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1.
Dermatomyositis in a patient undergoing nivolumab therapy for metastatic melanoma: a case report and review of the literature.
Kosche, C, Stout, M, Sosman, J, Lukas, RV, Choi, JN
Melanoma research. 2020;(3):313-316
Abstract
Checkpoint inhibitor immunotherapy is a transformative treatment for advanced malignancies, but can be associated with numerous immune-related adverse events (irAEs). The majority of irAEs include those that closely resemble known cutaneous and neurocutaneous autoimmune or autoinflammatory diseases, such as scleroderma, psoriasis, and dermatomyositis. We present the case of a 63-year-old man with metastatic melanoma undergoing treatment with nivolumab who developed significant motor weakness, paresthesias of both hands, swollen fingers, and a pruritic rash over the face, chest, and upper back after two cycles. Creatine kinase was elevated. Electromyography revealed a myopathic pattern, muscle biopsy of the deltoid revealed an inflammatory myopathy, and skin biopsy showed interface dermatitis. There were no detectable autoantibodies except positive antinuclear antibody. He was diagnosed with immunotherapy-induced dermatomyositis, nivolumab was held, and he was treated with oral prednisone and intravenous immunoglobulin with overall improvement in myopathic and cutaneous symptoms. Dermatomyositis is an inflammatory myopathy with a characteristic dermatologic presentation that can occur spontaneously, as a paraneoplastic phenomenon, or as a drug reaction. This is the second known case of nivolumab-induced dermatomyositis. A review of the literature revealed seven total cases of immunotherapy-induced dermatomyositis. Functionally disabling autoimmune adverse effects of this severity would frequently persuade providers to discontinue immunotherapy in patients with metastatic disease.
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2.
Chemoprevention of Skin Carcinomas in High-Risk Transplant Recipients.
Savoia, P, Zavattaro, E, Cremona, O
Current medicinal chemistry. 2018;(6):687-697
Abstract
BACKGROUND Long-term immunosuppressive therapy, as provided to solid organ transplant recipients, inevitably results in a significant inhibition of immune defenses; this leads to frequent skin infections and malignancies, which represent an important cause of morbidity and mortality for transplanted patients. The incidence and risk of skin carcinomas are elevated in solid organ transplant recipients in comparison with the general population, with a 10-fold increased risk for basal cell carcinoma and a 50-100-fold for squamous cell carcinoma. The schedule of immunosuppressive drugs influences the type and timing of skin malignancies, but a crucial role is also played by endogenous and exogenous risk factors. METHODS & RESULTS Here, we will review the state-of-the-art in chemoprevention of epidermal carcinomas in order to provide useful information for clinicians involved in the management of transplant recipients. One-hundred and forteen paper, published on peerreviewed journals, has been included. CONCLUSION Chemoprevention would be key in controlling skin carcinogenesis in high-risk patients.
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3.
Nicotinamide for skin cancer chemoprevention.
Damian, DL
The Australasian journal of dermatology. 2017;(3):174-180
Abstract
Nicotinamide (vitamin B3 ) has a range of photoprotective effects in vitro and in vivo; it enhances DNA repair, reduces UV radiation-induced suppression of skin immune responses, modulates inflammatory cytokine production and skin barrier function and restores cellular energy levels after UV exposure. Pharmacological doses of nicotinamide have been shown to reduce actinic keratoses and nonmelanoma skin cancer incidence in high-risk individuals, making this a nontoxic and accessible option for skin cancer chemoprevention in this population.
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4.
Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review.
Gauci, ML, Laly, P, Vidal-Trecan, T, Baroudjian, B, Gottlieb, J, Madjlessi-Ezra, N, Da Meda, L, Madelaine-Chambrin, I, Bagot, M, Basset-Seguin, N, et al
Cancer immunology, immunotherapy : CII. 2017;(11):1399-1410
Abstract
Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect.
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5.
The Systemic Management of Advanced Melanoma in 2016.
Heppt, MV, Dietrich, C, Graf, SA, Ruzicka, T, Tietze, JK, Berking, C
Oncology research and treatment. 2016;(10):635-642
Abstract
Melanoma is a common type of skin cancer with a high propensity to metastasize. Tyrosine kinase inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway and immune checkpoint blockade have recently revolutionized the management of unresectable and metastatic disease. However, acquired resistance and primary non-response to therapy require novel treatment strategies and combinations. The purpose of this review is to provide a brief and up-to-date overview on the clinical management and current trial landscape in melanoma. We summarize the most pertinent studies on BRAF/MEK inhibitors and blockade of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Although most agents show robust antitumor efficacy as single agents, further improvements have been achieved by the combination of both approved and developing drugs. We discuss ongoing trials and evaluate future approaches that may provide additional efficacy with less toxicity.
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6.
Targeting damage-associated molecular pattern molecules (DAMPs) and DAMP receptors in melanoma.
Boone, BA, Lotze, MT
Methods in molecular biology (Clifton, N.J.). 2014;:537-52
Abstract
Damage-associated molecular pattern molecules (DAMPs) are proteins released from cells under stress due to nutrient deprivation, hypoxia, trauma, or treatment with chemotherapy, among a variety of other causes. When released, DAMPs activate innate immunity, providing a pathway to a systemic inflammatory response in the absence of infection. By regulating inflammation in the tumor microenvironment, promoting angiogenesis, and increasing autophagy with evasion of apoptosis, DAMPs facilitate cancer growth. DAMPs and DAMP receptors have a key role in melanoma pathogenesis. Due to their crucial role in the development of melanoma and chemoresistance, DAMPs represent intriguing targets at a time when novel treatments are desperately needed.
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7.
Germline melanoma susceptibility and prognostic genes: a review of the literature.
Ward, KA, Lazovich, D, Hordinsky, MK
Journal of the American Academy of Dermatology. 2012;(5):1055-67
Abstract
In recent years, there have been increasing efforts to identify germline genetic variants that may alter melanoma susceptibility and prognosis. The findings of these studies have indicated the presence of rare, high-penetrance alleles with large effects, such as CDKN2A and CDK4, more common, moderately penetrant genes like MC1R, and very common, low-penetrance polymorphisms with small effects that are related to pigmentation, nevus count, immune responses, DNA repair, metabolism, and the vitamin D receptor. The study of these low-penetrance single nucleotide polymorphisms is relatively new; thus many of them are termed 'candidate melanoma susceptibility or prognostic genes.' This review summarizes the research on germline polymorphisms that have been implicated in melanoma susceptibility and prognosis in order to provide a framework for additional studies to meet the ultimate goal of predicting a patient's risk of, and prognosis in, cutaneous malignant melanoma.
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8.
The effects of gp100 and tyrosinase peptide vaccinations on nevi in melanoma patients.
Cassarino, DS, Miller, WJ, Auerbach, A, Yang, A, Sherry, R, Duray, PH
Journal of cutaneous pathology. 2006;(5):335-42
Abstract
BACKGROUND A new approach to prevent disease recurrence in high-risk melanoma patients involves immunization with gp100 and tyrosinase peptides. This is the first study to examine the effects of such treatments on nevi. DESIGN We studied biopsies of 'clinically atypical' nevi from 10 patients before and after peptide vaccination. All had a cutaneous melanoma measuring at least 1.5 mm in depth, satellite metastases, or at least one positive lymph node. We performed immunohistochemical stains for CD3, CD4, CD8, MHC-I, MHC-II, CD1a, HMB-45, MART-1, tyrosinase, bcl-2, p53, and Ki-67 (mib-1). RESULTS Immunohistochemistry showed no differences in staining due to vaccination in either the immunologic or melanocytic markers. However, there was a significant increase in both p53 and bcl-2 staining, and a trend toward decreased Ki-67 staining, in the nevi post-treatment. DISCUSSION The primary goal of peptide vaccinations with gp100 and tyrosinase is to activate melanoma-specific T cells in order to prevent melanoma recurrence. Nevi were studied in order to assess the effects on benign melanocytes. No significant changes in lymphocytes, langerhans cells, expression of MHC antigens, or melanocytic markers were found. The increase in p53 and bcl-2 raises the possibility that vaccination with melanocytic antigens stimulates a response in benign melanocytes.
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9.
Photochemoprevention of ultraviolet B signaling and photocarcinogenesis.
Afaq, F, Adhami, VM, Mukhtar, H
Mutation research. 2005;(1-2):153-73
Abstract
Exposure to solar radiation, particularly its ultraviolet (UV) B component, has a variety of harmful effects on human health. Some of these effects include sunburn cell formation, basal and squamous cell cancers, melanoma, cataracts, photoaging of the skin, and immune suppression. Amongst these various adverse effects of UV radiation, skin cancer is of the greatest concern. Over the years, changes in lifestyle has led to a significant increase in the amount of UV radiation that people receive, and this consequently has led to a surge in the incidence of skin cancer. The development of skin cancer is a complex multistage phenomenon involving three distinct stages exemplified by initiation, promotion and progression stages. Each of these stages is mediated via alterations in various cellular, biochemical, and molecular changes. Initiation, the first step in the carcinogenesis process is essentially an irreversible step in which genetic alterations occur in genes that ultimately leads to DNA modification and fixation of mutation. Tumor promotion is the essential process in cancer development involving clonal expansion of initiated cells giving rise to pre-malignant and then to malignant lesions, essentially by alterations in signal transduction pathways. Tumor progression involves the conversion of pre-malignant and malignant lesions into an invasive and potentially metastatic malignant tumor. All these processes for skin cancer development involve stimulation of DNA synthesis, DNA damage and proliferation, inflammation, immunosuppression, epidermal hyperplasia, cell cycle dysregulation, depletion of antioxidant defenses, impairment of signal transduction pathways, induction of cyclooxygenase, increase in prostaglandin synthesis, and induction of ornithine decarboxylase. Photochemoprevention has been appreciated as a viable approach to reduce the occurrence of skin cancer and in recent years, the use of agents, especially botanical antioxidants, present in the common diet and beverages consumed by human population have gained considerable attention as photochemopreventive agents for human use. Many such agents have also found a place in skin care products. Although this is more common in oriental countries, its popularity is significantly growing in western countries. In this article, we have summarized the available information of laboratory studies on UVB-mediated signaling that can be exploited as targets for photochemoprevention. We suggest that the use of skin care products supplemented with proven chemopreventive agents in conjunction with the use of sunscreens along with educational efforts may be an effective strategy for reducing UV-induced photodamage and skin cancer in humans. The mechanistic basis for the use of such products is discussed.
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10.
[Laboratory markers of melanoma progression].
Bánfalvi, T, Edesné, MB, Gergye, M, Udvarhelyi, N, Orosz, Z, Gilde, K, Kremmer, T, Ottó, S, Tímár, J
Magyar onkologia. 2003;(1):89-104
Abstract
Extracellular tumour markers may have potential role in the follow-up of patients with malignant melanoma, in therapy monitoring and in prediction of prognosis. In our article circulating tumour markers in melanoma (melanoma inhibitory activity, lipid bound sialic acid, neuron specific enolase, TA90 immune complex, S-100B protein, 5-S-cysteinyldopa, tyrosinase, cytokines, metalloproteinases, LDH) were reviewed. Among laboratory melanoma markers the S-100B protein is the most investigated. S-100B protein has high specificity, appropriate sensitivity and proved to be significant prognostic factor independent from stages. High serum values are associated with shorter survival. However, before S-100B monitoring immunohistochemistry for the detection of S-100B is required. In the case of malignant melanomas with low expression serum S-100B monitoring may not be sensitive enough to follow disease progression. Although the serum concentration of 5-S-cysteinyldopa did not prove to be independent prognostic factor in our previous studies comprising the highest patient number in the literature, the marker was suggested for therapy monitoring. The survival analysis indicated that the elevated 5-S-cysteinyldopa level predicts shorter survival. In spite of the calculated low correlation between the two markers, parallel elevation of S-100B protein and 5-S-cysteinyldopa indicated shorter survival. On the basis of the literature LDH is the most appropriate tumour marker in stage IV to predict prognosis, but its sensitivity and specificity could not achieve that of S-100B protein. S-100B and LDH proved to be similarly reliable in respect to the clinical outcome. Determination of serum concentration of MIA and tyrosinase are also reliable markers in malignant melanoma. The other investigated markers are not well known yet or do not provide useful information to the clinicians.