Melanoma Research最新文献

Malignant melanoma is a broad and heterogeneous class of malignant tumors derived from melanocytes and classified as cutaneous (skin), uveal, and mucosal melanoma. The incidence of melanoma has increased worldwide in recent decades. Surgery remains the mainstay of treatment, but a dramatic change in systemic treatment occurred when immune checkpoint inhibitors (ICIs) entered the therapeutic armamentarium for metastatic melanoma. Pembrolizumab and nivolumab, both anti-programmed death antibodies, demonstrated superiority over standard therapies with a 5-year survival rate. Toxicities resulting from ICIs have an autoimmune etiology and can affect any organ system. We then present a case of a patient with metastatic melanoma treated with an ICI strategy who developed endocrine toxicity such as the syndrome of inappropriate antidiuresis (SIAD). A previous case report concerning an anti-programmed death ligand 1 antibody suggests that this pathway may be involved in the development of SIAD.

BRAF and MEK inhibitor (BRAFi + MEKi) therapy has improved the treatment of solid tumors with BRAF mutation. However, their neurologic adverse events (nAEs) have been largely unexplored. This study aimed to provide clinicians with more updated knowledge on nAEs associated with BRAFi + MEKi therapy in patients with malignant melanoma compared with nonmelanoma cancers. The United States Food and Drug Administration Adverse Event Reporting System was queried from 2011 to 2022 to capture nAEs reported for the BRAFi + MEKi therapies, vemurafenib plus cobimetinib (V + C), dabrafenib plus trametinib (D + T), and encorafenib plus binimetinib (E + B). A disproportionality analysis was performed to calculate their reporting odds ratios (RORs) and 95% confidence intervals (CIs) using a control group of antineoplastic medications. There were 2881 BRAFi + MEKi therapy-associated nAE cases, the majority of which listed malignant melanoma as the reason for use (87.5, 66.7, and 62.0% for V + C, D + T, and E + B, respectively). Several novel associations were identified; including epidural lipomatosis (ROR: 320.07, 95% CI: 123.76-827.77 for V + C), peripheral nerve lesion (ROR: 185.64, 95% CI: 73.95-466.03 for V + C), Guillain-Barre syndrome (RORs: 8.80, 2.94, and 11.79, 95% CIs: 3.65-21.22, 1.40-6.19, and 5.87-23.66 for V + C, D + T, and E + B), demyelinating polyneuropathy (RORs: 24.72 and 78.98, 95% CI: 8.16-74.86 and 24.84-251.13 for D + T and E + B), and multiple sclerosis (ROR: 5.90, 95% CI: 3.06-11.40 for D + T) in melanoma patients. nAEs in the setting of BRAFi + MEKi therapy should be a safety consideration when utilizing these medications.

Myeloid-derived suppressor cells (MDSCs) are expanded in cancer patients, have an intrinsic immunosuppressive function, and thus may play a role in resistance to immunotherapy. Ulceration of the melanoma primary is associated with more aggressive disease and is an independent prognostic factor for melanoma-specific survival. However, the underlying factors contributing to this more aggressive phenotype are not completely understood. The current study aims to correlate changes in circulating MDSC during immunotherapy in patients with ulcerated vs non-ulcerated melanoma primary tumors. Longitudinal changes in levels of circulating MDSCs were analyzed via flow cytometry in melanoma patients receiving immune checkpoint inhibitors (ICIs) and stratified by ulceration status. Following the initiation of therapy, the percentage of total MDSCs increased significantly in patients with both ulcerated ( P  = 0.003) and non-ulcerated ( P  < 0.001) tumors. When MDSCs were stratified by subset, the proportion of granulocytic MDSC (PMN-MDSC) decreased in patients with non-ulcerated tumors ( P  = 0.023), while the proportion remained stable in patients with ulcerated tumors ( P  = 0.121). The reduction in the proportion PMN-MDSC in non-ulcerated patients coincided with a statistically significant increase in the proportion of CD14 + /CD15 + MDSC ( P  = 0.008), resulting in a greater proportion of CD14 + /CD15 + MDSC in non-ulcerated patients as compared to ulcerated melanoma patients following two infusions of ICIs (27.3 ± 19.2% vs 16.1 ± 19.2%; P  = 0.008). The trajectories of the MDSC populations described here provide insight into the altered tumor microenvironment in ulcerated melanoma and highlight key changes in a cell population that could contribute to immunotherapy resistance.

The objective of this study was to provide an overview of the current practice of patient-reported outcome (PRO) assessments in trials investigating treatment with BRAF inhibitors in patients with advanced melanomas. In addition, we extracted information on symptomatic adverse events (AEs) reported by clinicians to inform future PRO measurement strategies. For our systematic scoping review, we investigated randomized controlled trials (RCTs) evaluating treatment with BRAF inhibitors that had a primary, secondary or exploratory PRO endpoint and were indexed on PubMed. Two independent reviewers extracted information on general RCT characteristics, clinical results (e.g. survival, treatment response and symptomatic AEs) and the PRO measurement and results. Quality of PRO reporting using the CONSORT-PRO checklist was also assessed. We identified nine RCTs meeting the inclusion criteria, in which PROs were secondary or exploratory endpoints. In all trials but one, PROs were measured with the generic EORTC QLQ-C30 questionnaire. The quality of PRO reporting showed substantial variation across the different types of information, with information on handling of missing data and on PRO hypotheses lacking most frequently. Our analysis identified 29 relevant symptomatic AEs that could be reported directly by patients. Our findings may inform the planning of the PRO component of future RCTs, in particular regarding what symptoms and AEs should be covered by PRO measures to provide a comprehensive assessment of treatment tolerability. Our results also indicate a need for improving the quality of PRO reporting, to maximize the impact of PRO findings in real-word practice.

Acquired generalized lipodystrophy (AGL) is a rare complication of immune checkpoint inhibitors (ICIs) and is associated with immune-mediated loss of adipose tissue, peripheral resistance to insulin, and serious metabolic complications. Here we report a new case of ICI-induced AGL and provide an updated literature review of published cases. We report a 39-year-old female patient treated with adjuvant pembrolizumab for stage IIIC nevoid melanoma with ICI-induced AGL. After six cycles of pembrolizumab, she developed a 40 lb weight loss with fat wasting, a decreased leptin level, significant liver function abnormalities, hepatic steatosis, hypertriglyceridemia, and subsequently was found to have severe insulin dependence and resistance. No corticosteroids were given and pembrolizumab was discontinued. AGL persists at 3-year follow up and patient remains free of melanoma progression. Literature review identified an additional seven patients who developed ICI-induced acquired lipodystrophy, predominantly female. Of the identified cases, three patients received steroids without resolution of their acquired lipodystrophy, while one patient had resolution without steroid treatment. Five patients and our case were treated with ICIs for melanoma, and all had at least a partial response to treatment. ICI-induced acquired lipodystrophy is an exceedingly rare event with profound clinical consequences. Our case report and literature review better characterized the clinical course and treatment outcomes of these patients. With the increasing utilization of ICIs in treating cancer, further studies to better understand the underlying mechanism and to guide clinical management of the metabolic complications are needed.

Temozolomide is used in melanoma therapy, but the comparative efficacy and safety of monotherapy vs combination therapies are unclear. This meta-analysis evaluates temozolomide monotherapy vs combination therapies in melanoma patients. PubMed, Embase, and Cochrane Library were searched up to August 2024 for studies comparing temozolomide monotherapy with combination therapies in melanoma. Primary outcomes were 1-year survival and objective response rates (RR); secondary outcomes included hematologic and non-hematologic toxicities. Data were pooled using risk ratios with 95% confidence intervals (CIs). Seven studies were included. Combination therapies improved objective RR over temozolomide monotherapy (risk ratio 0.68, 95% CI: 0.53-0.88). One-year survival did not differ significantly between groups (risk ratio 0.81, 95% CI: 0.59-1.12). Temozolomide monotherapy was associated with reduced incidence of leukopenia (risk ratio 0.54, 95% CI: 0.30-0.95). Adding interferon-alpha (IFN-α) to temozolomide significantly improved 1-year survival (risk ratio 0.54, 95% CI: 0.35-0.84) and objective RR (risk ratio 0.57, 95% CI: 0.42-0.78) compared to temozolomide alone, without significantly increasing toxicity. Combination therapies enhance objective RR over temozolomide monotherapy, with similar 1-year survival. Temozolomide monotherapy offers a better hematologic safety profile. Combining temozolomide with IFN-α significantly improves survival and RR without increasing toxicity. Clinicians should balance efficacy and safety when choosing melanoma treatments.

Vitiligo-like hypopigmentation induced by immune checkpoint inhibitors (ICIs) has been largely associated with improved survival outcomes in metastatic melanoma. However, its development during adjuvant ICI therapy and its role as a prognostic factor in this setting remain unclear. We aimed to describe ICI-induced vitiligo in a cohort of patients with resected stage III melanoma treated with adjuvant ICI and to identify differences in progression-free survival (PFS) and distant metastasis-free survival (DMFS) between those who developed vitiligo and those who did not. Patients and data were collected from two institutions, both retrospectively and prospectively, from January 2018 to February 2024. Patients were divided into 'vitiligo' and 'non-vitiligo' groups for comparisons. Of 40 patients, 22.5% developed ICI-induced vitiligo [median follow-up: 23 months (1-73)]. Treatments received were nivolumab (70%) and pembrolizumab (30%). Fifty-five percent of the patients completed 1 year of treatment, 37.5% discontinued and 7.5% were still ongoing. Vitiligo and non-vitiligo groups differed in the cause of treatment discontinuation (severe toxicity in vitiligo vs. progression in non-vitiligo, P  = 0.005) and the occurrence of progression (none in vitiligo vs. 52% in non-vitiligo, P  = 0.001). Survival analyses showed longer PFS in vitiligo group ( P  = 0.013) and no differences in DMFS ( P  = 0.111). ICI-induced vitiligo typically affected photo-exposed areas, with a median time to onset of 4 months (1-27). These preliminary results on ICI-induced vitiligo in adjuvant treatment are in agreement with those reported in advanced melanoma treatment, so its development in the adjuvant setting could be a sign of good prognosis as well.

The management of head and neck melanoma (HNM) is constantly being fine-tuned in the era of immunotherapy. HNM have different metastatic patterns and a worse prognosis than melanoma of the trunk, asking for a more fine-tuned managing strategy. In clinically node-negative HNM patients, the ultrasound (US) with fine needle aspiration cytology (FNAC) and chest X-ray (CXR) are optional modalities in the preoperative staging workup. The contribution of imaging seems limited in this stage of disease. This study aims to research the value of the US-FNAC and CXR in clinically node-negative HNM patients. Clinical stage I-II HNM patients from 2016 to 2021 were retrospectively reviewed. A total of 373 patients were analyzed. Patient characteristics, surgery and follow-up details, recurrences, tumor characteristics, staging, imaging, sentinel node procedure (SNP) details, and lab results were collected from the patient files. All patients received preoperative US. A total of 65 FNACs were performed, which found metastatic lymph nodes in two patients (0.54%). The CXR was performed in 336/373 patients and did not find any pulmonary metastases. The SNP was performed in 242 patients and demonstrated 40 positive patients, with 86% having micrometastases, isolated tumor cells, or submicrometastases. This study demonstrated a low number of relevant findings by both the US and CXR. We can conclude that both imaging modalities do not have a significant contribution to the routine staging procedure of clinical stage I-II HNM in our study group, with our results being in line with current general melanoma guidelines.

Our primary objective was to estimate the overall response rate to immune checkpoint inhibitors (ICIs) in patients with locally advanced, multiply recurrent, or metastatic conjunctival melanoma treated with ICIs. A retrospective review of all consecutive conjunctival melanoma patients who were treated with ICI between October 2017 and January 2024 was carried out. The study included 16 patients with a median age of 66 years. The indications for ICI were locally extensive conjunctival melanoma in the eye/orbital area without nodal or distant metastasis in 10 patients, local recurrence of conjunctival melanoma and simultaneous nodal or distant metastasis in four patients, and metastatic conjunctival melanoma without local recurrence in two patients. Five patients received PD-1 inhibitor monotherapy with nivolumab or pembrolizumab; the other 11 received ipilimumab (CTLA-4 inhibitor) and nivolumab for several cycles and were then continued on nivolumab monotherapy ( n = 6) or not given additional ICI therapy ( n = 3). The number of cycles of ICI ranged from 2 to 25 (median, 13). Eight patients achieved a complete response. Six patients had progressive disease. The overall rate of objective response to ICI therapy was 63% (10 of 16), and for the subset of patients with local disease only, the objective response rate was 70% (7 of 10). In 14 patients (88%), orbital exenteration or additional extensive surgery was avoided; two patients had progression despite ICI and eventually needed an orbital exenteration. Future studies should aim to correlate biomarker data with response to ICI therapy in patients with conjunctival melanoma.