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Melanoma: HELP
Articles from Ukraine
Based on 24 articles published since 2008
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These are the 24 published articles about Melanoma that originated from Ukraine during 2008-2019.
 
+ Citations + Abstracts
1 Editorial Can we use rare-earth nanocrystals to target glycans for the visualization of melanoma? 2015

Bilyy, Rostyslav / Podhorodecki, Artur. ·Danylo Halytsky Lviv National Medical University, Pekarska Street 69, Lviv 79010, Ukraine. · Institute of Cell Biology NAS of Ukraine, Drahomanov Street 14/16, Lviv 79005, Ukraine. · Department of Experimental Physics, Wroclaw University of Technology, Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland. ·Nanomedicine (Lond) · Pubmed #26084444.

ABSTRACT: -- No abstract --

2 Clinical Trial MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial. 2018

Dreno, Brigitte / Thompson, John F / Smithers, Bernard Mark / Santinami, Mario / Jouary, Thomas / Gutzmer, Ralf / Levchenko, Evgeny / Rutkowski, Piotr / Grob, Jean-Jacques / Korovin, Sergii / Drucis, Kamil / Grange, Florent / Machet, Laurent / Hersey, Peter / Krajsova, Ivana / Testori, Alessandro / Conry, Robert / Guillot, Bernard / Kruit, Wim H J / Demidov, Lev / Thompson, John A / Bondarenko, Igor / Jaroszek, Jaroslaw / Puig, Susana / Cinat, Gabriela / Hauschild, Axel / Goeman, Jelle J / van Houwelingen, Hans C / Ulloa-Montoya, Fernando / Callegaro, Andrea / Dizier, Benjamin / Spiessens, Bart / Debois, Muriel / Brichard, Vincent G / Louahed, Jamila / Therasse, Patrick / Debruyne, Channa / Kirkwood, John M. ·Department of Dermatooncology, Hotel Dieu Nantes University Hospital, Nantes, France. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. · Queensland Melanoma Project, Discipline of Surgery, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia. · Melanoma Sarcoma Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. · Service d'Oncologie Médicale, Hôpital François Mitterrand, Pau, France. · Skin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Hannover, Germany. · Petrov Research Institute of Oncology, St Petersburg, Russia. · Department of Soft Tissue, Bone Sarcoma, and Melanoma, Maria Sklodowska-Curie Institute, Oncology Center, Warsaw, Poland. · Department of Dermatology and Skin Cancers, La Timone APHM Hospital, Aix-Marseille University, Marseille, France. · Department of Skin and Soft Tissue Tumours, National Cancer Institute, Kiev, Ukraine. · Swissmed Centrum Zdrowia, Gdansk, Poland; Department of Surgical Oncology, Gdansk Medical University, Gdansk, Poland. · Dermatology Department, Hôpital Robert Debré, Université de Reims Champagne-Ardenne, Reims, France. · Department of Dermatology, Centre Hospitalier Universitaire, Tours, France; UFR de Médecine, Université François-Rabelais, Tours, France. · Melanoma Immunology and Oncology Group, Centenary Institute, University of Sydney, Sydney, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. · Dermato-oncology Department, General University Hospital, Prague, Czech Republic. · Columbus Clinic Center, Milan, Italy. · Division of Hematology & Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. · Département de Dermatologie, Centre Hospitalier Universitaire, Hôpital Saint-Éloi, Montpellier, France. · Department of Medical Oncology, Erasmus MC Cancer institute, Rotterdam, Netherlands. · Cancer Research Center, Moscow, Russia. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Seattle Cancer Care Alliance, University of Washington, Seattle, WA, USA. · Department of Oncology and Medical Radiology, Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine. · Centrum Medyczne Bieńkowski, Klinika Chirurgii Plastycznej, Bydgoszcz, Poland; Department of Oncological Surgery, Oncology Center, Bydgoszcz, Poland. · Melanoma Unit, Dermatology Department, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain. · Instituto de Oncología Ángel H Roffo, Universidad de Buenos Aires, Buenos Aires, Argentina. · Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Kiel, Germany. · Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands. · GlaxoSmithKline, Rixensart, Belgium. Electronic address: fernando.x.ulloa-montoya@GSK.com. · GlaxoSmithKline, Rixensart, Belgium. · GlaxoSmithKline, Rixensart, Belgium; Immunology Translational Medicine, UCB, Brussels, Belgium. · GlaxoSmithKline, Rixensart, Belgium; Biostatistics Department, Janssen Research & Development, Beerse, Belgium. · GlaxoSmithKline, Rixensart, Belgium; ViaNova Biosciences, Brussels, Belgium. · GlaxoSmithKline, Rixensart, Belgium; Laboratoires Servier, Paris, France. · GlaxoSmithKline, Rixensart, Belgium; University Hospitals Leuven, Leuven, Belgium. · UPMC Hillman Cancer Center, Pittsburgh, PA, USA. ·Lancet Oncol · Pubmed #29908991.

ABSTRACT: BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

3 Clinical Trial Adjuvant vemurafenib in resected, BRAF 2018

Maio, Michele / Lewis, Karl / Demidov, Lev / Mandalà, Mario / Bondarenko, Igor / Ascierto, Paolo A / Herbert, Christopher / Mackiewicz, Andrzej / Rutkowski, Piotr / Guminski, Alexander / Goodman, Grant R / Simmons, Brian / Ye, Chenglin / Yan, Yibing / Schadendorf, Dirk / Anonymous981080. ·Division of Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy. Electronic address: mmaiocro@gmail.com. · University of Colorado Comprehensive Cancer Center, Aurora, CO, USA. · N N Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russia. · Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine. · Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. · Bristol Haematology and Oncology Centre, Bristol, UK. · Department of Cancer Immunology, Poznan University for Medical Sciences, Med-POLONIA, Poznan, Poland. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland. · Melanoma Translational Research Group, Melanoma Institute Australia, Wollstonecraft, NSW, Australia. · Genentech, Inc, South San Francisco, CA, USA. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. ·Lancet Oncol · Pubmed #29477665.

ABSTRACT: BACKGROUND: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF METHODS: BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAF FINDINGS: The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. INTERPRETATION: The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAF FUNDING: F Hoffman-La Roche Ltd.

4 Clinical Trial Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. 2017

Long, G V / Flaherty, K T / Stroyakovskiy, D / Gogas, H / Levchenko, E / de Braud, F / Larkin, J / Garbe, C / Jouary, T / Hauschild, A / Chiarion-Sileni, V / Lebbe, C / Mandalà, M / Millward, M / Arance, A / Bondarenko, I / Haanen, J B A G / Hansson, J / Utikal, J / Ferraresi, V / Mohr, P / Probachai, V / Schadendorf, D / Nathan, P / Robert, C / Ribas, A / Davies, M A / Lane, S R / Legos, J J / Mookerjee, B / Grob, J-J. ·Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, North Sydney, Australia. · Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, USA. · Moscow City Oncology Hospital #62, Moscow, Russia. · First Department of Medicine, "Laiko" General Hospital, National and Kapodistrian University of Athens, Athens, Greece. · Petrov Research Institute of Oncology, Saint Petersburg, Russia. · Dipartimento di Medicina Oncologica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Royal Marsden NHS Foundation Trust, London, UK. · Department of Dermatology, University of Tübingen, Tübingen, Germany. · Service D'oncologie Médicale, Hopital Francois Mitterrand, Pau, France. · Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany. · Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padova, Italy. · APHP Dermatology and CIC Departments, INSERM U976, University Paris Diderot, Paris, France. · Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Medical Oncology Department, Sir Charles Gairdner Hospital, Perth, Australia. · Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. · Dnipropetrovsk State Medical Academy, Clinical Hospital #4, Dnipropetrovsk, Ukraine. · Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. · Skin Cancer Unit, German Cancer Research Center (DKFZ) and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim and Heidelberg, Germany. · Department of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy. · Dermatologisches Zentrum Buxtehude, Elbe Kliniken Buxtehude, Buxtehude, Germany. · Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine. · Department of Dermatology, University Hospital Essen, Essen, Germany. · German Cancer Consortium, Heidelberg, Germany. · Mount Vernon Cancer Centre, Northwood, UK. · Gustave Roussy, Département de Médecine Oncologique, Service de Dermatologie et Université Paris-Sud, Faculté de Médecine, Villejuif, France. · Department of Medicine, Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, USA. · Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Novartis Pharmaceuticals Corporation, East Hanover, USA. · Service de Dermatologie, Centre Hospitalo-Universitaire Timone, Aix-Marseille Université, Marseille, France. ·Ann Oncol · Pubmed #28475671.

ABSTRACT: Background: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. Patients and methods: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. Results: Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. Conclusions: These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

5 Clinical Trial Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. 2015

Long, Georgina V / Stroyakovskiy, Daniil / Gogas, Helen / Levchenko, Evgeny / de Braud, Filippo / Larkin, James / Garbe, Claus / Jouary, Thomas / Hauschild, Axel / Grob, Jean-Jacques / Chiarion-Sileni, Vanna / Lebbe, Celeste / Mandalà, Mario / Millward, Michael / Arance, Ana / Bondarenko, Igor / Haanen, John B A G / Hansson, Johan / Utikal, Jochen / Ferraresi, Virginia / Kovalenko, Nadezhda / Mohr, Peter / Probachai, Volodymr / Schadendorf, Dirk / Nathan, Paul / Robert, Caroline / Ribas, Antoni / DeMarini, Douglas J / Irani, Jhangir G / Swann, Suzanne / Legos, Jeffrey J / Jin, Fan / Mookerjee, Bijoyesh / Flaherty, Keith. ·Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Moscow City Oncology Hospital, Moscow, Russia. · Department of Medicine, University of Athens, Medical School, Athens, Greece. · Petrov Research Institute of Oncology, Saint Petersburg, Russia. · Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. · Royal Marsden Hospital, London, UK. · Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany. · Department of Dermatology, Hôpital Saint André, CHU Bordeaux, Bordeaux, France. · University Hospital Schleswig-Holstein, Kiel, Germany. · Aix-Marseille University and APHM Hospital CHU Timone, Marseille, France. · Melanoma and Oesophageal Oncology Unit, Veneto Oncology Institute-IRCCS, Padua, Italy. · APHP Dermatology CIC Hôpital Saint Louis, University Paris Diderot, INSERM U976, Paris, France. · Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA, Australia. · Department of Medical Oncology, Hospital Clinic and Translational Genomics and Targeted Therapeutics in Solid Tumors, Barcelona, Spain. · Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine. · Netherlands Cancer Institute, Amsterdam, Netherlands. · Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden. · University Medical Center Mannheim, Heidelberg University, Mannheim, Germany; German Cancer Research Center, Heidelberg, Germany. · Istituto Nazionale Tumori Regina Elena, Rome, Italy. · Volograd Regional Oncology Dispensary #3, Volzhsky, Russia. · Elbe Klinikum Stade, Stade, Germany. · Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council, Dnipropetrovsk, Ukraine. · University Hospital Essen, Essen, Germany. · Mount Vernon Cancer Centre, Northwood, UK. · Gustave Roussy, Villejuif-Paris-Sud, France; Paris Sud University, Le Kremlin Bicêtre, France. · David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. · Merck & Co, Kenilworth, NJ, USA. · Massachusetts General Hospital Cancer Center, Boston MA, USA. ·Lancet · Pubmed #26037941.

ABSTRACT: BACKGROUND: Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. METHODS: We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. FINDINGS: Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. INTERPRETATION: The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. FUNDING: GlaxoSmithKline.

6 Clinical Trial Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. 2015

Schadendorf, Dirk / Amonkar, Mayur M / Stroyakovskiy, Daniil / Levchenko, Evgeny / Gogas, Helen / de Braud, Filippo / Grob, Jean-Jacques / Bondarenko, Igor / Garbe, Claus / Lebbe, Celeste / Larkin, James / Chiarion-Sileni, Vanna / Millward, Michael / Arance, Ana / Mandalà, Mario / Flaherty, Keith T / Nathan, Paul / Ribas, Antoni / Robert, Caroline / Casey, Michelle / DeMarini, Douglas J / Irani, Jhangir G / Aktan, Gursel / Long, Georgina V. ·Universitätsklinikum Essen, Hufelandstr. 55, Essen 45147, Germany. Electronic address: Dirk.Schadendorf@uk-essen.de. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: mayur.m.amonkar@gsk.com. · Moscow City Oncology Hospital #62, Moscow 143423, Russia. Electronic address: sdaniel@mail.ru. · Petrov Research Institute of Oncology, 68 Leningradskaya Street, Saint Petersburg 197758, Russia. Electronic address: levchenko@newmail.ru. · University of Athens, Aghiou Thoma 17, Athens 11527, Greece. Electronic address: hgogas@hol.gr. · Fondazione IRCCS Istituto Nazionale Tumori, via Giacomo Venezian, 1, Milan, Italy. Electronic address: filippo.debraud@istitutotumori.mi.it. · Service de Dermatologie, Centre Hospitalo-Universitaire Sainte-Marguerite, 270 Boulevard de Sainte-Marguerite, Marseille 13009, France. Electronic address: jean-jacques.grob@ap-hm.fr. · Dnepropetrovsk State Medical Academy, Dzerzhyns'koho Street 9, Dnepropetrovsk 49044, Ukraine. Electronic address: oncology@dsma.dp.ua. · Department of Dermatology, University Hospital Tuebingen, Liebermeisterstraße 25, Tuebingen 72076, Germany. Electronic address: claus.garbe@med.uni-tuebingen.de. · APHP Dermatology CIC Hôpital Saint Louis, University Paris Diderot, INSERM U976, Avenue Claude Vellefaux, Paris 75010, France. Electronic address: celeste.lebbe@sls.aphp.fr. · Royal Marsden Hospital, Fulham Road, London SW3 6JJ, United Kingdom. Electronic address: james.larkin@rmh.nhs.uk. · Melanoma and Esophageal Oncology Unit, Veneto Oncology Institute-IRCCS, via Gattamelata, 64, Padua 35128, Italy. Electronic address: mgaliz@tiscali.it. · Sir Charles Gairdner Hospital, Hospital Avenue, Perth, WA 6009, Australia. Electronic address: michael.millward@uwa.edu.au. · Hospital Clinic, Carrer Villarroel 170, Barcelona 08036, Spain. Electronic address: amarance@clinic.ub.es. · Papa Giovanni XIII Hospital, Piazza OMS 1, Bergamo 24127, Italy. Electronic address: mmandala@hpg23.it. · Massachusetts General Hospital Cancer Center, 55 Fruit St, Boston 02114, MA, United States. Electronic address: kflaherty@partners.org. · Mount Vernon Cancer Centre, Rickmansworth Road, Northwood HA6 2RN, United Kingdom. Electronic address: p.nathan@nhs.net. · David Geffen School of Medicine, UCLA, 10833 Le Conte Avenue, Los Angeles 90095, CA, United States. Electronic address: aribas@mednet.ucla.edu. · Gustave Roussy and Paris 11 University, 114 Rue Edouard Vaillant, Villejuif-Paris-Sud 94805, France. Electronic address: Caroline.Robert@igr.fr. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: meshellcasey@yahoo.com. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: douglas.j.demarini@gsk.com. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: jhangir.g.irani@gsk.com. · GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426, United States. Electronic address: gursel.aktan@gmail.com. · Melanoma Institute Australia & The University of Sydney, 40 Rocklands Road, Sydney 2060, Australia. Electronic address: georgina.long@sydney.edu.au. ·Eur J Cancer · Pubmed #25794603.

ABSTRACT: AIM: To present the impact of treatments on health-related quality of life (HRQoL) from the double-blind, randomised phase III COMBI-d study that investigated the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600E/K-mutant metastatic melanoma. COMBI-d showed significantly prolonged progression-free survival for the combination. METHODS: HRQoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, a generic cancer questionnaire (completed at baseline, during study treatment, at progression and post progression) assessing various dimensions (global health/QoL, functional status, and symptom impact). A mixed-model, repeated-measures analyses of covariance evaluated differences between arms. RESULTS: Questionnaire completion rates were >95% at baseline, >85% to week 40 and >70% at disease progression. Baseline scores across both arms were comparable for all dimensions. Global health dimension scores were significantly better at weeks 8, 16 and 24 for patients receiving the combination during treatment and at progression. The majority of functional dimension scores (physical, social, role, emotional and cognitive functioning) trended in favour of the combination. Pain scores were significantly improved and clinically meaningful (6-13 point difference) for patients receiving the combination for all follow-up assessments versus those receiving dabrafenib monotherapy. For other symptom dimensions (nausea and vomiting, diarrhoea, dyspnoea, and constipation), scores trended in favour of dabrafenib monotherapy. CONCLUSION: This analysis demonstrates that the combination of dabrafenib and trametinib provides better preservation of HRQoL and pain improvements versus dabrafenib monotherapy while also delaying progression. (Clinicaltrials.gov registration number: NCT01584648).

7 Clinical Trial Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. 2015

Maio, Michele / Grob, Jean-Jacques / Aamdal, Steinar / Bondarenko, Igor / Robert, Caroline / Thomas, Luc / Garbe, Claus / Chiarion-Sileni, Vanna / Testori, Alessandro / Chen, Tai-Tsang / Tschaika, Marina / Wolchok, Jedd D. ·Michele Maio, University Hospital of Siena, Siena · Vanna Chiarion-Sileni, Veneto Oncology Institute-Istituto Di Ricovero e Cura a Carattere Scientifico, Padova · Alessandro Testori, Istituto Europeo di Oncologia, Milan, Italy · Jean-Jacques Grob, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Hôpital Timone, Marseille · Luc Thomas, Lyon 1 University, Centre Hospitalier Lyon Sud, Pierre Bénite · Caroline Robert, Institute Gustave Roussy, Villejuif, France · Steinar Aamdal, Oslo University Hospital and Radium Hospital, Oslo, Norway · Igor Bondarenko, Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine · Claus Garbe, University Medical Center, Tübingen, Germany · Tai-Tsang Chen and Marina Tschaika, Bristol-Myers Squibb, Wallingford, CT · and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY. ·J Clin Oncol · Pubmed #25713437.

ABSTRACT: PURPOSE: There is evidence from nonrandomized studies that a proportion of ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial. PATIENTS AND METHODS: A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received ipilimumab in a phase III trial. Patients were randomly assigned 1:1 to receive ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Eligible patients could receive maintenance ipilimumab or placebo every 12 weeks beginning at week 24. A safety analysis was conducted on patients who survived at least 5 years and continued to receive ipilimumab as maintenance therapy. RESULTS: The 5-year survival rate was 18.2% (95% CI, 13.6% to 23.4%) for patients treated with ipilimumab plus dacarbazine versus 8.8% (95% CI, 5.7% to 12.8%) for patients treated with placebo plus dacarbazine (P = .002). A plateau in the survival curve began at approximately 3 years. In patients who survived at least 5 years and continued to receive ipilimumab, grade 3 or 4 immune-related adverse events were observed exclusively in the skin. CONCLUSION: The additional survival benefit of ipilimumab plus dacarbazine is maintained with twice as many patients alive at 5 years compared with those who initially received placebo plus dacarbazine. These results demonstrate a durable survival benefit with ipilimumab in advanced melanoma.

8 Article Store-and-forward teledermatology for the most common skin neoplasms in Ukraine. 2018

Kravets, Kira / Vasylenko, Olga / Dranyk, Zhanna / Bogomolets, Olga. ·Kharkiv Medical Academy of Postgraduate Education, Kyiv, Ukraine. · Dr. Bogomolets Institute of Dermatocosmetology, Kyiv, Ukraine. ·Acta Dermatovenerol Alp Pannonica Adriat · Pubmed #29945264.

ABSTRACT: BACKGROUND: Among all malignancies in Ukraine in 2016, the group of non-melanoma skin cancers headed the list in men and made up 21.6%. This group was second in women and made up 17.6%. The diagnostics of skin tumors are becoming increasingly relevant. METHODS: The store-and-forward (SAF) method was used. The study included patients that were remotely diagnosed with melanocytic nevi, seborrheic keratoses, skin cancer, and skin melanoma. Patients signed up for remote diagnostics, were examined in person by dermatologists, and had tumors excised with a subsequent histological examination. RESULTS: Using telemedicine, 108 melanocytic nevi, 97 seborrheic keratoses, 62 skin cancers, and 47 skin melanomas were diagnosed and selected. The accuracy of teledermatological examination and teledermoscopy compared to clinical examination and dermoscopy was 90.3 to 100.0%. The accuracy of teledermatological examination and teledermoscopy compared to histopathological diagnoses was 85.1 to 98.9%. CONCLUSIONS: Teledermatological diagnosis showed a high ability for detecting skin neoplasms in Ukraine.

9 Article USE OF CIRCULATING TUMOR DNA FOR DETECTION OF BRAF V600E MUTATION AND TREATMENT MONITORING IN MELANOMA PATIENTS. 2018

Shapochka, D / Shapochka, T / Seleznyov, O / Matveeva, A / Dudin, V. ·Pathology laboratory CSD Health Care, Department of molecular pathology; Bogomolets National Medical University, Faculty Of General Medicine, Kyiv, Ukraine. ·Georgian Med News · Pubmed #29697386.

ABSTRACT: Detection of BRAF V600E mutation in circulating tumor DNA may be important tool for primary diagnostic and therapeutic monitoring in patients with melanoma. For the first time in Ukraine, the sensitivity of BRAF V600E testing on circulating tumor DNA was analyzed, as well as the possibility of its application for monitoring the course of the disease. Allele-specific semi-quantitative Real-time PCR for BRAF V600E mutation was performed on DNA extracted from 28 plasma samples of 18 patients with known BRAF V600E melanoma. At baseline, BRAF V600E ctDNA was detected in 67% of all patients (n=11/17) and in 75% (n=11/15) of patients with IV stage. In 7 cases we have more than one blood sample from patient. In 2 of 3 patients with positive BRAF V600E ctDNA at the baseline, mutation became undetectable during therapy that was associated with stable disease and partial response. In 2 cases patients had stage II and after surgery BRAF V600E ctDNA was undetectable, but then mutation was detected prior to clinical disease progression (PD) in one case and simultaneously with PD in another. One patient with resected brain metastasis of melanoma with unknown primary also had negative baseline and second sample (after 5 months) but BRAF V600E was detected in third sample (after 11 months) without radiological evidence of progression. ctDNA in plasma is a good source for BRAF V600E primary testing in case of absence or low quality of FFPE tissue and potential instrument for monitoring of disease flowing. Its potential role in management of patients with malignant melanoma requires further evaluation.

10 Article Young and advanced tumor-some 2D electrodynamic distinctions: melanoma and satellite during a vascular occlusion test: feasibility study. 2018

Babich, Y / Nuzhdina, M / Syniuta, S. ·Amosov National Institute of Cardiovascular Surgery, M. Amosova St., 6, Kiev, 03038, Ukraine. babich@ua.fm. · Taras Shevchenko National University of Kiev, Astronomical Observatory, Observatorna St., 3, Kiev, 04053, Ukraine. · Institute of Nuclear Medicine and Diagnostic Radiology, NAMS of Ukraine, Mayborody St. 32, Kiev, 04050, Ukraine. ·Med Biol Eng Comput · Pubmed #28691130.

ABSTRACT: Conventional methods of electrobioimpedance imaging are not suited for adequate visualization of the skin electrical impedance landscape (SEL) because they do not provide high spatial resolution at large enough area of view. The skin electrodynamics introscopy (SEI) enabled dynamic spectral imaging of the SEL at 32 × 64 mm

11 Article Tissue-protective activity of selenomethionine and D-panthetine in B16 melanoma-bearing mice under doxorubicin treatment is not connected with their ROS scavenging potential. 2017

Panchuk, Rostyslav R / Skorokhyd, Nadia R / Kozak, Yuliya S / Lehka, Liliya V / Moiseenok, Andrey G / Stoika, Rostyslav S. ·Rostyslav R. Panchuk, Institute of Cell Biology, National Academy of Sciences of Ukraine, Drahomanov Street 14/16, 79005, Lviv, Ukraine, rpanchuk@ukr.net. ·Croat Med J · Pubmed #28409500.

ABSTRACT: AIM: To evaluate molecular mechanisms of tissue-protective effects of antioxidants selenomethionine (SeMet) and D-pantethine (D-Pt) applied in combination with doxorubicin (Dx) in B16 melanoma-bearing-mice. METHODS: Impact of the chemotherapy scheme on a survival of tumor-bearing animals, general nephro- and hepatotoxicity, blood cell profile in vivo, and ROS content in B16 melanoma cells in vitro was compared with the action of Dx applied alone. Nephrotoxicity of the drugs was evaluated by measuring creatinine indicator assay, hepatotoxicity was studied by measuring the activity of ALT/AST enzymes, and myelotoxicity was assessed by light microscopic analysis of blood smears. Changes in ROS content in B16 melanoma cells under Dx, SeMet, and D-Pt action in vitro were measured by incubation with fluorescent dyes dihydrodichlorofluoresceindiacetate (DCFDA, H2O2-specific) and dihydroethidium (DHE, O2--specific), and further analysis at FL1 (DCFDA) or FL2 channels (DHE) of FACScan flow cytometer. The impact of aforementioned compounds on functional status of mitochondria was measured by Rhodamine 123 assay and further analysis at FL1 channel of FACScan flow cytometer. RESULTS: Selenomethionine (1200 µg/kg) and D-pantethine (500 mg/kg) in combination with Dx (10 mg/kg) significantly reduced tumor-induced neutrophilia, lymphocytopenia, and leukocytosis in comparison to Dx treatment alone. Moreover, SeMet and D-Pt decreased several side effects of Dx, namely an elevated creatinine level in blood and monocytosis, thus normalizing health conditions of B16 melanoma-bearing animals. CONCLUSIONS: Our results showed that antioxidants selenomethionine and D-pantethine possess significant nephroprotective and myeloprotective activity toward Dx action on murine B16 melanoma in vivo, but fail to boost a survival of B16 melanoma-bearing animals. The observed cytoprotective effects of studied antioxidants are not directly connected with their ROS scavenging.

12 Article Nitric oxide donor augments antineoplastic effects of arginine deprivation in human melanoma cells. 2017

Mayevska, Oksana / Chen, Oleh / Karatsai, Olena / Bobak, Yaroslav / Barska, Maryna / Lyniv, Liliana / Pavlyk, Iuliia / Rzhepetskyy, Yuriy / Igumentseva, Natalia / Redowicz, Maria Jolanta / Stasyk, Oleh. ·Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, 14/16 Drahomanov Str., 79005 Lviv, Ukraine. · Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, 14/16 Drahomanov Str., 79005 Lviv, Ukraine; Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Str., 02-093 Warsaw, Poland. · Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Str., 02-093 Warsaw, Poland. · Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, 14/16 Drahomanov Str., 79005 Lviv, Ukraine. Electronic address: stasyk@cellbiol.lviv.ua. ·Exp Cell Res · Pubmed #28390676.

ABSTRACT: Anticancer therapy based on recombinant arginine-degrading enzymes has been proposed for the treatment of several types of malignant cells deficient in arginine biosynthesis. One of the predicted side effects of such therapy is restricted bioavailability of nitric oxide as arginine catabolic product. Prolonged NO limitation may lead to unwanted disturbances in NO-dependent vasodilation, cardiovascular and immune systems. This problem can be overcome by co-supplementation with exogenous NO donor. However, NO may potentially counteract anticancer effects of therapy based on arginine deprivation. In this study, we evaluate for the first time the effects of an exogenous NO donor, sodium nitroprusside, on viability and metastatic properties of two human melanoma cell lines SK-MEL-28 and WM793 under arginine-deprived conditions. It was revealed that NO did not rescue melanoma cells from specific effects evoked by arginine deprivation, namely decreased viability and induction of apoptosis, dramatically reduced motility, invasiveness and clonogenic potential. Moreover, sodium nitroprusside co-treatment augmented several of these antineoplastic effects. We report that a combination of NO-donor and arginine deprivation strongly and specifically impaired metastatic behavior of melanoma cells. Thus, sodium nitroprusside can be considered as an adjuvant for the more efficient treatment of malignant melanoma and possibly other tumors with arginine-degrading enzymes.

13 Article More than 5000 patients with metastatic melanoma in Europe per year do not have access to recommended first-line innovative treatments. 2017

Kandolf Sekulovic, L / Peris, K / Hauschild, A / Stratigos, A / Grob, J-J / Nathan, P / Dummer, R / Forsea, A-M / Hoeller, C / Gogas, H / Demidov, L / Lebbe, C / Blank, C / Olah, J / Bastholt, L / Herceg, D / Neyns, B / Vieira, R / Hansson, J / Rutkowski, P / Krajsova, I / Bylaite-Bucinskiene, M / Zalaudek, I / Maric-Brozic, J / Babovic, N / Banjin, M / Putnik, K / Weinlich, G / Todorovic, V / Kirov, K / Ocvirk, J / Zhukavets, A / Kukushkina, M / De La Cruz Merino, L / Ymeri, A / Risteski, M / Garbe, C. ·Department of Dermatology, Medical Faculty, Military Medical Academy, Belgrade, Serbia. · Institute of Dermatology, Catholic University of the Sacred Heart, Rome, Italy. · Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany. · National and Kapodistrian University of Athens, Greece. · Service de Dermatologie et Cancérologie Cutanée, Hopital de la Timone, Marseille, France. · Mount Vernon Cancer Centre, Northwood, United Kingdom. · UniversitätsSpital Zürich-Skin Cancer Center, University Hospital, Zürich, Switzerland. · Carol Davila University of Medicine and Pharmacy, Elias University Hospital Bucharest, Romania. · Department of Dermatology, Medical University of Vienna, Vienna, Austria. · NN Blokhin Russian Cancer Research Center, Moscow, Russia. · APHP Hospital Saint Louis, Paris, France. · Netherland Cancer Institute, Amsterdam, Netherlands. · Department of Dermatology and Allergology, University of Szeged, Hungary. · Department of Oncology, Odense University Hospital, Denmark. · Department of Oncology, University Hospital Zagreb, Croatia. · Department of Medical Oncology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium. · Department of Dermatology, Medical Faculty, University of Coimbra, Portugal. · Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden. · Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warszawa, Poland. · General Teaching Hospital, Prague, Czech Republic. · Department of Dermatology, Vilnius University, Lithuania. · Division of Dermatology and Venerology, Medical University of Graz, Graz, Austria. · University Hospital Center Sestre Milosrdnice, Zagreb, Croatia. · Institute of Oncology and Radiology of Serbia, Belgrade, Serbia. · Department of Oncology, University Hospital Sarajevo, Bosnia and Herzegovina. · North Estonia Medical Centre, Tallinn, Estonia. · Department of Dermatology & Venerology & Allergy, Medical University Innsbruck, Austria. · Clinic for Oncology and Radiotherapy, Podgorica, Montenegro. · Clinic of Oncodermatology, National Cancer Center, Sofia, Bulgaria. · Institute of Oncology Ljubljana, Ljubljana, Slovenia. · N.N. Alexandrov National Cancer Сenter of Belarus (NCCB), Minsk, Belarus. · National Cancer Institute, Kiev, Ukraine. · Department of Clinical Oncology, Hospital Universitario Virgen Macarena, Sevilla, Spain. · University Hospital Mother Theresa, Tirana, Albania. · University Clinic of Radiotherapy and Oncology, Skopje, Former Yugoslav Republic of Macedonia. · Centre for Dermatooncology, Department of Dermatology, Eberhard Karls University, Tuebingen, Germany. ·Eur J Cancer · Pubmed #28264791.

ABSTRACT: BACKGROUND: Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europe and estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF). MATERIALS AND METHODS: Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes. RESULTS: The recommended BRAF inhibitor (BRAFi) + MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), (r = 0.662; p < 0.001), health expenditure per capita (r = 0.695; p < 0.001) and the Mackenbach score of health policy performance (r = 0.765; p < 0.001) with the percentage of patients treated with innovative medicines and a number of reimbursed medicines. CONCLUSIONS: Great discrepancy exists in metastatic melanoma treatment across Europe. It is crucial to increase the awareness of national and European policymakers, oncological societies, melanoma patients' associations and pharma industry.

14 Article Preparation, properties and anticancer effects of mixed As 2017

Bujňáková, Z / Baláž, M / Zdurienčíková, M / Sedlák, J / Čaplovičová, M / Čaplovič, Ľ / Dutková, E / Zorkovská, A / Turianicová, E / Baláž, P / Shpotyuk, O / Andrejko, S. ·Institute of Geotechnics, Slovak Academy of Sciences, Watsonova 45, 04001 Košice, Slovakia. Electronic address: bujnakova@saske.sk. · Institute of Geotechnics, Slovak Academy of Sciences, Watsonova 45, 04001 Košice, Slovakia. · Cancer Research Institute, BMC Slovak Academy of Sciences, Dúbravská 9, 84505 Bratislava, Slovakia. · STU Centre for Nanodiagnostics, Slovak University of Technology, Vazovova 5, 81243 Bratislava, Slovakia. · Faculty of Materials Science and Technology, Slovak University of Technology, Paulínska 16, 91724 Trnava, Slovakia. · Scientific Research Company "Carat", Stryjska 202, 79031 Lviv, Ukraine; Institute of Physics, Jan Dlugosz University, Armii Krajowej 13/15., 42200 Czestochowa, Poland. · Faculty of Medicine, P.J. Šafárik University, Trieda SNP 1, 04011 Košice, Slovakia. ·Mater Sci Eng C Mater Biol Appl · Pubmed #27987742.

ABSTRACT: Arsenic sulfide compounds have a long history of application in a traditional medicine. In recent years, realgar has been studied as a promising drug in cancer treatment. In this study, the arsenic sulfide (As

15 Article Metastasis of two malignant tumors of different genesis in axillary lymph node (a case report). 2016

Rusin, A V / Petrosov, O V / Chumak, A I / Kushnir, V M. ·Department of Oncology, Medical Faculty, Uzhhorod National University, Uzhhorod 88000, Ukraine. · Transcarpathian Regional Clinical Oncologic Hospital, Uzhhorod 88000, Ukraine. ·Exp Oncol · Pubmed #27685530.

ABSTRACT: This case report describes a rare clinical condition: metastasis of synchronous multiple primary tumors - skin melanoma and breast cancer in one axillary lymph node, confirmed with the results of clinical, morphological and immunohistochemical study of surgical material from 40 year-old woman.

16 Article A blast without power - cell death induced by the tuberculosis-necrotizing toxin fails to elicit adequate immune responses. 2016

Maueröder, C / Chaurio, R A / Dumych, T / Podolska, M / Lootsik, M D / Culemann, S / Friedrich, R P / Bilyy, R / Alexiou, C / Schett, G / Berens, C / Herrmann, M / Munoz, L E. ·Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany. · Danylo Halytsky Lviv National Medical University, Lviv, Ukraine. · Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv, Ukraine. · ENT Clinic, Section of Experimental Oncology and Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung Professorship, University Hospital Erlangen, Erlangen, Germany. · Institute of Molecular Pathogenesis, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Jena, Germany. ·Cell Death Differ · Pubmed #26943324.

ABSTRACT: In this study, we deploy a doxycycline-dependent suicide switch integrated in a tumor challenge model. With this experimental setup, we characterized the immunological consequences of cells dying by four distinct cell death stimuli in vivo. We observed that apoptotic cell death induced by expression of the truncated form of BH3 interacting-domain death agonist (tBid) and a constitutively active form of caspase 3 (revC3), respectively, showed higher immunogenicity than cell death induced by expression of the tuberculosis-necrotizing toxin (TNT). Our data indicate that the early release of ATP induces the silent clearance of dying cells, whereas the simultaneous presence of 'find me' signals and danger-associated molecular patterns (DAMPs) promotes inflammatory reactions and increased immunogenicity. This proposed model is supported by findings showing that the production and release of high concentrations of IL-27 by bone-marrow-derived macrophages (BMDM) is limited to BMDM exposed to those forms of death that simultaneously released ATP and the DAMPs heat-shock protein 90 (HSP90) and high-mobility group box-1 protein (HMGB1). These results demonstrate that the tissue microenvironment generated by dying cells may determine the subsequent immune response.

17 Article Cytotoxic activity of immune cells following administration of xenogeneic cancer vaccine in mice with melanoma B-16. 2015

Fedosova, N I / Voeykova, I M / Karaman, О М / Symchych, T V / Didenko, G V / Lisovenko, G S / Evstratieva, L М / Potebnia, G P. ·R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv 03022, Ukraine. ·Exp Oncol · Pubmed #26112941.

ABSTRACT: AIM: To study the effects of xenogeneic cancer vaccine (XCV) developed on the basis of nervous tissue antigen from rat embryo of late gestation period and protein-containing metabolite of Bacillus subtilis with molecular weight of 70 kDa, on specific and unspecific antitumor reactions of cellular and humoral chains of immune system, and to analyze possible mechanisms of its antimetastatic action. MATERIALS AND METHODS: XCV was administered triply with 3-day intervals after surgical removal of experimental melanoma В-16 in C57Bl/6 mice. Cytotoxic activity (CTA) of splenocytes against target cells К-562 as well as CTA of splenocytes, peritoneal macrophages (PM) and blood serum against melanoma В-16 target cells were determined using МТТ test. The content of circulating immune complexes (CIC) in blood serum was evaluated by precipitation reaction. RESULTS: Immunologic effects of XCV vaccination in experimental animals with surgically removed melanoma B-16 in comparison with similarly treated unvaccinated mice were as follows: prevention of medium molecular weight CIC accumulation in blood serum during all observation period, significant increase (р < 0.05) of CTA of effectors of unspecific antitumor immunity (natural killer cells - NK - by 25.5 ± 1.7 vs 12.5 ± 5.4%, and PM - by 37.3 ± 0.6 vs 32.0 ± 0.9%, respectively) at 37(th) day after the surgery, and also preservation of functional activity of specific cytotoxic lymphocytes at the level of intact control. CONCLUSION: The results of the study allow propose that antimetastatic effect of XCV vaccination could be based on increased CTA of NK and PM, and preservation of CTL functional activity at late terms after surgical removal of B-16 primary tumors.

18 Article Multi-modal acousto-optic/ultrasound imaging of ex vivo liver tumors at 790 nm using a Sn2 P2 S6 wavefront adaptive holographic setup. 2015

Laudereau, Jean-Baptiste / À La Guillaume, Emilie Benoit / Servois, Vincent / Mariani, Pascale / Grabar, Alexander A / Tanter, Mickaël / Gennisson, Jean-Luc / Ramaz, François. ·Institut Langevin, Ondes et Images, ESPCI ParisTech, PSL Research University, CNRS UMR 7587, INSERM U979, Université Paris VI - Pierre et Marie Curie, 1 rue Jussieu, 75005, Paris, France. · Department of Medical Imaging, Institut Curie, 26 rue d'Ulm, 75005, Paris, France. · Department of Surgery, Institut Curie, 26 rue d'Ulm, 75005, Paris, France. · Institute of Solid State Physics and Chemistry, 88000, Ukraine, Uzhgorod, Voloshyn st. 54. ·J Biophotonics · Pubmed #25236956.

ABSTRACT: Biological tissues are very strong light-scattering media. As a consequence, current medical imaging devices do not allow deep optical imaging unless invasive techniques are used. Acousto-optic imaging is a light-ultrasound coupling technique that takes advantage of the ballistic propagation of ultrasound in biological tissues to access optical contrast with a millimeter resolution. We have developed a photorefractive-crystal-based system that performs self-adaptive wavefront holography and works within the optical therapeutic window. As it works at an appropriate wavelength range for biological tissues imaging, it was tested on ex vivo liver samples containing tumors as a pre-clinical study. Optical contrast was obtained even if acoustical one was not significant. Ultrasound image (left) and acousto-optic image (right) of a liver biopsy with tumors. Acousto-optic imaging exhibits tumors that are not detected through ultrasound.

19 Article Visualization of melanoma tumor with lectin-conjugated rare-earth doped fluoride nanocrystals. 2014

Dumych, Tetiana / Lutsyk, Maxym / Banski, Mateusz / Yashchenko, Antonina / Sojka, Bartlomiej / Horbay, Rostyslav / Lutsyk, Alexander / Stoika, Rostyslav / Misiewicz, Jan / Podhorodecki, Artur / Bilyy, Rostyslav. ·Rostyslav Bilyy, Drahomnanov Str. 14/16, 79005, Lviv, Ukraine, r.bilyy@gmail.com. ·Croat Med J · Pubmed #24891277.

ABSTRACT: AIM: To develop specific fluorescent markers for melanoma tumor visualization, which would provide high selectivity and reversible binding pattern, by the use of carbohydrate-recognizing proteins, lectins, combined with the physical ability for imaging deep in the living tissues by utilizing red and near infrared fluorescent properties of specific rare-earth doped nanocrystals (NC). METHODS: B10F16 melanoma cells were inoculated to C57BL/6 mice for inducing experimental melanoma tumor. Tumors were removed and analyzed by lectin-histochemistry using LABA, PFA, PNA, HPA, SNA, GNA, and NPL lectins and stained with hematoxylin and eosin. NPL lectin was conjugated to fluorescent NaGdF4:Eu(3+)-COOH nanoparticles (5 nm) via zero length cross-linking reaction, and the conjugates were purified from unbound substances and then used for further visualization of histological samples. Fluorescent microscopy was used to visualize NPL-NaGdF4:Eu(3+) with the fluorescent emission at 600-720 nm range. RESULTS: NPL lectin selectively recognized regions of undifferentiated melanoblasts surrounding neoangiogenic foci inside melanoma tumor, PNA lectin recognized differentiated melanoblasts, and LCA and WGA were bound to tumor stroma regions. NPL-NaGdF4:Eu(3+) conjugated NC were efficiently detecting newly formed regions of melanoma tumor, confirmed by fluorescent microscopy in visible and near infrared mode. These conjugates possessed high photostability and were compatible with convenient xylene-based mounting systems and preserved intensive fluorescent signal at samples storage for at least 6 months. CONCLUSION: NPL lectin-NaGdF4:Eu(3+) conjugated NC permitted distinct identification of contours of the melanoma tissue on histological sections using red excitation at 590-610 nm and near infrared emission of 700-720 nm. These data are of potential practical significance for development of glycans-conjugated nanoparticles to be used for in vivo visualization of melanoma tumor.

20 Article Use of xenogeneic vaccine modified with embryonal nervous tissue antigens in the treatment of B16-melanoma-bearing mice. 2014

Voeykova, I M / Fedosova, N I / Karaman, O M / Yudina, O Yu / Didenko, G V / Lisovenko, G S / Evstratieva, L M / Potebnya, G P. ·R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv 03022, Ukraine. ·Exp Oncol · Pubmed #24691280.

ABSTRACT: METHODS: Immunological methods and methods of experimental oncology were used. Effects of XCV on primary and secondary organs of immune system of experimental animals, its anticancer and antimetastatic efficacy were evaluated. RESULTS: It has been shown that XCV did not induced toxic effects on organism, and did not caused inflammatory reactions. The relation between the degree of XCV anticancer efficacy with the regimen of its use and the presence of primary tumor has been analyzed. It has been demonstrated that the developed XCV possesses significant antimetastatic activity if it is used after surgical removal of the primary tumor: in this case lung metastasis inhibition index reached 97.4%. CONCLUSION: High immunogenecity of new XCV creates perspectives for detailed study of its mechanisms of action.

21 Article Involvement of human beta-defensin-2 in regulation of malignant potential of cultured human melanoma cells. 2014

Gerashchenko, O / Zhuravel, E / Skachkova, O / Khranovska, N / Pushkarev, V / Pogrebnoy, P / Soldatkina, M. ·R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv 03022, Ukraine. · National Cancer Institute MPH of Ukraine, Kyiv 03022, Ukraine. · Institute of Endocrinology and Metabolism, AMS of Ukraine, Kyiv, Ukraine. ·Exp Oncol · Pubmed #24691279.

ABSTRACT: BACKGROUND AND AIM: Human beta-defensin-2 (hBD-2) is an antimicrobial cationic peptide capable to control human carcinoma cell growth via cell cycle regulation. The present study was aimed on determination of hBD-2 influence on the growth patterns and malignant potential of cultured human melanoma cells. METHODS: The study was performed on cultured human melanoma cells of mel Z and mel Is lines treated with recombinant hBD-2 (rec-hBD-2); cell viability, proliferation, cell cycle distribution, and anchorage-independent growth were analyzed using MTT test, direct cell counting, flow cytometry, and colony forming assay respectively. Expression and/or phosphorylation levels of proteins involved in cell cycle control were evaluated by Western blotting. RESULTS: The treatment of mel Z and mel Is cells with rec-hBD-2 in a concentration range of 100-1000 nM resulted in a concentration-dependent suppression of cell proliferation, viability, and colony forming activity. It has been shown that rec-hBD-2 exerts its growth suppression effects via significant downregulation of B-Raf expression, activation of pRB and upregulation of p21(WAF1) expression, downregulation of cyclin D1 and cyclin E resulting in cell cycle arrest at G1/S checkpoint. CONCLUSION: According to obtained results, hBD-2 exerts its growth suppression effect toward human melanoma cells via downregulation of B-Raf, cyclin D1 and cyclin E expression, upregulation of p21(WAF1) expression and activation of pRB.

22 Article The effect of monotherapy and combined therapy with NSC-631570 (ukrain) on growth of low- and high-metastasizing B16 melanoma in mice. 2011

Skivka, Lm / Susak, Yam / Trompak, Oo / Kudryavets, Yui / Bezdeneznikh, N / Semesiuk, N / Lykhova, O. ·Microbiology and General Immunology (sub)department, Biological Department, Taras Shevchenko Kyiv National University, Kyiv, Ukraine. realmed@i.com.ua ·J Oncol Pharm Pract · Pubmed #20817651.

ABSTRACT: BACKGROUND: NSC-631570 (ukrain) is a semisynthetic derivative of the Chelidonium majus alcaloids and the alkylans thiotepa. It exerts a selective cytotoxic effect on tumor cells in vitro and in vivo and shows the ability to modulate immunocyte functions. Purpose. The aim of our work was to carry out a comparative investigation of the effects of NSC-631570 alone or in combination with pathogen-associated molecules (PAM) on the growth of low- and high-metastasizing melanoma B16 in mice. METHODS: NSC-631570 was administered intravenously and PAM intramuscularly to tumor-bearing mice seven times every third day, starting from the second day after the transplantation of tumor cells. The effect of monotherapy and combined therapy on tumor growth was evaluated by the indices of tumor growth inhibition in experimental animals. Cell cycle distribution of cancer cells was determined by flow cytometry. TAP1 and TAP2 expression was evaluated by RT-PCR. The metabolic activity of phagocytes was determined by NBT-test, phagocytosis was tested by flow cytometry, and arginase activity was estimated by colorimetric determination of urea. RESULTS: Combined therapy and monotherapy with NSC-631570 resulted in significant inhibition of tumor growth in melanoma-bearing mice. Monotherapy with Ukrain was more effective in mice with high-metastasizing tumors. The therapeutic efficacy of NSC-631570 used in combination with PAM was more expressed in mice with low-metastasizing melanoma. CONCLUSION: The effectiveness of monotherapy and combined therapy with NSC-631570 in the treatment of melanoma B16 depends on the biological properties of the tumor and the immune state of the organism.

23 Article The effect of NSC-631570 (ukrain) alone and in combination with pathogen-associated molecules on cell cycle distribution and apoptosis induction of mouse melanoma cells with different biological properties. 2010

Skivka, L M / Trompak, O O / Kudryavets, Yu I / Bezdenezhnykh, N A / Susak, Ya M. ·T. Shevchenko Kyiv National University, Vladymyrska 64, Kyiv 01033, Ukraine. realmed@i.com.ua ·Exp Oncol · Pubmed #20693969.

ABSTRACT: AIM: To carry out comparative investigation of the effect of Ukrain used alone and in combination with pathogen associated molecules (PAM) on mitotic cycle and apoptosis induction in mouse melanoma cell lines with different biological properties. METHODS: Two cell lines with different biological properties (rate of cell division, level of hematogenous metastasis, sensitivity to tumor necrosis factor (TNF)-induced apoptosis) established from B16 mouse melanoma cell line, were used. Apoptosis induction and cell viability were analyzed using trypan blue exclusion test, morphological criteria, DNA gel electrophoresis and flow cytometry. Cell cycle distribution of tumor cells was determined by flow cytometry. Transporters associated with antigen processing (TAP) genes expression was analyzed using reverse transcriptase-polymerase chain reaction (RT-PCR) method. RESULTS: The melanoma cells with different metastatic capabilities differed markedly by the growth rate, sensitivity to apoptosis inducers, and the character of TAP gene expression. Treatment of melanoma cells with Ukrain resulted in apoptosis induction in a dose dependent manner. Melanoma cells with high-metastatic properties were more sensitive to Ukrain than their low metastatic variants. However combined use of drug with PAM induced apoptosis more effectively in melanoma cells with low-metastatic potential. CONCLUSION: Sensitivity to Ukrain in vitro may depend on biological properties of melanoma cells and may be modified by combined treatment of cells with TLR ligands. The results can be useful to optimize the regimen of mono and combined treatment of melanoma with Ukrain.

24 Article The use of doxorubicine at low doses for elevation of LAK-activity toward explants and cells of MC-rhabdomyosarcoma and B16 melanoma resistant to doxorubicin. 2008

Berezhnaya, N M / Vinnichuk, Yu D / Belova, O B. ·R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv, Ukraine. berezh@onconet.kiev.ua ·Exp Oncol · Pubmed #18438341.

ABSTRACT: AIM: To study the influence of doxorubicin at low doses on antitumor action of activated (LAK) and non-activated lymphocytes from lymph nodes toward tumor cells of mice bearing doxorubicin-resistant and doxorubicin-sensitive transplantable MC-rhabdomyosarcoma and B16 melanoma. MATERIALS AND METHODS: The study was carried out on BALB/c mice bearing MC-rhabdomyosarcoma and 57BL/6 mice bearing 16 melanoma. Explants, tumor cells and lymphocytes were cultivated in diffusion chambers, filters were stained with hematoxylin by Karachi, and morphology of preparations was examined. RESULTS: At the day 7 of tumor growth in mice bearing resistant MC-rhabdomyosarcoma, non-activated lymphocytes pretreated with low-dose doxorubicin possess the highest antitumor activity, and in mice bearing doxorubicin-resistant B16 melanoma the highest antitumor activity was detected for lymphocytes after combined cultivation with IL-2 and doxorubicin. At the day 14 of tumor growth, LAK obtained from lymphocytes pretreated with doxorubicin possess the highest cytotoxic activity toward resistant tumor cells both of MC-rhabdomyosarcoma and B16 melanoma. There was no such effect in the case of sensitive tumors. CONCLUSION: To elevate antitumor activity of LAK toward MC-rhabdomyosarcoma and B16 melanoma cells, low doses of doxorubicin could be used at certain conditions of LAK generation.