Evolution of Melanocytic Nevi under Vemurafenib, Followed by Combination Therapy with Dabrafenib and Trametinib for Metastatic Melanoma

ABSTRACT Treatment of advanced melanoma with selective BRAF and MEK inhibitors is associated with a series of mucocutaneous side effects, among which morphological changes in preexisting nevi and the development of new melanocytic lesions, both benign and malignant.Objective was to describe the changes observed in melanocytic nevi under vemurafenib therapy, followed by combination therapy with dabrafenib and trametinib for metastatic melanoma.The melanocytic lesions of a 51-year-old Caucasian male patient diagnosed with stage IV melanoma were monitored both clinically and dermoscopically throughout vemurafenib, followed by combined treatment with dabrafenib and trametinib.The 65 monitored nevi presented different behaviors under vemurafenib treatment: 18 reticular nevi, 9 reticular-homogenous nevi, 3 reticular-globular nevi, and 2 globular nevi showed a diffuse decrease in pigmentation. Ten reticular nevi remained unchanged, while the rest of the nevi, independent of the dermoscopic pattern, presented a gradual increase in pigmentation. On the other hand, under dabrafenib and trametinib treatment 57 of these nevi showed gradual decrease in pigmentation and central involution, while 7 reticular nevi and 1 globular nevus remained unchanged; none of the monitored nevi increased in pigmentation nor presented new globules following this combination therapy.Systematic total body skin examination is mandatory in patients receiving BRAF inhibitors. The divergent course of melanocytic nevi during vemurafenib vs. dabrafenib and trametinib therapy remains to be elucidated by further research. KEY WORDS: melanoma; pigmented nevus; dermoscopy; vemurafenib</p

Evolution of Melanocytic Nevi under Vemurafenib, Followed by Combination Therapy with Dabrafenib and Trametinib for Metastatic Melanoma

ABSTRACT Treatment of advanced melanoma with selective BRAF and MEK inhibitors is associated with a series of mucocutaneous side effects, among which morphological changes in preexisting nevi and the development of new melanocytic lesions, both benign and malignant.Objective was to describe the changes observed in melanocytic nevi under vemurafenib therapy, followed by combination therapy with dabrafenib and trametinib for metastatic melanoma.The melanocytic lesions of a 51-year-old Caucasian male patient diagnosed with stage IV melanoma were monitored both clinically and dermoscopically throughout vemurafenib, followed by combined treatment with dabrafenib and trametinib.The 65 monitored nevi presented different behaviors under vemurafenib treatment: 18 reticular nevi, 9 reticular-homogenous nevi, 3 reticular-globular nevi, and 2 globular nevi showed a diffuse decrease in pigmentation. Ten reticular nevi remained unchanged, while the rest of the nevi, independent of the dermoscopic pattern, presented a gradual increase in pigmentation. On the other hand, under dabrafenib and trametinib treatment 57 of these nevi showed gradual decrease in pigmentation and central involution, while 7 reticular nevi and 1 globular nevus remained unchanged; none of the monitored nevi increased in pigmentation nor presented new globules following this combination therapy.Systematic total body skin examination is mandatory in patients receiving BRAF inhibitors. The divergent course of melanocytic nevi during vemurafenib vs. dabrafenib and trametinib therapy remains to be elucidated by further research. KEY WORDS: melanoma; pigmented nevus; dermoscopy; vemurafenib</p

Position statement of the EADV Melanoma Task Force on recommendations for the management of cutaneous melanoma patients during COVID‐19

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ECCO essential requirements for quality cancer care : Melanoma

Background ECCO essential requirements for quality cancer care (ERQCC) are explanations and descriptions of challenges, organisation and actions that are necessary to give high-quality care to patients who have a specific type of cancer. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. Melanoma: essential requirements for quality care: Melanoma, the most-deadly skin cancer, is rising in incidence among fair-skinned people in Europe. Increasing complexity of care for advanced disease in clinical areas such as staging and new therapies requires attention to a number of challenges and inequalities in a diverse patient group. Care for advanced melanoma must only be carried out in, or in collaboration with, specialist melanoma centres which have both a core multidisciplinary team and an extended team of allied professionals, and which are subject to quality and audit procedures. Access to such units is far from universal in all European countries. It is essential that, to meet European aspirations for high-quality comprehensive cancer control, healthcare organisations implement the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis to treatment and follow-up, to improve survival and quality of life for patients. Conclusion: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality service for melanoma. The ERQCC expert group is aware that it is not possible to propose a 'one size fits all' system for all countries, but urges that access to multidisciplinary teams and specialised treatments is guaranteed to all patients with melanoma.Peer reviewe

Delphi Consensus Among International Experts on the Diagnosis, Management, and Surveillance for Lentigo Maligna

Introduction: Melanoma of the lentigo maligna (LM) type is challenging. There is lack of consensus on the optimal diagnosis, treatment, and follow-up. Objectives: To obtain general consensus on the diagnosis, treatment, and follow-up for LM. Methods: A modified Delphi method was used. The invited participants were either members of the International Dermoscopy Society, academic experts, or authors of published articles relating to skin cancer and melanoma. Participants were required to respond across three rounds using a 4-point Likert scale). Consensus was defined as >75% of participants agreeing/strongly agreeing or disagreeing/strongly disagreeing. Results: Of the 31 experts invited to participate in this Delphi study, 29 participants completed Round 1 (89.9% response rate), 25/31 completed Round 2 (77.5% response rate), and 25/31 completed Round 3 (77.5% response rate). Experts agreed that LM diagnosis should be based on a clinical and dermatoscopic approach (92%) followed by a biopsy. The most appropriate primary treatment of LM was deemed to be margin-controlled surgery (83.3%), although non-surgical modalities, especially imiquimod, were commonly used either as alternative off-label primary treatment in selected patients or as adjuvant therapy following surgery; 62% participants responded life-long clinical follow-up was needed for LM. Conclusions: Clinical and histological diagnosis of LM is challenging and should be based on macroscopic, dermatoscopic, and RCM examination followed by a biopsy. Different treatment modalities and follow-up should be carefully discussed with the patient

Wirkungsmechanismen von Bisphosphonaten in Melanomzelllinien in vitro

TITLE PAGE AND TABLE OF CONTENTS 1\. INTRODUCTION 1 1.1 STRUCTURE PHARMACOLOGY AND MECHANISM OF ACTION OF BISPHOSPHONATES 1 1.1.1 Structure 1 1.1.2 Mechanism of action 4 1.1.3 Pharmacology 7 1.2 USE OF BISPHOSPHONATES IN TUMOR THERAPY 9 1.2.1 In vitro studies of anti-tumor effect of bisphosphonates 10 1.2.2 Antitumor effects of bisphosphonates in animal model 11 1.2.3 Clinical trials 12 1.3 MELANOMA: CLINICAL COURSE, PROGNOSTIC PARAMETERS, THERAPEUTIC MEASURES 14 1.3.1 Clinical course 14 1.3.2 Prognostic parameters 17 1.3.3 Therapeutic procedures 18 1.3.3.1 Surgical therapy 18 1.3.3.2 Elective lymph node dissection (ELND) 19 1.3.3.3 Adjuvant therapy 19 1.3.3.4 Palliative therapy of metastasing melanoma (stage IV) 21 1.3.3.5 Experimental therapeutic approach 22 1.4 OBJECTIVE OF THE STUDY 25 2. MATERIAL AND METHODS 26 2.1 Materials 26 2.1.1 Reagents 26 2.1.2 Cell culture materials 26 2.1.3 Antibodies 27 2.1.4 Cell lines 27 2.1.5 Equipment 28 2.2 Methods 29 2.2.1 Cell culture 29 2.2.1.1 Cell culture media and solutions 29 2.2.1.2 Cultivation of cells 30 2.2.1.3 Freezing and thawing of cells 30 2.2.2 Cell biological techniques 31 2.2.2.1 Measurement of cell proliferation 31 2.2.2.2 Cytoxicity assay 32 2.2.2.3 Detection of apoptosis 33 2.2.3 Protein analysis 35 2.2.3.1 Determination of protein concentration 35 2.2.3.2 SDS-polyacrylamide gel electrophoresis 36 2.2.3.3 Western blotting 40 2.2.3.4 Immunodetection of blotted poroteins 42 2.2.4 Cell fractionation 44 2.2.5 Cell cycle analysis 46 3. Results 49 3.1 Bisphosphonates inhibit melanoma cell proliferation in vitro 49 3.2 Bisphosphonates have no cytotoxic effect in melanoma cells in vitro 51 3.3 Bisphosphonates induce apoptosis in human melanoma cells in vitro 52 3.3.1 Bisphosphonates induce apoptosis in melanoma cells in vitro in time- dependent manner 54 3.3.2 Bcl-2 overexpression does not prevent bisphosphonate-induced apoptosis in cultured melanoma cells 55 3.3.3 Effect of short-time exposure of melanoma cells to bisphosphonates 56 3.3.4 Éffect of combination of pamidronate and DTIC in melanoma cells 58 3.3.5 Cytochrome c release is not involved in bisphosphonate-induces apoptosis in vitro 59 3.4 Effects of bisphosphonates on cell cycle progression in melanoma cell in vitro 61 4. DISCUSSION 65 SUMMARY 76 5. REFERENCES 78 6. LIST OF PUBLICATIONS 90 ABBREVIATIONS 91 ACKNOWLEDGMENTS 94Bisphosphonates are synthetic pyrophosphate-analogues well established in the treatement of osteoclast -mediated resorbtive bone diseases including osteoporosis, Paget's disease and tumor-induced osteolysis. Recent studies suggest that , beside inhibiting bone resorbtion, bisphosphonates may also exert a direct antitumor effect, and this class of drugs has been shown to inhibit proliferation and to induce apoptosis in vitro in different human tumor cell lines. For the nitrogen- containing sub- class of bisphosphonates, this anti-neoplastic activity could be related to the inhibition of the mevalonate pathway and, consequently, of the prenylation of signalling proteins such as the small GTPases. The present study compared for the first time the in vitro effects of different bisphosphonates on melanoma cell lines. Three compounds with different mechanism of action and different antiresorptive potency were analysed: a non-amino-bisphosphonate (clodronate) and two amino- bisphosphonates, pamidronate and zoledronate, which is the most potent antiresorptive agent known to date. Their effects on cell proliferation, induction of apoptosis and cell cycle progression in the melanoma cell lines A375 and M186 and in the Bcl-2 overexpressing cell line A375/ Bcl-2 have been investigated in detail. In this experimental model, it could be shown that the nitrogen-containing bisphosphonates inhibit cell proliferation, induce apoptosis and alter cell cycle progression causing accumulation of cells in the S phase of the cycle. The antiproliferative and proapoptotic activity of the two compounds in vitro did not correlate well with their known antiresorptive potency in vivo. Apoptosis induced by the amino-bisphosphonates was dose and time dependent and acute exposure to pamidronate over 6h was sufficient to induce apoptosis. The pro-apoptotic effect of pamidronate and zoledronate was not inhibited by overexpression of Bcl-2 protein and did not appear to involve of cytochrome c release from the mitochondria, suggesting that these compounds may stimulate a mitochondria- independent pathway for inducing apoptotosis. In contrast, the non-amino- bishophonate clodronate had no effect on cell proliferation, apoptosis induction or cell cycle progression in melanoma cell lines, even at high concentrations. In conclusion, amino-bisphosphonates manifest a direct antitumoral effect on melanoma cells in vitro, and may thus represent a promising novel class of agents for the treatment/prevention of melanoma metastasis. Further studies are required, in order to describe the exact mechanism of action of these compounds, their most effective structures and ultimately their potential place in new strategies for adjuvant therapy schedules in malignant melanoma.Bisphosphonate stellen eine Klasse der synthetischen Analoga des endogenen Pyrophosphats dar, die heutzutage einen breiten klinischen Einsatz in der Therapie der Osteoklast-vermittelten Knochenstoffwechselerkrankungen wie Morbus Paget, Osteoporose und Tumorosteolyse haben. Neuere Studien weisen darauf hin, dass Bisphosphonate ausserhalb ihres osteoprotektiven Effekts, auch eine direkte antitumorale Wirkung zeigen und antiproliferativ und pro- apoptotisch in verschiedenen Typen von humanen Tumoren in vitro wirken. Im Fall der stickstoffhaltigen Bisphosphonate könnte die antineoplasische Wirkung durch die Hemmung der Enzyme des Mevalonat-Stoffwechselweges erklärt werden, die zur Inhibition der Prenylierung und dadurch zur Inaktivierung unterschiedlicher Signalmoleküle führt. In der vorliegenden Arbeit wurden die Effekte von verschiedenen Bisphosphonaten mit unterschiedlichen antiresorptiven Wirkungen und Wirkungsmechanismen in Melanom-Zelllinien in vitro untersucht. Der Einfluss der Aminobisphosphonate Pamidronat und Zoledronate sowie des Nichtaminobisphosphonates Clodronat auf die Zellproliferation, Apoptoseinduktion und Zellzyklusprogression in der Melanomzelllinien A 375, M186 und in der Bcl-2 überexprimierenden Zelllinie A 375/Bcl-2 wurde bestimmt. Es konnte gezeigt werden, dass die stickstoffhaltigen Bisphosphonate die Zellproliferation hemmen, Apoptosis auslösen und die Zellzyklusprogression durch eine Akkumulation der Zellen in der S Phase beeinträchtigen. Diese Wirkungen waren konzentrationsabhängig und korrelierten nicht mit der klinisch beschriebenen antiresorptiven Potenz der Medikamente. Die durch stickstoffhaltige Bisphosphonate ausgelöste Apoptose war zeitabhängig und konnte nach 6 Std Inkubation mit Pamidronat nachgewiesen werden. Die proapoptotische Wirkung der Aminobisphosphonate lies sich durch die Überexpression des Proteins Bcl-2 nicht hemmen und schien unabhängig von der Cytochrome C-Freisetzung zu sein, so dass die Auslösung der Apoptose mittels Amninobisphosphonate durch einen Mitochondrien-unabhängigen Weg angenommen werden kann. Im Gegensatz dazu konnte der Einfluss des Nichtaminobisphosphonates Clodronat auf die Zellproliferation, Apoptoseinduktion oder Zellzyklusprogression in den untersuchten Zelllinien nicht nachgewiesen werden. Diese Ergebnisse unterstützen weiterhin die Hypothese, dass Amino-bzw Nichtaminobisphosphonate über unterschiedliche Mechanismen ihre Wirkung entfalten können. Zusammenfassend kann festgehalten werden, dass Aminobisphosphonate eine direkte antitumorale Wirkung in Melanomzellen in vitro zeigen und dadurch eine interessante Möglichkeit für die Entwicklung neuer Strategien für die Behandlung bzw. Prävention der Melanom-Metastasen darstellen

Priorities and challenges for skin cancer prevention in Europe: An expert survey

The incidence, mortality, and survival rates of melanoma vary significantly across Europe, likely related to persistent inequalities between European countries in the areas of skin cancer early detection, case registration, and prevention. To enhance the planning of prevention strategies for skin cancer in Europe, we solicited the direct opinion of European experts in the field of dermato-oncology on the main obstacles, needs, and priorities for the reduction of the skin cancer burden on this continent. We surveyed European dermatologists with leading positions in European and international organizations active in skin cancer prevention by means of written, single-choice and multiple-choice questionnaires. Fifty-two dermatologists from 32 European countries completed the survey (response rate 80%). Fewer respondents in Eastern Europe compared with Western Europe reported the presence of governmental (12 vs. 46%) or nongovernmental (35 vs. 65%) initiatives for skin cancer prevention. Most respondents in Eastern (73%) and Western Europe (69%) reported the existence of national cancer registries, but the confidence in the accuracy of melanoma registration was low. Public and professional education for early detection were top priorities for skin cancer campaigns across Europe and the perceived obstacles were similar in both regions: the lack of a national program of public education, insufficient public authority initiatives, and insufficient training of physicians on skin cancer. Our survey highlighted several areas requiring intervention for skin cancer prevention and found that the main issues and obstacles appear to be similar across Europe, creating the premise for coordinated, pan-European action. © 2013 Wolters Kluwer HealthSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Melanoma prognosis in Europe: Far from equal

Background Comprehensive, population-based analysis of melanoma survival throughout Europe is hindered by the uneven coverage and quality of European cancer registries, and by logistical and financial shortcomings. Mortality-to-incidence ratios (MIRs) have been used as a proxy for estimating survival for multiple cancers and to model melanoma prognosis, higher MIR values reflecting poorer prognosis. Updated and improved pan-European estimates of mortality and incidence rates for melanoma have become available through the International Agency for Research of Cancer project Globocan 2008, showing marked differences among European countries. Objectives To analyse MIRs for melanoma across Europe and their relationship with national health expenditures, aiming to identify countries and regions with disproportionately poor prognosis. Methods Estimated age-standardized rates of melanoma incidence and mortality provided by Globocan 2008 were used to calculate the MIR for each European country and region. Total health expenditures per capita in European countries for 2008 were provided by the World Health Organization/Global Health Observatory. The potential correlation between MIR and total health expenditure per capita was analysed through Pearson's correlation. Results Mortality-to-incidence ratios for melanoma ranged between 0·09 in Switzerland and 0·44 in Latvia. The regional average MIR was the highest in Central and Eastern Europe at 0·35; the lowest was in Western Europe, at 0·13. We found a strong inverse correlation between the individual nation's total health expenditure per capita and the calculated melanoma MIR (r = -0·76, P < 0·05). Conclusions While further improvement of melanoma registration is necessary, our findings reveal sharp disparities in the prognosis of melanoma across the Continent, correlated with significant differences in health care expenditures. What's already known about this topic? No comprehensive analysis of melanoma survival is available for the whole European continent. Mortality-to-incidence ratios (MIR) have been used to estimate survival for multiple cancers and to model melanoma prognosis. What does this study add? This is the first pan-European estimate of melanoma prognosis based on MIRs, revealing wide variation across Europe. Central and Eastern Europe had the highest MIR values, reflecting the poorest prognosis. Melanoma prognosis, modelled through MIR, correlated strongly with national health expenditures. © 2014 British Association of Dermatologists.SCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe