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Lorenz, Anna, Mateusz Kozłowski, Sebastian Lenkiewicz, Sebastian Kwiatkowski, and Aneta Cymbaluk-Płoska. "Cutaneous Melanoma versus Vulvovaginal Melanoma—Risk Factors, Pathogenesis and Comparison of Immunotherapy Efficacy." Cancers 14, no. 20 (October 19, 2022): 5123. http://dx.doi.org/10.3390/cancers14205123.
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Cutaneous melanoma is a relatively common neoplasm, with fairly well understood pathogenesis, risk factors, prognosis and therapeutic protocols. The incidence of this disease is increasing every year. The situation is different for rare malignancies such as vulvar melanomas and for the even rarer vaginal melanomas. The risk factors for vulvovaginal tumors are not fully understood. The basis of treatment in both cases is surgical resection; however, other types of treatments such as immunotherapy are available. This paper focuses on comparing the pathogenesis and risk factors associated with these neoplasms as well as the efficacy of two groups of drugs—anti-PD-L1 and anti-CTLA4 inhibitors—against both cutaneous melanoma and melanoma of the lower genital tract (vulva and vagina). In the case of cutaneous melanoma, the situation looks more optimistic than for vulvovaginal melanoma, which has a much worse prognosis and, as it turns out, shows a poorer response to immune therapy.
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Ascierto, Paolo A., John M. Kirkwood, Francesco M. Marincola, and Giuseppe Palmieri. "Melanoma: From Research to Treatment." Journal of Skin Cancer 2011 (2011): 1–2. http://dx.doi.org/10.1155/2011/710697.
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Carbó-Bagué, Anna, Jordi Rubió-Casadevall, Montserrat Puigdemont, Arantza Sanvisens, Glòria Oliveras, Mònica Coll, Bernat del Olmo, Ferran Perez-Bueno, and Rafael Marcos-Gragera. "Epidemiology and Molecular Profile of Mucosal Melanoma: A Population-Based Study in Southern Europe." Cancers 14, no. 3 (February 3, 2022): 780. http://dx.doi.org/10.3390/cancers14030780.
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Background: Mucosal melanoma is a rare neoplasm on which few epidemiological population-based studies have been published. A good surgical approach is the standard treatment, but the prognosis is worse than that of skin melanoma. The analysis of mucosal melanoma’s mutational profile can help to develop target therapies in advanced disease or adjuvant settings. Methods: We analyzed the database of the Cancer Registry of Girona, a region located in the north-east of Spain, in the period of 1994–2018. We selected cases of primary invasive melanoma, excluding those located in the skin, eye, central nervous system and an unknown primary site. Epidemiological analysis included incidence and survival. Mutational profile analysis was performed with a custom gene panel. Results: Forty-two patients were identified: 14 (33%) had vulvar-vaginal melanoma, 15 (35.7%) had rectal melanoma, 12 (28.6%) had melanoma located in the head and neck sphere and 1 male patient had a urethral melanoma. European age-standardized incidence rates for vulvar-vaginal, rectal and head and neck melanoma were 0.09, 0.1 and 0.09 cases/100,000 inhabitant-years, respectively. Five-year observed survival rates were 37.5%, 20% and 25% for these types of cancers. NRAS Q61 was the most frequent mutation found. Conclusion: Our study confirms the steady incidence and low survival of mucosal melanomas in a region of southern Europe. NRAS and NF1 play a role in the molecular landscape of mucosal melanoma. MEK and PI3K/mTOR inhibitors could be reasonable treatment options and are being studied in clinical trials.
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Chacón, Matías, Yanina Pfluger, Martín Angel, Federico Waisberg, and Diego Enrico. "Uncommon Subtypes of Malignant Melanomas: A Review Based on Clinical and Molecular Perspectives." Cancers 12, no. 9 (August 21, 2020): 2362. http://dx.doi.org/10.3390/cancers12092362.
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Malignant melanoma represents the most aggressive type of skin cancer. Modern therapies, including targeted agents and immune checkpoint inhibitors, have changed the dismal prognosis that characterized this disease. However, most evidence was obtained by studying patients with frequent subtypes of cutaneous melanoma (CM). Consequently, there is an emerging need to understand the molecular basis and treatment approaches for unusual melanoma subtypes. Even a standardized definition of infrequent or rare melanoma is not clearly established. For that reason, we reviewed this challenging topic considering clinical and molecular perspectives, including uncommon CMs—not associated with classical V600E/K BRAF mutations—malignant mucosal and uveal melanomas, and some unusual independent entities, such as amelanotic, desmoplastic, or spitzoid melanomas. Finally, we collected information regarding melanomas from non-traditional primary sites, which emerge from locations as unique as meninges, dermis, lymph nodes, the esophagus, and breasts. The aim of this review is to summarize and highlight the main scientific evidence regarding rare melanomas, with a particular focus on treatment perspectives.
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Huang, Yu-Yun, Tzu-Yu Hou, Wei-Kuang Yu, Chieh-Chih Tsai, Shu-Ching Kao, Wen-Ming Hsu, and Jui-Ling (Catherine) Liu. "The Clinical Feature and Treatment Outcome of Ocular Melanoma: A 34-Year Experience in a Tertiary Referral Center." Cancers 13, no. 23 (November 25, 2021): 5926. http://dx.doi.org/10.3390/cancers13235926.
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Malignant melanoma can arise from melanocytes in various structures of the eye, orbit, and ocular adnexa. We reviewed the clinical features and long-term results of all subjects with histologically proved melanoma originating from any of the ocular and periocular structures in a tertiary referral center. Overall, 88 patients including 47 men were recruited. The tumor was primarily located in the uvea, followed by the conjunctiva, orbit, eyelid, and lacrimal sac. Patients with uveal melanoma were diagnosed at a relatively younger age (47.0 years), while those with orbital and eyelid melanomas were older at presentation (79.5 years and 78.5 years, respectively). The overall local recurrence rate was 9% at a median follow-up of 41.0 months, among which orbital and eyelid melanomas recurred most commonly. The overall mortality rate was 41% in a median duration of 27.2 months (IQR, 13–58 months) from diagnosis, with the highest for lacrimal sac melanoma, followed by melanoma of the orbit, uveal, conjunctiva, and eyelid. Despite prompt local control, the risk for metastasis and mortality was high. Therefore, efficient modalities for early diagnosis and treatment of ocular melanoma are necessary.
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Song, Jung Min, Joel Daniel Marcus, Carolyn Stanek, Michael J. McNamara, Brian Gastman, Ahmad A. Tarhini, and Pauline Funchain. "Single center experience of dermatologic and oncologic surveillance patterns for late stage melanomas that progressed from early stage melanoma." Journal of Clinical Oncology 36, no. 7_suppl (March 1, 2018): 182. http://dx.doi.org/10.1200/jco.2018.36.7_suppl.182.
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182 Background: Recent data suggests a greater proportion and greater absolute number of thin (T1) melanomas contribute to melanoma death than thicker melanomas (Whiteman et al., J Invest Dermatol 2015). NCCN guidelines for early stage melanoma, defined as stages IA-IIA, suggest at least yearly skin check and H&P, but do not specify if dermatologic and/or oncologic surveillance should be pursued. Methods: We reviewed internal and external records of 16 consecutive patients with new, non-de novo diagnoses of unresectable stage III or IV melanoma undergoing active cancer treatment, i.e. late stage melanoma, from 2016-2017 that had progressed from a preceding primary early stage (IA-IIA) melanoma. Results: Primary early stage melanomas were diagnosed a median of 10.5 years (range, 4 to 29) prior to advanced disease progression. Two of 16 patients (13%) had oncologic follow up. Seven (44%) had continuous dermatology follow-up, of which 6 (38%) were followed only by dermatology. Only one patient had both dermatology and oncology follow-up at the time of progression. Follow up could not be determined for 8 patients due to lack of sufficient records, it is notable however that these 8 (50%) were not following dermatology or oncology at the time of progression. Conclusions: Only a small minority of patients who progressed from early stage melanoma to advanced stage melanoma requiring treatment were followed regularly by medical oncology, despite half having at least regular dermatology follow-up. We conclude that survivorship plans are important for early stage melanomas, and there is a need to effectively educate a larger early stage melanoma population about the infrequent but real oncologic issue of progressing to late stage melanoma.
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Kasakovski, Dimitri, Marina Skrygan, Thilo Gambichler, and Laura Susok. "Advances in Targeting Cutaneous Melanoma." Cancers 13, no. 9 (April 26, 2021): 2090. http://dx.doi.org/10.3390/cancers13092090.
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To date, the skin remains the most common cancer site among Caucasians in the western world. The complex, layered structure of human skin harbors a heterogenous population of specialized cells. Each cell type residing in the skin potentially gives rise to a variety of cancers, including non-melanoma skin cancer, sarcoma, and cutaneous melanoma. Cutaneous melanoma is known to exacerbate and metastasize if not detected at an early stage, with mutant melanomas tending to acquire treatment resistance over time. The intricacy of melanoma thus necessitates diverse and patient-centered targeted treatment options. In addition to classical treatment through surgical intervention and radio- or chemotherapy, several systemic and intratumoral immunomodulators, pharmacological agents (e.g., targeted therapies), and oncolytic viruses are trialed or have been recently approved. Moreover, utilizing combinations of immune checkpoint blockade with targeted, oncolytic, or anti-angiogenic approaches for patients with advanced disease progression are promising approaches currently under pre-clinical and clinical investigation. In this review, we summarize the current ‘state-of-the-art’ as well as discuss emerging agents and regimens in cutaneous melanoma treatment.
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Lyle, Megan, and Georgina V. Long. "Diagnosis and Treatment ofKIT-Mutant Metastatic Melanoma." Journal of Clinical Oncology 31, no. 26 (September 10, 2013): 3176–81. http://dx.doi.org/10.1200/jco.2013.50.4662.
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A 52-year-old man has unresectable locally recurrent melanoma of the left foot ( Fig 1 ) and pulmonary metastases. Nine months before this presentation, he underwent a wide local excision and sentinel node biopsy for an acral melanoma on his left heel. Pathology disclosed Breslow thickness of 4.8 mm, Clark level IV, and tumor ulceration with a mitotic rate of 37 mitoses/mm2. Both sentinel nodes in the left groin were positive for melanoma cells, which expressed S100, HMB45, and melan A. At subsequent left inguinal dissection, seven more nodes showed no additional nodal metastases. Within 3 months of his original surgery, the patient developed a local recurrence in the foot, and over the subsequent 6 months, he underwent serial local excisions and topical diphencyprone treatment. A recent staging scan showed at least 20 foci of in-transit disease in the left lower leg and foot, as well as a solitary lung metastasis (12 mm). His Eastern Cooperative Oncology Group performance status is 1, with no significant comorbidities. High-resolution melt followed by sequencing of an in-transit metastasis showed there is no BRAF exon 15 mutation. However, Sanger sequencing of KIT exons 9, 11, 13, and 17, performed as screening for a clinical trial enrolling patients with metastatic acral and mucosal melanomas, showed an exon 13 K642E mutation.
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Satish, Tejus, Shaheer Khan, Matt Levin, Richard Carvajal, and Angela J. Yoon. "Treatment of recurrent mucosal melanoma of the oral cavity with topical imiquimod and pembrolizumab achieves complete histopathologic remission." Journal for ImmunoTherapy of Cancer 9, no. 10 (October 2021): e001219. http://dx.doi.org/10.1136/jitc-2020-001219.
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Mucosal melanomas constitute a subtype of melanoma with less effective treatments than cutaneous melanomas. We present a case of oral mucosal melanoma that recurred despite multiple resections and adjuvant temozolomide. Treatment with topical imiquimod combined with pembrolizumab achieved remission. A 56-year-old woman presented with a pigmented mass on her left anterior hard palate. Biopsy revealed malignant melanoma. The patient had resection with neck dissection with 3 months of adjuvant temozolomide due to positive margins. Malignant melanoma involving the hard palate recurred 1 year later requiring additional resection. Two years later, two additional pigmented lesions were found; further resections were deferred due to expected morbidity. Following 6 weeks of topical imiquimod treatment, the lesions shrunk significantly. Adjuvant pembrolizumab was added and complete histopathologic remission was observed in 6 months. The patient remained in remission for 4 years before new melanoma in situ was diagnosed, requiring five additional months of imiquimod. As of April 2021, there is no clinical evidence of melanoma. There are limited reports of oral melanoma treated with topical imiquimod. Here, imiquimod administered in combination with pembrolizumab achieved complete pathologic response.
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Varghese, Sruthy, Snigdha Pramanik, Rishika Prasad, Hannah Hodges, Leila Williams, Weiyi Peng, Hussein Tawbi, and Vashisht Yennu Nanda. "Abstract PR06: The glutaminase inhibitor CB-839 potentiates antimelanoma activity of standard-of-care targeted therapies and immunotherapies." Cancer Research 80, no. 19_Supplement (October 1, 2020): PR06. http://dx.doi.org/10.1158/1538-7445.mel2019-pr06.
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Abstract Nearly all metastatic melanoma patients who respond to targeted therapies will relapse with the disease within a year. Although more durable responses are seen with immune therapies, about half of the melanoma patients do not respond to them, and a significant number of responders eventually relapse. Most relapsed melanomas also exhibit post-treatment resistance to these treatments. Hence, there is a clear and present need to develop therapeutics that counteract resistance associated with relapse. We and others earlier showed that melanomas with elevated mitochondrial activity possess improved cellular rigor and are intrinsically resistant to the antitumor effects of BRAF and MEK inhibitors. In many other instances, melanomas that initially respond to these inhibitors acquire resistance by elevating mitochondrial activity. Mitochondrial activity is elevated in part by increased cellular uptake of glutamine, and its conversion to alpha-ketoglutarate in the TCA cycle, with glutaminase enzyme playing a rate-limiting role. In this study, we show that BRAFV600E-mutant melanomas with intrinsic or acquired resistance to MAPK pathway inhibitors have lower glucose uptake and increased glutamine uptake compared to those that are sensitive. Treatment of these resistant melanomas with single-agent glutaminase inhibitor, CB-839, moderately inhibited their growth. However, a more robust inhibition of their growth was achieved when CB-839 was combined with BRAF and MEK inhibitors. In addition, CB-839 increased the in vivo activity of tumor-infiltrating lymphocytes (TILs) in a mouse vaccine model and also enhanced the proapoptotic effect of human autologous patient-derived TILs on their cognate melanoma cells. Seahorse bioenergetics stress tests showed that CB-839 inhibited mitochondrial OxPhos in tumor cells to a greater extent than in activated TILs. Additional molecular studies are currently in progress. A recent clinical trial in melanoma patients showed that combination treatment with CB-839 and the immune checkpoint blocker, nivolumab, caused an objective response in three melanoma patients who had earlier progressed on treatment with immune checkpoint blockade. Our preclinical results complement this clinical finding and suggest that CB-839 combination could potentiate the efficacy of targeted and immune therapies in refractory melanomas. Citation Format: Sruthy Varghese, Snigdha Pramanik, Rishika Prasad, Hannah Hodges, Leila Williams, Weiyi Peng, Hussein Tawbi, Vashisht Yennu Nanda. The glutaminase inhibitor CB-839 potentiates antimelanoma activity of standard-of-care targeted therapies and immunotherapies [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR06.
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Funck-Brentano, Elisa, Estelle Charvet, Louise Chaplain, Amelie Gantzer, Oula Kassem, Christine Longvert, Astrid Blom, et al. "Second primary melanoma in advanced melanoma patients treated with anti-PD-1 monoclonal antibodies." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e22025-e22025. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e22025.
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e22025 Background: Development of a second primary melanoma (SCPM) has not been reported in melanoma patients treated with anti-PD-1 monoclonal antibodies (mAb), in contrast with those reported in BRAF-inhibitor-treated patients. Our aim was to report arising SCPM in patients with advanced melanoma treated with anti-PD-1 therapy. Methods: Retrospective study, conducted in 2 referral centres, including advanced melanoma patients who developed a SCPM after anti-PD-1 mAb initiation, between September 2010 and May 2019. BRAF or NRAS mutational status was assessed by targeted NGS panels, real-time PCR, and immunohistochemistry. Results: Among a total of 509 patients treated with anti-PD-1 mAb, 4 had a SCPM (incidence: 0.8%; 95%CI: 0.02-1.57%). All patients were treated with nivolumab, in first (N = 3) or second line after progression with BRAF + MEK inhibitors (N = 1). No immune-related adverse event greater than grade 2 according to Common Terminology Criteria for Adverse Events version 5.0. was observed in these 4 cases; a vitiligo-like depigmentation (grade 1) was observed in two patients. The median time from the first nivolumab infusion to the SCPM diagnosis was 17.5 months (range: 5-21). All patients developed the SCPM after achieving a complete response. Nivolumab administration had been discontinued (4 months prior) in one patient. Histology revealed 4 superficial spreading melanomas (SSM): one invasive (without BRAFV600 mutation) and 3 intraepidermal melanomas (2 with a BRAFV600E mutation and one with a NRASQ61H mutation). 3 patients had risk factors for developing multiple melanomas: a dysplastic nevus syndrome, a high number of nevi (≥100 nevi), and a family history of melanoma in first-degree relatives and constitutional heterozygous mutation of exon 2 of the CDKN2A gene. Occurrence of SPCM did not alter advanced melanoma treatment. With a median follow-up of 29 months [range: 18-41] from the first anti-PD-1 mAb infusion, all patients had prolonged CR, and treatment was discontinued in all patients, without relapse after a median 11.5 months [0-18] off therapy. The median duration of nivolumab treatment was 15.5 months [10-24]. Conclusions: Although anti-PD-1 mAb could theoretically decrease the risk of developing another melanoma in metastatic melanoma patients, we found 4 such cases, highlighting the importance of regular clinical screenings for new primary melanoma in patients with metastatic melanoma even when responsive to anti-PD-1 therapy. Immune checkpoint inhibitors do not totally prevent the risk of occurrence a SCPM.
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Bishop, Kenneth D., and Adam J. Olszewski. "Melanoma of ocular, mucosal, and genital sites: Epidemiology and survival outcomes." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 9051. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.9051.
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9051 Background: Melanomas arising from noncutaneous sites are rare entities with poorly defined staging, prognosis and no evidence-based treatment guidelines. Methods: We analyzed melanoma cases in the Surveillance, Epidemiology and End Results database between 1988 and 2007. Differences in clinical and pathologic features, treatment, and mortality were studied according to primary site of disease. The risk of melanoma-related death was calculated from life tables based on expected survival. Relative survival was compared in a multivariable parametric model using individual data. Results: We identified 209,861 cases of melanoma, of which 9,267 (4.4%) were noncutaneous. These were notable for older age, higher proportion of women, racial minorities, and advanced-stage disease. Mortality was high, even in subgroups with localized stage at diagnosis. Mucosal melanomas of the gastrointestinal and genitourinary tract had the highest excess mortality hazard ratios (HR) in the multivariate model. A substantial proportion of patients underwent organ-specific radical resection (32% eye enucleation, 40% radical head/neck surgery, 31% gastrectomy, 23% abdominoperineal resection). Conclusions: Melanoma arising from mucosal sites portends markedly worse prognosis than cutaneous melanoma. Prospective studies of systemic adjuvant treatment are needed for this disease, which is rarely curable even with aggressive local therapy. [Table: see text]
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Majem, M., J. L. Manzano, I. Marquez-Rodas, K. Mujika, E. Muñoz-Couselo, E. Pérez-Ruiz, L. de la Cruz-Merino, E. Espinosa, M. Gonzalez-Cao, and A. Berrocal. "SEOM clinical guideline for the management of cutaneous melanoma (2020)." Clinical and Translational Oncology 23, no. 5 (March 2, 2021): 948–60. http://dx.doi.org/10.1007/s12094-020-02539-9.
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AbstractMelanoma affects about 6000 patients a year in Spain. A group of medical oncologists from Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines to homogenize the management of these patients. The diagnosis must be histological and determination of BRAF status has to be performed in patients with stage ≥ III. Stage I–III resectable melanomas will be treated surgically. In patients with stage III melanoma, adjuvant treatment with immunotherapy or targeted therapy is also recommended. Patients with unresectable or metastatic melanoma will receive treatment with immunotherapy or targeted therapy, the optimal sequence of these treatments remains unclear. Brain metastases require a separate consideration, since, in addition to systemic treatment, they may require local treatment. Patients must be followed up closely to receive or change treatment as soon as their previous clinical condition changes, since multiple therapeutic options are available.
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Weber, Daniela D., Maheshwor Thapa, Sepideh Aminzadeh-Gohari, Anna-Sophia Redtenbacher, Luca Catalano, René G. Feichtinger, Peter Koelblinger, et al. "Targeted Metabolomics Identifies Plasma Biomarkers in Mice with Metabolically Heterogeneous Melanoma Xenografts." Cancers 13, no. 3 (January 23, 2021): 434. http://dx.doi.org/10.3390/cancers13030434.
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Melanomas are genetically and metabolically heterogeneous, which influences therapeutic efficacy and contributes to the development of treatment resistance in patients with metastatic disease. Metabolite phenotyping helps to better understand complex metabolic diseases, such as melanoma, and facilitates the development of novel therapies. Our aim was to characterize the tumor and plasma metabolomes of mice bearing genetically different melanoma xenografts. We engrafted the human melanoma cell lines A375 (BRAF mutant), WM47 (BRAF mutant), WM3000 (NRAS mutant), and WM3311 (BRAF, NRAS, NF1 triple-wildtype) and performed a broad-spectrum targeted metabolomics analysis of tumor and plasma samples obtained from melanoma-bearing mice as well as plasma samples from healthy control mice. Differences in ceramide and phosphatidylcholine species were observed between melanoma subtypes irrespective of the genetic driver mutation. Furthermore, beta-alanine metabolism differed between melanoma subtypes and was significantly enriched in plasma from melanoma-bearing mice compared to healthy mice. Moreover, we identified beta-alanine, p-cresol sulfate, sarcosine, tiglylcarnitine, two dihexosylceramides, and one phosphatidylcholine as potential melanoma biomarkers in plasma. The present data reflect the metabolic heterogeneity of melanomas but also suggest a diagnostic biomarker signature for melanoma screening.
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Freiberger, Sandra N., Grégoire B. Morand, Patrick Turko, Ulrich Wager, Reinhard Dummer, Martin Hüllner, David Holzmann, Niels J. Rupp, and Mitchell P. Levesque. "Morpho-Molecular Assessment Indicates New Prognostic Aspects and Personalized Therapeutic Options in Sinonasal Melanoma." Cancers 11, no. 9 (September 7, 2019): 1329. http://dx.doi.org/10.3390/cancers11091329.
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Sinonasal melanoma is a rare subtype of melanoma and little is known about its molecular fingerprint. Systemic treatment options are limited, as targetable BRAF mutations are rare compared to cutaneous melanoma. Currently, metastatic sinonasal melanoma is being treated according to the guidelines of cutaneous melanoma. In this study, we investigated the molecular profile of 19 primary sinonasal melanomas, using a novel customized melanoma-specific next generation sequencing (NGS) panel (MelArray) of 190 genes. Results were correlated to histological and clinical features to further characterize this rare, aggressive type of melanoma and screen for prognostic markers and possible treatment options. Molecular profiles encompassed predominantly mutations in NRAS (25%), whereas KIT or BRAF p.V600 mutations were not detected. Tumor mutational burden was overall low. High level of copy number variations (CNVs) were associated with alterations in DNA-repair genes and shorter distant metastasis-free survival (p = 0.005). Monomorphic (vs. pleomorphic) morphology was found to be significantly associated with worse disease-specific survival (p < 0.001), however no correlation between morphology and molecular aberrations was found. A variety of alterations in different pathways were detected, justifying molecular testing and opening potential personalized treatment options in current study or compassionate use settings.
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Liu, Can, Si-Qi He, Xiao-Qing Chen, Hui-Qing Xie, Yong Chen, Rui Liu, Ke Cao, and Jian-Da Zhou. "Research Advances in the Treatment of Melanoma by Treat Melanoma." Current Topics in Medicinal Chemistry 16, no. 2 (September 22, 2015): 242–50. http://dx.doi.org/10.2174/1568026615666150812121439.
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Bok, Ilah, Jordan Reff, Arianna Nenci, Jose G. Gonzalez, and Florian A. Karreth. "Abstract A17: A versatile mouse-modeling platform for rapid in vivo melanoma studies." Cancer Research 80, no. 19_Supplement (October 1, 2020): A17. http://dx.doi.org/10.1158/1538-7445.mel2019-a17.
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Abstract Melanoma accounts for about 1% of skin cancers but causes the majority of skin cancer-related deaths. Despite progress in treating melanoma with immunotherapy and targeted therapy, melanoma patients still suffer from relapse due to resistance to these treatments. A better understanding of the molecular mechanisms that contribute to melanomagenesis and resistance may provide novel avenues for the development of improved treatment strategies. To accelerate the speed, increase the throughput, and lower the cost of delineating such mechanisms in vivo, we developed a novel embryonic stem cell-genetically engineered mouse-modeling (ESC-GEMM) platform. We generated ESC lines harboring twelve combinations of four common driver mutations (BRAF-V600E, NRAS-Q61R, loss of PTEN, loss of CDKN2A) that can be efficiently targeted by recombination-mediated cassette exchange (RMCE) to introduce inducible alleles of interest. Importantly, all of our ESC lines are capable of producing high-contribution chimeras, which exhibit the same melanoma kinetics and overall survival as conventionally bred mice. Thus, our platform offers readily adaptable melanoma models whose melanoma phenotypes range from long latency/low penetrance to aggressive melanoma with complete penetrance. We employed our ESC-GEMM approach to compare the efficiency of gene depletion by conditional knockout, CRISPR/Cas9, or RNAi. We found that CRISPR/Cas9 depletion of Pten on a Braf-V600E background produces fewer melanomas but with nearly the same latency as conditional knockout using the Cre-lox system. Silencing of Pten with inducible shRNA resulted in significantly increased latency as well as in melanomas with a distinct macroscopic appearance and widespread lymph node metastases. While inducible shRNAs allowed us to restore Pten expression in established melanomas, depletion of Pten with inducible CRISPR enabled us to control the number of moles/melanomas by limiting the duration of Cas9 expression. We also used inducible CRISPR to sequentially activate Braf-V600E and delete Pten, which more closely mimics the sequence of events in human melanomas. Interestingly, while sequential introduction of these genetic changes had no effect on the overall survival, a subset of mice developed a significantly greater number of tumors. Finally, we established melanoma cell lines from untargeted chimeras, which can be targeted with Tet-inducible expression cassettes and transplanted into syngeneic hosts. Taken together, we have established a speedy mouse-modeling platform that will stimulate and accelerate in vivo melanoma research, provide a powerful resource to investigate the pathobiology of melanomagenesis, and allow the genetic and pharmacologic evaluation of novel treatments. Citation Format: Ilah Bok, Jordan Reff, Arianna Nenci, Jose G. Gonzalez, Florian A. Karreth. A versatile mouse-modeling platform for rapid in vivo melanoma studies [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A17.
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Çakır, Uğur, Anna Hajdara, Balázs Széky, Balázs Mayer, Sarolta Kárpáti, Éva Mezey, Pálma Silló, et al. "Mesenchymal-Stromal Cell-like Melanoma-Associated Fibroblasts Increase IL-10 Production by Macrophages in a Cyclooxygenase/Indoleamine 2,3-Dioxygenase-Dependent Manner." Cancers 13, no. 24 (December 7, 2021): 6173. http://dx.doi.org/10.3390/cancers13246173.
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Melanoma-associated fibroblasts (MAFs) are integral parts of melanoma, providing a protective network for melanoma cells. The phenotypical and functional similarities between MAFs and mesenchymal stromal cells (MSCs) prompted us to investigate if, similarly to MSCs, MAFs are capable of modulating macrophage functions. Using immunohistochemistry, we showed that MAFs and macrophages are in intimate contact within the tumor stroma. We then demonstrated that MAFs indeed are potent inducers of IL-10 production in various macrophage types in vitro, and this process is greatly augmented by the presence of treatment-naïve and chemotherapy-treated melanoma cells. MAFs derived from thick melanomas appear to be more immunosuppressive than those cultured from thin melanomas. The IL-10 increasing effect is mediated, at least in part, by cyclooxygenase and indoleamine 2,3-dioxygenase. Our data indicate that MAF-induced IL-10 production in macrophages may contribute to melanoma aggressiveness, and targeting the cyclooxygenase and indoleamine 2,3-dioxygenase pathways may abolish MAF–macrophage interactions.
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Pires, Layla, Valentin Demidov, Brian C. Wilson, Ana Gabriela Salvio, Lilian Moriyama, Vanderlei S. Bagnato, I. Alex Vitkin, and Cristina Kurachi. "Dual-Agent Photodynamic Therapy with Optical Clearing Eradicates Pigmented Melanoma in Preclinical Tumor Models." Cancers 12, no. 7 (July 18, 2020): 1956. http://dx.doi.org/10.3390/cancers12071956.
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Treatment using light-activated photosensitizers (photodynamic therapy, PDT) has shown limited efficacy in pigmented melanoma, mainly due to the poor penetration of light in this tissue. Here, an optical clearing agent (OCA) was applied topically to a cutaneous melanoma model in mice shortly before PDT to increase the effective treatment depth by reducing the light scattering. This was used together with cellular and vascular-PDT, or a combination of both. The effect on tumor growth was measured by longitudinal ultrasound/photoacoustic imaging in vivo and by immunohistology after sacrifice. In a separate dorsal window chamber tumor model, angiographic optical coherence tomography (OCT) generated 3D tissue microvascular images, enabling direct in vivo assessment of treatment response. The optical clearing had minimal therapeutic effect on the in control, non-pigmented cutaneous melanomas but a statistically significant effect (p < 0.05) in pigmented lesions for both single- and dual-photosensitizer treatment regimes. The latter enabled full-depth eradication of tumor tissue, demonstrated by the absence of S100 and Ki67 immunostaining. These studies are the first to demonstrate complete melanoma response to PDT in an immunocompromised model in vivo, with quantitative assessment of tumor volume and thickness, confirmed by (immuno) histological analyses, and with non-pigmented melanomas used as controls to clarify the critical role of melanin in the PDT response. The results indicate the potential of OCA-enhanced PDT for the treatment of pigmented lesions, including melanoma.
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Guo, Jun. "Abstract IA16: The landscape of mucosal melanoma: A long way to go." Cancer Research 80, no. 19_Supplement (October 1, 2020): IA16. http://dx.doi.org/10.1158/1538-7445.mel2019-ia16.
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Abstract Mucosal melanoma is a rare disease, accounting for approximately 1.4% of all Caucasians’ melanomas and 22% of Asian melanomas, which are commonly found in the nasal cavity or sinuses, anorectum, and vulvovagina. Nearly half of the mucosal melanomas are amelanotic. The most common sites of metastatic disease are the liver and the lungs. The prognosis may be similar regardless of anatomic site of origin. The genetics of mucosal melanoma thatg originates from melanocytes within mucosal epithelia has not been fully explored. Data suggest BRAF may occur in only 3–15% of all cases of mucosal melanoma. Mutations in KIT can be identified in 7–17% of all patients with mucosal melanoma. As to the adjuvant therapy, the only published randomized evidence supporting adjuvant therapy after resection of mucosal melanoma was from Lian et al. They randomized 189 patients with resected mucosal melanoma to observation, 1 year of high-dose IFN-α2b, or thrice-weekly chemotherapy with temozolomide plus cisplatin for six cycles. Adjuvant therapy was associated with a trend toward improved survival and HDI was less effective than temozolomide-based chemotherapy for patients with resected mucosal melanoma in respect to RFS. The preliminary interim analysis of a phase III trial (NCT03435302) of 204 patients with mucosal melanoma comparing temozolomide-based chemotherapy with HDI showed that the chemo was superior to HDI. Several clinical trials on adjuvant therapy of mucosal melanomas are ongoing, including NCT03178123 (a phase III trial of PD-1 inhibitors VS HDI) and NCT03241186 (phase II trial of nivolumab + ipilimumab). The clinical trials for systemic treatment of unresectable or metastatic mucosal melanoma were limited. A pooled analysis of the outcomes of patients with metastatic mucosal melanoma treated in trials either with single-agent nivolumab or the combination of ipilimumab and nivolumab compared outcomes to those of patients with cutaneous melanoma. The ORR for mucosal melanoma receiving nivolumab monotherapy or nivolumab combined with ipilimumab were lower than cutaneous melanoma, 23.3% vs. 40.9%, 37.1% vs. 60.4%. PD-1 monoclonal antibody was less effective in mucosal melanomas maybe because of low PD-L1 expression and tumor mutation burden (TMB). At the 2018 ASCO meeting, the results of phase II study of JS001 (PD-1 inhibitors) were reported. 128 melanoma patients were enrolled. Subgroup analysis showed that patients with mucosal origin were less effective (mucosal 0%). How to increase the efficacy for the mucosal melanoma? As we all know, liver metastases are common in mucosal melanomas and difficult to handle. A phase Ic study of oncolytic virus (OrienX010) injected into liver metastases demonstrated good tolerance and efficacy in Chinese patients. The next step is to combine oncolytic virus injected into liver lesions with PD-1 antibody to improve the efficacy of liver metastasis. On the other hand, TKIs are found to have an influence on microenvironment in tumor and facilitate immunotherapy. We conducted a phase Ib study of JS001 in combination with axitinib in metastatic mucosal melanoma. The results were reported in ASCO 2018, which were encouraging to achieve ORR of 66.7%. Recurrent activating mutations in KIT have been identified in 15% of patients, but KIT inhibitors have not produced durable clinical responses. Patients with mucosal melanoma have a poor prognosis in part due to the lack of targeted therapies. Imatinib may remain the first-choice treatment option for patients with a KIT mutation. For mucosal melanoma patients, there is still a long way to go. Citation Format: Jun Guo. The landscape of mucosal melanoma: A long way to go [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA16.
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Ahn, Antonio, Euan J. Rodger, Jyoti Motwani, Gregory Gimenez, Peter A. Stockwell, Matthew Parry, Peter Hersey, Aniruddha Chatterjee, and Michael R. Eccles. "Transcriptional Reprogramming and Constitutive PD-L1 Expression in Melanoma Are Associated with Dedifferentiation and Activation of Interferon and Tumour Necrosis Factor Signalling Pathways." Cancers 13, no. 17 (August 24, 2021): 4250. http://dx.doi.org/10.3390/cancers13174250.
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Melanoma is the most aggressive type of skin cancer, with increasing incidence worldwide. Advances in targeted therapy and immunotherapy have improved the survival of melanoma patients experiencing recurrent disease, but unfortunately treatment resistance frequently reduces patient survival. Resistance to targeted therapy is associated with transcriptomic changes and has also been shown to be accompanied by increased expression of programmed death ligand 1 (PD-L1), a potent inhibitor of immune response. Intrinsic upregulation of PD-L1 is associated with genome-wide DNA hypomethylation and widespread alterations in gene expression in melanoma cell lines. However, an in-depth analysis of the transcriptomic landscape of melanoma cells with intrinsically upregulated PD-L1 expression is lacking. To determine the transcriptomic landscape of intrinsically upregulated PD-L1 expression in melanoma, we investigated transcriptomes in melanomas with constitutive versus inducible PD-L1 expression (referred to as PD-L1CON and PD-L1IND). RNA-Seq analysis was performed on seven PD-L1CON melanoma cell lines and ten melanoma cell lines with low inducible PD-L1IND expression. We observed that PD-L1CON melanoma cells had a reprogrammed transcriptome with a characteristic pattern of dedifferentiated gene expression, together with active interferon (IFN) and tumour necrosis factor (TNF) signalling pathways. Furthermore, we identified key transcription factors that were also differentially expressed in PD-L1CON versus PD-L1IND melanoma cell lines. Overall, our studies describe transcriptomic reprogramming of melanomas with PD-L1CON expression.
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Torres-Collado, Antoni, Jeffrey Knott, and Ali Jazirehi. "Reversal of Resistance in Targeted Therapy of Metastatic Melanoma: Lessons Learned from Vemurafenib (BRAFV600E-Specific Inhibitor)." Cancers 10, no. 6 (May 24, 2018): 157. http://dx.doi.org/10.3390/cancers10060157.
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Malignant melanoma is the most aggressive form of skin cancer and has a very low survival rate. Over 50% of melanomas harbor various BRAF mutations with the most common being the V600E. BRAFV600E mutation that causes constitutive activation of the MAPK pathway leading to drug-, immune-resistance, apoptosis evasion, proliferation, survival, and metastasis of melanomas. The ATP competitive BRAFV600E selective inhibitor, vemurafenib, has shown dramatic success in clinical trials; promoting tumor regression and an increase in overall survival of patients with metastatic melanoma. Regrettably, vemurafenib-resistance develops over an average of six months, which renders melanomas resistant to other therapeutic strategies. Elucidation of the underlying mechanism(s) of acquisition of vemurafenib-resistance and design of novel approaches to override resistance is the subject of intense clinical and basic research. In this review, we summarize recent developments in therapeutic approaches and clinical investigations on melanomas with BRAFV600E mutation to establish a new platform for the treatment of melanoma.
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Barceló, Carla, Pol Sisó, Oscar Maiques, Inés de la Rosa, Rosa M. Martí, and Anna Macià. "T-Type Calcium Channels: A Potential Novel Target in Melanoma." Cancers 12, no. 2 (February 8, 2020): 391. http://dx.doi.org/10.3390/cancers12020391.
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T-type calcium channels (TTCCs) are overexpressed in several cancers. In this review, we summarize the recent advances and new insights into TTCC biology, tumor progression, and prognosis biomarker and therapeutic potential in the melanoma field. We describe a novel correlation between the Cav3.1 isoform and the increased basal autophagy in BRAFV600E-mutant melanomas and after acquired resistance to BRAF inhibitors. Indeed, TTCC blockers reduce melanoma cell viability and migration/invasion in vitro and tumor growth in mice xenografts in both BRAF-inhibitor-sensitive and -resistant scenarios. These studies open a new, promising therapeutic approach for disseminated melanoma and improved treatment in BRAFi relapsed melanomas, but further validation and clinical trials are needed for it to become a real therapeutic option.
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Eddy, Kevinn, and Suzie Chen. "Glutamatergic Signaling a Therapeutic Vulnerability in Melanoma." Cancers 13, no. 15 (July 31, 2021): 3874. http://dx.doi.org/10.3390/cancers13153874.
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Like other cancers, melanomas are associated with the hyperactivation of two major cell signaling cascades, the MAPK and PI3K/AKT pathways. Both pathways are activated by numerous genes implicated in the development and progression of melanomas such as mutated BRAF, RAS, and NF1. Our lab was the first to identify yet another driver of melanoma, Metabotropic Glutamate Receptor 1 (protein: mGluR1, mouse gene: Grm1, human gene: GRM1), upstream of the MAPK and PI3K/AKT pathways. Binding of glutamate, the natural ligand of mGluR1, activates MAPK and PI3K/AKT pathways and sets in motion the deregulated cellular responses in cell growth, cell survival, and cell metastasis. In this review, we will assess the proposed modes of action that mediate the oncogenic properties of mGluR1 in melanoma and possible application of anti-glutamatergic signaling modulator(s) as therapeutic strategy for the treatment of melanomas.
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Sabbah, Malak, Ahmad Najem, Mohammad Krayem, Ahmad Awada, Fabrice Journe, and Ghanem E. Ghanem. "RTK Inhibitors in Melanoma: From Bench to Bedside." Cancers 13, no. 7 (April 2, 2021): 1685. http://dx.doi.org/10.3390/cancers13071685.
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MAPK (mitogen activated protein kinase) and PI3K/AKT (Phosphatidylinositol-3-Kinase and Protein Kinase B) pathways play a key role in melanoma progression and metastasis that are regulated by receptor tyrosine kinases (RTKs). Although RTKs are mutated in a small percentage of melanomas, several receptors were found up regulated/altered in various stages of melanoma initiation, progression, or metastasis. Targeting RTKs remains a significant challenge in melanoma, due to their variable expression across different melanoma stages of progression and among melanoma subtypes that consequently affect response to treatment and disease progression. In this review, we discuss in details the activation mechanism of several key RTKs: type III: c-KIT (mast/stem cell growth factor receptor); type I: EGFR (Epidermal growth factor receptor); type VIII: HGFR (hepatocyte growth factor receptor); type V: VEGFR (Vascular endothelial growth factor), structure variants, the function of their structural domains, and their alteration and its association with melanoma initiation and progression. Furthermore, several RTK inhibitors targeting the same receptor were tested alone or in combination with other therapies, yielding variable responses among different melanoma groups. Here, we classified RTK inhibitors by families and summarized all tested drugs in melanoma indicating the rationale behind the use of these drugs in each melanoma subgroups from preclinical studies to clinical trials with a specific focus on their purpose of treatment, resulted effect, and outcomes.
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Mazzei, Maria Eugenia, Jimena Hochman, Gonzalo Manrique, Ana Luisa Marino, Lucia Beatriz Delgado, and Miguel Angel Martínez. "Determination of the BRAF V600E mutation in Uruguayan melanoma patients." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e19007-e19007. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e19007.
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e19007 Background: Vemurafenib approval by the FDA determines a new era for the treatment of metastatic melanoma in those patients with BRAF V600E mutation. This mutation is reported in about 50% of melanomas and is more common in melanomas on skin without chronic sun induced damage. The aim of this study was to evaluate the frequency of BRAF V600E mutation in Uruguayan melanoma patients, in order to analyze whether the use of vemurafenib would impact on our population. Methods: Formalin fixed, paraffin embedded tissues from 27 primary cutaneous melanomas, were obtained from files of the the Dermatopathology Unit, Department of Dermatology, Hospital de Clínicas in Montevideo, Uruguay. Most were Superficial Spreading Melanomas from skin without chronic sun induced damage. Microdissection of melanoma cells from paraffin embedded tissue was performed under microscopic visualization using a micromanipulator equipment. ADN extraction was performed and the BRAF V600E was detected by ASO-PCR. Results: Of the 27 melanoma samples analyzed, we detected the BRAF V600E mutation in 21. This determines a 77.8% frequency of mutation, a higher percentage than reported in the literature. This could be explained in different ways. The demographic characteristics of Uruguayan population are very peculiar, complying with a genetic admixture of Europeans(mostly from Spain), Amerindians (10%) and alow percentage of Africans (6%), which could explain the high incidence of BRAF V600E mutation. On the other hand, these melanomas were from skin without chronic sun induced damage, this type of melanomas have the highest rate of mutation. Finally, this mutation was analyzed in samples microdissected from melanoma biopsies, the fact that the cells were precisely removed from the tumor could also explain the high frequency of mutation. Conclusions: In this study we found a high frequency of BRAF V600E mutation in Uruguayan malignant melanoma patients, this could be explained by population genetic admixture, the melanoma subtype or technical characteristics. Further studies comparing techniques should be performed in our country to clarify this point.
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de Meza, Melissa Melanie, Rawa Ismail, Willeke Blokx, Christian U. Blank, Alfonsus Johannes Maria van den Eertwegh, Maureen J. B. Aarts, Alexander Christopher Jonathan Van Akkooi, et al. "Is adjuvant treatment for melanoma in clinical practice comparable to trials? The first population-based results." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e21523-e21523. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e21523.
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e21523 Background: Little is known about the outcome of adjuvant therapy in melanoma patients beyond the clinical trial setting. The Dutch Melanoma treatment Registry (DMTR) is a population-based registry, set up in July 2013 to monitor the safety and quality of melanoma care. Since 2019, adjuvant treated melanoma patients have also been registered in the DMTR, following approval and reimbursement of adjuvant treatment in the Netherlands in December 2018. Methods: Analyses were performed on melanoma patients treated with adjuvant anti-PD1 therapy included in the DMTR between 01-07-2018 and 31-12-2019. Descriptive statistics were used to analyze patient-, and treatment characteristics, and death as well as relapse rates. Results: Six hundred and fifty-seven patients treated with adjuvant systemic therapy were included in the DMTR. The majority (94%) of these patients was treated with anti-PD1. Twenty percent of the anti-PD1-treated patients developed grade ≥3 toxicity. Of the 279 patients with a minimum follow-up of one year after start of anti-PD1, 170 (61%) prematurely discontinued therapy. Relapse and death occurred in respectively, 38% and 12% of patients within one year of follow-up. Relapse was significantly more frequent in older patients, with high Breslow thickness and ulcerated melanomas. Conclusions: These data show more frequent premature discontinuation of adjuvant anti-PD1 in daily clinical practice than reported in the registration trials. Moreover, incidence of severe toxicity, relapse and death during adjuvant treatment appears higher in the real-world setting.
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Cormier, Janice N., Yan Xing, Meichun Ding, Jeffrey E. Lee, Paul F. Mansfield, Jeffrey E. Gershenwald, Merrick I. Ross, and Xianglin L. Du. "Population-Based Assessment of Surgical Treatment Trends for Patients With Melanoma in the Era of Sentinel Lymph Node Biopsy." Journal of Clinical Oncology 23, no. 25 (September 1, 2005): 6054–62. http://dx.doi.org/10.1200/jco.2005.21.360.
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Purpose The surgical staging of melanoma dramatically changed with the introduction of sentinel lymph node (SLN) biopsy. In this study, Surveillance, Epidemiology, and End Results (SEER) data were examined to determine how surgical treatment is being carried out and whether SLN biopsy is being performed in melanoma patients in conformance with National Comprehensive Cancer Network (NCCN) guidelines. Patients and Methods The SEER database (1998 to 2001) was searched for all patients with invasive melanoma. NCCN guidelines were used to define optimal stage-specific surgical treatment. Treatment trends in patients with stages I to III disease were summarized, and multivariate analyses were performed to identify factors associated with nonadherence with treatment guidelines. Results A total of 21,867 melanoma patients were identified; 18,499 of these patients met the inclusion criteria. The number of patients diagnosed with stage III melanoma increased by 55.7% over the study period, and this corresponded to a 53% increase in the number of SLN biopsies performed annually. The odds ratios for nonadherence were 2.32, 2.27, and 1.54 for stages IB, II, and III disease, respectively, compared with stage IA melanoma. Multivariate analyses revealed that age more than 65 years, marital status, minority populations, and primary tumor location were associated with nonadherence with guidelines. Treatment patterns among tumor registries also varied significantly. Conclusion Stage migration is evident in the SEER registries in consort with increasing use of SLN biopsy. Although treatment trends are improving, SLN biopsy continues to be underused, particularly in the elderly and minority populations, in patients with truncal and head/neck melanomas, and also in some geographic regions of the United States.
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Cai, Lifang, Dongsheng Chen, Qin Zhang, Qianqian Duan, Yaqin Liu, Si Li, and Mingzhe Xiao. "PREX2 mutation serves as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e21504-e21504. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e21504.
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e21504 Background: Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)-a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes. Previous work suggested that PREX2 alterations may enrich for responses to immune checkpoint inhibitors (ICI), validation of function in melanoma is needed. Methods: Using 539-gene target-capture next generation sequencing, we analyzed the PREX2 mutation in 3547 tumor tissue or plasma ctDNA samples (including 122 melanoma) from different patients, and the public database of TACG was also compared. Data from Snyder-64 study (n = 64, anti- CTLA-4 therapy) was retrieved and analysed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Results: In clinical cohort, the frequency of PREX2 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients was 5.94 % (211 in 3547). Meanwhile, the frequency of PREX2 mutation in TCGA cohort was 5.06 % (555 in 10953). In melanoma datebase, the frequency of PREX2 mutation in 122 melanoma tumor tissue or plasma ctDNA samples from different patients was 6.55 % (78 in 122). Meanwhile, the frequency of PREX2 mutation in melanoma in TCGA cohort was 25.56 % (113 in 422). We further analyzed Kaplan-Meier curves from Snyder-64 study (n = 64, anti- CTLA-4 therapy). In Snyder-64 study melanoma cohort, mutation of PREX2 was associated with higher neoantigen load (P = 0.02) and higher mutation count (P = 0.0027) in melanoma. PREX2 mutation was associated with prolonged overall survival (OS) trend compared with PREX2 wt in melanoma cohort (P = 0.09). Conclusions: In our study, the frequency of PREX2 mutation in pan cancers and melanoma was investigated in clinical and TCGA cohort, which might provide useful information to guide precision medicine. PREX2 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma via upregulating neoantigen load and mutation count.
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Moschos, Stergios J., Zeynep Eroglu, Elizabeth Mary Gaughan, Theresa Michelle Medina, Peng Wang, Elizabeth Claire Dees, Leanne Cartee, et al. "NCI 9922: Phase 2 study of ibrutinib in treatment-refractory distant metastatic cutaneous melanoma (DMCM)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS9592. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps9592.
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TPS9592 Background: We have previously shown that the IL-2 inducible kinase (ITK) is highly expressed in primary melanomas compared with nevi due to promoter hypomethylation (Conway PCMR 2011). We have also shown using 2-color immunofluorescence (2CIF) that ITK protein expression is increased even more in metastatic compared to primary melanomas (S100+) and that molecular targeting (shRNA) or pharmacologic inhibition of ITK (BI 10N) in various melanoma cell lines, various melanoma xenografts and an immunocompetent melanoma mouse model suppresses cell proliferation and retards tumor growth without inducing cell death (Carson CCR 2015). We have also shown by intracellular stain of peripheral blood mononuclear cells (PBMC) that ITK is expressed in PBMC obtained from patients (pts) treated with MAPK or CTLA-4 inhibitors. Other groups have shown that ITK and BTK are expressed in Th2 cells, myeloid-derived suppressor cells, and tumor-associated macrophages. We have also shown that ibrutinib suppresses proliferation of various melanoma cell lines in low nM concentrations depending on tumoral expression of ITK. We hypothesize that targeting DMCM with ibrutinib alone will induce antitumor responses and/or prolong survival if DMCM expresses high levels of melanoma-associated ITK by 2CIF (S100/ITK). Methods: This is an open-label, single-arm, multicenter, phase II study of DMCM refractory to or ineligible for PD-1 and MAPK inhibitors. Ibrutinib will be dosed at 840 mg p.o. qd. The null hypothesis is that an ineffective drug will confer a 5% response rate (RR) and 18% 6-month PFS (6m PFS), whereas ibrutinib will confer > = 20% RR and > = 35% 6m PFS (KEYNOTE-002). This trial accrues in two stages; if either the RR and/or 6m PFS endpoint are met after 18 patients, then 14 additional pts will be accrued for a total of 32. The Simon’s design will reject the null hypothesis if > = 4 responses are observed or > = 9 pts have PFS better than 6 months out of 32 patients. All pts are required to have baseline tumor tissue available for analysis of ITK expression by 2CIF. Immune monitoring will be performed on PBMC collected at baseline and various time points during treatment. Trial is currently recruiting pts (NCT02581930). Clinical trial information: NCT02581930.
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Goldinger, Simone M., Cédric Panje, and Paul Nathan. "Treatment of melanoma brain metastases." Current Opinion in Oncology 28, no. 2 (March 2016): 159–65. http://dx.doi.org/10.1097/cco.0000000000000270.
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Carlino, Matteo S., Gerald B. Fogarty, and Georgina V. Long. "Treatment of Melanoma Brain Metastases." Cancer Journal 18, no. 2 (2012): 208–12. http://dx.doi.org/10.1097/ppo.0b013e31824b2890.
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Velez, Augustine, Debra Walsh, and Constantine P. Karakousis. "Treatment of unknown primary melanoma." Cancer 68, no. 12 (December 15, 1991): 2579–81. http://dx.doi.org/10.1002/1097-0142(19911215)68:12<2579::aid-cncr2820681209>3.0.co;2-g.
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Jochems, Anouk, Monique K. van der Kooij, Marta Fiocco, Maartje G. Schouwenburg, Maureen J. Aarts, Alexander C. van Akkooi, Franchette W. P. J. van den Berkmortel, et al. "Metastatic Uveal Melanoma: Treatment Strategies and Survival—Results from the Dutch Melanoma Treatment Registry." Cancers 11, no. 7 (July 18, 2019): 1007. http://dx.doi.org/10.3390/cancers11071007.
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Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Up to 50% of UM patients will develop metastases. We present data of 175 metastatic UM patients diagnosed in the Netherlands between July 2012 and March 2018. In our cohort, elevated lactate dehydrogenase level (LDH) is an important factor associated with poorer survival (Hazard Ratio (HR) 9.0, 95% Confidence Interval (CI) 5.63–14.35), and the presence of liver metastases is negatively associated with survival (HR 2.09, 95%CI 1.07–4.08). We used data from the nation-wide Dutch Melanoma Treatment Registry (DMTR) providing a complete overview of the location of metastases at time of stage IV disease. In 154 (88%) patients, the liver was affected, and only 3 patients were reported to have brain metastases. In 63 (36%) patients, mutation analysis was performed, showing a GNA11 mutation in 28.6% and a GNAQ mutation in 49.2% of the analyzed patients. In the absence of standard care of treatment options, metastatic UM patients are often directed to clinical trials. Patients participating in clinical trials are often subject to selection and usually do not represent the entire metastatic UM population. By using our nation-wide cohort, we are able to describe real-life treatment choices made in metastatic UM patients and 1-year survival rates in selected groups of patients.
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Bajčiová, Viera. "Malignant melanoma and new options of treatment." Onkologie 10, no. 6 (December 1, 2016): 256–62. http://dx.doi.org/10.36290/xon.2016.054.
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Rager, Taylor, Adam Eckburg, Meet Patel, Rong Qiu, Shahina Gantiwala, Katrina Dovalovsky, Kelly Fan, et al. "Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies." Cancers 14, no. 15 (August 3, 2022): 3779. http://dx.doi.org/10.3390/cancers14153779.
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Melanoma possesses invasive metastatic growth patterns and is one of the most aggressive types of skin cancer. In 2021, it is estimated that 7180 deaths were attributed to melanoma in the United States alone. Once melanoma metastasizes, traditional therapies are no longer effective. Instead, immunotherapies, such as ipilimumab, pembrolizumab, and nivolumab, are the treatment options for malignant melanoma. Several biomarkers involved in tumorigenesis have been identified as potential targets for molecularly targeted melanoma therapy, such as tyrosine kinase inhibitors (TKIs). Unfortunately, melanoma quickly acquires resistance to these molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been employed and have been shown to improve the prognosis of melanoma patients compared to monotherapy. This review discusses several combination therapies that target melanoma biomarkers, such as BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K. Several of these regimens are already FDA-approved for treating metastatic melanoma, while others are still in clinical trials. Continued research into the causes of resistance and factors influencing the efficacy of these combination treatments, such as specific mutations in oncogenic proteins, may further improve the effectiveness of combination therapies, providing a better prognosis for melanoma patients.
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Walz, Solange N., Jérôme Martineau, Matteo Scampa, Daniel F. Kalbermatten, and Carlo M. Oranges. "Melanoma of the Upper Limb and Shoulder: A Surveillance, Epidemiology, and End Results Analysis of Epidemiology and Survival 2000–2019." Cancers 14, no. 22 (November 18, 2022): 5672. http://dx.doi.org/10.3390/cancers14225672.
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(1) Background: Melanoma is the most common life-threatening cancer among skin cancers. Almost all locations of the skin can be affected by melanoma, and the upper limbs are one of the most frequent locations. We aimed to study the epidemiology and survival outcomes of patients with melanoma localized in the upper extremities compared with other sites. (2) Methods: The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database is considered the most representative of the U.S. population; we extracted melanoma cases diagnosed between 2000 and 2019. Several characteristics, including demographical, pathological, and therapeutic, were recorded, and upper extremity melanomas and melanomas from other areas were compared. Overall survival was assessed, and the groups were compared. (3) Results: 69,436 patients had melanoma in the upper limbs and shoulders and 204,794 in other body parts. Overall, 35,267 patients with upper extremity melanoma were males, 34,169 were females, and the mean age was 60. For the rest of the body, there were 118,654 males and 86,140 females, with a mean age of 59. Surgery alone was the most commonly used treatment, while radiation therapy was the least used for all sites. Women appear to have better survival than men. Superficial spreading melanoma is the least lethal subtype, while nodular melanoma is the most dangerous. (4) Conclusion: Women under 50 are more at risk than men of the same age. The trend reverses after age 50 where men are at greater risk. In addition to gender and age, disease stage and major histologic subtypes influence survival.
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Podhorec, Ján, Radek Lakomý, Alexandr Poprach, and Igor Kiss. "Immunotherapy for the treatment of metastatic uveal melanoma." Onkologie 16, no. 3 (May 16, 2022): 130–33. http://dx.doi.org/10.36290/xon.2022.026.
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Bandovkina, Valeria, Elena Mikhaylovna Frantsiyants, Irina V. Kaplieva, Lidia K. Trepitaki, Yulia A. Pogorelova, Natalia D. Cheryarina, Irina Valerevna Neskubina, et al. "Ratio of some fibrinolytic system components and biological aggressiveness of melanoma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e21069-e21069. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e21069.
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e21069 Background: Melanomas of early stages in a horizontal growth phase can masquerade as a melanocytic nevus or other benign skin lesions. Activation of plasmin/plasminogen system is typical of both physiologic and pathologic processes. Cell remodeling and neoangiogenesis play critical role in melanoma invasion and metastasis. The purpose of the study was comparative analysis of plasmin/plasminogen system in tissues of nevi and melanomas of different sizes and extension. Methods: Activity of plasmin and plasminogen was studied and antigen and activity assays (ELISA) were performed for uPA, tPA and PAI-1 in tissues of nevi (n = 30) and melanomas pТ1-2N0M0 (n = 17) and pТ3-4N0-1M0 (n = 23). Intact tissue (n = 15) obtained in surgical treatment of patients without cancer was used for the control. Results: Plasminogen levels were decreased by 2 times in tissues of nevi and pТ1-2N0M0 melanoma, while plasmin was unchanged. pТ1-2N0M0 melanoma significantly differed from nevi by a marked activation of uPA without PAI-1 increase. Activation of plasminogen system in both рТ1-2N0M0 melanoma and in nevi was not accompanied by plasmin accumulation. The main difference between tissues of nevi and pТ1-2N0M0 melanoma was the uPA/PAI-1 ratio reduction by more than 40 times in nevi. pТ3-4N0-1M0 melanoma was characterized by plasmin level increase by more than 19 times and uPA activity and content increase by 2.5 times, compared to pТ1-2N0M0, without an increase in PAI-1 activity. The uPA/PAI-1 ratio almost doubled. Conclusions: Normal plasmin levels in nevi and melanomas in a horizontal growth phase are probably the result of its inhibitors activity. Increased activity of fibrinolytic system, plasmin accumulation and uPA/PAI-1 increase in a vertical growth phase determine proliferative, invasive and metastatic potential of tumors.
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Pardella, Elisa, Erica Pranzini, Angela Leo, Maria Letizia Taddei, Paolo Paoli, and Giovanni Raugei. "Oncogenic Tyrosine Phosphatases: Novel Therapeutic Targets for Melanoma Treatment." Cancers 12, no. 10 (September 29, 2020): 2799. http://dx.doi.org/10.3390/cancers12102799.
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Despite a large number of therapeutic options available, malignant melanoma remains a highly fatal disease, especially in its metastatic forms. The oncogenic role of protein tyrosine phosphatases (PTPs) is becoming increasingly clear, paving the way for novel antitumor treatments based on their inhibition. In this review, we present the oncogenic PTPs contributing to melanoma progression and we provide, where available, a description of new inhibitory strategies designed against these enzymes and possibly useful in melanoma treatment. Considering the relevance of the immune infiltrate in supporting melanoma progression, we also focus on the role of PTPs in modulating immune cell activity, identifying interesting therapeutic options that may support the currently applied immunomodulating approaches. Collectively, this information highlights the value of going further in the development of new strategies targeting oncogenic PTPs to improve the efficacy of melanoma treatment.
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Bacchiocchi, Antonella, Silvia Coma, Sanjib Chowdhury, Mario Sznol, Ruth Halaban, and Jonathan A. Pachter. "Abstract 1179: Rational combinations with the dual RAF/MEK inhibitor VS-6766 for treatment of cutaneous melanoma harboring BRAF, NRAS, NF1 or CRAF mutations." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1179. http://dx.doi.org/10.1158/1538-7445.am2022-1179.
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Abstract VS-6766 is a unique dual RAF/MEK inhibitor which blocks MEK activity without the compensatory MEK activation that limits the efficacy of MEKi. VS-6766 produced clinical responses as a single agent in gynecological cancers and KRAS mutant non-small cell lung cancer (NSCLC) (Guo Lancet Oncology 2020). Clinical responses were also observed with VS-6766 in combination with the focal adhesion kinase (FAK) inhibitor defactinib in patients with low-grade serous ovarian cancer and KRAS mutant NSCLC. In patients with advanced cutaneous melanoma, mutations in the RAS/RAF/MEK/ERK (MAPK) pathway occur mainly in BRAF (41%), NRAS (27%), NF1 (25%) and CRAF (2.6%) (AACR Genie v10). Although several selective BRAFV600 inhibitors (BRAFi) are FDA-approved alone or in combination with MEK-only inhibitors (MEKi) for melanomas with BRAFV600E/K, there is still a need for agents to improve response rate, duration of response, and tolerability. There are no targeted therapy options for melanoma patients carrying NRAS or NF1 mutations following progression on immune checkpoint inhibitors. Using low passage cell lines derived from patients with metastatic melanoma and extensively profiled for genomic alterations together with commercially available immortalized human melanoma cell lines, all of which carried mutations in the MAPK pathway, we tested the activity of VS-6766 alone or in combination with other agents. In vitro proliferation assays showed that VS-6766 is as potent as BRAFi in BRAFV600E melanoma cell lines and is more potent than pan-RAF inhibitors in melanoma cell lines bearing NRAS, NF1 or CRAF mutations. We next tested rational combinations of VS-6766 with other agents in specific genetic backgrounds. In BRAFV600E melanoma cell lines, combination of VS-6766 with BRAFi (encorafenib, vemurafenib, dabrafenib) showed greater synergy than combination of MEKi (binimetinib, cobimetinib, trametinib) with BRAFi. Since ~65% of BRAF or NRAS mutant melanomas co-express mutations in the PI3K/AKT/mTOR pathway, we tested the combination of VS-6766 with the mTOR inhibitor everolimus. VS-6766 was synergistic with everolimus in reducing the viability of melanoma cells harboring BRAF or NRAS mutations. Because CDK4/6 pathway activation has been correlated with poor progression-free survival in melanoma patients treated with BRAFi combined with MEKi, we tested the combination of VS-6766 with the CDK4/6 inhibitor abemaciclib. We found that VS-6766 was synergistic with abemaciclib in reducing viability of melanoma cell lines. Additional combinations with VS-6766 are currently being tested and will be reported. These preclinical data support clinical testing of VS-6766 in rational combinations for treatment of cutaneous melanoma with BRAF, NRAS, NF1 or CRAF mutations. In clinical trials, a recommended phase 2 dose has been defined for the combination of VS-6766 with everolimus. Citation Format: Antonella Bacchiocchi, Silvia Coma, Sanjib Chowdhury, Mario Sznol, Ruth Halaban, Jonathan A. Pachter. Rational combinations with the dual RAF/MEK inhibitor VS-6766 for treatment of cutaneous melanoma harboring BRAF, NRAS, NF1 or CRAF mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1179.
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Ye, Qiang, Zi Li, Yang Li, Yirong Li, Yan Zhang, Runlin Gui, Yue Cui, et al. "Exosome-Derived microRNA: Implications in Melanoma Progression, Diagnosis and Treatment." Cancers 15, no. 1 (December 23, 2022): 80. http://dx.doi.org/10.3390/cancers15010080.
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Melanoma is a malignant and aggressive cancer, and its progression is greatly affected by interactions between melanoma cells and their surroundings. Exploration on mechanism of melanoma and improved diagnostic and therapeutic strategies are becoming increasingly important. Unlike extracellular messengers that mainly work on targeted cells through corresponding receptors, exosomes are essential intercellular messengers that deliver biologically active substances such as nucleic acids and proteins to target cells for cell–cell communication. Of them, microRNAs (miRNAs) are common and important exosomal components that can regulate the expression of a wide range of target genes. Accordingly, exosome-derived miRNAs play a significant role in melanoma progression, including invasion and metastasis, microenvironment establishment, angiogenesis, and immune escape. MiRNA signatures of exosomes are specific in melanoma patients compared to healthy controls, thus circulating miRNAs, especially exosomal miRNAs, become potential diagnostic markers and therapeutic targets for melanoma. This review aims to summarize recent studies on the role of exosomal miRNAs in melanoma as well as ongoing efforts in melanoma treatment.
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van Breeschoten, Jesper, Alfonsus Johannes Maria van den Eertwegh, Liesbeth De Wreede, Erik W. van Zwet, Doranne Hilarius, John B. A. G. Haanen, Christian U. Blank, et al. "Hospital variation in cancer treatments and survival outcomes of advanced melanoma patients: Nationwide quality assurance in the Netherlands." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e18641-e18641. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e18641.
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e18641 Background: The introduction of new systemic treatments for advanced melanoma has markedly changed the outcome of patients with metastatic melanoma. To assure high quality of care for patients treated in Dutch melanoma centers, hospital variation in treatment patterns and outcomes are evaluated in the Dutch Melanoma Treatment Registry. The aim of this study was to assess center variation in treatments and 2-year survival probabilities of patients diagnosed between 2013-2017 in the Netherlands. Methods: We selected patients diagnosed between 2013-2017 with unresectable stage IIIC or IV melanoma, registered in the Dutch Melanoma Treatment Registry. Centers’ performance on 2-year survival was compared by means of a multivariable Cox proportional hazards model with a random effect for center ID. Variation between centers was expressed by median hazard ratios. Therapy with BRAF/MEK inhibitors, anti-PD-1 antibodies or ipilimumab plus nivolumab was added to the Cox proportional hazards model as a time dependent covariate to assess the influence of new systemic therapies on center variation. Results: Between 2013-2017, 3820 patients were diagnosed with unresectable stage IIIC or IV melanoma. For patients diagnosed between 2013-2015, significant center variation in 2-year survival probabilities was observed. Median hazard ratio was 1.17 (95%CI: 1.09-1.31) for patients diagnosed between 2013-2015 after correcting for case-mix and treatment with BRAF/MEK inhibitors, anti-PD-1 antibodies or ipilimumab plus nivolumab. Use of new systemic therapies had a significant effect on up to 2-year survival (hazard ratio = 0.83, 95%CI (0.73-0.94)) with no use of the new systemic therapies as a reference. From 2016 onwards, no significant difference in 2-years survival was observed between centers. Conclusions: The different use of new cancer treatment of metastatic melanoma had an effect on survival outcomes in the Netherlands. A platform such as the Dutch Melanoma Treatment Registry, in which melanoma centers collaborate and have insight in variation in treatment patterns and outcomes between centers, results in fast implementation of new clinical developments across all Dutch melanoma centers.
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Salama, Yousef, Satoshi Takahashi, Yuko Tsuda, Yoshio Okada, Koichi Hattori, and Beate Heissig. "YO2 Induces Melanoma Cell Apoptosis through p53-Mediated LRP1 Downregulation." Cancers 15, no. 1 (December 31, 2022): 288. http://dx.doi.org/10.3390/cancers15010288.
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The multifunctional endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1) has been implicated in melanoma growth. However, the mechanism of LRP1 expression in melanoma cells remains only partially understood. In most melanomas, the TP53 tumor suppressor is retained as a non-mutated, inactive form that fails to suppress tumors. We identify TP53 as a regulator of LRP1-mediated tumor growth. TP53 enhances the expression of miRNA miR-103/107. These miRNAs target LRP1 expression on melanoma cells. TP53 overexpression in human and murine melanoma cells was achieved using lentivirus or treatment with the small molecule YO-2, a plasmin inhibitor known to induce apoptosis in various cancer cell lines. TP53 restoration enhanced the expression of the tumor suppressor miR-103/107, resulting in the downregulation of LRP1 and suppression of tumor growth in vivo and in vitro. Furthermore, LRP1 overexpression or p53 downregulation prevented YO-2-mediated melanoma growth inhibition. We identified YO-2 as a novel p53 inducer in melanoma cells. Cotreatment of YO-2 with doxorubicin blocked tumor growth in vivo and in a murine melanoma model, suggesting that YO-2 exerts anti-melanoma effects alone or in combination with conventional myelosuppressive drugs.
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Truong, Thach-Giao, Kirun Chohan, Angeles Price, Helene B. Fevrier, Peter D. Peng, Maihgan A. Kavanagh, Maris S. Jones, et al. "Early case ascertainment and prospective multidisciplinary review for management of new melanoma diagnoses within an integrated healthcare system: The Kaiser Permanente Northern California experience." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 6523. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.6523.
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6523 Background: Appropriate surgical treatment of early-stage melanoma yields a high cure rate, but this management can be nuanced. In particular, surgical management, including sentinel lymph node biopsy (SLNB), of thin melanoma (≤1.0mm) is not well-defined. Methods: Biopsies with new melanoma diagnoses were identified electronically and manually reviewed. In a community oncology setting, we organized a review panel of physicians specialized in melanoma from dermatology, medical oncology, nuclear medicine, radiation oncology, and surgical subspecialties (oncology, plastics, head and neck). Patients were assigned to care pathways based on NCCN and ASCO guidelines, including guidance on SLNB for thin melanomas with high-risk features like lymphovascular invasion, high mitotic rate, positive deep margin, and ulceration. These recommendations were documented in the chart and communicated directly to the patients care team. Results: From 11/2016 through 10/2018, our multidisciplinary committee reviewed 3626 patients with new melanoma from 22 sites in our integrated, regional hospital system. Median age was 66 (range 19-99); 60% were male. cT2N0 tumors comprised 7%, cT3 3%, and cT4 2%. Thin melanomas ≤1.0mm represented 71% of cases, of which 34% were ≤0.5mm. SLNB was performed in 9.8% of thin melanomas, and 18% were positive, much higher than historical positive rates of 3-4%. Conclusions: Early case ascertainment and prospective multidisciplinary review in a community oncology setting resulted in increased identification of high-risk thin melanoma, and consequently increased identification of nodal disease through SLNB. Positive SLNB triggers important clinical decision-making regarding need for node dissection versus clinical surveillance, and need for adjuvant therapy, which have been shown to improve survival. This clinical practice structure improved risk-stratification and adherence to national guidelines. We plan to further study the impact of these improvements to melanoma care on disease-free survival and overall survival.
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Woodman, S. E., J. C. Trent, K. Stemke-Hale, A. Lazar, S. Pricl, G. M. Pavan, N. Papadopoulos, P. Hwu, G. B. Mills, and M. A. Davies. "Selective activity of dasatinib for the most common KIT mutation in melanoma (L576P)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 9019. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.9019.
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9019 Background: Point mutations in the KIT receptor tyrosine kinase gene have recently been identified in melanomas from mucosal, acral lentiginous (AL), and chronically sun-damaged (CSD) sites. An improved understanding of the molecular characteristics of melanoma-prevalent KIT mutations may lead to more effective therapeutic approaches. Methods: Human melanoma cell lines were screened by mass-spectroscopy based genotyping for KIT mutations, and a cell line with an endogenous L576P KIT mutation was identified. The cell line was treated in vitro with a panel of small molecule KIT inhibitors and the effects on cell viability were quantified. Molecular modeling of the interaction of the inhibitors with the KIT L576P mutant protein was determined to estimate binding affinity. PET/CT studies were performed on patients with mucosal melanoma harboring the L576P mutation pre- and post-dasatinib treatment. Results: We have identified the first human melanoma cell line with an endogenous L576P mutation, the most common KIT mutation in melanoma. In vitro testing demonstrated that this cell line is resistant to imatinib, nilotinib and sorafenib (0 - 1 uM), KIT inhibitors shown to be effective in non-melanoma cells with other KIT mutations. However, the mutant cell line was inhibited by dasatinib at concentrations as low as 10 nM, and was significantly more sensitive than melanoma cell lines with wild-type KIT (p = 0.02). No difference in sensitivity to Src inhibitors was observed, supporting that this sensitivity was due to KIT inhibition. Molecular modeling demonstrated that the L576P mutation induces structural changes in KIT that reduce the affinity for imatinib but not for dasatinib. Two metastatic melanoma patients with the L576P KIT mutation were treated with dasatinib, including one patient previously treated with imatinib. Both patients had marked reduction and elimination of tumor FDG- avidity by PET imaging after dasatinib treatment. Conclusions: This data supports that dasatinib has a selective inhibitory effect against the most common KITmutation in melanoma and has implications for the development of AL, CSD, and mucosal melanoma treatment. [Table: see text]
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Kong, Yan, Lu Si, Xiao wei Xu, Keith T. Flaherty, Zhi Hong Chi, Chuan Liang Cui, Xi Nan Sheng, et al. "Association of the activation of the mTOR pathway with prognosis in Chinese melanoma patients." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8561. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8561.
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8561 Background: mTOR is a ubiquitously expressed protein kinase and a validated target in the treatment of cancer. However, the characterization of mTOR pathway in Asian melanoma populations has not been reported. Methods: This study involved primary tumor samples from 173 melanoma patients (79 acral melanomas, 57 mucosal melanomas, 17 melanomas on skin with chronic sun-induced damage, 20 melanomas on skin without chronic sun-induced damage) in Peking University Cancer Hospital & Institute. Clinical data were collected. Immunohistochemistry assays using antibodies against pmTOR, pS6RP, p4E-BP1 and pAKT were performed on formalin-fixed, paraffin-embedded specimens. Somatic mutations within the hotspot regions of frequently mutated genes in mTOR pathway (AKT1, TSC1, PI3K genes, etc) were analyzed by PCR amplification and Sanger sequencing. Results: Among the 173 samples, 26% of the cases (45/173) demonstrated positive staining with pmTOR. Expression of pS6RP was observed in 37% (64/173) of cases. Expression of p4E-BP1 was observed in 27% (46/173) of cases. pAKT was expressed by 22% (38/173) of cases. Somatic mutations in examined genes were detected. The median survival time for patients with expression of pmTOR was significantly shorter than patients with absence of pmTOR expression (25.3 vs 62.9 months, P =0.048). In addition, statistical differences were found for ulceration rates between melanomas with or without pS6RP (64.1%vs 35.9%, P= 0.049). Moreover, the median survival time for mucosal melanoma patients with pAKT expression was significantly shorter than for patients with absence of pAKT expression (20.4 vs 52.1 months, P =0.022). Conclusions: These data demonstrate that activation of the mTOR signaling pathway carries prognostic significance in Asia patients with melanoma. Targeted therapies to mTOR pathway may offer a therapeutic benefit for these melanoma patients.
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Zhou, Sarah, Daniel Sikorski, Honghao Xu, Andrei Zubarev, May Chergui, François Lagacé, Wilson H. Miller, et al. "Defining the Criteria for Reflex Testing for BRAF Mutations in Cutaneous Melanoma Patients." Cancers 13, no. 9 (May 10, 2021): 2282. http://dx.doi.org/10.3390/cancers13092282.
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Targeted therapy has been developed through an in-depth understanding of molecular pathways involved in the pathogenesis of melanoma. Approximately ~50% of patients with melanoma have tumors that harbor a mutation of the BRAF oncogene. Certain clinical features have been identified in BRAF-mutated melanomas (primary lesions located on the trunk, diagnosed in patients <50, visibly pigmented tumors and, at times, with ulceration or specific dermatoscopic features). While BRAF mutation testing is recommended for stage III–IV melanoma, guidelines differ in recommending mutation testing in stage II melanoma patients. To fully benefit from these treatment options and avoid delays in therapy initiation, advanced melanoma patients harboring a BRAF mutation must be identified accurately and quickly. To achieve this, clear definition and implementation of BRAF reflex testing criteria/methods in melanoma should be established so that patients with advanced melanoma can arrive to their first medical oncology appointment with a known biomarker status. Reflex testing has proven effective for a variety of cancers in selecting therapies and driving other medical decisions. We overview the pathophysiology, clinical presentation of BRAF-mutated melanoma, current guidelines, and present recommendations on BRAF mutation testing. We propose that reflex BRAF testing should be performed for every melanoma patient with stages ≥IIB.
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McArthur, Grant A., Richard J. Young, Karen E. Sheppard, Victoria Mar, Kelly Waldeck, Stephen B. Fox, Fergal C. Kelleher, et al. "Clinical significance of genomic alterations of the CDK4-pathway and sensitivity to the CDK4 inhibitor PD 0332991 in melanoma." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8520. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8520.
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8520 Background: Activation of CDK4 by amplification, increased expression of Cyclin D1 (CCND1) or reduced expression of the CDK inhibitor p16 (CDKN2A) can contribute to transformation of melanocytes indicating that CDK4 can act as an oncogene in melanoma.To explore if CDK4 may be a viable target for the treatment of human melanoma we have analyzed the frequency and clinico-pathological associations of genomic alterations of the CDK4 pathway in primary human melanoma and examined the genomic predictors of sensitivity to the highly selective CDK4/6 inhibitor PD 0332991 (991) in a panel of melanoma cell lines. Methods: A series of 167 primary melanomas with clinical, molecular and pathological annotation, including median follow up of 6.6 years, were analyzed for copy number variation (CNV)- gain of CDK4 or CCND1 (average gene copy >2.4) or loss of CDKN2A (average gene copy <1.4), by fluorescence in situ hybridization. A panel of 39 cell lines were treated with 991 in vitro and GI50s calculated. The mean GI50 of the melanoma cell lines was used to define sensitivity. Gene expression profiling and mutation or CNV in CDKN2A were used to identify predictors of sensitivity. Results: 75% of primary melanomas had at least one CNV (75%, 70% and 82% for BRAF, NRAS or wild-type BRAF/NRAS mutation status respectively). 55% showed loss of CDKN2A. 28% of melanomas had two or more CNVs. Melanomas with two or more CNVs involving CCND1 had worse overall survival (HR 5.56, p=0.02). Low CDKN2A mRNA expression or mutation or loss of CDKN2A predicted sensitivity to 991 with 30/33 mutant/loss lines being sensitive compared to only 2/6 wild type lines (p<0.006). Expression of CDK4, CCND1 or other cyclins or CDK-inhibitors did not predict sensitivity to 991. Conclusions: Genomic alterations in the CDK4 pathway are frequent in melanoma and are associated with worse survival, particularly when melanomas harbor two or more CNVs involving CCND1. Mutation, loss or low expression of CDKN2A in melanoma cell lines predicted sensitivity to the CDK4 inhibitor 991. Taken together these data support evaluation of CDK4 inhibitors in melanoma and suggest that CDKN2A maybe a genomic predictor of sensitivity to these agents.
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Hungerford, J. L. "Surgical treatment of ocular melanoma." Melanoma Research 3, no. 5 (October 1993): 305–12. http://dx.doi.org/10.1097/00008390-199310000-00001.
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