic therapy for metastatic disease. Most frequent adverse events included fatigue (48 %), arthralgia (45 %), rash (41 %), photosensitivity (34 %) and skin neoplasms (21 %). Grade 3/4 adverse events occurred in 156 patients (52 %), including cutaneous squamous cell carcinoma (including keratoacanthoma; 16 %), fatigue (6 %) and arthralgia (5 %). The ORR was 28 % (95 % CI 23-34 %). Responses occurred in patients with brain metastases (18 %), elevated baseline lactate dehydrogenase (19 %) and poor performance status (15 %), and elderly patients (22 %). Median PFS was 5.8 (95 % CI 5.0-6.4) months; median OS was 10.5 (95 % CI 9.5-13.5) months. CONCLUSION: Our results for Spanish patients in the vemurafenib safety study indicate similar efficacy and a comparable safety profile in Spanish patients with no new safety signals compared with the overall population. Clinical benefit was demonstrated in poor-prognosis patients and in those with favourable baseline characteristics, suggesting that poor-prognosis patients may also benefit from vemurafenib treatment.

13 Clinical Trial Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. 2014

Larkin, James / Del Vecchio, Michele / Ascierto, Paolo A / Krajsova, Ivana / Schachter, Jacob / Neyns, Bart / Espinosa, Enrique / Garbe, Claus / Sileni, Vanna Chiarion / Gogas, Helen / Miller, Wilson H / Mandalà, Mario / Hospers, Geke A P / Arance, Ana / Queirolo, Paola / Hauschild, Axel / Brown, Michael P / Mitchell, Lada / Veronese, Luisa / Blank, Christian U. ·Royal Marsden Hospital NHS Foundation Trust, London, UK. Electronic address: james.larkin@rmh.nhs.uk. · Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy. · Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. · Dermatooncology Department, General University Hospital, Prague, Czech Republic. · Ella Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel. · Universitair Ziekenhuis Brussel, Brussels, Belgium. · Service of Oncology-Hospital La Paz, Madrid, Spain. · Universität Tübingen-Hautklinik, Tübingen, Germany. · Melanoma Oncology Unit, Veneto Oncology Institute, Gattamelata, Padova, Italy. · Medical Oncology, University of Athens, Greece. · Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada. · Papa Giovanni XXIII Hospital, Bergamo, Italy. · Department of Medical Oncology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands. · Department of Medical Oncology, Hospital Clínic, Barcelona, Spain. · IRCCS San Martino Hospital-IST, Genoa, Italy. · University Hospital Schleswig-Holstein, Department of Dermatology, Kiel, Germany. · Cancer Clinical Trials Unit, Royal Adelaide Hospital, and Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia. · F Hoffmann-La Roche, Basel, Switzerland. · Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands. Electronic address: c.blank@nki.nl. ·Lancet Oncol · Pubmed #24582505.

ABSTRACT: BACKGROUND: The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAF(V600) mutations who had few treatment options. METHODS: In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAF(V600) mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397. FINDINGS: Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 [49%]), arthralgia (1259 [39%]), fatigue (1093 [34%]), photosensitivity reaction (994 [31%]), alopecia (826 [26%]), and nausea (628 [19%]). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 [12%]), rash (155 [5%]), liver function abnormalities (165 [5%]), arthralgia (106 [3%]), and fatigue (93 [3%]). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 [59%, 95% CI 53-65] and ten [4%, 2-7], respectively) than in those younger than 75 years (n=2965; 1286 [43%, 42-45] and 82 [3%, 2-3], respectively). INTERPRETATION: Vemurafenib safety in this diverse population of patients with BRAF(V600) mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug. FUNDING: F Hoffmann-La Roche.

14 Clinical Trial Phase II study of weekly Kahalalide F in patients with advanced malignant melanoma. 2009

Martín-Algarra, Salvador / Espinosa, Enrique / Rubió, Jordi / López López, Juan José / Manzano, José Luis / Carrión, Lorenzo Alonso / Plazaola, Arrate / Tanovic, Adnan / Paz-Ares, Luis. ·Clínica Universitaria de Navarra, Pamplona, Spain. smalgarra@unav.es ·Eur J Cancer · Pubmed #19186051.

ABSTRACT: This phase II clinical trial evaluated the antitumour response of Kahalalide F (KF) 650 microg/m(2) given as a 1-h weekly infusion in advanced malignant melanoma patients, both untreated and those who relapsed or progressed after one line of systemic therapy. Of 24 enrolled patients (median age, 55 years; range, 28-89), 14 patients had been previously treated with chemotherapy or biological therapy. No RECIST responses occurred; five chemotherapy-naïve patients with cutaneous melanoma had disease stabilisation for > or = 3 months; median progression-free survival was 1.7 months (95% CI, 1.2-1.9 months); and median overall survival was 10.8 months (95% CI, 5.0-upper limit not reached). The most common laboratory toxicities were non-cumulative increase of transaminases (ALT/AST) and gamma-glutamyltransferase (GGT). No patients experienced leukopenia and thrombocytopenia during the study. KF was a well-tolerated and safe chemotherapy regimen. Despite a favourable safety profile, this trial was closed after the first stage because of the lack of objective response in patients with malignant melanoma.

15 Article Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program. 2017

González-Cao, M / Arance, A / Piulats, J M / Marquez-Rodas, I / Manzano, J L / Berrocal, A / Crespo, G / Rodriguez, D / Perez-Ruiz, E / Berciano, M / Soria, A / Castano, A G / Espinosa, E / Montagut, C / Alonso, L / Puertolas, T / Aguado, C / Royo, M A / Blanco, R / Rodríguez, J F / Muñoz, E / Mut, P / Barron, F / Martin-Algarra, S / Anonymous4770892. ·Translational Cancer Research Unit, Dr. Rosell Oncology Institute, Quiron Dexeus University Hospital, 08028, Barcelona, Spain. mgonzalezcao@oncorosell.com. · Hospital Clinic I Provincial, Barcelona, Spain. · Catalan Institute of Oncology, Barcelona, Spain. · Gregorio Marañón Institute of Health Research, Madrid, Spain. · Germans Trias I Pujol University Hospital, Barcelona, Spain. · General University Hospital, Valencia, Spain. · Burgos University Hospital, Burgos, Spain. · Insular University Hospital of Gran Canaria, Canary Islands, Spain. · Costa del Sol Hospital, Marbella, Malaga, Spain. · Regional University Hospital of Malaga, Malaga, Spain. · Ramony Cajal Hospital, Madrid, Spain. · Marqués de Valdecilla University Hospital, Santander, Spain. · La Paz University Hospital, Madrid, Spain. · Del Mar University Hospital, Barcelona, Spain. · Virgen de la Victoria Hospital, Malaga, Spain. · Miguel Servet University Hospital, Zaragoza, Spain. · San Carlos Hospital, Madrid, Spain. · Dr. Peset Hospital, Valencia, Spain. · Consorci Sanitari de Terrassa, Barcelona, Spain. · Clara Campal Hospital, Madrid, Spain. · Valld'Hebron University Hospital, Barcelona, Spain. · Son Llatzer University Hospital, Mallorca, Spain. · National Cancer Institute, Mexico City, Mexico. · Navarra University Clinic, Pamplona, Spain. ·Clin Transl Oncol · Pubmed #28054320.

ABSTRACT: BACKGROUND: The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. METHODS: Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. RESULTS: Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. CONCLUSION: Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.

16 Article Treatment patterns of adjuvant interferon-α2b for high-risk melanoma: a retrospective study of the Grupo Español Multidisciplinar de Melanoma - Prima study. 2016

Espinosa, Enrique / Soriano, Virtudes / Malvehy, Josep / Berrocal, Alfonso / Martínez de Prado, Purificación / Quindós, María / Soria, Ainara / Márquez-Rodas, Iván / Palacio, Isabel / Cerezuela, Pablo / López-Vivanco, Guillermo / Alonso, Lorenzo / Samaniego, Elia / Ballesteros, Ana / Puértolas, Teresa / Díaz-Beveridge, Rodrigo / de la Cruz-Merino, Luis / López Castro, Rafael / López López, Rafael / Stevinson, Kendall / Del Barrio, Patricia / Tornamira, Maria V / Guillém, Vicente / Martín-Algarra, Salvador. ·aMedical Oncology Service, Hospital Universitario La Paz bMedical Oncology Service, Hospital Ramón y Cajal cMedical Oncology Service, Instituto de Investigación Sanitaria Gregorio Marañon dMedical Oncology Service, Hospital La Princesa eMedical Affairs, Merck Sharp & Dohme, Madrid fMedical Oncology Service, Instituto Valenciano de Oncología gMedical Oncology Service, Hospital General Universitario de Valencia hMedical Oncology Service, Hospital La Fe, Valencia iMedical Oncology Service, Hospital Clinic de Barcelona, Barcelona jMedical Oncology Service, Hospital de Basurto, Bilbao kMedical Oncology Service, Hospital Teresa Herrera, La Coruña lMedical Oncology Service, Hospital Central de Asturias, Oviedo mMedical Oncology Service, Hospital General Universitario Santa Lucía, Cartagena nMedical Oncology Service, Hospital de Cruces, San Vicente de Baracaldo oMedical Oncology Service, Hospital Universitario Virgen de la Victoria, Málaga pDermatology Service, Complejo Asistencial Universitario de León, León qMedical Oncology Service, Hospital Miguel Servet, Zaragoza rMedical Oncology Service, Hospital Virgen de la Macarena, Sevilla sMedical Oncology Service, Hospital Clínico Universitario de Valladolid, Valladolid tMedical Oncology Service, Hospital Clínico Universitario de Santiago, Santiago de Compostela uMedical Oncology Service, Clínica Universitaria de Navarra, Pamplona, Spain vGlobal Health Outcomes Research, Merck Sharp & Dohme, Kenilworth, New Jersey, USA. ·Melanoma Res · Pubmed #26958991.

ABSTRACT: Adjuvant interferon-α2b (IFN-α2b) has been studied extensively in clinical trials, but there have been few studies of real-world use. The aim of this study is to describe the IFN-α2b real-world patterns in patients with high-risk melanoma in Spain. This was a retrospective and multicentre chart review study of an unselected cohort of patients with melanoma at high risk for relapse (stage IIB/IIC/III) treated with IFN-α2b. Patterns were assessed in terms of dose and compliance to planned treatment. A survival analysis was carried out for the full population and according to Kirkwood scheme compliance and the presence of ulceration. Of 327 patients treated with IFN-α2b, 318 received a high-dose regimen following the standard Kirkwood scheme; thus, patterns are described for this regimen. A total of 121 (38%) and 88 (28%) patients had at least one dose reduction during the induction and maintenance phases, respectively. Dose delay was required in fewer than 10% of patients. A total of 78, 40 and 38% of the patients completed the induction phase, maintenance phase and completed treatment, respectively. The median progression-free and overall survival for the full population were 3.2 and 10.5 years, respectively. There were no differences in progression-free survival and overall survival according to Kirkwood scheme compliance and the presence of ulceration. The most frequent adverse events were neutropenia (31%) and fatigue (30%). High-dose IFN-α2b is the most frequently used regimen in Spain as an adjuvant systemic treatment for high-risk melanoma. Despite poor compliance, in this retrospective study, IFN-α2b treatment provided a benefit consistent with that described previously.

17 Article Melanoma cell lysosome secretory burst neutralizes the CTL-mediated cytotoxicity at the lytic synapse. 2016

Khazen, Roxana / Müller, Sabina / Gaudenzio, Nicolas / Espinosa, Eric / Puissegur, Marie-Pierre / Valitutti, Salvatore. ·Inserm, U1043, Toulouse F-31300, France. · CNRS, U5282, Toulouse 31300, France. · Université de Toulouse, UPS, Centre de Physiopathologie Toulouse-Purpan (CPTP), Toulouse F-31300, France. · Departement of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse 31059, France. ·Nat Commun · Pubmed #26940455.

ABSTRACT: Human melanoma cells express various tumour antigens that are recognized by CD8(+) cytotoxic T lymphocytes (CTLs) and elicit tumour-specific responses in vivo. However, natural and therapeutically enhanced CTL responses in melanoma patients are of limited efficacy. The mechanisms underlying CTL effector phase failure when facing melanomas are still largely elusive. Here we show that, on conjugation with CTL, human melanoma cells undergo an active late endosome/lysosome trafficking, which is intensified at the lytic synapse and is paralleled by cathepsin-mediated perforin degradation and deficient granzyme B penetration. Abortion of SNAP-23-dependent lysosomal trafficking, pH perturbation or impairment of lysosomal proteolytic activity restores susceptibility to CTL attack. Inside the arsenal of melanoma cell strategies to escape immune surveillance, we identify a self-defence mechanism based on exacerbated lysosome secretion and perforin degradation at the lytic synapse. Interfering with this synaptic self-defence mechanism might be useful in potentiating CTL-mediated therapies in melanoma patients.

18 Article Clinical use of ipilimumab for metastatic melanoma in Spain: towards a more consistent approach. 2016

Martín-Algarra, S / de la Cruz-Merino, L / Soriano, V / Manzano, J L / Espinosa, E. ·Department of Oncology, Clínica Universidad de Navarra. Instituto de Investigación Sanitaria de Navarra (IDISNA), Av. Pío XII, 36, 31008, Pamplona, Navarra, España, Spain. smalgarra@unav.es. · Department of Clinical Oncology, Hospital Virgen Macarena, Seville, Spain. · Department of Oncology, Instituto Valenciano Oncología, Valencia, Spain. · Department of Oncology, Hospital Germans Trias i Pujol. ICO-Badalona, Barcelona, Spain. · Department of Oncology, Hospital La Paz, Madrid, Spain. ·Clin Transl Oncol · Pubmed #26801342.

ABSTRACT: INTRODUCTION: Ipilimumab has been approved in patients with advanced melanoma by different regulatory bodies worldwide, but its use in clinical practice is not fully consistent among oncologists. We have surveyed a representative sample of Spanish medical oncologists on issues related to the use of ipilimumab. MATERIALS AND METHODS: The survey was based on the Delphi method, where experts respond anonymously to two rounds of a questionnaire. Questionnaire consisted of 42 statements divided among the following eight categories: Pathology and Diagnosis; Patterns of Response; Parameters affecting Treatment Selection; Patient Profile; Sequencing of Treatment; Definition of Long-Term Survivors; Quality of Life; Concept of Immuno-oncology. The experts were asked to rate each statement on a scale of 1-9, where 1 meant "completely disagree" and 9 meant "completely agree". RESULTS: Thirty-three oncologists responded to both rounds of the survey (62.3 % of total surveyed). On issues related to pathology and diagnosis, patterns of response, and immuno-oncology, the specialists reached a high level of consensus. There was also a high level of agreement, albeit without consensus on assessment of BRAF mutations before deciding on treatment with ipilimumab. However, there was a lower level of agreement on sequencing treatment with BRAF inhibitors and ipilimumab, on predictive factors, on the use of corticosteroids, and on patient quality of life. CONCLUSIONS: The disparity in many of these topics suggests that oncologists need more information on certain aspects of ipilimumab treatment. We need to define generally accepted algorithms of treatment, especially with regard to issues that were shown to be controversial or unclear.

19 Article SEOM guidelines for the management of Malignant Melanoma 2015. 2015

Berrocal, A / Arance, A / Espinosa, E / Castaño, A G / Cao, M G / Larriba, J L G / Martín, J A L / Márquez, I / Soria, A / Algarra, S M. ·Servicio de Oncología Médica, Consorcio Hospital General Universitario de Valencia, Avda. Tres Cruces 2, 46014, Valencia, Spain. berrocal.alf@gmail.com. · Hospital Clinic I Provincial de Barcelona, Barcelona, Spain. · Hospital Universitario la Paz, Madrid, Spain. · Hospital Universitario Marqués de Valdecilla, Santander, Spain. · Hospital Universitario Quirón Dexeus, Barcelona, Spain. · Hospital Universitario Clínico San Carlos, Madrid, Spain. · Hospital Universitario 12 de Octubre, Madrid, Spain. · Hospital General Universitario Gregorio Marañón, Madrid, Spain. · Hospital Universitario Ramón y Cajal, Madrid, Spain. · Clínica Universitaria de Navarra, Pamplona, Spain. ·Clin Transl Oncol · Pubmed #26669314.

ABSTRACT: All melanoma patients must be confirmed histologically and resected according to Breslow. Sentinel node biopsy must be done when tumor is over 1 mm or if less with high-risk factors. Adjuvant therapy with interferon must be offered for patients with high-risk melanoma and in selected cases radiotherapy can be added. Metastatic melanoma treatment is guided by mutational BRAF status. BRAF wild type patients must receive anti-PD1 therapy and BRAF mutated patients BRAF/MEK inhibitors or anti-PD1 therapy. Up to 10 years follow up is recommended for melanoma patients with dermatologic examinations and physical exams.

20 Article Melanoma early detection and awareness: how countries developing melanoma awareness programs could benefit from melanoma-proficient countries. 2015

Wainstein, Alberto / Algarra, Salvador Martin / Bastholt, Lars / Cinat, Gabriela / Demidov, Lev / Grob, Jean Jacques / Guo, Jun / Hersey, Peter / Espinosa, Enrique / Schachter, Jacob / Whitaker, Dagmar / Quirt, Ian / Hauschild, Axel / Rutkowski, Piotr. ·1Faculdade de Ciências Médicas, Minas Gerais, Brazil; 2Clinica Universitaria de Navarra, Pamplona, Spain; 3Odense University Hospital, Odense, Denmark; 4Instituto de Oncologia Angel Rolfo, Buenos Aires, Argentina; 5Blokhin Cancer Center, Moscow, Russia; 6Hospital Sainte Marguerite, Marseilles, France; 7Beijing Cancer Hospital, Beijing, China; 8Newcastle University, Newcastle, Australia; 9Hospital La Paz, Madrid, Spain; 10Sheba Medical Center, Tel Hashomer, Israel; 11Melanoma Advisory Board South Africa, Cape Town, South Africa; 12Princess Margaret Hospital, Toronto, Canada; 13University of Kiel, Kiel, Germany; 14M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. ·Am J Ther · Pubmed #24914500.

ABSTRACT: Risk factors for melanoma are well known and have guided plans for primary and secondary prevention. The presentation of the disease, however, varies widely depending on the geographic area, ethnicity, and socioeconomic status. For this reason, many countries have developed specific strategies to increase public awareness and favor early diagnosis. Awareness campaigns, doctor education, and screening of high-risk subjects have all contributed to improve disease outcome in developed countries. The role of primary care physicians is particularly relevant in this regard. Developing countries are trying to implement similar measures. Future efforts to further improve the efficacy of preventive strategies should focus on populations that usually escape campaigns, such as elderly men and people with low socioeconomic status. Fast-growing tumors also require specific attention.

21 Article Ipilimumab for advanced melanoma: experience from the Spanish Expanded Access Program. 2014

Berrocal, Alfonso / Arance, Ana / Lopez Martin, Jose Antonio / Soriano, Virtudes / Muñoz, Eva / Alonso, Lorenzo / Espinosa, Enrique / Lopez Criado, Pilar / Valdivia, Javier / Martin Algarra, Salvador / Anonymous350801. ·aMedical Oncology, Hospital General Valencia bMedical Oncology, Instituto Valenciano de Oncologia, Valencia cMedical Oncology, Hospital Clinic i Provincial dMedical Oncology, Hospital Vall d´Hebron, Barcelona eMedical Oncology, Hospital 12 de Octubre fMedical Oncology, Hospital La Paz gMedical Oncology, Hospital MD Anderson Cancer Center, Madrid hMedical Oncology, Hospital ClinicoVirgen de la Victoria, Malaga iMedical Oncology, Hospital Virgen de las Nieves, Granada jMedical Oncology, Clinica Universitaria de Navarra, Pamplona, Spain. ·Melanoma Res · Pubmed #25046550.

ABSTRACT: Ipilimumab, a fully human, recombinant, monoclonal antibody to cytotoxic T-lymphocyte antigen 4 improves overall survival (OS) in previously treated and untreated metastatic melanoma. This retrospective analysis reports data gathered by a questionnaire on the demographics, outcomes, and toxicity of ipilimumab administered through an Expanded Access Program (EAP). Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for four cycles to adults with metastatic melanoma. Efficacy outcomes included complete response, partial response (PR), progressive disease, stabilized disease, and OS. EAP data were collected from EAP physicians. A subgroup analysis examined efficacy in elderly patients (≥70 years) and factors predictive of survival were identified. Of 355 requests for ipilimumab, resulting in 288 treatments, completed questionnaires were received for 153 ipilimumab recipients (median age 58 years, 57.2% men). Efficacy was evaluated in 144 patients: complete response in 1.3%, PR in 9.6%, PR with previous progression 8.4%, stabilized disease in 14.5%, and progressive disease in 66.2%. The median OS was 6.5 months (199 days); 1-year survival was 32.9%. Predictive survival factors included lymphocytes over 1000/ml (P=0.0008) and lactate dehydrogenase more than 1.5×upper limit of normal (P=0.003). Cutaneous, hepatic, and gastrointestinal toxicities were mild. In 30 patients aged more than 70 years, ipilimumab efficacy and tolerability was similar to that of the overall population. In the clinical practice setting, ipilimumab is effective and well tolerated in patients with advanced melanoma, including elderly patients, when administered at the recommended dosage. Ipilimumab improves treatment options for patients who, until recently, have had little hope of an improved prognosis.