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Melanoma: HELP
Articles by Salvador Martín-Algarra
Based on 28 articles published since 2008
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Between 2008 and 2019, S. Martin-Algarra wrote the following 28 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 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.

2 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.

3 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.

4 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.

5 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.

6 Review A new era in the treatment of melanoma: from biology to clinical practice. 2011

Márquez-Rodas, I / Martín Algarra, S / Avilés Izquierdo, J A / Custodio Cabello, S / Martín, M. ·Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain. ivanpantic@hotmail.com ·Clin Transl Oncol · Pubmed #22082642.

ABSTRACT: Melanoma is the deadliest cutaneous malignancy and its incidence continues to grow. Until 2011, the treatment options for metastatic melanoma were scarce and without any overall survival benefit. The emergence of new targeted therapies for BRAF mutant melanoma (vemurafenib) and immunotherapy (ipilimumab) has changed the standard of care for this disease. The objective of the present review is to summarise the biological background of the new therapeutic approaches in melanoma, focusing on apoptosis resistance, immune modulation and angiogenesis, and the direct translation into clinical practice.

7 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.

8 Clinical Trial Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine. 2014

Grob, J-J / Amonkar, M M / Martin-Algarra, S / Demidov, L V / Goodman, V / Grotzinger, K / Haney, P / Kämpgen, E / Karaszewska, B / Mauch, C / Miller, W H / Millward, M / Mirakhur, B / Rutkowski, P / Chiarion-Sileni, V / Swann, S / Hauschild, A. ·Aix-Marseille University, APHM, Hôpital Timone, Marseille, France jean-jacques.grob@ap-hm.fr. · GlaxoSmithKline, Collegeville, USA. · Department of Medical Oncology, Clínica Universidad de Navarra, Pamplona, Spain. · Department of Tumor Biotherapy, N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation. · Department of Dermatology, Skin Cancer Center, University Hospital Erlangen, Erlangen, Germany. · Przychodnia Lekarska KOMED, Konin, Poland. · Department for Dermatology and Venereology and CIO KölnBonn, University Hospital Cologne, Cologne, Germany. · Departments of Oncology and Medicine, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Canada. · Department of Medical Oncology, Sir Charles Gairdner Hospital and School of Medicine and Physiology, University of Western Australia, Perth, Australia. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. · Melanoma Cancer Unit, Veneto Oncology Institute-IRCCS, Padova, Italy. · Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany. ·Ann Oncol · Pubmed #24769640.

ABSTRACT: BACKGROUND: In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18-0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial. METHODS: The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits. RESULTS: For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks. CONCLUSIONS: This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient. ClinicalTrials.gov Identifier: NCT01227889.

9 Clinical Trial Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. 2012

Hauschild, Axel / Grob, Jean-Jacques / Demidov, Lev V / Jouary, Thomas / Gutzmer, Ralf / Millward, Michael / Rutkowski, Piotr / Blank, Christian U / Miller, Wilson H / Kaempgen, Eckhart / Martín-Algarra, Salvador / Karaszewska, Boguslawa / Mauch, Cornelia / Chiarion-Sileni, Vanna / Martin, Anne-Marie / Swann, Suzanne / Haney, Patricia / Mirakhur, Beloo / Guckert, Mary E / Goodman, Vicki / Chapman, Paul B. ·University Hospital, Schleswig-Holstein, Department of Dermatology, Kiel, Germany. ahauschild@dermatology.unikiel.de ·Lancet · Pubmed #22735384.

ABSTRACT: BACKGROUND: Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in studies of phase 1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma. We studied the efficacy of dabrafenib in patients with BRAF(V600E)-mutated metastatic melanoma. METHODS: We enrolled patients in this open-label phase 3 trial between Dec 23, 2010, and Sept 1, 2011. This report is based on a data cutoff date of Dec 19, 2011. Patients aged 18 years or older with previously untreated, stage IV or unresectable stage III BRAF(V600E) mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m(2) intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was investigator-assessed progression-free survival and was analysed by intention to treat; safety was assessed per protocol. This study is registered with ClinicalTrials.gov, number NCT01227889. FINDINGS: Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median progression-free survival was 5·1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18-0·51; p<0·0001). At data cutoff, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomised treatment. Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia. Grade 3-4 adverse events were uncommon in both groups. INTERPRETATION: Dabrafenib significantly improved progression-free survival compared with dacarbazine. FUNDING: GlaxoSmithKline.

10 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.

11 Clinical Trial Preliminary results of the combination of bevacizumab and weekly Paclitaxel in advanced melanoma. 2008

González-Cao, M / Viteri, S / Díaz-Lagares, A / González, A / Redondo, P / Nieto, Y / Espinós, J / Chopitea, A / Ponz, M / Martín-Algarra, S. ·Department of Oncology, University Clinic of Navarra, Navarra University, Pamplona, Spain. ·Oncology · Pubmed #18536525.

ABSTRACT: BACKGROUND: Pretreated advanced melanoma is a poor prognosis scenario with few, if any, active therapeutic options. The antibody against vascular endothelial growth factor, bevacizumab, has demonstrated increased activity in combination with chemotherapy in many tumors. We intended to evaluate the activity of the combination of weekly paclitaxel and bevacizumab in previously treated metastatic melanoma. PATIENTS AND METHODS: Patients with previously treated metastatic melanoma received paclitaxel 70 mg/m(2) weekly and bevacizumab 10 mg/kg biweekly for 5 consecutive weeks every 6 weeks. RESULTS: Twelve patients were treated. Two patients (16.6%) achieved a partial response and 7 patients (58.3%) stable disease. Responses were seen in soft tissue, lung and brain metastases. Median disease-free and overall survival times were 3.7 and 7.8 months, respectively. Treatment was well tolerated. Main toxicities were grade 3 asymptomatic lymphopenia in 6 patients, grade 3 leucopenia in 2 patients, and grade 3 thrombocytopenia in 1 patient. CONCLUSIONS: Our preliminary results suggest that the combination of bevacizumab and weekly paclitaxel is active and safe in patients with metastatic melanoma, warranting further investigation.

12 Article Dabrafenib plus trametinib for compassionate use in metastatic melanoma: A STROBE-compliant retrospective observational postauthorization study. 2017

Martín Algarra, Salvador / Soriano, Virtudes / Fernández-Morales, Luis / Berciano-Guerrero, Miguel-Ángel / Mujika, Karmele / Manzano, José Luis / Puértolas Hernández, Teresa / Soria, Ainara / Rodríguez-Abreu, Delvys / Espinosa Arranz, Enrique / Medina Martínez, Javier / Márquez-Rodas, Ivan / Rubió-Casadevall, Jordi / Ortega, María Eugenia / Jurado García, José Miguel / Lecumberri Biurrun, María José / Palacio, Isabel / Rodríguez de la Borbolla Artacho, María / Altozano, Javier Pérez / Castellón Rubio, Victoria Eugenia / García, Almudena / Luna, Pablo / Ballesteros, Anabel / Fernández, Ovidio / López Martín, Jose Antonio / Berrocal, Alfonso / Arance, Ana. ·Medical Oncology, Clínica Universidad de Navarra, Pamplona. · Instituto Valenciano de Oncología, Valencia. · Medical Oncology, Parc Taulí Sabadell Hospital Universitario, Sabadell. · Oncología Intercentros, Hospitales Universitarios Regional y Virgen de la Victoria (HURyVV) and Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga. · Onkologikoa, Instituto Oncológico de Kutxa, San Sebastian. · Instituto Catalán de Oncología, ICO-Badalona, Hospital Germans Trías I Pujol, Barcelona. · Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza. · Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid. · Medical Oncology, Complejo Hospitalario Universitario Insular-Materno Infantil de Gran Canaria, Las Palmas de Gran Canaria. · Medical Oncology, Hospital Universitario La Paz, Madrid. · Medical Oncology, Hospital Virgen de la Salud, Toledo. · Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid. · Instituto Catalán de Oncología Girona, Girona. · Medical Oncology, Hospital Universitario Arnau de Vilanova, Lleida. · Medical Oncology, Hospital Universitario San Cecilio, Granada. · Medical Oncology, Complejo Hospitalario de Navarra, Pamplona. · Medical Oncology, Hospital Universitario Central de Asturias, Oviedo. · Medical Oncology, Hospital Universitario Nuestra Señora de Valme, Sevilla. · Medical Oncology, Hospital General Universitario de Elche, Alicante. · Medical Oncology, Complejo Hospitalario Torrecárdenas de Almería, Almería. · Medical Oncology, Hospital Marqués de Valdecilla, Santander. · Medical Oncology, Hospital Universitario Son Espases, Palma de Mallorca. · Medical Oncology, Hospital Universitario La Princesa, Madrid. · Medical Oncology, Complejo Hospitalario Universitario Ourense, Ourense. · Medical Oncology, Hospital Universitario 12 de Octubre, Madrid. · Medical Oncology, Hospital General Universitario de Valencia, Valencia. · Medical Oncology, Hospital Clínic Barcelona, Barcelona, Spain. ·Medicine (Baltimore) · Pubmed #29384960.

ABSTRACT: The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma.This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded-access program at 30 Spanish centers.Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively. All patients showed BRAF mutations in their primary or metastatic lesions; 3 were positive for V600K while the remainder had V600E or V600+. A positive response to treatment was reported in 89.3% of the patients. Overall survival rates at 12 and 24 months were 59.6% (95% confidence interval [CI], 52.5-68.9%) and 36.4% (95% CI, 27.8-45%), respectively. Progression-free survival rates at 12 and 24 months were 39.3% (95% CI, 31.1-47.5%) and 21.6% (95% CI, 14.5-28.7%), respectively. Fifty-seven patients (42.2%) reported cutaneous toxicity of any type, mainly hyperkeratosis (14.8%) and rash (11.9%). The most frequent adverse events were pyrexia (27.4%), asthenia (19.3%), arthralgia (16.9%), and diarrhoea (13.2%).Our results suggest that both dabrafenib alone or in combination with trametinib are effective for compassionate use in terms of response and/or survival rates. However, differences in patients' prognostic features ought to be considered. No new findings were revealed regarding the safety profiles of either regimen. This is the first study to evaluate the efficacy of these 2 selective BRAF and mitogen-activated extracellular signal-regulated kinase inhibitors in a real-world setting in Spain.

13 Article Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. 2017

Riaz, Nadeem / Havel, Jonathan J / Makarov, Vladimir / Desrichard, Alexis / Urba, Walter J / Sims, Jennifer S / Hodi, F Stephen / Martín-Algarra, Salvador / Mandal, Rajarsi / Sharfman, William H / Bhatia, Shailender / Hwu, Wen-Jen / Gajewski, Thomas F / Slingluff, Craig L / Chowell, Diego / Kendall, Sviatoslav M / Chang, Han / Shah, Rachna / Kuo, Fengshen / Morris, Luc G T / Sidhom, John-William / Schneck, Jonathan P / Horak, Christine E / Weinhold, Nils / Chan, Timothy A. ·Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR 97213, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Medical Oncology, Clínica Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98105, USA. · Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. · Department of Surgery and University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. · Bristol-Myers Squibb, Princeton, NJ 08648, USA. · Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: weinholn@mskcc.org. · Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: chant@mskcc.org. ·Cell · Pubmed #29033130.

ABSTRACT: The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.

14 Article Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients. 2017

Sanmamed, M F / Perez-Gracia, J L / Schalper, K A / Fusco, J P / Gonzalez, A / Rodriguez-Ruiz, M E / Oñate, C / Perez, G / Alfaro, C / Martín-Algarra, S / Andueza, M P / Gurpide, A / Morgado, M / Wang, J / Bacchiocchi, A / Halaban, R / Kluger, H / Chen, L / Sznol, M / Melero, I. ·Department of Immunobiology, Yale University School of Medicine, New Haven, USA. · Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain. · CIBERONC (Centro de Investigación Biomedica en Red de Cáncer). · Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. · Comprehensive Cancer Center Section of Medical Oncology, Yale University School of Medicine, New Haven, CT, USA. · Department of Biochemistry, Clínica Universidad de Navarra, Pamplona, Spain. · Centro de Investigación Biomédica en Red de Oncología (CIBERONC), Spain. · Department of Dermatology, Yale University School of Medicine, New Haven, USA. ·Ann Oncol · Pubmed #28595336.

ABSTRACT: Background: Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. Patients and methods: Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2-4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann-Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves. Results: Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P <0.001), and significantly increased upon progression (P =  0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P =  0.013). Early changes in serum IL-8 levels (2-4 weeks after treatment initiation) were strongly associated with response (P <0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P =  0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P =  0.001) and NSCLC (P =  0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression. Conclusions: Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.

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 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.

18 Article Circulating melanoma exosomes as diagnostic and prognosis biomarkers. 2016

Alegre, Estibaliz / Zubiri, Leyre / Perez-Gracia, Jose Luis / González-Cao, María / Soria, Lourdes / Martín-Algarra, Salvador / González, Alvaro. ·Laboratory of Biochemistry, University Clinic of Navarra, Spain. · Department of Medical Oncology, University Clinic of Navarra, Spain. · Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain. · Laboratory of Biochemistry, University Clinic of Navarra, Spain. Electronic address: agonzaleh@unav.es. ·Clin Chim Acta · Pubmed #26724367.

ABSTRACT: BACKGROUND: Malignant melanoma is an aggressive cancer with an increasing incidence. Exosomes are actively secreted microvesicles, whose characteristics reflect those of the cell they are originated in. The aim of this study was to identify and evaluate the presence of the melanoma biomarkers MIA, S100B and tyrosinase-related protein 2 (TYRP2) in exosomes and their potential clinical utility. METHODS: Serum samples were obtained from stage IV melanoma patients, melanoma-free patients and healthy controls. Exosomes were precipitated and TYRP2, MIA and S100B concentrations were quantified in serum, exosomes, and exosome-free serum. RESULTS: Both MIA and S100B were detected in exosomes and correlated significantly with serum concentrations (S100B: r=0.968; MIA: r=0.799; p<0.001). MIA and S100B concentrations in exosomes were significantly higher in melanoma patients than in healthy controls and disease-free patients. However, TYRP2 concentrations in exosomes did not differ between these three groups. ROC curves analysis rendered AUCs for MIA of 0.883 (p<0.01) and of 0.840 for S100B (p<0.01). Patients with exosome MIA concentration higher than 2.5 μg/L showed shorter median survival related to those with lower level (4 versus 11 months; p<0.05). CONCLUSIONS: MIA and S100B can be detected in exosomes from melanoma patients and their quantification presents diagnostic and prognostic utility.

19 Article BRAF mutation analysis in circulating free tumor DNA of melanoma patients treated with BRAF inhibitors. 2015

Gonzalez-Cao, Maria / Mayo-de-Las-Casas, Clara / Molina-Vila, Miguel A / De Mattos-Arruda, Leticia / Muñoz-Couselo, Eva / Manzano, Jose L / Cortes, Javier / Berros, Jose P / Drozdowskyj, Ana / Sanmamed, Miguel / Gonzalez, Alvaro / Alvarez, Carlos / Viteri, Santiago / Karachaliou, Niki / Martin Algarra, Salvador / Bertran-Alamillo, Jordi / Jordana-Ariza, Nuria / Rosell, Rafael. ·aTranslational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital bPangaea Biotech S.L cHospital Vall d'Hebron dCatalan Institute of Oncology, Hospital Germans Trias i Pujol Badalona eMORe Foundation, Barcelona fHospital Central Asturias, Oviedo gPivotal SL, Madrid hCUN, Pamplona, Spain. ·Melanoma Res · Pubmed #26366702.

ABSTRACT: BRAFV600E is a unique molecular marker for metastatic melanoma, being the most frequent somatic point mutation in this malignancy. Detection of BRAFV600E in blood could have prognostic and predictive value and could be useful for monitoring response to BRAF-targeted therapy. We developed a rapid, sensitive method for the detection and quantification of BRAFV600E in circulating free DNA (cfDNA) isolated from plasma and serum on the basis of a quantitative 5'-nuclease PCR (Taqman) in the presence of a peptide-nucleic acid. We validated the assay in 92 lung, colon, and melanoma archival serum and plasma samples with paired tumor tissue (40 wild-type and 52 BRAFV600E). The correlation of cfDNA BRAFV600E with clinical parameters was further explored in 22 metastatic melanoma patients treated with BRAF inhibitors. Our assay could detect and quantify BRAFV600E in mixed samples with as little as 0.005% mutant DNA (copy number ratio 1 : 20 000), with a specificity of 100% and a sensitivity of 57.7% in archival serum and plasma samples. In 22 melanoma patients treated with BRAF inhibitors, the median progression-free survival was 3.6 months for those showing BRAFV600E in pretreatment cfDNA compared with 13.4 months for those in whom the mutation was not detected (P=0.021). Moreover, the median overall survival for positive versus negative BRAFV600E tests in pretreatment cfDNA differed significantly (7 vs. 21.8 months, P=0.017). This finding indicates that the sensitive detection and accurate quantification of low-abundance BRAFV600E alleles in cfDNA using our assay can be useful for predicting treatment outcome.

20 Article Frequency and characteristics of familial melanoma in Spain: the FAM-GEM-1 Study. 2015

Márquez-Rodas, Iván / Martín González, Manuel / Nagore, Eduardo / Gómez-Fernández, Cristina / Avilés-Izquierdo, Jose Antonio / Maldonado-Seral, Cayetana / Soriano, Virtudes / Majem-Tarruella, Margarita / Palomar, Virginia / Maseda, Rocio / Martín-Carnicero, Alfonso / Puertolas, Teresa / Godoy, Elena / Cerezuela, Pablo / Ochoa de Olza, Maria / Campos, Begoña / Perez-Ruiz, Elisabeth / Soria, Ainara / Gil-Arnaiz, Irene / Gonzalez-Cao, Maria / Galvez, Elisa / Arance, Ana / Belon, Joaquin / de la Cruz-Merino, Luis / Martín-Algarra, Salvador / Anonymous731066. ·Servicio de Oncología Médica, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. · Servicio de Dermatología, Hospital Ramón y Cajal, Madrid, Spain. · Servicio de Dermatología, Instituto Valenciano de Oncología, Valencia, Spain. · Servicio de Dermatología, Hospital La Paz, Madrid, Spain. · Servicio de Dermatología, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. · Servicio de Deramtología, Hospital Universitario Central de Asturias, Oviedo, Spain. · Servicio de Oncología Médica, Instituto Valenciano de Oncología, Valencia, Spain. · Servicio de Oncología Médcica, Hospital de Sant Pau, Barcelona, Spain. · Servicio de Oncología Médica, Hospital General de Valencia, Valencia, Spain. · Servicio de Oncología Médica, Hospital de San Pedro, Logroño, Spain. · Servicio de Oncología, Hospital Universitario Miguel Servet, Zaragoza, Spain. · Servicio de Dermatología, Hospital de Cabueñes, Gijon, Spain. · Servicio de Oncología Médica, Hospital General Universitario Santa Lucia, Cartagena, Spain. · Servicio de Oncología Médica, Instituto Catalan de Oncología, Hospitalet, Spain. · Servicio de Oncología Médica, Hospital Lucus Augusti, Lugo, Spain. · Servicio de Oncología Médica, Hospital Costa del Sol, Marbella, Spain. · Servicio de Oncología Médica, Hospital Ramón y Cajal, Madrid, Spain. · Servicio de Oncología Medica, Hospital Reina Sofía, Tudela, Spain. · Servico de Oncología Médica, Instituto Dexeus, Barcelona, Spain. · Servicio de Oncología Médica, Hospital de Elda, Alicante, Spain. · Servicio de Oncología Medica, Hospital Clinic, Barcelona, Spain. · Servicio de Oncología Médica, Clínica Oncogranada, Granada, Spain. · Servicio de Oncología Médica, Hospital Virgen de la Macarena, Sevilla, Spain. · Departamento de Oncología, Clínica Universidad de Navarra, Pamplona, Spain. ·PLoS One · Pubmed #25874698.

ABSTRACT: INTRODUCTION: Familial history of melanoma is a well-known risk factor for the disease, and 7% melanoma patients were reported to have a family history of melanoma. Data relating to the frequency and clinical and pathological characteristics of both familial and non-familial melanoma in Spain have been published, but these only include patients from specific areas of Spain and do not represent the data for the whole of Spain. PATIENTS AND METHODS: An observational study conducted by the Spanish Group of Melanoma (GEM) analyzed the family history of patients diagnosed with melanoma between 2011 and 2013 in the dermatology and oncology departments. RESULTS: In all, 1047 patients were analyzed, and 69 (6.6%) fulfilled criteria for classical familial melanoma (two or more first-degree relatives diagnosed with melanoma). Taking into account other risk factors for familial melanoma, such as multiple melanoma, pancreatic cancer in the family or second-degree relatives with melanoma, the number of patients fulfilling the criteria increased to 165 (15.8%). Using a univariate analysis, we determined that a Breslow index of less than 1 mm, negative mitosis, multiple melanoma, and a history of sunburns in childhood were more frequent in familial melanoma patients, but a multivariate analysis revealed no differences in any pathological or clinical factor between the two groups. CONCLUSIONS: Similar to that observed in other countries, familial melanoma accounts for 6.6% of melanoma diagnoses in Spain. Although no differences in the multivariate analysis were found, some better prognosis factors, such as Breslow index, seem more frequent in familial melanoma, which reflect a better early detection marker and/or a different biological behavior.

21 Article Quantitative cell-free circulating BRAFV600E mutation analysis by use of droplet digital PCR in the follow-up of patients with melanoma being treated with BRAF inhibitors. 2015

Sanmamed, Miguel F / Fernández-Landázuri, Sara / Rodríguez, Carmen / Zárate, Ruth / Lozano, María D / Zubiri, Leyre / Perez-Gracia, José Luis / Martín-Algarra, Salvador / González, Alvaro. ·Department of Medical Oncology. · Department of Biochemistry, and. · Centro de Investigación Médica Aplicada (CIMA) Lab-Diagnostic, Pamplona, Navarra, Spain. · Department of Pathology, University Clinic of Navarra, Pamplona, Spain; · Department of Biochemistry, and agonzaleh@unav.es. ·Clin Chem · Pubmed #25411185.

ABSTRACT: BACKGROUND: Around 50% of cutaneous melanomas harbor the BRAF(V600E) mutation and can be treated with BRAF inhibitors. DNA carrying this mutation can be released into circulation as cell-free BRAF(V600E) (cfBRAF(V600E)). Droplet digital PCR (ddPCR) is an analytically sensitive technique for quantifying small concentrations of DNA. We studied the plasma concentrations of cfBRAF(V600E) by ddPCR in patients with melanoma during therapy with BRAF inhibitors. METHODS: Plasma concentrations of cfBRAF(V600E) were measured in 8 controls and 20 patients with advanced melanoma having the BRAF(V600E) mutation during treatment with BRAF inhibitors at baseline, first month, best response, and progression. RESULTS: The BRAF(V600E) mutation was detected by ddPCR even at a fractional abundance of 0.005% in the wild-type gene. Agreement between tumor tissue BRAF(V600E) and plasma cfBRAF(V600E) was 84.3%. Baseline cfBRAF(V600E) correlated with tumor burden (r = 0.742, P < 0.001). cfBRAF(V600E) concentrations decreased significantly at the first month of therapy (basal median, 216 copies/mL; Q1-Q3, 27-647 copies/mL; first response median, 0 copies/mL; Q1-Q3, 0-49 copies/mL; P < 0.01) and at the moment of best response (median, 0 copies/mL; Q1-Q3, 0-33 copies/mL; P < 0.01). At progression, there was a significant increase in the concentration of cfBRAF(V600E) compared with best response (median, 115 copies/mL; Q1-Q3, 3-707 copies/mL; P = 0.013). Lower concentrations of basal cfBRAF(V600E) were significantly associated with longer overall survival and progression-free survival (27.7 months and 9 months, respectively) than higher basal concentrations (8.6 months and 3 months, P < 0.001 and P = 0.024, respectively). CONCLUSIONS: cfBRAF(V600E) quantification in plasma by ddPCR is useful as a follow-up to treatment response in patients with advanced melanoma.

22 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.

23 Article Study of circulating microRNA-125b levels in serum exosomes in advanced melanoma. 2014

Alegre, Estibaliz / Sanmamed, Miguel F / Rodriguez, Carmen / Carranza, Omar / Martín-Algarra, Salvador / González, Alvaro. ·From the Laboratory of Biochemistry (Drs Alegre and González and Ms Rodriguez) and the Department of Medical Oncology (Drs Sanmamed and Martín-Algarra and Dr Carranza), University Clinic of Navarra, Pamplona, Navarra, Spain. ·Arch Pathol Lab Med · Pubmed #24878024.

ABSTRACT: CONTEXT: Malignant melanoma is an aggressive tumor that produces exosomes, which contain microRNAs (miRNAs) that could be of utility in following tumoral cell dysregulation. MicroR-125b is a miRNA whose down-regulation seems to be implicated in melanoma progression. OBJECTIVE: To analyze miR-125b levels in serum, and in exosomes obtained from serum, from patients with advanced melanoma. DESIGN: Serum samples were obtained from 21 patients with advanced melanoma, from 16 disease-free patients with melanoma, and from 19 healthy volunteers. Exosomes were isolated from serum by precipitation, and miR-16 and miR-125b levels were quantified by real-time polymerase chain reaction. RESULTS: MicroR-16, but not miR-125b, was detected in all samples, and miR-16 levels were significantly higher in serum than they were in exosomes. MicroR-16 expression levels did not differ significantly between the 2 groups (patients with melanoma and healthy donors). There was a significant relationship between miR-125b and miR-16 levels in exosomes. Additionally, miR-125b levels in exosomes were significantly lower in patients with melanoma compared with disease-free patients with melanoma and healthy controls. CONCLUSIONS: Exosomes can provide a suitable material to measure circulating miRNA in melanoma, and miR-16 can be used as an endogenous normalizer. Lower levels of miR-125b in exosomes obtained from serum are associated with advanced melanoma disease, probably reflecting the tumoral cell dysregulation.

24 Article Relevance of MIA and S100 serum tumor markers to monitor BRAF inhibitor therapy in metastatic melanoma patients. 2014

Sanmamed, Miguel F / Fernández-Landázuri, Sara / Rodríguez, Carmen / Lozano, María D / Echeveste, José I / Pérez Gracia, Jose Luis / Alegre, Estibaliz / Carranza, Omar / Zubiri, Leyre / Martín-Algarra, Salvador / González, Alvaro. ·Department of Medical Oncology, University Clinic of Navarra, Spain. · Laboratory of Biochemistry, University Clinic of Navarra, Spain. · Department of Pathology, University Clinic of Navarra, Spain. · Laboratory of Biochemistry, University Clinic of Navarra, Spain. Electronic address: agonzaleh@unav.es. ·Clin Chim Acta · Pubmed #24333389.

ABSTRACT: BRAF V600 mutation has been reported in more than 50% of melanoma cases and its presence predicts clinical activity of BRAF inhibitors (iBRAF). We evaluated the role of MIA, S100 and LDH to monitor iBRAF efficiency in advanced melanoma patients presenting BRAF V600 mutations. This was a prospective study of melanoma patients harboring the BRAF V600 mutation and treated with iBRAF within a clinical trial (dabrafenib) or as part of an expanded access program (vemurafenib). MIA, S100 and LDH were analyzed in serum at baseline, and every 4-6 weeks during treatment. Eighteen patients with melanoma stages IIIc-IV were enrolled with 88.8% of response rate to iBRAF. Baseline concentrations of all the tumor markers correlated with tumor burden. MIA and S100 concentrations decreased significantly one month after the beginning of treatment and, upon progression, their concentrations increased significantly above the minimum levels previously achieved. MIA levels lower than 9 μg/L one month after the beginning of treatment and S100 concentrations lower than 0.1 μg/L at the moment of best response were associated with improved progression-free survival. In conclusion, MIA and S100 are useful to monitor response in melanoma patients treated with iBRAF.

25 Article CD8 T cell priming in the presence of IFN-α renders CTLs with improved responsiveness to homeostatic cytokines and recall antigens: important traits for adoptive T cell therapy. 2012

Hervas-Stubbs, Sandra / Mancheño, Uxua / Riezu-Boj, Jose-Ignacio / Larraga, Ana / Ochoa, Maria C / Alignani, Diego / Alfaro, Carlos / Morales-Kastresana, Aizea / Gonzalez, Iranzu / Larrea, Esther / Pircher, Hanspeter / Le Bon, Agnes / Lopez-Picazo, Jose M / Martín-Algarra, Salvador / Prieto, Jesus / Melero, Ignacio. ·Division of Gene Therapy and Hepatology, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain. mshervas@unav.es ·J Immunol · Pubmed #22925929.

ABSTRACT: Previous mouse and human studies have demonstrated that direct IFN-α/β signaling on naive CD8 T cells is critical to support their expansion and acquisition of effector functions. In this study, we show that human naive CD8 T cells primed in the presence of IFN-α possess a heightened ability to respond to homeostatic cytokines and to secondary Ag stimulation, but rather than differentiating to effector or memory CTLs, they preserve nature-like phenotypic features. These are qualities associated with greater efficacy in adoptive immunotherapy. In a mouse model of adoptive transfer, CD8 T cells primed in the presence of IFN-α are able to persist and to mediate a robust recall response even after a long period of naturally driven homeostatic maintenance. The long-lasting persistence of IFN-α-primed CD8 T cells is favored by their enhanced responsiveness to IL-15 and IL-7, as demonstrated in IL-15(-/-) and IL-7(-/-) recipient mice. In humans, exposure to IFN-α during in vitro priming of naive HLA-A2(+) CD8 T cells with autologous dendritic cells loaded with MART1(26-35) peptide renders CD8 T cells with an improved capacity to respond to homeostatic cytokines and to specifically lyse MART1-expressing melanoma cells. Furthermore, in a mouse model of melanoma, adoptive transfer of tumor-specific CD8 T cells primed ex vivo in the presence of IFN-α exhibits an improved ability to contain tumor progression. Therefore, exposure to IFN-α during priming of naive CD8 T cells imprints decisive information on the expanded cells that can be exploited to improve the efficacy of adoptive T cell therapy.

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