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  1. Advanced Melanoma Facebook Live Event

    Science.gov (United States)

    In case you missed it, watch this recent Facebook Live event about the current state of research and treatment for advanced stage melanoma. To learn more, see our evidence-based information about skin cancer, including melanoma.

  2. Melanoma Biopsy Results Can Differ, Worrying Patients

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_166955.html Melanoma Biopsy Results Can Differ, Worrying Patients Doctor discovers ... her dermatologist said her skin biopsy indicated possible melanoma, she knew just what to do -- get a ...

  3. Living with 'melanoma' … for a day: a phenomenological analysis of medical students' simulated experiences.

    Science.gov (United States)

    Corr, M; Roulston, G; King, N; Dornan, T; Blease, C; Gormley, G J

    2017-09-01

    Despite the rising incidence of melanoma, medical students have progressively fewer opportunities to encounter patients with this important condition. Curricula tend to attach the greatest value to intellectual forms of learning. However, compared with intellectual learning, experiential learning affords students deep insights about a condition. Doctors who experience ill health are more empathic towards patients. However, opportunities to learn about cancer experientially are limited. Temporary transfer tattoos can simulate the ill health associated with melanoma. We reasoned that if doctors who have been sick are more empathic temporarily 'having' melanoma might have a similar effect. To explore the impact of wearing a melanoma tattoo on medical students' understanding of patienthood and attitudes towards patients with melanoma. Ten fourth-year medical students were recruited to a simulation. They wore a melanoma tattoo for 24 h and listened to a patient's account of receiving their diagnosis. Data were captured using audio diaries and face-to-face interviews, transcribed and analysed phenomenologically using the template analysis method. There were four themes: (i) melanoma simulation: opening up new experiences; (ii) drawing upon past experiences; (iii) a transformative introduction to patienthood; (iv) doctors in the making: seeing cancer patients in a new light. By means of a novel simulation, medical students were introduced to lived experiences of having a melanoma. Such an inexpensive simulation can prompt students to reflect critically on the empathetic care of such patients in the future. © 2017 British Association of Dermatologists.

  4. Psychosocial care to patients with Malignant Melanoma

    DEFF Research Database (Denmark)

    Thorup, Charlotte Brun

    Psychosocial care to patients with Malignant Melanoma Intensions: The intension of this project is to link new knowledge with the nurses experience based knowledge within the psychosocial care to patients, who have been diagnosed with Malignant Melanoma (MM), thereby improving the care...

  5. Functional profiling of live melanoma samples using a novel automated platform.

    Directory of Open Access Journals (Sweden)

    Adam Schayowitz

    Full Text Available AIMS: This proof-of-concept study was designed to determine if functional, pharmacodynamic profiles relevant to targeted therapy could be derived from live human melanoma samples using a novel automated platform. METHODS: A series of 13 melanoma cell lines was briefly exposed to a BRAF inhibitor (PLX-4720 on a platform employing automated fluidics for sample processing. Levels of the phosphoprotein p-ERK in the mitogen-activated protein kinase (MAPK pathway from treated and untreated sample aliquots were determined using a bead-based immunoassay. Comparison of these levels provided a determination of the pharmacodynamic effect of the drug on the MAPK pathway. A similar ex vivo analysis was performed on fine needle aspiration (FNA biopsy samples from four murine xenograft models of metastatic melanoma, as well as 12 FNA samples from patients with metastatic melanoma. RESULTS: Melanoma cell lines with known sensitivity to BRAF inhibitors displayed marked suppression of the MAPK pathway in this system, while most BRAF inhibitor-resistant cell lines showed intact MAPK pathway activity despite exposure to a BRAF inhibitor (PLX-4720. FNA samples from melanoma xenografts showed comparable ex vivo MAPK activity as their respective cell lines in this system. FNA samples from patients with metastatic melanoma successfully yielded three categories of functional profiles including: MAPK pathway suppression; MAPK pathway reactivation; MAPK pathway stimulation. These profiles correlated with the anticipated MAPK activity, based on the known BRAF mutation status, as well as observed clinical responses to BRAF inhibitor therapy. CONCLUSION: Pharmacodynamic information regarding the ex vivo effect of BRAF inhibitors on the MAPK pathway in live human melanoma samples can be reproducibly determined using a novel automated platform. Such information may be useful in preclinical and clinical drug development, as well as predicting response to targeted therapy in

  6. Targeting Brain Metastases in Patients with Melanoma

    Directory of Open Access Journals (Sweden)

    Dionysis Papadatos-Pastos

    2013-01-01

    Full Text Available Patients with brain metastases from malignant melanoma historically have a very poor outcome. Surgery and radiotherapy can be used, but for the majority of patients the disease will progress quickly. In the recent past, patients with brain metastases derived only minimal benefit from cytotoxic chemotherapy. Novel therapies that have been shown to be superior to chemotherapy in metastatic melanoma have made their way in clinic and data regarding their use in patients with treated or untreated brain metastases are encouraging. In this paper we describe the use of vemurafenib, dabrafenib, and ipilimumab in patients with melanoma disseminated to the brain in addition to other treatments currently in development.

  7. Reproducibility of self-reported melanoma risk factors in melanoma patients

    NARCIS (Netherlands)

    Waal, A.C. de; Rossum, M.M. van; Kiemeney, L.A.L.M.; Aben, K.K.H.

    2014-01-01

    As melanoma researchers continue to investigate environmental and lifestyle-related risk factors, questionnaire data remain important. The reproducibility of a questionnaire on melanoma risk factors was investigated using a test-retest approach in 389 Dutch melanoma patients. In 2011, 389 melanoma

  8. Reproducibility of self-reported melanoma risk factors in melanoma patients

    NARCIS (Netherlands)

    Waal, A.C. de; Rossum, M.M. van; Kiemeney, L.A.L.M.; Aben, K.K.H.

    2014-01-01

    As melanoma researchers continue to investigate environmental and lifestyle-related risk factors, questionnaire data remain important. The reproducibility of a questionnaire on melanoma risk factors was investigated using a test-retest approach in 389 Dutch melanoma patients. In 2011, 389 melanoma p

  9. Risk factors for second primary melanoma among Dutch patients with melanoma

    NARCIS (Netherlands)

    Schuurman, M.S.; Waal, A.C. de; Thijs, E.J.M.; Rossum, M.M. van; Kiemeney, L.A.L.M.; Aben, K.K.H.

    2017-01-01

    BACKGROUND: Patients with melanoma are at increased risk of developing subsequent primary melanomas. Knowledge about risk factors for these subsequent primaries is scarce. More evidence may help clinicians in tailoring surveillance schedules by selecting patients who could benefit from intensified

  10. Circulating tumor cells in melanoma patients.

    Directory of Open Access Journals (Sweden)

    Gary A Clawson

    Full Text Available Circulating tumor cells (CTCs are of recognized importance for diagnosis and prognosis of cancer patients. With melanoma, most studies do not show any clear relationship between CTC levels and stage of disease. Here, CTCs were enriched (∼400X from blood of melanoma patients using a simple centrifugation device (OncoQuick, and 4 melanocyte target RNAs (TYR, MLANA, MITF, and MIF were quantified using QPCR. Approximately one-third of melanoma patients had elevated MIF and MLANA transcripts (p<0.0001 and p<0.001, respectively compared with healthy controls. In contrast, healthy controls had uniformly higher levels of TYR and MITF than melanoma patients (p<0.0001. There was a marked shift of leukocytes into the CTC-enriched fractions (a 430% increase in RNA recovery, p<0.001, and no relationship between CTC levels and stage of disease was found. CTCs were captured on microfabricated filters and cultured. Captured melanoma CTCs were large cells, and consisted of 2 subpopulations, based on immunoreactivity. One subpopulation (∼50% stained for both pan-cytokeratin (KRT markers and the common leukocyte marker CD-45, whereas the second subpopulation stained for only KRT. Since similar cells are described in many cancers, we also examined blood from colorectal and pancreatic cancer patients. We observed analogous results, with most captured CTCs staining for both CD-45/KRT markers (and for the monocyte differentiation marker CD-14. Our results suggest that immature melanocyte-related cells (expressing TYR and MITF RNA may circulate in healthy controls, although they are not readily detectable without considerable enrichment. Further, as early-stage melanomas develop, immature melanocyte migration into the blood is somehow curtailed, whereas a significant proportion of patients develop elevated CTC levels (based on MIF and MLANA RNAs. The nature of the captured CTCs is consistent with literature describing leukocyte/macrophage-tumor cell fusion hybrids

  11. Melanoma

    Science.gov (United States)

    Melanoma is the most serious type of skin cancer. Often the first sign of melanoma is a change in the size, shape, color, or feel of a mole. Most melanomas have a black or black-blue area. Melanoma ...

  12. Psychosocial care to patients with Malignant Melanoma

    DEFF Research Database (Denmark)

    Thorup, Charlotte Brun

    Psychosocial care to patients with Malignant Melanoma Intensions: The intension of this project is to link new knowledge with the nurses experience based knowledge within the psychosocial care to patients, who have been diagnosed with Malignant Melanoma (MM), thereby improving the care...... to this group of patients. Background: MM is the type of cancer, which over the past 50 years has increased the most in newly discovered cases, and is the most aggressive type of skin cancer. The statement above shows that this group of patients will increase in the future. It is therefore important...... to elaborate the care to these patients. Method: In 2007 the nurses from our ward gained experience from the psychosocial care to these patients. These experiences are a starting point to the study of literature the group has made. A group of five nurses have from this literature study, substantiated...

  13. Sarcoidosis in Melanoma Patients: Case Report and Literature Review

    Energy Technology Data Exchange (ETDEWEB)

    Beutler, Bryce D., E-mail: brycebeutler@hotmail.com [School of Allied Health Sciences, University of Nevada, Las Vegas, 1060 Wiegand Road, Encinitas, CA 92024 (United States); Cohen, Philip R., E-mail: brycebeutler@hotmail.com [Department of Dermatology, University of California San Diego, 10991 Twinleaf Court, San Diego, CA 92131 (United States)

    2015-06-15

    Sarcoidosis is a systemic inflammatory disease characterized by the development of noncaseating granulomas in multiple organ systems. Many hematologic malignancies and solid tumors, including melanoma, have been associated with sarcoidosis. We describe the clinical and pathologic findings of a 54-year-old man with melanoma-associated sarcoidosis. In addition, we not only review the literature describing characteristics of other melanoma patients with sarcoidosis, but also the features of melanoma patients with antineoplastic therapy-associated sarcoidosis. Sarcoidosis has been described in 80 melanoma patients; sufficient information for analysis was provided in 39 of these individuals. In 43.6% of individuals (17 out of 39), sarcoidosis was directly associated with melanoma; in 56.4% of oncologic patients (22 out of 39), sarcoidosis was induced by antineoplastic therapy that had been administered for the treatment of their metastatic melanoma. The discovery of melanoma preceded the development of sarcoidosis in 12 of the 17 (70.5%) individuals who did not receive systemic treatment. Pulmonary and/or cutaneous manifestations of sarcoidosis were common among both groups of patients. Most patients did not require treatment for sarcoidosis. Melanoma patients—either following antineoplastic therapy or without systemic treatment—may be at an increased risk to develop sarcoidosis. In antineoplastic therapy naive melanoma patients, a common etiologic factor—such as exposure to ultraviolet light—may play a role in their developing melanoma and sarcoidosis.

  14. Sarcoidosis in Melanoma Patients: Case Report and Literature Review

    Science.gov (United States)

    Beutler, Bryce D.; Cohen, Philip R.

    2015-01-01

    Sarcoidosis is a systemic inflammatory disease characterized by the development of noncaseating granulomas in multiple organ systems. Many hematologic malignancies and solid tumors, including melanoma, have been associated with sarcoidosis. We describe the clinical and pathologic findings of a 54-year-old man with melanoma-associated sarcoidosis. In addition, we not only review the literature describing characteristics of other melanoma patients with sarcoidosis, but also the features of melanoma patients with antineoplastic therapy-associated sarcoidosis. Sarcoidosis has been described in 80 melanoma patients; sufficient information for analysis was provided in 39 of these individuals. In 43.6% of individuals (17 out of 39), sarcoidosis was directly associated with melanoma; in 56.4% of oncologic patients (22 out of 39), sarcoidosis was induced by antineoplastic therapy that had been administered for the treatment of their metastatic melanoma. The discovery of melanoma preceded the development of sarcoidosis in 12 of the 17 (70.5%) individuals who did not receive systemic treatment. Pulmonary and/or cutaneous manifestations of sarcoidosis were common among both groups of patients. Most patients did not require treatment for sarcoidosis. Melanoma patients—either following antineoplastic therapy or without systemic treatment—may be at an increased risk to develop sarcoidosis. In antineoplastic therapy naive melanoma patients, a common etiologic factor—such as exposure to ultraviolet light—may play a role in their developing melanoma and sarcoidosis. PMID:26083934

  15. Recombinant Interferon Alfa-2b in Treating Patients With Melanoma

    Science.gov (United States)

    2016-05-17

    Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma

  16. Sentinel node biopsy for melanoma: a study of 241 patients

    DEFF Research Database (Denmark)

    Chakera, Annette Hougaard; Drzewiecki, Krzysztof Tadeusz; Jakobsen, Annika Loft

    2004-01-01

    The aim of this study was to evaluate the sentinel node biopsy (SNB) technique for melanoma using both radiocolloid and blue dye in 241 clinically N0 patients with melanomas >1.0 mm, or thinner lesions exhibiting regression/ulceration. We showed that an increase in injected radioactivity increased...

  17. Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab

    NARCIS (Netherlands)

    Weide, Benjamin; Martens, Alexander; Hassel, Jessica C.; Berking, Carola; Postow, Michael A.; Bisschop, Kees; Simeone, Ester; Mangana, Johanna; Schilling, Bastian; Di Giacomo, Anna Maria; Brenner, Nicole; Kaehler, Katharina; Heinzerling, Lucie; Gutzmer, Ralf; Bender, Armin; Gebhardt, Christoffer; Romano, Emanuela; Meier, Friedegund; Martus, Peter; Maio, Michele; Blank, Christian; Schadendorf, Dirk; Dummer, Reinhard; Ascierto, Paolo A.; Hospers, Geke; Garbe, Claus; Wolchok, Jedd D.

    2016-01-01

    Purpose: Biomarkers for outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence. We aimed to identify baseline factors associated with overall survival (OS) after pembrolizumab treatment in melanoma patients. Experimental Design:

  18. New Therapies Offer Valuable Options for Patients with Melanoma

    Science.gov (United States)

    Two phase III clinical trials of new therapies for patients with metastatic melanoma presented in June at the 2011 ASCO conference confirmed that vemurafenib and ipilimumab (Yervoy™) offer valuable new options for the disease.

  19. Malignant cutaneous melanoma in patients from Las Tunas province

    Directory of Open Access Journals (Sweden)

    Alicia María Yabor Palomo

    2015-11-01

    Full Text Available Background: malignant melanoma is a highly aggressive skin neoplasia, whose incidence shows a constant and rapid increase.Objective: to characterize variables in patients diagnosed with cutaneous melanoma, whose biopsies were analyzed in the pathologic anatomy department of "Dr. Ernesto Guevara de la Serna" General Teaching Hospital from January, 2008 to December, 2014.Methods: a descriptive and cross-sectional study was performed in 31 patients treated in the place and period of time mentioned above. The official form of biopsy was used as a secondary source of collecting information and it was processed using descriptive statistics.Results: the 10,6 % of the biopsies analyzed corresponded with cutaneous melanoma, its frequency prevailed in 2011 and 2010, with a 25,8 % and 19,3 % respectively. It was evident a higher percentage in males (67,7 % and in the age group between 60 and 69 years old, with a 35,4 %. Caucasian patients were the most affected ones, with a 90,3 % and the predominant location was in the lower limbs in 45,1 % of the cases. The prevailing Clark invasion level was IV, evident by the 32,2 % of the sample, and the most frequent histological variety was the malignant nodular melanoma in 19 patients, for a 61,2 %.Conclusions: cutaneous melanoma prevailed in lower extremities in males and it had a belated diagnosis, since there was prevalence of IV Clark invasion level and nodular melanoma as the most frequent histological type.

  20. Prognostic significance of hematological profiles in melanoma patients.

    Science.gov (United States)

    Gandini, Sara; Ferrucci, Pier Francesco; Botteri, Edoardo; Tosti, Giulio; Barberis, Massimo; Pala, Laura; Battaglia, Angelo; Clerici, Alessandra; Spadola, Giuseppe; Cocorocchio, Emilia; Martinoli, Chiara

    2016-10-01

    Cancer-related inflammation may play an important role in disease progression and patient outcome, and could be easily monitored through indirect parameters routinely evaluated at diagnosis. Here, we investigated if peripheral blood cells and the ratios of neutrophils to lymphocytes (NLR) and of lymphocytes to monocytes (LMR) as surrogate markers of cancer related inflammation are associated with disease progression and survival of melanoma patients at any stage of the disease. Records of 1,182 melanoma patients included in an Institutional tumor registry in the period 2000-2010, were reviewed. Among them, 584 patients with a cutaneous or unknown primary melanoma and available pre-operative blood tests were analyzed. Survival was estimated with the Kaplan-Meier method, and analyzed using Log-rank test, Cox regression and multivariate Cox proportional hazard models. We found that patients presenting with distant metastases had higher leukocytes, neutrophils and monocytes, and lower lymphocytes compared to Stage I-III patients. Furthermore, at a single-patient level, hematological profiles changed on disease progression from regional to distant metastatic, with significantly increased circulating leukocytes, neutrophils and monocytes, and decreased lymphocytes. Peripheral blood cell counts were not associated with survival of patients with a localized or regionally metastasized melanoma. Instead, in Stage IV patients, leukocytes (p = 0.001), neutrophils (p = 0.0002), monocytes (p = 0.002), NLR (p melanoma. © 2016 UICC.

  1. Psychoeducational intervention for patients with cutaneous malignant melanoma

    DEFF Research Database (Denmark)

    Boesen, Ellen H; Ross, Lone; Frederiksen, Kirsten

    2005-01-01

    PURPOSE: In 1993, a randomized intervention study among patients with malignant melanoma showed a significant decrease in psychological distress and increased coping capacity 6 months after the intervention and enhanced survival 6 years later. We applied a similar intervention with a few modifica......PURPOSE: In 1993, a randomized intervention study among patients with malignant melanoma showed a significant decrease in psychological distress and increased coping capacity 6 months after the intervention and enhanced survival 6 years later. We applied a similar intervention with a few...... modifications in a randomized controlled trial among Danish patients with malignant melanoma and evaluated results on immediate and long-term effects on psychological distress and coping capacity. PATIENTS AND METHODS: A total of 262 patients with primary cutaneous malignant melanoma were randomly assigned...... significantly more active-behavioral and active-cognitive coping than the patients in the control group. The improvements were only significant at first follow-up. CONCLUSION: The findings of this study support the results of an earlier intervention study among patients with malignant melanoma and indicate...

  2. Melanoma patient imaging in the era of effective systemic therapies.

    Science.gov (United States)

    Stodell, M; Thompson, J F; Emmett, L; Uren, R F; Kapoor, R; Saw, R P M

    2017-08-01

    Imaging plays a critical role in the current multi-disciplinary management of patients with melanoma. It is used for primary disease staging, surgical planning, and surveillance in high-risk patients, and for monitoring the effects of systemic or loco-regional therapies. Several different imaging modalities have been utilised in the past. Contemporary imaging practises vary geographically depending on clinical guidelines, physician preferences, availability and cost. Targeted therapies and immunotherapies have revolutionised the treatment of patients with metastatic melanoma over the last few years. With this have come new patterns of disease that were not observed after conventional therapies, and new criteria to assess therapeutic responses. In this article we review the role of imaging for patients with melanoma in the era of effective systemic therapies and discuss likely future developments. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

  3. Melanoma

    Science.gov (United States)

    ... from generations ago. Back in your parents' and grandparents' day, most people (including doctors) thought it was safe and even ... it again somewhere else) Although it's less likely, people can still get melanoma even if they're dark skinned, young, and have no family history. Even for them, ...

  4. Testing New Drugs for Treatment of Melanoma Patients Applying Connectivity Map Database Analysis with Melanoma Gene Signatures

    Science.gov (United States)

    2012-10-01

    AD_________________ Award Number: W81XWH-11-1-0794 TITLE: Testing New Drugs for Treatment of...TYPE Final 3. DATES COVERED 15 September 2011 – 14 September 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Testing New Drugs for Treatment of...4 Introduction: Project Title: Testing New Drugs for treatment of Melanoma Patients Applying Connectivity Map Database Analysis with Melanoma

  5. Asymptomatic brain metastases in patients with cutaneous metastatic malignant melanoma

    DEFF Research Database (Denmark)

    Zukauskaite, Ruta; Schmidt, Henrik; Asmussen, Jon T

    2013-01-01

    The aim of the study was to identify the frequency of asymptomatic brain metastases detected by computed tomography (CT) scans in patients with metastatic cutaneous melanoma referred to first-line systemic treatment. Between 1995 and 2009, 697 Danish patients were screened with a contrast...

  6. Management of a patient with advanced BRAF-mutant melanoma.

    Science.gov (United States)

    Ashworth, Michelle T; Daud, Adil

    2014-03-01

    A 49-year-old man initially diagnosed in 1995 with cutaneous melanoma presented to the authors' institution in 2009 with metastatic, BRAF V600E-mutant melanoma. His treatment course to date has included surgery, adjuvant radiotherapy, and interferon, metastasectomies, granulocyte-macrophage colony-stimulating factors, a clinical trial with the BRAF inhibitor vemurafenib (PLX-4032), clinical trial with combination BRAF plus MEK inhibition with vemurafenib plus GDC-0973, and combination targeted and immune therapy with vemurafenib plus the anti-CTLA4 antibody ipilimumab. This case report illustrates the long-term management of a patient with metastatic melanoma using targeted and immune therapy, evolution in treatment guidelines, next directions in research, and the critical role of clinical trials in advancement of patient care.

  7. Stage IV Melanoma : Completely Resectable Patients are Scarce

    NARCIS (Netherlands)

    Wevers, K. P.; Hoekstra, H. J.

    In melanoma, about 1 in 5 patients develops distant metastases and suffers a very poor prognosis. Common treatment options comprise surgery, systemic medical therapy, and radiotherapy, depending on the number, the location, and the resectability of distant metastases. Previous studies suggested that

  8. Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Stage IV Melanoma

    Science.gov (United States)

    2016-05-06

    Acral Lentiginous Malignant Melanoma; Lentigo Maligna Malignant Melanoma; Nodular Malignant Melanoma; Recurrent Melanoma; Solar Radiation-related Skin Melanoma; Stage IV Melanoma; Superficial Spreading Malignant Melanoma

  9. Transarterial chemoembolization of liver metastases in patients with uveal melanoma

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    Huppert, P.E., E-mail: huppert@klinikum-darmstadt.d [Department of Diagnostic and Interventional Radiology, Klinikum Darmstadt, Darmstadt (Germany); Fierlbeck, G., E-mail: gerhard.fierlbeck@med.uni-tuebingen.d [Department of Dermatology, University of Tuebingen, Liebermeisterstrasse 25, D-72076 Tuebingen (Germany); Pereira, P., E-mail: philippe.pereira@slk-kliniken.d [Department of Diagnostic Radiology, University of Tuebingen, Hoppe-Seyler-Strasse 3, D-72076 Tuebingen (Germany); Schanz, S., E-mail: stefan.schanz@med.uni-tuebingen.d [Department of Dermatology, University of Tuebingen, Liebermeisterstrasse 25, D-72076 Tuebingen (Germany); Duda, S.H., E-mail: stephan.duda@t-online.d [Department of Diagnostic Radiology, University of Tuebingen, Hoppe-Seyler-Strasse 3, D-72076 Tuebingen (Germany); Wietholtz, H., E-mail: hubertus.wietholtz@klinikum-darmstadt.d [Department of Internal Medicine II, Klinikum Darmstadt, Darmstadt (Germany); Rozeik, C., E-mail: rozeik.christoph@klinloe.d [Department of Diagnostic and Interventional Radiology, Klinikum Darmstadt, Darmstadt (Germany); Claussen, C.D., E-mail: claus.claussen@med.uni-tuebingen.d [Department of Diagnostic Radiology, University of Tuebingen, Hoppe-Seyler-Strasse 3, D-72076 Tuebingen (Germany)

    2010-06-15

    Summary: Metastases from uveal melanoma are often confined to the liver. Palliative hepatic chemoembolization has been considered to be a reasonable treatment approach. We enrolled 14 patients with hepatic metastases from uveal melanoma into a pilot trial of transarterial chemoembolization (TACE). All patients received additional systemic immuno-chemotherapy or best supportive care. In 31 procedures 100 mg/m{sup 2} of cisplatine was continuously infused by means of a power injector preceding embolization by manual injection of polyvinyl alcohol particles. In three procedures cisplatine was replaced by 200 mg/m{sup 2} carboplatine because of increased serum creatinine levels. Tumor response was evaluated using RECIST criteria. Fourteen patients received 34 TACE's (mean: 2.4 treatments). Eight patients (57%) achieved partial response (PR), four patients (29%) had stable disease and two patients (14%) tumor progression. Median time to progression was 8.5 months (5-35 months). Median survival after first TACE was 14.5 months in responders compared to 10 months in non-responders (p = 0.18, not significant) and 11.5 months (3-69 months) in all patients. In seven patients with metastases occupying less than 25% of liver volume median survival was 17 months compared to 11 months in seven patients with tumor involvement of more than 25% (p = 0.02) with partial response rate of 86% and 29%, respectively. TACE of liver metastases from uveal melanoma is well tolerated and may prolong survival in patients with limited tumor extension.

  10. Telomerase reverse transcriptase (TERT) promoter mutations in Korean melanoma patients.

    Science.gov (United States)

    Roh, Mi Ryung; Park, Kyu-Hyun; Chung, Kee Yang; Shin, Sang Joon; Rha, Sun Young; Tsao, Hensin

    2017-01-01

    Telomerase reverse transcriptase (TERT) is the reverse transcriptase component of the telomeric complex, which synthesizes terminal DNA to protect chromosomal ends and to maintain genomic integrity. In melanoma, mutation in TERT promoter region is a common event and theses promoter variants have been shown to be associated with increased gene expression, decreased telomere length and poorer outcome. In this study, we determined the frequency of TERT promoter mutation in 88 Korean primary melanoma patients and aimed to see the association of TERT promoter mutation status to other major molecular features, such as BRAF, NRAS, KIT mutations and correlate with clinicopathological features. In our study, acral melanoma (n=46, 52.3%) was the most common type. Overall, TERT promoter mutation was observed in 15 cases (17%) with ten c. -124C>T altertions and five c. -146C>T alterations. None of our samples showed CC>TT mutation which is considered pathognomonic of UV induction. Among the 46 acral melanoma patients, 5 patients (10.9%) harbored TERT promoter mutation. Tumors with TERT promoter mutation showed significantly greater Breslow thickness compared to WT tumors (P=0.039). A combined analysis for the presence of TERT promoter and BRAF mutations showed that patients with both TERT promoter and BRAF mutation showed decreased survival compared with those with only TERT promoter mutation, only BRAF mutation, or without mutations in either TERT promoter or BRAF (P=0.035). Our data provides additional evidence that UV-induced TERT promoter mutation frequencies vary depending on melanoma subtype, but preserves its prognostic value.

  11. Detection of circulating tumor lysate-reactive CD4+ T cells in melanoma patients

    DEFF Research Database (Denmark)

    Ladekarl, Morten; Agger, Ralf; Fleischer, Charlotte C

    2004-01-01

    PURPOSE: We wanted to study whether an allogeneic melanoma lysate would be a feasible stimulatory antigen source for detection of a peripheral CD4+ T-cell immune response in patients with medically untreated malignant melanoma. The lysate was produced from a melanoma cell line (FM3.29) which expr...

  12. Sentinel node biopsy for melanoma: a study of 241 patients

    DEFF Research Database (Denmark)

    Chakera, Annette Hougaard; Drzewiecki, Krzysztof Tadeusz; Jakobsen, Annika Loft

    2004-01-01

    The aim of this study was to evaluate the sentinel node biopsy (SNB) technique for melanoma using both radiocolloid and blue dye in 241 clinically N0 patients with melanomas >1.0 mm, or thinner lesions exhibiting regression/ulceration. We showed that an increase in injected radioactivity increased...... both the number of visualized nodes at lymphoscintigraphy and the number of SNs removed surgically. At least one SN was removed in 98% (236) of patients, and all nodes were identified with the probe. Seventy-four per cent of the 194 patients injected with blue dye had stained SNs. In 46% (144......) of the lymph node basins, there was a discrepancy between the nodes visualized at lymphoscintigraphy and the nodes removed at surgery. There were 38 unusually located nodes. Only eight of these were removed surgically; none contained metastases. SN metastases were detected in 22% (53) of patients. There were...

  13. Multicenter phase II study of matured dendritic cells pulsed with melanoma cell line lysates in patients with advanced melanoma

    Directory of Open Access Journals (Sweden)

    Hernandez Jackie

    2010-09-01

    Full Text Available Abstract Background Several single center studies have provided evidence of immune activation and antitumor activity of therapeutic vaccination with dendritic cells (DC in patients with metastatic melanoma. The efficacy of this approach in patients with favorable prognosis metastatic melanoma limited to the skin, subcutaneous tissues and lung (stages IIIc, M1a, M1b was tested in a multicenter two stage phase 2 study with centralized DC manufacturing. Methods The vaccine (IDD-3 consisted 8 doses of autologous monocyte-derived matured DC generated in serum-free medium with granulocyte macrophage colony stimulating factor (GM-CSF and interleukin-13 (IL-13, pulsed with lysates of three allogeneic melanoma cell lines, and matured with interferon gamma. The primary endpoint was antitumor activity. Results Among 33 patients who received IDD-3 there was one complete response (CR, two partial responses (PR, and six patients had stable disease (SD lasting more than eight weeks. The overall prospectively defined tumor growth control rate was 27% (90% confidence interval of 13-46%. IDD-3 administration had minimal toxicity and it resulted in a high frequency of immune activation to immunizing melanoma antigens as assessed by in vitro immune monitoring assays. Conclusions The administration of matured DC loaded with tumor lysates has significant immunogenicity and antitumor activity in patients with limited metastatic melanoma. Clinical trial registration NCT00107159.

  14. Dutch Melanoma Treatment Registry: Quality assurance in the care of patients with metastatic melanoma in the Netherlands.

    Science.gov (United States)

    Jochems, Anouk; Schouwenburg, Maartje G; Leeneman, Brenda; Franken, Margreet G; van den Eertwegh, Alfons J M; Haanen, John B A G; Gelderblom, Hans; Uyl-de Groot, Carin A; Aarts, Maureen J B; van den Berkmortel, Franchette W P J; Blokx, Willeke A M; Cardous-Ubbink, Mathilde C; Groenewegen, Gerard; de Groot, Jan Willem B; Hospers, Geke A P; Kapiteijn, Ellen; Koornstra, Rutger H; Kruit, Wim H; Louwman, Marieke W; Piersma, Djura; van Rijn, Rozemarijn S; Ten Tije, Albert J; Vreugdenhil, Gerard; Wouters, Michel W J M; van der Hoeven, Jacobus J M

    2017-02-01

    In recent years, the treatment of metastatic melanoma has changed dramatically due to the development of immune checkpoint and mitogen-activated protein (MAP) kinase inhibitors. A population-based registry, the Dutch Melanoma Treatment Registry (DMTR), was set up in July 2013 to assure the safety and quality of melanoma care in the Netherlands. This article describes the design and objectives of the DMTR and presents some results of the first 2 years of registration. The DMTR documents detailed information on all Dutch patients with unresectable stage IIIc or IV melanoma. This includes tumour and patient characteristics, treatment patterns, clinical outcomes, quality of life, healthcare utilisation, informal care and productivity losses. These data are used for clinical auditing, increasing the transparency of melanoma care, providing insights into real-world cost-effectiveness and creating a platform for research. Within 1 year, all melanoma centres were participating in the DMTR. The quality performance indicators demonstrated that the BRAF inhibitors and ipilimumab have been safely introduced in the Netherlands with toxicity rates that were consistent with the phase III trials conducted. The median overall survival of patients treated with systemic therapy was 10.1 months (95% confidence interval [CI] 9.1-11.1) in the first registration year and 12.7 months (95% CI 11.6-13.7) in the second year. The DMTR is the first comprehensive multipurpose nationwide registry and its collaboration with all stakeholders involved in melanoma care reflects an integrative view of cancer management. In future, the DMTR will provide insights into challenging questions regarding the definition of possible subsets of patients who benefit most from the new drugs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Eleven Primary Melanomas, Colon Cancer, and Atypical Nevi in the Same Patient: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Lea Juul Nielsen

    2016-01-01

    Full Text Available Background. As the incidence of cutaneous malignant melanoma increases in the Caucasian population, an increasing population of melanoma survivors is at risk of developing multiple primary melanomas (MPM as well as secondary primary cancers. Objective. To present a case of a patient with atypical nevi, 11 primary melanomas over 33 years, and colon cancer and to review the literature on multiple primary melanomas, atypical nevi, and correlation of nonmelanoma cancers. Conclusion. The literature indicates that patients with MPM are not uncommon, although 11 primary melanomas are rarely described, that patients with MPM may have a better survival than patients with single primary melanoma, that atypical nevi are a risk marker of not only melanoma in general but also MPM, and that melanoma patients have a significantly increased risk of developing nonmelanoma skin and other cancers, which may be even higher for patients with MPM.

  16. Vaccine-specific local T cell reactivity in immunotherapy-associated vitiligo in melanoma patients.

    NARCIS (Netherlands)

    Jacobs, J.F.M.; Aarntzen, E.H.J.G.; Sibelt, L.A.G.; Blokx, W.A.M.; Boullart, A.C.I.; Gerritsen, M.J.P.; Hoogerbrugge, P.M.; Figdor, C.G.; Adema, G.J.; Punt, C.J.A.; Vries, I.J.M. de

    2009-01-01

    The occurrence of vitiligo in patients with melanoma is especially reported for patients undergoing immunotherapy. While vitiligo in these patients is thought to be related to an immune response directed against melanoma cells, solid evidence is lacking. Here we report local cytotoxic T cell reactiv

  17. Lymph node dissection in patients with malignant melanoma is associated with high risk of morbidity

    DEFF Research Database (Denmark)

    Ul-Mulk, Jamshaid; Hölmich, Lisbet Rosenkrantz

    2012-01-01

    Malignant melanoma is one of the most rapidly increasing cancer types globally, and it is by far the most serious skin cancer. Patients with a melanoma ≥ 1 mm in Breslow thickness are offered sentinel node (SN) biopsy and subsequent radical lymph node dissection if the biopsy is positive. The obj......Malignant melanoma is one of the most rapidly increasing cancer types globally, and it is by far the most serious skin cancer. Patients with a melanoma ≥ 1 mm in Breslow thickness are offered sentinel node (SN) biopsy and subsequent radical lymph node dissection if the biopsy is positive...

  18. The Experience of Melanoma Follow-Up Care: An Online Survey of Patients in Australia

    OpenAIRE

    Janine Mitchell; Peta Callaghan; Jackie Street; Susan Neuhaus; Taryn Bessen

    2014-01-01

    Investigating patients’ reports on the quality and consistency of melanoma follow-up care in Australia would assist in evaluating if this care is effective and meeting patients’ needs. The objective of this study was to obtain and explore the patients’ account of the technical and interpersonal aspects of melanoma follow-up care received. An online survey was conducted to acquire details of patients’ experience. Participants were patients treated in Australia for primary melanoma. Qualitative...

  19. Psychosocial, clinical and demographic features related to worry in patients with melanoma.

    Science.gov (United States)

    Rogers, Zoe; Elliott, Faye; Kasparian, Nadine A; Bishop, D Timothy; Barrett, Jennifer H; Newton-Bishop, Julia

    2016-10-01

    The aim of this study was to investigate clinical, demographic and psychosocial predictors of melanoma-related worry. A questionnaire-based study in a population-ascertained cohort of individuals diagnosed with melanoma in the previous 3-6 months was carried out to identify factors associated with worry about melanoma shortly after diagnosis. A total of 520 patients felt worried about their future with respect to melanoma and 1568 patients felt confident about their future with respect to melanoma. Worry was less likely in men with partners than women with partners [adjusted odds ratio (OR)=0.51, 95% confidence interval (CI) (0.39-0.67)], and increasing age was protective against worry [adjusted OR=0.96 per year, 95% CI (0.95-0.97)]. Worry was more likely for patients with stage III/IV melanoma [adjusted OR=1.90, 95% CI (1.41-2.56) compared with stages IB-IIC], melanoma arising in sun-protected sites (compared with a limb), no occupation (compared with workers), those who reported insufficient emotional support from healthcare providers [adjusted OR=2.20, 95% CI (1.56-3.09) compared with sufficient support], lower knowledge of melanoma [adjusted OR=4.50, 95% CI (2.82-7.18) compared with well informed], perceived financial hardship compared with no financial hardship and over three previous negative life events compared with none/one. Worry about melanoma outcomes after diagnosis is multifactorial in origin.

  20. Pentoxifylline Inhibits WNT Signalling in β-Cateninhigh Patient-Derived Melanoma Cell Populations.

    Directory of Open Access Journals (Sweden)

    Beata Talar

    Full Text Available The heterogeneity of melanoma needs to be addressed and combination therapies seem to be necessary to overcome intrinsic and acquired resistance to newly developed immunotherapies and targeted therapies. Although the role of WNT/β-catenin pathway in melanoma was early demonstrated, its contribution to the lack of the melanoma patient response to treatment was only recently recognized. Using patient-derived melanoma cell populations, we investigated the influence of pentoxifylline on melanoma cells with either high or low expression of β-catenin.Our results indicate that pentoxifylline inhibits the activity of the canonical WNT pathway in melanoma cell populations with high basal activity of this signalling. This is supported by lowered overall activity of transcription factors TCF/LEF and reduced nuclear localisation of active β-catenin. Moreover, treatment of β-cateninhigh melanoma cell populations with pentoxifylline induces downregulation of genes that are targets of the WNT/β-catenin pathway including connective tissue growth factor (CTGF and microphthalmia-associated transcription factor (MITF-M, a melanocyte- and melanoma cell-specific regulator.These results suggest that pentoxifylline, a drug approved by the FDA in the treatment of peripheral arterial disease, might be tested in a subset of melanoma patients with elevated activity of β-catenin. This pharmaceutical might be tested as an adjuvant drug in combination therapies when the response to immunotherapy is prevented by high activity of the WNT/β-catenin pathway.

  1. Pentoxifylline Inhibits WNT Signalling in β-Cateninhigh Patient-Derived Melanoma Cell Populations

    Science.gov (United States)

    Talar, Beata; Gajos-Michniewicz, Anna; Talar, Marcin; Chouaib, Salem; Czyz, Malgorzata

    2016-01-01

    Background The heterogeneity of melanoma needs to be addressed and combination therapies seem to be necessary to overcome intrinsic and acquired resistance to newly developed immunotherapies and targeted therapies. Although the role of WNT/β-catenin pathway in melanoma was early demonstrated, its contribution to the lack of the melanoma patient response to treatment was only recently recognized. Using patient-derived melanoma cell populations, we investigated the influence of pentoxifylline on melanoma cells with either high or low expression of β-catenin. Findings Our results indicate that pentoxifylline inhibits the activity of the canonical WNT pathway in melanoma cell populations with high basal activity of this signalling. This is supported by lowered overall activity of transcription factors TCF/LEF and reduced nuclear localisation of active β-catenin. Moreover, treatment of β-cateninhigh melanoma cell populations with pentoxifylline induces downregulation of genes that are targets of the WNT/β-catenin pathway including connective tissue growth factor (CTGF) and microphthalmia-associated transcription factor (MITF-M), a melanocyte- and melanoma cell-specific regulator. Conclusions These results suggest that pentoxifylline, a drug approved by the FDA in the treatment of peripheral arterial disease, might be tested in a subset of melanoma patients with elevated activity of β-catenin. This pharmaceutical might be tested as an adjuvant drug in combination therapies when the response to immunotherapy is prevented by high activity of the WNT/β-catenin pathway. PMID:27351373

  2. Doctors' recognition and management of melanoma patients' risk: An Australian population-based study.

    Science.gov (United States)

    Madronio, C M; Armstrong, B K; Watts, C G; Goumas, C; Morton, R L; Curtin, A; Menzies, S W; Mann, G J; Thompson, J F; Cust, A E

    2016-12-01

    Guidelines recommend that health professionals identify and manage individuals at high risk of developing melanoma, but there is limited population-based evidence demonstrating real-world practices. A population-based, observational study was conducted in the state of New South Wales, Australia to determine doctors' knowledge of melanoma patients' risk and to identify factors associated with better identification and clinical management. Data were analysed for 1889 patients with invasive, localised melanoma in the Melanoma Patterns of Care study. This study collected data on all melanoma diagnoses notified to the state's cancer registry during a 12-month period from 2006 to 2007, as well as questionnaire data from the doctors involved in their care. Three-quarters (74%) of patients had doctors who were aware of their risk factor status with respect to personal and family history of melanoma and the presence of many moles. Doctors working in general practice, skin cancer clinics and dermatology settings had better knowledge of patients' risk factors than plastic surgeons. Doctors were 15% more likely to know the family history of younger melanoma patients (melanoma patients' risk and could be the focus of strategies for improving care. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Routine X-ray of the chest is not justified in staging of cutaneous melanoma patients

    DEFF Research Database (Denmark)

    Gjorup, Caroline Asirvatham; Hendel, Helle Westergren; Pilegaard, Rita Kaae

    2016-01-01

    value was 8%, and the negative predictive value was 100%. CONCLUSION: Our results suggest that CXR cannot be justified in the initial staging of cutaneous melanoma patients. The guideline for the treatment of melanoma in Denmark is under revision: The use of CXR has been omitted. FUNDING: This study......INTRODUCTION: The incidence of cutaneous melanoma is increasing in Denmark and worldwide. However, the prevalence of distant metastases at the time of diagnosis has decreased to 1%. We therefore questioned the value of routine preoperative chest X-ray (CXR) for staging asymptomatic melanoma...... patients and hypothesised that routine CXR is not justified. METHODS: A retrospective study was conducted on patients undergoing wide local excision and sentinel lymph node biopsy for cutaneous melanoma in the period from 2010 to 2014. RESULTS: A total of 603 patients were included. The mean time of follow...

  4. Interferon-associated retinopathy in a patient with metastatic melanoma

    Directory of Open Access Journals (Sweden)

    Lara Borrego-Sanz

    2014-10-01

    Full Text Available We present the unusual case of a 35 year-old woman with stage IV melanoma and widespread metastases, who was undergoing treatment with interferon alpha-2b and who presented with interferon-associated retinopathy. The patient, who had been taking interferon treatment for three months, complained of a sudden loss of visual acuity in the left eye. An ocular examination revealed multiple cotton wool spots along the retina and macular involvement. Interferon treatment was suspended. Although rare, retinopathy represents a potentially serious adverse effect of interferon treatment. Although normally patients are asymptomatic, complications derived of its use may arise, which can lead to significant visual impairment. We therefore suggest that before initiating treatment with this drug, patients should be informed of its potential ocular risks, and that regular eye examinations are conducted along with the treatment.

  5. Lymph node dissection in patients with malignant melanoma is associated with high risk of morbidity

    DEFF Research Database (Denmark)

    Ul-Mulk, Jamshaid; Hölmich, Lisbet Rosenkrantz

    2012-01-01

    Malignant melanoma is one of the most rapidly increasing cancer types globally, and it is by far the most serious skin cancer. Patients with a melanoma ≥ 1 mm in Breslow thickness are offered sentinel node (SN) biopsy and subsequent radical lymph node dissection if the biopsy is positive...

  6. Persistent postoperative pain and sensory changes following lymph node excision in melanoma patients: a topical review

    DEFF Research Database (Denmark)

    Slagelse, Charlotte; Petersen, Karin L; Dahl, Jørgen Berg

    2014-01-01

    Studies on complications related to chronic nerve injury following sentinel lymph node biopsy (SLNB) and complete lymph node dissection (CLND) for melanoma are sparse. This review summarizes the existing literature on pain and neuropathic complications in melanoma patients undergoing SLNB with or...

  7. Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics

    DEFF Research Database (Denmark)

    Mercer, Louise K; Askling, Johan; Raaschou, Pauline;

    2017-01-01

    OBJECTIVES: Some studies have reported a possible association between exposure to tumour necrosis factor (TNF) inhibitors and an increased risk of melanoma. The aim of this study was to investigate the incidence of invasive cutaneous melanomas in patients with rheumatoid arthritis (RA) treated wi...

  8. Lymph node dissection in patients with malignant melanoma is associated with high risk of morbidity

    DEFF Research Database (Denmark)

    Ul-Mulk, Jamshaid; Hölmich, Lisbet Rosenkrantz

    2012-01-01

    Malignant melanoma is one of the most rapidly increasing cancer types globally, and it is by far the most serious skin cancer. Patients with a melanoma ≥ 1 mm in Breslow thickness are offered sentinel node (SN) biopsy and subsequent radical lymph node dissection if the biopsy is positive. The obj...

  9. Serum interleukin-6 as a prognostic biomarker in patients with metastatic melanoma

    DEFF Research Database (Denmark)

    Hoejberg, Lise; Bastholt, Lars; Johansen, Julia S

    2012-01-01

    Interleukin-6 (IL-6) is an immunomodulatory cytokine produced by both normal cells and tumor cells, including melanoma cells. The specific biological function of IL-6 in melanoma is unknown. The present study examined whether the serum concentration of IL-6 can predict prognosis in patients with ...

  10. Interpretation of Melanoma Risk Feedback in First-Degree Relatives of Melanoma Patients

    Directory of Open Access Journals (Sweden)

    Jennifer L. Hay

    2012-01-01

    Full Text Available Little is known about how individuals might interpret brief genetic risk feedback. We examined interpretation and behavioral intentions (sun protection, skin screening in melanoma first-degree relatives (FDRs after exposure to brief prototypic melanoma risk feedback. Using a 3 by 2 experimental pre-post design where feedback type (high-risk mutation, gene environment, and nongenetic and risk level (positive versus negative findings were systematically varied, 139 melanoma FDRs were randomized to receive one of the six scenarios. All scenarios included an explicit reminder that melanoma family history increased their risk regardless of their feedback. The findings indicate main effects by risk level but not feedback type; positive findings led to heightened anticipated melanoma risk perceptions and anticipated behavioral intentions. Yet those who received negative findings often discounted their family melanoma history. As such, 25%, 30%, and 32% of those who received negative mutation, gene-environment, and nongenetic feedback, respectively, reported that their risk was similar to the general population. Given the frequency with which those who pursue genetic testing may receive negative feedback, attention is needed to identify ideal strategies to present negative genetic findings in contexts such as direct to consumer channels where extensive genetic counseling is not required.

  11. Pathological assessment of tumor biopsy specimen and surgical sentinel lymph node dissection in patients with melanoma.

    Science.gov (United States)

    Nodiţi, Gheorghe; Nica, Cristian C; Petrescu, Horaţiu Pompiliu; Ivan, Codruţ; Crăiniceanu, Zorin Petrişor; Bratu, Tiberiu; Dema, Alis

    2014-01-01

    Actual trends of cutaneous malignant melanoma show a faster increase then other forms of cancer. Early detection and diagnosis, and accurate pathologic interpretation of the biopsy specimen is extremely important for the treatment and prognosis of clinically localized melanoma. The surgical approach to cutaneous melanoma patients with clinically uninvolved regional lymph nodes remains controversial. A retrospective study of melanoma cases was conducted in the "Casa Austria" Department of Plastic and Reconstructive Surgery, Emergency County Hospital, Timisoara, Romania. We have analyzed the medical records of 21 patients that underwent surgical treatment for different stages of melanoma in the period 2008-2012. For histopathological diagnosis of melanoma and the sentinel lymph node(s) status, tissular fragments were routinely processed. For the difficult cases, additional immunohistochemical investigation was done. A positive family history was noted in two cases. The presence of different sizes and localization of pigmented nevi was found in 38% of the cases. Different types of melanoma like superficial spreading melanoma, nodular melanoma or lentigo malignant melanoma and acral lentiginous melanoma was described. The surgical treatment consisted in all cases in wide excision of the primary tumor and prophylactic dissection of sentinel lymph node after lymphoscintigraphy examination. A positive biopsy of the sentinel lymph node was noted in 4.9% of the cases. The surgical treatment combining the wide excision of the primary tumor with respect to safe oncological limits with the prophylactic dissection of sentinel lymph node after lymphoscintigraphy examination had the confirmation done by the pathologic interpretation of the biopsy specimen showing that all the patients had a Breslow index more than 1.5 mm.

  12. Study Suggests Smaller Melanoma Excision Margins May Be Option for Some Patients

    Science.gov (United States)

    A randomized controlled trial of patients with stage IIA–C cutaneous melanoma thicker than 2-mm found that a 2-cm surgical resection margin is sufficient and is as safe for patients as a 4-cm margin.

  13. The risk of melanoma and hematologic cancers in patients with psoriasis.

    Science.gov (United States)

    Reddy, Shivani P; Martires, Kathryn; Wu, Jashin J

    2017-04-01

    The risk of melanoma and hematologic cancers in patients with psoriasis is controversial. We sought to assess the risk of melanoma and hematologic cancers in patients with psoriasis, and the association with different treatments. We used case-control and retrospective cohort designs to determine melanoma or hematologic cancer risk in patients with psoriasis. Risk with treatment type was assessed using Fisher exact test. Patients with psoriasis had 1.53 times greater risk of developing a malignancy compared with patients without psoriasis (P psoriasis and malignancy did not have significantly worse survival than patients without psoriasis. It is possible that patients developed malignancy subsequent to the follow-up time included in the study. Patients with psoriasis may experience an elevated risk of melanoma and hematologic cancers, compared with the general population. The risk is not increased by systemic or biologic psoriasis therapies. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  14. A phase II study of thalidomide in patients with brain metastases from malignant melanoma

    DEFF Research Database (Denmark)

    Vestermark, Lene; Larsen, Susanne; Lindeløv, Birgit;

    2008-01-01

    Introduction. Brain metastases develop in nearly half of the patients with advanced melanoma and in 15 to 20% of these patients CNS is the first site of relapse. Overall median survival is short, ranging from 2 to 4 months. Thalidomide has antiangiogenic and immunomodulatory effects. Results...... obtained in prior trials indicate that Thalidomide acts as a cytostatic agent in metastatic melanoma. We evaluated single agent antitumour activity and toxicity of Thalidomide in a phase II setting in patients with brain metastases associated with metastatic melanoma. Material and methods. Patients...

  15. Patients highly value routine follow-up of skin cancer and cutaneous melanoma

    DEFF Research Database (Denmark)

    Themstrup, Lotte; Jemec, Gregor E; Lock-Andersen, Jørgen

    2013-01-01

    INTRODUCTION: Skin cancer follow-up is a substantial burden to outpatient clinics. Few studies have investigated patients' views on skin cancer follow-up and cutaneous melanoma. The objective was to investigate patients' perceived benefits and the impact of follow-up. MATERIAL AND METHODS......: This study included an open sample of patients attending routine follow-up at the outpatient Departments of Plastic Surgery and Dermatology, Roskilde Hospital. A total of 218 follow-up patients diagnosed with cutaneous malignant melanoma (MM), non-melanoma skin cancer (NMSC) or actinic keratosis (AK...

  16. What Happens after Treatment for Melanoma Skin Cancer?

    Science.gov (United States)

    ... Skin Cancer After Treatment Living as a Melanoma Skin Cancer Survivor For many people with melanoma, treatment can ... Cancers After Melanoma Skin Cancer More In Melanoma Skin Cancer About Melanoma Skin Cancer Causes, Risk Factors, and ...

  17. Intravital Microscopy for Identifying Tumor Vessels in Patients With Stage IA-IV Melanoma That is Being Removed by Surgery

    Science.gov (United States)

    2016-01-13

    Recurrent Melanoma; Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma

  18. The absence of the ERBB4 hotspot mutations in melanomas in patients from southern China

    Institute of Scientific and Technical Information of China (English)

    Qi-Ming Zhou; Wei Li; Yuan-Xiang Guan; Xing Zhang; Xin-Chun Chen; Ya Ding; Xi-Zhi Wen

    2013-01-01

    V-erb-a erythroblastic leukemia viral oncogene homolog 4 (ERBB4) has been reported to be somatically mutated in 19% of melanoma cases.To investigate the prevalence of ERBB4 mutations in melanoma patients from southern China,we analyzed 117 formalin-fixed,paraffin-embedded melanoma samples archived in the Sun Yat-sen University Cancer Center.A matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) platform was used to screen for mutations.No ERBB4 hotspot mutations were detected.Our results indicate that ERBB4 mutations may play a limited role in melanomas in China; therefore,targeting the ERBB4 mutation in melanoma patients from southern China may not be a promising strategy.

  19. Comparison of the Serum Tumor Markers S100 and Melanoma-inhibitory Activity (MIA) in the Monitoring of Patients with Metastatic Melanoma Receiving Vaccination Immunotherapy with Dendritic Cells.

    Science.gov (United States)

    Uslu, Ugur; Schliep, Stefan; Schliep, Klaus; Erdmann, Michael; Koch, Hans-Uwe; Parsch, Hans; Rosenheinrich, Stina; Anzengruber, Doris; Bosserhoff, Anja Katrin; Schuler, Gerold; Schuler-Thurner, Beatrice

    2017-09-01

    In patients with melanoma, early dissemination via lymphatic and hematogenous routes is frequently seen. Thus, besides clinical follow-up examination and imaging, reliable melanoma-specific serological tumor markers are needed. We retrospectively compared two serum markers for melanoma, S100 and melanoma-inhibitory activity (MIA), for monitoring of patients with metastatic melanoma under either adjuvant or therapeutic vaccination immunotherapy with dendritic cells (DC). Serum was obtained from a total of 100 patients (28 patients in stage III and 72 patients in stage IV, according to the American Joint Committee on Cancer 2002) at regular intervals during therapy, accompanied by follow-up imaging. When relapse was detected, both markers often remained within normal range. In contrast, in patients with metastatic measurable disease receiving therapeutic and not adjuvant DC vaccination, an increase of both markers was a strong indicator for disease progression. When comparing both markers in the whole study population, MIA showed a superior sensitivity to detect disease progression. S100 and MIA are highly sensitive tumor markers for monitoring of patients with melanoma with current metastases, but less sensitive for monitoring of tumor-free patients. In the current study, MIA had a slightly superior sensitivity to detect progressive disease compared to S100 and seems to be more useful in monitoring of patients with metastatic melanoma receiving immunotherapy. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  20. Interval Sentinel Lymph Nodes: An Unusual Localization in Patients with Cutaneous Melanoma

    Directory of Open Access Journals (Sweden)

    A. M. Manganoni

    2011-01-01

    Full Text Available Background. Recent studies have demonstrated that there exists a great variation in the lymphatic drainage in patients with malignant melanoma. Some patients have drainage to lymph nodes outside of conventional nodal basins. The lymph nodes that exist between a primary melanoma and its regional nodal basin are defined “interval nodes”. Interval node occurs in a small minority of patients with forearm melanoma. We report our experience of the Melanoma Unit of University Hospital Spedali Civili Brescia, Italy. Methods. Lymphatic mapping using cutaneous lymphoscintigraphy (LS has become a standard preoperative diagnostic procedure to locate the sentinel lymph nodes (SLNs in cutaneous melanoma. We used LS to identify sentinel lymph nodes biopsy (SLNB in 480 patients. Results. From over 2100 patients affected by cutaneous melanoma, we identified 2 interval nodes in 480 patients with SLNB . The melanomas were both located in the left forearm. The interval nodes were also both located in the left arm. Conclusion. The combination of preoperative LS and intraoperative hand-held gamma detecting probe plays a remarkable role in identifying these uncommon lymph node locations. Knowledge of the unusual drainage patterns will help to ensure the accuracy and the completeness of sentinel nodes identification.

  1. Prognosis of sentinel node staged patients with primary cutaneous melanoma.

    Directory of Open Access Journals (Sweden)

    Otmar Elsaesser

    Full Text Available BACKGROUND: This study investigated survival probabilities and prognostic factors in sentinel lymph node biopsy (SLNB staged patients with cutaneous melanoma (CM with the aim of defining subgroups of patients who are at higher risk for recurrences and who should be considered for adjuvant clinical trials. METHODS: Patients with primary CM who underwent SLNB in the Department of Dermatology, University of Tuebingen, Germany, between 1996 and 2009 were included into this study. Survival probabilities and prognostic factors were evaluated by Kaplan-Meier and multivariate Cox proportional hazard models. RESULTS: 1909 SLNB staged patients were evaluated. Median follow-up time was 44 months. Median tumor thickness was 1.8 mm, ulceration was present in 31.8% of cases. The 5-year Overall Survival (OS was 90.3% in SLNB negative patients (IB 96.2%, IIA 87.0%, IIB 78.1%, IIC 72.6%. Patients with micrometastases (stage IIIA/B had a 5-year OS rate of 70.9% which was clearly less favorable than for stages I-II. Multivariate analysis revealed tumor thickness, ulceration, body site, histopathologic subtype and SLNB status as independent significant prognostic factors. CONCLUSION: Survival rates of patients with primary CM in stages I-II were shown to be much more favorable than previously reported from non sentinel node staged collectives. For future clinical trials, sample size calculations should be adapted using survival probabilities based on sentinel node staging.

  2. Liquid Biopsy Utility for the Surveillance of Cutaneous Malignant Melanoma Patients

    Science.gov (United States)

    Huang, Sharon K.; Hoon, Dave S.B.

    2017-01-01

    Cutaneous melanoma is one of the highest incident-rate cancers with increasing prevalence in Western societies. Despite the advent of new approved therapeutics, the 5-year overall survival rate of stage IV melanoma patients remains below 15%. Current treatments for late-stage disease have shown higher efficacy when treated at a lower disease burden. Thus, blood-based biomarkers capable of detecting melanoma prior to clinically evident distant metastasis, will improve the treatment and outcomes for melanoma patients. To that end, effective treatment of melanoma necessitates identification of patients at risk for developing distant metastases. Furthermore, employing blood biomarkers that monitor cancer progression over the course of treatment, is a promising solution to post-treatment drug resistance often developed in melanoma patients. Non-invasive blood biomarker assays allow for regular dynamic monitoring of disease. “Liquid Biopsy” of blood, which exploits circulating tumor cells (CTCs), cell-free circulating tumor DNA (ctDNA) and cell-free circulating microRNA (cmiRNA), has been shown to detect prognostic factors for relapse in AJCC stage III and stage IV melanoma patients. Moreover, molecular characterization of CTC and analysis of various forms of ctDNA present promising potential in development of individualized therapy for melanoma patients. New approaches such as massive parallel sequencing (MPS) provide a comprehensive view of the disease progression, allowing for the selection of therapeutic options for individual patients. With advancements of improving molecular assays, liquid biopsy analysis as a powerful, routine clinical assay for melanoma patients, is highly promising prospective. PMID:26778792

  3. Clinical significance of serum laminin and type-IV collagen levels in cutaneous melanoma patients.

    Science.gov (United States)

    Tas, Faruk; Bilgin, Elif; Karabulut, Senem; Duranyildiz, Derya

    2016-07-01

    Laminin and type-IV collagen constitute a significant portion of the extracellular matrix. The objective of the present study was to evaluate whether the serum concentrations of laminin and type-IV collagen may serve as biomarkers for cutaneous melanoma. Sixty pathologically confirmed melanoma patients were enrolled in the study. Serum laminin and type-IV collagen levels were assessed using an ELISA. Thirty healthy controls were also examined. No significant differences in the baseline serum levels of laminin were identified between melanoma patients and healthy controls (P=0.45). However, the baseline serum levels of type-IV collagen were significantly elevated in melanoma patients compared with those in the control group (PIV collagen (P>0.05). Furthermore, the serum levels of laminin and type-IV collagen had no prognostic value regarding the outcome for melanoma patients (P=0.36 and P=0.26, respectively). While laminin levels showed no diagnostic value, the serum concentrations of type-IV collagen were indicated to serve as a diagnostic marker in patients with cutaneous melanoma. In conclusion, type-IV collagen levels may be used as a diagnostic marker for cutaneous melanoma, while being void of any prognostic value.

  4. Analysis of gene mutations and clinical features in elderly patients with melanoma

    Institute of Scientific and Technical Information of China (English)

    王轩

    2013-01-01

    Objective To investigate the gene mutation status in Chinese elderly patients with melanoma and to explore the correlation of gene mutation with clinical characteristics and prognosis.Methods Melanoma tissue samples from Chinese elderly patients were analyzed for gene mutations of KIT,BRAF and NRAS in genomic DNA by polymerase chain reaction (PCR) amplification and Sanger sequencing.The correlations of gene mutations with clinicopathologic features and prognosis were statistically

  5. Living with HIV: Patients Perspective

    Centers for Disease Control (CDC) Podcasts

    2009-06-04

    This podcast showcases three people who are living with HIV. The patients share their experiences of being diagnosed with HIV, of the treatments they are undergoing, and on taking responsibility for their health.  Created: 6/4/2009 by Division of HIV and AIDS Prevention (DHAP), National Center for HIV, Hepatitis, STD, and Tuberculosis Prevention ( NCHHSTP).   Date Released: 6/4/2009.

  6. Comparing Melanoma Invasiveness in Dermatologist- versus Patient-Detected Lesions: A Retrospective Chart Review

    Directory of Open Access Journals (Sweden)

    Cindy L. Lamerson

    2012-01-01

    Full Text Available This study examined whether patient-identified melanomas were more advanced than dermatologist-identified tumors at routine clinic visits, and whether a personal or family history of skin cancer was associated with patterns of detection. A retrospective chart review was performed on melanoma patients (N=201 in a private dermatology clinic. Variables included age, gender, pattern of detection (i.e., patient or a board certified dermatologist, personal or family history of skin cancer, skin type, and previous sun exposure, as well as tumor location and severity. Dermatologist-diagnosed melanomas were less invasive (P<0.0005, and more likely present on the chest, back, and legs (P<0.01. Conversely, patient-identified lesions were more likely to occur on the face, neck and scalp, be associated with younger patients, and a family history of melanoma, but not other types of skin cancer (P<0.01. In a post-hoc analysis examining these factors as predictors of tumor invasiveness, only diagnostic source was significant. Specifically, dermatologist-identified tumors were significantly less invasive than patient-identified tumors. Although age, family history, and tumor location played roles in the early detection of melanomas, the most important factor was diagnostic source. Thus, board-certified dermatologists play a key role in the early detection of malignant melanoma.

  7. GNA11 Mutation in a Patient With Cutaneous Origin Melanoma

    Science.gov (United States)

    Patel, Sapna P.; Kim, Dae Won; Lacey, Carol L.; Hwu, Patrick

    2016-01-01

    Abstract The rapid advances in the molecular biology and genetics have improved the understanding of molecular pathogenesis of v-Raf murine sarcoma viral oncogene homolog B (BRAF), feline sarcoma viral oncogene v-kit (KIT), and neuroblastoma v-Ras oncogene homolog (NRAS) mutant melanomas with the subsequent development of targeted therapeutic agents. However, only limited data are available for melanoma harboring other somatic than BRAF, KIT, and NRAS mutations. Mutations in guanine nucleotide-binding protein Q polypeptide (GNAQ) and guanine nucleotide-binding protein alpha-11 (GNA11), alpha subunits of heterotrimeric G proteins, constitutively activate mitogen-activated protein kinase (MAPK) pathway in uveal melanoma. However, there are no reports of GNA11 mutations in cutaneous melanomas. A 48-year-old woman was diagnosed with cutaneous nodular melanoma on the left scalp. Mutation analysis of the tumor revealed a GNA11 Q209L mutation. There was no evidence of uveal melanoma or malignant blue nevus in ophthalmologic exam, imaging studies, and pathology review. To our knowledge, this is the first case report to demonstrate cutaneous origin melanoma harboring a GNA11 Q209L mutation. PMID:26825879

  8. Detection of Exosomal miRNAs in the Plasma of Melanoma Patients

    Directory of Open Access Journals (Sweden)

    Susan R. Pfeffer

    2015-12-01

    Full Text Available MicroRNAs (miRNAs are a class of 22–25 nucleotide RNAs that control gene expression at the post-transcriptional level. MiRNAs have potential as cancer biomarkers. Melanoma is a highly aggressive form of skin cancer accounting for almost 4% of cancers among men and women, and ~80% of skin cancer-related deaths in the US. In the present study we analyzed plasma-derived exosomal miRNAs from clinically affected and unaffected familial melanoma patients (CDKN2A/p16 gene carriers and compared them with affected (nonfamilial melanoma and unaffected control subjects in order to identify novel risk biomarkers for melanoma. Intact miRNAs can be isolated from the circulation because of their presence in exosomes. A number of differentially regulated miRNAs identified by NanoString human V2 miRNA array were validated by quantitative PCR. Significantly, miR-17, miR-19a, miR-21, miR-126, and miR-149 were expressed at higher levels in patients with metastatic sporadic melanoma as compared with familial melanoma patients or unaffected control subjects. Surprisingly, no substantial differences in miRNA expression were detected between familial melanoma patients (all inclusive and unaffected control subjects. The miRNAs differentially expressed in the different patient cohorts, especially in patients with metastatic melanoma, may play important roles in tumor progression and metastasis, and may be used as predictive biomarkers to monitor remission as well as relapse following therapeutic intervention.

  9. Malignant Melanoma in Association With a Thymic Nevus in a Patient With a Giant Congenital Nevus.

    Science.gov (United States)

    Shvartser-Beryozkin, Yulia; Yakobson, Alexander; Benharroch, Daniel; Saute, Milton; Feinmesser, Meora

    2017-07-01

    Nevi and melanocytic proliferations are known to appear in multiple extracutaneous sites, including lymph nodes and meninges. We report a case of an anterior mediastinal mass in a patient with a giant congenital nevus and neurofibromatosis type I. Histologically, the tumor was found to be a malignant melanoma in the thymus arising in association with a nevus that involved most of the thymic tissue. There was no sign of cutaneous melanoma on skin examination. We suggest that the tumor originated from the benign nevus in the thymus, a rare extracutaneous location for nevi and malignant melanoma.

  10. Patients highly value routine follow-up of skin cancer and cutaneous melanoma

    DEFF Research Database (Denmark)

    Themstrup, Lotte; Jemec, Gregor E; Lock-Andersen, Jørgen

    2013-01-01

    : This study included an open sample of patients attending routine follow-up at the outpatient Departments of Plastic Surgery and Dermatology, Roskilde Hospital. A total of 218 follow-up patients diagnosed with cutaneous malignant melanoma (MM), non-melanoma skin cancer (NMSC) or actinic keratosis (AK......INTRODUCTION: Skin cancer follow-up is a substantial burden to outpatient clinics. Few studies have investigated patients' views on skin cancer follow-up and cutaneous melanoma. The objective was to investigate patients' perceived benefits and the impact of follow-up. MATERIAL AND METHODS......) completed a structured interview. RESULTS: A total of 97% patients found follow-up useful. Continuity and consistency were important. One third of patients felt some degree of pre follow-up anxiety. The number of anxious MM patients was significantly greater than that of NMSC patients. No significant...

  11. Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies.

    Directory of Open Access Journals (Sweden)

    Amy E Gilbert

    Full Text Available Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10 to primary and metastatic melanoma cells compared to healthy volunteers (n = 10 (P<0.0001. Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21 (P<0.0001. Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800 compared to 2% of cultures from healthy controls (n = 600 produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.

  12. Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma.

    Science.gov (United States)

    Girotti, Maria Romina; Gremel, Gabriela; Lee, Rebecca; Galvani, Elena; Rothwell, Dominic; Viros, Amaya; Mandal, Amit Kumar; Lim, Kok Haw Jonathan; Saturno, Grazia; Furney, Simon J; Baenke, Franziska; Pedersen, Malin; Rogan, Jane; Swan, Jacqueline; Smith, Matthew; Fusi, Alberto; Oudit, Deemesh; Dhomen, Nathalie; Brady, Ged; Lorigan, Paul; Dive, Caroline; Marais, Richard

    2016-03-01

    Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). We also developed circulating tumor cell-derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine in patients with melanoma. Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments. ©2015 American Association for Cancer Research.

  13. Aggressive Behaviour of Metastatic Melanoma in a Patient with Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    Robert W. Foley

    2015-01-01

    Full Text Available Malignant melanoma is a common skin neoplasm bearing poor prognosis when presenting with metastases. Rarely melanoma metastases present without an identifiable primary cutaneous lesion despite exhaustive workup. We describe the case of a solitary lung metastasis in a patient with neurofibromatosis type 1 without an identifiable primary tumour. The rapid progression of this malignant neoplasm that led to the patient’s death within 1 year is described.

  14. Adoptive Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for the Treatment of Patients With Refractory Metastatic Melanoma

    National Research Council Canada - National Science Library

    Mark E. Dudley; John R. Wunderlich; James C. Yang; Richard M. Sherry; Suzanne L. Topalian; Nicholas P. Restifo; Richard E. Royal; Udai Kammula; Don E. White; Sharon A. Mavroukakis; Linda J. Rogers; Gerald J. Gracia; Stephanie A. Jones; David P. Mangiameli; Michelle M. Pelletier; Juan Gea-Banacloche; Michael R. Robinson; David M. Berman; Armando C. Filie; Andrea Abati; Steven A. Rosenberg

    2005-01-01

    We investigated the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of patients with refractory metastatic melanoma...

  15. Role of FDG-PET/CT in stage 1–4 malignant melanoma patients

    DEFF Research Database (Denmark)

    Eldon, Mai; Kjerkegaard, Ulrik Knap; Ørndrup, Mette Heisz

    2017-01-01

    Background: The number of patients diagnosed with malignant melanoma (MM) has increased over several years. Despite early diagnosis of MM and therefore better prognosis, the number of FDG-PET/CT scans (PET/CT) seems to be increasing. This study aimed to describe all MM patients who were PET....../CT scanned in 2012 at a department of plastic surgery and to analyze the pattern of referral and outcome of PET/CT scans of these patients all back from early diagnosis of the patient in the period 2008–2012. Methods: All patients with MM stages 1–4 (AJCC stages) and melanoma of unknown primary (MUP) who...

  16. Increased level of circulating U2 small nuclear RNA fragments indicates metastasis in melanoma patients.

    Science.gov (United States)

    Kuhlmann, Jan Dominik; Wimberger, Pauline; Wilsch, Katja; Fluck, Michael; Suter, Ludwig; Brunner, Georg

    2015-03-01

    Background: Melanoma is the most aggressive skin cancer and, despite recent advances in therapy, about 20% of the patients die of their disease. Early relapse detection and monitoring of therapy response are crucial for efficient treatment of advanced melanoma. Thus, there is a need for blood-based biomarkers in melanoma management. Serum-derived U2 small nuclear RNA fragments (RNU2-1f) were previously shown to be blood-based biomarkers for gastrointestinal and gynecologic malignancies. Here we examined whether RNU2-1f may also serve as diagnostic biomarker in advanced melanoma. Circulating RNU2-1f levels were quantified by comparative reverse transcription PCR in a training cohort of patients with metastatic melanoma (n=33, thereof regionally metastasized to skin and lymph nodes, n=23, and distantly metastasized, n=10) vs. patients with benign naevi (n=16) vs. healthy controls (n=39). RESULTS were validated in an independent patient cohort with distant metastasis (n=16) vs. controls (n=18). Circulating RNU2-1f levels in the training cohort were significantly increased in serum of regionally and distantly metastatic patients, compared with patients with benign naevi or healthy controls (p<0.0001) and allowed accurate detection of regional (AUC 0.80) as well as distant (AUC 0.84) metastasis. In the validation cohort, increased RNU2-1f levels were confirmed and enabled highly specific detection of distant metastasis (sensitivity 81%, specificity 100%, AUC 0.94). This is the first report to suggest a blood-based snRNA serving as a diagnostic biomarker for melanoma metastasis. Our data provide a rationale for further defining clinical utility of circulating RNU2-1f in metastasis detection in the management of melanoma patients at risk of relapse and/or with advanced disease.

  17. Down-regulation of the interferon signaling pathway in T lymphocytes from patients with metastatic melanoma.

    Directory of Open Access Journals (Sweden)

    Rebecca J Critchley-Thorne

    2007-05-01

    Full Text Available Dysfunction of the immune system has been documented in many types of cancers. The precise nature and molecular basis of immune dysfunction in the cancer state are not well defined.To gain insights into the molecular mechanisms of immune dysfunction in cancer, gene expression profiles of pure sorted peripheral blood lymphocytes from 12 patients with melanoma were compared to 12 healthy controls. Of 25 significantly altered genes in T cells and B cells from melanoma patients, 17 are interferon (IFN-stimulated genes. These microarray findings were further confirmed by quantitative PCR and functional responses to IFNs. The median percentage of lymphocytes that phosphorylate STAT1 in response to interferon-alpha was significantly reduced (Delta = 16.8%; 95% confidence interval, 0.98% to 33.35% in melanoma patients (n = 9 compared to healthy controls (n = 9 in Phosflow analysis. The Phosflow results also identified two subgroups of patients with melanoma: IFN-responsive (33% and low-IFN-response (66%. The defect in IFN signaling in the melanoma patient group as a whole was partially overcome at the level of expression of IFN-stimulated genes by prolonged stimulation with the high concentration of IFN-alpha that is achievable only in IFN therapy used in melanoma. The lowest responders to IFN-alpha in the Phosflow assay also showed the lowest gene expression in response to IFN-alpha. Finally, T cells from low-IFN-response patients exhibited functional abnormalities, including decreased expression of activation markers CD69, CD25, and CD71; TH1 cytokines interleukin-2, IFN-gamma, and tumor necrosis factor alpha, and reduced survival following stimulation with anti-CD3/CD28 antibodies compared to controls.Defects in interferon signaling represent novel, dominant mechanisms of immune dysfunction in cancer. These findings may be used to design therapies to counteract immune dysfunction in melanoma and to improve cancer immunotherapy.

  18. Down-regulation of the interferon signaling pathway in T lymphocytes from patients with metastatic melanoma.

    Directory of Open Access Journals (Sweden)

    Rebecca J Critchley-Thorne

    2007-05-01

    Full Text Available BACKGROUND: Dysfunction of the immune system has been documented in many types of cancers. The precise nature and molecular basis of immune dysfunction in the cancer state are not well defined. METHODS AND FINDINGS: To gain insights into the molecular mechanisms of immune dysfunction in cancer, gene expression profiles of pure sorted peripheral blood lymphocytes from 12 patients with melanoma were compared to 12 healthy controls. Of 25 significantly altered genes in T cells and B cells from melanoma patients, 17 are interferon (IFN-stimulated genes. These microarray findings were further confirmed by quantitative PCR and functional responses to IFNs. The median percentage of lymphocytes that phosphorylate STAT1 in response to interferon-alpha was significantly reduced (Delta = 16.8%; 95% confidence interval, 0.98% to 33.35% in melanoma patients (n = 9 compared to healthy controls (n = 9 in Phosflow analysis. The Phosflow results also identified two subgroups of patients with melanoma: IFN-responsive (33% and low-IFN-response (66%. The defect in IFN signaling in the melanoma patient group as a whole was partially overcome at the level of expression of IFN-stimulated genes by prolonged stimulation with the high concentration of IFN-alpha that is achievable only in IFN therapy used in melanoma. The lowest responders to IFN-alpha in the Phosflow assay also showed the lowest gene expression in response to IFN-alpha. Finally, T cells from low-IFN-response patients exhibited functional abnormalities, including decreased expression of activation markers CD69, CD25, and CD71; TH1 cytokines interleukin-2, IFN-gamma, and tumor necrosis factor alpha, and reduced survival following stimulation with anti-CD3/CD28 antibodies compared to controls. CONCLUSIONS: Defects in interferon signaling represent novel, dominant mechanisms of immune dysfunction in cancer. These findings may be used to design therapies to counteract immune dysfunction in melanoma and to

  19. Patient-derived tumor xenograft strategies for informed management of patients with metastatic melanoma.

    Science.gov (United States)

    Qassemyar, Ahmad; Gabert, Pierre-Elliott; Kluza, Jerome; Duquennoy-Martinot, Véronique; Mortier, Laurent; Marchetti, Philippe; Guerreschi, Pierre

    2016-06-01

    Metastatic melanoma has benefited from immunotherapy and targeted therapy advances. Faced with the inescapable onset of treatment resistance, the choice of a second-line treatment can be guided by a patient-derived tumor xenograft (PDTX). This new approach requires an excellent multidisciplinary collaboration where the surgeon has a key role to play. Each patient included (stage IIIC or IV) presented with subcutaneous melanoma metastasis that could be surgically resected. The surgeon performed orthotopic PDTX on CB17-SCID mice. To validate the model, tumor material was amplified over three successive generations of animals to obtain cohorts compatible with carrying out a study to compare treatment response by targeted therapy (vemurafenib versus controls). Tumors were characterized (histologically and genetically) at all stages of the generations' amplification. Functional imaging by fluorine-18 fluorodeoxyglucose PET scan was performed for the third generation PDTX. Seventeen patients with a mutated BRAF V600E subcutaneous metastasis were included, yielding 257 PDTX. Clinical, histological, and genetic characteristics of the grafted tumors were stable over the three mice generations. The treatment response to vemurafenib was observed for all PDTX. The fluorine-18 fluorodeoxyglucose PET scan evidenced a decreased in glucose uptake in the treated tumors. PDTX models are being widely used in fundamental research and are more compatible with clinical issues. If PDTX are simple and easily reproducible in metastatic melanoma, an organized multidisciplinary platform is essential to implement them. In our experience, surgeons have a key role to play in the cohesion of this new therapeutic approach.

  20. Safety and Efficacy of 188-Rhenium-Labeled Antibody to Melanin in Patients with Metastatic Melanoma

    Directory of Open Access Journals (Sweden)

    M. Klein

    2013-01-01

    Full Text Available There is a need for effective “broad spectrum” therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of 188Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10 mCi 188Re-6D2 were given while unlabeled antibody preload was escalated. In Phase Ib, the dose of 188Re-6D2 was escalated to 54 mCi. SPECT/CT revealed 188Re-6D2 uptake in melanoma metastases. The mean effective half-life of 188Re-6D2 was 12.4 h. Transient HAMA was observed in 9 patients. Six patients met the RECIST criteria for stable disease at 6 weeks. Two patients had durable disease stabilization for 14 weeks and one for 22 weeks. Median overall survival was 13 months with no dose-limiting toxicities. The data demonstrate that 188Re-6D2 was well tolerated, localized in melanoma metastases, and had antitumor activity, thus warranting its further investigation in patients with metastatic melanoma.

  1. The Experience of Melanoma Follow-Up Care: An Online Survey of Patients in Australia

    Directory of Open Access Journals (Sweden)

    Janine Mitchell

    2014-01-01

    Full Text Available Investigating patients’ reports on the quality and consistency of melanoma follow-up care in Australia would assist in evaluating if this care is effective and meeting patients’ needs. The objective of this study was to obtain and explore the patients’ account of the technical and interpersonal aspects of melanoma follow-up care received. An online survey was conducted to acquire details of patients’ experience. Participants were patients treated in Australia for primary melanoma. Qualitative and quantitative data about patient perceptions of the nature and quality of their follow-up care were collected, including provision of melanoma specific information, psychosocial support, and imaging tests received. Inconsistencies were reported in the provision and quality of care received. Patient satisfaction was generally low and provision of reassurance from health professionals was construed as an essential element of quality of care. “Gaps” in follow-up care for melanoma patients were identified, particularly provision of adequate psychosocial support and patient education. Focus on strategies for greater consistency in the provision of support, information, and investigations received, may generate a cost dividend which could be reinvested in preventive and supportive care and benefit patient well-being.

  2. Association of TNFRSF10D DNA-methylation with the survival of melanoma patients.

    Science.gov (United States)

    Ratzinger, Gudrun; Mitteregger, Simone; Wolf, Barbara; Berger, Regina; Zelger, Bernhard; Weinlich, Georg; Fritsch, Peter; Goebel, Georg; Fiegl, Heidelinde

    2014-07-07

    In this retrospective pilot study, the DNA-methylation status of genes that have been demonstrated to be involved in melanoma carcinogenesis was analyzed in order to identify novel biomarkers for the risk assessment of melanoma patients. We analyzed DNA extracted from punch-biopsies from 68 formalin-fixed paraffin-embedded (FFPE) melanoma specimens. Using MethyLight PCR, we examined 20 genes in specimens from a training set comprising 36 melanoma patients. Selected candidate genes were validated in a test set using FFPE tissue samples from 32 melanoma patients. First, we identified the TNFRSF10D DNA-methylation status (TNFRSF10D methylated vs. unmethylated) as a prognostic marker for overall (p = 0.001) and for relapse-free survival (p = 0.008) in the training set. This finding was confirmed in the independent test set (n = 32; overall survival p = 0.041; relapse-free survival p = 0.012). In a multivariate Cox-regression analysis including all patients, the TNFRSF10D DNA-methylation status remained as the most significant prognostic parameter for overall and relapse-free survival (relative-risk (RR) of death, 4.6 (95% CI: 2.0-11.0; p < 0.001), RR of relapse, 7.2 (95% CI: 2.8-18.3; p < 0.001)). In this study, we demonstrate that TNFRSF10D DNA-methylation analysis of a small tissue-punch from archival FFPE melanoma tissue is a promising approach to provide prognostic information in patients with melanoma.

  3. Association of TNFRSF10D DNA-Methylation with the Survival of Melanoma Patients

    Directory of Open Access Journals (Sweden)

    Gudrun Ratzinger

    2014-07-01

    Full Text Available In this retrospective pilot study, the DNA-methylation status of genes that have been demonstrated to be involved in melanoma carcinogenesis was analyzed in order to identify novel biomarkers for the risk assessment of melanoma patients. We analyzed DNA extracted from punch-biopsies from 68 formalin-fixed paraffin-embedded (FFPE melanoma specimens. Using MethyLight PCR, we examined 20 genes in specimens from a training set comprising 36 melanoma patients. Selected candidate genes were validated in a test set using FFPE tissue samples from 32 melanoma patients. First, we identified the TNFRSF10D DNA-methylation status (TNFRSF10D methylated vs. unmethylated as a prognostic marker for overall (p = 0.001 and for relapse-free survival (p = 0.008 in the training set. This finding was confirmed in the independent test set (n = 32; overall survival p = 0.041; relapse-free survival p = 0.012. In a multivariate Cox-regression analysis including all patients, the TNFRSF10D DNA-methylation status remained as the most significant prognostic parameter for overall and relapse-free survival (relative-risk (RR of death, 4.6 (95% CI: 2.0–11.0; p < 0.001, RR of relapse, 7.2 (95% CI: 2.8–18.3; p < 0.001. In this study, we demonstrate that TNFRSF10D DNA-methylation analysis of a small tissue-punch from archival FFPE melanoma tissue is a promising approach to provide prognostic information in patients with melanoma.

  4. Treatment with Ipilimumab: A Case Report of Complete Response in a Metastatic Malignant Melanoma Patient

    Directory of Open Access Journals (Sweden)

    Alfredo Addeo

    2013-05-01

    Full Text Available Introduction: Over the past year, 3 agents have been approved for the treatment of melanoma by the Food and Drug Administration. These include pegylated interferon α-2b for stage III melanoma, vemurafenib for unresectable or metastatic melanoma with BRAF V600E mutation, and ipilimumab for unresectable or metastatic melanoma. Case Presentation: We present here the case of a 65-year-old Caucasian male diagnosed with advanced melanoma in April 2011 and treated with ipilimumab (Yervoy®, a monoclonal antibody targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4, as second-line treatment after progression with dacarbazine, for (wild-type BRAF metastatic melanoma. The patient was referred to us for several painful lumps on his right arm. A biopsy of one of them revealed melanoma. CT and PET scans did not show any other lesions or a primary site. The patient was started on first-line chemotherapy with dacarbazine 850 mg/m2 on day 1, every 3 weeks. After 3 cycles, the patient showed disease progression with an increase in size of the skin metastasis. Second-line treatment was started with ipilimumab 3 mg/kg on day 1, every 3 weeks. At the end of the treatment, after 4 cycles, we documented a complete clinical response with total resolution of the skin metastasis. At the time of writing this paper, our patient had finished his treatment more than 9 months earlier and is still in complete remission. Conclusion: This is a paradigmatic case where, despite extensive metastatic disease, treatment with ipilimumab has confirmed its efficacy. It is still an open question why only a minority of patients have such a remarkable response, and further trials are warranted to address this important question.

  5. Interactive Tailored Website to Promote Sun Protection and Skin Self-Check Behaviors in Patients With Stage 0-III Melanoma

    Science.gov (United States)

    2017-02-15

    Stage 0 Skin Melanoma; Stage I Skin Melanoma; Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage II Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage III Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma

  6. High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients.

    Science.gov (United States)

    van den Hurk, Karin; Balint, Balazs; Toomey, Sinead; O'Leary, Patrick C; Unwin, Louise; Sheahan, Kieran; McDermott, Enda W; Murphy, Ian; van den Oord, Joost J; Rafferty, Mairin; FitzGerald, Dara M; Moran, Julie; Cummins, Robert; MacEneaney, Owen; Kay, Elaine W; O'Brien, Cathal P; Finn, Stephen P; Heffron, Cynthia C B B; Murphy, Michelle; Yela, Ruben; Power, Derek G; Regan, Padraic J; McDermott, Clodagh M; O'Keeffe, Allan; Orosz, Zsolt; Donnellan, Paul P; Crown, John P; Hennessy, Bryan T; Gallagher, William M

    2015-06-01

    Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is--BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (PBRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)(-) mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease.

  7. Primary localization and tumor thickness as prognostic factors of survival in patients with mucosal melanoma.

    Directory of Open Access Journals (Sweden)

    Tarun Mehra

    Full Text Available Data on survival with mucosal melanoma and on prognostic factors of are scarce. It is still unclear if the disease course allows for mucosal melanoma to be treated as primary cutaneous melanoma or if differences in overall survival patterns require adapted therapeutic approaches. Furthermore, this investigation is the first to present 10-year survival rates for mucosal melanomas of different anatomical localizations.116 cases from Sep 10 1984 until Feb 15 2011 retrieved from the Comprehensive Cancer Center and of the Central Register of the German Dermatologic Society databases in Tübingen were included in our analysis. We recorded anatomical location and tumor thickness, and estimated overall survival at 2, 5 and 10 years and the mean overall survival time. Survival times were analyzed with the Kaplan-Meier method. The log-rank test was used to compare survival times by localizations and by T-stages.We found a median overall survival time of 80.9 months, with an overall 2-year survival of 71.7%, 5-year survival of 55.8% and 10-year survival of 38.3%. The 10-year survival rates for patients with T1, T2, T3 or T4 stage tumors were 100.0%, 77.9%, 66.3% and 10.6% respectively. 10-year survival of patients with melanomas of the vulva was 64.5% in comparison to 22.3% of patients with non-vulva mucosal melanomas.Survival times differed significantly between patients with melanomas of the vulva compared to the rest (p = 0.0006. It also depends on T-stage at the time of diagnosis (p < 0.0001.

  8. No longer an untreatable disease: how targeted and immunotherapies have changed the management of melanoma patients.

    Science.gov (United States)

    Girotti, Maria Romina; Saturno, Grazia; Lorigan, Paul; Marais, Richard

    2014-09-12

    The discovery that BRAF is a driver oncogene in cancer, and complementary improvements in our understanding of the immune system have resulted in new targeted and immune-therapies for metastatic melanoma. Targeted therapies achieve impressive clinical results in carefully selected patients but the development of resistance seems inevitable in most cases. Conversely, immune-checkpoints inhibitors can achieve long-term remission and cures, but in a smaller proportion of patients, and biomarkers to predict which patients will respond are not available. Nevertheless, melanoma has led the evolution of cancer treatment from relatively nonspecific cytotoxic agents to highly selective therapies and here we review the lessons from this paradigm shift in treatment and the opportunities for further improvements in outcomes for melanoma patients. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  9. COMPARATIVE ESTIMATION OF QUALITY OF LIFE IN PATIENTS WITH CHOROIDAL MELANOMA AFTER DIFFERENT TREATMENT OPTIONS

    Directory of Open Access Journals (Sweden)

    I. Ye. Panova

    2012-01-01

    Full Text Available The paper analyzes quality-of-life indicators in patients with choroidal melanoma after organ-removing and organ-saving treatments. Their quality of life after different treatments was found to have no statistically significant differences. Enucleation in patients with choroidal melanoma ensured higher values in the block of emotional well-being after surgery. After organ-saving treatment, the patients showed a significant reduction in quality of life as a total score in the late follow-up period. 

  10. Characterization of ex vivo expanded tumor infiltrating lymphocytes from patients with malignant melanoma for clinical application

    DEFF Research Database (Denmark)

    Junker, Niels; Thor Straten, Per; Andersen, Mads Hald

    2011-01-01

    Clinical trials of adoptive transfer of autologous tumor infiltrating lymphocytes (TILs) to patients with advanced malignant melanoma have shown remarkable results with objective clinical responses in 50% of the treated patients. In order to initiate a clinical trial in melanoma, we have...... established a method for expanding TILs to clinical relevant quantities in two steps with in 8 weeks. Further characterization of expanded TILs revealed an oligoclonal composition of T-cells with an effector memory like phenotype. When autologous tumor was available, TILs showed specific activity in all...... patients tested. TIL cultures contained specificity towards tumor cells as well as peptides derived from tumor-associated antigens (TAAs) during expansion procedures....

  11. Acral lentiginous melanoma - a skin cancer with unfavourable prognostic features. A study of the German Central Malignant Melanoma Registry (CMMR) in 2050 patients.

    Science.gov (United States)

    Teramoto, Y; Keim, U; Gesierich, A; Schuler, G; Fiedler, E; Tüting, T; Ulrich, C; Wollina, U; Hassel, J C; Gutzmer, R; Goerdt, S; Zouboulis, C; Leiter, U; Eigentler, T K; Garbe, C

    2017-07-14

    Acral lentiginous melanoma (ALM) is one of the four major subtypes in cutaneous melanoma (CM). Although ALM has a poorer prognosis than other CM subtypes, the prognostic factors of ALM have been verified only in small-sized cohorts because of the low incidence of ALM worldwide. To investigate clinical characteristics of ALM and to evaluate their prognostic values based on a large dataset from the Central Malignant Melanoma Registry (CMMR) of the German Dermatologic Society. The Kaplan-Meier method was used to estimate the potential influence of clinical and histological parameters on ALM disease-specific survival (DSS) curves, which were compared using log-rank test. A cox proportional hazards model was used to identify independent prognostic factors for DSS. 2,050 ALM patients were identified from 58,949 CM patients recorded by CMMR with follow-up data. In multivariate analyses, age (p=0.006), ulceration (p = 0.013), tumour thickness (p < 0.001) and tumour spread (p < 0.001) turned out to be significant prognostic factors for DSS in ALM whereas gender, nevus association and level of invasion were not independent factors. Acral lentiginous melanoma has the same prognostic factors as the other subtypes of melanoma. Unfavourable prognosis probably derives from the delay of diagnosis in comparison to other melanoma subtypes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  12. CDKN2A and MC1R variants found in Cypriot patients diagnosed with cutaneous melanoma

    Indian Academy of Sciences (India)

    GEORGIA KOULERMOU; CHRISTOS SHAMMAS; ANDREAS VASSILIOU; TASSOS C. KYRIAKIDES; CONSTANTINA COSTI; VASSOS NEOCLEOUS; LEONIDAS A. PHYLACTOU; MARIA PANTELIDOU

    2017-03-01

    The prevalence of genetic variants associated to cutaneous melanoma (CM) has never been determined within Cypriot melanomas. This study evaluates the frequency of variants in cyclin-dependent kinase inhibitor 2A (CDKN2A) andmelanocortin-1 receptor (MC1R) in 32 patients diagnosed with CM. Other characteristics and risk factors were also assessed. CDKN2A p.Ala148Thr was detected in three of 32 patients, while the control group revealed no variationswithin CDKN2A. MC1R screening in 32 patients revealed the following variations: p.Val60Leu in 11 patients, p.Arg142His in four patients, p.Thr314Thr in one patient, p.Arg160Trp in one patient, p.Val92Met/p.Thr314Thr in one patient andp.Val92Met/p.Arg142His/p.Thr314Thr in one patient. The control group revealed only p.Val60Leu (in 10 of 45 individuals), which is frequently found in general populations. Two unrelated patients carried CDKN2A p.Ala148Thr in combination with MC1R p.Arg142His, suggesting digenic inheritance that may provide evidence of different gene variants acting synergistically to contribute for CM development. This study confirms the presence of CDKN2A and MC1R variants among Cypriot melanomas and supports existing evidence of a role for these variants in susceptibility to melanoma.

  13. Targeted BRAF inhibition impacts survival in melanoma patients with high levels of Wnt/β-catenin signaling.

    Directory of Open Access Journals (Sweden)

    Andy J Chien

    Full Text Available Unprecedented clinical responses have been reported in advanced stage metastatic melanoma patients treated with targeted inhibitors of constitutively activated mutant BRAF, which is present in approximately half of all melanomas. We and others have previously observed an association of elevated nuclear β-catenin with improved survival in molecularly-unselected melanoma patients. This study sought to determine whether levels of Wnt/β-catenin signaling in melanoma tumors prior to treatment might predict patient responses to BRAF inhibitors (BRAFi. We performed automated quantification of β-catenin immunohistochemical expression in pretreatment BRAF-mutant tumors from 32 BRAFi-treated melanoma patients. Unexpectedly, patients with higher nuclear β-catenin in their tumors did not exhibit the survival advantage previously observed in molecularly-unselected melanoma patients who did not receive BRAFi. In cultured melanoma cells treated with long-term BRAFi, activation of Wnt/β-catenin signaling is markedly inhibited, coinciding with a loss of the enhancement of BRAFi-induced apoptosis by WNT3A observed in BRAFi-naïve cells. Together, these observations suggest that long-term treatment with BRAFi can impact the interaction between BRAF/MAPK and Wnt/β-catenin signaling to affect patient outcomes. Studies with larger patient cohorts are required to determine whether nuclear β-catenin expression correlates with clinical responses to BRAFi and to specific mechanisms of acquired resistance to BRAFi. Understanding these pathway interactions will be necessary to facilitate efforts to individualize therapies for melanoma patients.

  14. ON NEVI AND MELANOMAS IN DYSPLASTIC NEVUS SYNDROME PATIENTS

    NARCIS (Netherlands)

    CRIJNS, MB; BERGMAN, W; Berger, MJ; HERMANS, J; SOBER, AJ

    1993-01-01

    Cutaneous melanoma may occur as isolated, so-called 'sporadic' cases or in association with multiple atyical naevi and in familial clusters, in which case it is referred to as the familial dysplastic naevus syndrome (DNS). In this retrospective study (a) the number and body distribution of naevocyti

  15. Sentinel node biopsy for melanoma: a study of 241 patients

    DEFF Research Database (Denmark)

    Chakera, Annette Hougaard; Drzewiecki, Krzysztof Tadeusz; Jakobsen, Annika Loft;

    2004-01-01

    nine haematoxylin and eosin (HE)-negatives, all of which were found by immunohistochemistry. The false negative rate for the SNB procedure was 4% (2/55). The complication rate was 6% after SNB and 29% after complete node dissection. In conclusion, SN status is a strong prognostic factor in melanoma...

  16. Survival after a psychoeducational intervention for patients with cutaneous malignant melanoma: a replication study

    DEFF Research Database (Denmark)

    Boesen, Ellen H; Boesen, Sidsel H; Frederiksen, Kirsten

    2007-01-01

    The results of a randomized, intervention study done in 1993 of psychoeducation for patients with early-stage malignant melanoma showed a beneficial effect on recurrence and survival 6 years after the intervention. In the present study, we replicated the study with 258 Danish patients with malign...

  17. Protein signatures correspond to survival outcomes of AJCC stage III melanoma patients.

    Science.gov (United States)

    Mactier, Swetlana; Kaufman, Kimberley L; Wang, Penghao; Crossett, Ben; Pupo, Gulietta M; Kohnke, Philippa L; Thompson, John F; Scolyer, Richard A; Yang, Jean Y; Mann, Graham J; Christopherson, Richard I

    2014-11-01

    Outcomes for melanoma patients with stage III disease differ widely even within the same subcategory. Molecular signatures that more accurately predict prognosis are needed to stratify patients according to risk. Proteomic analyses were used to identify differentially abundant proteins in extracts of surgically excised samples from patients with stage IIIc melanoma lymph node metastases. Analysis of samples from patients with poor (n = 14, 4 yr) survival outcomes identified 84 proteins that were differentially abundant between prognostic groups. Subsequent selected reaction monitoring analysis verified 21 proteins as potential biomarkers for survival. Poor prognosis patients are characterized by increased levels of proteins involved in protein metabolism, nucleic acid metabolism, angiogenesis, deregulation of cellular energetics and methylation processes, and decreased levels of proteins involved in apoptosis and immune response. These proteins are able to classify stage IIIc patients into prognostic subgroups (P < 0.02). This is the first report of potential prognostic markers from stage III melanoma using proteomic analyses. Validation of these protein markers in larger patient cohorts should define protein signatures that enable better stratification of stage III melanoma patients.

  18. Phase II study of E7070 in patients with metastatic melanoma.

    NARCIS (Netherlands)

    Smyth, J.F.; Aamdal, S.; Awada, A.; Dittrich, C.; Caponigro, F.; Schoffski, P.; Gore, M.; Lesimple, T.; Djurasinovic, N.; Baron, B.; Ravic, M.; Fumoleau, P.; Punt, C.J.A.

    2005-01-01

    E7070 is a synthetic chloro-indolyl sulphonamide that is being developed as an anti cancer agent. In this phase II study, 28 patients with metastatic melanoma received 700 mg/m(2) of E7070 as a 60-min infusion repeated every 3 weeks. Although therapy was well tolerated, with one patient receiving 14

  19. POSTEROLATERAL NECK DISSECTION IN PATIENTS WITH MELANOMA OF THE SKIN OF THE POSTERIOR SCALP

    NARCIS (Netherlands)

    VERMEY, A; PLUKKER, JTM; ROODENBURG, JLN; OLDHOFF, J

    1993-01-01

    19 consecutive patients underwent a posterolateral neck dissection (PLND) in continuity with a wide excision of the primary melanoma on the posterior scalp. After a mean follow-up of 74 months, 5 patients are alive with minimal morbidity. PLND can safely be performed, even bilaterally, as an

  20. Factors affecting results of lymph node dissection in patients with skin Melanoma, 1987-92

    Directory of Open Access Journals (Sweden)

    Mir M

    1998-08-01

    Full Text Available In this paper, factors affecting the result of prophylactic lymph node dissection in 125 patients with skin melanoma during the period between 1987-1992 in the cancer institute were evaluated and prognostic parameters ascertained. The result showed prevalence of head and neck melanoma in men were two times more than in women with a preponderance of regional and lymphatic recurrence. Majority of patients presented with advanced clark levels (76.8 Pct. Clinical and histologic evaluation of the regional lymph nodes failed to show any meaningful relation.

  1. Correlation of TGF-β1 and oxidative stress in the blood of patients with melanoma: a clue to understanding melanoma progression?

    Science.gov (United States)

    Santos Bernardes, Sara; de Souza-Neto, Fernando Pinheiro; Pasqual Melo, Gabriella; Guarnier, Flávia Alessandra; Marinello, Poliana Camila; Cecchini, Rubens; Cecchini, Alessandra L

    2016-08-01

    TGF-β1 and oxidative stress are involved in cancer progression, but in melanoma, their role is still controversial. Our aim was to correlate plasma TGF-β1 levels and systemic oxidative stress biomarkers in patients with melanoma, with or without disease metastasis, to understand their participation in melanoma progression. Thirty patients were recruited for melanoma surveillance, together with 30 healthy volunteers. Patients were divided into two groups: Non-metastasis, comprising patients with tumor removal and no metastatic episode for 3 years; and Metastasis, comprising patients with a metastatic episode. The plasmatic cytokines TGF-β1, IL-1 β, and TNF-α were analyzed by ELISA. For oxidative stress, the following assays were performed: malondialdehyde (MDA), advanced oxidation protein products (AOPP) levels, total radical-trapping antioxidant parameter (TRAP) and thiol in plasma, and lipid peroxidation, SOD and catalase activity and GSH in erythrocytes. Patients with a metastatic episode had less circulating TGF-β1 and increased TRAP, thiol, AOPP and lipid peroxidation levels. MDA was increased in both melanoma groups, while catalase, GSH, and IL-1β was decreased in Non-metastasis patients. Significant negative correlations were observed between TGF-β1 levels and systemic MDA, and TGF-β1 levels and systemic AOPP, while a positive correlation was observed between TGF-β1 levels and erythrocyte GSH. Lower levels of TGF-β1 were related to increased oxidative stress in Metastasis patients, reinforcing new evidence that in melanoma TGF-β1 acts as a tumor suppressor, inhibiting tumor relapse. These findings provide new knowledge concerning this cancer pathophysiology, extending the possibilities of investigating new therapies based on this evidence.

  2. The interval between primary melanoma excision and sentinel node biopsy is not associated with survival in sentinel node positive patients - An EORTC Melanoma Group study.

    Science.gov (United States)

    Oude Ophuis, C M C; Verhoef, C; Rutkowski, P; Powell, B W E M; van der Hage, J A; van Leeuwen, P A M; Voit, C A; Testori, A; Robert, C; Hoekstra, H J; Grünhagen, D J; Eggermont, A M M; van Akkooi, A C J

    2016-12-01

    Worldwide, sentinel node biopsy (SNB) is the recommended staging procedure for stage I/II melanoma. Most melanoma guidelines recommend re-excision plus SNB as soon as possible after primary excision. To date, there is no evidence to support this timeframe. To determine melanoma specific survival (MSS) for time intervals between excisional biopsy and SNB in SNB positive patients. Between 1993 and 2008, 1080 patients were diagnosed with a positive SNB in nine Melanoma Group centers. We selected 1015 patients (94%) with known excisional biopsy date. Time interval was calculated from primary excision until SNB. Kaplan-Meier estimated MSS was calculated for different cutoff values. Multivariable analysis was performed to correct for known prognostic factors. Median age was 51 years (Inter Quartile Range (IQR) 40-62 years), 535 (53%) were men, 603 (59%) primary tumors were located on extremities. Median Breslow thickness was 3.00 mm (IQR 1.90-4.80 mm), 442 (44%) were ulcerated. Median follow-up was 36 months (IQR 20-62 months). Median time interval was 47 days (IQR 32-63 days). Median Breslow thickness was equal for both melanoma excision until SNB was no prognostic factor for MSS in this SNB positive cohort. This information can be used to counsel patients. Copyright © 2016 Elsevier Ltd and British Association of Surgical Oncology/European Society of Surgical Oncology. All rights reserved.

  3. Should high-dose interleukin-2 still be the preferred treatment for patients with metastatic melanoma?

    Science.gov (United States)

    Dillman, Robert O; Barth, Neil M; VanderMolen, Louis A; Mahdavi, Khosrow; McClure, Stephanie E

    2012-08-01

    For more than 20 years interleukin-2 (IL2) was the preferred treatment for medically fit metastatic melanoma patients, but recently two new agents, ipilimumab and vemurafenib, were approved for stage IV disease. Single-institution data were used to determine the long-term survival rate for IL2-treated melanoma patients, and whether use of inpatient IL2 had declined recently. Between May 1987 and April 2010, 150 patients were hospitalized for high-dose, intravenous (i.v.) IL2. The average number of IL2 patients increased from 5.4 per year during 1987-1991 to 5.8 during 1992-1997 after regulatory approval of IL2, to 8.3 during 1998-2006 after a marketing indication in metastatic melanoma was granted, but dropped to 3.0 during 2007-2010. At the time of treatment, median age was 52 years; 27% were 60 years of age or older. At the time of analysis 122 patients were deceased. Median survival from the start date of IL2 treatment was 15.6 months, with a 20% 5-year survival. Among patients enrolled in clinical trials, there were as many nonresponders who survived 5 years as responders, which is consistent with a delayed immunotherapy benefit. In the absence of long-term survival data for these newer agents, IL2 probably should still be the preferred initial treatment for most patients with metastatic melanoma who are medically fit.

  4. Treatment of Ipilimumab Induced Graves’ Disease in a Patient with Metastatic Melanoma

    Directory of Open Access Journals (Sweden)

    Umal Azmat

    2016-01-01

    Full Text Available Objective. Thyroid disease has been reported among the endocrinopathies that can occur after treatment with ipilimumab. Graves’ disease, however, has been rarely reported with this medication. Here we report a case of Graves’ disease diagnosed after initiation of ipilimumab in a patient with melanoma. Methods. We present the clinical presentation and management course of this patient followed by a related literature review. Results. A 67-year-old male with metastatic melanoma was started on ipilimumab. He developed hyperthyroidism after two doses of ipilimumab. The cause of hyperthyroidism was determined to be Graves’ disease. Ipilimumab was held and the patient was started on methimazole with return to euthyroid status. Ipilimumab was resumed and the patient continued methimazole during the course of ipilimumab therapy, with controlled hyperthyroidism. Restaging studies following four cycles of ipilimumab showed complete response in the lungs, with residual melanoma in the neck. The patient then underwent total thyroidectomy and left neck dissection as a definitive treatment for both hyperthyroidism and residual melanoma. Conclusion. Graves’ disease can develop after starting ipilimumab and methimazole can be an effective treatment. For patients whose hyperthyroidism is well-controlled on methimazole, ipilimumab may be resumed with close monitoring.

  5. Relationship Between LAPTM4B Gene Polymorphism and Susceptibility of Malignant Melanoma in Chinese Patients

    Directory of Open Access Journals (Sweden)

    Meng Zhang

    2014-10-01

    Full Text Available Lysosomal-associated protein transmembrane 4 beta (LAPTM4B is known as an oncogene associated with many human malignant tumors. There are two alleles of the gene, LAPTM4B*1 and LAPTM4B*2. Previous studies have shown that LAPTM4B polymorphism contributes to the risk of many cancers. This case-control study was to investigate the relationship between LAPTM4B gene polymorphism and susceptibility of malignant melanoma. The genotypes of LAPTM4B were determined in 617 control subjects and 220 patients with malignant melanoma by utilizing polymerase chain reaction based on specific primers. The genotypic distribution of LAPTM4B and Hardy–Weinberg equilibrium were analyzed by χ2 test. Odds ratio and 95% confidence interval was calculated by unconditional logistic regression. The distributions of LAPTM4B genotypes were significantly different between melanoma patients (45.9% for *1/1, 46.4% for *1/2 and 7.7 for *2/2 and controls (54.5% for *1/1, 39.9% for *1/2 and 5.7 for *2/2. LAPTM4B *1/2 and LAPTM4B *2/2 had a 1.396-fold and 1.619-fold higher risk for melanoma occurrence than *1/1, and subjects with LAPTM4B*2 have a 1.308-fold higher risk than LAPTM4B*1 carriers. No association between LAPTM4B genotypes and gender, age, subtype, Clark level of invasion, Breslow thickness, ulceration, clinical stage, and C-KIT, BRAF gene mutation status was observed. LAPTM4B*2 is associated with the high risk of malignant melanoma and carrying LAPTM4B *2 may be a susceptible factor to Chinese melanoma patients.

  6. Towards personalized therapy for patients with malignant melanoma: molecular insights into the biology of BRAF mutations.

    Science.gov (United States)

    Bradish, Joshua R; Montironi, Rodolfo; Lopez-Beltran, Antonio; Post, Kristin M; MacLennan, Gregory T; Cheng, Liang

    2013-02-01

    BRAF mutations have been identified as the most common oncogene mutation in melanomas, especially important in those originating on nonchronically sun-damaged skin. There is a large and continually growing body of evidence regarding the importance of this mutation in targeted therapy for melanoma. In this review, we outline these findings including: molecular pathways used by BRAF, the importance in nonmalignant neoplasms, histologic associations, the relationship of BRAF to KIT and NRAS mutations, and their impact on survival, as well as resistance mechanisms to BRAF inhibitors employed by melanoma. Understanding these topics and how they relate to one another may facilitate the development of new treatments and eventually improve the prognosis for those patients afflicted with this disease.

  7. Cutaneous melanoma.

    Science.gov (United States)

    Eggermont, Alexander M M; Spatz, Alan; Robert, Caroline

    2014-03-01

    In the past decade, major advances have been made in the understanding of melanoma. New predisposition genes have been reported and key somatic events, such as BRAF mutation, directly translated into therapeutic management. Surgery for localised melanoma and regional lymph node metastases is the standard of care. Sentinel-node biopsy provides precise staging, but has not been reported to affect survival. The effect of lymph-node dissection on survival is a topic of investigation. Two distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF-mutated melanoma. The combination of BRAF inhibitors and MEK inhibitors might improve progression-free survival further and, possibly, increase overall survival. Response patterns differ substantially-anti-CTLA4 immunotherapy can induce long-term responses, but only in a few patients, whereas targeted drugs induce responses in most patients, but nearly all of them relapse because of pre-existing or acquired resistance. Thus, the long-term prognosis of metastatic melanoma remains poor. Anti-PD1 and anti-PDL1 antibodies have emerged as breakthrough drugs for melanoma that have high response rates and long durability. Biomarkers that have predictive value remain elusive in melanoma, although emerging data for adjuvant therapy indicate that interferon sensitivity is associated with ulceration of the primary melanoma. Intense investigation continues for clinical and biological markers that predict clinical benefit of immunotherapeutic drugs, such as interferon alfa or anti-CTLA4 antibodies, and the mechanisms that lead to resistance of targeted drugs.

  8. Prognosis and determinants of outcome following locoregional or distant recurrence in patients with cutaneous melanoma

    NARCIS (Netherlands)

    Francken, Anne Brecht; Accortt, Neil A.; Shaw, Helen M.; Wiener, Martin; Soong, Seng-jaw; Hoekstra, Harald J.; Thompson, John F.

    Objective: Information on prognosis for patients with cutaneous melanoma after locoregional or distant recurrence is sparse and controversial. The aim of this study was to analyze factors influencing outcome after the development of a first relapse. Methods: Information was extracted from the Sydney

  9. Risk of non-melanoma skin cancer in myasthenia patients treated with azathioprine

    DEFF Research Database (Denmark)

    Pedersen, E G; Pottegård, A; Hallas, J

    2014-01-01

    The association between use of azathioprine and risk of non-melanoma skin cancer (NMSC) in patients with myasthenia was evaluated in a nationwide setting. Treatment of autoimmune myasthenia frequently involves long-term exposure to immunosuppressants, including azathioprine. Use of azathioprine...

  10. Prognosis and determinants of outcome following locoregional or distant recurrence in patients with cutaneous melanoma

    NARCIS (Netherlands)

    Francken, Anne Brecht; Accortt, Neil A.; Shaw, Helen M.; Wiener, Martin; Soong, Seng-jaw; Hoekstra, Harald J.; Thompson, John F.

    2008-01-01

    Objective: Information on prognosis for patients with cutaneous melanoma after locoregional or distant recurrence is sparse and controversial. The aim of this study was to analyze factors influencing outcome after the development of a first relapse. Methods: Information was extracted from the Sydney

  11. Investigation of the relationship between dermoscopic features and histopathological prognostic indicators in patients with cutaneous melanoma

    Directory of Open Access Journals (Sweden)

    Özlem Özbağçıvan

    2015-09-01

    Full Text Available Background and Design: Dermoscopy has an important role in the diagnosis of melanoma nowadays. Dermoscopic findings of melanoma had been associated with Breslow thickness and invasion status in previous studies but the relationship between dermatoscopic findings and other histopathological prognostic indicators has not been investigated until today. In this study, our aim is to investigate the relationship between dermatoscopic findings and histopathologic prognostic indicators such as Breslow thickness, invasion status, mitotic rate, lymphovascular invasion (LVI, ulceration and regression in patients who had been diagnosed with melanoma due to their clinical, dermatoscopic and histopatological findings. Materials and Methods: Dermoscopic and histopathological findings of 47 cases of melanoma who applied to our clinic between the years 2000 and 2014 were evaluated. The relationship between the dermoscopic findings which had been reported to be observed in melanomas in previous research and the histopathologic prognostic indicators such as Breslow thickness, invasion status, mitotic rate, lymphovascular invasion, ulceration and regression were investigated. Results: Irregular dots/globules, atypical pigment network, multifocal hypopigmentation, radial streaks and moth-eaten borders have been associated with good prognostic indicators whereas comedo like openings, regular blotch, exophytic papillary structures, dotted, glomerular, lineer irregular vessels, pink/red and blue/gray colors were associated with poor prognostic indicators. Additionally some dermatoscopic findings which are more observed in benign lesions such as multiple milia-like cysts, comedo like openings, moth-eaten borders, regular blotch, exophytic papillary structures and finger print areas have been observed in melanomas in our study. Conclusion: Many dermoscopic findings have demonstrated statistically significant association with the histopathological prognostic indicators

  12. Analysis of Dermatologic Events in Vemurafenib-Treated Patients With Melanoma

    Science.gov (United States)

    Duvic, Madeleine; Hauschild, Axel; Prieto, Victor G.; Robert, Caroline; Schadendorf, Dirk; Kim, Caroline C.; McCormack, Christopher J.; Myskowski, Patricia L.; Spleiss, Olivia; Trunzer, Kerstin; Su, Fei; Nelson, Betty; Nolop, Keith B.; Grippo, Joseph F.; Lee, Richard J.; Klimek, Matthew J.; Troy, James L.; Joe, Andrew K.

    2013-01-01

    Background. Vemurafenib has been approved for the treatment of patients with advanced BRAFV600E-mutant melanoma. This report by the Vemurafenib Dermatology Working Group presents the characteristics of dermatologic adverse events (AEs) that occur in vemurafenib-treated patients, including cutaneous squamous cell carcinoma (cuSCC). Methods. Dermatologic AEs were assessed from three ongoing trials of BRAFV600E mutation-positive advanced melanoma. Histologic central review and genetic characterization were completed for a subset of cuSCC lesions. Results. A total of 520 patients received vemurafenib. The most commonly reported AEs were dermatologic AEs, occurring in 92%–95% of patients. Rash was the most common AE (64%–75% of patients), and the most common types were rash not otherwise specified, erythema, maculopapular rash, and folliculitis. Rash development did not appear to correlate with tumor response. Photosensitivity occurred in 35%–63% of patients, and palmar-plantar erythrodysesthesia (PPE) occurred in 8%–10% of patients. The severity of rash, photosensitivity, and PPE were mainly grade 1 or 2. In all, 19%–26% of patients developed cuSCC, mostly keratoacanthomas (KAs). The majority of patients with cuSCC continued therapy without dose reduction after resection. Genetic analysis of 29 cuSCC/KA samples demonstrated HRAS mutations in 41%. Conclusions. Dermatologic AEs associated with vemurafenib treatment in patients with melanoma were generally manageable with supportive care measures. Dose interruptions and/or reductions were required in <10% of patients. PMID:23457002

  13. Improving outcomes in patients with melanoma: strategies to ensure an early diagnosis

    Directory of Open Access Journals (Sweden)

    Voss RK

    2015-11-01

    Full Text Available Rachel K Voss,1 Tessa N Woods,1 Kate D Cromwell,1 Kelly C Nelson,2 Janice N Cormier1 1Department of Surgical Oncology, 2Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: Patients with thin, low-risk melanomas have an excellent long-term prognosis and higher quality of life than those who are diagnosed at later stages. From an economic standpoint, treatment of early stage melanoma consumes a fraction of the health care resources needed to treat advanced disease. Consequently, early diagnosis of melanoma is in the best interest of patients, payers, and health care systems. This review describes strategies to ensure that patients receive an early diagnosis through interventions ranging from better utilization of primary care clinics, to in vivo diagnostic technologies, to new “apps” available in the market. Strategies for screening those at high risk due to age, male sex, skin type, nevi, genetic mutations, or family history are discussed. Despite progress in identifying those at high risk for melanoma, there remains a lack of general consensus worldwide for best screening practices. Strategies to ensure early diagnosis of recurrent disease in those with a prior melanoma diagnosis are also reviewed. Variations in recurrence surveillance practices by type of provider and country are featured, with evidence demonstrating that various imaging studies, including ultrasound, computed tomography, positron emission tomography, and magnetic resonance imaging, provide only minimal gains in life expectancy, even for those with more advanced (stage III disease. Because the majority of melanomas are attributable to ultraviolet radiation in the form of sunlight, primary prevention strategies, including sunscreen use and behavioral interventions, are reviewed. Recent international government regulation of tanning beds is described, as well as issues surrounding the continued use artificial ultraviolet

  14. Improved Survival in Male Melanoma Patients in the Era of Sentinel Node Biopsy.

    Science.gov (United States)

    Koskivuo, I; Vihinen, P; Mäki, M; Talve, L; Vahlberg, T; Suominen, E

    2017-03-01

    Sentinel node biopsy is a standard method for nodal staging in patients with clinically localized cutaneous melanoma, but the survival advantage of sentinel node biopsy remains unsolved. The aim of this case-control study was to investigate the survival benefit of sentinel node biopsy. A total of 305 prospective melanoma patients undergoing sentinel node biopsy were compared with 616 retrospective control patients with clinically localized melanoma whom have not undergone sentinel node biopsy. Survival differences were calculated with the median follow-up time of 71 months in sentinel node biopsy patients and 74 months in control patients. Analyses were calculated overall and separately in males and females. Overall, there were no differences in relapse-free survival or cancer-specific survival between sentinel node biopsy patients and control patients. Male sentinel node biopsy patients had significantly higher relapse-free survival ( P = 0.021) and cancer-specific survival ( P = 0.024) than control patients. In females, no differences were found. Cancer-specific survival rates at 5 years were 87.8% in sentinel node biopsy patients and 85.2% in controls overall with 88.3% in male sentinel node biopsy patients and 80.6% in male controls and 87.3% in female sentinel node biopsy patients and 89.8% in female controls. Sentinel node biopsy did not improve survival in melanoma patients overall. While females had no differences in survival, males had significantly improved relapse-free survival and cancer-specific survival following sentinel node biopsy.

  15. Vemurafenib-associated Dupuytren- and Ledderhose palmoplantar fibromatosis in metastatic melanoma patients.

    Science.gov (United States)

    Vandersleyen, V; Grosber, M; Wilgenhof, S; De Kock, J; Neyns, B; Gutermuth, J

    2016-07-01

    The BRAF-inhibitor vemurafenib, used in patients with metastatic melanoma, induces multiple cutaneous side-effects. The aim of this work was to evaluate the development of palmoplantar fibromatosis in a population of patients treated with the BRAF inhibitor vemurafenib. Between April 2011 and February 2013, we initiated a treatment with vemurafenib in 53 patients with an unresectable stage IIIC or stage IV melanoma. The patients were followed-up on a regular base to monitor possible side-effects. A plantar or palmar fibromatosis was observed in five of 53 patients treated with vemurafenib. In four of these patients other risk factors for the development of palmoplantar fibromatosis were absent. The BRAF-inhibitor vemurafenib might induce palmoplantar fibromatosis. © 2015 European Academy of Dermatology and Venereology.

  16. Dutch Melanoma Treatment Registry : Quality assurance in the care of patients with metastatic melanoma in the Netherlands

    NARCIS (Netherlands)

    Jochems, Anouk; Schouwenburg, Maartje G.; Leeneman, Brenda; Franken, Margreet G.; van den Eertwegh, Alfons J. M.; Haanen, John B. A. G.; Gelderblom, Hans; Uyl-de Groot, Carin A.; Aarts, Maureen J. B.; van den Berkmortel, Franchette W. P. J.; Blokx, Willeke A. M.; Cardous-Ubbink, Mathilde C.; Groenewegen, Gerard; de Groot, Jan Willem B.; Hospers, Geke A. P.; Kapiteijn, Ellen; Koornstra, Rutger H.; Kruit, Wim H.; Louwman, Marieke W. J.; Piersma, Djura; van Rijn, Rozemarijn S.; ten Tije, Albert J; Vreugdenhil, Gerard; Wouters, Michel W. J. M.; van der Hoeven, Jacobus J M

    Background: In recent years, the treatment of metastatic melanoma has changed dramatically due to the development of immune checkpoint and mitogen-activated protein (MAP) kinase inhibitors. A population-based registry, the Dutch Melanoma Treatment Registry (DMTR), was set up in July 2013 to assure

  17. Long-term survival in advanced melanoma patients using repeated therapies: successive immunomodulation improving the odds?

    Directory of Open Access Journals (Sweden)

    Coventry BJ

    2015-04-01

    Full Text Available Brendon J Coventry, Dominique Baume, Carrie Lilly Discipline of Surgery, Royal Adelaide Hospital, University of Adelaide, Adelaide, SA, Australia Background: Patients with advanced metastatic melanoma are often confronted with little prospect of medium- to longer-term survival by any currently available therapeutic means. However, most clinicians are aware of exceptional cases where survival defies the notion of futility. Prolonged survival from immunotherapies, including interleukin-2, vaccines and antibodies to cytotoxic lymphocyte antigen-4, and programmed death-1 receptor inhibitory monoclonal antibody, implies a role for immune system modulation. We aimed to identify cases where exceptional survival from advanced melanoma occurred prior to recent novel therapies to facilitate better understanding of this phenomenon. Methods: Cases of long-term survival of ≥3 years' duration (from diagnosis of metastatic disease were identified from the database of one clinician; these cases were treated before the availability of newer immunotherapies, and they were documented and examined. A literature search for reported outcome measures from published studies using older and recent therapies for advanced melanoma was conducted to enable the comparison of data. Results: Eighteen cases were identified that identified survival of ≥3 years' duration from metastatic disease (12 American Joint Committee on Cancer [AJCC] Stage IV cases; six AJCC III cases diagnosis. These were assessed and reported to detail the clinical course. Standard clinical prognostication methods predicted high risk of early mortality in those patients. No identifiable differences could be detected between these and other patients with similar patterns of disease. At evaluation, 17 patients (94% had survived ≥5 years, and eleven patients (61% had survived ≥10 years (range: 3–15 years. The median survival duration with metastatic disease was 11 years; 15 remained alive and three

  18. High frequency of T cells specific for cryptic epitopes in melanoma patients

    Science.gov (United States)

    Andersen, Rikke Sick; Andersen, Sofie Ramskov; Hjortsø, Mads Duus; Lyngaa, Rikke; Idorn, Manja; Køllgård, Tania Maria; Met, Özcan; thor Straten, Per; Hadrup, Sine Reker

    2013-01-01

    A number of cytotoxic T-cell epitopes are cryptic epitopes generated from non-conventional sources. These include epitopes that are encoded by alternative open reading frames or in generally non-coding genomic regions, such as introns. We have previously observed a frequent recognition of cryptic epitopes by tumor infiltrating lymphocytes isolated from melanoma patients. Here, we show that such cryptic epitopes are more frequently recognized than antigens of the same class encoded by canonical reading frames. Furthermore, we report the presence of T cells specific for three cryptic epitopes encoded in intronic sequences, as a result of incomplete splicing, in the circulation of melanoma patients. One of these epitopes derives from antigen isolated from immunoselected melanoma 2 (AIM2), while the two others are encoded in an alternative open reading frame of an incompletely spliced form of N-acetylglucosaminyl-transferase V (GNT-V) known as NA17-A. We have detected frequent T-cell responses against AIM2 and NA17-A epitopes in the blood of melanoma patients, both prior and after one round of in vitro peptide stimulation, but not in the circulation of healthy individuals and patients with breast or renal carcinoma. In summary, our findings indicate that the T-cell reactivity against AIM2 and NA17-A in the blood of melanoma patients is extensive, suggesting that—similar to melan A (also known as MART1)—these antigens might be used for immunomonitoring or as model antigens in several clinical and preclinical settings. PMID:24073381

  19. Limited genomic heterogeneity of circulating melanoma cells in advanced stage patients

    Science.gov (United States)

    Ruiz, Carmen; Li, Julia; Luttgen, Madelyn S.; Kolatkar, Anand; Kendall, Jude T.; Flores, Edna; Topp, Zheng; Samlowski, Wolfram E.; McClay, Edward; Bethel, Kelly; Ferrone, Soldano; Hicks, James; Kuhn, Peter

    2015-02-01

    Purpose. Circulating melanoma cells (CMCs) constitute a potentially important representation of time-resolved tumor biology in patients. To date, genomic characterization of CMCs has been limited due to the lack of a robust methodology capable of identifying them in a format suitable for downstream characterization. Here, we have developed a methodology to detect intact CMCs that enables phenotypic, morphometric and genomic analysis at the single cell level. Experimental design. Blood samples from 40 metastatic melanoma patients and 10 normal blood donors were prospectively collected. A panel of 7 chondroitin sulfate proteoglycan 4 (CSPG4)-specific monoclonal antibodies (mAbs) was used to immunocytochemically label CMCs. Detection was performed by automated digital fluorescence microscopy and multi-parametric computational analysis. Individual CMCs were captured by micromanipulation for whole genome amplification and copy number variation (CNV) analysis. Results. Based on CSPG4 expression and nuclear size, 1-250 CMCs were detected in 22 (55%) of 40 metastatic melanoma patients (0.5-371.5 CMCs ml-1). Morphometric analysis revealed that CMCs have a broad spectrum of morphologies and sizes but exhibit a relatively homogeneous nuclear size that was on average 1.5-fold larger than that of surrounding PBMCs. CNV analysis of single CMCs identified deletions of CDKN2A and PTEN, and amplification(s) of TERT, BRAF, KRAS and MDM2. Furthermore, novel chromosomal amplifications in chr12, 17 and 19 were also found. Conclusions. Our findings show that CSPG4 expressing CMCs can be found in the majority of advanced melanoma patients. High content analysis of this cell population may contribute to the design of effective personalized therapies in patients with melanoma.

  20. Ascertaining serum levels of trace elements in melanoma patients using PIXE and HR-ICPMS

    Energy Technology Data Exchange (ETDEWEB)

    Bernardes, S., E-mail: suene@if.usp.br [Physics Institute, University of São Paulo (Brazil); Tabacniks, M.H. [Physics Institute, University of São Paulo (Brazil); Santos, I.D.A.O.; Oliveira, A.F.; Shie, J.N. [São Paulo Federal University (UNIFESP), São Paulo (Brazil); Sarkis, J.E.S.; Oliveira, T. [Institute of Energy and Nuclear Research (IPEN), Laboratory of Chemical Characterization (LCQ), Center for Chemistry and the Environment - CQMA, Sao Paulo (Brazil)

    2014-01-01

    Melanoma is a serious and deadly form of skin cancer. However, patients’ chances of survival and recovery are considerably increased when it is diagnosed and treated in its early stages. In this study, trace element concentrations in serum samples from patients with melanoma were measured using PIXE (Proton Induced X-ray Emission) and HR-ICPMS (High-Resolution Inductively Coupled Plasma Mass Spectrometry), with the purpose of correlating these concentrations with the disease. Blood samples from 30 melanoma patients and 116 healthy donors were collected at São Paulo Hospital (protocol CEP 1036/08 UNIFESP). Relevant clinical information on the patients has also been included in the statistical analysis. Analysis of the control group showed different P and Mg concentrations in individuals above and below 40 years of age. P, S, Ca, Cu and Zn concentrations in healthy individuals differed according to gender, highlighting the necessity to include age and gender variables in the case-control analysis. There were also differences in K, S, Ca and Se concentrations between the control and melanoma groups.

  1. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab.

    Science.gov (United States)

    Meyer, Christiane; Cagnon, Laurène; Costa-Nunes, Carla M; Baumgaertner, Petra; Montandon, Nicole; Leyvraz, Loredana; Michielin, Olivier; Romano, Emanuela; Speiser, Daniel E

    2014-03-01

    Metastatic melanoma has a poor prognosis with high resistance to chemotherapy and radiation. Recently, the anti-CTLA-4 antibody ipilimumab has demonstrated clinical efficacy, being the first agent to significantly prolong the overall survival of inoperable stage III/IV melanoma patients. A major aim of patient immune monitoring is the identification of biomarkers that predict clinical outcome. We studied circulating myeloid-derived suppressor cells (MDSC) in ipilimumab-treated patients to detect alterations in the myeloid cell compartment and possible correlations with clinical outcome. Lin(-) CD14(+) HLA-DR(-) monocytic MDSC were enriched in peripheral blood of melanoma patients compared to healthy donors (HD). Tumor resection did not significantly alter MDSC frequencies. During ipilimumab treatment, MDSC frequencies did not change significantly compared to baseline levels. We observed high inter-patient differences. MDSC frequencies in ipilimumab-treated patients were independent of baseline serum lactate dehydrogenase levels but tended to increase in patients with severe metastatic disease (M1c) compared to patients with metastases in skin or lymph nodes only (M1a), who had frequencies comparable to HD. Interestingly, clinical responders to ipilimumab therapy showed significantly less lin(-) CD14(+) HLA-DR(-) cells as compared to non-responders. The data suggest that the frequency of monocytic MDSC may be used as predictive marker of response, as low frequencies identify patients more likely benefitting from ipilimumab treatment. Prospective clinical trials assessing MDSC frequencies as potential biomarkers are warranted to validate these observations.

  2. Influence of ipilimumab on expanded tumour derived T cells from patients with metastatic melanoma

    DEFF Research Database (Denmark)

    Bjørn, Jon; Lyngaa, Rikke Birgitte; Andersen, Rikke

    2017-01-01

    Introduction: Tumour infiltrating lymphocyte (TIL) based adoptive cell therapy (ACT) is a promising treatment for patients with advanced melanoma. Retrospective studies suggested an association between previous treatment with anti-CTLA-4 antibodies and long term survival after subsequent ACT. Thus......, we hypothesized that treatment with anti-CTLA-4 antibodies can induce favourable changes to be detected in TILs.Results: Expanded T cells from Ipilimumab treated patients had a higher proportion of cells expressing CD27, intracellular CTLA-4, TIM-3 and LAG-3. In addition, broader and more frequent T...... cell responses against common tumour antigens were detected in patients treated with Ipilimumab as compared to anti-CTLA-4 naive patients.Materials and methods: Expanded TILs were obtained from patients with advanced melanoma who had received Ipilimumab in the previous six months, or had not received...

  3. Antibody Therapy Targeting CD47 and CD271 Effectively Suppresses Melanoma Metastasis in Patient-Derived Xenografts.

    Science.gov (United States)

    Ngo, Michael; Han, Arum; Lakatos, Anita; Sahoo, Debashis; Hachey, Stephanie J; Weiskopf, Kipp; Beck, Andrew H; Weissman, Irving L; Boiko, Alexander D

    2016-08-09

    The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti-phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade of CD47 coupled with targeting of CD271(+) melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts. This therapeutic effect is mediated by drastic changes in the tumor and metastatic site immune microenvironments, both of whichwhich exhibit greatly increased density of differentiated macrophages and significantly fewer inflammatory monocytes, pro-metastatic macrophages (CCR2(+)/VEGFR1(+)), and neutrophils, all of which are associated with disease progression. Thus, antibody therapy that activates the innate immune response in combination with selective targeting of CD271(+) melanoma cells represents a powerful therapeutic approach against metastatic melanoma.

  4. Antibody Therapy Targeting CD47 and CD271 Effectively Suppresses Melanoma Metastasis in Patient-Derived Xenografts

    Directory of Open Access Journals (Sweden)

    Michael Ngo

    2016-08-01

    Full Text Available The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti-phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade of CD47 coupled with targeting of CD271+ melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts. This therapeutic effect is mediated by drastic changes in the tumor and metastatic site immune microenvironments, both of whichwhich exhibit greatly increased density of differentiated macrophages and significantly fewer inflammatory monocytes, pro-metastatic macrophages (CCR2+/VEGFR1+, and neutrophils, all of which are associated with disease progression. Thus, antibody therapy that activates the innate immune response in combination with selective targeting of CD271+ melanoma cells represents a powerful therapeutic approach against metastatic melanoma.

  5. Side effects in melanoma patients receiving adjuvant interferon alfa-2b therapy: a nurse's perspective.

    Science.gov (United States)

    Rubin, Krista M; Vona, Karen; Madden, Kathleen; McGettigan, Suzanne; Braun, Ilana M

    2012-08-01

    The aim of this review was to examine the toxicity profile of adjuvant interferon (IFN) alfa-2b in melanoma patients from a nursing perspective and to summarize practical information to guide the effective management of common IFN toxicities to improve patient comfort. This is a narrative summary of both research and review articles identified by searching PubMed, National Cancer Institute, and American Cancer Society websites. It also assesses recognized guidelines on the management of adjuvant IFN toxicity relevant to nurses who are caring for patients receiving adjuvant IFN therapy. Adjuvant high-dose IFN alfa-2b (HDI) as compared with observation significantly prolongs relapse-free survival in patients with melanoma at high risk for recurrence after surgical resection; however, treatment compliance and patient quality of life can be compromised by its toxicity profile. HDI toxicities affect a number of organ systems and the majority of patients will experience some side effects. Common toxicities such as flu-like symptoms, fatigue, anorexia, neuropsychiatric symptoms, and laboratory abnormalities are discussed, along with both pharmacological and nonpharmacological management strategies. The considerable side effects of HDI can be managed using established strategies. Oncology nurses play a significant role in the management of patients with melanoma receiving adjuvant HDI, and their prompt recognition of side effects, together with an understanding of effective pharmacological and nonpharmacological interventions, will improve patient comfort; this has the potential to positively influence treatment adherence and completion of the recommended treatment course.

  6. Characterization of the Microenvironment in Positive and Negative Sentinel Lymph Nodes from Melanoma Patients.

    Directory of Open Access Journals (Sweden)

    Meriem Messaoudene

    Full Text Available Melanomas are aggressive skin tumors characterized by high metastatic potential. Our previous results indicate that Natural Killer (NK cells may control growth of melanoma. The main defect of blood NK cells was a decreased expression of activating NCR1/NKp46 receptor and a positive correlation of NKp46 expression with disease outcome in stage IV melanoma patients was found. In addition, in stage III melanoma patients, we identified a new subset of mature NK cells in macro-metastatic Lymph nodes (LN. In the present studies, we evaluated the numbers of NK cells infiltrating primary cutaneous melanoma and analyzed immune cell subsets in a series of sentinel lymph nodes (SLN. First, we show that NKp46+ NK cells infiltrate primary cutaneous melanoma. Their numbers were related to age of patients and not to Breslow thickness. Then, a series of patients with tumor-negative or -positive sentinel lymph nodes matched for Breslow thickness of the cutaneous melanoma was constituted. We investigated the distribution of macrophages (CD68, endothelial cells, NK cells, granzyme B positive (GrzB+ cells and CD8+ T cells in the SLN. Negative SLN (SLN- were characterized by frequent adipose involution and follicular hyperplasia compared to positive SLN (SLN+. High densities of macrophages and endothelial cells (CD34, prominent in SLN+, infiltrate SLN and may reflect a tumor favorable microenvironment. Few but similar numbers of NK and GrzB+ cells were found in SLN- and SLN+: NK cells and GrzB+ cells were not correlated. Numerous CD8+ T cells infiltrated SLN with a trend for higher numbers in SLN-. Moreover, CD8+ T cells and GrzB+ cells correlated in SLN- not in SLN+. We also observed that the numbers of CD8+ T cells negatively correlated with endothelial cells in SLN-. The numbers of NK, GrzB+ or CD8+ T cells had no significant impact on overall survival. However, we found that the 5 year-relapse rate was higher in SLN with higher numbers of NK cells.

  7. Ocular Melanoma

    Science.gov (United States)

    ... Español Eye Health / Eye Health A-Z Ocular Melanoma Sections What is Ocular Melanoma? Ocular Melanoma Causes ... Melanoma Diagnosis Ocular Melanoma Treatment What is Ocular Melanoma? Leer en Español: ¿Qué Es el Melanoma Ocular? ...

  8. HOTAIR role in melanoma progression and its identification in the blood of patients with advanced disease.

    Science.gov (United States)

    Cantile, Monica; Scognamiglio, Giosuè; Marra, Laura; Aquino, Gabriella; Botti, Chiara; Falcone, Maria Rosaria; Malzone, Maria Gabriella; Liguori, Giuseppina; Di Bonito, Maurizio; Franco, Renato; Ascierto, Paolo Antonio; Botti, Gerardo

    2017-12-01

    The molecular mechanisms responsible for the metastatic progression of melanoma have not been fully defined yet. We have recently shown that an important role in this process is certainly played by HOX genes, whose regulation is under control of particular non-coding RNAs, some of which are present within the HOX locus. HOTAIR is the most studied among them, whose aberrant expression is associated with the metastatic progression of many malignancies. The aim of this study was to verify the role played by HOTAIR in metastatic progression of melanoma and to evaluate the circulating levels of HOTAIR in the blood of patients with metastatic melanoma. A series of melanocytic lesions were selected to evaluate the potential changes in the expression of HOTAIR during the evolution of the disease through in situ and molecular approaches. None of the benign melanocytic lesions showed the presence of HOTAIR. The staining of HOTAIR resulted very weak in the primary pT1 lesions, while it was very strong in all pairs of primary tissues and corresponding metastases. Surprisingly, we found the presence of HOTAIR in some intratumoral lymphocytes, while this positivity decreased in lymphocyte component further away from the tumor. HOTAIR was also detected in the serum of selected metastatic patients. These data allowed us to speculate on the fundamental role played by HOTAIR in tumor evolution of melanoma. Its presence in intratumoral lymphocytes might suggest that its involvement in the modulation of tumor microenvironment and the detection in the serum could be used in the management of melanoma patients. © 2017 Wiley Periodicals, Inc.

  9. Localized Epidermal Cysts as a Radiation Recall Phenomenon in a Melanoma Patient Treated with Radiotherapy and the BRAF Inhibitor Vemurafenib

    Directory of Open Access Journals (Sweden)

    Carine Houriet

    2014-09-01

    Full Text Available BRAF inhibitors are broadly used for metastatic melanoma with BRAF mutations. Their use results in various cutaneous side effects, such as the development of keratoacanthomas and squamous cell carcinomas. We report a patient with metastatic melanoma treated with vemurafenib who developed dozens of histologically confirmed epidermal cysts within 2 months after initiation of vemurafenib administration. The cystic lesions were observed only in the localized area where a large exophytic melanoma tumor mass had been previously irradiated. Localized epidermal cysts may constitute an unusual radiation recall reaction in patients treated with BRAF inhibitors.

  10. Conjunctival melanoma: survival analysis in twenty-two Mexican patients

    Directory of Open Access Journals (Sweden)

    Rosa Angélica Salcedo-Hernández

    2014-06-01

    Full Text Available Objetivo: Descrever o intervalo livre de doença (DFI e sobrevida global (OS de pacientes com melanoma conjuntival (CM. Método: Prontuários de 22 pacientes que foram internados em dois hospitais entre 1985 e 2006 foram revisados para dados pertinentes, incluindo dados demográficos, local de envolvimento na conjuntiva e outros locais de acometimento, tratamento cirúrgico e tratamento adjuvante. Resultados: Dez (45,45% homens e 12 (54,55% mulheres foram selecionados. A média de idade foi de 52,3 anos. Em 15 pacientes (68,1% CM envolveu a conjuntiva bulbar, e em 7 (31,9% envolveu a conjuntiva palpebral. Dos 22 pacientes, 72,72% tinham história de melanose conjuntival. O tamanho médio do tumor foi de 20,4 mm. Oito (36,36% pacientes foram submetidos à exenteração orbital, 2 (9,06% à enucleação, 5 (22,72% à ampla excisão da lesão seguida de radioterapia, 2 (9,06% à exenteração orbital com esvaziamento cervical e os restantes 5 pacientes (22,72% foram considerados adequadamente tratados apenas com excisão ampla. Oito (36,36% pacientes receberam tratamento adjuvante. Sobrevida livre de doença em 5 anos foi de 51% e sobrevida global em 5 e 10 anos foi de 50% e 37%, respectivamente. Conclusão: Melanoma conjuntival é uma entidade rara. Comportamento do tumor é agressivo, e o melhor tratamento é a cirurgia com terapia adjuvante.

  11. PD-1 Blockade in Advanced Melanoma in Patients with Hepatitis C and/or HIV

    Directory of Open Access Journals (Sweden)

    Diwakar Davar

    2015-01-01

    Full Text Available On the basis of remarkable antitumor activity, programmed death receptor-1 (PD-1 inhibitors pembrolizumab and nivolumab were approved for the treatment of advanced melanoma in the second-line setting following progression on either CTLA-4 inhibitor ipilimumab or BRAF/MEK inhibitors (for BRAF mutated melanoma. Given hypothesized risk of triggering exacerbations of autoimmune diseases and/or chronic viral infections, clinical trials (including regulatory studies evaluating checkpoint blocking antibodies PD-1 and CTLA-4 have excluded patients with autoimmune diseases, chronic hepatitis B/C virus (HBV/HCV, and/or human immunodeficiency virus (HIV infections. Herein, we describe two patients with advanced melanoma and concomitant HCV/HIV infections treated with PD-1 inhibitor pembrolizumab. Patient 2 with HIV/HCV coinfection progressed after 2 doses of pembrolizumab. Patient 1 who had HCV alone was treated with pembrolizumab with initial partial response. HCV viral load remained stable after 9 cycles of pembrolizumab following which 12-week course of HCV-directed therapy was commenced, resulting in prompt reduction of HCV viral load below detectable levels. Response is ongoing and HCV viral load remains undetectable. In both patients, no significant toxicities were observed when pembrolizumab was initiated. We argue for the further investigation of checkpoint inhibition in cancer patients with underlying chronic viral infections in the context of carefully designed clinical trials.

  12. The antibody response against MART-1 differs in patients with melanoma-associated leucoderma and vitiligo.

    Science.gov (United States)

    Teulings, Hansje-Eva; Willemsen, Karin J; Glykofridis, Iris; Krebbers, Gabrielle; Komen, Lisa; Kroon, Marije W; Kemp, E Helen; Wolkerstorfer, Albert; van der Veen, J P Wietze; Luiten, Rosalie M; Tjin, Esther P M

    2014-11-01

    Patients with melanoma may develop skin depigmentation spontaneously or following therapy, referred to as melanoma-associated leucoderma (MAL). As clinical presentation of MAL may precede primary/metastatic melanoma detection, recognition of MAL is important to prevent its misdiagnosis as vitiligo and the subsequent application of immunosuppressive treatment. To reveal the immunity involved in MAL development, we investigated the presence of antibody and T-cell immune responses directed against the melanocyte-differentiation-antigens MART-1 (Melan-A), tyrosinase and gp100 in patients with MAL, as compared to patients with vitiligo. Autoantibodies to gp100 and tyrosinase were commonly found in both diseases. Interestingly, MART-1 antibodies were only present in patients with MAL. Melanocyte antigen-specific T cells were found in all patients, with relatively more specific T cells in patients with active vitiligo. Although MAL and vitiligo may appear clinically similar, our results indicate that the humoral immune responses against MART-1 differ between these diseases, which can help to differentiate MAL from vitiligo.

  13. Melanoma hereditário: prevalência de fatores de risco em um grupo de pacientes no Sul do Brasil Hereditary melanoma: prevalence of risk factors in a group of patients in Southern Brazil

    Directory of Open Access Journals (Sweden)

    Charles André Carvalho

    2004-02-01

    Full Text Available FUNDAMENTOS: Aproximadamente 10% dos casos de melanoma são atribuíveis a mutações em genes de predisposição, sendo, portanto, hereditários. OBJETIVOS: Este estudo avalia a prevalência de fatores de risco para melanoma hereditário em um grupo de pacientes com melanoma no sul do Brasil. CASUÍSTICA E MÉTODOS: Foram estudados 195 pacientes com diagnóstico de melanoma admitidos consecutivamente no Hospital de Clínicas de Porto Alegre entre janeiro de 1999 e junho de 2000. RESULTADOS: A idade média ao diagnóstico de melanoma foi de 48 anos em homens e 44,9 anos em mulheres. Dos 133 pacientes cuja história familiar encontrava-se registrada no prontuário, 13 (9,8% apresentavam história familiar de melanoma. A presença de ao menos um fator de risco importante para predisposição hereditária ao melanoma foi constatada em 31 pacientes (16%; IC 95% 10,9% - 21,1%. CONCLUSÃO: A possibilidade de influência do fator hereditário no Brasil estimula a procura ativa de fatores de risco genético em pacientes com melanoma, já que a identificação de famílias de alto risco pode ter grande impacto sobre a morbimortalidade de seus integrantes.BACKGROUND: Approximately 10% of melanoma cases are attributable to cell line mutations in predisposition genes, and are therefore hereditary. OBJECTIVES: The present study evaluates the prevalence of hereditary melanoma risk factors in a group of patients diagnosed with the disorder in Southern Brazil. PATIENTS AND METHODS: One-hundred and ninety-five patients diagnosed with melanoma who were consecutively admitted to the Hospital de Clinicas de Porto Alegre between January 1999 and June 2000 were studied. RESULTS: The mean age at diagnosis of melanoma was 48 years in men and 45 years in women. From the 133 patients who had their family history registered in the hospital records, 13 (9.8% had a family history of melanoma. The presence of at least one important risk factor for hereditary melanoma was

  14. Shared decision making in dermato-oncology: preference for involvement of melanoma patients.

    Science.gov (United States)

    Albrecht, Karoline J; Nashan, Dorothée; Meiss, Frank; Bengel, Jürgen; Reuter, Katrin

    2014-02-01

    Increasing importance is being conferred to the implementation of shared decision making (SDM) in clinical practice for medical, ethical, and sociological reasons. In Germany, SDM has recently been adopted as an explicit goal in the S3-melanoma treatment guideline. The aim of this study is to present data on how melanoma patients want to be involved in treatment decisions and second on the dynamic of these preferences for involvement. This was investigated in consecutively recruited melanoma patients (stages I-III) in two German Skin Cancer Centers as part of a longitudinal questionnaire study. The Control Preference Scale assessed patients' preferences at baseline (n=405) and was readministered 1 year later (n=314) to detect potential changes. In addition, the perceived realization of SDM in the adjuvant interferon-α treatment decision was investigated in a subgroup of patients (n=108) using the nine-item Shared Decision Making Questionnaire (SDM-Q-9). More than 80% of the patients want to play an active role (autonomous or collaborative) in treatment decisions and only 17% want to delegate their decision to the doctor. We found a significant preference shift within a year in 43% of the patients, predominantly toward more active involvement. The results of the SDM-Q-9 indicate a moderate degree of perceived participation, with differing perceived implementation of the individual the SDM process steps. With the majority of melanoma patients preferring an active role in treatment decisions and improvable implementation of the SDM process steps in clinical practice, our findings support the relevance of SDM in dermato-oncology.

  15. TIL therapy broadens the tumor-reactive CD8+ T cell compartment in melanoma patients

    Science.gov (United States)

    Kvistborg, Pia; Shu, Chengyi Jenny; Heemskerk, Bianca; Fankhauser, Manuel; Thrue, Charlotte Albæk; Toebes, Mireille; van Rooij, Nienke; Linnemann, Carsten; van Buuren, Marit M.; Urbanus, Jos H.M.; Beltman, Joost B.; thor Straten, Per; Li, Yong F.; Robbins, Paul F.; Besser, Michal J.; Schachter, Jacob; Kenter, Gemma G.; Dudley, Mark E.; Rosenberg, Steven A.; Haanen, John B.A.G.; Hadrup, Sine Reker; Schumacher, Ton N.M.

    2012-01-01

    There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8+ T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products. PMID:22754759

  16. TIL therapy broadens the tumor-reactive CD8(+) T cell compartment in melanoma patients.

    Science.gov (United States)

    Kvistborg, Pia; Shu, Chengyi Jenny; Heemskerk, Bianca; Fankhauser, Manuel; Thrue, Charlotte Albæk; Toebes, Mireille; van Rooij, Nienke; Linnemann, Carsten; van Buuren, Marit M; Urbanus, Jos H M; Beltman, Joost B; Thor Straten, Per; Li, Yong F; Robbins, Paul F; Besser, Michal J; Schachter, Jacob; Kenter, Gemma G; Dudley, Mark E; Rosenberg, Steven A; Haanen, John B A G; Hadrup, Sine Reker; Schumacher, Ton N M

    2012-07-01

    There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8(+) T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products.

  17. The diagnostic value of adding dynamic scintigraphy to standard delayed planar imaging for sentinel node identification in melanoma patients

    DEFF Research Database (Denmark)

    Nielsen, Marie Kristina Rue; Chakera, Annette H; Hesse, Birger;

    2011-01-01

    The aim of this study was to compare early dynamic imaging combined with delayed static imaging and single photon emission computed tomography (SPECT)/CT with delayed, planar, static imaging alone for sentinel node (SN) identification in melanoma patients....

  18. Investigating coping strategies and social support among Canadian melanoma patients: A survey approach.

    Science.gov (United States)

    Kalbfleisch, Melanie; Cyr, Annette; Gregorio, Nancy; Nyhof-Young, Joyce

    2015-01-01

    Complex support needs are involved in coping with a diagnosis of melanoma. The purpose of this study was to determine the perceived social support levels and utilization of adaptive and maladaptive coping strategies by Canadian melanoma patients. The impact of social support level on coping strategy utilization was also examined. Social support and coping strategies were assessed using the Medical Outcomes Study Social Support Survey (MOS-SSS) and the 28-item Brief COPE, respectively. Perceived levels of emotional/informational support were significantly lower than affectionate support and positive social interaction. Acceptance, active coping, and use of emotional support were the most frequently utilized coping strategies. Patients with higher perceived levels of social support had significantly higher adaptive coping scores than patients with lower levels of social support. Health care professionals have an important role in promoting awareness of and access to emotional and informational support resources in order to improve perceived social support levels.

  19. Melanoma patients' disease-specific knowledge, information preference, and appreciation of educational YouTube videos for self-inspection.

    Science.gov (United States)

    Damude, S; Hoekstra-Weebers, J E H M; van Leeuwen, B L; Hoekstra, H J

    2017-08-01

    Informing and educating melanoma patients is important for early detection of a recurrence or second primary. This study aimed to investigate Dutch melanoma patients' disease-specific knowledge, and their opinions on information provision and the value of e-Health videos. All AJCC stage I-II melanoma patients in follow-up between March 2015 and March 2016 at a single melanoma center were invited to complete 19 online questions, addressing respondents' characteristics, knowledge on melanoma, and opinions on melanoma-specific information received and the educational YouTube videos. In total, 100 patients completed the survey (response = 52%); median age was 60 years and 51% were female. Breslow tumor thickness was unknown by 34% and incorrectly indicated by 19%, for presence of ulceration this was 33% and 11%, for mitosis 65% and 14%, and for AJCC stage 52% and 23%, respectively. Only 5% correctly reproduced all four tumor characteristics. Orally delivered information regarding warning signs, severity, treatment possibilities, and importance of self-inspection was clearest for patients, compared to information in the melanoma brochure. According to 77% of patients, YouTube videos regarding self-inspection of the skin and regional lymph nodes had additional value. Altogether, 63% preferred receiving information in multiple ways; 92% orally by their physician, 62% through videos, and 43% through brochures. Patients' melanoma-specific knowledge appears to be limited. There is an urgent need for further improvement of providing information and patient education. In addition to oral and written information, e-Health videos seem to be a convenient supplemental and easy accessible method for patient education. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

  20. Mutation Profile of B-Raf Gene Analyzed by fully Automated System and Clinical Features in Japanese Melanoma Patients.

    Science.gov (United States)

    Ide, Masaru; Koba, Shinichi; Sueoka-Aragane, Naoko; Sato, Akemi; Nagano, Yuri; Inoue, Takuya; Misago, Noriyuki; Narisawa, Yutaka; Kimura, Shinya; Sueoka, Eisaburo

    2017-01-01

    BRAF gene mutations have been observed in 30-50 % of malignant melanoma patients. Recent development of therapeutic intervention using BRAF inhibitors requires an accurate and rapid detection system for BRAF mutations. In addition, the clinical characteristics of the melanoma associated with BRAF mutations in Japanese patients have not been investigated on a large scale evaluation. We recently established quenching probe system (QP) for detection of an activating BRAF mutation, V600E and evaluated 113 melanoma samples diagnosed in Saga University Hospital from 1982 to 2011. The QP system includes fully automated genotyping, based on analysis of the probe DNA melting curve, which binds the target mutated site using a fluorescent guanine quenched probe. BRAF mutations were detected in 54 of 115 (47 %) including 51 of V600E and 3 of V600 K in Japanese melanoma cases. Among clinical subtypes of melanoma, nodular melanoma showed high frequency (12 of 15; 80 %) of mutation followed by superficial spreading melanoma (13 of 26; 50 %). The QP system is a simple and sensitive method to determine BRAF V600E mutation, and will be useful tool for patient-oriented therapy with BRAF inhibitors.

  1. [Initial evaluation, diagnosis, staging, treatment, and follow-up of patients with primary cutaneous malignant melanoma. Consensus statement of the Network of Catalan and Balearic Melanoma Centers].

    Science.gov (United States)

    Mangas, C; Paradelo, C; Puig, S; Gallardo, F; Marcoval, J; Azon, A; Bartralot, R; Bel, S; Bigatà, X; Curcó, N; Dalmau, J; del Pozo, L J; Ferrándiz, C; Formigón, M; González, A; Just, M; Llambrich, A; Llistosella, E; Malvehy, J; Martí, R M; Nogués, M E; Pedragosa, R; Rocamora, V; Sàbat, M; Salleras, M

    2010-03-01

    The consensus statement on the management of primary cutaneous melanoma that we present here was based on selection, discussion, review, and comparison of recent literature (including national and international guidelines). The protocols for the diagnosis, treatment, and follow-up used in the hospital centers throughout Catalonia and the Balearic Isles belonging to the Network of Catalan and Balearic Melanoma Centers were also considered. The main objective of this statement was to present the overall management of melanoma patients typically used in our region at the present time. As such, the statement was not designed to be an obligatory protocol for health professionals caring for this group of patients, and neither can it nor should it be used for this purpose. Professionals reading the statement should not therefore consider it binding on their practice, and in no case can this text be used to guarantee or seek responsibility for a given medical opinion. The group of dermatologists who have signed this statement was created 3 years ago with the aim of making our authorities aware of the importance of this complex tumor, which, in comparison with other types of cancer, we believe does not receive sufficient attention in Spain. In addition, the regular meetings of the group have produced interesting proposals for collaboration in various epidemiological, clinical, and basic applied research projects on the subject of malignant melanoma in our society.

  2. Successful desensitization protocol for hypersensitivity reaction probably caused by dabrafenib in a patient with metastatic melanoma.

    Science.gov (United States)

    Bar-Sela, Gil; Abu-Amna, Mahmoud; Hadad, Salim; Haim, Nissim; Shahar, Eduardo

    2015-09-01

    Vemurafenib and dabrafenib are both orally bioavailable small molecule agents that block mitogen activated protein kinase signalling in patients with melanoma and BRAF(V600E) mutation. Generalized hypersensitivity reactions to vemurafenib or dabrafenib have not been described. Continuing vemurafenib or dabrafenib therapy despite hypersensitivity reaction is especially important in patients with melanoma and BRAF(V600E) mutation, in whom this mutation plays a critical role in tumour growth. Desensitization protocols to overcome hypersensitivity reactions by gradual reintroduction of small amounts of the offending drug up to full therapeutic doses are available for many anti-cancer agents, including vemurafenib but, to the best of our knowledge, have not been reported for dabrafenib. We describe a patient with metastatic melanoma who developed Type I hypersensitivity reaction to vemurafenib and to subsequent treatment with dabrafenib, and who was successfully treated by drug desensitization which allowed safe prolonged continuation of dabrafenib. The development of hypersensitivity reactions for both dabrafenib and vemurafinib in the current case could be because these drugs have a similar chemical structure and cause a cross-reactivity. However, hypersensitivity reaction to a non-medicinal ingredient shared by the two drugs is also possible. Oral desensitization appears to be an option for patients with hypersensitivity Type I to dabrafenib. This approach may permit clinicians to safely administer dabrafenib to patients who experience hypersensitivity reactions to this life-prolonging medication. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Multiple primary cutaneous melanomas in patients with FAMMM syndrome and sporadic atypical mole syndrome (AMS): what's worse?

    Science.gov (United States)

    Tchernev, Georgi; Ananiev, Julian; Cardoso, José-Carlos; Chokoeva, Anastasiya Atanasova; Philipov, Stanislav; Penev, Plamen Kolev; Lotti, Torello; Wollina, Uwe

    2014-08-01

    Atypical Mole Syndrome is the most important phenotypic risk factor for cutaneous melanoma, a malignancy that accounts for about 80% of deaths from skin cancer. Since early diagnosis of melanoma is of great prognostic relevance, the identification of Atypical Mole Syndrome carriers (sporadic and familial) is essential, as well as the recommendation of preventative measures that must be undertaken by these patients.We report two rare cases concerning patients with multiple primary skin melanomas in the setting of a familial and a sporadic syndrome of dysplastic nevi: the first patient is a 67-year-old patient with a history of multiple superficial spreading melanomas localized on his back. The second patient presented with multiple primary melanomas in advanced stage in the context of the so-called sporadic form of the syndrome of dysplastic nevi-AMS (atypical mole syndrome). In the first case, excision of the melanomas was carried out with an uneventful post-operative period. In the second case, disseminated metastases were detected, involving the right fibula, the abdominal cavity as well as multiple lesions in the brain. The patient declined BRAF mutation tests as well as chemotherapy or targeted therapies, and suffered a rapid deterioration in his general condition leading to death. We classified the second case as a sporadic form of the atypical mole syndrome, associated with one nodular and two superficial spreading melanomas.There are no data in the literature to allow us to understand if, in patients with multiple primary melanomas, there is any difference in terms of prognosis between those with and without a family history of a similar phenotype. To answer this and other questions related to these rare cases, further studies with a significant number of patients should be carried out.

  4. The diagnostic value of adding dynamic scintigraphy to standard delayed planar imaging for sentinel node identification in melanoma patients

    DEFF Research Database (Denmark)

    Nielsen, Marie Kristina Rue; Chakera, Annette H; Hesse, Birger;

    2011-01-01

    The aim of this study was to compare early dynamic imaging combined with delayed static imaging and single photon emission computed tomography (SPECT)/CT with delayed, planar, static imaging alone for sentinel node (SN) identification in melanoma patients.......The aim of this study was to compare early dynamic imaging combined with delayed static imaging and single photon emission computed tomography (SPECT)/CT with delayed, planar, static imaging alone for sentinel node (SN) identification in melanoma patients....

  5. Prolonged survival of a patient with metastatic leptomeningeal melanoma treated with BRAF inhibition-based therapy: a case report

    OpenAIRE

    Kim, Dae Won; Barcena, Edelyn; Mehta, Urvi N.; Rohlfs, Michelle L; Kumar, Ashok J.; Penas-Prado, Marta; Kim, Kevin B

    2015-01-01

    Background Leptomeningeal metastasis of melanoma is a devastating complication with a grave prognosis, and there are no known effective standard treatments. Although selective BRAF inhibitors have demonstrated a significant clinical activity in patients with metastatic melanoma harboring a BRAF mutation, the clinical benefit of BRAF inhibitor-based therapy in leptomeningeal disease is not clear. Case presentation We present a case of prolonged survival of a patient with BRAF V600E-mutant lept...

  6. Malignant Melanoma

    Directory of Open Access Journals (Sweden)

    Eshini Perera

    2013-12-01

    Full Text Available Melanomas are a major cause of premature death from cancer. The gradual decrease in rates of morbidity and mortality has occurred as a result of public health campaigns and improved rates of early diagnosis. Survival of melanoma has increased to over 90%. Management of melanoma involves a number of components: excision, tumor staging, re-excision with negative margins, adjuvant therapies (chemo, radiation or surgery, treatment of stage IV disease, follow-up examination for metastasis, lifestyle modification and counseling. Sentinel lymph node status is an important prognostic factor for survival in patients with a melanoma >1 mm. However, sentinel lymph node biopsies have received partial support due to the limited data regarding the survival advantage of complete lymph node dissection when a micrometastasis is detected in the lymph nodes. Functional mutations in the mitogen-activated pathways are commonly detected in melanomas and these influence the growth control. Therapies that target these pathways are rapidly emerging, and are being shown to increase survival rates in patients. Access to these newer agents can be gained by participation in clinical trials after referral to a multidisciplinary team for staging and re-excision of the scar.

  7. ELEVATED SERUM S-100B LEVELS WITH NEGATIVE PET/TC AND CT-SCAN IN A METASTATIC MELANOMA PATIENT.

    Directory of Open Access Journals (Sweden)

    Francesco Spagnolo

    2012-01-01

    Full Text Available The incidence of melanoma is increasing worldwide. Prognosis for metastatic melanoma is poor; early detection of recurrent or metastatic disease may improve therapy strategies and survival. Several possible biomarkers for melanoma have been investigated. S-100B was found to be a sensitive and specific serological tumor marker; furthermore, its concentrations are correlated with the clinical stage of disease. Serum S-100B is also an independent prognostic factor for survival and can be used to monitor response to treatment. We present the case of a 55 year old woman, whose diagnosis of melanoma distant metastases was suggested by a progressive increase in serum S-100B levels, while other blood tests, physical exam and imaging techniques, including PET/TC and CT-scan, were negative. S-100B is currently the most accurate biomarker in melanoma patients; its role in the management of melanoma patients has been the object of study and it has been documented as a valuable independent prognostic factor. The case we present shows that S-100B levels may also be useful in the early detection of melanoma recurrences, even when imaging techniques are negative.

  8. Immunological correlates of treatment and response in stage IV malignant melanoma patients treated with Ipilimumab

    DEFF Research Database (Denmark)

    Bjoern, Jon; Nitschke, Nikolaj Juul; Zeeberg Iversen, Trine;

    2016-01-01

    Introduction: Ipilimumab is effective in the treatment of metastatic malignant melanoma, but few biomarkers reliably predict treatment response. Methods: Patients were treated with Ipilimumab for metastatic malignant melanoma. Blood and serum samples were collected before and during treatment....... Mononuclear cells in peripheral blood were subjected to immune phenotypic analyses and cytokine levels were measured in serum samples. Results were correlated with clinical data. Results: A total of 40 patients were included in the analyses. Clinical response were associated with an increase after one series...... of treatment in absolute lymphocyte count (ALC) (p = 0.008), absolute T cell count (p = 0.02) and the absolute number of activated T cells in peripheral blood (p = 0.003). A high frequency of myeloid derived suppressor cells (MDSC) and a higher level of IL6 were associated with treatment failure, though...

  9. Elevated Levels of SOX10 in Serum from Vitiligo and Melanoma Patients, Analyzed by Proximity Ligation Assay.

    Directory of Open Access Journals (Sweden)

    Andries Blokzijl

    Full Text Available The diagnosis of malignant melanoma currently relies on clinical inspection of the skin surface and on the histopathological status of the excised tumor. The serum marker S100B is used for prognostic estimates at later stages of the disease, but analyses are marred by false positives and inadequate sensitivity in predicting relapsing disorder.To investigate SOX10 as a potential biomarker for melanoma and vitiligo.In this study we have applied proximity ligation assay (PLA to detect the transcription factor SOX10 as a possible serum marker for melanoma. We studied a cohort of 110 melanoma patients. We further investigated a second cohort of 85 patients with vitiligo, which is a disease that also affects melanocytes.The specificity of the SOX10 assay in serum was high, with only 1% of healthy blood donors being positive. In contrast, elevated serum SOX10 was found with high frequency among vitiligo and melanoma patients. In patients with metastases, lack of SOX10 detection was associated with treatment benefit. In two responding patients, a change from SOX10 positivity to undetectable levels was seen before the response was evident clinically.We show for the first time that SOX10 represents a promising new serum melanoma marker for detection of early stage disease, complementing the established S100B marker. Our findings imply that SOX10 can be used to monitor responses to treatment and to assess if the treatment is of benefit at stages earlier than what is possible radiologically.

  10. Respuesta completa tras tratamiento con bioquimioterapia en un caso de melanoma cutáneo diseminado Complete response in a patient with a metastatic cutaneous melanoma

    Directory of Open Access Journals (Sweden)

    M.J. Bermejo-Pérez

    2011-08-01

    Full Text Available Fundamento. El pronóstico del melanoma diseminado es muy sombrío. Actualmente no hay consenso sobre el tratamiento estándar en primera línea para el melanoma metastático. Se presenta un caso por su comportamiento excepcional. Resultados. Varón de 43 años diagnosticado en 1999 de melanoma maligno estadio IIA. En mayo de 2000 se objetivaron metástasis hepáticas y esplénicas. Recibió 6 ciclos de bioquimioterapia (cisplatino y DTIC junto con interleukina-2 e interferón-α cada 21 días y otros 6 ciclos con inmunoterapia sola (interleukina-2 e interferón-α. Actualmente el paciente sigue vivo y sin evidencia de enfermedad. Conclusión. El melanoma cutáneo metastático, en ocasiones, presenta una inusual evolución favorable. Es de esperar que los métodos de detección de marcadores moleculares logren determinar factores implicados en este tipo de respuesta y que los nuevos tratamientos dirigidos consigan mantener esta tendencia positiva.Background. The management of patients with disseminated disease is a difficult problem. There is currently no consensus on the standard first-line treatment for metastatic melanoma. We present a case because of his exceptional evolution. Results. A 43 year old male diagnosed in 1999 with malignant melanoma stage IIA. In May 2000, hepatic and splenic metastases were detected. He received 6 cycles of biochemotherapy (cisplatin and DTIC, plus interleukin-2 and interferon-α and another 6 cycles with single immunotherapy (interleukin-2 and interferon-α. Today, the patient is still alive and without evidence of disease. Conclusion. Metastatic cutaneous melanoma, sometimes, presents and unusual and favourable evolution. In the near future, the methods of detection of molecular markers are expected to identify factors involved in this type of response. Furthermore, new targeted therapies may become essential to maintain this positive trend.

  11. Neurotropic melanoma with prominent melanization.

    Science.gov (United States)

    Barnhill, R L; Bolognia, J L

    1995-10-01

    Neurotropic melanoma has generally been described in the context of desmoplastic melanoma. The vast majority of melanomas displaying neurotropism contain relatively little or no melanin. Herein, we report an unusual case of neurotropic melanoma with prominent melanin content. The patient developed a tumor notable for pagetoid (superficial spreading) melanoma with partial regression and a deep component characterized by perineurial aggregates of melanophages and intraneural infiltration by melanoma cells. This case serves to alert dermatopathologists to the fact that the spectrum of neurotropic melanoma includes tumors with perineurial aggregates of pigment-containing cells.

  12. Sentinel node biopsy for melanoma. Analysis of our experience (125 patients).

    Science.gov (United States)

    Soliveres Soliveres, Edelmira; García Marín, Andrés; Díez Miralles, Manuel; Nofuentes Riera, Carmen; Candela Gomis, Asunción; Moragón Gordon, Manuel; Antón Leal, María Ángeles; García García, Salvador

    2014-11-01

    The objective of this study is to analyze our experience in the use of sentinel node biopsy (SNB) in melanoma and identify the predictive factors of positive SNB and multiple drainage. Retrospective study of patients who underwent SNB for melanoma between August of 2000 and February of 2013. SNB was performed in 125 patients with a median of age of 55,6 (±15) years. The anatomic distribution was: 44 (35,2%) in legs, 24 (19,2%) in arms, 53 (42,4%) trunk and 3 (2,4%) in head and neck. The median Breslow index was 1,81 (0,45-5). Between 1 and 6 nodes were isolated. The drainage was unique in 98 (78,4%) and multiple in 27 (21,6%). The trunk was the localization of 25 (92,6%) nodes with multiple drainage. The definitive result of sentinel node (SN) was positive in 18 cases (7,1%). Breslow thickness (p=0,01) was statistically significant predictor of a positive SNB. The SNB allows patients to be selected for lymphadenectomy. Melanoma of the trunk was the principle location of multiple drainage. The only predictive factor of positive SNB was Breslow thickness. Copyright © 2013 AEC. Published by Elsevier Espana. All rights reserved.

  13. BRAFV600E Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts

    Directory of Open Access Journals (Sweden)

    Kristel Kemper

    2016-06-01

    Full Text Available The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs, derived from BRAFV600E, NRASQ61, or BRAFWT/NRASWT melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAFV600E protein harboring a kinase domain duplication (BRAFV600E/DK in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAFV600E/DK depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAFV600E/DK-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.

  14. Which melanoma patient carries a BRAF-mutation? A comparison of predictive models

    Science.gov (United States)

    Eigentler, Thomas; Assi, Zeinab; Hassel, Jessica C.; Heinzerling, Lucie; Starz, Hans; Berneburg, Mark; Bauer, Jürgen; Garbe, Claus

    2016-01-01

    Background In patients with advanced melanoma the detection of BRAF mutations is considered mandatory before the initiation of an expensive treatment with BRAF/MEK inhibitors. Sometimes it is difficult to perform such an analysis if archival tumor tissue is not available and fresh tissue has to be collected. Results 514 of 1170 patients (44%) carried a BRAF mutation. All models revealed age and histological subtype of melanoma as the two major predictive variables. Accuracy ranged from 0.65–0.71, being best in the random forest model. Sensitivity ranged 0.76–0.84, again best in the random forest model. Specificity was low in all models ranging 0.51–0.55. Methods We collected the clinical data and mutational status of 1170 patients with advanced melanoma and established three different predictive models (binary logistic regression, classification and regression trees, and random forest) to forecast the BRAF status. Conclusions Up to date statistical models are not able to predict BRAF mutations in an acceptable accuracy. The analysis of the mutational status by sequencing or immunohistochemistry must still be considered as standard of care. PMID:27150060

  15. BRAF Mutation (V600E Prevalence in Mexican Patients Diagnosed with Melanoma

    Directory of Open Access Journals (Sweden)

    Priscilla Denise Zepeda-Lopez

    2016-04-01

    Full Text Available Background: B-Raf is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. It has been shown that 50% of melanomas harbor activating BRAF mutations, with over 90% being the V600E mutation. Objective: The goal of this research was to determine the prevalence of the BRAF V600E mutation in patients from Central Mexico diagnosed with primary melanoma. Methods: Skin biopsies from 47 patients with melanoma were obtained from the dermatology department of the Hospital General ‘Dr. Manuel Gea González' in Mexico City. For BRAF mutation determination, after DNA isolation, the gene region where the mutation occurs was amplified by PCR. Subsequently, the presence or absence of the V600E mutation was detected by Sanger sequencing performed at the private molecular diagnostic laboratory Vitagénesis in Monterrey, Mexico. Results: Of the 47 patients sampled, 6.4% harbored the V600E mutation. No statistical significance was found between mutations and the type of tumor.

  16. Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma.

    Science.gov (United States)

    Ott, Patrick A; Carvajal, Richard D; Pandit-Taskar, Neeta; Jungbluth, Achim A; Hoffman, Eric W; Wu, Bor-Wen; Bomalaski, John S; Venhaus, Ralph; Pan, Linda; Old, Lloyd J; Pavlick, Anna C; Wolchok, Jedd D

    2013-04-01

    Background Arginine deiminase (ADI) is an enzyme that degrades arginine, an amino acid that is important for growth and development of normal and neoplastic cells. Melanoma cells are auxotrophic for arginine, because they lack argininosuccinatesynthetase (ASS), a key enzyme required for the synthesis of arginine. Patients and methods Patients with advanced melanoma were treated with 40, 80 or 160 IU/m(2) ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by (18)FDG-PET, pharmacodynamic (PD) effects upon circulating arginine levels, and argininosuccinate synthetase tumor expression by immunohistochemistry. Results 31 previously treated patients were enrolled. The main toxicities were grade 1 and 2 adverse events including injection site pain, rash, and fatigue. No objective responses were seen. Nine patients achieved stable disease (SD), with 2 of these durable for >6 months. Four of the 9 patients with SD had uveal melanoma. PD analysis showed complete plasma arginine depletion in 30/31 patients by day 8. Mean plasma levels of ADI-PEG 20 correlated inversely with ADI-PEG 20 antibody levels. Immunohistochemical ASS expression analysis in tumor tissue was negative in 24 patients, whereas 5 patients had arginine depletion. Although no RECIST responses were observed, the encouraging rate of SD in uveal melanoma patients indicates that it may be worthwhile to evaluate ADI-PEG 20 in this melanoma subgroup.

  17. A systematic review of health-related quality of life in cutaneous melanoma.

    NARCIS (Netherlands)

    D. Cornish; C. Holterhues (Cynthia); L.V. van de Poll-Franse (Lonneke); J.W.W. Coebergh (Jan Willem); T.E.C. Nijsten (Tamar)

    2009-01-01

    textabstractMelanoma can be considered an emerging chronic disease that may considerably affect patients' lives. The authors systematically reviewed the available literature on health-related quality of life (HRQOL) and melanoma. Of reviews and the selected studies, reference lists were hand-searche

  18. Sentinel lymph node biopsy: is it possible to reduce false negative rates by excluding patients with nodular melanoma?

    LENUS (Irish Health Repository)

    Corrigan, M A

    2012-02-03

    OBJECTIVE: The aim of this study was to review the outcome of sentinel lymph node biopsy (SLNB) in patients with melanoma and to delineate whether patients with nodular melanoma are more likely to develop nodal recurrence despite negative SLNB. METHODS: Consecutive patients with cutaneous melanoma undergoing SLNB were identified from a departmental database between 1997 and 2005. Factors including demographic data, site, histological subtype, depth and outcome were examined. RESULTS: Of 131 patients, 103 were node negative and eligible for study. The median age was 53 (16-82) years with 46 patients being male (45%) and 57 female (55%). Primary melanoma sites included lower limb (49; 48%), upper limb (29; 28%), head (12; 11%), trunk (7; 7%) and back (6; 6%). The median Breslow thickness was 2mm. Superficial spreading accounted for 43% of melanoma with nodular accounting for 42%. Median follow-up was 40 (3-90) months. Of 20 relapses, seven recurred in the same nodal basin, three were satellite recurrences, one recurred with both satellite and nodal lesions simultaneously, and nine experienced haematogenous spread. Of the eight patients who developed recurrence in the same nodal basin, four were of nodular histological subtype (p=NS). All of the three patients with satellite lesions had nodular melanoma histologically (p=0.02). When nodal and satellite recurrences were combined, eight of 11 were histologically nodular (p=0.01). CONCLUSIONS: This study indicates that lymphatic recurrence occurs more often in SLNB negative patients with nodular melanoma. Further evaluation of the inclusion criteria for sentinel node biopsy is warranted.

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

    Science.gov (United States)

    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

    2015-12-01

    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. Dabrafenib Plus Trametinib for Advanced Melanoma

    Science.gov (United States)

    A summary of results from two phase III trials show that patients with metastatic melanoma whose tumors have specific mutations in the BRAF gene lived longer following treatment with dabrafenib (Tafinlar®), a BRAF inhibitor, plus trametinib (Mekinist®), a

  1. A dermatological questionnaire for general practitioners in England with a focus on melanoma; misdiagnosis in black patients compared to white patients.

    Science.gov (United States)

    Lyman, M; Mills, J O; Shipman, A R

    2017-04-01

    Malignant melanoma presents a significant health burden in the UK in terms of mortality and financial cost. This aggressive and often fatal disease is under-diagnosed among patients with darker skin tones (type 5 and 6) such as Afro-Caribbean patients. A lack of both patient and practitioner awareness leads to a later diagnosis in patients with black compared to white skin. There is currently a paucity of literature looking at the diagnosis rates of melanoma between patients of different ethnicities in the UK and the reasons behind these differences. The primary aim was to obtain data on the diagnosis rate of melanoma in the primary care setting, with particular attention to white vs. black skin types. An online questionnaire was sent to 2975 general practitioner (GP) practices in England and 287 responses were received. The questionnaire contained 20 high-quality picture questions of differing common skin conditions. The participants were asked to choose their diagnosis from 20 potential diagnoses. Only 4/20 questions were melanomas, two on white and two on black skin. No accompanying histories were provided. The mean score for the questionnaire was 11.6/20 (58%) with a range from 5% to 100%. Of the two black skin melanoma pictures, 177/287 (62%) and 90/287 (31%) responses were incorrectly identified, compared to 37/287 (13%) and 19/287 (7%) in the white skin melanoma pictures. The questionnaire results show a clear increased misdiagnosis of melanoma in black patients in primary care vs. white. The results suggest that vigilance is needed when diagnosing possible melanoma in black patients and better quality melanoma teaching is required in GP training concentrating on pigmented skin. This pilot study should encourage more research into ethnic skin inequalities in the UK. © 2016 European Academy of Dermatology and Venereology.

  2. Prediction of positron emission tomography/computed tomography (PET/CT) positivity in patients with high-risk primary melanoma

    Science.gov (United States)

    Danielsen, Maria; Kjaer, Andreas; Wu, Max; Martineau, Lea; Nosrati, Mehdi; Leong, Stanley PL; Sagebiel, Richard W; III, James R Miller; Kashani-Sabet, Mohammed

    2016-01-01

    Positron emission tomography/computed tomography (PET/CT) is an important tool to identify occult melanoma metastasis. To date, it is controversial which patients with primary cutaneous melanoma should have staging PET/CT. In this retrospective analysis of more than 800 consecutive patients with cutaneous melanoma, we sought to identify factors predictive of PET/CT positivity in the setting of newly-diagnosed high-risk primary melanoma to determine those patients most appropriate to undergo a PET/CT scan as part of their diagnostic work up. 167 patients with newly-diagnosed high-risk primary cutaneous melanoma underwent a PET/CT scan performed as part of their initial staging. Clinical and histologic factors were evaluated as possible predictors of melanoma metastasis identified on PET/CT scanning using both univariate and multivariate logistic regression. In all, 32 patients (19.2%) had a positive PET/CT finding of metastatic melanoma. In more than half of these patients (56.3%), PET/CT scanning identified disease that was not detectable on clinical examination. Mitotic rate, tumor thickness, lymphadenopathy, and bleeding were significantly predictive of PET/CT positivity. A combinatorial index constructed from these factors revealed a significant association between number of high-risk factors observed and prevalence of PET/CT positivity, which increased from 5.8% (with the presence of 0-2 factors) to 100.0%, when all four factors were present. These results indicate that combining clinical and histologic prognostic factors enables the identification of patients with a higher likelihood of a positive PET/CT scan.

  3. The Danish Melanoma Database

    DEFF Research Database (Denmark)

    Hölmich, Lisbet Rosenkrantz; Klausen, Siri; Spaun, Eva

    2016-01-01

    AIM OF DATABASE: The aim of the database is to monitor and improve the treatment and survival of melanoma patients. STUDY POPULATION: All Danish patients with cutaneous melanoma and in situ melanomas must be registered in the Danish Melanoma Database (DMD). In 2014, 2,525 patients with invasive......, nature, and treatment hereof is registered. In case of death, the cause and date are included. Currently, all data are entered manually; however, data catchment from the existing registries is planned to be included shortly. DESCRIPTIVE DATA: The DMD is an old research database, but new as a clinical...

  4. FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients.

    Science.gov (United States)

    Streit, S; Mestel, D S; Schmidt, M; Ullrich, A; Berking, C

    2006-06-19

    A single nucleotide polymorphism in the gene for FGFR4 (-Arg388) has been associated with progression in various types of human cancer. Although fibroblast growth factors (FGFs) belong to the most important growth factors in melanoma, expression of FGF receptor subtype 4 has not been investigated yet. In this study, the protein expression of this receptor was analysed in 137 melanoma tissues of different progression stages by immunohistochemistry. FGFR4 protein was expressed in 45% of the specimens and correlated with pTNM tumour stages (UICC, P = 0.023 and AJCC, P = 0.046), presence of microulceration (P = 0.009), tumour vascularity (P = 0.001), metastases (P = 0.025), number of primary tumours (P = 0.022), overall survival (P = 0.047) and disease-free survival (P = 0.024). Furthermore, FGFR4 Arg388 polymorphism was analysed in 185 melanoma patients by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The Arg388 allele was detected in 45% of the melanoma patients and was significantly associated with tumour thickness (by Clark's level of invasion (P = 0.004) and by Breslow in mm (P = 0.02)) and the tumour subtype nodular melanoma (P = 0.002). However, there was no correlation of the FGFR4 Arg388 allele with overall and disease-free survival. In conclusion, the Arg388 genotype and the protein expression of FGFR4 may be potential markers for progression of melanoma.

  5. Mek inhibition results in marked antitumor activity against metastatic melanoma patient-derived melanospheres and in melanosphere-generated xenografts.

    Science.gov (United States)

    Sette, Giovanni; Fecchi, Katia; Salvati, Valentina; Lotti, Fiorenza; Pilozzi, Emanuela; Duranti, Enrico; Biffoni, Mauro; Pagliuca, Alfredo; Martinetti, Daniela; Memeo, Lorenzo; Milella, Michele; De Maria, Ruggero; Eramo, Adriana

    2013-11-16

    One of the key oncogenic pathways involved in melanoma aggressiveness, development and progression is the RAS/BRAF/MEK pathway, whose alterations are found in most patients. These molecular anomalies are promising targets for more effective anti-cancer therapies. Some Mek inhibitors showed promising antitumor activity, although schedules and doses associated with low systemic toxicity need to be defined. In addition, it is now accepted that cancers can arise from and be maintained by the cancer stem cells (CSC) or tumor-initiating cells (TIC), commonly expanded in vitro as tumorspheres from several solid tumors, including melanoma (melanospheres). Here, we investigated the potential targeting of MEK pathway by exploiting highly reliable in vitro and in vivo pre-clinical models of melanomas based on melanospheres, as melanoma initiating cells (MIC) surrogates. MEK inhibition, through PD0325901, provided a successful strategy to affect survival of mutated-BRAF melanospheres and growth of wild type-BRAF melanospheres. A marked citotoxicity was observed in differentated melanoma cells regardless BRAF mutational status. PD0325901 treatment, dramatically inhibited growth of melanosphere-generated xenografts and determined impaired tumor vascularization of both mutated- and wild type-BRAF tumors, in the absence of mice toxicity. These results suggest that MEK inhibition might represent a valid treatment option for patients with both mutated- or wild type-BRAF melanomas, affecting tumor growth through multiple targets.

  6. [Sentinel lymph node biopsy in melanoma patients: methods, indications, and clinical significance].

    Science.gov (United States)

    Kaikaris, Vygintas; Valiukeviciene, Skaidra; Rimdeika, Rytis; Gollnick, Harald; Ulrich, Jens

    2003-01-01

    The incidence of melanoma in Lithuania has doubled over the last decade. Sentinel lymph node biopsy, currently becoming a standard method in the US and Europe, is a minimal invasive and highly sensitive surgical procedure. It can be used for the detection of melanoma micrometastasis in regional lymph nodes in cases when non-invasive methods fail to reveal them. Both disease-free survival and disease-specific survival were significantly better for patients with a negative sentinel lymph node biopsy. A. Breslow thickness, W. H. Clark level, and ulceration of the melanoma were strong predictors, but not as strong as the histological status of the sentinel lymph node. The procedure for sentinel lymph node biopsy is nowadays standardized, including preoperative dynamic lymphoscintigraphy combined with intraoperative gamma probe guidance and blue-dye injection. The aim of this article is to present an update of the sentinel lymph node biopsy method and the prognostic significance of this procedure on the basis of more than 400 sentinel lymph node biopsy's carried out at the Department of Dermatology of the Otto-von-Guericke University, Magdeburg since 1997 and the results of recently published studies in the literature.

  7. Cytotoxicity of lymphocytes from melanoma patients against autologous tumor cells and its potentiation in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Bykovskaya, S.N.; Iobadze, M.S.; Kupriyanova, T.A.; Demidov, L.V.

    1987-06-01

    The specific and natural cytotoxicity of peripheral blood lymphocytes from patients with melanomas was compared and stimulation with autologous tumor cells or a pool of allogeneic lymphocytes from five healthy blood donors also was used to potentiate the specific antitumor activity of the patients' lymphocytes. To assess cytolytic ability, cells of an autologous tumor, cells of the K-562 line, autologous peripheral blood lymphocytes, and blast cells obtained from these lymphocytes after stimulation by phytohemagglutinin were used as the target cells. The target cells were incubated in a medium containing sodium chromate and were labelled with the chromium 51 isotope.

  8. Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of patients with melanoma

    Directory of Open Access Journals (Sweden)

    Gualberto Antonio

    2008-05-01

    Full Text Available Abstract Background CTLA4-blocking antibodies induce tumor regression in a subset of patients with melanoma. Analysis of immune parameters in peripheral blood may help define how responses are mediated. Methods Peripheral blood from HLA-A*0201-positive patients with advanced melanoma receiving tremelimumab (formerly CP-675,206 at 10 mg/kg monthly was repeatedly sampled during the first 4 cycles. Samples were analyzed by 1 tetramer and ELISPOT assays for reactivity to CMV, EBV, MART1, gp100, and tyrosinase; 2 activation HLA-DR and memory CD45RO markers on CD4+/CD8+ cells; and 3 real-time quantitative PCR of mRNA for FoxP3 transcription factor, preferentially expressed by T regulatory cells. The primary endpoint was difference in MART1-specific T cells by tetramer assay. Immunological data were explored for significant trends using clustering analysis. Results Three of 12 patients eligible for immune monitoring had tumor regression lasting > 2 years without relapse. There was no significant change in percent of MART1-specific T cells by tetramer assay. Additionally, there was no generalized trend toward postdosing changes in other antigen-specific CD8+ cell populations, FoxP3 transcripts, or overall changes in surface expression of T-cell activation or memory markers. Unsupervised hierarchical clustering based on immune monitoring data segregated patients randomly. However, clustering according to T-cell activation or memory markers separated patients with clinical response and most patients with inflammatory toxicity into a common subgroup. Conclusion Administration of CTLA4-blocking antibody tremelimumab to patients with advanced melanoma results in a subset of patients with long-lived tumor responses. T-cell activation and memory markers served as the only readout of the pharmacodynamic effects of this antibody in peripheral blood. Clinical trial registration number NCT00086489

  9. The Danish Melanoma Database

    DEFF Research Database (Denmark)

    Hölmich, Lisbet Rosenkrantz; Klausen, Siri; Spaun, Eva;

    2016-01-01

    AIM OF DATABASE: The aim of the database is to monitor and improve the treatment and survival of melanoma patients. STUDY POPULATION: All Danish patients with cutaneous melanoma and in situ melanomas must be registered in the Danish Melanoma Database (DMD). In 2014, 2,525 patients with invasive...... melanoma and 780 with in situ tumors were registered. The coverage is currently 93% compared with the Danish Pathology Register. MAIN VARIABLES: The main variables include demographic, clinical, and pathological characteristics, including Breslow's tumor thickness, ± ulceration, mitoses, and tumor...... quality register. The coverage is high, and the performance in the five Danish regions is quite similar due to strong adherence to guidelines provided by the Danish Melanoma Group. The list of monitored indicators is constantly expanding, and annual quality reports are issued. Several important scientific...

  10. Sentinel Lymph Node Detection Using Laser-Assisted Indocyanine Green Dye Lymphangiography in Patients with Melanoma

    Directory of Open Access Journals (Sweden)

    Vikalp Jain

    2013-01-01

    Full Text Available Introduction. Sentinel lymph node (SLN biopsy is a vital component of staging and management of multiple cancers. The current gold standard utilizes technetium 99 (tech99 and a blue dye to detect regional nodes. While the success rate is typically over 90%, these two methods can be inconclusive or inconvenient for both patient and surgeon. We evaluated a new technique using laser-assisted ICG dye lymphangiography to identify SLN. Methods. In this retrospective analysis, we identified patients with melanoma who were candidates for SLN biopsy. In addition to tech99 and methylene blue, patients received a dermal injection of indocyanine green (ICG. The infrared signal was detected with the SPY machine (Novadaq, and nodes positive by any method were excised. Results. A total of 15 patients were evaluated, with 40 SLNs removed. Four patients were found to have nodal metastases on final pathology. 100% of these 4 nodes were identified by ICG, while only 75% (3/4 were positive for tech99 and/or methylene blue. Furthermore, none of the nodes missed by ICG (4/40 had malignant cells. Conclusion. ICG dye lymphangiography is a reasonable alternative for locating SLNs in patients with melanoma. Prospective studies are needed to better ascertain the full functionality of this technique.

  11. Surgical treatment of iris and ciliary body melanoma: follow-up of a 25-year series of patients

    DEFF Research Database (Denmark)

    Klauber, Stefan; Jensen, Peter K; Prause, Jan U

    2010-01-01

    had died of melanoma-related causes. Only one patient had a local recurrence, which was successfully treated by cryotherapy. The quality of life-related questions demonstrated that most patients (40) suffered from photophobia, and eight patients had changed their driving habits, not driving at night...

  12. microRNA Expression in Sentinel Nodes from Progressing Melanoma Patients Identifies Networks Associated with Dysfunctional Immune Response

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    Viviana Vallacchi

    2016-12-01

    Full Text Available Sentinel node biopsy (SNB is a main staging biomarker in melanoma and is the first lymph node to drain the tumor, thus representing the immunological site where anti-tumor immune dysfunction is established and where potential prognostic immune markers can be identified. Here we analyzed microRNA (miR profiles in archival tumor-positive SNBs derived from melanoma patients with different outcomes and performed an integrated analysis of transcriptional data to identify deregulated immune signaling networks. Twenty-six miRs were differentially expressed in melanoma-positive SNB samples between patients with disease progression and non-progressing patients, the majority being previously reported in the regulation of immune responses. A significant variation in miR expression levels was confirmed in an independent set of SNB samples. Integrated information from genome-wide transcriptional profiles and in vitro assessment in immune cells led to the identification of miRs associated with the regulation of the TNF receptor superfamily member 8 (TNFRSF8 gene encoding the CD30 receptor, a marker increased in lymphocytes of melanoma patients with progressive disease. These findings indicate that miRs are involved in the regulation of pathways leading to immune dysfunction in the sentinel node and may provide valuable markers for developing prognostic molecular signatures for the identification of stage III melanoma patients at risk of recurrence.

  13. A comparison of noninvasive imaging modalities in the melanoma patient

    Energy Technology Data Exchange (ETDEWEB)

    Doiron, M.J.; Bernardino, M.E.

    1981-06-01

    The results of radionuclide (RN) liver scans, computed tomography (CT), and ultrasonography (US) were compared in 163 patients. Thirty-eight patients had all three studies, while ten were examined by CT and RN liver scans. One hundred fifteen patients had only US and RN studies. Radionuclide liver scanning demonstrated more false positive and negative studies than CT or US. Also, CT and US demonstrated more areas of metastasis during a single examination than RN liver scans. Ultrasonography displayed roughly the same accuracy of CT when a technically adequate examination was obtained. However, US was hampered by technically inadequate studies in 19% of 153 patients because of interfering intestinal gas. Computed tomography proved the most accurate and reliable modality in 48 patients.

  14. Cross-cultural development of a quality-of-life measure for patients with melanoma: phase 3 testing of an EORTC Melanoma Module.

    Science.gov (United States)

    Winstanley, Julie B; Young, Teresa E; Boyle, Frances M; Bergenmar, Mia; Bottomley, Andrew; Burmeister, Bryan; Campana, Luca G; Garioch, Jennifer J; King, Madeleine; Nikolic, Dejan V; van de Poll-Franse, Lonneke V; Saw, Robyn; Thompson, John F; White, Edward G

    2015-02-01

    Melanoma is an increasingly common skin cancer worldwide. Recent treatment advances have provided patients and healthcare professionals (HCPs) with choices where quality of life (QoL) and toxicity are important considerations. A melanoma-specific QoL questionnaire is being developed in a cross-cultural setting using a four phase process developed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group. In phase 1, a literature search identified a list of pertinent QoL issues; this was shown to HCPs and patients in eight countries and rated for importance and relevance. Questions were constructed for the highest-rated issues (phase 2) and piloted in another patient sample (phase 3). Using EORTC Quality of Life Group criteria and sequential use of factor and Rasch analysis, scales were hypothesized for field testing (phase 4). Seven QoL domains (disease symptoms, treatment issues, financial issues, access/quality of information, satisfaction with care, psychosocial issues and support), comprising 73 QoL issues, were rated by 46 HCPs and 78 patients. Fifty-six issues were rephrased as questions and piloted with 132 patients. A 38-item questionnaire (QLQ-MEL38) is available for field testing in conjunction with the EORTC QLQ-C30. This study has shown that melanoma patients have important QoL issues that have been incorporated into a new cross-culturally validated instrument. Future testing of this EORTC module is planned and will be an important step forward in providing reliable QoL data to aid future decision-making in the management and clinical trials of this complex group of patients.

  15. Molecular staging of pathologically negative sentinel lymph nodes from melanoma patients using multimarker, quantitative real-time rt-PCR.

    Science.gov (United States)

    Hilari, Josep M; Mangas, Cristina; Xi, Liqiang; Paradelo, Cristina; Ferrándiz, Carlos; Hughes, Steven J; Yueh, Cindy; Altomare, Ivy; Gooding, William E; Godfrey, Tony E

    2009-01-01

    The aim of this study was to evaluate the prognostic potential of quantitative reverse-transcription, polymerase chain reaction (qRT-PCR) in melanoma patients with pathologically negative sentinel lymph nodes (SLN). Our study included 195 node-negative melanoma patients with a Breslow thickness greater than 0.76 mm (n = 158), or less than 0.76 mm but who had Clark level IV-V, microscopic ulceration, or pathological signs of regression (n = 32), and five patients with melanoma of unknown thickness. SLNs were examined by serial-section histopathology. A portion of each SLN was frozen for qRT-PCR analysis using markers Tyrosinase, MART1, SSX2, MAGEA3, PAX3, and GalNAc-T. In addition, two other markers (PLAB and L1CAM) were evaluated for melanoma specificity but not for SLN analysis. Median follow-up was 64 months, during which time there were 15 (7.7%) recurrences. A total of 370 lymph nodes were analyzed by qRT-PCR. No association was found between quantitative expression level of any marker and disease recurrence. Previously published primer designs were tested for PAX3 and GalNAc-T and revealed that alternative PAX3 transcripts are differentially expressed in melanoma and benign lymph nodes. No associations with recurrence were found regardless of the transcripts amplified by different primer sets. PLAB and L1CAM did not appear to differentiate between malignant melanoma and benign melanocytes or lymph nodes in our analysis. We conclude that, in this large cohort of patients, multimarker qRT-PCR analysis of SLNs did not correlate with disease recurrence. Our data support specific PAX3 splice variants but not GalNAc-T, PLAB or L1CAM as possible markers for melanoma metastasis to SLNs.

  16. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma

    DEFF Research Database (Denmark)

    Ascierto, Paolo A; Del Vecchio, Michele; Robert, Caroline

    2017-01-01

    BACKGROUND: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile...... of ipilimumab 10 mg/kg versus 3 mg/kg. METHODS: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint...... for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one...

  17. Multivariate Analysis of Prognostic Factors Among 2,313 Patients With Stage III Melanoma: Comparison of Nodal Micrometastases Versus Macrometastases

    Science.gov (United States)

    Balch, Charles M.; Gershenwald, Jeffrey E.; Soong, Seng-jaw; Thompson, John F.; Ding, Shouluan; Byrd, David R.; Cascinelli, Natale; Cochran, Alistair J.; Coit, Daniel G.; Eggermont, Alexander M.; Johnson, Timothy; Kirkwood, John M.; Leong, Stanley P.; McMasters, Kelly M.; Mihm, Martin C.; Morton, Donald L.; Ross, Merrick I.; Sondak, Vernon K.

    2010-01-01

    Purpose To determine the survival rates and independent predictors of survival using a contemporary international cohort of patients with stage III melanoma. Patients and Methods Complete clinicopathologic and follow-up data were available for 2,313 patients with stage III disease in an updated and expanded American Joint Committee on Cancer (AJCC) melanoma staging database. Kaplan-Meier and Cox multivariate survival analyses were performed. Results Among all 2,313 patients with stage III disease, 81% had micrometastases, and 19% had clinically detectable macrometastases. The 5-year overall survival was 63%; it was 67% for patients with nodal micrometastases, and it was 43% for those with nodal macrometastases (P Multivariate analysis demonstrated that in patients with nodal micrometastases, number of tumor-containing lymph nodes, primary tumor thickness, patient age, ulceration, and anatomic site of the primary independently predicted survival (all P < .01). When added to the model, primary tumor mitotic rate was the second-most powerful predictor of survival after the number of tumor-containing nodes. In contrast, for patients with nodal macrometastases, the number of tumor-containing nodes, primary ulceration, and patient age independently predicted survival (P < .01). Conclusion In this multi-institutional analysis, we demonstrated remarkable heterogeneity of prognosis among patients with stage III melanoma, especially among those with nodal micrometastases. These results should be incorporated into the design and interpretation of future clinical trials involving patients with stage III melanoma. PMID:20368546

  18. Effectiveness of carboplatin and paclitaxel as first- and second-line treatment in 61 patients with metastatic melanoma.

    Directory of Open Access Journals (Sweden)

    Annette Pflugfelder

    Full Text Available BACKGROUND: Patients with metastatic melanoma have a very unfavorable prognosis with few therapeutic options. Based on previous promising experiences within a clinical trial involving carboplatin and paclitaxel a series of advanced metastatic melanoma patients were treated with this combination. METHODS: Data of all patients with cutaneous metastatic melanoma treated with carboplatin and paclitaxel (CP at our institution between October 2005 and December 2007 were retrospectively evaluated. For all patients a once-every-3-weeks dose-intensified regimen was used. Overall and progression free survival were calculated using the method of Kaplan and Meier. Tumour response was evaluated according to RECIST criteria. RESULTS: 61 patients with cutaneous metastatic melanoma were treated with CP. 20 patients (85% M1c received CP as first-line treatment, 41 patients (90.2% M1c had received at least one prior systemic therapy for metastatic disease. Main toxicities were myelosuppression, fatigue and peripheral neuropathy. Partial responses were noted in 4.9% of patients, stable disease in 23% of patients. No complete response was observed. Median progression free survival was 10 weeks. Median overall survival was 31 weeks. Response, progression-free and overall survival were equivalent in first- and second-line patients. 60 patients of 61 died after a median follow up of 7 months. Median overall survival differed for patients with controlled disease (PR+SD (49 weeks compared to patients with progressive disease (18 weeks. CONCLUSIONS: Among patients with metastatic melanoma a subgroup achieved disease control under CP therapy which may be associated with a survival benefit. This potential advantage has to be weighed against considerable toxicity. Since response rates and survival were not improved in previously untreated patients compared to pretreated patients, CP should thus not be applied as first-line treatment.

  19. Improvement of overall survival in stage IV melanoma patients during 2011-2014: analysis of real-world data in 441 patients of the German Central Malignant Melanoma Registry (CMMR).

    Science.gov (United States)

    Forschner, Andrea; Eichner, Felizitas; Amaral, Teresa; Keim, Ulrike; Garbe, Claus; Eigentler, Thomas Kurt

    2017-03-01

    During 2011 and 2014, new treatment modalities like tyrosine kinase inhibitors and checkpoint inhibitors were introduced into the therapy of metastatic melanoma. This study addresses the question whether overall survival (OS) of metastatic melanoma patients has already been improved in 441 patients diagnosed with metastatic melanoma between 2011 and 2014 in the real-world setting at the University Hospital Tuebingen. All patients were documented with their different therapies by the CMMR and followed up until March 2016. Survival probabilities were calculated by Kaplan-Meier estimators, and log-rank tests were used to evaluate significances. Hazard ratios were estimated by Cox regression analysis for survival probabilities and prognostic factors in stage IV melanoma. Best OS was observed in patients (n = 93) treated by metastasectomy as primary treatment with the intention to completely excise all metastases (3-year OS 61%). OS for patients with first-line systemic treatment (n = 258) was unfavorable in general (3-year OS 23%). Of those, the most favorable outcome was observed in patients without brain metastasis and treated with immunotherapy (mostly ipilimumab), as first-line treatment (median OS 35 months, 3-year OS 43%). In case of brain metastases, patients with targeted therapy had a better OS (median 14 months) than patients with ipilimumab treatment (median 7 months). Among all patients with first-line systemic treatment, outcome of patients diagnosed in the years 2013/2014, compared to 2011 and 2012, showed an improved survival. Three-year OS for patients that entered stage IV in 2013/2014 was 37% compared to those that entered stage IV in 2011 (18%) and 2012 (20%). The analysis of real-world data of treatment of metastatic melanoma showed an improvement of OS with both immunotherapy and targeted therapy. In case of cerebral metastasis, patients treated with targeted therapy showed a longer median OS than patients treated with ipilimumab.

  20. Fibrin sealant does not decrease seroma output or time to drain removal following inguino-femoral lymph node dissection in melanoma patients: A randomized controlled trial (NCT00506311

    Directory of Open Access Journals (Sweden)

    Mansfield Paul F

    2008-06-01

    Full Text Available Abstract Background This study assessed the impact of closed suction drains and evaluated whether the intraoperative use of a fibrin sealant decreased time to drain removal and wound complications in melanoma patients undergoing inguino-femoral lymph node dissection. Methods A pilot study (n = 18 assessed the impact of a closed suction drain following inguino-femoral lymph node dissection. A single-institution, prospective trial was then performed in which patients were randomized to a group that received intraoperative application of a fibrin sealant following inguino-femoral lymph node dissection or to a control group that did not receive sealant. Results The majority of the patients enrolled felt the drains caused moderate or severe discomfort and difficulties with activities of daily living. Thirty patients were then randomized; the median time to drain removal in the control group (n = 14 was 30 days (range, 13–74 compared to 29 days (range, 11–45 in the fibrin sealant group (n = 16; P = 0.6. Major and minor complications were similar in the two groups. Conclusion Postoperative closed suction drains were associated with major patient inconvenience. Applying a fibrin sealant at the time of inguino-femoral lymph node dissection in melanoma patients did not reduce the time to drain removal or postoperative morbidity. Alternative strategies are needed.

  1. High Percentage of ADAM-10 Positive Melanoma Cells Correlates with Paucity of Tumor-Infiltrating Lymphocytes but Does Not Predict Prognosis in Cutaneous Melanoma Patients

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    Piotr Donizy

    2015-01-01

    Full Text Available ADAM-10 (CDw156, CD156c, and kuzbanian is a protein belonging to a superfamily of metalloproteases, enzymes capable of degrading the extracellular matrix. ADAMs have also been shown to be primarily involved in ectodomain cleavage. The aim of the study was to assess the expression and intracellular location of ADAM-10 in 104 primary skin melanomas and 16 metastatic lesions from regional lymph nodes. Also, prognostic significance of ADAM-10 expression in primary tumor cells and metastatic lesion cells was evaluated during 5-year observation. It was revealed that high expression of ADAM-10 positive cells was strictly related with lower intensity of tumor-infiltrating lymphocytes (P=0.037, which suggests that ADAM-10 regulates immunoresponse in melanoma initiation and progression. No statistically significant correlations were found between ADAM-10 expression in primary tumor cells and nodal metastases and other histopathological parameters analyzed. Decreased immunoreactivity of ADAM-10 in cancer cells from regional lymph nodes was correlated with worse prognosis; however this correlation was statistically nonsignificant (P=0.065. Review of the literature shows that our study is the first one ever to describe the significance of ADAM-10 expression in correlation with detailed histopathological parameters of the primary tumor and data on long-term survival of cutaneous melanoma patients.

  2. Surveillance strategies in the follow-up of melanoma patients: too much or not enough?

    Science.gov (United States)

    Kurtz, James; Beasley, Georgia M; Agnese, Doreen; Kendra, Kari; Olencki, Thomas E; Terando, Alicia; Howard, J Harrison

    2017-06-15

    After appropriate initial therapy for patients with stage II-III melanoma, there is no consensus regarding surveillance. Thus, follow-up is highly variable among institutions and individual providers. The National Comprehensive Cancer Network recommends routine clinical examination and consideration of imaging for stage IIB-IIIC every 3-12 mo with no distinction between stages. Detection of recurrence is important as novel systemic therapies and surgical resection of recurrence may provide survival benefits. We retrospectively reviewed 369 patients with stage II and III melanoma treated at Ohio State University from 2009-2015, who underwent surgery as primary therapy. Two hundred forty-seven patients who were followed for a minimum of 6 mo after surgical resection to achieve no evidence of disease status (NED) were included in this analysis. One hundred twenty-two were lost to follow-up after surgery and were excluded. The rate of recurrence for stage IIA/IIB patients was 11% (14/125). Eleven of the 14 (79%) recurrences were detected by clinical symptoms or physical examination. Thirty-nine percent (49/125) of stage IIA or IIB patients were followed by clinical examination only, whereas 61% (76/125) were followed with at least two serial chest x-rays. The median time to first chest x-ray after NED status was 4.7 mo (n = 76), median time to second chest x-ray after NED status was 12.7 mo (n = 76), and 66% (50/76) continued to have additional serial chest x-rays. At median follow-up of 35 mo for the 125 patients with stage IIA/IIB, there was no difference in survival between those followed clinically (95% [95% CI: 0.88-0.99]) versus those followed with at least two serial x-rays (96% [95% CI: 0.89-0.98]). For stage IIC/IIIA-C patients, recurrence was detected in 23% (28/122) at median follow-up 31.2 mo. Fifty percent of recurrences were detected by imaging in asymptomatic patients, whereas 50% (14/28) had recurrence detected on imaging associated clinical

  3. Melanoma immunotherapy.

    Science.gov (United States)

    Sivendran, Shanthi; Glodny, Bradley; Pan, Michael; Merad, Miriam; Saenger, Yvonne

    2010-01-01

    Melanoma immunotherapy has been an area of intense research for decades, and this work is now yielding more tangible results for patients. Work has focused on 4 main areas: cytokine therapy, administration of immune-modulating antibodies, adoptive T-cell therapy, and vaccines. Cytokine therapy is an established treatment for advanced melanoma, and immune-modulating antibodies have recently emerged as an exciting new area of drug development with efficacy now established in a phase III trial. Adoptive T-cell therapy provides the proof of principle that T cells can attack and eliminate tumors. It has been challenging, however, to adapt this treatment for widespread use. Vaccines have generally yielded poor results, but intratumor pathogen-based strategies have shown encouraging results in recent trials, perhaps due to stronger immune stimulation. A review of the field of melanoma immunotherapy is provided here, with emphasis on those agents that have reached clinical testing. Novel strategies to induce the immune system to attack melanomas are reviewed. In the future, it is envisioned that immunotherapy will have further application in combination with cytotoxic and targeted therapies.

  4. Neoplastic leptomeningitis presenting in a melanoma patient treated with dabrafenib (a V600EBRAF inhibitor: a case report

    Directory of Open Access Journals (Sweden)

    Simeone Ester

    2012-05-01

    Full Text Available Abstract Introduction Leptomeningeal metastases are occurring at higher frequency in cancer patients. The prognosis of leptomeningeal metastases is poor and standard treatment, which includes radiotherapy and chemotherapy, is mostly ineffective. Melanoma represents one of the tumors with the highest incidence of leptomeningeal metastases. For such a disease, the BRAF inhibitors have recently been demonstrated to be effective on melanoma brain metastases harboring the V600EBRAF mutation. Case presentation We report a case of a 39-year-old Italian woman with advanced melanoma with brain, lung and peritoneum metastases harboring the V600EBRAF mutation. In August 2010 she was enrolled into the BRIM3 trial and after the randomization process she received dacarbazine. After two cycles, there was evidence of disease progression in her peritoneum and lung. For this reason, she was enrolled into another clinical trial with the GSK2118436 BRAF inhibitor, dabrafenib, as a second line of therapy. She had a partial response that was maintained until 13 weeks of treatment. In January 2011 she developed symptoms typical for brain metastases and received a diagnosis of leptomeningeal involvement of melanoma cells after an examination of her cerebral spinal fluid; magnetic resonance imaging was negative for meningitis or brain metastases. Analysis of her cerebral spinal fluid sample confirmed that the melanoma cells still carried the V600EBRAF mutation. After a few days, our patient went into a coma and died. Conclusion Starting with a clinical case, we discuss the pathogenesis of leptomeningeal metastases and whether the leptomeninges may represent a sanctuary where melanoma cells may generate resistance and/or BRAF inhibitors cannot reach an adequate concentration for significant activity. We assess whether treatment with BRAF inhibitors in melanoma patients should be interrupted as soon as disease progression appears or continued beyond progression, through

  5. Interferon alpha-induced reduction in the values of myeloid-derived suppressor cells in melanoma patients

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    Stanojević Ivan

    2015-01-01

    Full Text Available Background/Aim. Interaction between tumor cells and host’s immunoregulatory cells in creation of microenvironment that supports tumor progression is the focus of numerous investigations in recent years. Myeloid-derived suppressor cells (MDSCs are heterogeneous population of immature dendritic cells, macrophages and granulocytes. In cancer patients, these cells accumulate in tumor microenvironment, tumor-draining lymph nodes, peripheral blood and the liver and their numbers correlate with the stage of the disease and the metastatic disease. The aim of the study was to investigate the effect of interferon alpha on MDSCs percentage in peripheral blood of melanoma patients. Methods. The interferon treated melanoma patients were given subcutaneously interferon alpha, in optimal dose, for a period of at least 6 months before the analysis. Blood samples were collected from the melanoma patients (n = 91 and the age/sex matched healthy controls (n = 8. The following anti-human monoclonal antibodies were used for immunostaining: anti-CD15-FITC, anti-CD33-PE, anti-CD45-ECD, anti-HLA-DR PE/Cy5, anti-CD14-FITC, anti-CD16-PE and anti-CD11b-PE. Results. Comparison of myeloid-derived suppressor cells values in the stage 2 melanoma patients with and without interferon alpha therapy did not show a significant difference. When we compared the MDSCs values in the patients within stage 3 melanoma, we found a significant difference in granulocytic subset values between the interferon alpha-treated and the untreated group. Comparison of values of all suppressor cells populations between the interferon alpha-treated patients and healthy controls showed a significant increase in suppressor cells percentage in the melanoma patients. The granulocytic and total MDSCs values were significantly lower in the interferon alpha treated melanoma patients with progression in comparison with untreated patients with stable disease. Conclusion. We confirmed that interferon alpha

  6. Modulation of Cell Signaling Networks after CTLA4 Blockade in Patients with Metastatic Melanoma

    Science.gov (United States)

    Comin-Anduix, Begoña; Sazegar, Hooman; Chodon, Thinle; Matsunaga, Douglas; Jalil, Jason; von Euw, Erika; Escuin-Ordinas, Helena; Balderas, Robert; Chmielowski, Bartosz; Gomez-Navarro, Jesus; Koya, Richard C.; Ribas, Antoni

    2010-01-01

    Background The effects on cell signalling networks upon blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA4) using the monoclonal antibody tremelimumab were studied in peripheral blood mononuclear cell (PBMC) samples from patients with metastatic melanoma. Methodology/Principal Findings Intracellular flow cytometry was used to detect phosphorylated (p) signaling molecules downstream of the T cell receptor (TCR) and cytokine receptors. PBMC from tremelimumab-treated patients were characterized by increase in pp38, pSTAT1 and pSTAT3, and decrease in pLck, pERK1/2 and pSTAT5 levels. These changes were noted in CD4 and CD8 T lymphocytes but also in CD14 monocytes. A divergent pattern of phosphorylation of Zap70, LAT, Akt and STAT6 was noted in patients with or without an objective tumor response. Conclusions/Significance The administration of the CTLA4-blocking antibody tremelimumab to patients with metastatic melanoma influences signaling networks downstream of the TCR and cytokine receptors both in T cells and monocytes. The strong modulation of signaling networks in monocytes suggests that this cell subset may be involved in clinical responses to CTLA4 blockade. Clinical Trial Registration clinicaltrials.gov; Registration numbers NCT00090896 and NCT00471887 PMID:20856802

  7. Modulation of cell signaling networks after CTLA4 blockade in patients with metastatic melanoma.

    Directory of Open Access Journals (Sweden)

    Begoña Comin-Anduix

    Full Text Available BACKGROUND: The effects on cell signalling networks upon blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA4 using the monoclonal antibody tremelimumab were studied in peripheral blood mononuclear cell (PBMC samples from patients with metastatic melanoma. METHODOLOGY/PRINCIPAL: Findings Intracellular flow cytometry was used to detect phosphorylated (p signaling molecules downstream of the T cell receptor (TCR and cytokine receptors. PBMC from tremelimumab-treated patients were characterized by increase in pp38, pSTAT1 and pSTAT3, and decrease in pLck, pERK1/2 and pSTAT5 levels. These changes were noted in CD4 and CD8 T lymphocytes but also in CD14 monocytes. A divergent pattern of phosphorylation of Zap70, LAT, Akt and STAT6 was noted in patients with or without an objective tumor response. CONCLUSIONS/SIGNIFICANCE: The administration of the CTLA4-blocking antibody tremelimumab to patients with metastatic melanoma influences signaling networks downstream of the TCR and cytokine receptors both in T cells and monocytes. The strong modulation of signaling networks in monocytes suggests that this cell subset may be involved in clinical responses to CTLA4 blockade. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; Registration numbers NCT00090896 and NCT00471887.

  8. INCREASED LEVELS OF MIRNA-146A IN SERUM AND HISTOLOGIC SAMPLES OF PATIENTS WITH UVEAL MELANOMA

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    ANDREA RUSSO

    2016-11-01

    Full Text Available Purpose: to analyze MiRs expression in serum of UM patients, respect to healthy donors, and to compare this data with MiRs expressed in formalin-fixed, paraffin-embedded UM samples.Methods: Expression profile of 754 miRNAs was performed in serum from patients with uveal melanoma that underwent primary enucleation. The level of miRNAs increased in serum was individually analyzed on FFPE UM samples and compared to choroidal melanocytes from unaffected eyes.Results: 14 patients with uveal melanoma were included in the study. We found 8 serum miRNAs differentially expressed compared to normal controls: 2 upregulated miRNAs (miR-146a, miR-523; 6 downregulated miRNAs (miR-19a, miR-30d, miR-127, miR-451, miR-518f, miR-1274B. When data on upregulated miRNAs were singularly validated only a significant overexpression of miR-146a was found. A statistically significant upregulation of miRNA-146a was also found on FFPE UM samples, compared to choroidal melanocytes from unaffected eyes. Conclusions: miRNA-146a is increased in serum of patients with UM and in FFPE tumour samples. Further studies will show if it could be considered a potential marker of UM in the blood.

  9. Positron emission tomography in the follow-up of cutaneous malignant melanoma patients

    DEFF Research Database (Denmark)

    Danielsen, Maria; Højgaard, Liselotte; Kjær, Andreas

    2014-01-01

    Cutaneous malignant melanoma (CMM) has a high risk of dissemination to regional lymph nodes and visceral organs. Recurrences are most frequently seen within the first 2-3 years after initial treatment, but these patients have a life-long risk of relapse. The prognosis is highly dependent on lymph...... node involvement and distant metastases, accentuating the importance of close surveillance to identify disease progression at an early stage, and thereby detect recurrences amenable to treatment. Positron emission tomography (PET) has already been proven useful in the staging of CMM, but the utility...

  10. Primary Anorectal Melanoma: An Update

    Directory of Open Access Journals (Sweden)

    P Carcoforo, M.T Raiji, G.M Palini, M Pedriali, U Maestroni, G Soliani, A Detroia, M.V Zanzi, A.L Manna, J.G Crompton, R.C Langan, A Stojadinovic, I Avital

    2012-01-01

    Full Text Available The anorectum is a rare anatomic location for primary melanoma. Mucosal melanoma is a distinct biological and clinical entity from the more common cutaneous melanoma. It portrays worse prognosis than cutaneous melanoma, with distant metastases being the overwhelming cause of morbidity and mortality. Surgery is the treatment of choice, but significant controversy exists over the extent of surgical resection. We present an update on the state of the art of anorectal mucosal melanoma. To illustrate the multimodality approach to anorectal melanoma, we present a typical patient.

  11. Vaccination with melanoma lysate-pulsed dendritic cells, of patients with advanced colorectal carcinoma: report from a phase I study

    DEFF Research Database (Denmark)

    Burgdorf, S K; Fischer, A; Claesson, M H;

    2006-01-01

    Immune therapy have shown new and exciting perspectives for cancer treatment. Aim of our study was to evaluate toxicity and possible adverse effects from vaccination of patients with advanced colorectal cancer with autologous dendritic cells (DC) pulsed with lysate from a newly developed melanoma...... and selected melanoma cell line enriched in expression of MAGE-A antigens and deficient in expression of melanoma differentiation antigens: tyrosinase, MART-1 and gp100. Vaccinations were administered intradermally on the proximal thigh with a total of five given vaccines at 2 weeks intervals. Each vaccine...... contained 3-5 x 10(6) DCs. Five of the six patients received all five vaccines. The treatment was well tolerated in all patients without any observed vaccine-correlated adverse effects. Treatment with this DC-based cancer vaccine proved safe and non-toxic....

  12. Radioembolization as Locoregional Therapy of Hepatic Metastases in Uveal Melanoma Patients

    Energy Technology Data Exchange (ETDEWEB)

    Klingenstein, A., E-mail: annemarie.klingenstein@med.uni-muenchen.de [Ludwig-Maximilians University, Department of Ophthalmology (Germany); Haug, A. R. [Ludwig-Maximilians University, Department of Nuclear Medicine (Germany); Zech, C. J. [Ludwig-Maximilians University, Department of Radiology (Germany); Schaller, U. C. [Klinikum Augsburg, Department of Ophthalmology (Germany)

    2013-02-15

    To retrospectively evaluate the overall survival, safety, and efficacy of metastatic uveal melanoma patients after radioembolization as salvage therapy. Thirteen patients were treated with radioembolization of branches of the hepatic artery with resin-based yttrium-90 ({sup 90}Y)-labelled microspheres. Twelve patients underwent a single application, and 1 patient underwent 4 interventions. Dosages from 644 to 2,450 MBq (mean activity 1,780) were applied. Treatment response was evaluated by way of liver magnetic resonance imaging and computed tomography (CT) as well as whole-body fluorodeoxyglucose positron emission tomography (PET)/CT with evaluation of percentage changes in SUV{sub max} before and at 2-3 months after therapy. Kaplan-Meier analysis was calculated to determine overall survival. Partial remission (PR) was observed in 8 (62 %), stable disease (SD) in 2 (15 %), and progressive disease (PD) in 3 (23 %) patients under terms of standard criteria and PR in 3 (23 %), SD in 3 (23 %), and PD in 7 (54 %) patients according to PET criteria. Neither RECIST nor PET criteria showed a significant difference in predicting overall survival (P = 0.12 and 0.11, respectively). Median survival time after radioembolization was 7 months. No acute toxicity with in-hospital morbidity was observed. One patient developed hepatomegaly, and 1 patient developed gastric ulceration. Throughout follow-up, progression of extrahepatic metastases was observed. Radioembolization may be a promising therapy in uveal melanoma patients with predominant hepatic metastases. At first follow-up, we observed PR or SD in 77 % patients under terms of standard criteria with an acceptable toxicity profile.

  13. ADAM15 expression is downregulated in melanoma metastasis compared to primary melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Ungerer, Christopher; Doberstein, Kai [Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt, Frankfurt am Main (Germany); Buerger, Claudia; Hardt, Katja; Boehncke, Wolf-Henning [Department of Dermatology, Clinic of the Goethe-University, Theodor-Stern-Kai, Frankfurt (Germany); Boehm, Beate [Division of Rheumatology, Goethe University, Frankfurt am Main (Germany); Pfeilschifter, Josef [Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt, Frankfurt am Main (Germany); Dummer, Reinhard [Department of Pathology, Institute of Surgical Pathology, University Hospital, Zurich (Switzerland); Mihic-Probst, Daniela [Department of Dermatology, University Hospital Zurich (Switzerland); Gutwein, Paul, E-mail: p.gutwein@med.uni-frankfurt.de [Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt, Frankfurt am Main (Germany)

    2010-10-22

    Research highlights: {yields} Strong ADAM15 expression is found in normal melanocytes. {yields} ADAM15 expression is significantly downregulated in patients with melanoma metastasis. {yields} TGF-{beta} can downregulate ADAM15 expression in melanoma cells. {yields} Overexpression of ADAM15 in melanoma cells inhibits migration, proliferation and invasion of melanoma cells. {yields} Conclusion: ADAM15 represents an tumor suppressor protein in melanoma. -- Abstract: In a mouse melanoma metastasis model it has been recently shown that ADAM15 overexpression in melanoma cells significantly reduced the number of metastatic nodules on the lung. Unfortunately, the expression of ADAM15 in human melanoma tissue has not been determined so far. In our study, we characterized the expression of ADAM15 in tissue micro-arrays of patients with primary melanoma with melanoma metastasis. ADAM15 was expressed in melanocytes and endothelial cells of benign nevi and melanoma tissue. Importantly, ADAM15 was significantly downregulated in melanoma metastasis compared to primary melanoma. We further demonstrate that IFN-{gamma} and TGF-{beta} downregulate ADAM15 protein levels in melanoma cells. To investigate the role of ADAM15 in melanoma progression, we overexpressed ADAM15 in melanoma cells. Importantly, overexpression of ADAM15 in melanoma cells reduced the migration, invasion and the anchorage dependent and independent cell growth of melanoma cells. In summary, the downregulation of ADAM15 plays an important role in melanoma progression and ADAM15 act as a tumorsuppressor in melanoma.

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

    NARCIS (Netherlands)

    Larkin, James; Del Vecchio, Michele; Ascierto, Paolo A.; Krajsova, Ivana; Schachter, Jacob; Neyns, Bart; Espinosa, Enrique; Garbe, Claus; Sileni, Vanna Chiarion; Gogas, Helen; Miller, Wilson H.; Mandala, Mario; Hospers, Geke A. P.; Arance, Ana; Queirolo, Paola; Hauschild, Axel; Brown, Michael P.; Mitchell, Lada; Veronese, Luisa; Blank, Christian U.

    2014-01-01

    Background The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression- free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced m

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

    NARCIS (Netherlands)

    Larkin, James; Del Vecchio, Michele; Ascierto, Paolo A.; Krajsova, Ivana; Schachter, Jacob; Neyns, Bart; Espinosa, Enrique; Garbe, Claus; Sileni, Vanna Chiarion; Gogas, Helen; Miller, Wilson H.; Mandala, Mario; Hospers, Geke A. P.; Arance, Ana; Queirolo, Paola; Hauschild, Axel; Brown, Michael P.; Mitchell, Lada; Veronese, Luisa; Blank, Christian U.

    2014-01-01

    Background The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression- free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced m

  16. Risk of Non-melanoma Skin Cancer in Patients with Atopic Dermatitis Treated with Oral Immunosuppressive Drugs

    NARCIS (Netherlands)

    Garritsen, Floor M.; Van der Schaft, Jorien; Van den Reek, Juul M.; Politiek, Klaziena; Van Osmedendorp, Harmieke; Van Dijk, Marijke; Hijnen, Dirk J.; De Graaf, Marlies; Bruijnzeel-Koomen, Carla A.; De Jong, Elke M.; Schuttelaar, Marie-Louise A.; De Bruin-Weller, Marjolein S.

    There is uncertainty about the risk of developing non-melanoma skin cancer (NMSC), including basal cell carcinoma and squamous cell carcinoma (SCC), in patients with atopic dermatitis (AD) treated with oral immunosuppressive drugs. A total of 557 patients with AD treated with these drugs in the

  17. Immunohistochemical analysis of immune response in breast cancer and melanoma patients after laser immunotherapy

    Science.gov (United States)

    Nordquist, Robert E.; Bishop, Shelly L.; Ferguson, Halie; Vaughan, Melville B.; Jose, Jessnie; Kastl, Katherine; Nguyen, Long; Li, Xiaosong; Liu, Hong; Chen, Wei R.

    2011-03-01

    Laser immunotherapy (LIT) has shown great promise in pre-clinical studies and preliminary clinical trials. It could not only eradicate treated local tumors but also cause regression and elimination of untreated metastases at distant sites. Combining a selective photothermal therapy with an active immunological stimulation, LIT can induce systemic anti-tumor immune responses. Imiquimod (IMQ), a toll-like receptor agonist, was used for the treatment of late-stage melanoma patients and glycated chitosan (GC), a biological immunological modulator, was used for the treatment of late-stage breast cancer patients, in combination of irradiation of a near-infrared laser light. To observe the immunological changes before and after LIT treatment, the pathological tissues of melanoma and breast cancer patients were processed for immunohistochemical analysis. Our results show that LIT changed the expressions of several crucial T cell types. Specifically, we observed significant decreases of CD3+ T-cells and a significant increase of CD4+,CD8+, and CD68+ T-cells in the tumor samples after LIT treatment. While not conclusive, our study could shed light on one the possible mechanisms of anti-tumor immune responses induced by LIT. Further studies will be conducted to identify immunological biomarkers associated with LIT-induced clinical response.

  18. Prognostic Value of RT-PCR Tyrosinase Detection in Peripheral Blood of Melanoma Patients

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    Esmeralda Carrillo

    2006-01-01

    Full Text Available Malignant melanoma (MM prognosis has been related to tumour thickness and clinical stage and metastasis risk has been associated with presence of tumour cells in peripheral blood. The aim of this study was to determine the relationship between presence of tyrosinase in peripheral blood of MM patients and their clinical prognosis. Blood samples from 58 MM patients (stage I–IV were analysed, using RT-PCR assay to detect tyrosinase mRNA. The results showed that positive RT-PCR assay for tyrosinase were significantly associated with clinical status and tumour thickness. After a median follow-up of 24 months, RT-PCR results were found to be significant correlated with recurrence (p < 0.05 and clinical stage III (p < 0.05. Separate analysis of stage III tumours to determine the prognostic value of tyrosinase presence in peripheral blood showed an overall 24-month survival rate of 70% in the RT-PCR negative group versus 10% in the positive group (p < 0.02. These results suggest that detection of circulating melanoma cells may be especially relevant in stage III patients, in whom RT-PCR positivity defines a subpopulation at high risk of recurrence.

  19. Pembrolizumab in a BRAF-mutant metastatic melanoma patient following a severe immune-related adverse event with ipilimumab.

    Science.gov (United States)

    Aya, Francisco; Fernández-Martínez, Aranzazu; Gaba, Lydia; Victoria, Iván; Tosca, Mónica; Carrera, Cristina; Prat, Aleix; Arance, Ana

    2016-06-01

    Currently, limited data exist on the safety of pembrolizumab in patients with metastatic melanoma who have developed severe immune-related adverse events following treatment with ipilimumab. We report a 45-year-old male patient with BRAF-mutant metastatic melanoma who discontinued treatment with ipilimumab due to treatment-related grade 3 colitis and was subsequently treated with the anti-programmed cell death 1 protein (PD-1) antibody pembrolizumab. He has been on treatment with pembrolizumab for more than 20 months with no major toxicities and has achieved an objective partial response, which is ongoing.

  20. Isolated asymptomatic masseter muscle metastasis as first sign of metastatic disease in a patient with known melanoma

    DEFF Research Database (Denmark)

    Gjorup, Caroline Asirvatham; Hendel, Helle Westergren; Svane, Inge Marie

    2016-01-01

    A 65-year-old woman diagnosed with a nodular melanoma on the right shoulder had a PET/CT scan 13 months later demonstrating a FDG-avid mass in the left masseter muscle, which was asymptomatic and not clinically evident. Pathologic analysis confirmed metastasis of melanoma. Further subcutaneous......, intramuscular and bone metastases developed and the patient was treated with surgery and immunotherapy. The patient is in complete-remission with no evident metastases seen on PET/CT 2.5 years after treatment with adoptive cell therapy using tumor-infiltrating lymphocytes (TIL therapy). Asymptomatic skeletal...

  1. [Targeted therapies for melanoma].

    Science.gov (United States)

    Leiter, U; Meier, F; Garbe, C

    2014-07-01

    Since the discovery of activating mutations in the BRAF oncogene and also stimulation of immune mediated antitumor response in melanoma, there has been remarkable progress in the development of targeted therapies for unresectable and metastatic melanoma. This article addresses the latest developments of BRAF/MEK/ERK pathway signaling. In addition, the development of drugs to attack alternative mutations in melanoma, such as NRAS and KIT is described. Strategies for the management of BRAF inhibitor resistance, such as with combination therapy, are outlined. Antitumor immune therapies with monoclonal antibodies such as ipilimumab which acts by promoting T-cell activation or antibody blockade of programmed death-1 (PD-1) led to a long term response in metastatic melanoma. Results of latest clinical studies including the toxicity profile are described. Due to selective kinase inhibitors and immune checkpoint blockade, the therapy of unresectable metastatic melanoma has greatly improved and long-term survival of patients with metastatic melanoma seems a real possibility.

  2. EXPERIENCE OF SUCCESSFUL ACNEFORM ERUPTIONS TREATMENT IN PATIENT WITH MULTIPLE MELANOMA

    Directory of Open Access Journals (Sweden)

    O. V. Minkina

    2016-01-01

    Full Text Available Objective: to describe the results of the joint monitoring and diversified treatment of oncologists and dermatologists those patient with multiple recurrent melanoma who received over a long period a targeted anti-cancer therapy, which was complicated by side-effect as widespread acneform rush, resistant to traditional treatment. Patient A., born in 1988, was followed up and got a treatment more than 2 years in oncology out-patient clinic diagnosed with “Melanoma of the front surface of the left leg T2bN0M0 IIA”. Subsequently, the patient was verified metastasis in the inginal lymph nodes, in the soft tissues of the hips, to liver. Acute adverse reaction has developed in a short time after getting the anti-tumor target therapy as generalized acneform rush and itching of the skin. Skin symptoms accompanied by pronounced psychological and emotional stress, therefore, dermatologists have been invited to provide additional medical assistance to this patient. Due to the fact that subsequent traditional anti-acne algorithms of topical and oral treatment was not such effective, there was made a decision to use an alternative supporting external therapy, which did not have similar examples of usage previously. Results. External application of tacrolimus ointment in combination with other drugs and then as a mono-therapy, allows us in a rather short period achieve a stable and pronounced regression of skin pathological lesions, to return to the previously cancelled initial drug dose of the anti-tumor target therapy, to change significantly components of the patient’s quality of life. Conclusion. The search for additional and alternative treatment approaches for similar patients, as in our case, remains relevant for specialists and patients themselves. This case is an example of alternative approach to the tacrolimus topical application in patient with drug-mediated acneform rush.

  3. CTLA4 blockade increases Th17 cells in patients with metastatic melanoma

    Directory of Open Access Journals (Sweden)

    Comin-Anduix Begonya

    2009-05-01

    Full Text Available Abstract Background Th17 cells are CD4+ cells that produce interleukin 17 (IL-17 and are potent inducers of tissue inflammation and autoimmunity. We studied the levels of this T cell subset in peripheral blood of patients treated with the anti-CTLA4 antibody tremelimumab since its major dose limiting toxicities are inflammatory and autoimmune in nature. Methods Peripheral blood mononuclear cells (PBMC were collected before and after receiving tremelimumab within two clinical trials, one with tremelimumab alone (21 patients and another together with autologous dendritic cells (DC pulsed with the melanoma epitope MART-126–35 (6 patients. Cytokines were quantified directly in plasma from patients and after in vitro stimulation of PBMC. We also quantified IL-17 cytokine-producing cells by intracellular cytokine staining (ICS. Results There were no significant changes in 13 assayed cytokines, including IL-17, when analyzing plasma samples obtained from patients before and after administration of tremelimumab. However, when PBMC were activated in vitro, IL-17 cytokine in cell culture supernatant and Th17 cells, detected as IL-17-producing CD4 cells by ICS, significantly increased in post-dosing samples. There were no differences in the levels of Th17 cells between patients with or without an objective tumor response, but samples from patients with inflammatory and autoimmune toxicities during the first cycle of therapy had a significant increase in Th17 cells. Conclusion The anti-CTLA4 blocking antibody tremelimumab increases Th17 cells in peripheral blood of patients with metastatic melanoma. The relation between increases in Th17 cells and severe autoimmune toxicity after CTLA4 blockade may provide insights into the pathogenesis of anti-CTLA4-induced toxicities. Trial Registration Clinical trial registration numbers: NCT0090896 and NCT00471887

  4. Preoperative FDG-PET/CT Is an Important Tool in the Management of Patients with Thick (T4) Melanoma.

    Science.gov (United States)

    Arrangoiz, Rodrigo; Papavasiliou, Pavlos; Stransky, Carrie A; Yu, Jian Q; Tianyu, Li; Sigurdson, Elin R; Berger, Adam C; Farma, Jeffrey M

    2012-01-01

    The yield of preoperative PET/CT (PET/CT) for regional and distant metastases for thin/intermediate thickness melanoma is low. Objective of this study is to determine if PET/CT performed for T4 melanomas helps guide management and alter treatment plans. Methods. Retrospective cohort of 216 patients with T4 melanomas treated at two tertiary institutions. Fifty-six patients met our inclusion criteria (T4 lesion, PET/CT and no clinical evidence of metastatic disease). Results. Fifty-six patients (M: 32, F: 24) with median tumor thickness of 6 mm were identified. PET/CT recognized twelve with regional and four patients with metastatic disease. Melanoma-related treatment plan was altered in 11% of the cases based on PET/CT findings. PET/CT was negative 60% of the time, in 35% of the cases; it identified incidental findings that required further evaluation. Conclusion. Patients with T4 lesions, PET/CT changed the treatment plan 18% of the time. Regional findings changed the surgical treatment plan in 11% and the adjuvant plan in 7% of our cases due to the finding of metastatic disease. Additionally 20 patients had incidental findings that required further workup. In this subset of patients, we feel there is a benefit to PET/CT, and further studies should be performed to validate our findings.

  5. Preoperative FDG-PET/CT Is an Important Tool in the Management of Patients with Thick (T4 Melanoma

    Directory of Open Access Journals (Sweden)

    Rodrigo Arrangoiz

    2012-01-01

    Full Text Available The yield of preoperative PET/CT (PET/CT for regional and distant metastases for thin/intermediate thickness melanoma is low. Objective of this study is to determine if PET/CT performed for T4 melanomas helps guide management and alter treatment plans. Methods. Retrospective cohort of 216 patients with T4 melanomas treated at two tertiary institutions. Fifty-six patients met our inclusion criteria (T4 lesion, PET/CT and no clinical evidence of metastatic disease. Results. Fifty-six patients (M: 32, F: 24 with median tumor thickness of 6 mm were identified. PET/CT recognized twelve with regional and four patients with metastatic disease. Melanoma-related treatment plan was altered in 11% of the cases based on PET/CT findings. PET/CT was negative 60% of the time, in 35% of the cases; it identified incidental findings that required further evaluation. Conclusion. Patients with T4 lesions, PET/CT changed the treatment plan 18% of the time. Regional findings changed the surgical treatment plan in 11% and the adjuvant plan in 7% of our cases due to the finding of metastatic disease. Additionally 20 patients had incidental findings that required further workup. In this subset of patients, we feel there is a benefit to PET/CT, and further studies should be performed to validate our findings.

  6. Living in a Patient-Centric Universe.

    Science.gov (United States)

    Kraus, Dennis H

    2016-12-01

    Patients with head and neck cancer face a number of challenges in terms of treatment, cure of their underlying malignant condition, and quality of survivorship. This presentation will focus on the patient perception of both the quality of care and the empathy and availability of the head and neck oncology team. It has become evident that the quality of survivorship plays a central role in the patient's decision-making process. The process of decision making by the patient facing head and neck cancer and the impact on treatment choices will be explored. The ability of the patient and her or his support system to navigate through the increasingly complicated health care system will be considered, with an emphasis on strategies for success. Finally, the role of the of the head and neck surgeon, and the need for physician wellness in predicating successful patient outcomes will be considered. The ultimate goal of achieving optimal care, superior patient outcomes, and patient satisfaction is the true objective of the concept of living in a patient-centric universe.

  7. Increased frequency of minimal homozygous deletions is associated with poor prognosis in primary malignant melanoma patients.

    Science.gov (United States)

    Boi, Sebastiana; Tebaldi, Toma; Re, Angela; Cantaloni, Chiara; Adami, Valentina; Barbareschi, Mattia; Cristofolini, Mario; Pasini, Luigi; Quattrone, Alessandro

    2014-06-01

    Identification of prognostic melanoma-associated copy number alterations (CNAs) is still an area of active research. Here, we investigated by high-resolution array comparative genomic hybridization (aCGH) a cohort of 31 paraffin-preserved primary malignant melanomas (MMs), whose prognosis was not predictable on the basis of conventional histopathological parameters. Although we identified a variety of highly recurrent sites of genomic lesions, the total number of CNAs per patient was not a discriminator of MM outcome. Furthermore, validation of aCGH by quantitative PCR on an extended population of 65 MM samples confirmed the absence of predictive value for the most recurrent CNA loci. Instead, our analysis revealed specific prognostic potential of the frequency of homozygous deletions (representing less than 3% of the total CNAs on average per sample), which was strongly associated with sentinel lymph node (SLN) invasion (P = 0.003), and distant metastasis (P = 0.003). Increased number of homozygous deletions was also indicative of poor patient survival (P = 0.01), both in our samples and in an independent validation of public dataset of primary and metastatic MMs. Moreover, we identified 77 hotspots of minimal common homozygous deletions, enriched in genes involved in cell adhesion processes and cell-communication functions, which preferentially accumulated in primary MMs showing the most severe outcome. Therefore, specific loss of gene loci in regions of minimal homozygous deletion may represent a pivotal type of genomic alteration accumulating during MM progression with potential prognostic implication.

  8. Diarrhoea in a patient with metastatic melanoma:Ipilimumab ileocolitis treated with infliximab

    Institute of Scientific and Technical Information of China (English)

    Rob; ME; Slangen; Alfonsus; JM; van; den; Eertwegh; Adriaan; A; van; Bodegraven; Nanne; KH; de; Boer

    2013-01-01

    Administration of ipilimumab,a cytotoxic T-lymphocyte associated antigen-4-blocking monoclonal antibody,leads to enhancement of the anti-tumor T-cell respons and as a result shows a significant survival benefit in metastatic melanoma patients.Therefore patients are currently receiving this promising therapy as a secondline strategy.Unfortunately,by activation of the T-cell immune reponse,ipilimumab therapy may lead to an unwanted induction of different autoimmune phenomena.Diarrhoea and colitis occur in up to one third of patients.Here we present a case of ipilimumab induced ileocolitis which was successfully treated with infliximab,an anti-tumor necrosis factor monoclonal antibody,after corticosteroid therapy failure.Although formal trials are lacking,recently publicated series suggest that infusional therapy of infliximab is effective in ipilimumab induced ileocolitis.

  9. Melanoma during pregnancy

    DEFF Research Database (Denmark)

    de Haan, Jorine; Lok, Christianne A; de Groot, Christianne J M

    2017-01-01

    The management of melanoma during pregnancy is challenging as maternal benefits and fetal risks need to be balanced. Here, we present an overview of the incidence, the demographic and clinical characteristics and the treatment modalities used. After analysis of obstetric, fetal and maternal outcome......, recommendations for clinical practice are provided. From the 'International Network on Cancer, Infertility and Pregnancy' database, pregnant patients with melanoma were identified and analysed. Sixty pregnancies were eligible for analysis. Fifty percent of the patients presented with advanced melanoma during...... pregnancy (14 stage III and 16 stage IV), and 27% were diagnosed with recurrent melanoma. Surgery was the main therapeutic strategy during pregnancy. Only four patients with advanced melanoma were treated during pregnancy with systemic therapy (n=1) or radiotherapy (n=3). Premature delivery was observed...

  10. A prolonged complete response in a patient with BRAF-mutated melanoma stage IV treated with the MEK1/2 inhibitor selumetinib (AZD6244).

    NARCIS (Netherlands)

    Boers-Sonderen, M.J.; Desar, I.M.E.; Blokx, W.A.M.; Timmer-Bonte, J.N.H.; Herpen, C.M.L. van

    2012-01-01

    In melanoma, the RAS/RAF/MEK/ERK pathway is frequently activated by mutations in BRAF and NRAS. Selumetinib (AZD6244) is an oral, selective, non-ATP-competitive inhibitor of MEK1/2. Here, we describe a patient with metastatic melanoma (T1N2cM1a) with a BRAF V600E mutation. She is currently being tre

  11. PD-1 Blockade Augments Th1 and Th17 and Suppresses Th2 Responses in Peripheral Blood From Patients With Prostate and Advanced Melanoma Cancer

    NARCIS (Netherlands)

    Dulos, John; Carven, Gregory J.; van Boxtel, Susan J.; Evers, Sabine; Driessen-Engels, Lilian J. A.; Hobo, Willemijn; Gorecka, Monika A.; de Haan, Anton F. J.; Mulders, Peter; Punt, Cornelis J. A.; Jacobs, Joannes F. M.; Schalken, Jack A.; Oosterwijk, Egbert; van Eenennaam, Hans; Boots, Annemieke M.

    2012-01-01

    Negative costimulation on T cells is exploited by both prostate cancer and melanoma to evade antitumor immunity. Blocking such mechanisms restores antitumor immunity as was demonstrated by the improved survival of patients with metastatic melanoma after treatment with an antibody blocking the CTLA-4

  12. PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer.

    NARCIS (Netherlands)

    Dulos, J.; Carven, G.J.; Boxtel, S.J. van; Evers, S.; Driessen-Engels, L.J.; Hobo, W.A.; Gorecka, M.A.; Haan, A.F.J. de; Mulders, P.; Punt, C.J.A.; Jacobs, J.F.M.; Schalken, J.A.; Oosterwijk, E.; Eenennaam, H. van; Boots, A.M.H.

    2012-01-01

    Negative costimulation on T cells is exploited by both prostate cancer and melanoma to evade antitumor immunity. Blocking such mechanisms restores antitumor immunity as was demonstrated by the improved survival of patients with metastatic melanoma after treatment with an antibody blocking the CTLA-4

  13. Acetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma.

    Science.gov (United States)

    Shirai, Takushi; Sano, Tasuku; Kamijo, Fuminao; Saito, Nana; Miyake, Tomomi; Kodaira, Minori; Katoh, Nagaaki; Nishie, Kenichi; Okuyama, Ryuhei; Uhara, Hisashi

    2016-01-01

    We reported an 81-year-old woman with metastatic melanoma, in whom myasthenia gravis and rhabdomyolysis developed after nivolumab monotherapy. The first symptom of myasthenia gravis was dyspnea. Ultrasonography detected hypokinesis of the bilateral diaphragm suggesting myasthenia gravis, although there was no abnormal finding of the lungs in computed tomography images. Acetylcholine receptor binding antibodies were low-titer positive in the preserved serum before administration of nivolumab, strongly suggesting that the myasthenia gravis was a nivolumab-related immune adverse event. Despite the remarkable clinical benefits of immune checkpoint inhibitors for patients with advanced melanoma, it is important to recognize unexpected immune-related adverse events.

  14. Clinical characteristics and management of melanoma families

    NARCIS (Netherlands)

    Rhee, Jasper Immanuel van der

    2013-01-01

    Being a member of a melanoma family is a major risk factor for cutaneous malignant melanoma. In this thesis clinical characteristics and management of melanoma families are discussed. In the first part of the thesis clinical and histological characteristics of melanoma (patients) from families with

  15. Clinical characteristics and management of melanoma families

    NARCIS (Netherlands)

    Rhee, Jasper Immanuel van der

    2013-01-01

    Being a member of a melanoma family is a major risk factor for cutaneous malignant melanoma. In this thesis clinical characteristics and management of melanoma families are discussed. In the first part of the thesis clinical and histological characteristics of melanoma (patients) from families with

  16. Cerebral MRI in neurological asymptomatic patients with malignant melanoma; Zerebrales MRT bei neurologisch asymptomatischen Patienten mit malignem Melanom

    Energy Technology Data Exchange (ETDEWEB)

    Schlamann, M.; Goericke, S.; Forsting, M.; Wanke, I. [Inst. fuer Diagnostische und Interventionelle Radiologie und Neuroradiologie, Universitaetsklinikum Essen (Germany); Loquai, C. [Klinik und Poliklinik fuer Dermatologie, Universitatsklinikum Mainz (Germany)

    2008-02-15

    Purpose: detection of metastasis in the whole body is important for sufficient the staging of malignant melanoma. Sufficient imaging of the brain is particularly important. Although there is evidence that clinical examination is not sufficient for prediction of cerebral metastasis, MRI scan is not always regarded as reasonable in neurological asymptomatic patients. Therefore, we explored the incidence of cerebral metastasis in our patient population in relation to the stage of disease to estimate the reasonability of this examination. Materials and methods: 120 consecutive patients with malignant melanoma were retrospectively evaluated. All patients were neurologically without pathological findings and received routine staging by cranial MRI. The incidence of brain metastasis was evaluated. The examination protocol consisted of an axial orientated flair and a T1 sequence. Ten minutes after administration of contrast agent, a T1 sequence in axial and coronal orientation was performed using the magnetization transfer technique. The type of melanoma, the thickness of the tumor, the Clark level, the location of the primary tumor, and the clinical stage were recorded from the clinical records. Results: 15 (12.5%) of the 120 patients (clinical stage I: 27 patients, stage II: 29 patients, stage III: 25 patients, stage IV: 39 patients) had cerebral metastasis in MRI. 14 patients were in stage III or IV at this time. Consequently 21.8% of the patients in stage III and IV had cerebral metastasis. Only one patient in stage He had cerebral metastasis. (orig.)

  17. Redirected lysis of human melanoma cells by a MCSP/CD3-bispecific BiTE antibody that engages patient-derived T cells.

    Science.gov (United States)

    Torisu-Itakura, Hitoe; Schoellhammer, Hans F; Sim, Myung-Shin; Irie, Reiko F; Hausmann, Susanne; Raum, Tobias; Baeuerle, Patrick A; Morton, Donald L

    2011-10-01

    Melanoma-associated chondroitin sulfate proteoglycan (MCSP; also called HMW-MAA, CSPG4, NG2, MSK16, MCSPG, MEL-CSPG, or gp240) is a well characterized melanoma cell-surface antigen. In this study, a new bispecific T-cell engaging (BiTE) antibody that binds to MCSP and human CD3 (MCSP-BiTE) was tested for its cytotoxic activity against human melanoma cell lines. When unstimulated peripheral mononuclear blood cells (PBMCs) derived from healthy donors were cocultured with melanoma cells at effector:target ratios of 1:1, 1:5, or 1:10, and treated with MCSP-BiTE antibody at doses of 10, 100, or 1000 ng/mL, all MCSP-expressing melanoma cell lines (n=23) were lysed in a dose-dependent and effector:target ratio-dependent manner, whereas there was no cytotoxic activity against MCSP-negative melanoma cell lines (n=2). To investigate whether T cells from melanoma patients could act as effector cells, we cocultured unstimulated PBMCs with allogeneic melanoma cells from 13 patients (4 stage I/II, 3 stage III, and 6 stage IV) or with autologous melanoma cells from 2 patients (stage IV). Although cytotoxic activity varied, all 15 PBMC samples mediated significant redirected lysis by the BiTE antibody. When PBMC or CD8 T cells were prestimulated by anti-CD3 antibody OKT-3 and interleukin-2, the MCSP-BiTE concentrations needed for melanoma cell lysis decreased up to 1000-fold. As MCSP is expressed on most human melanomas, immunotherapy with MCSP/CD3-bispecific antibodies merits clinical investigation.

  18. A 3-Year Follow-up of Sun Behavior in Patients With Cutaneous Malignant Melanoma

    DEFF Research Database (Denmark)

    Idorn, Luise Winkel; Datta, Pameli; Heydenreich, Jakob

    2014-01-01

    IMPORTANCE UV radiation (UVR) exposure is the primary environmental risk factor for developing cutaneous malignant melanoma (CMM). OBJECTIVE To measure changes in sun behavior from the first until the third summer after the diagnosis of CMM using matched controls as a reference. DESIGN, SETTING...... that measured time-related UVR in standard erythema dose (SED) and corresponding sun diaries (mean, 74 days per participant each participation year). RESULTS Patients' daily UVR dose and UVR dose in connection with various behaviors increased during follow-up (quantified as an increase in daily UVR dose each...... suggest that patients with CMM do not maintain a cautious sun behavior in connection with an increase in UVR exposure, especially on days with body exposure, when abroad, and on holidays....

  19. The role of FDG-PET/CT in preoperative staging of sentinel lymph node biopsy-positive melanoma patients

    DEFF Research Database (Denmark)

    Frary, Charles; Gad, Dorte; Bastholt, Lars;

    2016-01-01

    BACKGROUND: On April 1, 2015, Odense University Hospital (OUH) began a new diagnostic strategy, wherein all malignant melanoma (MM) patients in the Region of Southern Denmark with a positive sentinel lymph node biopsy (SLNB) underwent FDG-PET/CT preoperatively prior to lymph node dissection (LND...

  20. Benefit of adjuvant interferon alfa-2b (IFN-α) therapy in melanoma patients with high serum MMP-8 levels

    DEFF Research Database (Denmark)

    Vihinen, Pia; Tervahartiala, Taina; Sorsa, Timo

    2015-01-01

    Matrix metalloproteinases (MMPs) are important enzymes in tissue turnover and various inflammatory processes. In this study, it was evaluated whether serum MMP-8 can predict the response to adjuvant interferon alfa-2b (IFN-α) therapy in patients with operated high-risk cutaneous melanoma. Pre...

  1. Impact of sentinel node status and other risk factors on the clinical outcome of head and neck melanoma patients

    NARCIS (Netherlands)

    Leong, SPL; Accortt, NA; Essner, R; Ross, M; Gershenwald, JE; Pockaj, B; Hoekstra, HJ; Garberoglio, C; White, RL; Biel, M; Charney, K; Wanebo, H; Avisar, E; Vetto, J; Soong, SJ

    2006-01-01

    Objective: To determine the impact of sentinel lymph node (SLN) status and other risk factors on recurrence and overall survival in head and neck melanoma patients. Design: The SLN Working Group, based in San Francisco, Calif, with its 11 member centers, the John Wayne Cancer Institute, and The Univ

  2. Primary Dermal Melanoma in a Patient with a History of Multiple Malignancies: A Case Report with Molecular Characterization

    Directory of Open Access Journals (Sweden)

    Germana Sini

    2013-07-01

    Full Text Available Introduction: Primary dermal melanoma (PDM is a recently described clinical entity accounting for less than 1% of all melanomas. Histologically, it is located in the dermis or subcutaneous tissue, and it shows no connections with the overlying epidermis. The differential diagnosis is principally made along with that of metastatic cutaneous melanoma. Case Report: A 72-year-old Caucasian woman with a history of multiple cancers (metachronous bilateral breast cancer, meningioma, clear cell renal cell carcinoma, uterine fibromatosis and intestinal adenomatous polyposis, came to our attention with a nodular lesion on her back. After removal of the lesion, the histology report indicated malignant PDM or metastatic malignant melanoma. The clinical and instrumental evaluation of the patient did not reveal any other primary tumour, suggesting the primitive nature of the lesion. The absence of an epithelial component argued for a histological diagnosis of PDM. Subsequently, the patient underwent a wide surgical excision with sentinel node biopsy, which was positive for metastatic melanoma. Finally, the mutational status was studied in the main genes that regulate proliferation, apoptosis and cellular senescence. No pathogenetic mutations in CDKN2A, BRAF, NRAS, KRAS, cKIT, TP53 and PTEN genes were observed. This suggests that alternative pathways and low-frequency alterations may be involved. Conclusions: The differential diagnosis between PDM and isolated metastatic melanoma depends on the negativity of imaging studies and clinical findings for other primary lesions. This distinction is important because 5-year survival rates in such cases are higher than in metastatic cases (80-100 vs. 5-20%, respectively.

  3. Complete responses and long-term survivals after systemic chemotherapy for patients with advanced malignant melanoma.

    Science.gov (United States)

    Ahmann, D L; Creagan, E T; Hahn, R G; Edmonson, J H; Bisel, H F; Schaid, D J

    1989-01-15

    Five hundred three patients with advanced malignant melanoma were exposed to a number of clinical investigative chemotherapeutic regimens between 1971 and 1984 in an effort to assess the clinical activity of these regimens in this disease. Of the 503 patients participating in the studies, ten patients experienced a complete response. However, only three of these patients survived more than 5 years. Of this group of 503 patients, seven additional patients who did not experience a complete response survived more than five years. Of the ten patients surviving more than 5 years, two had immediate progression after institution of investigative regimens, whereas five remained stable for brief periods of time before progressive metastatic disease. Three patients experienced a complete response. It appeared that systemic therapeutic interventions in these trials were conspicuously ineffective for this large group of patients. A few long-term survivors attest to the capricious nature of this neoplasm and its association with likely spontaneous regressions. Although these long-term survivors did survive after institution of systemic chemotherapy, it is likely that this survival was related temporally, but perhaps not causally, to the institution of treatment.

  4. Nodal Melanoma Metastasis under Infliximab Therapy in a Patient with Nevoid Melanoma First Misdiagnosed as Benign Nevus: A Potentially Dangerous Diagnostic Pitfall in the Era of Biologic Therapies

    Directory of Open Access Journals (Sweden)

    Gilles Safa

    2013-10-01

    Full Text Available We report the case of a 53-year-old Caucasian woman who developed nodal melanoma metastasis under infliximab therapy 2 years after the removal of a nevoid melanoma, which was initially misdiagnosed as a benign compound nevus. This case illustrates the potential link between tumor necrosis factor (TNF-α inhibition and the reactivation of latent melanoma. Furthermore, this case highlights the need for a complete skin examination before using anti-TNF-α therapy to rule out atypical malignant lesions or melanomas that can easily be missed because of presentations such as nevoid melanoma.

  5. Thyroid dysfunction in 281 patients with metastatic melanoma or renal carcinoma treated with interleukin-2 alone.

    Science.gov (United States)

    Krouse, R S; Royal, R E; Heywood, G; Weintraub, B D; White, D E; Steinberg, S M; Rosenberg, S A; Schwartzentruber, D J

    1995-11-01

    The purpose of this prospective study was to determine the incidence of thyroid dysfunction in cancer patients receiving immunotherapy with interleukin-2 (IL-2) alone, and to assess the relationship of hypothyroidism to clinical response. A cohort of 281 consecutive patients with metastatic melanoma or renal carcinoma were treated with IL-2 alone from July 1, 1989 until June 30, 1993. The majority (n = 216) received high-dose IL-2 and the remainder (n = 65) received low-dose therapy. Thyroid function was measured before, during, and after immunotherapy. Forty-one percent of initially euthyroid patients developed thyroid dysfunction after starting high-dose IL-2-alone therapy. The most common abnormality was hypothyroidism, occurring in 35% of patients, although moderate or severe hypothyroidism requiring thyroid hormone replacement occurred in 9% of patients. Hypothyroidism was related to duration of IL-2 therapy and was not associated with clinical response. Hyperthyroidism developed in 7% of previously euthyroid patients receiving high-dose IL-2. Overall, the incidence of thyroid dysfunction was similar in the high- and low-dose IL-2 regimens. In conclusion, thyroid dysfunction is a common sequela of IL-2 therapy. Thyroid function should be measured routinely in cancer patients receiving IL-2-based treatment. It is recommended that thyroid hormone replacement be given to patients with moderate or severe hypothyroidism.

  6. Minimally invasive liver resection to obtain tumor-infiltrating lymphocytes for adoptive cell therapy in patients with metastatic melanoma

    Directory of Open Access Journals (Sweden)

    Alvarez-Downing Melissa M

    2012-06-01

    Full Text Available Abstract Background Adoptive cell therapy (ACT with tumor-infiltrating lymphocytes (TIL in patients with metastatic melanoma has been reported to have a 56% overall response rate with 20% complete responders. To increase the availability of this promising therapy in patients with advanced melanoma, a minimally invasive approach to procure tumor for TIL generation is warranted. Methods A feasibility study was performed to determine the safety and efficacy of laparoscopic liver resection to generate TIL for ACT. Retrospective review of a prospectively maintained database identified 22 patients with advanced melanoma and visceral metastasis (AJCC Stage M1c who underwent laparoscopic liver resection between 1 October 2005 and 31 July 2011. The indication for resection in all patients was to receive postoperative ACT with TIL. Results Twenty patients (91% underwent resection utilizing a closed laparoscopic technique, one required hand-assistance and another required conversion to open resection. Median intraoperative blood loss was 100 mL with most cases performed without a Pringle maneuver. Median hospital stay was 3 days. Three (14% patients experienced a complication from resection with no mortality. TIL were generated from 18 of 22 (82% patients. Twelve of 15 (80% TIL tested were found to have in vitro tumor reactivity. Eleven patients (50% received the intended ACT. Two patients were rendered no evidence of disease after surgical resection, with one undergoing delayed ACT with generated TIL after relapse. Objective tumor response was seen in 5 of 11 patients (45% who received TIL, with one patient experiencing an ongoing complete response (32+ months. Conclusions Laparoscopic liver resection can be performed with minimal morbidity and serve as an effective means to procure tumor to generate therapeutic TIL for ACT to patients with metastatic melanoma.

  7. Detection of ABCB5-tumour-antigen-specific CD8(+) T cells in Melanoma Patients and Implications for Immunotherapy.

    Science.gov (United States)

    Borchers, Sylvia; Masslo, Christoph; Müller, Christina Ann; Tahedl, Anika; Volkind, Jennifer; Nowak, Yvonne; Umansky, Viktor; Esterlechner, Jasmina; Frank, Markus Hermann; Ganss, Christoph; Kluth, Mark Andreas; Utikal, Jochen

    2017-09-23

    ABCB5 has been identified as a tumour initiating cell marker and is expressed in various malignancies, including melanoma. Moreover, treatment with anti-ABCB5 monoclonal antibodies has been shown to inhibit tumour growth in xenotransplantation models. Therefore, ABCB5 represents a potential target for cancer immunotherapy. However, cellular immune responses against ABCB5 in humans have not been described so far. Here, we investigated whether ABCB5-reactive T cells are present in human melanoma patients and tested the applicability of ABCB5-derived peptides for experimental induction of human T cell responses. Peripheral blood mononuclear cells (PBMNC) isolated from blood samples of melanoma patients (n=40) were stimulated with ABCB5 peptides, followed by intracellular cytokine staining (ICS) for IFN-γ and TNF-α. To evaluate immunogenicity of ABCB5 peptides in naïve healthy donors, CD8 T cells were co-cultured with ABCB5 antigen-loaded autologous dendritic cells (DC). ABCB5-reactivity in expanded T cells was likewise assessed by ICS. ABCB5-reactive CD8(+) T cells were detected ex vivo in 19 of 29 patients, MART-1-reactive CD8 T cells in 6 of 21 patients. In this small, heterogeneous cohort, reactivity against ABCB5 was significantly higher than against MART-1. It occurred significantly more often and independent of clinical characteristics. Reactivity against ABCB5 could be induced in 14 of 16 healthy donors in vitro by repeated stimulation with peptide-loaded autologous DC. Since ABCB5-reactive CD8 T cells can be found in the peripheral blood of melanoma patients and an ABCB5-specific response can be induced in vitro in naïve donors, ABCB5 could be a new target for immuno-therapies in melanoma. This article is protected by copyright. All rights reserved. © 2017 British Society for Immunology.

  8. Inoculation site from a cutaneous melanoma patient treated with an allogeneic therapeutic vaccine: a case report

    Directory of Open Access Journals (Sweden)

    Mariana eAris

    2015-03-01

    Full Text Available We have developed a therapeutic vaccine consisting of a mixture of lethally-irradiated allogeneic cutaneous melanoma cell lines with BCG and GM-CSF as adjuvants. The CSF-470 vaccine is currently being assayed in a Phase II-III trial against medium-dose IFN-a2b. All vaccinated patients immunized intradermally developed large edematous erythema reactions, which then transformed into subcutaneous nodules active for several months. However, vaccine injection sites were not routinely biopsied. We describe the case of a female patient, previously classified as stage III, but who, due to the simultaneous discovery of bone metastases, only received one vaccination, was withdrawn from the study and continued her treatment elsewhere. Patient #1 developed a post-vaccination nodule which was surgically removed 7 weeks later, and allowed to analyze the reactivity and immune profiling of the inoculation site. An inflammatory reaction with zones of fibrosis, high irrigation and brisk lymphoid infiltration, primarily composed of CD8+ and CD20+ lymphocytes, was observed. There were no remaining BCG bacilli, and scarce CD4+ and Foxp3+ T cells were observed. MART-1 Ag was found throughout the vaccination site. CD11c+ Ag presenting cells were either dispersed or forming dense nests. Some CD11c+ cells proliferated; most of them contained intracellular MART-1 Ag, and some interacted with CD8+ lymphocytes. These observations suggest a potent, long-lasting local inflammatory response with recruitment of Ag-presenting cells that incorporate melanoma Ags, probably leading to Ag presentation to naïve T cells.

  9. Autoimmunity Correlates With Tumor Regression in Patients With Metastatic Melanoma Treated With Anti–Cytotoxic T-Lymphocyte Antigen-4

    Science.gov (United States)

    Attia, Peter; Phan, Giao Q.; Maker, Ajay V.; Robinson, Michael R.; Quezado, Martha M.; Yang, James C.; Sherry, Richard M.; Topalian, Suzanne L.; Kammula, Udai S.; Royal, Richard E.; Restifo, Nicholas P.; Haworth, Leah R.; Levy, Catherine; Mavroukakis, Sharon A.; Nichol, Geoff; Yellin, Michael J.; Rosenberg, Steven A.

    2006-01-01

    Purpose Previously, we reported our experience treating 14 patients with metastatic melanoma using a fully human antibody to cytotoxic T-lymphocyte antigen-4 (anti–CTLA-4) in conjunction with peptide vaccination. We have now treated 56 patients to evaluate two different dose schedules of anti–CTLA-4 and to explore the relationship between autoimmunity and tumor regression. Patients and Methods A total of 56 patients with progressive stage IV melanoma were enrolled onto the study. All had Karnofsky performance status ≥60% with no prior history of autoimmunity. Twenty-nine patients received 3 mg/kg anti–CTLA-4 every 3 weeks, whereas 27 received 3 mg/kg as their initial dose with subsequent doses reduced to 1 mg/kg every 3 weeks. In both cohorts patients received concomitant vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). Results Two patients achieved a complete response (ongoing at 30 and 31 months, respectively) and five patients achieved a partial response (durations of 4, 6, 25+, 26+, and 34+ months, respectively), for an overall objective response rate of 13%. Tumor regression was seen in lung, liver, brain, lymph nodes, and subcutaneous sites. Of 14 patients with grade 3/4 autoimmune toxicity, five (36%) experienced a clinical response compared with only two responses in the 42 patients (5%) with no autoimmune toxicity (P = .008). There were no significant differences in response rate or toxicity between the two dose schedules. Conclusion Administration of anti–CTLA-4 monoclonal antibody plus peptide vaccination can cause durable objective responses, which correlate with the induction of autoimmunity, in patients with metastatic melanoma. PMID:16087944

  10. Preferences of German melanoma patients for interferon (IFN) α-2b toxicities (the DeCOG "GERMELATOX survey") versus melanoma recurrence to quantify patients' relative values for adjuvant therapy.

    Science.gov (United States)

    Kaehler, Katharina C; Blome, Christine; Forschner, Andrea; Gutzmer, Ralf; Haalck, Thomas; Heinzerling, Lucie; Kornek, Thomas; Livingstone, Elisabeth; Loquai, Carmen; Maul, Lara Valeska; Lang, Berenice M; Schadendorf, Dirk; Stade, Barbara; Terheyden, Patrick; Utikal, Jochen; Wagner, Tobias; Hauschild, Axel; Garbe, Claus; Augustin, Matthias

    2016-11-01

    Currently interferon alfa-2b (IFNα-2b) is an approved adjuvant drug for high-risk melanoma patients that leads to an improvement in disease-free survival (DFS). However, it is unclear whether it also impacts overall survival. Widespread use of adjuvant high-dose IFNα has been tempered by its significant toxicity and its limited efficacy. Current therapeutic strategies like immune checkpoint blockade or targeted therapy may also be useful in the adjuvant setting. Therefore, it is important to weigh the trade-offs between possible side effects and therapeutic benefit.We assessed patient utilities for health states associated with IFN therapy. Utilities are measures of preference for a specific health state on a scale of 0 (death) to 1 (perfect health).Utilities were determined for health states associated with adjuvant IFN among 130 German low-risk melanoma patients using the standard gamble technique. Four IFNα-2b toxicity scenarios and the following 3 posttreatment outcomes were assessed: disease-free health and melanoma recurrence (with or without previous use of IFNα-2b) resulting in cancer death. Patients were asked to trade-off the improvement in 5-year DFS and the IFN-related side effects.Utilities for melanoma recurrence (mean 0.60) were significantly lower than for all IFNα-2b toxicity scenarios (mean 0.81-0.90). Patients were willing to tolerate mild-to-moderate and severe toxicity for a 50% and 75% chance of 5-year DFS, respectively. Both utilities and threshold benefits were mostly independent from patient characteristics like gender, income, and social situation. Significant impact was only observed by age and previous personal experience with cancer.On average, German patients were willing to trade even severe IFNα-2b toxicity for reducing the rate of melanoma recurrence. This result points out the importance of a relapse-free survival for melanoma patients. The utilities measured in our study can be applied to decision-making processes in

  11. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis.

    Science.gov (United States)

    Dubin, Krista; Callahan, Margaret K; Ren, Boyu; Khanin, Raya; Viale, Agnes; Ling, Lilan; No, Daniel; Gobourne, Asia; Littmann, Eric; Huttenhower, Curtis; Pamer, Eric G; Wolchok, Jedd D

    2016-02-02

    The composition of the intestinal microbiota influences the development of inflammatory disorders. However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition. Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis. Here we conduct a prospective study of patients with metastatic melanoma undergoing ipilimumab treatment and correlate the pre-inflammation faecal microbiota and microbiome composition with subsequent colitis development. We demonstrate that increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis. Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis. Identification of these biomarkers may enable interventions to reduce the risk of inflammatory complications following cancer immunotherapy.

  12. Role of SPECT-CT in sentinel lymph node biopsy in patients diagnosed with head and neck melanoma.

    Science.gov (United States)

    López-Rodríguez, E; García-Gómez, F J; Álvarez-Pérez, R M; Martínez-Castillo, R; Borrego-Dorado, I; Fernández-Ortega, P; Zulueta-Dorado, T

    2016-01-01

    Assess the role of SPECT-CT in sentinel lymph node (SLN) biopsy in the accurate anatomical location of the SNL in patients with cutaneous head and neck melanoma. A retrospective study was conducted from February 2010 to June 2013 on 22 consecutive patients with a diagnosis of cutaneous head and neck melanoma (9 female, 13 male), with a mean age of 55 years old and who met the inclusion criteria for SLN biopsy. Patients underwent preoperative scanning after peri-scar injection of (99m)Tc-labeled-nanocolloid. Planar images of the injection-site, whole-body, and SPECT-CT scanning were acquired. Detection rate of SLN reached up to 91% (20/22 patients) by planar lymphoscintigraphy and 95.4% (21/22 patients) by SPECT-CT. SPECT-CT provided an accurate location of SLN in 14/22 patients, enabling to improve the surgical approach (clinical impact: 63.6%). SLN was positive for metastatic cells in 9.1% patients. SPECT-CT provides detailed anatomical SLN location and allows detecting a higher number of SLN than planar lymphoscintigraphy. Routine use of SPECT-CT is recommended in order to optimise the SLN detection and location in patients with head and neck melanoma. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

  13. Adoptive Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for the Treatment of Patients With Refractory Metastatic Melanoma

    Science.gov (United States)

    Dudley, Mark E.; Wunderlich, John R.; Yang, James C.; Sherry, Richard M.; Topalian, Suzanne L.; Restifo, Nicholas P.; Royal, Richard E.; Kammula, Udai; White, Don E.; Mavroukakis, Sharon A.; Rogers, Linda J.; Gracia, Gerald J.; Jones, Stephanie A.; Mangiameli, David P.; Pelletier, Michelle M.; Gea-Banacloche, Juan; Robinson, Michael R.; Berman, David M.; Filie, Armando C.; Abati, Andrea; Rosenberg, Steven A.

    2006-01-01

    Purpose We investigated the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of patients with refractory metastatic melanoma. Patients and Methods Thirty-five patients with metastatic melanoma, all but one with disease refractory to treatment with high-dose interleukin (IL)-2 and many with progressive disease after chemotherapy, underwent lymphodepleting conditioning with two days of cyclophosphamide (60 mg/kg) followed by five days of fludarabine (25 mg/m2). On the day following the final dose of fludarabine, all patients received cell infusion with autologous tumor-reactive, rapidly expanded tumor infiltrating lymphocyte cultures and high-dose IL-2 therapy. Results Eighteen (51%) of 35 treated patients experienced objective clinical responses including three ongoing complete responses and 15 partial responses with a mean duration of 11.5 ± 2.2 months. Sites of regression included metastases to lung, liver, lymph nodes, brain, and cutaneous and subcutaneous tissues. Toxicities of treatment included the expected hematologic toxicities of chemotherapy including neutropenia, thrombocytopenia, and lymphopenia, the transient toxicities of high-dose IL-2 therapy, two patients who developed Pneumocystis pneumonia and one patient who developed an Epstein-Barr virus-related lymphoproliferation. Conclusion Lymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes can mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma. PMID:15800326

  14. Dynamic infrared imaging of cutaneous melanoma and normal skin in patients treated with BNCT

    Energy Technology Data Exchange (ETDEWEB)

    Santa Cruz, G.A. [Dpto. de Instrumentacion y Control, Comision Nacional de Energia Atomica, Av. del Libertador 8250 (1429), Buenos Aires (Argentina)], E-mail: santacr@cnea.gov.ar; Bertotti, J.; Marin, J. [Universidad Favaloro, Solis 453 (1078), Buenos Aires (Argentina); Gonzalez, S.J. [Dpto. de Instrumentacion y Control, Comision Nacional de Energia Atomica, Av. del Libertador 8250 (1429), Buenos Aires (Argentina); CONICET, Avda. Rivadavia 1917 (1033), Buenos Aires (Argentina); Gossio, S. [FCEyN, Pabellon II, Ciudad Universitaria (1428), Buenos Aires (Argentina); Alvarez, D. [Fundacion Favaloro, Av. Belgrano 1746 (1093), Buenos Aires (Argentina); Roth, B.M.C.; Menendez, P. [Instituto de Oncologia Angel H. Roffo, Av. San Martin 5481 (1417), Buenos Aires (Argentina); Pereira, M.D. [Agencia Nacional de Promocion Cientifica y Tecnologica, PAV 22393 (Argentina); Albero, M.; Cubau, L.; Orellano, P. [INVAP S.E., F.P. Moreno 1089 (R8400AMU), S.C. de Bariloche, Rio Negro (Argentina); Liberman, S.J. [Dpto. de Instrumentacion y Control, Comision Nacional de Energia Atomica, Av. del Libertador 8250 (1429), Buenos Aires (Argentina)

    2009-07-15

    We recently initiated a program aimed to investigate the suitability of dynamic infrared imaging for following-up nodular melanoma patients treated with BNCT. The reason that makes infrared imaging attractive is the fact that it constitutes a functional and non-invasive imaging method, providing information on the normal and abnormal physiologic response of the nervous and vascular systems, as well as the local metabolic rate and inflammatory processes that ultimately appear as differences in the skin temperature. An infrared camera, with a focal plane array of 320x240 uncooled ferroelectric detectors is employed, which provides a video stream of the infrared emission in the 7-14 {mu}m wavelength band. A double blackbody is used as reference for absolute temperature calibration. After following a protocol for patient preparation and acclimatization, a basal study is performed. Subsequently, the anatomic region of interest is subjected to a provocation test (a cold stimulus), which induces an autonomic vasoconstriction reflex in normal structures, thus enhancing the thermal contrast due to the differences in the vasculature of the different skin regions. Radiation erythema reactions and melanoma nodules possess typically a faster temperature recovery than healthy, non-irradiated skin. However, some other non-pathological structures are also detectable by infrared imaging, (e.g. scars, vessels, arteriovenous anastomoses and injuries), thus requiring a multi-study comparison in order to discriminate the tumor signal. Besides the superficial nodules, which are readily noticeable by infrared imaging, we have detected thermal signals that are coincident with the location of non-palpable nodules, which are observable by CT and ultrasound. Diffuse regions of fast temperature recovery after a cold stimulus were observed between the third and sixth weeks post-BNCT, concurrent with the clinical manifestation of radiation erythema. The location of the erythematous visible and

  15. Local control after stereotactic radiosurgery for brain metastases in patients with melanoma with and without BRAF mutation and treatment.

    Science.gov (United States)

    Ly, David; Bagshaw, Hilary P; Anker, Christopher J; Tward, Jonathan D; Grossmann, Kenneth F; Jensen, Randy L; Shrieve, Dennis C

    2015-08-01

    BRAF inhibitors improve progression-free and overall survival in patients with metastatic melanoma. Brain metastases are common, and stereotactic radiosurgery (SRS) has been used, resulting in excellent local control. Because BRAF inhibitors are associated with intracranial responses, the authors hypothesized that BRAF inhibitors would improve local control in patients with melanoma who are receiving SRS for brain metastases. The authors retrospectively identified patients with metastatic melanoma who had been tested for BRAF mutation and treated with SRS for brain metastases. Patients with previous resection, multiple brain metastases, or multiple courses of SRS were eligible. SRS was delivered in a single fraction to a median dose of 2000 cGy. Patients with a BRAF mutation were treated with a BRAF inhibitor on the basis of physician preference. The authors identified 52 patients who were treated in 82 treatment sessions for 185 brain metastases and 13 tumor beds. At a median follow-up of 10.5 months, the 1-year local control rate was 69.2%. At 1 year, the local control rate for brain metastases in patients with BRAF mutation with BRAF treatment was 85.0%, and the local control rate for brain metastases in those without BRAF treatment was 51.5% (p = 0.0077). The rates of distant brain failure, freedom from whole-brain radiation, and overall survival were not different on the basis of BRAF mutation status or inhibitor therapy. The number of new intratumoral hemorrhages after SRS was increased significantly in patients with BRAF treatment. Treatment with BRAF inhibitors was associated with improved local control after SRS in patients with melanoma and brain metastases. An increased number of intratumoral hemorrhages was associated with BRAF inhibitor therapy.

  16. Familial malignant melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Kopf, A.W.; Hellman, L.J.; Rogers, G.S.; Gross, D.F.; Rigel, D.S.; Friedman, R.J.; Levenstein, M.; Brown, J.; Golomb, F.M.; Roses, D.F.; Gumport, S.L.

    1986-10-10

    Characteristics associated with familial compared with nonfamilial malignant melanoma were assessed. These data were obtained from consecutive prospectively completed questionnaires on 1169 cases of cutaneous malignant melanoma. Of these, 69 patients indicated a positive family history for this cancer. Among the various clinical and histological variables compared, those that significantly correlated with the familial occurrence of malignant melanoma include younger age at first diagnosis, smaller diameter of the lesion, lower Clark level, decreased frequency of nonmelanoma skin cancer, and reduced prevalence of noncutaneous cancer. Increased awareness of malignant melanoma among family members could account for some of these observations. Identification of the familial variety of malignant melanoma has practical implications concerning early detection and prompt intervention.

  17. Synchronous anorectal melanoma

    Institute of Scientific and Technical Information of China (English)

    Drinko Balicevic; Karla Tomic; Miroslav Bekavac-Beslin; Igor Kovacevic; August Mijic; Mladen Belicza; Bozo Kruslin

    2006-01-01

    Anorectal melanoma is a very rare tumor with poor prognosis. Rectal bleeding is the most frequent symptom and surgical treatment ranges from local excision to radical abdominoperineal resection. We report a case of a 75-years-old male patient who presented with a history of recurrent rectal bleeding, and whose histopathological diagnosis was melanoma. Macroscopically, we found two distinct tumors in anorectal region, 0.5 cm and 1.5 cm from dentate line. The first one was pedunculated, on a thin stalk, measuring 1 cm in greatest diameter, and the second one was sessile and nodular measuring up to 2.8 cm in largest diameter. Microscopic examination and immunohistochemical analysis of both tumors confirmed the diagnosis of melanoma. This case represents multiple synchronous primary melanoma of the anorectal region, with a possibility that one of the lesions is primary melanoma and the second one is a satellite lesion.

  18. Interleukin-6 and melanoma

    DEFF Research Database (Denmark)

    Hoejberg, Lise; Bastholt, Lars; Schmidt, Henrik

    2012-01-01

    Interleukin-6 (IL-6) is a pleiotropic immunomodulatory cytokine produced by various types of cells, including melanoma cells. IL-6 plays a major role in the pathogenesis and development of malignancies. It promotes tumour growth by inhibition of apoptosis and induces tumour angiogenesis. IL-6...... is deregulated in many types of cancers, and increased serum concentration of IL-6 has been correlated with a worse prognosis in patients with different cancers, including melanoma. Several serum cytokines including IL-6 play an important role in the development and progression of melanoma; however, the specific...... biological functions of IL-6 in progression of melanoma are unknown. In this review, we present studies on cell cultures and mouse models and summarize published clinical studies on IL-6 and melanoma....

  19. The role of FDG-PET/CT in preoperative staging of sentinel lymph node biopsy-positive melanoma patients

    DEFF Research Database (Denmark)

    Frary, Evan C; Gad, Dorte; Bastholt, Lars;

    2016-01-01

    BACKGROUND: On April 1, 2015, Odense University Hospital (OUH) began a new diagnostic strategy, wherein all malignant melanoma (MM) patients in the Region of Southern Denmark with a positive sentinel lymph node biopsy (SLNB) underwent FDG-PET/CT preoperatively prior to lymph node dissection (LND...... cohort study which included all patients with MM from all hospitals in the Region of Southern Denmark from April 1, 2015 to April 1, 2016 found to be SLNB-positive who subsequently underwent FDG-PET/CT. Patient information was acquired from the Danish Melanoma Database and was cross-referenced with OUH...... or uncover anything else of relevance. FDG-PET/CT did, however, provide false positive findings in 13 % (6/46) of these patients. These scans triggered additional, predominantly invasive, procedures, which did not ultimately have an impact on the therapeutic strategy. Thus, these findings indicate a need...

  20. Targeted therapies and immune checkpoint inhibitors in the treatment of metastatic melanoma patients: a guide and update for pathologists.

    Science.gov (United States)

    Kakavand, Hojabr; Wilmott, James S; Long, Georgina V; Scolyer, Richard A

    2016-02-01

    The previously dismal prospects for patients with advanced stage metastatic melanoma have greatly improved in recent years. Enhanced understanding of both the pathogenesis of melanoma and its molecular drivers, as well as the importance and regulation of anti-tumour immune responses, have provided new therapeutic opportunities for melanoma patients. There are two major distinct categories of systemic treatments with activity for patients with metastatic melanoma: (1) targeted therapies, which act to inhibit the oncogenes that drive the aberrant growth and dissemination of the tumour; and (2) immune checkpoint inhibitor therapies, which act to enhance anti-tumour immune responses by blocking negative regulators of immunity. Pathologists play a critical and expanding role in the selection of the most appropriate treatment for individual metastatic melanoma patients in the modern era of personalised/precision medicine. The molecular pathology testing of melanoma tumour tissue for the presence of targetable oncogenic mutations is already part of routine practice in many institutions. In addition, other potential oncogenic therapeutic targets continue to be identified and pathology testing techniques must readily adapt to this rapidly changing field. Recent research findings suggest that pathological assessment of tumour associated immune cells and immunosuppressive ligand expression of the tumour are likely to be important in identifying patients most likely to benefit from immune checkpoint inhibitors. Similarly, pathological and molecular observations of on-treatment tumour tissue biopsies taken from patients on targeted therapies have provided new insights into the mechanisms of action of targeted molecular therapies, have contributed to the identification of resistance mechanisms to these novel therapies and may be of higher value for selecting patients most likely to benefit from therapies. These data have already provided a rational biological basis for the

  1. Uveal melanoma: Estimating prognosis

    Directory of Open Access Journals (Sweden)

    Swathi Kaliki

    2015-01-01

    Full Text Available Uveal melanoma is the most common primary malignant tumor of the eye in adults, predominantly found in Caucasians. Local tumor control of uveal melanoma is excellent, yet this malignancy is associated with relatively high mortality secondary to metastasis. Various clinical, histopathological, cytogenetic features and gene expression features help in estimating the prognosis of uveal melanoma. The clinical features associated with poor prognosis in patients with uveal melanoma include older age at presentation, male gender, larger tumor basal diameter and thickness, ciliary body location, diffuse tumor configuration, association with ocular/oculodermal melanocytosis, extraocular tumor extension, and advanced tumor staging by American Joint Committee on Cancer classification. Histopathological features suggestive of poor prognosis include epithelioid cell type, high mitotic activity, higher values of mean diameter of ten largest nucleoli, higher microvascular density, extravascular matrix patterns, tumor-infiltrating lymphocytes, tumor-infiltrating macrophages, higher expression of insulin-like growth factor-1 receptor, and higher expression of human leukocyte antigen Class I and II. Monosomy 3, 1p loss, 6q loss, and 8q and those classified as Class II by gene expression are predictive of poor prognosis of uveal melanoma. In this review, we discuss the prognostic factors of uveal melanoma. A database search was performed on PubMed, using the terms "uvea," "iris," "ciliary body," "choroid," "melanoma," "uveal melanoma" and "prognosis," "metastasis," "genetic testing," "gene expression profiling." Relevant English language articles were extracted, reviewed, and referenced appropriately.

  2. NY-ESO-1-specific immunological pressure and escape in a patient with metastatic melanoma.

    Science.gov (United States)

    von Boehmer, Lotta; Mattle, Muriel; Bode, Peter; Landshammer, Alexandro; Schäfer, Carolin; Nuber, Natko; Ritter, Gerd; Old, Lloyd; Moch, Holger; Schäfer, Niklaus; Jäger, Elke; Knuth, Alexander; van den Broek, Maries

    2013-01-01

    During cancer progression, malignant cells may evade immunosurveillance. However, evidence for immunological escape in humans is scarce. We report here the clinical course of a melanoma patient whose initial tumor was positive for the antigens NY-ESO-1, MAGE-C1, and Melan-A. Upon immunization with a recombinant vaccinia/fowlpox NY-ESO-1 construct, the patient experienced a mixed clinical response and spreading of the NY-ESO-1 epitopes in the CD4+ T cell compartment. After NY-ESO-1 protein + CpG immunization, the patient's anti-NY-ESO-1 IgG response increased. Over the following years, progressing lesions were resected and found to be NY-ESO-1-negative while being positive for MAGE-C1, Melan-A, and MHC-I. The fatal, inoperable brain metastasis was analyzed after his death and also proved to be NY-ESO-1-negative, while being positive for MAGE-C1 and Melan-A, as well as MHC-I. We propose that cancer control and cancer escape in this patient were governed by NY-ESO-1-specific immunological pressure. Our findings provide evidence for the existence of immunoediting and immunoescape in this cancer patient.

  3. High-Dose Recombinant Interferon Alfa-2B, Ipilimumab, or Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery

    Science.gov (United States)

    2016-10-10

    Metastatic Non-Cutaneous Melanoma; Non-Cutaneous Melanoma; Recurrent Melanoma of the Skin; Recurrent Non-Cutaneous Melanoma; Stage III Mucosal Melanoma of the Head and Neck; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma; Stage IVA Mucosal Melanoma of the Head and Neck; Stage IVB Mucosal Melanoma of the Head and Neck; Stage IVC Mucosal Melanoma of the Head and Neck

  4. Vulval melanoma ;case report

    African Journals Online (AJOL)

    DR M.O.A. SAMAILA

    of exposure to sunlight and the amount of skin pigmentation present. ... radiation. The actual incidence of BCC world wide is not accurate because patients are often treated in. Physicians' ... McGovern V.S: The classification of melanoma.

  5. Melanoma genetics

    DEFF Research Database (Denmark)

    Read, Jazlyn; Wadt, Karin A W; Hayward, Nicholas K

    2016-01-01

    Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. Although the majority of genetic alterations associated with melanoma development are somatic, the underlying presence...... of heritable melanoma risk genes is an important component of disease occurrence. Susceptibility for some families is due to mutation in one of the known high penetrance melanoma predisposition genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP and TERT. However, despite such mutations being implicated...... in a combined total of approximately 50% of familial melanoma cases, the underlying genetic basis is unexplained for the remainder of high-density melanoma families. Aside from the possibility of extremely rare mutations in a few additional high penetrance genes yet to be discovered, this suggests a likely...

  6. Laser immunotherapy for treatment of patients with advanced breast cancer and melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Li Xiaosong [Department of Oncology, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing (China); Hode, Tomas; Guerra, Maria C [Immunophotonics Inc., 1601 South Providence Road, Columbia, Missouri 65211 (United States); Ferrel, Gabriela L [Hospital Nacional Edgardo Rebagliati Martins, Av. Edgardo Rebagliati 490 - Jesus Maria, Lima (Peru); Nordquist, Robert E [Wound Healing of Oklahoma, Inc., Oklahoma City, Oklahoma (United States); Chen, Wei R, E-mail: wchen@uco.edu [Department of Engineering and Physics, University of Central Oklahoma, Edmond, Oklahoma (United States)

    2011-02-01

    Laser immunotherapy (LIT) was developed for the treatment of metastatic tumors. It combines local selective photothermal interaction and active immunological stimulation to induce a long-term, systemic anti-tumor immunity. During the past sixteen years, LIT has been advanced from bench-top to bedside, with promising outcomes. In our pre-clinical and preliminary clinical studies, LIT has demonstrated the capability in inducing immunological responses, which not only can eradicate the treated primary tumors, but also can eliminate untreated metastases at distant sites. Specifically, LIT has been used to treat advanced melanoma and breast cancer patients during the past five years. LIT was shown to be effective in controlling both primary tumors and distant metastases in late-stage patients, who have failed conventional therapies such as surgery, chemotherapy, radiation, and other more advanced approaches. The methodology and the development of LIT are presented in this paper. The patients' responses to LIT are also reported in this paper. The preliminary results obtained in these studies indicated that LIT could be an effective modality for the treatment of patients with late-stage, metastatic cancers, who are facing severely limited options.

  7. Laser immunotherapy for treatment of patients with advanced breast cancer and melanoma

    Science.gov (United States)

    Li, Xiaosong; Hode, Tomas; Guerra, Maria C.; Ferrel, Gabriela L.; Nordquist, Robert E.; Chen, Wei R.

    2011-02-01

    Laser immunotherapy (LIT) was developed for the treatment of metastatic tumors. It combines local selective photothermal interaction and active immunological stimulation to induce a long-term, systemic anti-tumor immunity. During the past sixteen years, LIT has been advanced from bench-top to bedside, with promising outcomes. In our pre-clinical and preliminary clinical studies, LIT has demonstrated the capability in inducing immunological responses, which not only can eradicate the treated primary tumors, but also can eliminate untreated metastases at distant sites. Specifically, LIT has been used to treat advanced melanoma and breast cancer patients during the past five years. LIT was shown to be effective in controlling both primary tumors and distant metastases in late-stage patients, who have failed conventional therapies such as surgery, chemotherapy, radiation, and other more advanced approaches. The methodology and the development of LIT are presented in this paper. The patients' responses to LIT are also reported in this paper. The preliminary results obtained in these studies indicated that LIT could be an effective modality for the treatment of patients with late-stage, metastatic cancers, who are facing severely limited options.

  8. Comparison of prognostic indices in patients who undergo melanoma brain metastasis radiosurgery.

    Science.gov (United States)

    Kano, Hideyuki; Morales-Restrepo, Alejandro; Iyer, Aditya; Weiner, Gregory M; Mousavi, Seyed H; Kirkwood, John M; Tarhini, Ahmad A; Flickinger, John C; Lunsford, L Dade

    2017-01-20

    OBJECTIVE The goal of this study was to use 4 prognostic indices to compare survival times of patients who underwent Gamma Knife stereotactic radiosurgery (SRS) to treat melanoma brain metastases. METHODS The authors analyzed 422 consecutive patients (1440 brain metastases) who underwent Gamma Knife SRS. The median total brain tumor volume was 4.7 cm(3) (range 0.3-69.3 cm(3)), and the median number of metastases was 2 (range 1-32). One hundred thirty-two patients underwent whole-brain radiation therapy. Survival times were compared using recursive partitioning analysis (RPA), the Score Index for Radiosurgery (SIR), the Basic Score for Brain Metastases (BSBM), and the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA). RESULTS The overall survival times after SRS were compared. With the RPA index, survival times were 2.6 months (Class III, n = 27), 5.5 months (Class II, n = 348), and 13.0 months (Class I, n = 47). With the DS-GPA index, survival times were 2.8 months (Scores 0-1, n = 67), 4.2 months (Scores 1.5-2.0, n = 143), 6.6 months (Scores 2.5-3.0, n = 111), and 9.4 months (Scores 3.5-4.0, n = 101). With the SIR, survival times were 3.2 months (Scores 0-3, n = 56), 5.8 months (Scores 4-7, n = 319), and 12.7 months (Scores 8-10, n = 47). With the BSBM index, survival times were 2.6 months (BSBM0, n = 47), 5.4 months (BSBM1, n = 282), 11.0 months (BSBM2, n = 86), and 8.8 months (BSBM3, n = 7). The DS-GPA index was the most balanced by case numbers in each class and provided the overall best prognostic index for overall survival. CONCLUSIONS The DS-GPA index proved most balanced and predictive of survival for patients with melanoma who underwent SRS as part of management for brain metastases. Patients whose DS-GPA score was ≥ 2.5 had predictably improved survival times after SRS.

  9. Mucosal malignant melanoma - a clinical, oncological, pathological and genetic survey

    DEFF Research Database (Denmark)

    Mikkelsen, Lauge H; Larsen, Ann-Cathrine; von Buchwald, Christian

    2016-01-01

    melanoma must be excluded. Mutations in KIT are frequently found, while BRAF and NRAS mutations are rarely found - except in conjunctival melanomas that carry BRAF mutations. Mutations in the TERT promotor region are also found in mucosal melanomas. Complete surgical resection with free margins......Mucosal melanomas constitute 1.3% of all melanomas and they may develop in any mucosal membrane. Conjunctival melanomas (0.5/million/year) and melanomas in the sinonasal cavity (0.5/million/year) are the most common, followed by anorectal melanomas (0.4/million/year) and melanomas in the oral...... cavity (0.2/million/year). Anorectal melanoma occurs slightly more often in females, whereas oral melanoma has a male predilection. Mucosal melanoma most commonly develops in a patient's sixth or seventh decade of life, and no differences between races have been found except for sinonasal melanoma...

  10. Prognostic value of the standardized uptake value for {sup 18}F-fluorodeoxyglucose in patients with stage IIIB melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Bastiaannet, E.; Hoekstra, H.J. [University of Groningen, Department of Surgical Oncology, University Medical Centre Groningen, PO Box 30.001, Groningen (Netherlands); Hoekstra, O.S. [VU Amsterdam, Nuclear Medicine and PET Research, University Medical Centre, Amsterdam (Netherlands); Jong, J.R. de; Brouwers, A.H. [University of Groningen, Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen, Groningen (Netherlands); Suurmeijer, A.J.H. [University of Groningen, Department of Pathology, University Medical Centre Groningen, Groningen (Netherlands)

    2012-10-15

    FDG PET/CT is an excellent tool to detect melanoma metastases and also allows quantification of FDG uptake using standardized uptake value (SUV). The aim of this study was to prospectively investigate the potential prognostic value of SUV for disease-free survival (DFS) and disease-specific survival (DSS) for patients with stage IIIB melanoma. From November 2003 to March 2008, all consecutive patients were included in the present study. Inclusion criteria were: palpable, histology- or cytology-proven lymph node metastases of melanoma, and referred to the University Medical Centre Groningen for FDG PET and CT examination. Patients without distant metastases were evaluated. Multivariable survival analysis was performed to determine whether SUV was associated with DFS and DSS (Cox proportional hazard analysis). In 80 patients (without distant metastases, 65 %) SUV could be measured. Overall 5-year DFS was 41 % (95% CI 26-56 %) and 24 % (95% CI 12-38 %) in patients with a low and high SUVmean (p = 0.02), respectively. Overall 5-year DSS was 48 % (95% CI 31-62 %) and 30 % (95% CI 17-45 %) in patients with a low and high SUVmean (p = 0.04), respectively. In the multivariable analysis, SUVmean was associated with DFS (hazard ratio 1.7; p = 0.048), but was not associated with DSS (hazard ratio 1.6; p = 0.1). The number of positive nodes, extranodal growth and gender were also associated with survival. FDG uptake in clinically overt nodal melanoma metastases is inversely associated with DFS. Univariate analysis showed an association with DSS. However, after adjustment for potential confounders this association was no longer significant. If these findings are confirmed in larger studies, SUVmean could potentially be used (in addition to the number of positive nodes, tumour size and extranodal growth) as a factor in deciding on adjuvant systemic treatment. (orig.)

  11. The impact of nodal tumour burden on lymphoscintigraphic imaging in patients with melanomas

    Energy Technology Data Exchange (ETDEWEB)

    Kretschmer, Lutz; Bertsch, Hans Peter; Hellriegel, Simin; Thoms, Kai-Martin; Schoen, Michael Peter [Georg August University of Goettingen, Department of Dermatology, Venereology and Allergology, Goettingen (Germany); Bardzik, Pawel; Meller, Johannes; Sahlmann, Carsten Oliver [Georg-August-University of Goettingen, Department of Nuclear Medicine, Goettingen (Germany)

    2014-10-15

    To retrospectively study the influence of nodal tumour burden on lymphoscintigraphic imaging in 509 consecutive patients with melanomas. Bidirectional lymphatic drainage, the clear depiction of an afferent lymphatic vessel, time to depiction of the first sentinel lymph node (SLN) and number of depicted and excised nodes were recorded. Nodal tumour load was classified as SLN-negative, SLN micrometastases or macrometastases. In the overall population, using multivariate regression analysis, a short SLN depiction time was significantly associated with the depiction of a greater number of radioactive nodes, a short distance between the primary tumour site and the nodal basin, younger age and lower nodal tumour burden. The proportion of patients with clear depiction of an afferent lymphatic vessel depended on the nodal tumour load (46 % in SLN-negative patients, 57 % in SLN positive patients, and 69 % in patients with macrometastases; P = 0.009). Macrometastasis was significantly associated with delayed depiction of the first radioactive node and a greater number of depicted hotspots. In patients with clinically nonsuspicious nodes, i.e. the classical target group for SLN biopsy, clear depiction of an afferent vessel was significantly associated with a higher number of SLNs during dynamic acquisition, SLN micrometastasis and a higher overall number of metastatic lymph nodes after SLN biopsy plus completion lymphadenectomy. The excision of more than two SLNs did not increase the metastasis detection rate. In patients with bidirectional or tridirectional lymphatic drainage, the SLN positivity rates for the first, second and third basin were 25.4 %, 11.7 % and 0.0 %, respectively (P = 0.002). In patients with clinically nonsuspicious lymph nodes, clear depiction of an afferent lymph vessel may be a sign of micrometastasis. Macrometastasis is associated with prominent afferent vessels, delayed depiction of the first radioactive node and a higher number of depicted hotspots

  12. The impact of nodal tumour burden on lymphoscintigraphic imaging in patients with melanomas.

    Science.gov (United States)

    Kretschmer, Lutz; Bertsch, Hans Peter; Bardzik, Pawel; Meller, Johannes; Hellriegel, Simin; Thoms, Kai-Martin; Schön, Michael Peter; Sahlmann, Carsten Oliver

    2015-02-01

    To retrospectively study the influence of nodal tumour burden on lymphoscintigraphic imaging in 509 consecutive patients with melanomas. Bidirectional lymphatic drainage, the clear depiction of an afferent lymphatic vessel, time to depiction of the first sentinel lymph node (SLN) and number of depicted and excised nodes were recorded. Nodal tumour load was classified as SLN-negative, SLN micrometastases or macrometastases. In the overall population, using multivariate regression analysis, a short SLN depiction time was significantly associated with the depiction of a greater number of radioactive nodes, a short distance between the primary tumour site and the nodal basin, younger age and lower nodal tumour burden. The proportion of patients with clear depiction of an afferent lymphatic vessel depended on the nodal tumour load (46% in SLN-negative patients, 57% in SLN positive patients, and 69% in patients with macrometastases; P = 0.009). Macrometastasis was significantly associated with delayed depiction of the first radioactive node and a greater number of depicted hotspots. In patients with clinically nonsuspicious nodes, i.e. the classical target group for SLN biopsy, clear depiction of an afferent vessel was significantly associated with a higher number of SLNs during dynamic acquisition, SLN micrometastasis and a higher overall number of metastatic lymph nodes after SLN biopsy plus completion lymphadenectomy. The excision of more than two SLNs did not increase the metastasis detection rate. In patients with bidirectional or tridirectional lymphatic drainage, the SLN positivity rates for the first, second and third basin were 25.4%, 11.7% and 0.0 %, respectively (P = 0.002). In patients with clinically nonsuspicious lymph nodes, clear depiction of an afferent lymph vessel may be a sign of micrometastasis. Macrometastasis is associated with prominent afferent vessels, delayed depiction of the first radioactive node and a higher number of depicted

  13. Prognostic factors of melanoma patients with satellite or in-transit metastasis at the time of stage III diagnosis.

    Directory of Open Access Journals (Sweden)

    Benjamin Weide

    Full Text Available BACKGROUND: Prognosis of patients with loco-regional skin metastases has not been analyzed in detail and the presence or absence of concurrent lymph node metastasis represents the only established prognostic factor thus far. Most studies were limited to patients already presenting with skin lesions at the time of initial diagnosis. We aimed to analyze the impact of a broad penal of prognostic factors in patients with skin metastases at the time of first metastatic spread, including patients with synchronous lesions already present at the time of initial diagnosis, stage I/II patients with loco-regional recurrence and patients initially presenting with skin metastasis but unknown primary melanoma. PATIENTS AND METHODS: We investigated disease-specific survival of 380 patients treated at our department between 1996 and 2010 using Kaplan Meier survival probabilities and Cox-proportional hazard analysis. RESULTS: Five-year survival probability was 60.1% for patients with skin metastases only and 36.3% for those with synchronous nodal metastases. The number of involved nodes and a tumor thickness of at least 3 mm had independent negative impact on prognosis. A strong relationship was identified between the risk of death and the number of involved nodes. Neither ulceration nor the timing of the first occurrence of metastases as either in stage I/II patients, at the time of excision of the primary melanoma or initially in patients with unknown primary tumor, had additional effects on survival. CONCLUSION: Lymph node involvement was confirmed as the most important prognostic factor for melanoma patients with loco-regional skin metastasis including those with unknown primary tumor and stage I/II patients with skin recurrence. Consideration of the tumor thickness and of the number of involved lymph nodes instead of the exclusive differentiation into presence vs. absence of nodal disease may allow a more accurate prediction of prognosis for patients with

  14. Adoptive TIL Transfer in the Adjuvant Setting for Melanoma: Long-Term Patient Survival

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    Amir Khammari

    2014-01-01

    Full Text Available Two first analyses of our clinical trial on TIL as adjuvant therapy for melanoma were published in 2002 and 2007. We present here an update of the clinical results after a 17-year median followup. In this trial, disease-free patients were randomly assigned to receive either TIL/IL-2 or IL-2. The relapse-free survival (RFS was the primary objective. Eighty-eight patients were enrolled. A new analysis performed in May 2013 did not show significant changes in RFS or OS duration. However, our first finding on the association between the number of invaded lymph nodes and TIL effectiveness was strengthened. The Cox model adjusted on this interaction showed for the first time a significant treatment effect when considering the overall population, both on the RFS and OS. Patients treated with TIL had a longer RFS (P=0.023 or OS (P=0.020. This study being with a very long followup (17 years, confirmed the association between TIL effectiveness and the number of invaded lymph nodes, indicating that a low tumor burden could be a crucial factor enhancing the curative effect of TIL in possible microscopic residual disease. Moreover, we confirmed that a prolonged survival was associated with the presence of specific TIL and a decrease in Foxp3 expression.

  15. Assessment of Patients Who Underwent Nasal Reconstruction After Non-Melanoma Skin Cancer Excision.

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    Uzun, Hakan; Bitik, Ozan; Kamburoğlu, Haldun Onuralp; Dadaci, Mehmet; Çaliş, Mert; Öcal, Engin

    2015-06-01

    Basal and squamous cell carcinomas are the most common malignant cutaneous lesions affecting the nose. With the rising incidence of skin cancers, plastic surgeons increasingly face nasal reconstruction challenges. Although multiple options exist, optimal results are obtained when "like is used to repair like". We aimed to introduce a simple algorithm for the reconstruction of nasal defects with local flaps, realizing that there is always more than one option for reconstruction. We retrospectively reviewed 163 patients who underwent nasal reconstruction after excision of non-melanoma skin cancer between March 2011 and April 2014. We analyzed the location of the defects and correlated them with the techniques used to reconstruct them. There were 66 males and 97 females (age, 21-98 years). Basal cell carcinoma was diagnosed in 121 patients and squamous cell carcinoma in 42. After tumor excision, all the defects were immediately closed by either primary closure or local flap options such as Limberg, Miter, glabellar, bilobed, nasolabial, V-Y advancement, and forehead flaps. Obtaining tumor-free borders and a pleasing aesthetic result are major concerns in nasal reconstruction. Defect reconstruction and cosmesis are as important as rapid recovery and quick return to normal daily activities, and these should be considered before performing any procedure, particularly in elderly patients.

  16. Phase II Trial of Bevacizumab in Combination With Temozolomide as First-Line Treatment in Patients With Metastatic Uveal Melanoma

    Science.gov (United States)

    Diallo, Alhassane; Etienne-Grimaldi, Marie-Christine; Bidard, François-Clément; Rodrigues, Manuel; Plancher, Corine; Mariani, Pascale; Cassoux, Nathalie; Decaudin, Didier; Asselain, Bernard; Servois, Vincent

    2016-01-01

    Lessons Learned Trials dedicated to metastatic uveal melanoma are needed because of the poor prognosis of this rare cancer and because its biology is distinct from that of cutaneous melanoma. Agents targeting the MEK/ERK/MAP kinase pathways are being tested. Background. In experimental models, bevacizumab suppressed in vitro growth and in vivo hepatic metastasis of ocular melanoma cells. Additional preclinical data suggested a potential benefit when combining bevacizumab with dacarbazine. Methods. This noncomparative phase II study evaluated a combination of bevacizumab (10 mg/kg on days 8 and 22) with temozolomide (150 mg/m2 on days 1–7 and 15–21) in 36 patients with metastatic uveal melanoma (MUM). The primary endpoint was the progression-free rate (PFR) at 6 months. Using a modified 2-step Fleming plan, at least 10 of 35 patients were required to support a predefined PFR at 6 months of 40%. Secondary objectives were progression-free survival (PFS), overall survival (OS), and safety; liver perfusion computed tomography (CT) for response imaging; and impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics. Results. First- and second-step analyses revealed nonprogression at 6 months in 3 of 17 and 8 of 35 patients, respectively. Finally, the 6-month PFR was 23% (95% confidence interval [CI]: 10–39), with long-lasting stable disease in 5 patients (14%). Median PFS and OS were 12 weeks and 10 months, respectively. No unexpected toxicity occurred. Liver perfusion CT imaging was not useful in assessing tumor response, and VEGF-A gene polymorphisms were not correlated with toxicity or survival. Conclusion. In patients with MUM, a combination of bevacizumab plus temozolomide achieved a 6-month PFR of 23%. PMID:26911405

  17. Phase II trial of sorafenib in combination with carboplatin and paclitaxel in patients with metastatic uveal melanoma: SWOG S0512.

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    Shailender Bhatia

    Full Text Available BACKGROUND: Sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, inhibits the mitogen-activated protein kinase pathway that is activated in most uveal melanoma tumors. This phase II study was conducted by the SWOG cooperative group to evaluate the efficacy of sorafenib in combination with carboplatin and paclitaxel (CP in metastatic uveal melanoma. METHODS: Twenty-five patients with stage IV uveal melanoma who had received 0-1 prior systemic therapy were enrolled. Treatment included up to 6 cycles of carboplatin (AUC = 6 and paclitaxel (225 mg/m(2 administered IV on day 1 plus sorafenib (400 mg PO twice daily, followed by sorafenib monotherapy until disease progression. The primary endpoint was objective response rate (ORR; a two-stage design was used with the study to be terminated if no confirmed responses were observed in the first 20 evaluable patients. Secondary efficacy endpoints included progression-free survival (PFS and overall survival (OS. RESULTS: No confirmed objective responses occurred among the 24 evaluable patients (ORR = 0% [95% CI: 0-14%] and the study was terminated at the first stage. Minor responses (tumor regression less than 30% were seen in eleven of 24 (45% patients. The median PFS was 4 months [95% CI: 1-6 months] and the 6-month PFS was 29% [95% CI: 13%-48%]. The median OS was 11 months [95% CI: 7-14 months]. CONCLUSION: In this study, the overall efficacy of CP plus sorafenib in metastatic uveal melanoma did not warrant further clinical testing when assessed by ORR, although minor tumor responses and stable disease were observed in some patients. TRIAL REGISTRATION: ClinicalTrials.govNCT00329641.

  18. BRAF, KIT and NRAS mutations and expression of c-KIT, phosphorylated extracellular signal-regulated kinase and phosphorylated AKT in Japanese melanoma patients.

    Science.gov (United States)

    Oyama, Satomi; Funasaka, Yoko; Watanabe, Atsushi; Takizawa, Toshihiro; Kawana, Seiji; Saeki, Hidehisa

    2015-05-01

    To clarify the status of gene mutation and activation of growth signal in melanoma of Japanese patients in vivo, we analyzed the mutation of BRAF exon 15, NRAS exon 2, and KIT exons 9, 11, 13, 17 and 18 in melanoma cells obtained by laser capture microdissection, and performed direct sequencing in 20 cases of acral lentiginous melanoma (ALM) and 17 cases of superficial spreading melanoma (SSM). In the study of the mutation of BRAF, pyrosequencing was also done. To examine the cell proliferation signaling, immunohistochemistry for phosphorylated extracellular signal-regulated kinase (pERK), phosphorylated AKT (phosphorylated AKT) and c-KIT was done. The mutation of BRAF p.V600E was detected in 13 cases of ALM (65.0%) and 12 cases of SSM (70.6%). No NRAS mutation was found in all cases. The mutation in exons 9, 11, and 18 of KIT was detected in nine cases. The mutation of BRAF and KIT showed no correlation with clinical stage, lymph node metastasis, tumor thickness, ulceration and histology. pERK and pAKT was observed in small population of melanoma cells and there was no correlation with gene mutation. Our results indicate that the mutations of BRAF and KIT exist in Japanese melanoma patients, however, the cell growth signaling may be regulated by not only these mutated genes, but by other unknown regulatory factors, which may affect the prognosis of melanoma.

  19. GNA11 Mutation in a Patient With Cutaneous Origin Melanoma: A Case Report.

    Science.gov (United States)

    Patel, Sapna P; Kim, Dae Won; Lacey, Carol L; Hwu, Patrick

    2016-01-01

    The rapid advances in the molecular biology and genetics have improved the understanding of molecular pathogenesis of v-Raf murine sarcoma viral oncogene homolog B (BRAF), feline sarcoma viral oncogene v-kit (KIT), and neuroblastoma v-Ras oncogene homolog (NRAS) mutant melanomas with the subsequent development of targeted therapeutic agents. However, only limited data are available for melanoma harboring other somatic than BRAF, KIT, and NRAS mutations. Mutations in guanine nucleotide-binding protein Q polypeptide (GNAQ) and guanine nucleotide-binding protein alpha-11 (GNA11), alpha subunits of heterotrimeric G proteins, constitutively activate mitogen-activated protein kinase (MAPK) pathway in uveal melanoma. However, there are no reports of GNA11 mutations in cutaneous melanomas. A 48-year-old woman was diagnosed with cutaneous nodular melanoma on the left scalp. Mutation analysis of the tumor revealed a GNA11 Q209L mutation. There was no evidence of uveal melanoma or malignant blue nevus in ophthalmologic exam, imaging studies, and pathology review. To our knowledge, this is the first case report to demonstrate cutaneous origin melanoma harboring a GNA11 Q209L mutation.

  20. Whole brain radiotherapy after local treatment of brain metastases in melanoma patients - a randomised phase III trial

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    Forder Peta M

    2011-04-01

    Full Text Available Abstract Background Cerebral metastases are a common cause of death in patients with melanoma. Systemic drug treatment of these metastases is rarely effective, and where possible surgical resection and/or stereotactic radiosurgery (SRS are the preferred treatment options. Treatment with adjuvant whole brain radiotherapy (WBRT following neurosurgery and/or SRS is controversial. Proponents of WBRT report prolongation of intracranial control with reduced neurological events and better palliation. Opponents state melanoma is radioresistant; that WBRT yields no survival benefit and may impair neurocognitive function. These opinions are based largely on studies in other tumour types in which assessment of neurocognitive function has been incomplete. Methods/Design This trial is an international, prospective multi-centre, open-label, phase III randomised controlled trial comparing WBRT to observation following local treatment of intracranial melanoma metastases with surgery and/or SRS. Patients aged 18 years or older with 1-3 brain metastases excised and/or stereotactically irradiated and an ECOG status of 0-2 are eligible. Patients with leptomeningeal disease, or who have had previous WBRT or localised treatment for brain metastases are ineligible. WBRT prescription is at least 30 Gy in 10 fractions commenced within 8 weeks of surgery and/or SRS. Randomisation is stratified by the number of cerebral metastases, presence or absence of extracranial disease, treatment centre, sex, radiotherapy dose and patient age. The primary endpoint is the proportion of patients with distant intracranial failure as determined by MRI assessment at 12 months. Secondary end points include: survival, quality of life, performance status and neurocognitive function. Discussion Accrual to previous trials for patients with brain metastases has been difficult, mainly due to referral bias for or against WBRT. This trial should provide the evidence that is currently lacking in

  1. Metastatic melanoma of the heart.

    Science.gov (United States)

    Savoia, P; Fierro, M T; Zaccagna, A; Bernengo, M G

    2000-11-01

    Malignant melanoma has an unpredictable biologic behavior and is the neoplasm with the greatest propensity for cardiac involvement. Although relatively frequent at autopsy, cardiac metastases are rarely identified antemortem. We reviewed 2,810 patients with histologically confirmed malignant melanoma, who were diagnosed and followed up by our clinic. Clinical, histological, and imaging data are presented. Five cases of metastatic melanoma of the heart were identified out of 314 melanoma patients with visceral involvement. One case of a 53-year-old woman, who died unexpectedly during her first chemotherapy course, is described in detail. Postmortem examination determined the cause of death to be the presence of multiple melanoma metastases in the heart, even though the patient had shown no signs of cardiac involvement. The unpredictable biologic behavior of melanoma may lead to unusual metastatic sites, and, therefore, the heart also should be included in routine examinations. Copyright 2000 Wiley-Liss, Inc.

  2. Use of neoadjuvant electrochemotherapy to treat a large metastatic lesion of the cheek in a patient with melanoma

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    Mozzillo Nicola

    2012-06-01

    Full Text Available Abstract Background Approximately 200,000 new cases of melanoma are diagnosed worldwide each year. Skin metastases are a frequent event, occurring in 18.2% of cases. This can be distressing for the patient, as the number and size of cutaneous lesions increases, often worsened by ulceration, bleeding and pain. Electrochemotherapy (ECT is a local modality for the treatment of cutaneous or subcutaneous tumors that allows delivery of low- and non-permeant drugs into cells. ECT has been used in palliative management of metastatic melanoma to improve patients’ quality of life. This is, to our knowledge, the first application of ECT as neoadjuvant treatment of metastatic subcutaneous melanoma. Methods and results A 44-year-old Caucasian woman underwent extensive surgical resection of a melanoma, with a Breslow thickness of 1.5 mm, located on the right side of her scalp. No further treatment was given and the woman remained well until she came to our attention with a large nodule in her right cheek. Whole-body fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT was performed for staging and treatment monitoring. Baseline FDG PET/CT showed the lesion in the cheek to have a maximal standardized uptake value (SUVmax of 19.5 with no evidence of further disease spread. Fine needle aspiration cytology confirmed the presence of metastatic melanoma. The patient underwent two sessions of ECT with intravenous injections of bleomycin using a CliniporatorTM as neoadjuvant treatment permitting conservative surgery three months later. Follow-up PET/CT three months after the first ECT treatment showed a marked decrease in SUVmax to 5. Further monitoring was performed through monthly PET/CT studies. Multiple cytology examinations showed necrotic tissue. Conservative surgery was carried out three months after the second ECT. Reconstruction was easily achieved through a rotation flap. Pathological examination of the specimen showed

  3. BM-16INCREASED ACUTE RADIATION EFFECT (ARE) WITH IPILUMUMAB AND RADIOSURGERY IN PATIENTS WITH MELANOMA BRAIN METASTASES

    Science.gov (United States)

    Khoja, Leila; Kurtz, Goldie; Zadeh, Gelareh; Laperriere, Normand; Menard, Cynthia; Millar, Barbara-Ann; Bernstein, Mark; Kongkham, Paul; Joshua, Anthony; Hogg, David; Butler, Marcus; Chung, Caroline

    2014-01-01

    BACKGROUND: Ipilumumab (Ipi), an antibody that enhances T-cell activation, has been shown to improve survival in patients with metastatic melanoma. Ipilumumab may have synergistic effects with radiotherapy but this may result in increased toxicity. This study investigated the incidence of acute radiation effect (ARE) in patients with melanoma brain metastases treated with Ipi and radiosurgery (SRS) or whole brain radiotherapy (WBRT). METHODOLOGY: This retrospective study included metastatic melanoma patients treated at our institution from 2008-2013 who received SRS or WBRT for brain metastases within 4 months of Ipi treatment. We evaluated the incidence, timing and factors associated with acute radiation effect (ARE). RESULTS: From 159 patients treated with Ipi, 22 patients also received brain RT within 4 months of treatment. Three patients were excluded for lack of follow-up brain imaging, thus 19 were analysed: 14 males and 5 females, with median age 58 years (range 24-82). Ten were treated with SRS, 7 with WBRT, and 2 with SRS plus WBRT. Median dose for SRS was 21 Gy (range: 15-24 Gy). Five of 13 patients treated with SRS (38%) experienced symptomatic edema requiring steroids within 1 month of starting Ipi, and within 4 months of RT. One patient had a haemorrhage and 1 required surgical resection, which demonstrated viable disease. Therefore 3 patients (23%) treated with SRS developed isolated ARE. These metastases had volumes less than 4.2 cm3 and were treated within 4 months of Ipi to a median dose of 19.5 Gy (range 15-21 Gy). No patients with WBRT alone developed ARE. CONCLUSIONS: Following SRS for brain mets and Ipi, ARE was seen in 23% of patients within 4 months of starting Ipi treatment. This is greater than the commonly reported 10% risk of ARE after SRS alone for brain metastasis. No increased toxicity was seen with WBRT and Ipi.

  4. Natural killer T cells in advanced melanoma patients treated with tremelimumab.

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    F Javier Ibarrondo

    Full Text Available A significant barrier to effective immune clearance of cancer is loss of antitumor cytotoxic T cell activity. Antibodies to block pro-apoptotic/downmodulatory signals to T cells are currently being tested. Because invariant natural killer T cells (iNKT can regulate the balance of Th1/Th2 cellular immune responses, we characterized the frequencies of circulating iNKT cell subsets in 21 patients with melanoma who received the anti-CTLA4 monoclonal antibody tremelimumab alone and 8 patients who received the antibody in combination with MART-126-35 peptide-pulsed dendritic cells (MART-1/DC. Blood T cell phenotypes and functionality were characterized by flow cytometry before and after treatment. iNKT cells exhibited the central memory phenotype and showed polyfunctional cytokine production. In the combination treatment group, high frequencies of pro-inflammatory Th1 iNKT CD8(+ cells correlated with positive clinical responses. These results indicate that iNKT cells play a critical role in regulating effective antitumor T cell activity.

  5. Comparison of survival rates for patients with uveal melanoma after treatment with proton beam irradiation or enucleation

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    Seddon, J.M.; Gragoudas, E.S.; Albert, D.M.; Hsieh, C.C.; Polivogianis, L.; Friedenberg, G.R.

    1985-03-15

    A comparison was made of survival experiences for three groups with uveal melanoma: (1) 120 patients treated by proton beam irradiation from 1975 to 1981; (2) 235 patients treated by enucleation from 1953 to 1973 (enucleation group 1); and (3) 161 patients treated by enucleation from 1975 to 1981 (enucleation group 2). The following variables were predictive of melanoma-related deaths. Treatment: rate ratio (ratio of the rate of death for one category of the variable relative to the rate of death for another category) of 6.32 (95% confidence interval 1.70 to 23.51) for enucleation group 1 vs proton beam, 3.06 (0.81 to 11.54) for enucleation group 2 vs proton beam, and 2.07 (1.05 to 4.07) for enucleation group 1 vs enucleation group 2. Size: rate ratio of 3.61 (1.51 to 8.64) for large (16+ mm) vs small (less than 11 mm) tumors. Location: rate ratio of 3.19 (1.56 to 6.53) for tumors anterior vs posterior to the equator. When death from all causes was evaluated as the outcome, the estimated rate ratios were similar. When melanoma metastasis was evaluated as the outcome, the estimated rate ratios were reduced in magnitude.

  6. BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts.

    Science.gov (United States)

    Kemper, Kristel; Krijgsman, Oscar; Kong, Xiangjun; Cornelissen-Steijger, Paulien; Shahrabi, Aida; Weeber, Fleur; van der Velden, Daphne L; Bleijerveld, Onno B; Kuilman, Thomas; Kluin, Roel J C; Sun, Chong; Voest, Emile E; Ju, Young Seok; Schumacher, Ton N M; Altelaar, A F Maarten; McDermott, Ultan; Adams, David J; Blank, Christian U; Haanen, John B; Peeper, Daniel S

    2016-06-28

    The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAF(V600E), NRAS(Q61), or BRAF(WT)/NRAS(WT) melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAF(V600E) protein harboring a kinase domain duplication (BRAF(V600E/DK)) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAF(V600E/DK) depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF(V600E/DK)-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.

  7. Expression of MAGE-C1/CT7 and MAGE-C2/CT10 predicts lymph node metastasis in melanoma patients.

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    Alessandra Curioni-Fontecedro

    Full Text Available MAGE-C1/CT7 and MAGE-C2/CT10 are members of the large MAGE family of cancer-testis (CT antigens. CT antigens are promising targets for immunotherapy in cancer because their expression is restricted to cancer and germ line cells and a proportion of cancer patients presents with immune responses against CT antigens, which clearly demonstrates their immunogenicity. This study investigates the expression of MAGE-C1/CT7 and MAGE-C2/CT10 in primary and metastatic melanoma. Immunohistochemical staining of tissue microarrays that consisted of 59 primary malignant melanomas of the skin, 163 lymph node and distant melanoma metastases and 68 melanoma cell lines was performed. We found MAGE-C1/CT7 expression in 15 out of 50 (24% primary melanomas and 15 out of 50 (24% cell lines, whereas MAGE-C2/CT10 was detected in 17 out of 51 (33% primary melanomas and 14 out of 68 (17% cell lines. MAGE-C1/CT7 and MAGE-C2/CT10 were both detected in 40% of melanoma metastases. Patients with MAGE-C1/CT7 or MAGE-C2/CT10 positive primary melanoma had significantly more lymph node metastases (p = 0.005 and p<0.001, resp.. Prediction of lymph node metastasis by MAGE-C1/CT7 and MAGE-C2/CT10 was independent of tumor cell proliferation rate (Ki67 labeling index in a multivariate analysis (p = 0.01. Our results suggest that the expression of MAGE-C1/CT7 and MAGE-C2/CT10 in primary melanoma is a potent predictor of sentinel lymph node metastasis.

  8. Proteomics in uveal melanoma.

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    Ramasamy, Pathma

    2014-01-01

    Uveal melanoma is the most common primary intraocular malignancy in adults, with an incidence of 5-7 per million per year. It is associated with the development of metastasis in about 50% of cases, and 40% of patients with uveal melanoma die of metastatic disease despite successful treatment of the primary tumour. The survival rates at 5, 10 and 15 years are 65%, 50% and 45% respectively. Unlike progress made in many other areas of cancer, uveal melanoma is still poorly understood and survival rates have remained similar over the past 25 years. Recently, advances made in molecular genetics have improved our understanding of this disease and stratification of patients into low risk and high risk for developing metastasis. However, only a limited number of studies have been performed using proteomic methods. This review will give an overview of various proteomic technologies currently employed in life sciences research, and discuss proteomic studies of uveal melanoma.

  9. Microincisional vitrectomy for retinal detachment in I-125 brachytherapy-treated patients with posterior uveal malignant melanoma

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    Lonngi M

    2013-02-01

    Full Text Available Marcela Lonngi,1 Samuel K Houston,1 Timothy G Murray,1–3 Robert A Sisk,4 Christina L Decatur,1 Milena Cavalcante,1 Arnold M Markoe31Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, FL, USA; 2Murray Ocular Oncology and Retina, Miami, FL, USA; 3Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA; 4Department of Ophthalmology, Cincinnati Eye Institute, Cincinnati, OH, USAPurpose: To analyze functional and anatomical outcomes following 23/25+ gauge microincisional pars plana vitrectomy surgery (MIVS in patients with radiation-related retinal detachment after successful 125-iodine (I-125 brachytherapy treatment for malignant uveal melanoma.Patients and methods: Retrospective case series of 102 consecutive eyes of 102 patients with history of uveal melanoma treated with I-125 brachytherapy that underwent MIVS at the Bascom Palmer Eye Institute. All cases were evaluated for surgical complications and local tumor control. Extended follow-up included Snellen’s best-corrected visual acuity, intraocular pressure evaluation, quantitative echography, indirect ophthalmoscopy, and fundus imaging with optical coherence tomography/wide-field photography.Results: All patients had radiation-related complications, including retinal detachment (102 eyes, vasculopathy (91 eyes, optic neuropathy (32 eyes, and/or vitreous hemorrhage (8 eyes. Sixty-seven patients had vitreoretinal traction. Average follow-up after MIVS was 19.5 months, and from plaque removal was 57.7 months. Interval from plaque to MIVS was 38.1 months. Initial visual acuity was 20/258, which improved to 20/101 at 1 month, 20/110 at 3 months, 20/116 at 6 months, and 20/113 at 12 months (P < 0.05. No eyes required enucleation. Melanoma-related mortality was 0.9% (1/102. There was no intra- or extraocular tumor dissemination, and no tumor recurrence.Conclusion: MIVS was effective in improving

  10. Phase 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041).

    Science.gov (United States)

    Yamazaki, Naoya; Takenouchi, Tatsuya; Fujimoto, Manabu; Ihn, Hironobu; Uchi, Hiroshi; Inozume, Takashi; Kiyohara, Yoshio; Uhara, Hisashi; Nakagawa, Kazuhiko; Furukawa, Hiroshi; Wada, Hidefumi; Noguchi, Kazuo; Shimamoto, Takashi; Yokota, Kenji

    2017-04-01

    This phase I b study evaluated the safety and anti-tumor activity of pembrolizumab in Japanese patients with advanced melanoma. Pembrolizumab (2 mg/kg) was given every 3 weeks (Q3W) for up to 2 years or until confirmed progression or unacceptable toxicity. The tumor response was assessed as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by both investigator review and central review. Forty-two patients with advanced melanoma received pembrolizumab. A primary cutaneous histology was observed in 34 patients (81.0%), while a primary mucosal histology was observed in 8 patients (19.0%). Thirty-four patients (81.0%) experienced treatment-related adverse events (AEs). The most common treatment-related AEs were pruritus, maculopapular rash, malaise, and hypothyroidism. Grade 3-5 treatment-related AEs occurred in 8 patients (19.0%). The only grade 3-5 treatment-related AE reported in at least two patients was anemia. There were two treatment-related deaths (unknown cause and cerebral hemorrhage). Among the 37 evaluable patients, the confirmed overall response rates (ORRs) determined by central review were 24.1% (95% CI 10.3-43.5) for cutaneous melanoma and 25.0% (95% CI 3.2-65.1) for mucosal melanoma. The responses were durable, and the median duration of response was not reached in either population. The median overall survival (OS) was not reached, with a 12-month OS of 82.7% for cutaneous melanoma and 51.4% for mucosal melanoma. The safety profile of pembrolizumab in Japanese patients was similar to that reported in the previous clinical studies. Pembrolizumab provided promising anti-tumor activity in Japanese patients with advanced melanoma.

  11. Prognostic Factors Related to Clinical Response in Patients with Metastatic MelanomaTreated by CTL-Associated Antigen-4 Blockade

    Science.gov (United States)

    Downey, Stephanie G.; Klapper, Jacob A.; Smith, Franz O.; C.Yang, James; Sherry, Richard M.; Royal, Richard E.; Kammula, Udai S.; Hughes, Marybeth S.; Allen, Tamika E.; Levy, Catherine L.; Michael, Yellin; Nichol, Geoffrey; E.White, Donald; Steinberg, Seth M.; Rosenberg, Steven A.

    2007-01-01

    Purpose CTL-associated antigen 4 (CTLA-4) can inhibit T-cell activation and helps maintain peripheral self-tolerance. Previously, we showed immune-related adverse events (IRAE) and objective, durable clinical responses in patients with metastatic melanoma treated with CTLA-4 blockade.We have now treated139 patients in two trials and have sufficient follow-up to examine factors associated with clinical response. Experimental Design A total of 139 patients with metastatic melanoma were treated: 54 patients received ipilimumab in conjunction with peptide vaccinations and 85 patients were treated with intrapatient dose escalation of ipilimumab and randomized to receive peptides in accordance with HLA-A*0201status. Results Three patients achieved complete responses (CR; ongoing at 29+, 52+, and 53+ months); an additional 20 patients achieved partial responses (PR) for an overall objective response rate of 17%. The majority of patients (62%, 86 of 139) developed some form of IRAE, which was associated with a greater probability of objective antitumor response (P = 0.0004); all patients with CR had more severe IRAEs. Prior therapy with IFNα-2b was a negative prognostic factor, whereas prior high-dose interleukin-2 did not significantly affect the probability of response. There were no significant differences in the rate of clinical response or development of IRAEs between the two trials. The duration of tumor response was not affected by the use of high-dose steroids for abrogation of treatment-related toxicities (P = 0.23). There were no treatment-related deaths. Conclusion In patients with metastatic melanoma, ipilimumab can induce durable objective clinical responses, which are related to the induction of IRAEs. PMID:17982122

  12. Bortezomib improves progression-free survival in multiple myeloma patients overexpressing preferentially expressed antigen of melanoma

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    Qin Yazhen; Lu Jin; Bao Li; Zhu Honghu; Li Jinlan; Li Lingdi; Lai Yueyun

    2014-01-01

    Background Significant efforts have been made to identify factors that differentiate patients treated with novel therapies,such as bortezomib in multiple myeloma (MM).The exact expression pattern and prognostic value of the cancer/testis antigen preferentially expressed antigen of melanoma (PRAME) in MM are unknown and were explored in this study.Methods The transcript level of PRAME was detected in bone marrow specimens from 100 newly diagnosed MM patients using real-time quantitative polymerase chain reaction,and the prognostic value of PRAME was determined through retrospective survival analysis.PRAME expression higher than the upper limit of normal bone marrow was defined as PRAME overexpression or PRAME (+).Results Sixty-two patients (62.0%) overexpressed PRAME.PRAME overexpression showed no prognostic significance to either overall survival (n=100) or progression-free survival (PFS,n=96,all P >0.05) of patients.The patients were also categorized according to regimens with or without bortezomib.PRAME overexpression tended to be associated with a lower two-year PFS rate in patients treated with non-bortezomib-containing regimens (53.5% vs.76.9%,P=0.071).By contrast,it was not associated with the two-year PFS rate in patients with bortezomib-containing regimens (77.5% vs.63.9%,P >0.05).When the patients were categorized into PRAME (+) and PRAME (-) groups,treatment with bortezomib-containing regimens predicted a higher two-year PFS rate in PRAME (+) patients (77.5% vs.53.5%,P=0.027) but showed no significant effect on two-year PFS rate in PRAME (-) patients (63.9% vs.76.9%,P >0.05).Conclusion PRAME overexpression might be an adverse prognostic factor of PFS in MM patients treated with non-bortezomib-containing regimens.Bortezomib improves PFS in patients overexpressing PRAME.

  13. Isolated Malignant Melanoma Metastasis to the Pancreas

    Directory of Open Access Journals (Sweden)

    Anne K. Larsen, MD

    2013-11-01

    Full Text Available Summary: Malignant melanomas rarely develop isolated pancreatic metastases. We describe a unique patient who is still alive 22 years following an isolated pancreatic melanoma metastasis, and we review the sparse literature in the field.

  14. Nodular Histologic Subtype and Ulceration are Tumor Factors Associated with High Risk of Recurrence in Sentinel Node-Negative Melanoma Patients.

    Science.gov (United States)

    Faut, Marloes; Wevers, Kevin P; van Ginkel, Robert J; Diercks, Gilles F H; Hoekstra, Harald J; Kruijff, Schelto; Been, Lukas B; van Leeuwen, Barbara L

    2017-01-01

    Since its introduction, the sentinel lymph node biopsy (SLNB) has become the standard staging procedure in clinical node-negative melanoma patients. A negative SLNB, however, does not guarantee a recurrence-free survival. Insight into metastatic patterns and risk factors for recurrence in SLNB negative melanoma patients can provide patient tailored guidelines. Data concerning melanoma patients who underwent SLNB between 1996 and 2015 in a single center were prospectively collected. Cox regression analyses were used to determine variables associated with overall recurrence and distant first site of recurrence in SLNB-negative patients. In 668 patients, SLNBs were performed between 1996 and 2015. Of these patients, 50.4 % were male and 49.6 % female with a median age of 55.2 (range 5.7-88.8) years. Median Breslow thickness was 2.2 (range 0.3-20) mm. The SLNB was positive in 27.8 % of patients. Recurrence rates were 53.2 % in SLNB-positive and 17.9 % in SLNB-negative patients (p < 0.001). For SLNB-negative patients, the site of first recurrence was distant in 58.5 %. Melanoma located in the head and neck region (hazard ratio 4.88, p = 0.003) and increasing Breslow thickness (hazard ratio 1.15, p = 0.013) were predictive for distant first site of recurrence in SLNB-negative patients. SLNB-negative patients with a nodular melanoma and ulceration had a recurrence rate of 43.1 %; the site of recurrence was distant in 64 % of these patients. The recurrence rates of SLNB-negative nodular ulcerative melanoma patients approach those of SLNB-positive patients. Stringent follow-up is recommended in this subset of patients.

  15. The Knowledge, Perception, and Attitude of Patients Living with ...

    African Journals Online (AJOL)

    to determine the knowledge, perception, and attitude of patients living with glaucoma ... diagnosed glaucoma patients attending the eye clinic of the hospital during the ..... Michielutte R, Diseker RA, Stafford CL, Carr P. Knowledge of diabetes.

  16. Donor Transmission of Melanoma Following Renal Transplant

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    Kathryn T. Chen

    2012-01-01

    Full Text Available Donor transmission of melanoma is one of the more common and lethal of recipient malignancies, often presenting with systemic disease. Although some patients may receive durable remission of melanoma following explantation of the allograft and withdrawal of immunosuppression, donor transmission of melanoma is fatal in most patients. Here we present a case of a 44-year-old male who developed metastatic melanoma following renal transplant.

  17. Donor transmission of melanoma following renal transplant.

    Science.gov (United States)

    Chen, Kathryn T; Olszanski, Anthony; Farma, Jeffrey M

    2012-01-01

    Donor transmission of melanoma is one of the more common and lethal of recipient malignancies, often presenting with systemic disease. Although some patients may receive durable remission of melanoma following explantation of the allograft and withdrawal of immunosuppression, donor transmission of melanoma is fatal in most patients. Here we present a case of a 44-year-old male who developed metastatic melanoma following renal transplant.

  18. Isolated malignant melanoma metastasis to the pancreas

    DEFF Research Database (Denmark)

    Larsen, Anne K; Krag, Christen; Geertsen, Poul

    2013-01-01

    SUMMARY: Malignant melanomas rarely develop isolated pancreatic metastases. We describe a unique patient who is still alive 22 years following an isolated pancreatic melanoma metastasis, and we review the sparse literature in the field.......SUMMARY: Malignant melanomas rarely develop isolated pancreatic metastases. We describe a unique patient who is still alive 22 years following an isolated pancreatic melanoma metastasis, and we review the sparse literature in the field....

  19. Eosinophilic Fasciitis and Acute Encephalopathy Toxicity from Pembrolizumab Treatment of a Patient with Metastatic Melanoma.

    Science.gov (United States)

    Khoja, Leila; Maurice, Catherine; Chappell, MaryAnne; MacMillan, Leslie; Al-Habeeb, Ayman S; Al-Faraidy, Nada; Butler, Marcus O; Rogalla, Patrik; Mason, Warren; Joshua, Anthony M; Hogg, David

    2016-03-01

    Anti-PD-1 inhibitors have significant activity in metastatic melanoma. Responses often occur early and may be sustained. The optimal duration of treatment with these agents is unknown. Here, we report the case of a 51-year-old woman treated with pembrolizumab, as part of the Keynote-001 trial, as first-line treatment for metastatic disease. She experienced a complete response after 13.8 months of treatment with no adverse events. One month after the last drug infusion and 18 months from starting treatment, the patient presented with eosinophilic fasciitis. She then developed acute confusion and weakness, thought to be due to intracranial vasculitis. High-dose steroids were initiated with resolution of the fasciitis. Aspirin was commenced for presumed vasculitis with resolution of the neurologic symptoms. To our knowledge, there are no previous reports of eosinophilic fasciitis or cerebral vasculitis due to anti-PD-1 agents. This case demonstrates that toxicity may occur in association with pembrolizumab treatment after a prolonged period of treatment without toxicity. Future trials should explore the optimal duration of treatment with pembrolizumab.

  20. Effect of vaccination with N-glycolyl GM3/VSSP vaccine by subcutaneous injection in patients with advanced cutaneous melanoma.

    Science.gov (United States)

    Osorio, Marta; Gracia, Elias; Reigosa, Edmundo; Hernandez, Julio; de la Torre, Ana; Saurez, Giselle; Perez, Kirenia; Viada, Carmen; Cepeda, Meylán; Carr, Adriana; Avila, Yisel; Rodríguez, Migdalia; Fernandez, Luis E

    2012-01-01

    NeuGc-containing gangliosides have been described in melanoma cells and are an attractive target for cancer immunotherapy because they are minimally or not expressed in normal human tissues. Melanoma patients treated with a vaccine based on N-glycolyl gangliosides have shown benefit in progression free survival and overall survival. We conducted a multicenter Phase I/II clinical trial in patients with metastatic cutaneous melanoma treated with the N-gycolyl GM3/very-small-size proteoliposomes vaccine by the subcutaneous route. Selecting the optimal biological dose of the vaccine was the principal objective based on immunogenicity, efficacy, and safety results. Six dose levels were studied and the treatment schedule consisted of five doses administered every 2 weeks and then monthly until 15 doses had been given. Dose levels evaluated were 150, 300, 600, 900, 1200, and 1500 μg with five patients included in each dose level except the 900 μg dose (n = 10). Immunogenicity was determined by antibody titers generated in patients after vaccination. Antitumor effect was measured by response criteria of evaluation in solid tumors and safety was evaluated by common toxicity criteria of adverse events. The vaccine was safe and immunogenic at all doses levels. The most frequent adverse events related to vaccination were mild to moderate injection site reactions and flu-like symptoms. Vaccination induced specific anti-NeuGcGM3 immunoglobulin M and immunoglobulin G antibody responses in all patients. Disease control (objective response or stable disease) was obtained in 38.46% of patients. Global median overall survival was 20.20 months. Two patients achieved overall survival duration of about 4 and 5 years, respectively. The 900 μg dose resulted in overall survival duration of 19.40 months and was selected as the biological optimal dose.

  1. The Danish Melanoma Database

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    Hölmich Lr

    2016-10-01

    Full Text Available Lisbet Rosenkrantz Hölmich,1 Siri Klausen,2 Eva Spaun,3 Grethe Schmidt,4 Dorte Gad,5 Inge Marie Svane,6,7 Henrik Schmidt,8 Henrik Frank Lorentzen,9 Else Helene Ibfelt10 1Department of Plastic Surgery, 2Department of Pathology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, 3Institute of Pathology, Aarhus University Hospital, Aarhus, 4Department of Plastic and Reconstructive Surgery, Breast Surgery and Burns, Rigshospitalet – Glostrup, University of Copenhagen, Copenhagen, 5Department of Plastic Surgery, Odense University Hospital, Odense, 6Center for Cancer Immune Therapy, Department of Hematology, 7Department of Oncology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, 8Department of Oncology, 9Department of Dermatology, Aarhus University Hospital, Aarhus, 10Registry Support Centre (East – Epidemiology and Biostatistics, Research Centre for Prevention and Health, Glostrup – Rigshospitalet, University of Copenhagen, Glostrup, Denmark Aim of database: The aim of the database is to monitor and improve the treatment and survival of melanoma patients.Study population: All Danish patients with cutaneous melanoma and in situ melanomas must be registered in the Danish Melanoma Database (DMD. In 2014, 2,525 patients with invasive melanoma and 780 with in situ tumors were registered. The coverage is currently 93% compared with the Danish Pathology Register.Main variables: The main variables include demographic, clinical, and pathological characteristics, including Breslow’s tumor thickness, ± ulceration, mitoses, and tumor–node–metastasis stage. Information about the date of diagnosis, treatment, type of surgery, including safety margins, results of lymphoscintigraphy in patients for whom this was indicated (tumors > T1a, results of sentinel node biopsy, pathological evaluation hereof, and follow-up information, including recurrence, nature, and treatment hereof is registered. In case of death, the cause and date

  2. Common glycoproteins expressing polylactosamine-type glycans on matched patient primary and metastatic melanoma cells show different glycan profiles.

    Science.gov (United States)

    Kinoshita, Mitsuhiro; Mitsui, Yosuke; Kakoi, Naotaka; Yamada, Keita; Hayakawa, Takao; Kakehi, Kazuaki

    2014-02-07

    Recently, we reported comparative analysis of glycoproteins which express cancer-specific N-glycans on various cancer cells and identified 24 glycoproteins having polylactosamine (polyLacNAc)-type N-glycans that are abundantly present in malignant cells [ Mitsui et al., J. Pharm. Biomed. Anal. 2012 , 70 , 718 - 726 ]. In the present study, we applied the technique to comparative studies on common glycoproteins present in the matched patient primary and metastatic melanoma cell lines. Metastatic melanoma cells (WM266-4) contained a large amount of polyLacNAc-type N-glycans in comparison with primary melanoma cells (WM115). To identify the glycoproteins expressing these N-glycans, glycopeptides having polyLacNAc-type N-glycans were captured by a Datura stramonium agglutinin (DSA)-immobilized agarose column. The captured glycopeptides were analyzed by LC/MS after removing N-glycans, and some glycoproteins such as basigin, lysosome-associated membrane protein-1 (LAMP-1), and chondroitin sulfate proteoglycan 4 (CSPG4) were identified in both WM115 and WM266-4 cells. The expression level of polyLacNAc of CSPG4 in WM266-4 cells was significantly higher than that in WM115 cells. In addition, sulfation patterns of chondroitin sulfate (CS) chains in CSPG4 showed dramatic changes between these cell lines. These data show that characteristic glycans attached to common proteins observed in different stages of cancer cells will be useful markers for determining degree of malignancies of tumor cells.

  3. Stereotactic Radiosurgery for Melanoma Brain Metastases in Patients Receiving Ipilimumab: Safety Profile and Efficacy of Combined Treatment

    Energy Technology Data Exchange (ETDEWEB)

    Kiess, Ana P. [Department of Radiation Oncology, Johns Hopkins University, Baltimore, Maryland (United States); Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Wolchok, Jedd D. [Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Barker, Christopher A. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Postow, Michael A. [Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Tabar, Viviane [Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Huse, Jason T. [Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Chan, Timothy A.; Yamada, Yoshiya [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Beal, Kathryn, E-mail: bealk@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2015-06-01

    Purpose: Ipilimumab (Ipi), a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, has been shown to improve survival in patients with metastatic melanoma. In this single-institution study, we investigated the safety and efficacy of stereotactic radiosurgery (SRS) for patients with melanoma brain metastases (BMs) who also received Ipi. Methods and Materials: From 2005 to 2011, 46 patients with melanoma received Ipi and underwent single-fraction SRS for BMs. A total of 113 BMs (91% intact, 9% postoperative) were treated with a median dose of 21 Gy (range, 15-24 Gy). Ipi was given at 3 mg/kg (54%) or 10 mg/kg (46%) for a median of 4 doses (range, 1-21). Adverse events were recorded with the use of the Common Terminology Criteria for Adverse Events 3.0. Kaplan-Meier methods were used to estimate survival, and Cox regression was used to investigate associations. Results: Fifteen patients received SRS during Ipi, 19 received SRS before Ipi, and 12 received SRS after Ipi. Overall survival (OS) was significantly associated with the timing of SRS/Ipi (P=.035) and melanoma-specific graded prognostic assessment (P=.013). Patients treated with SRS during or before Ipi had better OS and less regional recurrence than did those treated with SRS after Ipi (1-year OS 65% vs 56% vs 40%, P=.008; 1-year regional recurrence 69% vs 64% vs 92%, P=.003). SRS during Ipi also yielded a trend toward less local recurrence than did SRS before or after Ipi (1-year local recurrence 0% vs 13% vs 11%, P=.21). On magnetic resonance imaging, an increase in BM diameter to >150% was seen in 50% of patients treated during or before Ipi but in only 13% of patients treated after Ipi. Grade 3 to 4 toxicities were seen in 20% of patients. Conclusion: Overall, the combination of Ipi and SRS appears to be well tolerated. Concurrent delivery of Ipi and SRS is associated with favorable locoregional control and possibly longer survival. It may also cause a temporary increase in tumor size, possibly

  4. Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96 in patients with metastatic melanoma

    Directory of Open Access Journals (Sweden)

    Bedikian Agop Y

    2010-01-01

    Full Text Available Abstract Background Glycoprotein-96, a non-polymorphic heat-shock protein, associates with intracellular peptides. Autologous tumor-derived heat shock protein-peptide complex 96 (HSPPC-96 can elicit potent tumor-specific T cell responses and protective immunity in animal models. We sought to investigate the feasibility, safety, and antitumor activity of HSPPC-96 vaccines prepared from tumor specimens of patients with metastatic melanoma. Methods Patients with a Karnofsky Performance Status >70% and stage III or stage IV melanoma had to have a metastasis >3 cm in diameter resectable as part of routine clinical management. HSPPC-96 tumor-derived vaccines were prepared in one of three dose levels (2.5, 25, or 100 μg/dose and administered as an intradermal injection weekly for 4 consecutive weeks. In vivo induction of immunity was evaluated using delayed-type hypersensitivity (DTH to HSPPC-96, irradiated tumor, and dinitrochlorobenzene (DNCB. The γ-interferon (IFNγ ELISPOT assay was used to measure induction of a peripheral blood mononuclear cell response against autologous tumor cells at baseline and at the beginning of weeks 3, 4, and 8. Results Among 36 patients enrolled, 72% had stage IV melanoma and 83% had received prior systemic therapy. The smallest tumor specimen from which HSPPC-96 was prepared weighed 2 g. Twelve patients (including 9 with stage IV and indicator lesions had a negative DNCB skin test result at baseline. All 36 patients were treated and evaluable for toxicity and response. There were no serious toxicities. There were no observed DTH responses to HSPPC-96 or to autologous tumor cells before or during treatment. The IFNγ-producing cell count rose modestly in 5 of 26 patients and returned to baseline by week 8, with no discernible association with HSPPC-96 dosing or clinical parameters. There were no objective responses among 16 patients with stage IV disease and indicator lesions. Among 20 patients treated in the adjuvant

  5. Impact of (18)F-FDG-PET/CT on surgical management in patients with advanced melanoma: an outcome based analysis.

    Science.gov (United States)

    Forschner, Andrea; Olthof, Susann-Cathrin; Gückel, Brigitte; Martus, Peter; Vach, Werner; la Fougère, Christian; Nikolaou, Konstantin; Keim, Ulrike; Eigentler, Thomas Kurt; Garbe, Claus; Pfannenberg, Christina

    2017-08-01

    To evaluate the influence of (18)F-FDG-PET/CT on clinical decision making and outcome in advanced melanoma patients planned for radical metastasectomy. A cohort of 333 patients with mainly stage III/IV melanoma having a PET/CT for clinical reasons was prospectively enrolled in our oncologic PET/CT registry between 2013 and 2015. Referring physicians completed questionnaires regarding their intended management for each patient before and after PET/CT. Management changes after PET/CT were classified as major and minor changes. A subgroup of 107 patients (stage I, N = 5; stage II, N = 3; stage III, N = 42; stage IV, N = 57) was planned for complete metastasectomy initially, based on conventional imaging. Management changes and outcome were evaluated by linkage with the information obtained from patients' medical records. In 28 of 107 patients (26%), the surgical treatment plan remained unchanged after PET/CT. In 24 patients (22%), minor changes were performed, such as enlargement or reduction of the surgical field. In 55 patients (51%, 95% CI 42%-61%) major changes of the intended treatment plan occurred; of those, 20 patients (19%) were classified to be tumor-free with PET/CT, 32 patients (30%) were found to have multiple previously unrecognized metastases and had to be treated by systemic therapy, three patients (3%) had to be changed to palliative radiotherapy or isolated extremity perfusion. The 1-year and 2-year overall survival (OS) in patients with complete metastasectomy (N = 52) was 90% and 79%, respectively. Systemically treated patients (N = 32) resulted in 1-year OS of 72% and 2-year OS of 61%. Eleven of 32 patients (34%) with systemic therapy experienced a complete response. Until December 2016, all 20 patients classified as tumor-free by PET/CT were alive. The study confirms the high impact of PET/CT on clinical management in patients with advanced melanoma planned for radical metastasectomy. PET/CT resulted in frequent management

  6. Oncogenes in melanoma: an update.

    Science.gov (United States)

    Kunz, Manfred

    2014-01-01

    Melanoma is a highly aggressive tumour with poor prognosis in the metastatic stage. BRAF, NRAS, and KIT are three well-known oncogenes involved in melanoma pathogenesis. Targeting of mutated BRAF kinase has recently been shown to significantly improve overall survival of metastatic melanoma patients, underscoring the particular role of this oncogene in melanoma biology. However, recurrences regularly occur within several months, which supposedly involve further oncogenes. Moreover, oncogenic driver mutations have not been described for up to 30% of all melanomas. In order to obtain a more complete picture of the mutational landscape of melanoma, more recent studies used high-throughput DNA sequencing technologies. A number of new oncogene candidates such as MAPK1/2, ERBB4, GRIN2A, GRM3, RAC1, and PREX2 were identified. Their particular role in melanoma biology is currently under investigation. Evidence for the functional relevance of some of these new oncogene candidates has been provided in in vitro and in vivo experiments. However, these findings await further validation in clinical studies. This review provides an overview on well-known melanoma oncogenes and new oncogene candidates, based on recent high-throughput sequencing studies. The list of genes discussed herein is of course not complete but highlights some of the most significant of recent findings in this area. The new candidates may support more individualized treatment approaches for metastatic melanoma patients in the future.

  7. A 3-year follow-up of sun behavior in patients with cutaneous malignant melanoma.

    Science.gov (United States)

    Idorn, Luise Winkel; Datta, Pameli; Heydenreich, Jakob; Philipsen, Peter Alshede; Wulf, Hans Christian

    2014-02-01

    IMPORTANCE UV radiation (UVR) exposure is the primary environmental risk factor for developing cutaneous malignant melanoma (CMM). OBJECTIVE To measure changes in sun behavior from the first until the third summer after the diagnosis of CMM using matched controls as a reference. DESIGN, SETTING, AND PARTICIPANTS Three-year follow-up, observational, case-control study performed from May 7 to September 22, 2009, April 17 to September 15, 2010, and May 6 to July 31, 2011, at a university hospital in Denmark of 21 patients with CMM and 21 controls matched to patients by sex, age, occupation, and constitutive skin type participated in the study. Exposure to UVR was assessed the first and second summers (n=20) and the first and third summers (n=22) after diagnosis. Data from 40 participants were analyzed. MAIN OUTCOMES AND MEASURES Exposure to UVR was assessed by personal electronic UVR dosimeters that measured time-related UVR in standard erythema dose (SED) and corresponding sun diaries (mean, 74 days per participant each participation year). RESULTS Patients' daily UVR dose and UVR dose in connection with various behaviors increased during follow-up (quantified as an increase in daily UVR dose each year; all days: mean, 0.3 SED; 95% CI, 0.05-0.5 SED; days with body exposure: mean, 0.6 SED; 95% CI, 0.07-1.2 SED; holidays: mean, 1.2 SED; 95% CI, 0.3-2.1 SED; days abroad: 1.9 SED; 95% CI, 0.4-3.4 SED; and holidays with body exposure: mean, 2.3 SED; 95% CI, 1.1-3.4 SED). After the second year of follow-up, patients' UVR dose was higher than that of controls, who maintained a stable UVR dose. No difference was found between groups in the number of days with body exposure or the number of days using sunscreen in the second and third years of follow-up. CONCLUSIONS AND RELEVANCE Our findings suggest that patients with CMM do not maintain a cautious sun behavior in connection with an increase in UVR exposure, especially on days with body exposure, when abroad, and on holidays.

  8. Management of melanoma during pregnancy.

    Science.gov (United States)

    Leachman, Sancy A; Jackson, Ryan; Eliason, Mark J; Larson, April A; Bolognia, Jean L

    2007-04-01

    There is no conclusive evidence that pregnancy adversely affects overall survival in patients with melanoma. Clinicians caring for pregnant patients should be as suspicious of changes in melanocytic nevi in these patients as they are for nonpregnant patients. Treatment of early-stage melanoma is the same irrespective of whether or not the patient is pregnant. Chemotherapeutic regimens for metastatic disease administered during pregnancy have not demonstrated significant efficacy.

  9. Radiogenic Side Effects After Hypofractionated Stereotactic Photon Radiotherapy of Choroidal Melanoma in 212 Patients Treated Between 1997 and 2007

    Energy Technology Data Exchange (ETDEWEB)

    Dunavoelgyi, Roman [Department of Ophthalmology, Medical University of Vienna, Vienna (Austria); Dieckmann, Karin [Department of Radiology, Medical University of Vienna, Vienna (Austria); Gleiss, Andreas [Section of Clinical Biometrics, Medical University of Vienna, Vienna (Austria); Sacu, Stefan; Kircher, Karl; Georgopoulos, Michael [Department of Ophthalmology, Medical University of Vienna, Vienna (Austria); Georg, Dietmar [Department of Radiology, Medical University of Vienna, Vienna (Austria); Zehetmayer, Martin, E-mail: martin.zehetmayer@meduniwien.ac.at [Department of Ophthalmology, Medical University of Vienna, Vienna (Austria); Poetter, Richard [Department of Radiology, Medical University of Vienna, Vienna (Austria)

    2012-05-01

    Purpose: To evaluate side effects of hypofractionated stereotactic photon radiotherapy for patients with choroidal melanoma. Patients and Methods: Two hundred and twelve patients with choroidal melanoma unsuitable for ruthenium-106 brachytherapy or local resection were treated stereotactically at the Medical University of Vienna between 1997 and 2007 with a Linac with 6-MV photon beams in five fractions with 10, 12, or 14 Gy per fraction. Examinations for radiogenic side effects were performed at baseline and every 3 months in the first 2 years, then every 6 months until 5 years and then once a year thereafter until 10 years after radiotherapy. Adverse side effects were assessed using slit-lamp examination, funduscopy, gonioscopy, tonometry, and, if necessary, fundus photography and fluorescein angiography. Evaluations of incidence of side effects are based on an actuarial analysis. Results: One hundred and eighty-nine (89.2%) and 168 (79.2%) of the tumors were within 3 mm of the macula and the optic disc, respectively. The five most common radiotherapy side effects were retinopathy and optic neuropathy (114 cases and 107 cases, respectively), cataract development (87 cases), neovascular glaucoma (46 cases), and corneal epithelium defects (41 cases). In total, 33.6%, 38.5%, 51.2%, 75.5%, and 77.6% of the patients were free of any radiation retinopathy, optic neuropathy, cataract, neovascular glaucoma, or corneal epithelium defects 5 years after radiotherapy, respectively. Conclusion: In centrally located choroidal melanoma hypofractionated stereotactic photon radiotherapy shows a low to moderate rate of adverse long-term side effects comparable with those after proton beam radiotherapy. Future fractionation schemes should seek to further reduce adverse side effects rate while maintaining excellent local tumor control.

  10. Peptidome profiling of human serum of uveal melanoma patients based on magnetic bead fractionation and mass spectrometry

    Directory of Open Access Journals (Sweden)

    Xiang-Yu Shi

    2017-06-01

    Full Text Available AIM: To find new biomarkers for uveal melanoma (UM by analyzing the serum peptidome profile. METHODS: Proteomic spectra in patients with UM before and after operation were analyzed and compared with those of healthy controls. Magnetic affinity beads were used to capture serum peptides and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF mass spectrometer were used to compile serum peptide profiles. RESULTS: A panel of 49 peptides were differentially expressed between UM patients and controls, of which 33 peptides were of higher intensities in patient group and 16 peptides were of higher intensities in control group. Based on combined use of these potential markers, peptides with mean molecular masses of 1467 and 9289.0 Da provide high sensitivity (83.3%, specificity (100% and accuracy rate (93.0% together to differentiate melanoma patients from healthy controls. At the time point of 6mo postoperatively, the levels of many peptides differentially expressed before surgery showed no more statistical difference between the patients and the control group. Fibrinogen α-chain precursors were identified as potential UM markers. CONCLUSION: We have shown that a convenient and fast proteomic technique, affinity bead separation and MALDI-TOF analysis combined with bioinformatic software, facilitates the identification of novel biomarkers for UM.

  11. Tumor DNA in cerebral spinal fluid reflects clinical course in a patient with melanoma leptomeningeal brain metastases.

    Science.gov (United States)

    Li, Yingmei; Pan, Wenying; Connolly, Ian D; Reddy, Sunil; Nagpal, Seema; Quake, Stephen; Gephart, Melanie Hayden

    2016-05-01

    Cerebral spinal fluid (CSF) from brain tumor patients contains tumor cellular and cell-free DNA (cfDNA), which provides a less-invasive and routinely accessible method to obtain tumor genomic information. In this report, we used droplet digital PCR to test mutant tumor DNA in CSF of a patient to monitor the treatment response of metastatic melanoma leptomeningeal disease (LMD). The primary melanoma was known to have a BRAF (V600E) mutation, and the patient was treated with whole brain radiotherapy and BRAF inhibitors. We collected 9 CSF samples over 6 months. The mutant cfDNA fraction gradually decreased from 53 % (time of diagnosis) to 0 (time of symptom alleviation) over the first 6 time points. Three months after clinical improvement, the patient returned with severe symptoms and the mutant cfDNA was again detected in CSF at high levels. The mutant DNA fraction corresponded well with the patient's clinical response. We used whole exome sequencing to examine the mutation profiles of the LMD tumor DNA in CSF before therapeutic response and after disease relapse, and discovered a canonical cancer mutation PTEN (R130*) at both time points. The cellular and cfDNA revealed similar mutation profiles, suggesting cfDNA is representative of LMD cells. This study demonstrates the potential of using cellular or cfDNA in CSF to monitor treatment response for LMD.

  12. PRIMARY ENDOPROSTHETIC REPLACEMENT OF THE ANOPHTHALMIC ORBIT IN PATIENTS WITH UVEAL MELANOMA: SIX-YEAR FOLLOW-UP RESULTS

    Directory of Open Access Journals (Sweden)

    A. A. Yarovoy

    2012-01-01

    Full Text Available A locomotor stump was formed in 36 patients (28 women and 8 men, by implanting an endoprosthesis for enucleation of the eyeball with uveal melanoma (UM. The indication for endoprosthesis implantation was no signs of extrabulbar growth. A modified 17–19 mm silicone implant covered with strips from a dura mater graft and medical mesh fabric was used as an orbital implant. The follow-up was 3 to 72 months (mean 32.5 months. All the patients achieved a satisfactory cosmetic effect. None patient was found to have a recurrent orbital tumor. Out of the complications, anterior implant surface denudation was noted in 4 patients. Two patients developed metastases. The absence of recurrent orbital UM at a 6-year follow-up enables primary endoprosthetic replacement of the orbit for UM to be regarded as a safe and reasonable method for patient cosmetic rehabilitation. 

  13. Ovarian metastasis from uveal melanoma with MLH1/PMS2 protein loss in a patient with germline MLH1 mutated Lynch syndrome: consequence or coincidence?

    Science.gov (United States)

    Lobo, João; Pinto, Carla; Freitas, Micaela; Pinheiro, Manuela; Vizcaino, Rámon; Oliva, Esther; Teixeira, Manuel R; Jerónimo, Carmen; Bartosch, Carla

    2017-03-01

    Currently, uveal melanoma is not considered within the Lynch syndrome tumor spectrum. However, there are studies suggesting a contribution of microsatellite instability in sporadic uveal melanoma tumorigenesis. We report a 45-year-old woman who was referred for genetic counseling due to a family history of Lynch syndrome caused by a MLH1 mutation. She originally underwent enucleation of the right eye secondary to a uveal spindle cell melanoma diagnosed at age 25. The tumor recurred 22 years later presenting as an ovarian metastasis and concurrently a microscopic endometrial endometrioid carcinoma, grade 1/3 was diagnosed. Subsequent studies highlighted that the uveal melanoma showed high microsatellite instability and loss of MLH1 and PMS2 protein expression, with no MLH1 promoter methylation or BRAF mutation. Additionally, a GNAQ mutation was found. We conclude that our patient's uveal melanoma is most likely related to MLH1 germline mutation and thus Lynch syndrome related. To the best of our knowledge, this is the first report of uveal melanoma showing MLH1/PMS2 protein loss in the context of Lynch syndrome.

  14. Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients.

    Science.gov (United States)

    Odunsi, Kunle; Matsuzaki, Junko; Karbach, Julia; Neumann, Antje; Mhawech-Fauceglia, Paulette; Miller, Austin; Beck, Amy; Morrison, Carl D; Ritter, Gerd; Godoy, Heidi; Lele, Shashikant; duPont, Nefertiti; Edwards, Robert; Shrikant, Protul; Old, Lloyd J; Gnjatic, Sacha; Jäger, Elke

    2012-04-10

    Recombinant poxviruses (vaccinia and fowlpox) expressing tumor-associated antigens are currently being evaluated in clinical trials as cancer vaccines to induce tumor-specific immune responses that will improve clinical outcome. To test whether a diversified prime and boost regimen targeting NY-ESO-1 will result in clinical benefit, we conducted two parallel phase II clinical trials of recombinant vaccinia-NY-ESO-1 (rV-NY-ESO-1), followed by booster vaccinations with recombinant fowlpox-NY-ESO-1 (rF-NY-ESO-1) in 25 melanoma and 22 epithelial ovarian cancer (EOC) patients with advanced disease who were at high risk for recurrence/progression. Integrated NY-ESO-1-specific antibody and CD4(+) and CD8(+) T cells were induced in a high proportion of melanoma and EOC patients. In melanoma patients, objective response rate [complete and partial response (CR+PR)] was 14%, mixed response was 5%, and disease stabilization was 52%, amounting to a clinical benefit rate (CBR) of 72% in melanoma patients. The median PFS in the melanoma patients was 9 mo (range, 0-84 mo) and the median OS was 48 mo (range, 3-106 mo). In EOC patients, the median PFS was 21 mo (95% CI, 16-29 mo), and median OS was 48 mo (CI, not estimable). CD8(+) T cells derived from vaccinated patients were shown to lyse NY-ESO-1-expressing tumor targets. These data provide preliminary evidence of clinically meaningful benefit for diversified prime and boost recombinant pox-viral-based vaccines in melanoma and ovarian cancer and support further evaluation of this approach in these patient populations.

  15. Use of Liposomes as Drug Delivery Vehicles for Treatment of Melanoma

    Science.gov (United States)

    Tran, Melissa A.; Watts, Rebecca J.; Robertson, Gavin P.

    2009-01-01

    Melanoma is a progressive disease that claims many lives each year due to lack of therapeutics effective for the long-term treatment of patients. Currently, the best treatment option is early detection followed by surgical removal. Better melanoma therapies that are effectively delivered to tumors with minimal toxicity for patients are urgently needed. Nanotechnologies provide one approach to encapsulate therapeutic agents leading to improvements in circulation time, enhanced tumor uptake, avoidance of the reticulo-endothelial system, and minimization of toxicity. Liposomes in particular are a promising nanotechnology that can be used for more effective delivery of therapeutic agents to treat melanoma. Liposomes delivering chemotherapies, siRNA, asODNs, DNA, and radioactive particles are just some of the promising new nanotechnology based therapies under development for the treatment of melanoma that are discussed in this review. PMID:19493316

  16. Patients at elevated risk of melanoma: individual predictors of non-compliance to GP referral for a dermatologist consultation.

    Science.gov (United States)

    Rat, Cédric; Quereux, Gaelle; Monegier du Sorbier, Marine; Gaultier, Aurélie; Bonnaud-Antignac, Angélique; Khammari, Amir; Dreno, Brigitte; Nguyen, Jean Michel

    2014-07-01

    The aim of this study is to assess whether patients at elevated risk of melanoma attended a dermatologist consultation after a General Practitioner referral and to determine individual predictors of non-compliance. This survey included 1506 high-risk French patients (selected using the Self-Assessment Melanoma Risk Score) referred to a dermatologist between April and October 2011. Compliance was evaluated from January to April 2012, based on attendance at a dermatologist consultation (or scheduling an appointment). Demographic data and factors mapping the Health Belief Model were tested as correlates using a multivariate logistic regression. Compliance with referral was 58.4%. The top seven factors associated with non-compliance were as follows: GP advice to consult was unclear (OR=13.22; [7.66-23.56]); no previous participation in cancer screenings, including smear tests (OR=5.03; [2.23-11.83]) and prostate screening (OR=2.04; [1.06-3.97]); lack of knowledge that melanoma was a type of cancer (OR=1.94; [1.29-2.92]); and reporting no time to make an appointment (OR=2.08; [1.82-2.38]), forgetting to make an appointment (OR=1.26; [1.08-1.46]), long delays in accessing an appointment (OR=1.25; [1.12-1.41]), not being afraid of detecting something abnormal (OR=1.54; [1.35-1.78]), no need to consult a dermatologist to feel secure (OR=1.28; [1.09-1.51]). Physicians should be aware of the factors predicting patient compliance with referrals for dermatologist consultations; better General Practitioner counseling might enhance compliance in high-risk populations. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Clinico-pathological features of patients with melanoma and positive sentinel lymph node biopsy: a single institution experience.

    Science.gov (United States)

    Homolak, Damir; Šitum, Mirna; Čupić, Hrvoje

    2015-01-01

    Sentinel lymph node biopsy (SLNB) is an established method for the assessment of tumor aggressiveness in patients with primary cutaneous melanoma (PCM). To improve the criteria for the selection of SLNB candidates, the aim of our study was to determine clinico-pathohistological parameters that can serve as predictors of metastatic progression. We retrospectively evaluated all available clinico-pathohistological parameters in 844 patients with PCM diagnosed between January 1, 2005 and December 31, 2010. SLNB was conducted in 484 (57.3%) patients, 122 (14.5%) of whom had a positive node. The association between predictors and SLNB outcomes (positive SLNB and metastatic development) was tested using logistic regression analysis. The main predictors of positive SLNB were Breslow thickness (adjusted odds ratio (AOR)=1.22; 95% confidence interval (CI)=1.11-1.33), Clark levels (AOR=1.78; 95% CI=1.31-2.40), ulceration (AOR=3.1; 95% CI=1.65-5.81), microsatellitosis, gender, and tumor localization. The predictors of metastatic spread were Breslow thickness (AOR=1,69; 95% CI=1.51-1.89), Clark level (AOR=3.59; 95% CI=2.79-4.62), nodular type of melanoma (AOR=8.21; 95% CI=1.70-39.53), ulceration, mitotic rate, microsatellitosis, gender, and tumor localization. It seems that these parameters should be taken into consideration when selecting patients for SLNB since tumor thickness is not a sufficient predictor of SLNB outcome, particularly in case of very thin lesions.

  18. Increased Levels of miRNA-146a in Serum and Histologic Samples of Patients with Uveal Melanoma

    Science.gov (United States)

    Russo, Andrea; Caltabiano, Rosario; Longo, Antonio; Avitabile, Teresio; Franco, Livio M.; Bonfiglio, Vincenza; Puzzo, Lidia; Reibaldi, Michele

    2016-01-01

    Purpose: To analyze MiRs expression in serum of UM patients, respect to healthy donors, and to compare this data with MiRs expressed in formalin-fixed, paraffin-embedded UM samples. Methods: Expression profile of 754 miRNAs was performed in serum of patients with uveal melanoma who underwent primary enucleation. The level of miRNAs increased in serum was individually analyzed on FFPE UM samples and compared to choroidal melanocytes from unaffected eyes. Results: Fourteen patients with uveal melanoma were included in the study. We found 8 serum miRNAs differentially expressed compared to normal controls: 2 upregulated miRNAs (miRNA-146a, miR-523); 6 downregulated miRNAs (miR-19a, miR-30d, miR-127, miR-451, miR-518f, miR-1274B). When data on upregulated miRNAs were singularly validated only a significant overexpression of miRNA-146a was found. A statistically significant upregulation of miRNA-146a was also found on FFPE UM samples, compared to choroidal melanocytes from unaffected eyes. Conclusions: miRNA-146a is increased in serum of patients with UM and in FFPE tumor samples. Further studies will show if it could be considered a potential marker of UM in the blood. PMID:27895580

  19. Adjuvant interferon-α for the treatment of high-risk melanoma: An individual patient data meta-analysis.

    Science.gov (United States)

    Ives, Natalie J; Suciu, Stefan; Eggermont, Alexander M M; Kirkwood, John; Lorigan, Paul; Markovic, Svetomir N; Garbe, Claus; Wheatley, Keith

    2017-09-01

    Many randomised trials assessing interferon-α (IFN-α) as adjuvant therapy for high-risk malignant melanoma have been undertaken. To better assess the role of IFN-α, an individual patient data (IPD) meta-analysis of these trials was undertaken. IPD was sought from all randomised trials of adjuvant IFN-α versus no IFN-α for high-risk melanoma. Primary outcomes were event-free survival (EFS) and overall survival (OS). Standard methods for quantitative IPD meta-analysis were used. Subgroup analyses by dose, duration of treatment and various patient and disease-specific parameters were performed. Fifteen trials were included in the analysis (eleven with IPD). EFS was significantly improved with IFN-α (hazard ratio [HR] = 0.86, CI 0.81-0.91; P analysis provides clear evidence that adjuvant IFN-α significantly reduces the risk of relapse and improves survival and shows no benefit for higher doses compared to lower doses. The increased benefit in patients with ulcerated tumours, and lack of benefit in patients without ulceration, needs further investigation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Therapy preferences in melanoma treatment--willingness to pay and preference of quality versus length of life of patients, physicians and healthy controls.

    Science.gov (United States)

    Krammer, Ramona; Heinzerling, Lucie

    2014-01-01

    New melanoma therapies, like e.g. ipilimumab, improve survival. However, only a small subset of patients benefits while 60% encounter side effects. Furthermore, these marginal benefits come at a very high price of €110'000 per treatment. This study examines attitudes towards melanoma therapy options of physicians, healthy individuals and patients, their willingness to pay and preference of quality versus length of life. Based on findings from a focus group questionnaires were developed and pretested. After obtaining ethical approval and informed consent surveys were conducted in a total of 90 participants (n = 30 for each group). Statistical analyses were conducted using R. Attitudes vastly differed between healthy participants, physicians and melanoma patients. Whereas melanoma patients show a high willingness to endure side effects despite very small survival gains (down to 1 extra week) or even only hope with no survival benefit, healthy controls are more critical, while physicians are the most therapy adverse. Consequently, if given €100'000 and the free decision what to spend the money on the willingness to pay for therapy was much higher in the patient group (68%) compared to 28% of healthy controls and only 43% of the physicians, respectively. When lowering the amount of cash that could be received instead of ipilimumab to €50'000 or €10'000 to test price sensitivity 69% (+1%) and 76% (+8%) of melanoma patients, respectively, preferred ipilimumab over cash. When judging on societal spending even melanoma patients opted for spending on ipilimumab in only 21%. The judgment about the benefits of new treatment options largely differs between groups, physicians being the most critical against therapy. Price elasticity was low.

  1. TIL therapy broadens the tumor-reactive CD8(+) T cell compartment in melanoma patients

    DEFF Research Database (Denmark)

    Kvistborg, Pia; Shu, Chengyi Jenny; Heemskerk, Bianca;

    2012-01-01

    There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-...

  2. Molecular Characterization and Patient Outcome of Melanoma Nodal Metastases and an Unknown Primary Site

    NARCIS (Netherlands)

    A. Gos (Aleksandra); M. Jurkowska (Monika); A.C.J. van Akkooi (Alexander); C. Robert (Caroline); H. Kosela-Paterczyk (Hanna); S. Koljenovic (Senada); N. Kamsukom (Nyam); W. Michej (Wanda); A. Jeziorski (Arkadiusz); P. Pluta (Piotr); C. Verhoef (Kees); J.A. Siedlecki (Janusz); A.M.M. Eggermont (Alexander); P. Rutkowski (Piotr)

    2014-01-01

    textabstractBackground Melanoma of unknown primary site (MUP) is not a completely understood entity with nodal metastases as the most common first clinical manifestation. The aim of this multicentric study was to assess frequency and type of oncogenic BRAF/NRAS/KIT mutations in MUP with clinically d

  3. Biological insights into BRAF(V600) mutations in melanoma patient

    DEFF Research Database (Denmark)

    Improta, Giuseppina; Pelosi, Giuseppe; Tamborini, Elena

    2013-01-01

    Some experimental evidence indicates that uncommon BRAF mutations consisting in the substitution of 2 adjacent nucleotides within codon 600 are in a cis configuration and associate with BRAF gene amplification. These findings suggest that BRAF(V600) mutations are unlikely to occur as homozygous a...... alterations in clinical melanoma samples, with gene amplification perhaps contributing to mask the heterozygous state....

  4. Elevation of glycoprotein nonmetastatic melanoma protein B in type 1 Gaucher disease patients and mouse models

    NARCIS (Netherlands)

    Kramer, Gertjan; Wegdam, Wouter; Donker-Koopman, Wilma; Ottenhoff, Roelof; Gaspar, Paulo; Verhoek, Marri; Nelson, Jessica; Gabriel, Tanit; Kallemeijn, Wouter; Boot, Rolf G.; Laman, Jon D.; Vissers, Johannes P. C.; Cox, Timothy; Pavlova, Elena; Moran, Mary Teresa; Aerts, Johannes M.; van Eijk, Marco

    2016-01-01

    Gaucher disease is caused by inherited deficiency of lysosomal glucocere-brosidase. Proteome analysis of laser-dissected splenic Gaucher cells revealed increased amounts of glycoprotein nonmetastatic melanoma protein B (gpNMB). Plasma gpNMB was also elevated, correlating with chitotriosidase and CCL

  5. Elevation of glycoprotein nonmetastatic melanoma protein B in type 1 Gaucher disease patients and mouse models

    NARCIS (Netherlands)

    Kramer, G.; Wegdam, W.; Donker-Koopman, W.; Ottenhoff, R.; Gaspar, P.; Verhoek, M.; Nelson, J.; Gabriel, T.; Kallemeijn, W.W.; Boot, R.G.; Laman, J.D.; Vissers, J.P.; Cox, T.; Pavlova, E.; Moran, M.T.; Aerts, J.M.F.G.; Eijk, van M.C.

    2016-01-01

    Gaucher disease is caused by inherited deficiency of lysosomal glucocerebrosidase. Proteome analysis of laser-dissected splenic Gaucher cells revealed increased amounts of glycoprotein nonmetastatic melanoma protein B (gpNMB). Plasma gpNMB was also elevated, correlating with chitotriosidase and CCL1

  6. Evidence for Natural Killer Cell-Mediated Protection from Metastasis Formation in Uveal Melanoma Patients

    NARCIS (Netherlands)

    Maat, Willem; van der Slik, Arno R.; Verhoeven, Dirk H. J.; Alizadeh, Behrooz Z.; Ly, Long V.; Verduijn, Willem; Luyten, Gregorius P. M.; Mulder, Arend; van Hall, Thorbald; Koning, Frits; Jager, Martine J.; van Bergen, Jeroen

    2009-01-01

    PURPOSE. In uveal melanoma, low human leukocyte antigen (HLA) class I expression on primary tumors is associated with a decreased risk of metastasis. Consequently, it has been suggested that natural killer (NK) cells, which detect decreased expression of HLA class I, are involved in the immune contr

  7. Impact of [F-18]fluorodeoxyglucose positron emission tomography on surgical management of melanoma patients

    NARCIS (Netherlands)

    Bastiaannet, E; Oyen, WJG; Meijer, S; Hoekstra, OS; Wobbes, T; Jager, PL; Hoekstra, HJ

    Background: Several studies have shown adequate sensitivity and specificity of [F-18]fluorodeoxyglucose positron emission tomography (FDG-PET) for the detection of metastases from melanoma, but few have addressed its impact on treatment. The aim of this retrospective study was to assess the impact

  8. Level of fluorodeoxyglucose uptake predicts risk for recurrence in melanoma patients presenting with lymph node metastases

    NARCIS (Netherlands)

    Bastiaannet, E; Hoekstra, OS; Oyen, WJG; Jager, PL; Wobbes, T; Hoekstra, HJ

    2006-01-01

    Background: The incidence of malignant melanoma has increased. Identification of additional prognostic factors may allow the development of individualized strategies. This multivariate analysis was undertaken to evaluate the potential role of the standard uptake value (SUV) in predicting disease-fre

  9. The prognostic role of blood lymphocyte subset distribution in patients with resected high-risk primary or regionally metastatic melanoma

    DEFF Research Database (Denmark)

    Hernberg, Micaela; Mattila, Petri S; Rissanen, Marjo;

    2007-01-01

    Cooperative Group adjuvant interferon study. The frequencies of peripheral blood lymphocyte subsets were monitored by flow cytometry using CD3, CD4, CD8, CD56, and CD69 monoclonal antibodies. Patients with low proportions of CD3+CD4+CD69+ cells and of CD3+CD56+ cells before treatment had an improved disease...... independent prognostic factors for overall survival. Our data show that both the proportions of CD3+CD4+CD69+ cells and of CD3+CD56+ cells seem to have a prognostic potential in the natural course of melanoma. These results need to be confirmed in larger studies. Udgivelsesdato: 2007-Oct...

  10. Retinal vasculitis and ocular vitreous metastasis following complete response to PD-1 inhibition in a patient with metastatic cutaneous melanoma.

    Science.gov (United States)

    Manusow, Joshua S; Khoja, Leila; Pesin, Nataly; Joshua, Anthony M; Mandelcorn, Efrem D

    2014-01-01

    We report on a 36-year-old woman treated with the anti PD-1 antibody Pembrolizumab for metastatic cutaneous melanoma in the first line setting. She achieved a complete response and then relapsed with metastases to the vitreous cavity with an associated angiographically determined retinal vasculitis. Vitreous metastasis without choroidal involvement is unusual and may be due to individual cell extravasation, vitreous hemorrhage containing malignant cells, or direct spread through the optic nerve. This finding highlights the need for immune sanctuary sites to be monitored in the presence of PD-1 inhibition and we hypothesize that the use of PD-1 inhibitor potentiated the patient's angiographically determined retinal vasculitis.

  11. 18F-FDG PET/CT Reveals Disease Remission in a Patient With Ipilimumab-Refractory Advanced Melanoma Treated With Pembrolizumab.

    Science.gov (United States)

    Sachpekidis, Christos; Hassel, Jessica C; Dimitrakopoulou-Strauss, Antonia

    2016-02-01

    Pembrolizumab is an anti-programmed cell death receptor 1 (anti-PD-1) antibody, recently approved for the treatment of ipilimumab-refractory metastatic melanoma. We report on a 49-year-old patient with unresectable metastatic melanoma initially treated with 4 cycles of ipilimumab. Because of demonstration of progressive disease on PET/CT, the patient was enrolled into a clinical trial of pembrolizumab. After completion of 4 cycles of pembrolizumab, the follow-up PET/CT scans performed early after and 7 months after the end of treatment exhibited complete disease remission, reflecting the potential role of the modality in treatment response evaluation of melanoma patients receiving anti-PD-1 therapy.

  12. EORTC recommended protocol for melanoma sentinel lymph node sectioning misclassifies up to 50% of the patients compared with complete step sectioning. Danish Society for Pathological Anatomy and Clinical Cytology

    DEFF Research Database (Denmark)

    Riber-Hansen, Rikke; Hastrup, N; Clemmensen, O.

    2010-01-01

    EORTC recommended protocol for melanoma sentinel lymph node sectioning misclassifies up to 50% of the patients compared with complete step sectioning. Danish Society for Pathological Anatomy and Clinical Cytology......EORTC recommended protocol for melanoma sentinel lymph node sectioning misclassifies up to 50% of the patients compared with complete step sectioning. Danish Society for Pathological Anatomy and Clinical Cytology...

  13. Patient's Guide to Living with Atrial Fibrillation

    Science.gov (United States)

    ... rhythms, thus helping you get a good night’s sleep. It is an important component of weight control. Patients who need medications to slow their heart rate may find that their heart rate does not ...

  14. Living with an Alzheimer patient in Turkey.

    Science.gov (United States)

    Taşc, Sultan; Tekinsoy Kartn, Pnar; Ceyhan, Ozlem; Sungur, Gönül; Göriş, Songül

    2012-08-01

    The research was performed to determine the problems that caregivers experience with patients with Alzheimer disease. The research was carried out qualitatively with those who were responsible for the care of eight Alzheimer patients who were being treated at the Neurology Polyclinics of Gevher Nesibe Hospital at Erciyes University in Kayseri, Turkey. Research data were collected through questionnaires designed to understand the characteristics of the individuals who provided care and focus group interviews. A written consent from the institution and an oral as well as written consent of the individuals were obtained. Focus groups were interviewed in the same setting at different times with two different groups, including four people who agreed to participate in the research. Each interview was conducted by three personnel: a moderator, a reporter, and an observer. Interviews were structured under four main titles: "The changes seen in the individual with Alzheimer disease"; "Physical, social, psychological, and socioeconomical problems that caregivers experienced"; "Precautions taken against the problems"; and "Patients' expectations of the care". The interviews lasted for approximately 2 hours. A voice recorder and a written registration form were also used to collect information. Six women and two men constituted the research group. The caregivers stated that the patients had such difficulties as forgetfulness, nervousness, jealousy, childish behavior, deterioration in speech, fear of water, hallucinations, and difficulty in carrying out daily life activities. Caregivers emphasized the fact that they perceived the changes in the patients as deliberate behaviors and thus became annoyed and quarreled with them before diagnosis; however, after diagnosis, they felt remorse and experienced guilt because of their ill-treatment of them. In addition, the caregivers hid the patients and their disease from social surroundings. Caregivers mentioned that they had felt as

  15. Image Guided Hypofractionated Radiation Therapy, Nelfinavir Mesylate, and Nivolumab in Treating Patients With Advanced Melanoma, Lung, or Kidney Cancer

    Science.gov (United States)

    2017-02-08

    Metastatic Renal Cell Cancer; Recurrent Melanoma; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Renal Cell Carcinoma; Stage IV Non-Small Cell Lung Cancer; Stage IV Renal Cell Cancer; Stage IV Skin Melanoma

  16. Assessment of Living Skills in Schizophrenic Patients by Kohlman Evaluation

    Directory of Open Access Journals (Sweden)

    Leila Kazazi

    2012-09-01

    Full Text Available Background: The living skills of schizophrenic patients are disrupted due to cognitive, perceptual, sensory-motor, psychological, and psychosocial problems. Therefore, the identification of some aspects of living skills that require medical intervention is essential in these patients. Accordingly, in this study, the living skills of schizophrenic patients were investigated with the Kohlman Evaluation of Living Skills.Materials and Methods: This study was conducted by using the cross-sectional descriptive and analytic approach in which 35 hospitalized and 51 outpatient schizophrenic patients and 35 healthy individuals were compared and the areas of living skills that needed help were determined.Results: According to the Kruskal-Wallis test, there was a significant difference between the mean scores of healthy, hospitalized and outpatients subjects, whereas the difference in the means scores was not significant between the two groups of patients (p=0.693. Schizophrenic patients showed more than 50% requirement for help in the following subscales; appearance, awareness of dangerous household situations, appropriate action for sickness and accidents, obtaining and maintaining a source of income, budgeting their monthly income, and leisure activities. Employment had a direct effect on the living skills of the subjects and the test mean scores of employed people (2.409 was better than unemployed persons (7.083.Conclusion: The living skills of schizophrenic patients are damaged in some areas through the course of the disease and its symptoms. Based on the Kohlman Evaluation of Living Skills, these people require most help in self-care, safety health, money management, and leisure activities.

  17. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037)

    DEFF Research Database (Denmark)

    Weber, Jeffrey S; D'Angelo, Sandra P; Minor, David

    2015-01-01

    BACKGROUND: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemothe......BACKGROUND: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice......, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg....../m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used...

  18. SNPase-ARMS qPCR: Ultrasensitive Mutation-Based Detection of Cell-Free Tumor DNA in Melanoma Patients.

    Directory of Open Access Journals (Sweden)

    Julia Stadler

    Full Text Available Cell-free circulating tumor DNA in the plasma of cancer patients has become a common point of interest as indicator of therapy options and treatment response in clinical cancer research. Especially patient- and tumor-specific single nucleotide variants that accurately distinguish tumor DNA from wild type DNA are promising targets. The reliable detection and quantification of these single-base DNA variants is technically challenging. Currently, a variety of techniques is applied, with no apparent "gold standard". Here we present a novel qPCR protocol that meets the conditions of extreme sensitivity and specificity that are required for detection and quantification of tumor DNA. By consecutive application of two polymerases, one of them designed for extreme base-specificity, the method reaches unprecedented sensitivity and specificity. Three qPCR assays were tested with spike-in experiments, specific for point mutations BRAF V600E, PTEN T167A and NRAS Q61L of melanoma cell lines. It was possible to detect down to one copy of tumor DNA per reaction (Poisson distribution, at a background of up to 200 000 wild type DNAs. To prove its clinical applicability, the method was successfully tested on a small cohort of BRAF V600E positive melanoma patients.

  19. Hypoxia-regulated gene expression explains differences between melanoma cell line-derived xenografts and patient-derived xenografts.

    Science.gov (United States)

    Bhadury, Joydeep; Einarsdottir, Berglind O; Podraza, Agnieszka; Bagge, Roger Olofsson; Stierner, Ulrika; Ny, Lars; Dávila López, Marcela; Nilsson, Jonas A

    2016-04-26

    Cell line-derived xenografts (CDXs) are an integral part of drug efficacy testing during development of new pharmaceuticals against cancer but their accuracy in predicting clinical responses in patients have been debated. Patient-derived xenografts (PDXs) are thought to be more useful for predictive biomarker identification for targeted therapies, including in metastatic melanoma, due to their similarities to human disease. Here, tumor biopsies from fifteen patients and ten widely-used melanoma cell lines were transplanted into immunocompromised mice to generate PDXs and CDXs, respectively. Gene expression profiles generated from the tumors of these PDXs and CDXs clustered into distinct groups, despite similar mutational signatures. Hypoxia-induced gene signatures and overexpression of the hypoxia-regulated miRNA hsa-miR-210 characterized CDXs. Inhibition of hsa-miR-210 with decoys had little phenotypic effect in vitro but reduced sensitivity to MEK1/2 inhibition in vivo, suggesting down-regulation of this miRNA could result in development of resistance to MEK inhibitors.

  20. Mucosal malignant melanoma - a clinical, oncological, pathological and genetic survey.

    Science.gov (United States)

    Mikkelsen, Lauge H; Larsen, Ann-Cathrine; von Buchwald, Christian; Drzewiecki, Krzysztof T; Prause, Jan U; Heegaard, Steffen

    2016-06-01

    Mucosal melanomas constitute 1.3% of all melanomas and they may develop in any mucosal membrane. Conjunctival melanomas (0.5/million/year) and melanomas in the sinonasal cavity (0.5/million/year) are the most common, followed by anorectal melanomas (0.4/million/year) and melanomas in the oral cavity (0.2/million/year). Anorectal melanoma occurs slightly more often in females, whereas oral melanoma has a male predilection. Mucosal melanoma most commonly develops in a patient's sixth or seventh decade of life, and no differences between races have been found except for sinonasal melanoma and conjunctival melanoma, which are very rare in Black people. The symptoms are not tumour-specific and are related to the organ system affected, and the disease is most often diagnosed at an advanced clinical stage. The diagnosis of a primary tumour is difficult, and metastatic cutaneous melanoma and choroidal melanoma must be excluded. Mutations in KIT are frequently found, while BRAF and NRAS mutations are rarely found - except in conjunctival melanomas that carry BRAF mutations. Mutations in the TERT promotor region are also found in mucosal melanomas. Complete surgical resection with free margins is the treatment of choice. The prognosis is poor, with the 5-year survival rate ranging from 0% (gastric melanoma) to 80% (conjunctival melanoma).

  1. Successful treatment with Ipilimumab and Interleukin‑2 in two patients with metastatic melanoma and systemic autoimmune disease

    DEFF Research Database (Denmark)

    Pedersen, Magnus; Andersen, Rikke; Larsen, Peter Nørgaard;

    2014-01-01

    Two patients were treated with immunotherapy for metastatic malignant melanoma (MM) despite suffering from systemic autoimmune disease, i.e., ulcerative colitis (UC) and Behcets disease (BD), respectively. Both patients benefitted from the treatment. The patient with UC achieved partial remission...... of all measurable parameters after treatment with Ipilimumab, while the patient with BD achieved a complete remission of MM after treatment with Interleukin-2 (IL-2) and Interferon-α (IFN-α). Moreover, no aggravation of symptoms related to the autoimmune diseases was seen during treatment, in contrast......, clinical indications of improvement were observed. These two cases illustrate that the presence of autoimmune disease does not necessarily predict increased autoimmune toxicity in connection with immunotherapy. They also raise the question of whether autoimmune disease should continue to be an absolute...

  2. Clinical Benefit of Allogeneic Melanoma Cell Lysate-Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal Cancer Patients

    DEFF Research Database (Denmark)

    Toh, Han Chong; Wang, Who-Whong; Chia, Whay Kuang

    2009-01-01

    PURPOSE: We evaluated the clinical benefit of an allogeneic melanoma cell lysate (MCL)-pulsed autologous dendritic cell (DC) vaccine in advanced colorectal cancer patients expressing at least one of six MAGE-A antigens overexpressed by the cell line source of the lysate. EXPERIMENTAL DESIGN: DCs...... patients received a total of 161 vaccinations. Treatment was well tolerated and quality of life measurements did not vary much across time. One patient experienced partial response [5%; 95% confidence interval (CI), 1-24%] and seven achieved stable disease (35%; 95% CI, 18-57%), one of whom also achieved......-free for >27 and >37 months, respectively. This result is particularly meaningful as all patients had progressive disease before treatment. Overall, DC vaccination was associated with a serial decline in regulatory T cells. Using an antibody array, we characterized plasma protein profiles in responding...

  3. Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-α 2b treatment

    Directory of Open Access Journals (Sweden)

    Ascierto Paolo A

    2010-08-01

    Full Text Available Abstract Background High-dose interferon-alpha 2b (IFN-α 2b is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-α 2b by measuring serum regulatory T cell (Treg, serum transforming growth factor-β (TGF-β, interleukin (IL-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-α 2b regimen. Methods Patients with melanoma received IFN-α 2b administered intravenously (20 MU/m2 each day from day 1 to day 5 for 4 consecutive weeks. Serum Treg levels were measured as whole lymphocytes in CD4+ cells using flow cytometry while TGF-β, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays. Results Twenty-two patients with melanoma received IFN-α 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (P = 0.001; Mann-Whitney test. Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week, statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (P = 0.082, early recurrence versus no recurrence (P = 0.017, deceased versus surviving patients (P = 0.021, and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant. No significant effects were observed on the levels of TGF-β, IL-10, and autoantibodies in patients with melanoma treated with IFN-α 2b. Conclusions Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-α 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response

  4. Genotyping of cutaneous melanoma.

    Science.gov (United States)

    Glitza, Isabella C; Davies, Michael A

    2014-09-01

    Until recently, treatment options for patients with metastatic melanoma were very limited. This landscape has evolved dramatically since the discovery of activating mutations in the BRAF gene in ~45% of cutaneous melanomas. Vemurafenib, dabrafenib, and trametinib have all received regulatory approval for the treatment of metastatic melanoma patients with a BRAF(V600) mutation. Based on the necessity to document the presence of a BRAF(V600) mutation to prescribe these agents, molecular testing is now the standard of care in this disease. However, the options and rationale for testing are evolving rapidly due to an improved understanding of the molecular drivers and heterogeneity of melanoma. Such testing may identify rational combinatorial approaches to prevent or overcome resistance for the approved BRAF inhibitors. In addition, new clinical strategies have been identified for a number of other molecular changes that are detected in this disease, including somatic changes in NRAS, PTEN, CDKN2A, and c-KIT, among others. This review summarizes the current understanding of the genetic landscape of mutations in melanoma, their associations with clinicopathological features, and their implications for clinical testing and treatment.

  5. Efficacy and toxicity of transarterial chemoembolization therapy using cisplatin and gelatin sponge in patients with liver metastases from uveal melanoma in an Asian population.

    Science.gov (United States)

    Shibayama, Yoshitsugu; Namikawa, Kenjiro; Sone, Miyuki; Takahashi, Akira; Tsutsumida, Arata; Sugawara, Shunsuke; Arai, Yasuaki; Aihara, Yukiko; Suzuki, Shigenobu; Nakayama, Juichiro; Imafuku, Shinichi; Yamazaki, Naoya

    2017-06-01

    Although both immune-checkpoint inhibitors and targeted therapies such as MEK inhibitors have been evaluated in metastatic uveal melanoma, the efficacy of these therapies is modest to date. The purpose of this study was to evaluate the efficacy and toxicity of transarterial chemoembolization (TACE) therapy for liver metastasis from uveal melanoma in an Asian population. We retrospectively assessed the clinical data of patients with liver metastases from uveal melanoma who received TACE therapy using cisplatin (70 mg/m(2)) and gelatin sponge between 1997 and 2008. We identified 29 eligible patients. The overall response rate was 21%. The median survival time was 23 months, and the 1-, 2-, and 5-year survival rates were 72.4, 39.4, and 0%, respectively. The favorable prognostic factors were partial response and stable disease, treatment options. However, considering the lack of long-term efficacy of this therapy, further treatment strategies need to be developed.

  6. Hand Hygiene Saves Lives: Patient Admission Video

    Centers for Disease Control (CDC) Podcasts

    2008-05-01

    This podcast is for hospital patients and visitors. It emphasizes two key points to help prevent infections: the importance of practicing hand hygiene while in the hospital, and that it's appropriate to ask or remind healthcare providers to practice hand hygiene.  Created: 5/1/2008 by National Center for Preparedness, Detection, and Control of Infectious Diseases (NCPDCID).   Date Released: 6/19/2008.

  7. An epitope common to gangliosides O-acetyl-GD3 and GD3 recognized by antibodies in melanoma patients after active specific immunotherapy.

    Science.gov (United States)

    Ravindranath, M H; Morton, D L; Irie, R F

    1989-07-15

    GD3 is a major ganglioside of human melanoma and was shown to be an effective target for passive immunotherapy with murine monoclonal antibodies. It was noted earlier that GD3 neither purified nor in melanoma cell vaccine (MCV), could elicit an antibody response in melanoma patients. In this study, we demonstrate that melanoma patients who received MCV had autoantibodies against a derivative of GD3, O-acetylated GD3 (O-AcGD3), a minor ganglioside expressed on human melanoma cells, and that the antibodies cross-reacted with GD3. Thin layer chromatographic immunostaining revealed that all of the sera containing antibodies against O-AcGD3 also reacted to GD3. None of the other sera responded only to GD3, although the MCV contained 7- to 12-fold higher GD3 than O-AcGD3. Furthermore, the antibody activity was completely abolished by absorption with animal erythrocytes expressing either O-acetyl disialogangliosides or GD3, indicating that the antibodies recognize an epitope commonly shared by GD3 and O-AcGD3. The antibodies bound only to the sialyloligosaccharide moiety but not to the ceramide portion of GD3 after endoglycosylceramidase treatment. The antibodies failed to bind to GD3 after neuraminidase treatment. These results indicate that the sialyloligosaccharides of the gangliosides are important components of the epitope. Periodate oxidation abolished reactivity of the antibodies to GD3 but not that to O-AcGD3, revealing that the glycerol side chain of the sialic acids in both GD3s was an important structure of the epitope. The binding of the antibodies to melanoma cell surface gangliosides was confirmed by an absorption with a GD3- and O-AcGD3-positive melanoma cell line. These results in the light of previous reports on the inability of GD3 to elicit immune response in humans suggest that anti-GD3 antibodies found in the melanoma patients were induced by immunization with O-AcGD3 and O-AcGD3 present in the MCV would serve as an antigen source for GD3-targeted

  8. CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit.

    Science.gov (United States)

    Yuan, Jianda; Gnjatic, Sacha; Li, Hao; Powel, Sarah; Gallardo, Humilidad F; Ritter, Erika; Ku, Geoffrey Y; Jungbluth, Achim A; Segal, Neil H; Rasalan, Teresa S; Manukian, Gregor; Xu, Yinyan; Roman, Ruth-Ann; Terzulli, Stephanie L; Heywood, Melanie; Pogoriler, Evelina; Ritter, Gerd; Old, Lloyd J; Allison, James P; Wolchok, Jedd D

    2008-12-23

    Blockade of inhibitory signals mediated by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has been shown to enhance T cell responses and induce durable clinical responses in patients with metastatic melanoma. The functional impact of anti-CTLA-4 therapy on human immune responses is still unclear. To explore this, we analyzed immune-related adverse events and immune responses in metastatic melanoma patients treated with ipilimumab, a fully human anti-CTLA-4 monoclonal antibody. Fifteen patients were selected on the basis of availability of suitable specimens for immunologic monitoring, and eight of these showed evidence of clinical benefit. Five of the eight patients with evidence of clinical benefit had NY-ESO-1 antibody, whereas none of seven clinical non-responders was seropositive for NY-ESO-1. All five NY-ESO-1 seropositive patients had clearly detectable CD4(+) and CD8(+) T cells against NY-ESO-1 following treatment with ipilimumab. One NY-ESO-1 seronegative clinical responder also had a NY-ESO-1 CD4(+) and CD8(+) T cell response, possibly related to prior vaccination with NY-ESO-1. Among five clinical non-responders analyzed, only one had a NY-ESO-1 CD4(+) T cell response and this patient did not have detectable anti-NY-ESO-1 antibody. Overall, NY-ESO-1-specific T cell responses increased in frequency and functionality during anti-CTLA-4 treatment, revealing a polyfunctional response pattern of IFN-gamma, MIP-1beta and TNF-alpha. We therefore suggest that CTLA-4 blockade enhanced NY-ESO-1 antigen-specific B cell and T cell immune responses in patients with durable objective clinical responses and stable disease. These data provide an immunologic rationale for the efficacy of anti-CTLA-4 therapy and call for immunotherapeutic designs that combine NY-ESO-1 vaccination with CTLA-4 blockade.

  9. Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients

    Directory of Open Access Journals (Sweden)

    Ellebaek Eva

    2012-08-01

    Full Text Available Abstract Background Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL, in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections. Methods This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625 including patients with metastatic melanoma, PS ≤1, age Results Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3–4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months, 2 patients had stable disease (4 and 5 months and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission. Conclusion Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.

  10. A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon.

    Directory of Open Access Journals (Sweden)

    Ena Wang

    Full Text Available PURPOSE: IFNa was the first cytokine to demonstrate anti-tumor activity in advanced melanoma. Despite the ability of high-dose IFNa reducing relapse and mortality by up to 33%, large majority of patients experience side effects and toxicity which outweigh the benefits. The current study attempts to identify genetic markers likely to be associated with benefit from IFN-a2b treatment and predictive for survival. EXPERIMENTAL DESIGN: We tested the association of variants in FOXP3 microsatellites, CTLA4 SNPs and HLA genotype in 284 melanoma patients and their association with prognosis and survival of melanoma patients who received IFNa adjuvant therapy. RESULTS: Univariate survival analysis suggested that patients bearing either the DRB1*15 or HLA-Cw7 allele suffered worse OS while patients bearing either HLA-Cw6 or HLA-B44 enjoyed better OS. DRB1*15 positive patients suffered also worse RFS and conversely HLA-Cw6 positive patients had better RFS. Multivariate analysis revealed that a five-marker genotyping signature was prognostic of OS independent of disease stage. In the multivariate Cox regression model, HLA-B38 (p = 0.021, HLA-C15 (p = 0.025, HLA-C3 (p = 0.014, DRB1*15 (p = 0.005 and CT60*G/G (0.081 were significantly associated with OS with risk ratio of 0.097 (95% CI, 0.013-0.709, 0.387 (95% CI, 0.169-0.889, 0.449 (95% CI, 0.237-0.851, 1.948 (95% CI, 1.221-3.109 and 1.484 (95% IC, 0.953-2.312 respectively. CONCLUSION: These results suggest that gene polymorphisms relevant to a biological occurrence are more likely to be informative when studied in concert to address potential redundant or conflicting functions that may limit each gene individual contribution. The five markers identified here exemplify this concept though prospective validation in independent cohorts is needed.

  11. New therapeutic targets in melanoma.

    Science.gov (United States)

    Martí, R M; Sorolla, A; Yeramian, A

    2012-09-01

    Research into molecular targets for drug development in melanoma is starting to bear fruit. Of the drugs tested to date in patients with metastatic melanoma, those that have yielded the best results are V600E BRAF inhibitors in melanomas carrying the V600E mutation; c-kit tyrosine kinase activity inhibitors in melanomas carrying c-kit mutations; and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, which block the mechanisms involved in immune tolerance. Many problems have yet to be resolved in these areas, however, such as the rapid development of resistance to BRAF and c-kit inhibitors and the lack of biomarkers to predict treatment response in the case of CTLA-4 blockers. We review the results of targeted therapy with these and other drugs in metastatic melanoma and discuss what the future holds for this field. Copyright © 2011 Elsevier España, S.L. and AEDV. All rights reserved.

  12. Pediatric melanoma.

    Science.gov (United States)

    Tracy, Elisabeth T; Aldrink, Jennifer H

    2016-10-01

    Childhood melanoma is a rare pediatric malignancy, with fewer than 500 new diagnoses annually. The incidence is increasing, particularly in the adolescent population. This review highlights the epidemiology, clinical presentation, and histopathologic challenges of pediatric melanoma. Surgical resection remains the cornerstone for localized and regionally advanced disease. Adjuvant therapies, including current options and potential novel therapeutics for this unique population will be discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Management of lipid disorders in patients living with HIV.

    Science.gov (United States)

    Myerson, Merle; Malvestutto, Carlos; Aberg, Judith A

    2015-09-01

    Since the discovery and development of antiretroviral therapy (ART), HIV has become a chronic disease with patients living longer lives and to ages where co-morbidities, such as cardiovascular disease (CVD) are prevalent. Diagnosis and management of risk factors for CVD, in particular dyslipidemia, have become an important part of the overall care for patients living with HIV infection. Existing guidelines and recommendations for the management of dyslipidemia for persons with HIV infection are largely based on guidelines for the general population. Clinical and epidemiologic research efforts are ongoing to provide information specific to patients living with HIV. This review offers a detailed guide for clinicians who manage dyslipidemia in patients infected with HIV. The first sections provide background information on dyslipidemia, risk stratification, and targets for lipid therapy. This is followed by a step-by-step approach for diagnosis and treatment with specific information on lipid drug use for patients with HIV. The recommendations presented here are based on existing guidelines for the general population, evidence from research in patients infected with HIV, and the clinical experience of the authors. Management issues for which little or no information is available specific to this patient population are noted and serve to highlight the many gaps in our knowledge that will need to be addressed.

  14. Living with a diagnosis of non-small cell lung cancer: patients' lived experiences.

    LENUS (Irish Health Repository)

    McCarthy, Ita

    2012-01-31

    The aim of this study was to explore patients\\' experience of living with non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC know that their treatment is not with curative intent and can expect distressing symptoms. In this phenomenological study, six adults with a diagnosis of NSCLC were interviewed. Data was analysed guided by van Manen\\'s six-step process. Four main themes were interpreted: \\'Maintaining my life\\'; \\'The enemy within\\'; \\'Staying on the train\\

  15. Reduction of circulating regulatory T cells by intravenous high-dose interferon alfa-2b treatment in melanoma patients.

    Science.gov (United States)

    Mozzillo, Nicola; Ascierto, Paolo

    2012-10-01

    High-dose interferon alfa-2b (IFNα-2b) is the only approved adjuvant systemic therapy for resected, high risk melanoma in the United States (Fecher and Flaherty, in Natl Compr Cancer Netw 7:295-304, 2009). Recently, two important meta-analyses of randomized trials (Wheatley et al., in J Clin Oncol, 2007; Mocellin et al. in J Natl Cancer Inst, 2010) investigating IFNα-2b versus observation in high risk melanoma patients, showed that adjuvant IFNα-2b has an impact both on relapse-free survival (RFS) and overall survival (OS) independently by dosage, duration and route compared with observation in high risk melanoma patients. Despite of an absolute benefits of 3 % (Wheatley et al., in J Clin Oncol, 2007), this treatment is associated with significant toxicity, which impacts on patient quality of life. A better understanding of the mechanism of action may help to potentiate the clinical efficacy and reduce the toxicity of IFNα-2b/Peg-IFNα-2b. Numerous studies suggest that interferon's mechanism of action in melanoma is primarily immunomodulatory (Table 1) (de La Salmoniere, in Clin Cancer Res 6:4713-4718, 2000; Stuckert, in J Clin Oncol 25:8506, 2007; Gogas et al., in N Engl J Med 354:709-718, 2006; Moschos et al., in J Clin Oncol 24:3164-3171, 2006; Ascierto and Kirkwood, in J Transl Med 6:62, 2008) Recent efforts to elucidate the mechanism of action for interferon have focused upon signal transducers and activators of transcription (STAT) (Simons et al., in J Transl Med 9:52, 2011) signaling and immunoregulatory responses mediated by regulatory T cells (Tregs) (Wang et al., in Clin Cancer Res 13:1523-1531, 2007; Clin Cancer Res 14:8314-8320, 2008). Tregs are a suppressive CD4+ T cell population that is present, along with primed effector T cells, in tumor and tumor-draining lymph nodes (Hiura et al. in J Immunol 175:5058-5066, 2005). Tregs express high levels of surface antigens such as CD25, cytotoxic T lymphocyte associated antigen 4 (CTLA-4), and

  16. Low back pain as the presenting sign in a patient with primary extradural melanoma of the thoracic spine - A metastatic disease 17 Years after complete surgical resection

    Directory of Open Access Journals (Sweden)

    Katalinic Darko

    2011-11-01

    Full Text Available Abstract Primary spinal melanomas are extremely rare lesions. In 1906, Hirschberg reported the first primary spinal melanoma, and since then only 40 new cases have been reported. A 47-year-old man was admitted suffering from low back pain, fatigue and loss of body weight persisting for three months. He had a 17-year-old history of an operated primary spinal melanoma from T7-T9, which had remained stable for these 17 years. Routine laboratory findings and clinical symptoms aroused suspicion of a metastatic disease. Multislice computed tomography and magnetic resonance imaging revealed stage-IV melanoma with thoracic, abdominal and skeletal metastases without the recurrence of the primary process. Transiliac crest core bone biopsy confirmed the diagnosis of metastatic melanoma. It is important to know that in all cases of back ore skeletal pain and unexplained weight loss, malignancy must always be considered in the differential diagnosis, especially in the subjects with a positive medical history. Patients who have back, skeletal, or joint pain that is unresponsive to a few weeks of conservative treatment or have known risk factors with or without serious etiology, are candidates for imaging studies. The present case demonstrates that complete surgical resection alone may result in a favourable outcome, but regular medical follow-up for an extended period, with the purpose of an early detection of a metastatic disease, is highly recommended.

  17. Review of clinical studies on dendritic cell-based vaccination of patients with malignant melanoma: assessment of correlation between clinical response and vaccine parameters

    DEFF Research Database (Denmark)

    Engell-Noerregaard, Lotte; Hansen, Troels Holz; Andersen, Mads Hald

    2009-01-01

    During the past years numerous clinical trials have been carried out to assess the ability of dendritic cell (DC) based immunotherapy to induce clinically relevant immune responses in patients with malignant diseases. A broad range of cancer types have been targeted including malignant melanoma...... which in the disseminated stage have a very poor prognosis and only limited treatment options with moderate effectiveness. Herein we describe the results of a focused search of recently published clinical studies on dendritic cell vaccination in melanoma and review different vaccine parameters which...

  18. BRAF mutations in conjunctival melanoma

    DEFF Research Database (Denmark)

    Larsen, Ann-Cathrine; Dahl, Christina; Dahmcke, Christina M.

    2016-01-01

    Purpose: To investigate incidence, clinicopathological features and prognosis of BRAF-mutated conjunctival melanoma in Denmark. Furthermore, to determine BRAF mutations in paired premalignant lesions and evaluate immunohistochemical BRAF V600E oncoprotein detection. Methods: Data from 139 patients...

  19. A Phase I Study of High-Dose Calcitriol in Combination with Temozolomide for Patients with Metastatic Melanoma

    Directory of Open Access Journals (Sweden)

    Erin Pettijohn

    2014-10-01

    Full Text Available Background: Temozolomide is efficacious as an oral alternative for patients with metastatic melanoma (MM. Calcitriol has anti-proliferative properties and vitamin D receptor (VDR polymorphisms are associated with alterations in melanoma susceptibility and progression. Methods: Tem 150 mg/m2 was administered on days 2–8 and 16–22 every 28 days. Calcitriol was given on days 1 and 15 every 28 days. VDR gene analysis was completed using PCR-RFLP based assays. Tolerability was the primary objective with secondary objectives of time to progression (TTP and overall survival (OS. Results: Twenty pts with MM were registered. Cytopenias and thrombosis were the most common grade 3 or 4 toxicities. Median TTP was 1.8 mo. Pts with high-risk VDR genotype tt+/−ff (n = 6 had an OS of 3.8 mo from time of enrollment, compared to 7.4 mo for those with non-tt/ff genotypes (n = 11, although not statistically significant (HR = 1.20, 95% CI 0.41–3.53, p = 0.74. Conclusions: The extended dosing of Tem with calcitriol is a well-tolerated regimen. The trend toward improved OS in non-tt/ff VDR genotypes is consistent with prior studies associating the tt/ff genotype with biologic aggressiveness.

  20. Nodular Histologic Subtype and Ulceration are Tumor Factors Associated with High Risk of Recurrence in Sentinel Node-Negative Melanoma Patients

    NARCIS (Netherlands)

    Faut, Marloes; Wevers, Kevin P; van Ginkel, Robert J; Diercks, Gilles F H; Hoekstra, Harald J; Kruijff, Schelto; Been, Lukas B; van Leeuwen, Barbara L

    2016-01-01

    BACKGROUND: Since its introduction, the sentinel lymph node biopsy (SLNB) has become the standard staging procedure in clinical node-negative melanoma patients. A negative SLNB, however, does not guarantee a recurrence-free survival. Insight into metastatic patterns and risk factors for recurrence i

  1. Serum YKL-40 Predicts Relapse-Free and Overall Survival in Patients With American Joint Committee on Cancer Stage I and II Melanoma

    DEFF Research Database (Denmark)

    Schmidt, Henrik; Johansen, Julia S; Sjoegren, Pia;

    2006-01-01

    PURPOSE: To evaluate the novel tumor biomarker YKL-40 in serial serum samples from patients with American Joint Committee on Cancer (AJCC) stage I and II melanoma from the time of diagnosis and during routine follow-up. Macrophages, neutrophils, and cancer cells secrete YKL-40, and a high serum...

  2. Induction of systemic CTL responses in melanoma patients by dendritic cell vaccination: Cessation of CTL responses is associated with disease progression

    DEFF Research Database (Denmark)

    Andersen, M.H.; Keikavoussi, P.; Brocker, E.B.

    2001-01-01

    by Western blotting was decreased in PBL at this time. In summary, our data confirm that DC-based vaccinations induce peptide-specific T cells in the peripheral blood of advanced-stage melanoma patients. Although successful induction of systemic tumor antigen-specific CTL may not lead to objective clinical...

  3. Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients

    Directory of Open Access Journals (Sweden)

    Arthur E. Frankel

    2017-10-01

    Full Text Available This is the first prospective study of the effects of human gut microbiota and metabolites on immune checkpoint inhibitor (ICT response in metastatic melanoma patients. Whereas many melanoma patients exhibit profound response to ICT, there are fewer options for patients failing ICT—particularly with BRAF-wild-type disease. In preclinical studies, specific gut microbiota promotes regression of melanoma in mice. We therefore conducted a study of the effects of pretreatment gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid Tumors response in 39 metastatic melanoma patients treated with ipilimumab, nivolumab, ipilimumab plus nivolumab (IN, or pembrolizumab (P. IN yielded 67% responses and 8% stable disease; P achieved 23% responses and 23% stable disease. ICT responders for all types of therapies were enriched for Bacteroides caccae. Among IN responders, the gut microbiome was enriched for Faecalibacterium prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P responders, the microbiome was enriched for Dorea formicogenerans. Unbiased shotgun metabolomics revealed high levels of anacardic acid in ICT responders. Based on these pilot studies, both additional confirmatory clinical studies and preclinical testing of these bacterial species and metabolites are warranted to confirm their ICT enhancing activity.

  4. The value of pre operative S-100B and SUV in clinically stage III melanoma patients undergoing therapeutic lymph node dissection

    NARCIS (Netherlands)

    Kruijff, S.; Bastiaannet, E.; Speijers, M. J.; Kobold, A. C. M.; Brouwers, A. H.; Hoekstra, H. J.

    2011-01-01

    Introduction: High preoperative serum S-100B values and Standardized Uptake Values (SUV) of Fluorodeoxyglucose (FDG) in PET for clinically stage III melanoma patients could be indicators of recurrence after surgical treatment. Aim was to assess the correlation and the prognostic value of these marke

  5. Ultrasound-guided fine needle aspiration cytology as an addendum to sentinel lymph node biopsy can perfect the staging strategy in melanoma patients

    NARCIS (Netherlands)

    C. Voit (Christiane); S.L.M. Gooskens (Saskia); P. Siegel (Petra); G. Schaefer (Gregor); A. Schöngen (Alfred); J. Röwert (Joachim); A.C.J. van Akkooi (Alexander); A.M.M. Eggermont (Alexander)

    2014-01-01

    textabstractBackground Ultrasound guided fine needle aspiration cytology (US-guided FNAC) can identify microscopic involvement of lymph nodes as in breast cancer and avoid surgical sentinel node (SN). Its utility in melanoma patients is controversial and subject of this study. Methods Between 2001 a

  6. [Choroidal melanoma - evolution and prognosis].

    Science.gov (United States)

    Chiruţa, Daria; Stan, Cristina

    2014-01-01

    Choroidal melanoma is the most common primary intraocular malignant tumor. We present the case of a 62 year old patient who was diagnosed with intraocular tumor in his right eye, for about three years. Regarding the fact that the patient refused any kind of treatment during this period, we just had the opportunity to monitor this case. Finally, the diagnosis was choroidal melanoma, confirmed by the histopathological exam.

  7. Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics: results from a collaborative project of 11 European biologic registers

    Science.gov (United States)

    Mercer, Louise K; Askling, Johan; Raaschou, Pauline; Dreyer, Lene; Hetland, Merete Lund; Strangfeld, Anja; Zink, Angela; Mariette, Xavier; Finckh, Axel; Canhao, Helena; Iannone, Florenzo; Zavada, Jakub; Morel, Jacques; Gottenberg, Jacques-Eric; Listing, Joachim

    2017-01-01

    Objectives Some studies have reported a possible association between exposure to tumour necrosis factor (TNF) inhibitors and an increased risk of melanoma. The aim of this study was to investigate the incidence of invasive cutaneous melanomas in patients with rheumatoid arthritis (RA) treated with TNF inhibitors (TNFi), other biologic disease modifying drugs and non-biologic therapy. Methods Eleven biologic registers from nine European countries participated in this collaborative project. According to predefined exposure definitions, cohorts of patients with RA were selected. Using the country-specific general population of each register as reference, age, sex and calendar year standardised incidence ratios (SIRs) of invasive histology-confirmed cutaneous melanoma were calculated within each register. Pooled SIR and incidence rate ratios (IRRs) comparing biologic cohorts to biologic-naïve were calculated across countries by taking the size of the register into account. Results Overall 130 315 RA patients with a mean age of 58 years contributing 579 983 person-years were available for the analysis and 287 developed a first melanoma. Pooled SIRs for biologic-naïve, TNFi and rituximab-exposed patients were 1.1 (95% CI 0.9 to 1.4), 1.2 (0.99 to 1.6) and 1.3 (0.6 to 2.6), respectively. Incidence rates in tocilizumab and abatacept-exposed patients were also not significantly increased. IRR versus biologic-naïve patients were: TNFi 1.1 (95% CI 0.8 to 1.6); rituximab 1.2 (0.5 to 2.9). Conclusions This large European collaborative project did not confirm an overall increased risk of melanoma following exposure to TNFi. PMID:27307502

  8. Novel Targeted Therapies for Metastatic Melanoma.

    Science.gov (United States)

    Iams, Wade T; Sosman, Jeffrey A; Chandra, Sunandana

    Oncogene-targeted therapy is a major component of precision oncology, and although patients with metastatic melanoma have experienced improved outcomes with this strategy, there are a number of potential therapeutic targets currently under study that may further increase the drug armamentarium for this patient population. In this review, we discuss the landscape of targeted therapies for patients with advanced melanoma, focusing on oncogene mutation-specific targets. In patients with typical BRAF V600-mutant melanoma, combination BRAF and MEK inhibition has surpassed outcomes compared with monotherapy with BRAF or MEK inhibition alone, and current strategies seek to address inevitable resistance mechanisms. For patients with NRAS-mutant melanoma, MEK inhibitor monotherapy and combined MEK and CDK4/6 inhibition are burgeoning strategies; for patients with KIT-mutant melanoma, tyrosine kinase inhibition is being leveraged, and for NF-1-mutant melanoma, mTOR and MEK inhibition is being actively evaluated. In patients with atypical, non-V600 BRAF-mutant melanoma, MEK inhibitor monotherapy is the potential novel targeted approach on the horizon. For advanced uveal melanoma, novel targets such as IMCgp100 and glembatumumab have shown activity in early studies. We review additional strategies that remain in the preclinical and early clinical pipeline, so there is much hope for the future of targeted agents for distinct molecular cohorts of patients with advanced melanoma.

  9. Molecular insights into melanoma brain metastases.

    Science.gov (United States)

    Westphal, Dana; Glitza Oliva, Isabella C; Niessner, Heike

    2017-06-01

    Substantial proportions of patients with metastatic melanoma develop brain metastases during the course of their disease, often resulting in significant morbidity and death. Despite recent advances with BRAF/MEK and immune-checkpoint inhibitors in the treatment of patients who have melanoma with extracerebral metastases, patients who have melanoma brain metastases still have poor overall survival, highlighting the need for further therapy options. A deeper understanding of the molecular pathways involved in the development of melanoma brain metastases is required to develop more brain-specific therapies. Here, the authors summarize the currently known preclinical data and describe steps involved in the development of melanoma brain metastases. Only by knowing the molecular background is it possible to design new therapeutic agents that can be used to improve the outcome of patients with melanoma brain metastases. Cancer 2017;123:2163-75. © 2017 American Cancer Society. © 2017 American Cancer Society.

  10. Prospective study of melanoma in the Paris Region in 2004

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    Souques, M.; Baccard, M.; Barrazza, V.; Havard, S.; Verrier, A.; Wechsler, J. [Prevention et Epidemiologie des Tumeurs en Region Ile de France (PETRI), Domus Medica, 75 - Paris (France)

    2006-07-01

    Introduction: Melanoma remains an important public health problem because of its increasing incidence and its responsibility for the deaths of young individuals. A first study was carried out by the P.E.T.R.I. association in 1994 to estimate the incidence of melanoma in the Paris region. A second one was carried out in 2004, with the same methodology, to estimate the increase of melanoma incidence in the Paris region and the main clinical and histological characteristics of these cancers, comparing to 1994 data. Methodology: Every pathologist of the region has been contacted to fill a questionnaire for each primary cutaneous melanoma excised between January 1. and December 31. 2004, from patients living in the Paris region (departments 75, 77, 91, 92, 93, 94, 95). The information requested included melanoma characteristics (localisation, type, Breslow thickness, Clark level, regression signs, pre existence of a nevus) and demographic data (age, sex, zip code of residence). Results: 98 % of pathologists in the region agree to participate in the study. They send 1453 questionnaires, among them 160 were excluded (double, non cutaneous melanoma, secondary lesion, non resident in the region, diagnoses out of the inclusion dates, biopsy followed by exeresis). The analyse included 1293 lesions in 1269 patients. More than 2/3 of diagnoses were confirmed by 2 laboratories and 10 laboratories (on 98) reported 86 % of the diagnoses. Incidence:The crude incidence of melanoma in the Paris region during 2004 was 11.4 cases per 100 000 inhabitants, by sex:11.1 per 100 000 males and 12.4 cases per 100 000 females. The sex ratio men/women was 0.82. The crude incidence of invasive melanoma (Clark 2 to 5) was 8,9 cases per 100 000 inhabitants, 9,2 per 100 000 women and 8,6 per 100 000 men, with a sex ratio men/women of 0,93. Demographic characteristics: Melanoma diagnosis was more often in women (54.9 %) than in men (45.1 %). The patients mean age was 59.3 years (S.D.: 17.3). The

  11. Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity

    OpenAIRE

    Bol, Kalijn F.; Aarntzen, Erik H. J. G.; Pots, Jeanette M.; Olde Nordkamp, Michel A. M.; van de Rakt, Mandy W. M. M.; Scharenborg, Nicole M.; de Boer, Annemiek J.; van Oorschot, Tom G. M.; Croockewit, Sandra A. J.; Blokx, Willeke A. M.; Oyen, Wim J. G.; Boerman, Otto C.; Mus, Roel D. M.; van Rossum, Michelle M.; van der Graaf, Chantal A. A.

    2016-01-01

    Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients, predominantly with DC matured with pro-inflammatory cytokines and prostaglandin E2. We studied the safety and efficacy of vaccination with monocyte-derived DC matured with a cocktail of prophylactic vaccines that contain clinical-grade Toll-like receptor ligands (BCG, Typhim, Act-HIB) and prostaglandin E2 (VAC-DC). Stage III and IV melanoma patients were vaccinated via intranodal injection (12 patients) or combi...

  12. Targeted Radionuclide Therapy of Melanoma.

    Science.gov (United States)

    Norain, Abdullah; Dadachova, Ekaterina

    2016-05-01

    An estimated 60,000 individuals in the United States and 132,000 worldwide are yearly diagnosed with melanoma. Until recently, treatment options for patients with stages III-IV metastatic disease were limited and offered marginal, if any, improvement in overall survival. The situation changed with the introduction of B-RAF inhibitors and anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed cell death protein 1 immunotherapies into the clinical practice. With only some patients responding well to the immune therapies and with very serious side effects and high costs of immunotherapy, there is still room for other approaches for the treatment of metastatic melanoma. Targeted radionuclide therapy of melanoma could be divided into the domains of radioimmunotherapy (RIT), radiolabeled peptides, and radiolabeled small molecules. RIT of melanoma is currently experiencing a renaissance with the clinical trials of alpha-emitter (213)Bi-labeled and beta-emitter (188)Rhenium-labeled monoclonal antibodies in patients with metastatic melanoma producing encouraging results. The investigation of the mechanism of efficacy of melanoma RIT points at killing of melanoma stem cells by RIT and involvement of immune system such as complement-dependent cytotoxicity. The domain of radiolabeled peptides for targeted melanoma therapy has been preclinical so far, with work concentrated on radiolabeled peptide analogues of melanocyte-stimulating hormone receptor and on melanin-binding peptides. The field of radiolabeled small molecule produced radioiodinated benzamides that cross the cellular membrane and bind to the intracellular melanin. The recent clinical trial demonstrated measurable antitumor effects and no acute or midterm toxicities. We are hopeful that the targeted radionuclide therapy of metastatic melanoma would become a clinical reality as a stand-alone therapy or in combination with the immunotherapies such as anti-PD1 programmed cell death protein 1 monoclonal antibodies

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

    Science.gov (United States)

    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

    2017-04-01

    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). 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. 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 melanoma treatment across Europe. It is crucial to increase the awareness of national and European policymakers, oncological societies, melanoma patients' associations and pharma industry. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. An ethical dilemma: malignant melanoma in a 51-year-old patient awaiting simultaneous kidney and pancreas transplantation for type 1 diabetes.

    Science.gov (United States)

    Kirby, L C; Banerjee, A; Augustine, T; Douglas, J F

    2016-07-01

    Malignant melanoma is a high-risk skin cancer that, in potential transplant recipients, is considered a substantial contraindication to solid organ transplantation due to significant risk of recurrence with immunosuppression. Current guidelines stipulate waiting between 3 and 10 years after melanoma diagnosis. However, in young patients with end-stage organ failure and malignant melanoma, complex ethical and moral issues arise. Assessment of the true risk associated with transplantation in these patients is difficult due to lack of prospective data, but an autonomous patient can make a decision that clinicians may perceive to be high risk. The national and worldwide shortage of available organs also has to be incorporated into the decision to maximize the net benefit and minimize the risk of graft failure and mortality. The incidence of malignant melanoma worldwide is increasing faster than that of any other cancer and continues to pose ethically challenging decisions for transplant specialists evaluating recipients for solid organ transplantation. © 2016 British Association of Dermatologists.

  15. Adoptive transfer of MART-1 T cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma

    Science.gov (United States)

    Chodon, Thinle; Comin-Anduix, Begonya; Chmielowski, Bartosz; Koya, Richard C; Wu, Zhongqi; Auerbach, Martin; Ng, Charles; Avramis, Earl; Seja, Elizabeth; Villanueva, Arturo; McCannel, Tara A.; Ishiyama, Akira; Czernin, Johannes; Radu, Caius G.; Wang, Xiaoyan; Gjertson, David W.; Cochran, Alistair J.; Cornetta, Kenneth; Wong, Deborah J.L.; Kaplan-lefko, Paula; Hamid, Omid; Samlowski, Wolfram; Cohen, Peter A.; Daniels, Gregory A.; Mukherji, Bijay; Yang, Lili; Zack, Jerome A.; Kohn, Donald B.; Heath, James R.; Glaspy, John A.; Witte, Owen N.; Baltimore, David; Economou, James S.; Ribas, Antoni

    2014-01-01

    Purpose It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short one-week manufacture protocol to determine the feasibility, safety and antitumor efficacy of this double cell therapy. Experimnetal Design A clinical trial (NCT00910650) adoptively transferring MART-1 T cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and re-infused with (n = 10) or without (n = 3) prior cryopreservation. Results 14 patients with metastatic melanoma were enrolled and nine out of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within two weeks of ACT indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared to cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using non-cryopreserved T cells. Conclusion Double cell therapy with ACT of TCR engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses. PMID:24634374

  16. Melanoma biomolecules: independently identified but functionally intertwined.

    Science.gov (United States)

    Dye, Danielle E; Medic, Sandra; Ziman, Mel; Coombe, Deirdre R

    2013-09-24

    The majority of patients diagnosed with melanoma present with thin lesions and generally these patients have a good prognosis. However, 5% of patients with early melanoma (CSPG4), and paired box 3 (PAX3). The goal is to provide context around what is known about the contribution of these biomarkers to melanoma biology and metastasis. Although each of these molecules have been independently identified as likely biomarkers, it is clear from our analyses that each are closely linked with each other, with intertwined roles in melanoma biology.

  17. Melanoma patients with unknown primary site or nodal recurrence after initial diagnosis have a favourable survival compared to those with synchronous lymph node metastasis and primary tumour.

    Directory of Open Access Journals (Sweden)

    Benjamin Weide

    Full Text Available BACKGROUND: A direct comparison of prognosis between patients with regional lymph node metastases (LNM detected synchronously with the primary melanoma (primary LNM, patients who developed their first LNM subsequently (secondary LNM and those with initial LNM in melanoma with unknown primary site (MUP is missing thus far. PATIENTS AND METHODS: Survival of 498 patients was calculated from the time point of the first macroscopic LNM using Kaplan Meier and multivariate Cox hazard regression analysis. RESULTS: Patients with secondary LNM (HR = 0.67; p = 0.009 and those with initial LNM in MUP (HR = 0.45; p = 0.008 had a better prognosis compared to patients with primary LNM (median survival time 52 and 65 vs. 24 months, respectively. A high number of involved nodes, the presence of in-transit/satellite metastases and male gender had an additional independent unfavourable effect. CONCLUSIONS: Survival of patients with LNM in MUP and with secondary LNM is similar and considerably more favourable compared to those with primary LNM. This difference needs to be considered during patient counselling and for stratification purposes in clinical trials. The assumption of an immune privilege of patients with MUP which is responsible for rejection of the primary melanoma, and results in a favourable prognosis is not supported by our data.

  18. Religious attitudes towards living kidney donation among Dutch renal patients

    NARCIS (Netherlands)

    S.Y. Ismail (Sohal); E.K. Massey (Emma); A.E. Luchtenburg; L. Claassen (Liesbeth); W.C. Zuidema (Wilij); J.J. van Busschbach (Jan); W. Weimar (Willem)

    2012-01-01

    textabstractTerminal kidney patients are faced with lower quality of life, restricted diets and higher morbidity and mortality rates while waiting for deceased donor kidney transplantation. Fortunately, living kidney donation has proven to be a better treatment alternative (e.g. in terms of waiting

  19. Reduced frequency of non-melanoma skin cancer in 72,739 patients with psoriasis: a retrospective study.

    Science.gov (United States)

    Paradisi, Andrea; Didona, Biagio; Tabolli, Stefano; Ricci, Francesco; Sobrino, Luciano; Panebianco, Annarita; Abeni, Damiano

    2017-08-01

    Chronic inflammatory conditions, such as psoriasis, may pose an increased risk of cancer due to impaired immunosurveillance resulting from chronic inflammation and immunosuppressive medications. To compare the risk of non-melanoma skin cancer (NMSC) in a retrospective cohort of 72,739 psoriasis patients and 25,956 non-dermatological patients. A record linkage was performed for data on hospitalizations, and the occurrence of NMSC was compared by computing the relative risk (RR) and modelled using multiple logistic regression. Overall, the occurrence of NMSC was 9.6‰ (95% CI: 8.9-10.3‰) in psoriasis patients and 19.6‰ (95% CI: 18.0-21.4‰) in non-dermatological patients (RR = 0.49; 95% CI: 0.44-0.55). The simultaneous adjustment for gender, age, and phototherapy yielded a RR of 0.84 (95% CI: 0.75-0.95). With regards to phototherapy, the occurrence of NMSC was significantly higher among psoriasis patients who underwent phototherapy relative to those who did not (27.0‰ vs. 9.3‰). In this large retrospective study, we found that patients with psoriasis had a 16% lower probability of having NMSC when compared to a group of non-dermatological patients. Further studies, preferably with a prospective longitudinal design to collect more precise data, are needed to corroborate our findings.

  20. Maintaining the will to live of patients with advanced cancer.

    Science.gov (United States)

    Khan, Luluel; Wong, Rebecca; Li, Madeline; Zimmermann, Camilla; Lo, Chris; Gagliese, Lucia; Rodin, Gary

    2010-01-01

    The will to live is a natural instinct experienced by all human beings. It tends to persist in humans, despite marked adversity such as that associated with advanced cancer. The will to live may be measured directly, or indirectly, by assessing the desire for hastened death. Factors that may affect it include age, life stage, and physical and psychological distress. In particular, states of depression and hopelessness may precede the loss of the will to live. Other psychosocial variables that may affect the will to live include physical suffering, attachment security, self-esteem, and spiritual well-being. A number of screening tools are available to identify risk factors for the loss of the will to live. Awareness of these factors can guide interventions to preserve morale and maintain hope in patients faced with a terminal illness. Critical among these are the alleviation of physical and psychosocial distress and the establishment of a therapeutic alliance that is sensitive to the specific support needs of individual patients. Comfort and facility with such supportive interventions in oncology will require greater attention to the development of communication and relationship skills at both undergraduate and postgraduate levels of training.

  1. The Long-term Risk of Upper-extremity Lymphedema is Two-fold Higher in Breast Cancer Patients than in Melanoma Patients

    Science.gov (United States)

    Voss, Rachel K.; Cromwell, Kate D.; Chiang, Yi-Ju; Armer, Jane M.; Ross, Merrick I.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Stewart, Bob R.; Shaitelman, Simona F.; Cormier, Janice N.

    2015-01-01

    Background and Objectives We assessed the cumulative incidence, symptoms, and risk factors for upper-extremity lymphedema in breast cancer and melanoma patients undergoing sentinel lymph node biopsy or axillary lymph node dissection. Methods Patients were recruited preoperatively (time 0) and assessed at 6, 12, and 18 months postoperatively. Limb volume change (LVC) was measured by perometry. Lymphedema was categorized as none, mild (LVC 5–9.9%), or moderate/severe (LVC≥10%). Symptoms were assessed with a validated lymphedema instrument. Longitudinal logistic regression analyses were conducted to identify risk factors associated with moderate/severe lymphedema. Results Among 205 breast cancer and 144 melanoma patients, the cumulative incidence of moderate/severe lymphedema at 18 months was 36.5% and 35.0, respectively. However, in adjusted analyses, factors associated with moderate/severe lymphedema were breast cancer (OR 2.0, p=0.03), body mass index ≥30 kg/m2 (OR 1.6, p=0.04), greater number of lymph nodes removed (OR 1.05, pLymphedema incidence increased over time in both cohorts. However, the adjusted risk of moderate/severe lymphedema was two-fold higher in breast cancer patients. These results may be attributed to surgical treatment of the primary tumor in the breast and more frequent use of radiation. PMID:26477877

  2. Long-term outcome in BRAFV600E melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression

    Science.gov (United States)

    Puzanov, Igor; Amaravadi, Ravi K.; McArthur, Grant A.; Flaherty, Keith T.; Chapman, Paul B.; Sosman, Jeffrey A.; Ribas, Antoni; Shackleton, Mark; Hwu, Patrick; Chmielowski, Bartosz; Nolop, Keith B.; Lin, Paul S.; Kim, Kevin B.

    2016-01-01

    Introduction Vemurafenib induces tumour regression in most patients with BRAFV600E-mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAFV600E melanoma treated in the phase 1 vemurafenib trial is reported. Methods Patients received vemurafenib 240–1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily. Clinical response was evaluated every 8 weeks by RECIST. Patients with PD amenable to local therapy (surgery or radiotherapy) were allowed to continue vemurafenib after progression. Overall survival (OS) from time of treatment initiation and from PD was estimated. Sites of PD were recorded. Results Forty-eight patients (escalation cohort, n = 16; extension cohort, n = 32) received therapeutic doses of vemurafenib (≥240 mg twice daily). Forty-three patients had PD by the time of this analysis, and 5 remained progression free (follow-up time, 1.2–56.1 months). Median OS was 14 months (range, 1.2–56.1); 3- and 4-year melanoma-specific survival rate in the extension cohort was 26% and 19%, respectively. Median OS was 26.0 months (range, 7.7–56.1) among 20 patients who continued vemurafenib after local therapy. Median treatment duration beyond initial PD was 3.8 months (range, 1.1–26.6). In the extension cohort, 6 and 5 patients were alive after 3 and 4 years, respectively, on vemurafenib monotherapy. Conclusions Some patients with melanoma achieved long-term survival with vemurafenib monotherapy. Continuation of vemurafenib after PD might be beneficial in some patients because remaining disease might continue to respond to BRAF inhibition. PMID:25980594

  3. A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation.

    Science.gov (United States)

    Plummer, Ruth; Lorigan, Paul; Steven, Neil; Scott, Lucy; Middleton, Mark R; Wilson, Richard H; Mulligan, Evan; Curtin, Nicola; Wang, Diane; Dewji, Raz; Abbattista, Antonello; Gallo, Jorge; Calvert, Hilary

    2013-05-01

    poly(ADP ribose) polymerase inhibition has been shown to potentiate the cytotoxicity of DNA damaging agents. A phase I study of rucaparib and temozolomide showed that full-dose temozolomide could be given during PARP inhibition. We report the results of a phase II study of intravenous rucaparib 12 mg/m(2) and oral temozolomide 200 mg/m(2) on days 1-5 every 28 days in patients with advanced metastatic melanoma. Patients with chemotherapy naïve measurable metastatic melanoma, performance status ≤2 and good end-organ function were recruited. Treatment was given until progression. A two stage phase II design was used, with response rate the primary endpoint. Population pharmacokinetics and pharmacodynamics were also explored. Forty-six patients were recruited with 37 patients receiving at least 2 cycles and 17 patients at least 6 cycles. Myelosuppression occurred with 25 patients (54 %) requiring a 25 % dose reduction in temozolomide. The response rate was 17.4 %, median time to progression 3.5 months, median overall survival 9.9 months, and 36 % of patients were progression-free at 6 months. This study showed that temozolomide (150-200 mg/m(2)/day) can safely be given with a PARP inhibitory dose of rucaparib, increasing progression-free survival over historical controls in metastatic melanoma patients.

  4. BRAF-V600 mutations have no prognostic impact in stage IV melanoma patients treated with monochemotherapy.

    Directory of Open Access Journals (Sweden)

    Diana Meckbach

    Full Text Available BACKGROUND: The impact of BRAF tumor mutations on the natural course of disease of melanoma patients is controversial. PATIENTS AND METHODS: We analyzed the mutational status and overall survival of 215 patients receiving treatment with dacarbazine or temozolomide. All patients who started first-line treatment at our institution between 2000 and 2010 were included to prevent selection and bias due to thereafter arising therapeutic options. RESULTS: No patient received BRAF- or MEK-inhibitors during follow-up. Survival was associated with the pattern of visceral involvement, the presence of brain metastases and the serum lactate dehydrogenase level (all p<0.001. The BRAF-V600 mutational status was not associated with survival and no differences in overall survival were detected according to age, gender or to the cytotoxic agent used for therapy. In Cox regression analysis the presence of brain metastases (hazard ratio 2.3; p<0.001 and an elevated serum LDH (hazard ratio 2.5; p<0.001 were the only factors, which independently predicted survival. CONCLUSIONS: No differences in prognosis were observed according to the BRAF mutational status in patients with distant metastasis treated with monochemotherapy.

  5. Isolation of tumorigenic circulating melanoma cells

    Science.gov (United States)

    Ma, Jie; Lin, Jennifer Y.; Alloo, Allireza; Wilson, Brian J.; Schatton, Tobias; Zhan, Qian; Murphy, George F.; Waaga-Gasser, Ana-Maria; Gasser, Martin; Hodi, F. Stephen; Frank, Natasha Y.; Frank, Markus H.

    2010-01-01

    Circulating tumor cells (CTC) have been identified in several human malignancies, including malignant melanoma. However, whether melanoma CTC are tumorigenic and cause metastatic progression is currently unknown. Here we isolate for the first time viable tumorigenic melanoma CTC and demonstrate that this cell population is capable of metastasis formation in human-to-mouse xenotransplantation experiments. The presence of CTC among peripheral blood mononuclear cells (PBMC) of murine recipients of subcutaneous (s.c.) human melanoma xenografts could be detected based on mRNA expression for human GAPDH and/or ATP-binding cassette subfamily B member 5 (ABCB5), a marker of malignant melanoma-initiating cells previously shown to be associated with metastatic disease progression in human patients. ABCB5 expression could also be detected in PBMC preparations from human stage IV melanoma patients but not healthy controls. The detection of melanoma CTC in human-to-mouse s.c. tumor xenotransplantation models correlated significantly with pulmonary metastasis formation. Moreover, prospectively isolated CTC from murine recipients of s.c. melanoma xenografts were capable of primary tumor initiation and caused metastasis formation upon xenotransplantation to secondary murine NOD-scid IL2Rγnull recipients. Our results provide initial evidence that melanoma CTC are tumorigenic and demonstrate that CTC are capable of causing metastatic tumor progression. These findings suggest a need for CTC eradication to inhibit metastatic progression and provide a rationale for assessment of therapeutic responses of this tumorigenic cell population to promising emerging melanoma treatment modalities. PMID:20977885

  6. Late development of splenic sarcoidosis-like lesions in a patient with metastatic melanoma and long-lasting clinical response to ipilimumab

    DEFF Research Database (Denmark)

    Andersen, Rikke; Nørgaard, Peter Henrik; Al-Jailawi, Mohamad Kadhem Mohamad

    2014-01-01

    A male patient with Stage IV melanoma was treated with ipilimumab resulting in a long-lasting partial response according to RECIST criteria. However, twenty months after ipilimumab treatment, routine follow-up CT scan revealed new splenic lesions initially interpreted as indicative of progressive...... months the splenic lesions slowly disappeared and to date the patient remains in remission. Ipilimumab is now widely used in the treatment of melanoma patients. Our case-report illustrates that physicians should consider the possibility of ipilimumab induced visceral sarcoidosis-like reactions, mimicking...... disease. Nevertheless, a biopsy was performed and histologic evaluation showed that the lesions did not contain malignant cells but rather constituted non-caseating epithelioid cell granulomas consistent with sarcoidosis. As the patient was asymptomatic no treatment was initiated and over the following...

  7. Cyclical thrombocytosis, acquired von Willebrand syndrome and aggressive non-melanoma skin cancers are common in patients with Philadelphia-negative myeloproliferative neoplasms treated with hydroxyurea.

    Science.gov (United States)

    Verner, Emma; Forsyth, Cecily; Grigg, Andrew

    2014-05-01

    Abstract Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea complications have been reported in Philadelphia-negative myeloproliferative neoplasms (MPNs), but their incidence and clinical consequences have not been defined in a large cohort of patients. We conducted a retrospective analysis of 188 consecutive patients with MPNs specifically addressing the incidence of these complications. Cyclical thrombocytosis was documented in 29 patients (15%), the majority of whom were receiving hydroxyurea. Acquired von Willebrand syndrome was identified in 17 of the 84 screened patients (20%), but was not associated with any major bleeding complications. Non-melanoma skin cancers were reported in 51 patients (27%). Hydroxyurea-related fever occurred in nine of 149 patients (6%) who received hydroxyurea. Seventy-three patients (39%) experienced a total of 98 major thrombotic events, with the majority of these occurring prior to or within 3 months of the diagnosis. Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea-related complications are not infrequent in MPNs and have important clinical consequences for management.

  8. What Is Melanoma Skin Cancer?

    Science.gov (United States)

    ... Z About Melanoma Skin Cancer What Is Melanoma Skin Cancer? Key Statistics for Melanoma Skin Cancer What’s New in Melanoma ... Policy . About Melanoma Skin Cancer What Is Melanoma Skin Cancer? Key Statistics for Melanoma Skin Cancer What’s New in Melanoma ...

  9. Is Full Lymph Node Removal Always Needed for Melanoma?

    Science.gov (United States)

    ... Is Full Lymph Node Removal Always Needed for Melanoma? Survival was just as long for those who ... all lymph nodes in the vicinity of a melanoma skin cancer may not increase a patient's overall ...

  10. [Factors of lonely living in old psychiatric patients].

    Science.gov (United States)

    Druz, V F; Oleinikova, I N

    2000-01-01

    70 lonely patients 60-83 years old were examined. Loneliness in the disintegrated first group (54 patients) resulted from the disintegrated family (the patients were early married). The loneliness in the second group was determined by the absence of their own family (16 patients). The main factors leading to loneliness were such diseases as schizophrenia and epilepsy, paranoic disorders of persecutive character directed to the nearest family, hypochondric depression, psychopathic-like disturbances, mental defect, personality disorders in premorbid state. Among social-psychologic factors the following ones had a significance: underestimation of the mental disorders in patients by their relatives, conflicts in the family, the patient's negative orientation to marriage, their deep emotional interrelation with the parents in young and mature age, alcoholism of married couple and special psychopathic features of the relatives. The events relating with the old age (loss of elderly couple), separation with adult children and parents, bad domestic living conditions were of less significance.

  11. Energy balance in patients with advanced NSCLC, metastatic melanoma and metastatic breast cancer receiving chemotherapy--a longitudinal study.

    Science.gov (United States)

    Harvie, M N; Howell, A; Thatcher, N; Baildam, A; Campbell, I

    2005-02-28

    Chemotherapy exerts a variable effect on nutritional status. It is not known whether loss of body fat or fat-free mass (FFM) during chemotherapy relates to diminished dietary intake, failure to meet elevated energy requirements, or to the presence of an acute-phase response. We sought to determine prospective measurements of body mass and composition, resting energy expenditure, energy and protein intake, and C-reactive protein over a course of chemotherapy in 82 patients with advanced cancer. There was a large dropout from the study. Prospective measurements were obtained in 19 patients with non-small-cell lung cancer (NSCLC), 12 with metastatic melanoma and 10 with metastatic breast cancer. There were significant increases in energy intake among patients with metastatic breast cancer, 873 (266-1480) kJ (mean 95% CI; Pcancer patients gained percentage body fat over the course of treatment, 2.1 (0.8-3.5%). Gain or loss of body fat correlated to mean energy intake throughout chemotherapy in patients with NSCLC (Rs=0.751; Pcancer (Rs=0.617; Pcancer and NSCLC, but did not prevent loss of FFM in these groups.

  12. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma

    OpenAIRE

    Schadendorf, Dirk; Dummer, Reinhard; Hauschild, Axel; Robert, Caroline; Hamid, Omid; Daud, Adil; van den Eertwegh, Alfons; Cranmer, Lee; O'Day, Steven; Puzanov, Igor; Schachter, Jacob; Blank, Christian; Salama, April; Loquai, Carmen; Mehnert, Janice M

    2016-01-01

    BACKGROUND In KEYNOTE-002, pembrolizumab significantly prolonged progression-free survival and was associated with a better safety profile compared with chemotherapy in patients with advanced melanoma that progressed after ipilimumab. We present health-related quality of life (HRQoL) outcomes from KEYNOTE-002. METHODS Patients were randomly assigned 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or investigator-choice chemotherapy. HRQoL was assessed using the European Organisati...

  13. Elevation of glycoprotein nonmetastatic melanoma protein B in type 1 Gaucher disease patients and mouse models.

    Science.gov (United States)

    Kramer, Gertjan; Wegdam, Wouter; Donker-Koopman, Wilma; Ottenhoff, Roelof; Gaspar, Paulo; Verhoek, Marri; Nelson, Jessica; Gabriel, Tanit; Kallemeijn, Wouter; Boot, Rolf G; Laman, Jon D; Vissers, Johannes P C; Cox, Timothy; Pavlova, Elena; Moran, Mary Teresa; Aerts, Johannes M; van Eijk, Marco

    2016-09-01

    Gaucher disease is caused by inherited deficiency of lysosomal glucocerebrosidase. Proteome analysis of laser-dissected splenic Gaucher cells revealed increased amounts of glycoprotein nonmetastatic melanoma protein B (gpNMB). Plasma gpNMB was also elevated, correlating with chitotriosidase and CCL18, which are established markers for human Gaucher cells. In Gaucher mice, gpNMB is also produced by Gaucher cells. Correction of glucocerebrosidase deficiency in mice by gene transfer or pharmacological substrate reduction reverses gpNMB abnormalities. In conclusion, gpNMB acts as a marker for glucosylceramide-laden macrophages in man and mouse and gpNMB should be considered as candidate biomarker for Gaucher disease in treatment monitoring.

  14. [Vulvar melanoma].

    Science.gov (United States)

    Chokoeva, A; Tchernev, G; Wollina, U

    2015-01-01

    Malignant melanoma of the vulva is a rare disease with aggressive behavior and poor prognosis. It consist melanoma in females, as the ratio of its manifestation, compared with the cutaneous melanoma is 1:71. Higher risk of developing melanoma of the vulva is established in white women, as the peak of the incidence is between 60 and 70 years of age. Clinically, MM of the vulva manifests as asymptomatic pigmented, rarely a pigmented lesion, as the usual clinical form is superficial spreading MM and much less common nodular MM, which is associated with a poorer prognosis in. general. The diagnosis is confirmed by histological examination. Conduction of PCR and DNA analysis for detection of BRAF mutations, NRAS mutations and KIT amplification is also appropriate. Advanced age, black race, tumor size, tumor thickness, ulceration, presence of satellite lesions, involvement of adjacent organs (vagina, urethra), and the presence of regional or distant metastases are identified as the most important prognostic markers. Radical wide excision followed by bilateral lymphadenectomy id considered as the optimal therapeutic approach.

  15. What Does Melanoma Look Like?

    Science.gov (United States)

    ... Skin Cancer Skin Cancer Screening Research What Does Melanoma Look Like? Melanoma is a type of cancer ... melanoma is itchy, tender, or painful. Photos of Melanoma A large, asymmetrical melanoma with an uneven color ...

  16. Site and Timing of First Relapse in Stage III Melanoma Patients: Implications for Follow-Up Guidelines

    Science.gov (United States)

    Romano, Emanuela; Scordo, Michael; Dusza, Stephen W.; Coit, Daniel G.; Chapman, Paul B.

    2010-01-01

    Purpose Stage III melanoma is associated with a high risk of relapse and mortality. Nevertheless, follow-up guidelines have largely been empirical rather than evidence-based. Patients and Methods Clinical records of stage III patients with no evidence of disease seen at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1992 and 2004, who ultimately relapsed, were reviewed retrospectively to evaluate date of first relapse, time to first relapse, method of first relapse detection, and survival. We also determined overall 5-year relapse-free survival (RFS) of all stage III patients seen at MSKCC during this period. Results The overall 5-year RFS for stage IIIA, IIIB, and IIIIC patients was 63%, 32%, and 11%, respectively. Among relapsing patients, 340 had adequate follow-up to be evaluable for all parameters. Site of first relapse was local/in-transit (28%), regional nodal (21%), or systemic (51%). First relapses were detected by the patient or family, physician, or by screening radiologic tests in 47%, 21%, and 32% of patients, respectively. Multivariate analysis revealed that better overall survival was associated with younger age and first relapse being local/in-transit or nodal, asymptomatic, or resectable. For each substage, we estimated site-specific risk of first relapse. Conclusion Patients detected almost half of first relapses. Our data suggest that routine physical examinations beyond 3 years for stage IIIA, 2 years for stage IIIB, and 1 year for stage IIIC patients and radiologic imaging beyond 3 years for stages IIIA and IIIB and 2 years for stage IIIC patients would be expected to detect few first systemic relapses. PMID:20479405

  17. Self-Efficacy and Comfort with Partner-Assisted Skin Examination in Patients Receiving Follow-Up Care for Melanoma

    Science.gov (United States)

    DiMillo, J.; Brosseau, D. C.; Gomez-Garibello, C.; Hall, N. C.; Ezer, H.; Wang, B.; Körner, A.

    2017-01-01

    The objective of this study was to examine the role of interpersonal variables on melanoma survivors' self-efficacy for performing skin self-examinations (SSEs) during melanoma follow-up care. Specifically, the impact of comfort with partner assistance for SSE, SSE support received from one's partner, general partner support, relationship…

  18. Melanoma risk prediction models

    Directory of Open Access Journals (Sweden)

    Nikolić Jelena

    2014-01-01

    Full Text Available Background/Aim. The lack of effective therapy for advanced stages of melanoma emphasizes the importance of preventive measures and screenings of population at risk. Identifying individuals at high risk should allow targeted screenings and follow-up involving those who would benefit most. The aim of this study was to identify most significant factors for melanoma prediction in our population and to create prognostic models for identification and differentiation of individuals at risk. Methods. This case-control study included 697 participants (341 patients and 356 controls that underwent extensive interview and skin examination in order to check risk factors for melanoma. Pairwise univariate statistical comparison was used for the coarse selection of the most significant risk factors. These factors were fed into logistic regression (LR and alternating decision trees (ADT prognostic models that were assessed for their usefulness in identification of patients at risk to develop melanoma. Validation of the LR model was done by Hosmer and Lemeshow test, whereas the ADT was validated by 10-fold cross-validation. The achieved sensitivity, specificity, accuracy and AUC for both models were calculated. The melanoma risk score (MRS based on the outcome of the LR model was presented. Results. The LR model showed that the following risk factors were associated with melanoma: sunbeds (OR = 4.018; 95% CI 1.724- 9.366 for those that sometimes used sunbeds, solar damage of the skin (OR = 8.274; 95% CI 2.661-25.730 for those with severe solar damage, hair color (OR = 3.222; 95% CI 1.984-5.231 for light brown/blond hair, the number of common naevi (over 100 naevi had OR = 3.57; 95% CI 1.427-8.931, the number of dysplastic naevi (from 1 to 10 dysplastic naevi OR was 2.672; 95% CI 1.572-4.540; for more than 10 naevi OR was 6.487; 95%; CI 1.993-21.119, Fitzpatricks phototype and the presence of congenital naevi. Red hair, phototype I and large congenital naevi were

  19. Efficacy and side effects of dacarbazine in comparison with temozolomide in the treatment of malignant melanoma: a meta-analysis consisting of 1314 patients.

    Science.gov (United States)

    Teimouri, Fatemeh; Nikfar, Shekoufeh; Abdollahi, Mohammad

    2013-10-01

    The widespread prevalence of melanoma, one of the most malignant forms of skin cancer, is increasing rapidly. Two chemotherapeutic regimens are commonly used for the palliative treatment of malignant melanoma: intravenous administration of single-agent dacarbazine or oral administration of temozolomide. The aim of this study was to compare the effectiveness and side effects of dacarbazine with those of temozolomide through a meta-analysis. A thorough literature bibliography search was conducted up to 2012 to gather and review all randomized clinical trials comparing the use of dacarbazine with that of temozolomide in the treatment of malignant melanoma. Three head-to-head randomized clinical trials comprising 1314 patients met the criteria and were included. Comparison of temozolomide with dacarbazine yielded a nonsignificant relative risk (RR) of 0.83 [95% confidence interval (CI) = 0.26-2.64, P = 0.76] for complete response, a nonsignificant RR of 1.05 (95% CI = 0.85-1.3, P = 0.65) for stable disease, and a nonsignificant RR of 2.64 (95% CI = 0.97-1.36, P = 0.11) for disease control rate. The RR for nonhematologic side effects and hematologic side effects, such as anemia, neutropenia, and thrombocytopenia, of temozolomide compared with dacarbazine in patients with malignant melanoma was nonsignificant in all cases, but the RR for lymphopenia of temozolomide compared with dacarbazine was 3.79 (95% CI = 1.38-10.39, P = 0.01), which was significant. Although it is easier to administer oral medication, according to the results, there is no significant difference in the efficacy and side effects of these two drugs. Owing to the higher cost of treatment with temozolomide and the increased prevalence of lymphopenia on using temozolomide, use of dacarbazine as the first choice treatment for malignant melanoma is suggested.

  20. The Prognostic Effect of American Joint Committee on Cancer Staging and Genetic Status in Patients With Choroidal and Ciliary Body Melanoma

    DEFF Research Database (Denmark)

    Bagger, Mette; Andersen, Morten T; Andersen, Klaus K

    2015-01-01

    PURPOSE: To evaluate the prognostic effect of a combination of American Joint Committee on Cancer (AJCC) staging (7th edition) and genetic status in patients with posterior uveal melanoma. METHODS: A consecutive cohort of 153 patients with posterior uveal melanoma treated at Copenhagen University...... prognostic effects of AJCC staging and cytogenetic changes were evaluated by cumulative incidence curves and Cox proportional hazard models. RESULTS: An overall 5-year survival rate of 62% (95% confidence interval [CI]: 0.50-0.73) was observed. A normal genetic status of chromosomes 3 and 8, as found in 42...... patients (30%), minimized the additional prognostic effect of AJCC staging. The frequency of tumors with normal genetic status decreased with increasing AJCC stage. Both AJCC stage III (hazard ratio [HR]: 11.0, 95% CI: 1.4-85.6) and abnormal copy number of chromosomes 3 (HR: 6.3, 95% CI: 1.4-28.3) and 8...

  1. Changes in peripheral blood level of regulatory T cells in patients with malignant melanoma during treatment with dendritic cell vaccination and low-dose IL-2

    DEFF Research Database (Denmark)

    Bjoern, J; Brimnes, M K; Andersen, M H

    2011-01-01

    In this study, changes in peripheral blood regulatory T cell (Treg) levels were evaluated in 46 progressive patients with melanoma treated with a dendritic cell-based vaccine and concomitant low-dose IFN-a and IL-2. The regulatory subset of CD4 T cells, characterized by CD25(high) , was prospecti......In this study, changes in peripheral blood regulatory T cell (Treg) levels were evaluated in 46 progressive patients with melanoma treated with a dendritic cell-based vaccine and concomitant low-dose IFN-a and IL-2. The regulatory subset of CD4 T cells, characterized by CD25(high......) , was prospectively analysed in fresh blood, and treatment-associated quantitative and qualitative changes were analysed. By the 4th vaccine, patients showed a marked increase in CD4+ CD25(high) T cell subset from 6% to 22% (P...

  2. Changes in peripheral blood level of regulatory T cells in patients with malignant melanoma during treatment with dendritic cell vaccination and low-dose IL-2

    DEFF Research Database (Denmark)

    Bjoern, J; Brimnes, M K; Andersen, M H

    2011-01-01

    In this study, changes in peripheral blood regulatory T cell (Treg) levels were evaluated in 46 progressive patients with melanoma treated with a dendritic cell-based vaccine and concomitant low-dose IFN-α and IL-2. The regulatory subset of CD4 T cells, characterized by CD25(high) , was prospecti......In this study, changes in peripheral blood regulatory T cell (Treg) levels were evaluated in 46 progressive patients with melanoma treated with a dendritic cell-based vaccine and concomitant low-dose IFN-α and IL-2. The regulatory subset of CD4 T cells, characterized by CD25(high......) , was prospectively analysed in fresh blood, and treatment-associated quantitative and qualitative changes were analysed. By the 4th vaccine, patients showed a marked increase in CD4+ CD25(high) T cell subset from 6% to 22% (P...

  3. Toxicity of combined treatment of adjuvant irradiation and interferon alpha2b in high-risk melanoma patients.

    Science.gov (United States)

    Conill, Carlos; Jorcano, Sandra; Domingo-Domènech, Josep; Marruecos, Jordi; Vilella, Ramón; Malvehy, Josep; Puig, Susana; Sánchez, Marcelo; Gallego, Rosa; Castel, Teresa

    2007-10-01

    Surgically resected stage III melanoma patients commonly receive adjuvant therapy with interferon (IFN) alpha2b. For those patients with high-risk features of draining node recurrence, radiation therapy can also be considered as a treatment option. The purpose of this retrospective study was to assess the efficacy and radiation-related toxicity of this combined therapy. Eighteen patients receiving adjuvant IFNalpha2b therapy during radiation therapy, or within 1 month of its completion, were reviewed retrospectively and analysed for outcome. Radiation was delivered at 600 cGy dose per fraction, in 16 out of 18 patients, twice a week, and at 200 cGy dose per fraction in two patients five times a week. Total radiation dose and number of fractions were as follows: 30 Gy/5 fr (n=8), 36 Gy/6 fr (n=8) and 50 Gy/25 fr (n=2). The percentage of disease-free patients, with no local recurrence, at 3 years was 88%. In 10 patients, IFNalpha2b was administered concurrently with radiotherapy; in three, within 30 days before or after radiation; and in five, more than 30 days after radiation. All the patients experienced acute skin reactions, grade I on the Radiation Therapy Oncology Group (RTOG) scale. Late radiation-related toxicity was seen in one patient with grade III (RTOG) skin reaction and two with grade IV (RTOG) radiation-induced myelitis. Concurrent use of adjuvant radiotherapy and IFNalpha2b might enhance radiation-induced toxicity, and special care should be taken when the spinal cord is included in the radiation field.

  4. Novel anti-melanoma treatment:focus on immunotherapy

    Institute of Scientific and Technical Information of China (English)

    Meng-Ze Hao; Wen-Ya Zhou; Xiao-Ling Du; Ke-Xin Chen; Guo-Wen Wang; Yun Yang; Ji-Long Yang

    2014-01-01

    Melanoma is an intractable cancer that is aggressive, lethal, and metastatic. The prognosis of advanced melanoma is very poor because it is insensitive to chemotherapy and radiotherapy. The incidence of melanoma has been ascending stably for years worldwide, accompanied by increasing mortality. New approaches to managing this deadly disease are much anticipated to enhance the cure rate and to extend clinical benefits to patients with metastatic melanoma. Due to its high degree of immunogenicity, melanoma could be a good target for immunotherapy, which has been developed for decades and has achieved certain progress. This article provides an overview of immunotherapy for melanoma.

  5. Intercellular crosstalk in human malignant melanoma.

    Science.gov (United States)

    Dvořánková, Barbora; Szabo, Pavol; Kodet, Ondřej; Strnad, Hynek; Kolář, Michal; Lacina, Lukáš; Krejčí, Eliška; Naňka, Ondřej; Šedo, Aleksi; Smetana, Karel

    2017-05-01

    Incidence of malignant melanoma is increasing globally. While the initial stages of tumors can be easily treated by a simple surgery, the therapy of advanced stages is rather limited. Melanoma cells spread rapidly through the body of a patient to form multiple metastases. Consequently, the survival rate is poor. Therefore, emphasis in melanoma research is given on early diagnosis and development of novel and more potent therapeutic options. The malignant melanoma is arising from melanocytes, cells protecting mitotically active keratinocytes against damage caused by UV light irradiation. The melanocytes originate in the neural crest and consequently migrate to the epidermis. The relationship between the melanoma cells, the melanocytes, and neural crest stem cells manifests when the melanoma cells are implanted to an early embryo: they use similar migratory routes as the normal neural crest cells. Moreover, malignant potential of these melanoma cells is overdriven in this experimental model, probably due to microenvironmental reprogramming. This observation demonstrates the crucial role of the microenvironment in melanoma biology. Indeed, malignant tumors in general represent complex ecosystems, where multiple cell types influence the growth of genetically mutated cancer cells. This concept is directly applicable to the malignant melanoma. Our review article focuses on possible strategies to modify the intercellular crosstalk in melanoma that can be employed for therapeutic purposes.

  6. Serum S100B, lactate dehydrogenase and brain metastasis are prognostic factors in patients with distant melanoma metastasis and systemic therapy.

    Directory of Open Access Journals (Sweden)

    Benjamin Weide

    Full Text Available BACKGROUND: Prognostic factors of melanoma with distant metastasis and systemic treatment are only poorly established. This study aimed to analyse the impact of S100B, lactate dehydrogenase (LDH and the type of treatment on survival in advanced patients receiving systemic treatment. PATIENTS AND METHODS: We analysed overall survival of 499 patients from the university department of dermatology in Tuebingen, Germany, with unresectable melanoma at the time point of initiation of first-line systemic therapy. Only patients who started treatment between the years 2000 and 2010 were included. Disease-specific survival was calculated by bivariate Kaplan Meier survival probabilities and multivariate Cox hazard regression analysis. RESULTS: In univariate analysis LDH, S100B, the site of distant metastasis (soft tissue vs. lung vs. other visceral, the presence of brain metastases and the type of treatment (monochemotherapy, polychemotherapy, immunotherapy or biochemotherapy were associated with overall survival (all p<0.001. In multivariate analysis LDH (Hazard ratio [HR] 1.6 [1.3-2.1]; p<0.001, S100B (HR 1.6 [1.2-2.1]; p<0.001 and the presence of brain metastases (HR 1.5 [1.1-1.9]; p = 0.009, but not the type of treatment had significant independent impact. Among those factors normal S100B was the best indicator of long-term survival, which was 12.3% after 5 years for this subgroup. CONCLUSION: Serum S100B is a prognostic marker predicting survival at the time of initiation of first-line treatment in unresectable melanoma patients. Compared to the other independent factors LDH and the presence of brain metastases it is most appropriate to predict long-term survival and requires further prospective investigation in patients treated with new and more potent drugs in metastatic melanoma.

  7. [ Spectrum of oncogene mutations is different in melanoma subtypes].

    Science.gov (United States)

    Mazurenko, N N; Tsyganova, I V; Lushnikova, A A; Ponkratova, D A; Anurova, O A; Cheremushkin, E A; Mikhailova, I N; Demidov, L V

    2015-01-01

    Melanoma is the most lethal malignancy of skin, which is comprised of clinically relevant molecular subsets defined by specific "driver" mutations in BRAF, NRAS, and KIT genes. Recently, the better results in melanoma treatment were obtained with the mutation-specific inhibitors that have been developed for clinical use and target only patients with particular tumor genotypes. The aim of the study was to characterize the spectrum of "driver" mutations in melanoma subtypes from 137 patients with skin melanoma and 14 patients with mucosal melanoma. In total 151 melanoma cases, the frequency of BRAF, NRAS, KIT, PDGFRA, and KRAS mutations was 55.0, 10.6, 4.0, 0.7, and 0.7%, respectively. BRAF mutations were found in 69% of cutaneous melanoma without UV exposure and in 43% of cutaneous melanoma with chronic UV exposure (p=0.045), rarely in acral and mucosal melanomas. Most of melanomas containing BRAF mutations, V600E (92%) and V600K (6.0%) were potentially sensitive to inhibitors vemurafenib and dabrafenib. NRAS mutations were more common in cutaneous melanoma with chronic UV exposure (26.0%), in acral and mucosal melanomas; the dominant mutations being Q61R/K/L (87.5%). KIT mutations were found in cutaneous melanoma with chronic UV exposure (8.7%) and mucosal one (28.6%), but not in acral melanoma. Most of KIT mutations were identified in exon 11; these tumors being sensitive to tyrosine kinase inhibitors. This is the first monitoring of BRAF, NRAS, KIT, PDGFRA, and KRAS hotspot mutations in different subtypes of melanoma for Russian population. On the base of data obtained, one can suppose that at the molecular level melanomas are heterogeneous tumors that should be tested for "driver" mutations in the each case for evaluation of the potential sensitivity to target therapy. The obtained results were used for treatment of melanoma patients.

  8. Health-related quality of life in patients with high-risk melanoma randomised in the Nordic phase 3 trial with adjuvant intermediate-dose interferon alfa-2b

    DEFF Research Database (Denmark)

    Brandberg, Y; Aamdal, S; Bastholt, Lars;

    2012-01-01

    To compare health-related quality of life (HRQoL) and side-effects in patients with high-risk melanoma participating in a randomised phase III trial of adjuvant interferon alfa-2b (IFN).......To compare health-related quality of life (HRQoL) and side-effects in patients with high-risk melanoma participating in a randomised phase III trial of adjuvant interferon alfa-2b (IFN)....

  9. Resiquimod as an Immunologic Adjuvant for NY-ESO-1 Protein Vaccination in Patients with High Risk Melanoma

    Science.gov (United States)

    Gnjatic, Sacha; Cruz, Crystal M.; Vengco, Isabelita; Hasan, Farah; Spadaccia, Meredith; Darvishian, Farbod; Chiriboga, Luis; Holman, Rose Marie; Escalon, Juliet; Muren, Caroline; Escano, Crystal; Yepes, Ethel; Sharpe, Dunbar; Vasilakos, John P.; Rolnitzsky, Linda; Goldberg, Judith; Mandeli, John; Adams, Sylvia; Jungbluth, Achim; Pan, Linda; Venhaus, Ralph; Ott, Patrick A.; Bhardwaj, Nina

    2015-01-01

    The TLR7/8 agonist, Resiquimod has been used as an immune adjuvant in cancer vaccines. We evaluated the safety and immunogenicity of the cancer testis antigen NY-ESO-1 given in combination with Montanide with or without Resiquimod in high-risk melanoma patients. In Part I of the study, patients received 100ug full length NY-ESO-1 protein emulsified in 1.25mL Montanide (day 1) followed by topical application of 1000mg of 0.2% Resiquimod gel on days 1 and 3 (Cohort 1) versus days 1, 3, and 5 (Cohort 2) of a 21 day cycle. In Part II, patients were randomized to receive 100ug NY-ESO-1 protein plus Montanide (day 1) followed by topical application of placebo gel (Arm-A; N=8) or 1000mg of 0.2% Resiquimod gel (Arm-B; N=12) using the dosing regimen established in Part I. The vaccine regimens were generally well-tolerated. NY-ESO-1-specific humoral responses were induced or boosted in all patients, many of whom had high titer antibodies. In Part II, 16 of 20 patients in both arms had NY-ESO-1-specific CD4+ T-cell responses. CD8+ T-cell responses were only seen in 3 of 12 patients in Arm B. Patients with TLR7 SNP rs179008 had a greater likelihood of developing NY-ESO-1-specific CD8+ responses. In conclusion, NY-ESO-1 protein in combination with Montanide with or without topical Resiquimod is safe and induces both antibody and CD4+ T-cell responses in the majority of patients; the small proportion of CD8+ T-cell responses suggests that the addition of topical Resiquimod to Montanide is not sufficient to induce consistent NY-ESO-1-specific CD8+ T-cell responses. PMID:25633712

  10. Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab.

    Directory of Open Access Journals (Sweden)

    Ahmad A Tarhini

    Full Text Available We evaluated neoadjuvant ipilimumab in patients with surgically operable regionally advanced melanoma in order to define markers of activity in the blood and tumor as assessed at baseline (before ipilimumab and early on-treatment. Patients were treated with ipilimumab (10 mg/kg intravenously every 3 weeks ×2 doses bracketing surgery. Tumor and blood biospecimens were obtained at baseline and at surgery. Flow cytometry and immunohistochemistry for select biomarkers were performed. Thirty five patients were enrolled; IIIB (3; N2b, IIIC (32; N2c, N3, IV (2. Worst toxicities included Grade 3 diarrhea/colitis (5; 14%, hepatitis (2; 6%, rash (1; 3%, elevated lipase (3; 9%. Median follow up was 18 months: among 33 evaluable patients, median progression free survival (PFS was 11 months, 95% CI (6.2-19.2. There was a significant decrease in circulating myeloid derived suppressor cells (MDSC. Greater decrease in circulating monocyte gate MDSC Lin1-/HLA-DR-/CD33⁺/CD11b⁺ was associated with improved PFS (p = 0.03. There was a significant increase in circulating regulatory T cells (Treg; CD4⁺CD25hi⁺Foxp3⁺ that, unexpectedly, was associated with improved PFS (HR = 0.57; p = 0.034. Baseline evidence of fully activated type I CD4⁺ and CD8⁺ antigen-specific T cell immunity against cancer-testis (NY-ESO-1 and melanocytic lineage (MART-1, gp100 antigens was detected and was significantly potentiated after ipilimumab. In tumor, there was a significant increase in CD8⁺ T cells after ipilimumab (p = 0.02. Ipilimumab induced increased tumor infiltration by fully activated (CD69⁺ CD3⁺/CD4⁺ and CD3⁺/CD8⁺ T cells with evidence of induction/potentiation of memory T cells (CD45RO⁺. The change in Treg observed within the tumor showed an inverse relationship with clinical benefit and greater decrease in tumor MDSC subset Lin1-/HLA-DR-/CD33⁺/CD11b⁺ was associated with improved PFS at one year. Neoadjuvant evaluation revealed a

  11. Melanoma therapy: Check the checkpoints.

    Science.gov (United States)

    Furue, Masutaka; Kadono, Takafumi

    2016-02-01

    Recent mutational and translational studies have revealed that the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway plays a key role in melanomagenesis. Mutations in NRAS and BRAF are found in the majority of melanomas resulting in the formation of constitutively active NRAS and BRAF molecules, which leads to the proliferation and survival of melanoma cells through the activation of MEK/ERK signals. Inhibitors of BRAF or MEK significantly extend the progression-free survival and overall survival of melanoma patients compared with conventional chemotherapies. Combining BRAF and MEK inhibitors further enhances the clinical effectiveness. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is an immune checkpoint molecule that downregulates T-cell activation by binding to B7 (CD80/CD86) molecules on antigen-presenting cells. Programmed death receptor ligand 1 on melanoma cells negatively regulates T-cell function by binding to the programmed death-1 (PD-1) receptor on T cells. Antibodies against CTLA-4 and PD-1 also enhance the survival of melanoma patients. In this review, we summarize the clinical effectiveness and adverse events of the BRAF inhibitors, MEK inhibitors and anti-immune checkpoint antibodies in melanoma treatment.

  12. Prospective assessment of a gene signature potentially predictive of clinical benefit in metastatic melanoma patients following MAGE-A3 immunotherapeutic (PREDICT)

    Science.gov (United States)

    Saiag, P.; Gutzmer, R.; Ascierto, P. A.; Maio, M.; Grob, J.-J.; Murawa, P.; Dreno, B.; Ross, M.; Weber, J.; Hauschild, A.; Rutkowski, P.; Testori, A.; Levchenko, E.; Enk, A.; Misery, L.; Vanden Abeele, C.; Vojtek, I.; Peeters, O.; Brichard, V. G.; Therasse, P.

    2016-01-01

    Background Genomic profiling of tumor tissue may aid in identifying predictive or prognostic gene signatures (GS) in some cancers. Retrospective gene expression profiling of melanoma and non-small-cell lung cancer led to the characterization of a GS associated with clinical benefit, including improved overall survival (OS), following immunization with the MAGE-A3 immunotherapeutic. The goal of the present study was to prospectively evaluate the predictive value of the previously characterized GS. Patients and methods An open-label prospective phase II trial (‘PREDICT’) in patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma. Results Of 123 subjects who received the MAGE-A3 immunotherapeutic, 71 (58.7%) displayed the predictive GS (GS+). The 1-year OS rate was 83.1%/83.3% in the GS+/GS− populations. The rate of progression-free survival at 12 months was 5.8%/4.1% in GS+/GS− patients. The median time-to-treatment failure was 2.7/2.4 months (GS+/GS−). There was one complete response (GS−) and two partial responses (GS+). The MAGE-A3 immunotherapeutic was similarly immunogenic in both populations and had a clinically acceptable safety profile. Conclusion Treatment of patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma with the MAGE-A3 immunotherapeutic demonstrated an overall 1-year OS rate of 83.5%. GS− and GS+ patients had similar 1-year OS rates, indicating that in this study, GS was not predictive of outcome. Unexpectedly, the objective response rate was lower in this study than in other studies carried out in the same setting with the MAGE-A3 immunotherapeutic. Investigation of a GS to predict clinical benefit to adjuvant MAGE-A3 immunotherapeutic treatment is ongoing in another melanoma study. This study is registered at www.clinicatrials.gov NCT00942162. PMID:27502712

  13. Association of Surgical Treatment, Systemic Therapy, and Survival in Patients With Abdominal Visceral Melanoma Metastases, 1965-2014: Relevance of Surgical Cure in the Era of Modern Systemic Therapy.

    Science.gov (United States)

    Deutsch, Gary B; Flaherty, Devin C; Kirchoff, Daniel D; Bailey, Mariel; Vitug, Sarah; Foshag, Leland J; Faries, Mark B; Bilchik, Anton J

    2017-07-01

    Systemic therapy for metastatic melanoma has evolved rapidly during the last decade, and patient treatment has become more complex. To evaluate the survival benefit achieved through surgical resection of melanoma metastatic to the abdominal viscera in patients treated in the modern treatment environment. This retrospective review of the institutional melanoma database from the John Wayne Cancer Institute at Providence St Johns Health Center, a tertiary-level melanoma referral center, included 1623 patients with melanoma diagnosed as having potentially resectable abdominal metastases before (1969-2003) and after (2004-2014) advances in systemic therapy. Overall survival (OS). Of the 1623 patients identified in the database with abdominal melanoma metastases, 1097 were men (67.6%), and the mean (SD) age was 54.6 (14.6) years. Of the patients with metastatic melanoma, 1623 (320 [19.7%] in the 2004-2014 period) had abdominal metastases, including 336 (20.7%) with metastases in the gastrointestinal tract, 697 (42.9%) in the liver, 138 (8.5%) in the adrenal glands, 38 (2.3%) in the pancreas, 109 (6.7%) in the spleen, and 305 (18.8%) with multiple sites. Median OS was superior in surgical (n = 392; 18.0 months) vs nonsurgical (n = 1231; 7.0 months) patients (P treatment with metastasectomy (HR, 0.59; 95% CI, 0.46-0.74; P treatment era did not significantly affect outcomes (HR, 0.82; 95% CI, 0.67-1.02; P = .15). Overall, patients with gastrointestinal tract metastases undergoing complete, curative resection derived the greatest benefit, with a median OS of 64 months. To our knowledge, this series is the largest single-institution experience with abdominal melanoma metastases, demonstrating that surgical resection remains an important treatment consideration even in the systemic treatment era.

  14. Living With Cluster Headache: A Qualitative Study of Patients' Perspectives.

    Science.gov (United States)

    Palacios-Ceña, Domingo; Talavera, Blanca; López-Ruiz, Pedro; Gutiérrez-Viedma, Álvaro; Palacios-Ceña, María; Arias, José A; Fernández-de-Las-Peñas, César; Cuadrado, María L

    2016-07-01

    Our aim was to explore the views and experiences of a group of Spanish men suffering from cluster headache (CH). CH has considerable effects on patients' quality of life, impairs everyday activities, and can modify lifestyle. This is the first time the experience of patients with CH is examined in a clinical study using a qualitative, phenomenological approach. We conducted a qualitative phenomenological study exploring how 20 male patients with CH, followed at the Headache Unit of a Spanish hospital, perceived their disease. Data were collected through in-depth interviews, researchers' field notes and patients' personal letters. A systematic text condensation analysis was performed following appropriate guidelines for qualitative research. Mean age was 41.15 years (standard deviation, 11.25). Seventeen patients had episodic CH and three patients had chronic CH. Five main themes describing the significance of suffering CH emerged: (a) meaning of disease, (b) experience of attacks, (c) meaning of treatment, (d) healthcare, and (e) social and family interaction. Patients with CH often live in fear and uncertainty because of their condition. Intensity and frequency of attacks, the use of ineffective treatments, skepticism perceived from social and workplace environments and physician unawareness play a significant role. Qualitative research offers insight into the way CH patients experience their disease, and may be helpful in establishing a fruitful relationship with these patients. © 2016 American Headache Society.

  15. Lack of XAGE-1b and NY-ESO-1 in metastatic lymph nodes may predict the potential survival of stage III melanoma patients.

    Science.gov (United States)

    Mori, Mariko; Funakoshi, Takeru; Kameyama, Kaori; Kawakami, Yutaka; Sato, Eiichi; Nakayama, Eiichi; Amagai, Masayuki; Tanese, Keiji

    2017-06-01

    The cancer-testis antigens (CTA) are a large family of tumor-associated antigens expressed by a variety of cancer cells and primitive germ cells of the adult testis and placenta. These tumor-restricted expressing patterns suggest that CTA would be ideal targets for tumor-specific immunotherapy. XAGE-1 is a CTA that was originally identified by computer-based screening, and four transcription variants, XAGE-1a, -1b, -1c and -1d, have been characterized to date. Although the presence of XAGE-1 transcripts has been reported in various cancers, the expression of XAGE-1b in melanoma has not been fully characterized. In this study, we performed immunohistochemical staining of XAGE-1b together with NY-ESO-1, a well-known CTA, in 113 melanoma samples obtained from 84 patients and evaluated their expression in tumor cells. The effects of expression on tumor progression and patient prognosis were analyzed. Both XAGE-1b and NY-ESO-1 were expressed at high levels in lymph node metastasis and skin metastasis samples compared with the primary site (P ESO-1). In a subgroup analysis of 22 patients with stage III lymph node metastasis, overall survival was significantly higher in the XAGE-1b and NY-ESO-1 double-negative group than in the other groups (P ESO-1 expression could have a positive influence on clinical outcome in patients with melanoma. © 2017 Japanese Dermatological Association.

  16. Radiopharmaceuticals targeting melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Pham, T.Q.; Berghofer, P.; Liu, X.; Greguric, I.; Dikic, B.; Ballantyne, P.; Mattner, F.; Nguyen, V.; Loc' h, C.; Katsifis, A. [Radiopharmaceuticals Research Institute, Australian Nuclear Science and Technology Organisation, Menai, N.S.W., Sydney (Australia)

    2008-02-15

    Melanoma is one of the most aggressive cancers known with a high rate of mortality and increasing global incidence. So, the development of radiopharmaceuticals for either diagnostic or therapeutic purposes could make enormous contributions to melanoma patient health care. We have been studying melanoma tumours through several targeting mechanisms including melanin or specific receptor based radiopharmaceuticals Structure activity studies indicate that the substitution patterns on radioiodinated benzamides significantly influence the uptake mechanism from melanin to sigma-receptor binding. Furthermore, the position of the iodine as well as the presence of key functional groups and substituents has resulted in compounds with varying degrees of activity uptake and retention in tumours. From these results, a novel molecule 2-(2-(4-(4-iodo benzyl)piperazin-1-yl)-2-oxo-ethyl)isoindoline- 1,3-dione (M.E.L.037) was synthesized, labelled with iodine-123 and evaluated for application in melanoma tumour scintigraphy and radiotherapy. The tumour imaging potential of {sup 123}IM.E.L.037 was studied in vivo in C.57 B.L./ 6 J female mice bearing the B.16 F.0. murine melanoma tumour and in BALB/c nude mice bearing the A.375 human amelanotic melanoma tumour by biodistribution, competition studies and by SPECT imaging. {sup 123}I-M.E.L.037 exhibited high and rapid uptake in the B.16 F.0 melanoma tumour at 1 h (13 % I.D./g) increasing with time to reach 25 % I.D./g at 6 h. A significant uptake was also observed in the eyes (2% I.D., at 3-6 h p.i.) of black mice. No uptake was observed in the tumour or in the eyes of nude mice bearing the A.375 tumour. Due to high uptake and long retention in the tumour and rapid body clearance, standardized uptake values(S.U.V.) of {sup 123}I-M.E.L.037 were 30 and 60, at 24 and 48 h p.i.,respectively. SPECT imaging of mice bearing the B.16 melanoma indicated the radioactivity was predominately located in the tumour followed by the eyes, while no

  17. Histone variants and melanoma: facts and hypotheses.

    Science.gov (United States)

    Konstantinov, Nikifor K; Ulff-Møller, Constance J; Dimitrov, Stefan

    2016-07-01

    Melanoma is the most aggressive form of skin cancer with rising incidence and morbidity. Despite advances in treatment, the 10-yr survival for patients with metastatic disease is less than 10%. During the past few years, ongoing research on different epigenomic aberrations in melanoma has catalyzed better understanding of its pathogenesis and identification of new therapeutics. In our review, we will focus on the role of histone variants, key epigenetic players in melanoma initiation and progression. Specifically, incorporation of histone variants enables additional layers of chromatin structure, and here, we will describe how alterations in this epigenetic behavior impact melanoma.

  18. Malignant melanoma of choroid

    Directory of Open Access Journals (Sweden)

    Manohar S

    1991-01-01

    Full Text Available Four cases of malignant melanoma of the choroid are reported due to rarity of the condition in India. One of the cases presented with Naevus of Ota. All the cases had typical clinical and investigative features. All cases were enucleated. Histopathologically three of them were of mixed type and one was of the epithelioid type. Two of the cases were seen in patients below 40 years of age.

  19. Patient-derived xenografts recapitulate molecular features of human uveal melanomas.

    Science.gov (United States)

    Laurent, Cécile; Gentien, David; Piperno-Neumann, Sophie; Némati, Fariba; Nicolas, André; Tesson, Bruno; Desjardins, Laurence; Mariani, Pascale; Rapinat, Audrey; Sastre-Garau, Xavier; Couturier, Jérôme; Hupé, Philippe; de Koning, Leanne; Dubois, Thierry; Roman-Roman, Sergio; Stern, Marc-Henri; Barillot, Emmanuel; Harbour, J William; Saule, Simon; Decaudin, Didier

    2013-06-01

    We have previously developed a new method for the development and maintenance of uveal melanoma (UM) xenografts in immunodeficient mice. Here, we compare the genetic profiles of the primary tumors to their corresponding xenografts that have been passaged over time. The study included sixteen primary UMs and corresponding xenografts at very early (P1), early (P4), and late (P9) in vivo passages. The tumors were analyzed for mutation status of GNAQ, GNA11, GNAS, GNA15, BAP1, and BRAF, chromosomal copy number alterations using Affymetrix GeneChip(®) Genome-Wide Human SNP6.0 arrays, gene expression profiles using GeneChip(®) Human Exon 1.0 ST arrays, BAP1 mRNA and protein expression, and MAPK pathway status using Reverse Phase Protein Arrays (RPPA). The UM xenografts accurately recapitulated the genetic features of primary human UMs and they exhibited genetic stability over the course of their in vivo maintenance. Our technique for establishing and maintaining primary UMs as xenograft tumors in immunodeficient mice exhibit a high degree of genetic conservation between the primary tumors and the xenograft tumors over multiple passages in vivo. These models therefore constitute valuable preclinical tool for drug screening in UM.

  20. Staged Radiosurgical Ablation for Choroid Melanoma: A Case Report with Emphasis on the Role of Patient Preparation, Treatment Planning, and Precision of Delivery.

    Science.gov (United States)

    Adamczyk, Marta; Janiga, Piotr

    2016-01-01

    The aim of reporting this case of choroid melanoma of the left eye is to introduce the in-house-designed treatment planning protocol for fractionated radiosurgical ablation of an intraocular lesion. This is a clinical case with emphasis on treatment preparation and delivery using the Accuray CyberKnife Robotic Radiosurgery System (Accuray, Sunnyvale, CA, USA) for a patient immobilized with a head mask and our in-house-made eye fixation system.

  1. Surgery of Primary Melanomas

    Energy Technology Data Exchange (ETDEWEB)

    Rutkowski, Piotr, E-mail: rutkowskip@coi.waw.pl; Zdzienicki, Marcin; Nowecki, Zbigniew I. [Soft Tissue/Bone Sarcoma and Melanoma Department, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw (Poland); Akkooi, Alexander C. J. van [Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam (Netherlands)

    2010-05-11

    Surgery remains the mainstay of melanoma therapy, regardless of the tumor site. Only the early diagnosis combined with proper surgical therapy currently gives patients affected by this malignancy the chance for a full cure. The main goal of surgical therapy is to provide the local control of the disease and to secure long-term survival of the patient without reasonable functional and esthetic impairment. The recommended method of biopsy—excisional biopsy, as an initial diagnostic and, to some extent, therapeutic procedure—is performed under local anesthesia as an elliptical incision with visual clear margins of 1–3 mm and with some mm of subcutaneous tissue. The extent of radical excision of the primary tumor (or scar after excisional biopsy) is based on the histopathologic characteristics of the primary tumor and usually consists of 1–2 cm margins with primary closure. The philosophy behind conducted randomized clinical trials has been to find the most conservative surgical approach that is able to guarantee the same results as more demolitive treatment. This has been the background of the trials designed to define the correct margins of excision around a primary cutaneous melanoma. Much less definition can be dedicated to the surgical management of patients with non-cutaneous melanomas.

  2. Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab.

    Science.gov (United States)

    Yuan, Jianda; Adamow, Matthew; Ginsberg, Brian A; Rasalan, Teresa S; Ritter, Erika; Gallardo, Humilidad F; Xu, Yinyan; Pogoriler, Evelina; Terzulli, Stephanie L; Kuk, Deborah; Panageas, Katherine S; Ritter, Gerd; Sznol, Mario; Halaban, Ruth; Jungbluth, Achim A; Allison, James P; Old, Lloyd J; Wolchok, Jedd D; Gnjatic, Sacha

    2011-10-04

    Ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte antigen 4 (CTLA-4), has been shown to improve survival in patients with advanced metastatic melanoma. It also enhances immunity to NY-ESO-1, a cancer/testis antigen expressed in a subset of patients with melanoma. To characterize the association between immune response and clinical outcome, we first analyzed NY-ESO-1 serum antibody by ELISA in 144 ipilimumab-treated patients with melanoma and found 22 of 140 (16%) seropositive at baseline and 31 of 144 (22%) seropositive following treatment. These NY-ESO-1-seropositive patients had a greater likelihood of experiencing clinical benefit 24 wk after ipilimumab treatment than NY-ESO-1-seronegative patients (P = 0.02, relative risk = 1.8, two-tailed Fisher test). To understand why some patients with NY-ESO-1 antibody failed to experience clinical benefit, we analyzed NY-ESO-1-specific CD4(+) and CD8(+) T-cell responses by intracellular multicytokine staining in 20 NY-ESO-1-seropositive patients and found a surprising dissociation between NY-ESO-1 antibody and CD8 responses in some patients. NY-ESO-1-seropositive patients with associated CD8(+) T cells experienced more frequent clinical benefit (10 of 13; 77%) than those with undetectable CD8(+) T-cell response (one of seven; 14%; P = 0.02; relative risk = 5.4, two-tailed Fisher test), as well as a significant survival advantage (P = 0.01; hazard ratio = 0.2, time-dependent Cox model). Together, our data suggest that integrated NY-ESO-1 immune responses may have predictive value for ipilimumab treatment and argue for prospective studies in patients with established NY-ESO-1 immunity. The current findings provide a strong rationale for the clinical use of modulators of immunosuppression with concurrent approaches to favor tumor antigen-specific immune responses, such as vaccines or adoptive transfer, in patients with cancer.

  3. A cancer vaccine induces expansion of NY-ESO-1-specific regulatory T cells in patients with advanced melanoma.

    Science.gov (United States)

    Ebert, Lisa M; MacRaild, Sarah E; Zanker, Damien; Davis, Ian D; Cebon, Jonathan; Chen, Weisan

    2012-01-01

    Cancer vaccines are designed to expand tumor antigen-specific T cells with effector function. However, they may also inadvertently expand regulatory T cells (Treg), which could seriously hamper clinical efficacy. To address this possibility, we developed a novel assay to detect antigen-specific Treg based on down-regulation of surface CD3 following TCR engagement, and used this approach to screen for Treg specific to the NY-ESO-1 tumor antigen in melanoma patients treated with the NY-ESO-1/ISCOMATRIX™ cancer vaccine. All patients tested had Treg (CD25(bright) FoxP3(+) CD127(neg)) specific for at least one NY-ESO-1 epitope in the blood. Strikingly, comparison with pre-treatment samples revealed that many of these responses were induced or boosted by vaccination. The most frequently detected response was toward the HLA-DP4-restricted NY-ESO-1(157-170) epitope, which is also recognized by effector T cells. Notably, functional Treg specific for an HLA-DR-restricted epitope within the NY-ESO-1(115-132) peptide were also identified at high frequency in tumor tissue, suggesting that NY-ESO-1-specific Treg may suppress local anti-tumor immune responses. Together, our data provide compelling evidence for the ability of a cancer vaccine to expand tumor antigen-specific Treg in the setting of advanced cancer, a finding which should be given serious consideration in the design of future cancer vaccine clinical trials.

  4. Development of allogeneic NK cell adoptive transfer therapy in metastatic melanoma patients: in vitro preclinical optimization studies.

    Directory of Open Access Journals (Sweden)

    Michal J Besser

    Full Text Available Natural killer (NK cells have long been considered as potential agents for adoptive cell therapy for solid cancer patients. Until today most studies utilized autologous NK cells and yielded disappointing results. Here we analyze various modular strategies to employ allogeneic NK cells for adoptive cell transfer, including donor-recipient HLA-C mismatching, selective activation and induction of melanoma-recognizing lysis receptors, and co-administration of antibodies to elicit antibody-dependent cell cytotoxicity (ADCC. We show that NK cell activation and induction of the relevant lysis receptors, as well as co-administration of antibodies yield substantial anti-cancer effects, which are functionally superior to HLA-C mismatching. Combination of the various strategies yielded improved effects. In addition, we developed various clinically-compatible ex vivo expansion protocols that were optimized according to fold expansion, purity and expression of lysis receptors. The main advantages of employing allogeneic NK cells are accessibility, the ability to use a single donor for many patients, combination with various strategies associated with the mechanism of action, e.g. antibodies and specific activation, as well as donor selection according to HLA or CD16 genotypes. This study rationalizes a clinical trial that combines adoptive transfer of highly potent allogeneic NK cells and antibody therapy.

  5. Elevated serum level of YKL-40 is an independent prognostic factor for poor survival in patients with metastatic melanoma

    DEFF Research Database (Denmark)

    Schmidt, Henrik; Johansen, Julia Sidenius; Gehl, Julie;

    2006-01-01

    that serum YKL-40 (hazard ratio       [HR] = 1.9; 95% confidence interval [CI], 1.2-2.8; P = 0.004) and serum       lactate dehydrogenase (LDH) (HR = 1.9; 95% CI, 1.2-2.9; P = 0.004) were       independent prognostic factors for survival. A combination variable of       elevated serum YKL-40 and LDH...... quadrupled the risk of early death (HR =       4.4; 95% CI, 2.5-7.7; P LDH had a stronger prognostic impact       than the American Joint Committee on Cancer (AJCC) Stage IV       classification. Furthermore, serum...... was an independent prognostic factor for poor       survival in patients with metastatic melanoma. When combining serum YKL-40       and LDH, patients could be separated into three prognostic groups based on       the number of elevated biomarkers. The findings should be validated in an       independent study...

  6. Immunotherapy of metastatic melanoma by reversal of immune suppression

    Energy Technology Data Exchange (ETDEWEB)

    Biggs, M.W.; Eiselein, J.E.

    1997-01-01

    Beginning with the observation that the human enteorvirus, Poliovirus Sabin 1, will lyse human melanoma cells in culture, clinical trials involving two patients with advance melanoma were performed. Parenteral injection of the viable Poliovirus into cutaneous melanoma metastases followed in 24 hours by oral administration of cyclophosphamide. The results of these two trials are described.

  7. Fine-mapping naturally occurring NY-ESO-1 antibody epitopes in melanoma patients' sera using short overlapping peptides and full-length recombinant protein.

    Science.gov (United States)

    Komatsu, Nobukazu; Jackson, Heather M; Chan, Kok-fei; Oveissi, Sara; Cebon, Jonathan; Itoh, Kyogo; Chen, Weisan

    2013-07-01

    The tumor antigen NY-ESO-1 is one of the most antigenic cancer-testis antigens, first identified by serologic analysis of a recombinant cDNA expression library (SEREX). NY-ESO-1 is expressed in different types of cancers including melanoma. NY-ESO-1-specific spontaneous humoral and cellular immune responses are detected in a large proportion of patients with advanced NY-ESO-1-expressing cancers. Therefore NY-ESO-1 is a good candidate antigen for immunotherapy. Although cellular immune responses to NY-ESO-1 are well characterized, much less is known about the humoral immune responses. In this study, we finely mapped linear antibody epitopes using sera from melanoma patients and shorter overlapping peptide sets. We have shown that melanoma patients' humoral immune systems responded to NY-ESO-1 differently in each individual with widely differing antibody specificity, intensity and antibody subtypes. This knowledge will help us further understand anti-tumor immunity and may also help us to monitor cancer progress and cancer vaccine efficacy in the future. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Subretinal lipid exudation associated with untreated choroidal melanoma

    Directory of Open Access Journals (Sweden)

    C K Minija

    2011-01-01

    Full Text Available Subretinal lipid exudation in an untreated choroidal melanoma is very rare. It is seen following plaque radiotherapy in choroidal melanoma. There is only one case report of untreated choroidal melanoma with massive lipid exudation in a patient with metastatic hypernephroma. We report here a rare case of untreated choroidal melanoma with lipid exudation. Subretinal exudation that is rarely seen following plaque brachytherapy was noted at the borders of this untreated tumor. Lipid exudation partially resolved following brachytherapy.

  9. Addison's disease as a presentation of metastatic malignant melanoma.

    Science.gov (United States)

    Srinivasan, B; Patel, M; Ethunandan, M; Ilankovan, V

    2016-01-01

    Melanoma accounts for 5% of all skin cancers. The risk of metastasis is related to the thickness of the tumour, and can affect local, regional and distant sites. Adrenal metastasis from melanoma of the head and neck is uncommon and often asymptomatic. Addison's disease as a presentation of metastatic melanoma is extremely rare and we are unaware of previous reports in the world literature. We report a case of a patient with metastatic melanoma presenting with signs and symptoms of Addison's disease.

  10. Metastatic Malignant Melanoma Presenting as an Appendiceal Mucocele

    Directory of Open Access Journals (Sweden)

    A. A. Alduaij

    2011-01-01

    Full Text Available Melanoma metastatic to the appendix is extremely rare. Here we describe a case of a 31-year-old female from Bolivia with a remote history of metastatic malignant melanoma first diagnosed as a cutaneous malignant melanoma ten years prior to this presentation. The patient was being followed for a mucocele which on resection was found to be metastatic melanoma. “Mucocele” is a generic diagnosis that warrants further characterization and treatment.

  11. The lived experience of patient prudence in health care.

    Science.gov (United States)

    Larrabee, J H; Bolden, L V; Knight, M R

    1998-10-01

    The purpose of this phenomenological study was to describe the lived experience of patient prudence in health care. Prudence has previously been defined as good judgement in setting realistic personal goals and using personal resources to achieve those goals. Audiotaped interviews were conducted with 10 hospitalized adults for whom health care providers had previously recommended life style changes for health reasons. Data were analysed using Colaizzi's method. Seventy-seven significant statements were identified and, from their formulated meanings, seven themes emerged that were integrated into a description of the fundamental structure of prudence. From the patient perspective, prudence in health care is a dynamic phenomenon that involves achieving well-being and self-perpetuation within the context of the patient's world of competing values and is experienced with emotions that range from harmony to fear and depression.

  12. Identification of TDP-43 as an oncogene in melanoma and its function during melanoma pathogenesis.

    Science.gov (United States)

    Zeng, Qinghai; Cao, Ke; Liu, Rui; Huang, Jinhua; Xia, Kun; Tang, Jintian; Chen, Xiang; Zhou, Ming; Xie, Huiqing; Zhou, Jianda

    2017-01-02

    Although recent studies have revealed TAR (trans-activating response region) DNA binding protein (TDP-43) as a potential therapeutic target for cancers, its role and clinical association with melanoma have not been explored. To identify the role and function of TDP-43 during melanoma pathogenesis. Firstly, the relationship between TDP-43 expression and patient survival was explored. Then TDP-43 expression level in melanoma tissue and different melanoma cell lines was measured. After silencing TDP-43 expression in melanoma cells, the impacts of TDP-43 on cellular proliferation, metastasis, glucose uptake, and glucose transporters levels were studied. In the end, effect of TDP-43 depletion on tumorigenicity of melanoma cells was tested in vivo. Our results showed that TDP-43 was overexpressed in melanoma paraffin samples compared with that in nevi tissues. The high expression level of TDP-43 was associated with poor patient survival. By silencing TDP-43, we saw significant inhibition of cell proliferation and metastasis in A375 and WM451 cells. TDP-43 knockdown could suppress glucose transporter type-4 (GLUT4) expression and reduce glucose uptake. And downregulation of GLUT4 in melanoma cells induced inhibition of cell proliferation and metastasis. TDP-43 knockdown significantly slowed down tumor growth and decreased GLUT4 expression in vivo. TDP-43 is a novel oncogene in melanoma and regulates melanoma proliferation and metastasis potentially through modulation of glucose metabolism.

  13. Dual-energy computed tomography in patients with cutaneous malignant melanoma: Comparison of noise-optimized and traditional virtual monoenergetic imaging.

    Science.gov (United States)

    Martin, Simon S; Wichmann, Julian L; Weyer, Hendrik; Albrecht, Moritz H; D'Angelo, Tommaso; Leithner, Doris; Lenga, Lukas; Booz, Christian; Scholtz, Jan-Erik; Bodelle, Boris; Vogl, Thomas J; Hammerstingl, Renate

    2017-10-01

    The aim of this study was to investigate the impact of noise-optimized virtual monoenergetic imaging (VMI+) reconstructions on quantitative and qualitative image parameters in patients with cutaneous malignant melanoma at thoracoabdominal dual-energy computed tomography (DECT). Seventy-six patients (48 men; 66.6±13.8years) with metastatic cutaneous malignant melanoma underwent DECT of the thorax and abdomen. Images were post-processed with standard linear blending (M_0.6), traditional virtual monoenergetic (VMI), and VMI+ technique. VMI and VMI+ images were reconstructed in 10-keV intervals from 40 to 100keV. Attenuation measurements were performed in cutaneous melanoma lesions, as well as in regional lymph node, subcutaneous and in-transit metastases to calculate objective signal-to-noise (SNR) and contrast-to-noise (CNR) ratios. Five-point scales were used to evaluate overall image quality and lesion delineation by three radiologists with different levels of experience. Objective indices SNR and CNR were highest at 40-keV VMI+ series (5.6±2.6 and 12.4±3.4), significantly superior to all other reconstructions (all PVMI+ reconstructions (median 5, respectively; P≤0.019) regarding overall image quality. Moreover, qualitative assessment of lesion delineation peaked in 40-keV VMI+ (median 5) and 50-keV VMI+ (median 4; P=0.055), significantly superior to all other reconstructions (all PVMI+ reconstructions substantially increase quantitative and qualitative image parameters, as well as subjective lesion delineation compared to standard image reconstruction and traditional VMI in patients with cutaneous malignant melanoma at thoracoabdominal DECT. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. CDKN2A (INK4A-ARF) mutation analysis to distinguish cutaneous melanoma metastasis from a second primary melanoma.

    NARCIS (Netherlands)

    Blokx, W.A.M.; Lesterhuis, W.J.; Andriessen, M.P.M.; Verdijk, M.A.J.; Punt, C.J.A.; Ligtenberg, M.J.L.

    2007-01-01

    The histologic differential diagnosis between a second primary cutaneous melanoma and cutaneous melanoma metastasis in a patient with a previous history of melanoma can be very difficult. This case report describes the first application of CDKN2A mutation analysis for discriminating a cutaneous

  15. The worth of radiotherapy in malignant melanomas.

    Science.gov (United States)

    Proppe, A H

    1978-08-01

    A new approach for the evaluation of the effectiveness of various forms of treatment of malignant melanomas is presented. Factors influencing the survival time from initiation of therapy until death were statistically analyzed in 548 patients who died from malignant melanoma. In slowly developing malignancies X-ray therapy was found to be superior to therapeutic methods.

  16. Cost-effectiveness of preoperative SPECT/CT combined with lymphoscintigraphy vs. lymphoscintigraphy for sentinel lymph node excision in patients with cutaneous malignant melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Stoffels, Ingo; Leyh, Julia; Schadendorf, Dirk; Klode, Joachim [University of Duisburg-Essen, Department of Dermatology, Venerology and Allergology, University-Hospital Essen, Essen (Germany); Mueller, Markus [University of Duisburg-Essen, Department of Medical controlling, University-Hospital Essen, Essen (Germany); Geisel, Marie Henrike [University of Duisburg-Essen, Institute for Medical Informatics, Biometry and Epidemiology, University-Hospital Essen, Essen (Germany); Poeppel, Thorsten [University of Duisburg-Essen, Department of Nuclear Medicine, University-Hospital Essen, Essen (Germany)

    2014-09-15

    Malignant melanoma has become a major growing interdisciplinary problem in public health worldwide. Sentinel lymph node excision (SLNE) in conjunction with preoperative SPECT/CT is considered the most sensitive and specific staging test for the detection of micrometastatic melanoma in regional lymph nodes. Among patients with clinically lymph node-negative melanoma, the use of SPECT/CT-aided SLNE compared with SLNE alone has been found to be associated with a higher frequency of metastatic involvement and a higher rate of disease-free survival. The aim of this study was to analyse the cost-effectiveness of SLNE with preoperative SPECT/CT for detecting sentinel lymph nodes versus that of standard SLNE with preoperative lymphoscintigraphy from a single-institution database. Cost-effectiveness analysis of two surgical approaches for SLNE for malignant melanoma at the University Hospital Essen, Skin Cancer Center in Essen, Germany. Between March 2003 and April 2011 464 patients eligible for SLNE were identified. Of these patients, 403 with clinically negative lymph nodes who underwent SLNE with or without preoperative SPECT/CT qualified for subsequent analysis. Between March 2003 and October 2008, 254 patients were operated upon with the standard technique. From November 2008, 149 patients underwent the SPECT/CT technique. Cost analysis showed a mean cost saving of EUR 710.50 when SPECT/CT was added to preoperative imaging. This was achieved by a reduction in operative time (median, Q1;Q3, 40 min, 40;50 min, vs. 45 min, 35;60 min; p = 0.002), hospital stay duration (5 days, 3;8 days, vs. 8 days, 4.5;14.5 days; p < 0.001) and more frequent use of local anaesthesia (90.6 % vs. 70.5 %; p < 0.001). The median cost of SLNE using SPECT/CT was EUR 1,619.7 (Q1;Q3 EUR 1,317.0;2,603.4) and of SLNE without SPECT/CT was EUR 2,330.2 (EUR 1,468.3;4,058.1; p < 0.001), a cost saving of 30.5 %. In patients with cutaneous melanoma, the use of preoperative SPECT/CT-aided SLNE compared

  17. The impact of ulcerative colitis on patients' lives compared to other chronic diseases: a patient survey.

    Science.gov (United States)

    Rubin, David T; Dubinsky, Marla C; Panaccione, Remo; Siegel, Corey A; Binion, David G; Kane, Sunanda V; Hopper, Joseph

    2010-04-01

    This study was designed to identify the impact chronic ulcerative colitis (UC) has on the lives of patients compared to other chronic conditions. Overall, 451 patients with UC, 309 with rheumatoid arthritis, 305 with asthma, and 305 with migraine headaches were recruited in an Internet survey designed to assess a variety of disease-impact indices. Patients with UC reported a mean of eight (self-defined) flare-ups in the previous 12 months. Significantly more patients with UC (81%) believed that the quantity of flare-ups they experienced was 'normal', compared to patients with migraine headaches (64%) or asthma (75%). Patients with UC also reported significantly more worry about disease complications (84%), depression (62%), and embarrassment (70%) than patients with the other chronic conditions. Compared to patients with other chronic conditions, patients with UC perceive substantially more negative impact upon their lives, especially with regard to the psychological burden.

  18. P11-3: Case Report: Early Detection of Melanoma with Sequential Digital Dermoscopy in a High Risk Patient

    OpenAIRE

    Martín*, Ignacio Gómez; Fernández, Sara Moreno; Vallverdú, Ramon M Pujol; Tigell, Sonia Segura; Takigami*, Caroline M.; Aguilera, Paula; Prodinger, Christine; Laimer, Martin; Kirchner, Clara; Longo, Caterina; Ragazzi, Moira; Gardini, Stefano; Peppelman*, Malou; Wolberink, Esther; Nguyen, Kim

    2015-01-01

    Introduction: Blue nevi are ectopic collections of dermal melanocytes present as solitary lesions, but multiple lesions may occur. They are grouped in a circumscribed area or, in rare cases, disseminated. Multiple blue nevi may present a diagnostic challenge and metastatic melanoma must be ruled out. Case 1: A 65-year-old Caucasian man with personal history of in situ melanoma on the trunk 8 years ago, was referred to evaluate multiple, agminated, dark brown macules adjacent to the balano-pre...

  19. Evaluation of 100 patients for living donor liver transplantation.

    Science.gov (United States)

    Trotter, J F; Wachs, M; Trouillot, T; Steinberg, T; Bak, T; Everson, G T; Kam, I

    2000-05-01

    The initial success of living donor liver transplantation (LDLT) in the United States has resulted in a growing interest in this procedure. The impact of LDLT on liver transplantation will depend in part on the proportion of patients considered medically suitable for LDLT and the identification of suitable donors. We report the outcome of our evaluation of the first 100 potential transplant recipients for LDLT at the University of Colorado Health Sciences Center (Denver, CO). All patients considered for LDLT had first been approved for conventional liver transplantation by the Liver Transplant Selection Committee and met the listing criteria of United Network for Organ Sharing status 1, 2A, or 2B. Once listed, those patients deemed suitable for LDLT were given the option to consider LDLT and approach potential donors. Donors were evaluated with a preliminary screening questionnaire, followed by formal evaluation. Of the 100 potential transplant recipients evaluated, 51 were initially rejected based on recipient characteristics that included imminent cadaveric transplantation (8 patients), refusal of evaluation (4 patients), lack of financial approval (6 patients), and medical, psychosocial, or surgical problems (33 patients). Of the remaining 49 patients, considered ideal candidates for LDLT, 24 patients were unable to identify a suitable donor for evaluation. Twenty-six donors were evaluated for the remaining 25 potential transplant recipients. Eleven donors were rejected: 9 donors for medical reasons and 2 donors who refused donation after being medically approved. The remaining 15 donor-recipient pairs underwent LDLT. Using our criteria for the selection of recipients and donors for LDLT gave the following results: (1) 51 of 100 potential transplant recipients (51%) were rejected for recipient issues, (2) only 15 of the remaining 49 potential transplant recipients (30%) were able to identify an acceptable donor, and (3) 15 of 100 potential living donor

  20. TRPM1 (melastatin) expression is an independent predictor of overall survival in clinical AJCC stage I and II melanoma patients.

    Science.gov (United States)

    Brożyna, Anna A; Guo, Huazhang; Yang, Sun-Eun; Cornelius, Lynn; Linette, Gerald; Murphy, Michael; Sheehan, Christine; Ross, Jeffrey; Slominski, Andrzej; Carlson, J Andrew

    2017-04-01

    The expression of TRPM1 (melastatin) mRNA is an independent marker, as measured by radioactive in situ hybridization (RISH), of disease-free survival in primary cutaneous melanoma (PM). The aim of the study was to determine if chromogenic in situ hybridization (CISH) can reproduce results examining diagnostic and prognostic utility of TRPM1 mRNA expression in melanocytic proliferations as measured by RISH. The expression of TRPM1 mRNA was detected by CISH in melanocytic nevi (MN, n = 61), PM (n = 145) and metastatic melanomas (MMs, n = 15). A progressive loss of TRPM1 was found moving from MN to PM to MM. The histologic stepwise model of melanoma progression revealed that loss of TRPM1 occurred at the transition of RGP PM to VGP PM. As a diagnostic marker, TRPM1 gradient loss showed 93.8% sensitivity and 52.4% specificity for PM. Loss of TRPM1 mRNA correlated with melanoma aggressiveness markers and was independent predictor of disease-free and overall survival. The corresponding survival curves for degree of melanoma pigmentation matched those for degree of loss of TPRM1 mRNA. Loss of TRPM1 mRNA expression appears to be a crucial event in the progression of melanoma to a more malignant, metastatic phenotype. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Living donor renal transplantation in patients with antiphospholipid syndrome

    Science.gov (United States)

    Choi, Ji Yoon; Jung, Joo Hee; Shin, Sung; Kim, Young Hoon; Han, Duck Jong

    2016-01-01

    Abstract Introduction: Antiphospholipid syndrome (APS), autoantibodies directed against phospholipid-binding proteins are associated with cause vascular thrombosis. Patients with APS requiring renal transplantation are at risk of early graft loss due to arterial or venous thrombosis, or thrombotic microangiopathy (TMA). Here, we report 3 cases of successful renal transplantation in patients with APS. Clinical Findings: A 53-year-old man with end-stage renal disease (ESRD) had experienced bilateral deep venous thrombosis (DVT) in the lower extremities 16 years ago and was administered warfarin. However, he frequently experienced recurrent DVT despite of anticoagulation therapy. Before the surgery, APS was confirmed based on positive results lupus anticoagulant in serological tests. A 40-year-old man with polycystic kidney disease and a history recurrent DVT tested positive for lupus anticoagulant and anticardiolipin antibodies. Lastly, a 42-year-old woman with ESRD was diagnosed with APS 7 years ago. She also developed DVT and tested positive for lupus anticoagulant and anti-B2-glycoprotein 1. The anticoagulation protocol was as follows in all cases: Warfarin was stopped 5 days before living donor renal transplantation and intravenous heparin therapy was started. During surgery, bolus heparin injections (3000 U) were administered to prevent arterial or venous thrombosis. Heparin was substituted with warfarin on postoperative day 4. The third patient (42/F) developed clinical rejection indicated by increased serum creatinine levels and donor-specific antibodies (DSA) and received steroid pulse therapy, plasmapheresis, and rituximab. This treatment restored graft function to within the normal range. The latest graft function in all patients was maintained at normal levels in the outpatient clinic. Conclusions: Living donor renal transplantation may be successful in patients with APS following perioperative anticoagulation therapy. However, because of the high risk of

  2. Um Melanoma “mascarado” Melanoma disfrazado A disguised Melanoma

    Directory of Open Access Journals (Sweden)

    Elias Ribeiro

    2012-08-01

    difícil diagnóstico, como se puede ver en este caso en que una úlcera en la planta del pie fue diagnosticada muy tarde, atrasando el diagnóstico de una neoplasia grave y de elevada tasa de mortalidad. Melanoma is a tumor that develops as a result of the malignant transformation of the melanocytes. There is a worldwide estimate of 132,000 new cases per year. This case study presents a 70-year-old male person with history of Diabetes Mellitus type 2 for 10 years and extensive psoriasis vulgaris for 6 years. The patient developed an ulcerated lesion in the plantar region of the right foot in one-year time period. The histological examination revealed an ulcerated malignant melanoma, Clark level V, 5.6 mm thick (Breslow. The lesion was surgically removed and the sentinel lymph node biopsy was negative. Initial conclusions revealed an advanced state of evolution of the primary tumor (TNM IIC. CAT scan detected gastric metastasis, reclassifying the illness as a TNM IV stage. Malignant melanoma may be difficult to diagnose, as it was possible to observe in this case study, where a foot ulcer was late diagnosed, delaying the diagnosis of a severe neoplasia with high mortality rate.

  3. Tumour-associated macrophages are related to progression in patients with      metastatic melanoma following interleukin-2 based immunotherapy

    DEFF Research Database (Denmark)

    Hansen, Bettina Dencker; Schmidt, Henrik; Maase, Hans von der

    2006-01-01

    The aim of the present study was to analyze whether leukocyte subsets in       peripheral blood and tumour biopsies obtained before treatment were able       to predict response or survival in patients with metastatic melanoma       following Interleukin-2 (IL-2) based immunotherapy. Flow cytometry......-associated       CD64(+) macrophages in tumour biopsies were statistically significantly       associated with poor response to treatment. Our data suggest that       tumour-associated macrophages may correlate negatively with response,       which may be of biological importance for IL-2 based immunotherapy...... of       malignant melanoma...

  4. Pembrolizumab for Ipilimumab-Resistant Melanoma

    Science.gov (United States)

    KEYNOTE-002 was designed to test the safety and efficacy of two doses of pembrolizumab compared with chemotherapy in patients with ipilimumab-resistant melanoma; interim results show that pembrolizumab improves progression-free survival for these patients

  5. Dissection of immune gene networks in primary melanoma tumors critical for antitumor surveillance of patients with stage II-III resectable disease.

    Science.gov (United States)

    Sivendran, Shanthi; Chang, Rui; Pham, Lisa; Phelps, Robert G; Harcharik, Sara T; Hall, Lawrence D; Bernardo, Sebastian G; Moskalenko, Marina M; Sivendran, Meera; Fu, Yichun; de Moll, Ellen H; Pan, Michael; Moon, Jee Young; Arora, Sonali; Cohain, Ariella; DiFeo, Analisa; Ferringer, Tammie C; Tismenetsky, Mikhail; Tsui, Cindy L; Friedlander, Philip A; Parides, Michael K; Banchereau, Jacques; Chaussabel, Damien; Lebwohl, Mark G; Wolchok, Jedd D; Bhardwaj, Nina; Burakoff, Steven J; Oh, William K; Palucka, Karolina; Merad, Miriam; Schadt, Eric E; Saenger, Yvonne M

    2014-08-01

    Patients with resected stage II-III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for transcriptome-wide profiling from formalin-fixed and paraffin-embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II-III FFPE primary melanomas was analyzed and a 53-immune-gene panel predictive of non-progression (area under the curve (AUC)=0.920) was defined. The signature predicted disease-specific survival (DSS P<0.001) and recurrence-free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a coexpression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally, the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001), and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger data set annotated on the basis of prospectively gathered data.

  6. Dissection of Immune Gene Networks in Primary Melanoma Tumors Critical for Antitumor Surveillance of Patients with Stage II–III Resectable Disease

    Science.gov (United States)

    Sivendran, Shanthi; Chang, Rui; Pham, Lisa; Phelps, Robert G.; Harcharik, Sara T.; Hall, Lawrence D.; Bernardo, Sebastian G.; Moskalenko, Marina M.; Sivendran, Meera; Fu, Yichun; de Moll, Ellen H.; Pan, Michael; Moon, Jee Young; Arora, Sonali; Cohain, Ariella; DiFeo, Analisa; Ferringer, Tammie C.; Tismenetsky, Mikhail; Tsui, Cindy L.; Friedlander, Philip A.; Parides, Michael K.; Banchereau, Jacques; Chaussabel, Damien; Lebwohl, Mark G.; Wolchok, Jedd D.; Bhardwaj, Nina; Burakoff, Steven J.; Oh, William K.; Palucka, Karolina; Merad, Miriam; Schadt, Eric E.; Saenger, Yvonne M.

    2014-01-01

    Patients with resected stage II–III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for transcriptome-wide profiling from formalin-fixed and paraffin-embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II–III FFPE primary melanomas was analyzed and a 53-immune-gene panel predictive of non-progression (area under the curve (AUC)=0.920) was defined. The signature predicted disease-specific survival (DSS P<0.001) and recurrence-free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a coexpression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally, the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001), and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger data set annotated on the basis of prospectively gathered data. PMID:24522433

  7. A Phase II Study of Fotemustine Plus Dacarbazine with Dendritic Cell Vaccines as First-Line Therapy for Chinese Patients with Advanced Acral Lentiginous Melanoma

    Institute of Scientific and Technical Information of China (English)

    Lu Si; Zhi-hong Chi; Xiang-qing Yuan; Chuan-liang Cui; Xi-nan Sheng; Jun Guo

    2009-01-01

    Objective: To investigate fotemustine plus dacarbazine (DTIC) with dendritic cell (DC) vaccines on patients with advanced acral lentiginous melanoma (ALM). Fotemustine is a cytotoxic alkylating agent with a remarkable antitumor activity as single agent but also in association with (DTIC). DC is the strongest antigen presenting cell which could induce durable clinical responses. Methods: This was a single-center study. Between July 2003 and June 2006, twenty-eight chemotherapy-naive patients of advanced ALM received fotemustine 100 mg/m2, d1, 12, DTIC 400 mg/d d2(6, DC vaccines subcutaneously d7, 9, 13 repeated every 28 days. Ten HLA-A02+24+ patients received vaccines pulsed with melanoma antigen derived peptides, melanoma antigen recognized by T-cells 1 (Mart-1) and S-100. Eighteen patients received DC loaded with allogeneic melanoma lysate. The primary end-point was progression free survival (PFS). Secondary end-points were overall survival (OS), overall response rate (ORR) and toxicity. Tumor assessment was performed every 8 weeks and evaluated according to response evaluation criteria in solid tumors (RECIST). Results: The 15 men and 13 women had a median age of 51 years. 16 patients had stage M1c disease and 11/16 had liver metastasis. Patients received an average of 3.82(1.25 cycles. Follow-up for the 18 surviving patients ranged from 7(41 months with a median of 12 months. Median PFS was 8.5 months (95% CI: 7.86(15.21) with 12 patients remaining progression free. Only 10 patients died. Median OS was 12 months (95% CI: 10.33(18.24). ORR (CR+PR) was 35.7% including 3 complete response (CR) and 7 partial response (PR). Six patients had disease stable. A total of 19 Grade III/IV toxicities were observed including thrombocytopenia (n=8), neutropenia (n=5), fatigue (n=6) and hypersensitivity reaction (n=1). One patient died of Grade IV thrombocytopenia. Conclusion: Fotemustine and dacarbazine plus DC vaccines are safe and tolerable to Chinese ALM patients. The

  8. ENTERIC PARASITES IN PATIENTS LIVING WITH HIV & AIDS

    Directory of Open Access Journals (Sweden)

    Ashwini

    2015-08-01

    Full Text Available CONTEXT: HIV is a major global public health issue. Most of the patients with HIV disease die of infections other than HIV. Gastrointestinal infections are very common in patients with HIV infection or AIDS . AIMS : To detect opportunistic intestinal parasi tes in patients living with HIV & AIDS and relate it with CD4 count. SETTINGS AND DESIGN: A single stool sample was obtained in sterile plastic containers from the patients attending pre ART. The stool samples were examined macroscopically and microscopica lly. Formalin ether concentration method was used. The modified Ziehl Neelsen staining method was used for the detection of the oocyst of coccidian parasites. CD4 count was measured on partec flow cytometry. RESULTS: Out of the 53 patient s, 33(62.26% were males and 20 (37.73% were femal es with age between 25 - 65 years . The study population consist of 4 patients with CD4 count > 500 cells/μl , 22 patients with CD4 count 200 - 499 cells/μl and 27 patients with CD4 count < 200 cells/μl. Enteric parasites we re detec ted by microscopy in 21 (39.62% stool samples . Number of samples showing parasites were Cryptospridium 11 (20.75%, Strongyloides stercoralis 3(5.6% , Cyclospora 1 (1.8%. Ascaris lumbricoides 3 (5.6%, Ancylostoma duodenale 1 (1.8% and Tenia eggs 2(3.7%. Ov erall, Cryptosporidium 11 (20.75% was the most frequently encountered pathogen in the study population. CONCLUSIONS: The results of our study highlight the importance of evaluation of HIV infected individuals with diarrhoea for intestinal parasitic infect ions which may help in better management of these patients.

  9. Nutrition and melanoma prevention.

    Science.gov (United States)

    Jensen, J Daniel; Wing, Gregory J; Dellavalle, Robert P

    2010-01-01

    Melanoma has continued to rise in incidence despite public efforts to promote sun protection behaviors. Because sunscreen use does not completely prevent skin cancer induced by ultraviolet radiation, additional chemopreventive methods for protecting against and reversing the effects of ultraviolet photodamage need evaluation. Recent years have brought increased interest in dietary factors, such as natural botanicals and vitamins, for the prevention of melanoma. This contribution provides a narrative review of the relevant, nutrition-related literature found by searching the keywords "melanoma chemoprevention," "nutrition and melanoma," "dietary botanicals and melanoma prevention," "green tea and melanoma," "vitamin D and melanoma," and "vitamin E and melanoma" in the PubMed database. Although randomized controlled trials of humans are lacking, basic science and epidemiologic studies show promising benefits of many natural products in chemoprevention for melanoma. Future studies, hopefully, will yield concrete answers and clarify the role of commonly available dietary nutrients in melanoma chemoprevention.

  10. Symptomatic Histologically Proven Necrosis of Brain following Stereotactic Radiation and Ipilimumab in Six Lesions in Four Melanoma Patients

    Directory of Open Access Journals (Sweden)

    Stephanie Du Four

    2014-01-01

    Full Text Available Four cases previously treated with ipilimumab with a total of six histologically confirmed symptomatic lesions of RNB without any sign of active tumour following stereotactic irradiation of MBM are reported. These lesions were all originally thought to be disease recurrence. In two cases, ipilimumab was given prior to SRT; in the other two ipilimumab was given after SRT. The average time from first ipilimumab to RNB was 15 months. The average time from SRT to RNB was 11 months. The average time from first diagnosis of MBM to last follow-up was 20 months at which time three patients were still alive, one with no evidence of disease. These cases represent approximately three percent of the total cases of melanoma and ten percent of those cases treated with ipilimumab irradiated in our respective centres collectively. We report this to highlight this new problem so that others may have a high index of suspicion, allowing, if clinically warranted, aggressive surgical salvage, possibly resulting in increased survival. Further studies prospectively collecting data to understand the denominator of this problem are needed to determine whether this problem is just the result of longer survival or whether there is some synergy between these two modalities that are increasingly being used together.

  11. Immunogenicity of HLA-A1-restricted peptides derived from S100A4 (metastasin 1) in melanoma patients

    DEFF Research Database (Denmark)

    Hofmeister-Mueller, Valeska; Vetter-Kauczok, Claudia S; Ullrich, Ramona

    2009-01-01

    S100A4 (metastasin 1) belongs to the S100 family of Ca(2+) binding proteins. While not present in most differentiated adult tissues, S100A4 is upregulated in the micromilieu of tumors. It is primarily expressed by tumor-associated macrophages, fibroblasts, and tumor endothelial cells. Due to its...... strong induction in tumors S100A4 is a promising target for cancer immunotherapy. By reverse immunology, using epitope prediction programs, we identified 3 HLA-A1-restricted peptide epitopes (S100A4 A1-1, A1-2, and A1-3) which are subject to human T cell responses as detected in peripheral blood...... of melanoma patients by means of IFN-gamma ELISPOT and cytotoxicity assays. In addition, IFN-gamma responses to S100A4 A1-2 can not only be induced by stimulation of T cells with peptide-loaded DC but also by stimulation with S100A4 protein-loaded DC, indicating that this epitope is indeed generated...

  12. Resiquimod as an immunologic adjuvant for NY-ESO-1 protein vaccination in patients with high-risk melanoma.

    Science.gov (United States)

    Sabado, Rachel Lubong; Pavlick, Anna; Gnjatic, Sacha; Cruz, Crystal M; Vengco, Isabelita; Hasan, Farah; Spadaccia, Meredith; Darvishian, Farbod; Chiriboga, Luis; Holman, Rose Marie; Escalon, Juliet; Muren, Caroline; Escano, Crystal; Yepes, Ethel; Sharpe, Dunbar; Vasilakos, John P; Rolnitzsky, Linda; Goldberg, Judith D; Mandeli, John; Adams, Sylvia; Jungbluth, Achim; Pan, Linda; Venhaus, Ralph; Ott, Patrick A; Bhardwaj, Nina

    2015-03-01

    The Toll-like receptor (TLR) 7/8 agonist resiquimod has been used as an immune adjuvant in cancer vaccines. We evaluated the safety and immunogenicity of the cancer testis antigen NY-ESO-1 given in combination with Montanide (Seppic) with or without resiquimod in patients with high-risk melanoma. In part I of the study, patients received 100 μg of full-length NY-ESO-1 protein emulsified in 1.25 mL of Montanide (day 1) followed by topical application of 1,000 mg of 0.2% resiquimod gel on days 1 and 3 (cohort 1) versus days 1, 3, and 5 (cohort 2) of a 21-day cycle. In part II, patients were randomized to receive 100-μg NY-ESO-1 protein plus Montanide (day 1) followed by topical application of placebo gel [(arm A; n = 8) or 1,000 mg of 0.2% resiquimod gel (arm B; n = 12)] using the dosing regimen established in part I. The vaccine regimens were generally well tolerated. NY-ESO-1-specific humoral responses were induced or boosted in all patients, many of whom had high titer antibodies. In part II, 16 of 20 patients in both arms had NY-ESO-1-specific CD4⁺ T-cell responses. CD8⁺ T-cell responses were only seen in 3 of 12 patients in arm B. Patients with TLR7 SNP rs179008 had a greater likelihood of developing NY-ESO-1-specific CD8⁺ responses. In conclusion, NY-ESO-1 protein in combination with Montanide with or without topical resiquimod is safe and induces both antibody and CD4⁺ T-cell responses in the majority of patients; the small proportion of CD8⁺ T-cell responses suggests that the addition of topical resiquimod to Montanide is not sufficient to induce consistent NY-ESO-1-specific CD8⁺ T-cell responses.

  13. Multiple primary melanoma in a Thai male: a case report.

    Science.gov (United States)

    Payapvipapong, Kittisak; Kanechorn-Na-Ayuthaya, Pinyapat

    2014-02-01

    Melanoma is a malignant tumor of melanocytes and the most threatening skin cancer documenting one of the highest in mortality rates in comparison to other non-skin cancers due to its potential to metastasize. Although the global incidence of melanoma has increased, the melanoma-related deaths decreased owing to the fact that melanoma is curable under the condition that early diagnosis is made and treatment is undertaken as soon as possible. Patients with primary melanoma developing a second primary melanoma are less common compared to the generalpopulation developing the first. Not only is melanoma less commonly found in Thaipatients but multiple primary melanomas (MPM) are rarely reported. The present report of a 48-year-old Thai male who presented with asymptomatic black patch on the right big toe nail and an atypical mole on the back, both ofwhich were histologically confirmed melanomas. Treatment included amputation of the right big toe and wide excision of melanoma on the back, which cleared the malignancy without recurrence until present. Although MPM are rare in Thais, the authors should be alert in cases displaying multiple moles for the possibility of melanomas. The total body examination, early diagnosis and regular follow-up are important to decrease the mortality rate in melanoma patient.

  14. Cytotoxic T lymphocyte responses against melanocytes and melanoma

    Directory of Open Access Journals (Sweden)

    Schwartz Erich J

    2011-07-01

    Full Text Available Abstract Background Vitiligo is a common toxicity associated with immunotherapy for melanoma. Cytotoxic T lymphocytes (CTLs against melanoma commonly target melanoma-associated antigens (MAAs which are also expressed by melanocytes. To uncouple vitiligo from melanoma destruction, it is important to understand if CTLs can respond against melanoma and melanocytes at different levels. Methods To understand the dichotomous role of MAA-specific CTL, we characterized the functional reactivities of established CTL clones directed to MAAs against melanoma and melanocyte cell lines. Results CTL clones generated from melanoma patients were capable of eliciting MHC-restricted, MAA-specific lysis against melanocyte cell lines as well as melanoma cells. Among the tested HLA-A*0201-restricted CTL clones, melanocytes evoked equal to slightly higher degranulation and cytolytic responses as compared to melanoma cells. Moreover, MAA-specific T cells from vaccinated patients responded directly ex vivo to melanoma and melanocytes. Melanoma cells express slightly higher levels of MART-1 and gp100 than melanocytes as measured by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR and immunohistochemistry. Conclusions Our data suggest that CTLs respond to melanoma and melanocytes equally in vitro and directly ex vivo.

  15. Adjuvant Therapy: Melanoma

    Directory of Open Access Journals (Sweden)

    Diwakar Davar

    2011-01-01

    Full Text Available With an incidence that is increasing at 2–5% per year, cutaneous melanoma is an international scourge that disproportionately targets young individuals. Despite much research, the treatment of advanced disease is still quite challenging. Immunotherapy with high-dose interferon-α2b or interleukin-2 benefits a select group of patients in the adjuvant and metastatic settings, respectively, with significant attendant toxicity. Advances in the biology of malignant melanoma and the role of immunomodulatory therapy have produced advances that have stunned the field. In this paper, we review the data for the use of interferon-α2b in various dosing ranges, vaccine therapy, and the role of radiotherapy in the adjuvant setting for malignant melanoma. Recent trials in the metastatic setting using anticytoxic T-lymphocyte antigen-4 (anti-CTLA-4 monoclonal antibody therapy and BRAF inhibitor therapy have demonstrated clear benefit with prolongation of survival. Trials investigating combinations of these novel agents with existing immunomodulators are at present underway.

  16. A disguised Melanoma

    Directory of Open Access Journals (Sweden)

    Cláudia Sofia Rego

    2012-02-01

    Full Text Available Melanoma is a tumor that develops as a result of the malignant transformation of the melanocytes. There is a worldwide estimate of 132,000 new cases per year. This case study presents a 70-year-old male person with history of Diabetes Mellitus type 2 for 10 years and extensive psoriasis vulgaris for 6 years. The patient developed an ulcerated lesion in the plantar region of the right foot in one-year time period. The histological examination revealed an ulcerated malignant melanoma, Clark level V, 5.6 mm thick (Breslow. The lesion was surgically removed and the sentinel lymph node biopsy was negative. Initial conclusions revealed an advanced state of evolution of the primary tumor (TNM IIC. CAT scan detected gastric metastasis, reclassifying the illness as a TNM IV stage. Malignant melanoma may be difficult to diagnose, as it was possible to observe in this case study, where a foot ulcer was late diagnosed, delaying the diagnosis of a severe neoplasia with high mortality rate.

  17. Melanoma Brain Metastasis: Mechanisms, Models, and Medicine.

    Science.gov (United States)

    Kircher, David A; Silvis, Mark R; Cho, Joseph H; Holmen, Sheri L

    2016-09-02

    The development of brain metastases in patients with advanced stage melanoma is common, but the molecular mechanisms responsible for their development are poorly understood. Melanoma brain metastases cause significant morbidity and mortality and confer a poor prognosis; traditional therapies including whole brain radiation, stereotactic radiotherapy, or chemotherapy yield only modest increases in overall survival (OS) for these patients. While recently approved therapies have significantly improved OS in melanoma patients, only a small number of studies have investigated their efficacy in patients with brain metastases. Preliminary data suggest that some responses have been observed in intracranial lesions, which has sparked new clinical trials designed to evaluate the efficacy in melanoma patients with brain metastases. Simultaneously, recent advances in our understanding of the mechanisms of melanoma cell dissemination to the brain have revealed novel and potentially therapeutic targets. In this review, we provide an overview of newly discovered mechanisms of melanoma spread to the brain, discuss preclinical models that are being used to further our understanding of this deadly disease and provide an update of the current clinical trials for melanoma patients with brain metastases.

  18. Sox2 is not required for melanomagenesis, melanoma growth and melanoma metastasis in vivo.

    Science.gov (United States)

    Cesarini, V; Guida, E; Todaro, F; Di Agostino, S; Tassinari, V; Nicolis, S; Favaro, R; Caporali, S; Lacal, P M; Botti, E; Costanzo, A; Rossi, P; Jannini, E A; Dolci, S

    2017-08-01

    Melanoma is a dangerous form of skin cancer derived from the malignant transformation of melanocytes. The transcription factor SOX2 is not expressed in melanocytes, however, it has been shown to be differentially expressed between benign nevi and malignant melanomas and to be essential for melanoma stem cell maintenance and expansion in vitro and in xenograft models. By using a mouse model in which BRaf(V600E) mutation cooperates with Pten loss to induce the development of metastatic melanoma, we investigated if Sox2 is required during the process of melanomagenesis, melanoma growth and metastasis and in the acquisition of resistance to BRAF inhibitors (BRAFi) treatments. We found that deletion of Sox2 specifically in Pten null and BRafV600E-expressing melanocytes did not prevent tumor formation and did not modify the temporal kinetics of melanoma occurrence compared to Sox2 wt mice. In addition, tumor growth was similar between Sox2 wt and Sox2 deleted (del) melanomas. By querying publicly available databases, we did not find statistically significant differences in SOX2 expression levels between benign nevi and melanomas, and analysis on two melanoma patient cohorts confirmed that Sox2 levels did not significantly change between primary and metastatic melanomas. Melanoma cell lines derived from both Sox2 genotypes showed a similar sensitivity to vemurafenib treatment and the same ability to develop vemurafenib resistance in long-term cultures. Development of vemurafenib resistance was not dependent on SOX2 expression also in human melanoma cell lines in vitro. Our findings exclude an oncogenic function for Sox2 during melanoma development and do not support a role for this transcription factor in the acquisition of resistance to BRAFi treatments.

  19. Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy.

    Science.gov (United States)

    Wyluda, Edward J; Cheng, Jihua; Schell, Todd D; Haley, Jeremy S; Mallon, Carol; Neves, Rogerio I; Robertson, Gavin; Sivik, Jeffrey; Mackley, Heath; Talamo, Giampaolo; Drabick, Joseph J

    2015-01-01

    We report 3 cases of durable complete response (CR) in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (high dose interleukin 2 followed by ipilimumab with or without concurrent radiation therapy). After progression during or post immunotherapy, these patients were given BRAF inhibitor therapy and developed rapid CRs. Based on the concomitant presence of autoimmune manifestations (including vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAF targeting agents. Accordingly, the inhibitors were gradually weaned off beginning at 3 months and were stopped completely at 9-12 months. The three patients remain well and in CR off of all therapy at up to 15 months radiographic follow-up. The institution of the BRAF therapy was associated with development of severe rheumatoid-like arthritis in 2 patients which persisted for months after discontinuation of therapy, suggesting it was not merely a known toxicity of BRAF inhibitors (arthralgias). On immunologic analysis, these patients had high levels of non-T-regulatory, CD4 positive effector phenotype T-cells, which persisted after completion of therapy. Of note, we had previously reported a similar phenomenon in patients with metastatic melanoma who failed high dose interleukin-2 and were then placed on a finite course of temozolomide with rapid complete responses that have remained durable for many years after discontinuation of temozolomide. We postulate that a finite course of cytotoxic or targeted therapy specific for melanoma given after apparent failure of prior immunotherapy can result in complete and durable remissions that may persist long after the specific cytotoxic or targeted agents have been discontinued suggesting the existence of sequence specific synergism between immunotherapy and these agents. Here, we discuss these cases in the context of the literature on

  20. BILLCD8 - A Multivariable Survival Model as a Simple and Clinically Useful Prognostic Tool to Identify High-risk Cutaneous Melanoma Patients.

    Science.gov (United States)

    Donizy, Piotr; Biecek, Przemyslaw; Halon, Agnieszka; Matkowski, Rafal

    2016-09-01

    To develop a multivariable survival model based on histopathological parameters that would provide the best possible estimate of the risk of death in cutaneous melanoma patients. Breslow thickness and Infiltrating Lymphocytes (BILL(CD8)) is based on two key parameters, namely Breslow thickness and tumor-infiltrating lymphocytes (TILs) shown to be the most important prognostic factors using logistic regression model. The next step was to apply a decision tree method to analyze the impact of the percentage of CD8+ lymphocytes on the risk of cancer death. A patient is given two points if Breslow thickness is >2 mm and one point if TILs are not found in the tumor. The probability of death over a 4-year follow-up is 75% if the patient's score is 3 points; in patients with 0 point score the risk of death is 0%. A significant positive impact of high percentage of CD8+ lymphocytes on the risk of death was shown in the subgroup of melanoma patients with Breslow thickness >2 mm where the risk of death is only 28%. In the case of low percentage of CD8+ lymphocytes in melanomas with Breslow thickness over 2 mm, the risk is as high as 67%. Breslow thickness and TILs, with the evaluation of the CD8+ lymphocytes, may be used for precise prognostic stratification of patients and may help intensify the follow-up, diagnose a relapse sooner and apply proper treatment. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  1. Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy.

    Science.gov (United States)

    Bowyer, S; Prithviraj, P; Lorigan, P; Larkin, J; McArthur, G; Atkinson, V; Millward, M; Khou, M; Diem, S; Ramanujam, S; Kong, B; Liniker, E; Guminski, A; Parente, P; Andrews, M C; Parakh, S; Cebon, J; Long, G V; Carlino, M S; Klein, O

    2016-05-10

    Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy. We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg(-1) for a maximum of four doses. Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient. Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance.

  2. Combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with stage IV melanoma-safety and efficacy in a phase II study.

    Science.gov (United States)

    Weide, Benjamin; Martens, Alexander; Wistuba-Hamprecht, Kilian; Zelba, Henning; Maier, Ludwig; Lipp, Hans-Peter; Klumpp, Bernhard D; Soffel, Daniel; Eigentler, Thomas K; Garbe, Claus

    2017-04-01

    Treatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis. The primary endpoint was the disease control rate according to immune-related response criteria at week 12; tolerability according to Common Terminology Criteria for Adverse Events criteria was secondary endpoint. No objective responses were observed in the 15 enrolled patients. Three patients had stable disease 12 weeks after starting treatment, yielding a disease control rate of 20%. Tolerability of this combination treatment was acceptable. Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred. Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone.

  3. Prognostic stratification of ulcerated melanoma

    DEFF Research Database (Denmark)

    Bønnelykke-Behrndtz, Marie L; Schmidt, Henrik; Christensen, Ib J

    2014-01-01

    OBJECTIVES: For patients with melanoma, ulceration is an important prognostic marker and interestingly also a predictive marker for the response of adjuvant interferon. A consensual definition and accurate assessment of ulceration are therefore crucial for proper staging and clinical management. We...... stratification of ulcerated lesions. METHODS: From H&E-stained sections, the status (presence vs absence), extent (percentage of the total tumor length), and type (infiltrative vs attenuative) of ulceration and epidermal involvement were evaluated from 385 patients with cutaneous melanoma. RESULTS: The presence...... of ulceration (hazard ratio [HR], 1.83), an attenuative type of ulceration (HR, 3.02), and excessive ulceration (HR, 3.57) were independent predictors of poor melanoma-specific survival. Further subdivision of minimal/moderate ulceration showed independent prognostic value only for lesions with epidermal...

  4. Clinical and morphological characteristics of cutaneous melanoma.

    Science.gov (United States)

    Balaban, Jagoda; Ninković Baroš, Djuka; Grujić, Dragana; Starović, Dragana; Ćelić, Milanka

    2014-01-01

    The incidence of cutaneous melanoma has increased significantly worldwide over the last several decades. The aim of this study is to determine clinical and morphology characteristics of primary melanoma, since some of them are important prognostic factors. This retrospective study included 172 patients. The data were collected by the Consulting team for malignant skin tumors in the Banja Luka Clinical Centre from 2009 to 2011. We did not use dermoscopy as a diagnostic tool in our investigation. We determined that melanoma occurs equally commonly in both sexes, in women in the sixth decade and the seventh in men. The most common sub-type was nodular melanoma (59.5%, P<0.05), followed by superficial spreading (27.8%) and acral lentiginous melanoma (11.4%). The most common localization was on the back in men (34.3%) and on the legs in women (P<0.05). More than half of our patients (55.8%) had melanoma thickness from 1.0 to 4.0 mm, and 38% had a melanoma thicker than 4.0 mm. The average Breslow thickness is 4.6 mm. More women than men had melanoma thicker than 4 mm (P<0.05). Spread of the primary tumor localization was found in 31.4% of patients, more frequently in men than in women (P<0.05). In most cases it was abstraction of lymph nodes (P<0.05). The average thickness of the melanoma in our patients is much higher than the average in the world and the countries of Europe. The results of this study indicate a need for better unique regional registry in this part of Bosnia and Herzegovina and improvement of preventive measures in the early diagnosis of melanoma.

  5. Update on the targeted therapy of melanoma.

    Science.gov (United States)

    Johnson, Douglas B; Sosman, Jeffrey A

    2013-06-01

    Melanoma is the most aggressive of the cutaneous malignancies, causing more than 9,000 deaths in the past year in the United States. Historically, systemic therapies have been largely ineffective, because melanoma is usually resistant to cytotoxic chemotherapy. However, during the past few years, several targeted therapies have proved effective in this challenging disease. These recent advances have been facilitated by an improved understanding of the driving genetic aberrations of melanoma, particularly mutations in the mitogen-activated protein kinase (MAPK) pathway. Vemurafenib, a BRAF inhibitor, demonstrated an overall survival advantage in phase III trials and is an appropriate option for first-line therapy in metastatic BRAF mutant melanoma. Dabrafenib, another BRAF inhibitor, and trametinib, a MEK inhibitor, also have been shown to be effective in phase III trials for BRAF mutant melanoma and may be additional treatment options as monotherapy or in combination pending regulatory approval. Additionally, imatinib is a promising targeted therapy for patients whose tumors harbor a KIT mutation in exons 11 and 13. Although these targeted agents cause objective responses and clinical benefit in patients with metastatic melanoma, resistance invariably develops. New targets and strategies to overcome acquired resistance are urgently needed. Furthermore, no effective targeted therapy has been developed for NRAS mutant tumors or in melanomas with as yet unknown driver mutations. In this review, we discuss current molecular targeted treatment options and promising ongoing research to develop new strategies to treat melanoma.

  6. Clinicopathological features and clinical outcomes associated with TP53 and BRAF(N)(on-)(V)(600) mutations in cutaneous melanoma patients.

    Science.gov (United States)

    Kim, Dae Won; Haydu, Lauren E; Joon, Aron Y; Bassett, Roland L; Siroy, Alan E; Tetzlaff, Michael T; Routbort, Mark J; Amaria, Rodabe N; Wargo, Jennifer A; McQuade, Jennifer L; Kemnade, Jan; Hwu, Patrick; Woodman, Scott E; Roszik, Jason; Kim, Kevin B; Gershenwald, Jeffrey E; Lazar, Alexander J; Davies, Michael A

    2017-04-15

    BRAF(V600) , NRAS, TP53, and BRAF(Non-V600) are among the most common mutations detected in non-acral cutaneous melanoma patients. Although several studies have identified clinical and pathological features associated with BRAF(V600) and NRAS mutations, limited data are available regarding the correlates and significance of TP53 and BRAF(Non-V600) mutations. This study analyzed the patient demographics, primary tumor features, and clinical outcomes of a large cohort of non-acral cutaneous melanoma patients who had undergone clinically indicated molecular testing (n = 926). The prevalence of BRAF(V600) , NRAS, TP53, and BRAF(Non-V600) mutations was 43%, 21%, 19%, and 7%, respectively. The presence of a TP53 mutation was associated with older age (P = .019), a head and neck primary tumor site (P = .0001), and longer overall survival (OS) from the diagnosis of stage IV disease in univariate (P = .039) and multivariate analyses (P = .015). BRAF(Non-V600) mutations were associated with older age (P = .005) but not with primary tumor features or OS from stage IV. Neither TP53 nor BRAF(Non-V600) mutations correlated significantly with OS with frontline ipilimumab treatment, and the TP53 status was not significantly associated with outcomes with frontline BRAF inhibitor therapy. Eleven patients with BRAF(Non-V600) mutations were treated with a BRAF inhibitor. Three patients were not evaluable for a response because of treatment cessation for toxicities; the remaining patients had disease progression as the best response to therapy. These results add to the understanding of the clinical features associated with TP53 and BRAF(Non-V600) mutations in advanced cutaneous melanoma patients, and they support the rationale for evaluating the prognostic significance of TP53 in other cohorts of melanoma patients. Cancer 2017;123:1372-1381. © 2016 American Cancer Society. © 2016 American Cancer Society.

  7. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC derived-exosomes: results of thefirst phase I clinical trial

    Directory of Open Access Journals (Sweden)

    Piperno Sophie

    2005-03-01

    Full Text Available Abstract Background DC derived-exosomes are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection. Here we report the feasability and safety of the first Phase I clinical trial using autologous exosomes pulsed with MAGE 3 peptides for the immunization of stage III/IV melanoma patients. Secondary endpoints were the monitoring of T cell responses and the clinical outcome. Patients and methods Exosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients fullfilling the inclusion criteria (stage IIIB and IV, HLA-A1+, or -B35+ and HLA-DPO4+ leukocyte phenotype, tumor expressing MAGE3 antigen were enrolled from 2000 to 2002 and received four exosome vaccinations. Two dose levels of either MHC class II molecules (0.13 versus 0.40 × 1014 molecules or peptides (10 versus 100 μg/ml were tested. Evaluations were performed before and 2 weeks after immunization. A continuation treatment was performed in 4 cases of non progression. Results The GMP process allowed to harvest about 5 × 1014 exosomal MHC class II molecules allowing inclusion of all 15 patients. There was no grade II toxicity and the maximal tolerated dose was not achieved. One patient exhibited a partial response according to the RECIST criteria. This HLA-B35+/A2+ patient vaccinated with A1/B35 defined CTL epitopes developed halo of depigmentation around naevi, a MART1-specific HLA-A2 restricted T cell response in the tumor bed associated with progressive loss of HLA-A2 and HLA-BC molecules on tumor cells during therapy with exosomes. In addition, one minor, two stable and one mixed responses were observed in skin and lymph node sites. MAGE3 specific CD4+ and CD8+ T cell responses could not be detected in peripheral blood. Conclusion The first exosome Phase I trial highlighted the feasibility of large scale exosome production and the safety of exosome administration.

  8. Socioeconomic status, sunlight exposure, and risk of malignant melanoma: the Western Canada Melanoma Study.

    Science.gov (United States)

    Gallagher, R P; Elwood, J M; Threlfall, W J; Spinelli, J J; Fincham, S; Hill, G B

    1987-10-01

    In a study of 261 male melanoma patients and age-and sex-matched controls, a strong positive univariate association between socioeconomic status, as determined by usual occupation, and risk of melanoma was detected. This association, however, was substantially explained by host constitutional factors and occupational, recreational, and vacation sunlight exposure. The study demonstrated an increased risk of melanoma in draftsmen and surveyors and a reduced risk of melanoma in construction workers and individuals employed in the finance, insurance, and real estate industry even after control for the effect of host factors and sunlight exposure.

  9. Prediction of Response to Immune Checkpoint Inhibitor Therapy Using Early-Time-Point (18)F-FDG PET/CT Imaging in Patients with Advanced Melanoma.

    Science.gov (United States)

    Cho, Steve Y; Lipson, Evan J; Im, Hyung-Jun; Rowe, Steven P; Gonzalez, Esther Mena; Blackford, Amanda; Chirindel, Alin; Pardoll, Drew M; Topalian, Suzanne L; Wahl, Richard L

    2017-09-01

    The purpose of this study was to evaluate (18)F-FDG PET/CT scanning as an early predictor of response to immune checkpoint inhibitors (ICIs) in patients with advanced melanoma. Methods: Twenty patients with advanced melanoma receiving ICI prospectively underwent (18)F-FDG PET/CT at 3 scan intervals: before treatment initiation (SCAN-1), at days 21-28 (SCAN-2), and at 4 mo (SCAN-3). This study was approved by the institutional review board, and informed consent was received from all patients who were enrolled between April 2012 and December 2013. Tumor response at each posttreatment time point was assessed according to RECIST 1.1, immune-related response criteria, PERCIST (PERCIST 1.0), and European Organization for Research and Treatment of Cancer (EORTC) criteria. Performance characteristics of each metric to predict best overall response (BOR) at ≥ 4 mo were assessed. Results: Twenty evaluable patients were treated with ipilimumab (n = 16), BMS-936559 (n = 3), or nivolumab (n = 1). BOR at ≥ 4 mo included complete response (n = 2), partial response (n = 2), stable disease (n = 1), and progressive disease (n = 15). Response evaluations at SCAN-2 using RECIST 1.1, immune-related response criteria, PERCIST, and EORTC criteria demonstrated accuracies of 75%, 70%, 70%, and 65%, respectively, to predict BOR at ≥ 4 mo. Interestingly, the optimal PERCIST and EORTC threshold values at SCAN-2 to predict BOR were >15.5% and >14.7%, respectively. By combining anatomic and functional imaging data collected at SCAN-2, we developed criteria to predict eventual response to ICI with 100% sensitivity, 93% specificity, and 95% accuracy. Conclusion: Combining functional and anatomic imaging parameters from (18)F-FDG PET/CT scans performed early in ICI appears predictive for eventual response in patients with advanced melanoma. These findings require validation in larger cohorts. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

  10. Avaliação do perfil epidemiológico e da mortalidade dos pacientes com diagnóstico de melanoma cutâneo primário no município de Florianópolis - SC, Brasil Evaluation of the epidemiological profile and the mortality rate of the patients with primary cutaneous melanoma in Florianopolis - SC, Brazil

    Directory of Open Access Journals (Sweden)

    Rúbia Battisti

    2009-08-01

    Full Text Available FUNDAMENTOS: O melanoma é o câncer cutâneo com maior letalidade. Santa Catarina é o estado brasileiro com maior número de casos desse tumor. OBJETIVOS: Estimar a taxa de mortalidade por melanoma no quinto ano de doença. MÉTODOS: A amostra compreendeu 81 laudos de melanoma primário cutâneo, em 75 pacientes, emitidos em Florianópolis - SC em 2002 e 2003. O protocolo de pesquisa incluiu idade, sexo, cor do paciente e localização anatômica, tipo histológico, grau de invasão, índice de Breslow, infiltrado inflamatório, ulceração, regressão, invasão angiolinfática e estadiamento do tumor. Foi feito contato telefônico com os pacientes para verificar seu status (vivo, morto por melanoma ou morto por outra causa. Para análise estatística, utilizou-se o teste exato de Fisher e a curva de sobrevida de Kaplan-Meier. RESULTADOS: O perfil dos pacientes foi: feminino, branco, 51,3 anos, melanoma invasivo em tronco ou membros, tipo extensivo superficial, Breslow 2,63 mm. A taxa de mortalidade por melanoma cutâneo foi de 7,0%, maior entre homens (11,1%, com Breslow superior a 4,0 mm (66,0%, com ulceração (33,3% e em estádio IV (80,0%. A sobrevida média foi de 56,7 meses. Conclusões: A taxa de mortalidade por melanoma primário cutâneo foi de 7,0%, e a ulceração e o estadiamento final foram os fatores com significância estatística sobre o resultado.BACKGROUND: Melanoma is the cutaneous cancer which has the greatest lethality. Santa Catarina is the Brazilian State that contributes the most to increase this rate. OBJECTIVES: To estimate the mortality rate of melanoma in the fifth year of illness. METHODS: The sample comprises 81 reports of primary cutaneous melanoma, in 75 patients, diagnosed in lorianopolis - SC in 2002 and 2003. The protocol of research includes age, sex, patient's color, anatomical location, histological type, degree of invasion, Breslow index, inflammatory reaction, ulceration, regression, angiolymphatic

  11. Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity.

    Science.gov (United States)

    Bol, Kalijn F; Aarntzen, Erik H J G; Pots, Jeanette M; Olde Nordkamp, Michel A M; van de Rakt, Mandy W M M; Scharenborg, Nicole M; de Boer, Annemiek J; van Oorschot, Tom G M; Croockewit, Sandra A J; Blokx, Willeke A M; Oyen, Wim J G; Boerman, Otto C; Mus, Roel D M; van Rossum, Michelle M; van der Graaf, Chantal A A; Punt, Cornelis J A; Adema, Gosse J; Figdor, Carl G; de Vries, I Jolanda M; Schreibelt, Gerty

    2016-03-01

    Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients, predominantly with DC matured with pro-inflammatory cytokines and prostaglandin E2. We studied the safety and efficacy of vaccination with monocyte-derived DC matured with a cocktail of prophylactic vaccines that contain clinical-grade Toll-like receptor ligands (BCG, Typhim, Act-HIB) and prostaglandin E2 (VAC-DC). Stage III and IV melanoma patients were vaccinated via intranodal injection (12 patients) or combined intradermal/intravenous injection (16 patients) with VAC-DC loaded with keyhole limpet hemocyanin (KLH) and mRNA encoding tumor antigens gp100 and tyrosinase. Tumor antigen-specific T cell responses were monitored in blood and skin-test infiltrating-lymphocyte cultures. Almost all patients mounted prophylactic vaccine- or KLH-specific immune responses. Both after intranodal injection and after intradermal/intravenous injection, tumor antigen-specific immune responses were detected, which coincide with longer overall survival in stage IV melanoma patients. VAC-DC induce local and systemic CTC grade 2 and 3 toxicity, which is most likely caused by BCG in the maturation cocktail. The side effects were self-limiting or resolved upon a short period of systemic steroid therapy. We conclude that VAC-DC can induce functional tumor-specific responses. Unfortunately, toxicity observed after vaccination precludes the general application of VAC-DC, since in DC maturated with prophylactic vaccines BCG appears to be essential in the maturation cocktail.

  12. Inability of a Fusion Protein of IL-2 and Diphtheria Toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to Eliminate Regulatory T Lymphocytes in Patients With Melanoma

    Science.gov (United States)

    Attia, Peter; Maker, Ajay V.; Haworth, Leah R.; Rogers-Freezer, Linda; Rosenberg, Steven A.

    2006-01-01

    Summary Elimination of regulatory T lymphocytes may provide a way to break self-tolerance and unleash the anti-tumor properties of circulating lymphocytes. The use of fusion proteins, which link cytotoxic molecules to receptor targets, provides one approach to this problem. This study examined the ability of a fusion protein of interleukin-2 (IL-2) and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes based on their expression of high-affinity IL-2 receptors. Thirteen patients (12 with metastatic melanoma, 1 with metastatic renal cell carcinoma) were treated at one of the two Food and Drug Administration–approved doses of Denileukin Diftitox (seven patients at 9 μg/kg, six patients at 18 μg/kg). None of the patients experienced an objective clinical response. Foxp3 expression did not decrease significantly overall, although it did decrease minimally among patients receiving 18 μg/kg (−2.01 ± 0.618 copies of Foxp3/103 copies of β-actin; P = 0.031). Denileukin Diftitox did not decrease the suppressive ability of CD4+CD25+ cells as quantified by an in vitro co-culture suppression assay. Furthermore, the increased numbers of lymphocytes in patients resulting from treatment with IL-2 were not susceptible to Denileukin Diftitox. Administration of Denileukin Diftitox does not appear to eliminate regulatory T lymphocytes or cause regression of metastatic melanoma. PMID:16224276

  13. Current Research and Development of Chemotherapeutic Agents for Melanoma

    Directory of Open Access Journals (Sweden)

    Kyaw Minn Hsan

    2010-04-01

    Full Text Available Cutaneous malignant melanoma is the most lethal form of skin cancer and an increasingly common disease worldwide. It remains one of the most treatment-refractory malignancies. The current treatment options for patients with metastatic melanoma are limited and in most cases non-curative. This review focuses on conventional chemotherapeutic drugs for melanoma treatment, by a single or combinational agent approach, but also summarizes some potential novel phytoagents discovered from dietary vegetables or traditional herbal medicines as alternative options or future medicine for melanoma prevention. We explore the mode of actions of these natural phytoagents against metastatic melanoma.

  14. Braf V600E mutation in melanoma: translational current scenario.

    Science.gov (United States)

    Guadarrama-Orozco, J A; Ortega-Gómez, A; Ruiz-García, E B; Astudillo-de la Vega, H; Meneses-García, A; Lopez-Camarillo, C

    2016-09-01

    Melanoma was one of the translational cancer examples in clinic, including target therapy related to specific biomarkers impacting in the outcome of melanoma patients. Melanomagenesis involved a wide variety of mutations during his evolution; many of these mutated proteins have a kinase activity. One of the most cited proteins in melanoma is BRAF (about 50-60 % of melanomas harbors activating BRAF mutations), for these the most common is a substitution of valine to glutamic acid at codon 600 (p.V600E). Therefore, the precise identification of this underlying somatic mutation is essential; knowing the translational implications has opened a wide view of melanoma biology and therapy.

  15. Overcoming intrinsic multi-drug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1Bhigh cells

    Science.gov (United States)

    Roesch, Alexander; Vultur, Adina; Bogeski, Ivan; Wang, Huan; Zimmermann, Katharina M.; Speicher, David; Körbel, Christina; Laschke, Matthias W.; Gimotty, Phyllis A.; Philipp, Stephan E.; Krause, Elmar; Pätzold, Sylvie; Villanueva, Jessie; Krepler, Clemens; Fukunaga-Kalabis, Mizuho; Hoth, Markus; Bastian, Boris; Vogt, Thomas; Herlyn, Meenhard

    2013-01-01

    Summary Despite success with BRAFV600E–inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic multi-drug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (OXPHOS) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1Bhigh subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anti-cancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation. PMID:23764003

  16. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells.

    Science.gov (United States)

    Roesch, Alexander; Vultur, Adina; Bogeski, Ivan; Wang, Huan; Zimmermann, Katharina M; Speicher, David; Körbel, Christina; Laschke, Matthias W; Gimotty, Phyllis A; Philipp, Stephan E; Krause, Elmar; Pätzold, Sylvie; Villanueva, Jessie; Krepler, Clemens; Fukunaga-Kalabis, Mizuho; Hoth, Markus; Bastian, Boris C; Vogt, Thomas; Herlyn, Meenhard

    2013-06-10

    Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic multidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1B(high) subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anticancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. A rare case of rynopharyngeal melanoma

    Science.gov (United States)

    Grecchi, Francesco; Podrecca, Stefano; Zollino, Ilaria; Candotto, Valentina; Gallo, Francesco; Rubino, Giuseppe; Bianco, Raffaella; Carinci, Francesco

    2012-01-01

    Primary mucosal melanomas (MM) of the head and neck region constitute 0.5-2% of all malignant melanomas. The rynopharynx is a region that is less often involved by malignant melanomas. Because most of mucosal melanotic lesions are painless in their early stages, the diagnosis is unfortunately often delayed until symptoms resulting from ulceration, growth, and/or bleeding are noted. Here, we document the rare case of a malignant rynopharynx melanoma of a 43 year old woman. Its treatment and the pertinent literature are discussed. No complication was recorded in the post-operative period and no further surgery was performed. The follow up showed no recurrence in the same position and with the same characteristics, even after six years. Mucosal melanomas are aggressive tumours and the prognosis in these patients is poor. Clinicians must use treatment strategies that provide functional benefit, so as to maintain quality of life without excessive toxicity. PMID:23814590

  18. Progression of cutaneous melanoma: implications for treatment

    Science.gov (United States)

    Leong, Stanley P. L.; Mihm, Martin C.; Murphy, George F.; Hoon, Dave S. B.; Kashani-Sabet, Mohammed; Agarwala, Sanjiv S.; Zager, Jonathan S.; Hauschild, Axel; Sondak, Vernon K.; Guild, Valerie; Kirkwood, John M.

    2015-01-01

    The survival rates of melanoma, like any type of cancer, become worse with advancing stage. Spectrum theory is most consistent with the progression of melanoma from the primary site to the in-transit locations, regional or sentinel lymph nodes and beyond to the distant sites. Therefore, early diagnosis and surgical treatment before its spread is the most effective treatment. Recently, new approaches have revolutionized the diagnosis and treatment of melanoma. Genomic profiling and sequencing will form the basis for molecular taxonomy for more accurate subgrouping of melanoma patients in the future. New insights of molecular mechanisms of metastasis are summarized in this review article. Sentinel lymph node biopsy has become a standard of care for staging primary melanoma without the need for a more morbid complete regional lymph node dissection. With recent developments in molecular biology and genomics, novel molecular targeted therapy is being developed through clinical trials. PMID:22892755

  19. Pregnancy and melanoma.

    Science.gov (United States)

    Driscoll, Marcia S; Martires, Kathryn; Bieber, Amy Kalowitz; Pomeranz, Miriam Keltz; Grant-Kels, Jane M; Stein, Jennifer A

    2016-10-01

    Malignant melanoma is the most common malignancy during pregnancy, and is diagnosed during childbearing age in approximately one-third of women diagnosed with melanoma. The impact of hormonal changes during pregnancy and from iatrogenic hormones on melanoma is controversial. Women undergo immunologic changes during pregnancy that may decrease tumor surveillance. In addition, hormone receptors are found on some melanomas. In spite of these observations, the preponderance of evidence does not support a poorer prognosis for pregnancy-associated melanomas. There is also a lack of evidence that oral contraceptives or hormone replacement therapy worsens melanoma prognosis.

  20. Long-term treatment with the oncolytic ECHO-7 virus Rigvir of a melanoma stage IV M1c patient, a small cell lung cancer stage IIIA patient, and a histiocytic sarcoma stage IV patient-three case reports.

    Science.gov (United States)

    Alberts, Pēteris; Olmane, Evija; Brokāne, Linda; Krastiņa, Zanda; Romanovska, Māra; Kupčs, Kārlis; Isajevs, Sergejs; Proboka, Guna; Erdmanis, Romualds; Nazarovs, Jurijs; Venskus, Dite

    2016-10-01

    Oncolytic virotherapy is a recent addition to cancer treatment. Here, we describe positive treatment outcomes in three patients using Rigvir virotherapy. One of the patients is diagnosed with melanoma stage IV M1c, one with small cell lung cancer stage IIIA, and one with histiocytic sarcoma stage IV. The diagnoses of all patients are verified by histology or cytology. All patients started Rigvir treatment within a few months after being diagnosed and are currently continuing Rigvir treatment. The degree of regression of the disease has been determined by computed tomography. Safety assessment of adverse events graded according to NCI CTCAE did not show any value above grade 1 during Rigvir(®) treatment. Using current standard treatments, the survival of patients with the present diagnoses is low. In contrast, the patients described here were diagnosed 3.5, 7.0, and 6.6 years ago, and their condition has improved and been stabile for over 1.5, 6.5, and 4 years, respectively. These observations suggest that virotherapy using Rigvir can successfully be used in long-term treatment of patients with melanoma stage IV M1c, small cell lung cancer stage IIIA, and histiocytic sarcoma stage IV and therefore could be included in prospective clinical studies.

  1. Small bowel perforation caused by advanced melanoma.

    Science.gov (United States)

    den Uil, Sjoerd H; Thomassen, Irene; Vermeulen, Erik Gj; Vuylsteke, Ronald Jclm; Stockmann, Hein Bac; de Vries, Mattijs

    2014-01-01

    The incidence of melanoma has been increasing over the years and it remains, despite the heterogeneous survival for different stages, a disease with high mortality. Dissemination occurs primarily by the lymphatic route, followed by the hematogenous route. Gastrointestinal metastases do occur, but they are mainly intraluminal mucosal melanomas. Peritoneal or primary mucosal melanomas are rare. Only a few cases have been described of patients presenting with acute abdominal pain due to a melanoma. In this report we present a young patient with no prior health problems. Due to silent progression of disease at first, and secondarily avoidance of medical consultation, she finally presented to our emergency department with signs of intestinal perforation. In the operating theater a massive metastasis in the intestines with perforation was seen, as well as many smaller intra-abdominal and cutaneous lesions. Approximately 35 cm of jejunum had to be resected. Furthermore, the primary melanoma on the left forearm was excised and turned out to be in almost complete regression. Although initial recovery after surgery was good, the patient died only one month after presentation due to the advanced nature of her disease, which points to the devastating effect of undiagnosed melanoma and gastrointestinal metastasis. Since the melanoma incidence is rising, similar cases may present in the near future. This emphasizes the importance of proper full physical examination in patients with atypical abdominal symptoms.

  2. Future perspectives in melanoma research: meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014.

    Science.gov (United States)

    Ascierto, Paolo A; Atkins, Michael; Bifulco, Carlo; Botti, Gerardo; Cochran, Alistair; Davies, Michael; Demaria, Sandra; Dummer, Reinhard; Ferrone, Soldano; Formenti, Silvia; Gajewski, Thomas F; Garbe, Claus; Khleif, Samir; Kiessling, Rolf; Lo, Roger; Lorigan, Paul; Arthur, Grant Mc; Masucci, Giuseppe; Melero, Ignacio; Mihm, Martin; Palmieri, Giuseppe; Parmiani, Giorgio; Puzanov, Igor; Romero, Pedro; Schilling, Bastian; Seliger, Barbara; Stroncek, David; Taube, Janis; Tomei, Sara; Zarour, Hassane M; Testori, Alessandro; Wang, Ena; Galon, Jérôme; Ciliberto, Gennaro; Mozzillo, Nicola; Marincola, Francesco M; Thurin, Magdalena

    2015-11-30

    The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved

  3. Pathogenesis, diagnosis and management of primary melanoma of the colon

    Directory of Open Access Journals (Sweden)

    Imam Ayesha

    2011-02-01

    Full Text Available Abstract Background Melanomas within the alimentary tract are usually metastatic in origin. On the other hand, primary melanomas of the gastrointestinal tract are relatively uncommon. There are several published reports of melanomas occurring in the esophagus, stomach, small bowel, and anorectum. The occurrence of primary melanoma of the colon has, however, only been rarely reported. The optimum modus operandi for the management of primary colonic melanoma remains nebulous due to the limited number of reports in literature. Methods A comprehensive search of Medline, Cochrane and Highwire was performed using the following keywords: 'melanoma', 'malignant melanoma', 'primary melanoma', 'colon', 'gastrointestinal tract', 'alimentary tract', 'digestive tract', and 'large bowel'. All patients with primary melanoma localized to the colon were included in the review. Patients with metastatic melanomas to the gastrointestinal (GI tract and primary melanomas localized to the GI tract in anatomic locations other than colon were excluded. Results There have been only 12 reported cases of primary melanoma of the colon to date. The average age of patients on presentation was 60.4 years without any significant gender predilection. Right colon (33% and cecum (33% were the most common sites for the occurrence of primary colonic melanoma while abdominal pain (58% and weight loss (50% were the most common presenting complaints. Colonoscopy is the most reliable diagnostic investigation and offers the additional advantage of obtaining tissue for diagnosis. S-100 and HMB-45 are highly sensitive and specific for the diagnosis of this malignancy. For primary colonic melanomas that have not metastasized to any distant parts of the body, surgical resection with wide margins appears to be the treatment of choice. Although the management was individualized in every case, most of the authors preferred traditional hemicolectomy as the favored surgical approach

  4. Mistletoe in the treatment of malignant melanoma

    Directory of Open Access Journals (Sweden)

    Esin Sakallı Çetin

    2014-03-01

    Full Text Available Malignant melanoma is a malignant neoplasia drives from melanocytes. Malignant melanoma, the most causing death, is seen in the third place at skin cancer. Malignant melanoma shows intrinsic resistance to chemotherapeutic agents and variability in the course of the disease which are distinct features separating from other solid tumors. These features prevent the development and standardization of non-surgical treatment models of malignant melanoma. Although there is a large number of chemotherapeutic agents used in the treatment of metastatic malignant melanoma, it hasn’t been demonstrated the survival advantage of adjuvant treatment with chemotherapeutic agents. Because of the different clinical course of malignant melanoma, the disease is thought to be closely associated with immune system. Therefore, immunomodulatory therapy models were developed. Mistletoe stimulates the immune system by increasing the number and activity of dendritic cells, thus it has been shown to effect on tumor growth and metastasis of malignant melanoma patient. Outlined in this review are the recent developments in the understanding the role of mistletoe as a complementary therapy for malignant melanoma. J Clin Exp Invest 2014; 5 (1: 145-152

  5. The majority of patients with metastatic melanoma are not represented in pivotal phase III immunotherapy trials

    DEFF Research Database (Denmark)

    Donia, Marco; Kimper-Karl, Marie Louise; Høyer, Katrine Lundby

    2017-01-01

    in 2014, were included in the analysis. Seven pre-defined eligibility criteria, all used to select patients for enrolment in five recent randomised phase III immunotherapy trials, were analysed. Results Fifty-five percent of the total population with MM did not meet one or more eligibility criteria (‘not...... worse baseline prognostic features. However, patients treated with immunotherapy had similar survival outcomes regardless of eligibility. Conclusion Over half of the patients evaluated for systemic treatment of MM are not represented in phase III registration immunotherapy trials. The data reveal a huge...... knowledge gap regarding the usefulness of new immunotherapies in the ‘real-world’ patient population, and urge additional testing of known regimens in selected poor prognosis cohorts....

  6. Dynamic hyperinflation during activities of daily living in COPD patients.

    Science.gov (United States)

    Silva, Cláudia S; Nogueira, Fabiana R; Porto, Elias F; Gazzotti, Mariana R; Nascimento, Oliver A; Camelier, Aquiles; Jardim, José R

    2015-08-01

    The objective of this study was to investigate whether some activities of daily living (ADLs) usually related to dyspnea sensation in patients with chronic obstructive pulmonary disease (COPD) are associated with dynamic lung hyperinflation (DH) and whether the use of simple energy conservation techniques (ECTs) might reduce this possible hyperinflation. Eighteen patients (mean age: 65.8 ± 9.8 years) with moderate-to-severe COPD performed six ADLs (walking on a treadmill, storing pots, walking 56 meters carrying a 5-kilogram weight, climbing stairs, simulating taking a shower, and putting on shoes) and had their inspiratory capacity (IC) measured before and after each task. The patients were moderately obstructed with forced expiratory volume in 1 second (FEV1): 1.4 ± 0.4 L (50% ± 12.4); FEV1/forced vital capacity: 0.4 ± 8.1; residual volume/total lung capacity: 52.7 ± 10.2, and a reduction in IC was seen after all six activities (p < 0.05): (1) going upstairs, 170 mL; (2) walking 56 meters carrying 5 kilogram weight, 150 mL; (3) walking on a treadmill without and with ECT, respectively, 230 mL and 235 mL; (4) storing pots without and with ECT, respectively, 170 mL and 128 mL; (5) taking a shower without and with ECT, respectively, 172 mL and 118 mL; and (6) putting on shoes without and with ECT, respectively, 210 mL and 78 mL). Patients with moderate to severe COPD develop DH after performing common ADLs involving the upper and lower limbs. Simple ECTs may avoid DH in some of these ADLs.

  7. Hereditary Melanoma: Update on Syndromes and Management - Genetics of familial atypical multiple mole melanoma syndrome

    Science.gov (United States)

    Soura, E.; Eliades, P.; Shannon, K.; Stratigos, A.; Tsao, H.

    2015-01-01

    Malignant melanoma is considered the most lethal skin cancer if not detected and treated at its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (i.e. unilateral lineage, multi-generational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. Such patients have a high risk of developing multiple primary melanomas and internal organ malignancies especially pancreatic cancer; thus, a multidisciplinary approach is necessary in many cases. The value of dermoscopy examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. But, this must be performed with care and only by qualified individuals trained in cancer risk analysis. PMID:26892650

  8. Tumoral Melanosis Associated with Pembrolizumab-Treated Metastatic Melanoma

    Science.gov (United States)

    Cohen, Philip R

    2017-01-01

    Tumoral melanosis is a form of completely regressed melanoma that usually presents as darkly pigmented lesions suspicious for malignant melanoma. Histology reveals dense dermal and subcutaneous infiltration of melanophages. Pembrolizumab is an antibody directed against programmed death receptor-1 (PD1) and is frontline treatment for advanced melanoma. An 81-year-old man with metastatic melanoma treated with pembrolizumab who developed tumoral melanosis at previous sites of metastases is described. The PubMed database was searched with the key words: antibody, immunotherapy, melanoma, melanosis, metastasis, pembrolizumab, and tumoral. The papers generated by the search and their references were reviewed. The patient was initially diagnosed with lentigo maligna melanoma on the left cheek three years earlier, and he was treated with wide local excision. The patient was subsequently diagnosed with epidermotropic metastatic malignant melanoma on the left parietal scalp 14 months later and was treated with wide local excision. Three months later, the patient was found to have metastatic melanoma in the same area of the scalp and was started on pembrolizumab immunotherapy. The patient was diagnosed with tumoral melanosis in the site of previous metastases nine months later. The patient remained free of disease 13 months after starting pembrolizumab. Tumoral melanosis may mimic malignant melanoma; hence a workup, including skin biopsy, should be undertaken. Extensive tumoral melanosis has been reported with ipilimumab, and we add a case following treatment with pembrolizumab. Additional cases of tumoral melanosis may present since immunotherapy has become frontline therapy for advanced melanoma.  PMID:28348944

  9. Influence of {sup 18}F-FDG PET/CT on therapy management in patients with stage III/IV malignant melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Schuele, Susann-Cathrin; Nikolaou, Konstantin; Pfannenberg, Christina [Eberhard-Karls-University Tuebingen, Department of Diagnostic and Interventional Radiology, Tuebingen (Germany); Eigentler, Thomas Kurt; Garbe, Claus [Eberhard-Karls-University Tuebingen, Skin Cancer Programme, Department of Dermatology, Tuebingen (Germany); Fougere, Christian la [Eberhard-Karls-University Tuebingen, Department of Nuclear Medicine, Tuebingen (Germany)

    2016-03-15

    To evaluate the influence of {sup 18}F-FDG PET/CT in comparison to CT alone on treatment decisions in patients with advanced melanoma and to analyse the 5-year survival data in comparison to literature data. Therapy management in 64 consecutive patients (primary staging n = 52; surveillance n = 12) with stage III/IV melanoma who underwent {sup 18}F-FDG PET/CT between 2004 and 2005 in our department was retrospectively analysed. Treatment decisions were made by two dermatooncologists for each patient twice, first based on the CT results and then based on the PET/CT results. Therapy changes based on the PET/CT results were classified as ''major'' (e.g. change from metastasectomy to systemic therapy) or ''minor'' (e.g. change from first to second line chemotherapy). The 5-year survival data of different patient cohorts were calculated. In the 52 patients in the primary staging group, the results of {sup 18}F-FDG PET/CT led to therapy change in 59 % and a major therapy change in 52 %. {sup 18}F-FDG PET/CT led to the avoidance of futile operations in 13 patients with suspicious lesions on CT that were deemed nontumorous on PET/CT. In the 12 patients in the surveillance group, the results of {sup 18}F-FDG PET/CT led to therapy change in 33 % and a major change in 17 %. The 5-year survival rates were 30 % in the entire cohort, 34 % in the primary staging group, and 17 % in the surveillance group. A significant overall survival benefit was observed in patients in whom {sup 18}F-FDG PET/CT excluded metastases or in whom metastases could be completely removed compared with patients who were not eligible for surgery (41 % vs. 10 %). Primary staging of patients with stage III/IV melanoma should be performed with {sup 18}F-FDG PET/CT, leading to higher diagnostic accuracy and enabling individualized therapeutic management, especially optimal patient selection for metastasectomy. This strategy may extend long-term survival even in patients

  10. Pembrolizumab superior to ipilimumab in melanoma.

    Science.gov (United States)

    2015-06-01

    In the first randomized trial to compare FDA-approved immune checkpoint inhibitors as first-line therapy for patients with advanced melanoma, pembrolizumab yielded significantly better treatment outcomes than ipilimumab.

  11. Nivolumab-Based Treatments for Advanced Melanoma

    Science.gov (United States)

    A summary of results from an international, double-blind, randomized phase III trial testing the combination of nivolumab (Opdivo®) and ipilimumab (Yervoy®) against nivolumab alone and ipilimumab alone in patients with advanced