Melanoma Research最新文献

Invasive cases of melanoma have increased by 44% annually in the past decade. B-Raf serine-threonine kinase (BRAF)/Mitogen-activated protein kinase kinase (MEK) inhibitors have become the standard of care for stage III/IV BRAF mutant melanoma. Due to limited adverse event (AE) data based on clinical trials, we aimed to describe and compare the AE and outcomes associated with melanoma therapies. A retrospective disproportionality analysis was conducted to assess and compare the trends of AEs associated with BRAF/MEK inhibitors and combinations. The primary data were extracted from the Food and Drug Administration (FDA) Adverse Event Reporting System database from 2012 to 2021. Study drugs included BRAF/MEK inhibitors (dabrafenib, trametinib, vemurafenib, cobimetinib, encorafenib, and binimetinib). A reporting odds ratio (ROR) was calculated for the most common AEs and outcomes reported. We found 195 640 unique AE reports associated with BRAF and MEK inhibitor usage, representing 52 772 patients. The leading AEs associated with BRAFi and MEKi use were as follows: pyrexia, fatigue, nausea, diarrhea, rash, vomiting, and arthralgia. Encorafenib and binimetinib had significant odds for nausea [ROR, 1.91 (1.73-2.11) and ROR, 1.91 (1.73-2.11), respectively]. The incidence of fatigue was highest in the encorafenib [ROR, 1.71 (1.54-1.90)], binimetinib [ROR, 1.74 (1.57-1.94)], and vemurafenib [ROR, 1.27 (1.14-1.27)] groups. Cobimetinib had significantly increased odds for developing a disability [ROR, 4.95 (4.28-5.74)], having a hospitalization [ROR, 2.08 (1.99-2.17)], and experiencing a life-threatening event [ROR, 1.78 (1.55-2.03)]. AE reports associated with melanoma therapies are sizable and significant. Healthcare professionals should be aware of the AE profiles attributable to the melanoma treatment and management.

Reexcisions for melanoma do rarely present residual melanoma. To analyze the number of positive margins in reexcisions of in situ and <1 mm melanomas. To see whether the immunohistochemical (IHC) panel (Preferentially expressed antigen of melanoma (PRAME), Sry-related HMg-Box gene 10 (SOX 10), Human melanoma black 45 (HMB45), and Melan A) detected additional cases of melanoma. Three pilot cohorts (retrospective, prospective, and direct safety margins) were analyzed on the persistence of melanoma in reexcisions. Among the 97 cases of the retrospective cohort (27 in situ and 69 invasive melanomas), one residual in situ melanoma was detected in the reexcisions. In the second cohort, among 81 cases (18 in situ and 63 invasive melanomas), two cases (2.5%) presented in situ melanoma. In the group where direct margins were taken ( n  = 21) 2 (9.5%) in situ melanoma were evidenced in the margins. The IHC panel was needed to confirm three additional in situ melanomas in cohort 2. In a total of 178 cases (97 + 81) of reexcision, three and five cases (1.7 and 3.4%) of in situ melanoma were evidenced after H/E and IHC, respectively. These pilot data could question the usefulness of reexcision in <1 mm melanomas, particularly as only cases of in situ melanoma were detected. Larges prospective series would be required to answer this issue.

Uveal melanoma is a rare malignancy with a strong propensity for late metastases, most commonly affecting the liver. Pulmonary metastases are less frequent and can manifest years or even decades after the primary diagnosis. This study presents three cases of pulmonary metastases secondary to uveal melanoma, highlighting clinical presentations, treatment strategies, and outcomes following surgical intervention. A retrospective analysis of 132 patients diagnosed with uveal melanoma between 2009 and 2022 at one institution was conducted. Clinical and pathological data were reviewed to assess primary tumor characteristics, metastatic patterns, treatment approaches, and patient outcomes. Three patients were identified with pulmonary metastases, diagnosed at least a decade after primary tumor treatment. The metastatic presentation varied, with one patient exhibiting bilateral multiple nodules, while the other two had solitary pulmonary lesions. All patients underwent video-assisted thoracoscopic surgery wedge resection, confirming metastatic melanoma. Two patients remained disease-free following resection, while one developed systemic progression with small bowel metastases, ultimately leading to fatal complications. Surgical resection of isolated pulmonary metastases from uveal melanoma may offer clinical benefit in highly selected patients. While not a standard treatment modality, pulmonary metastasectomy may be appropriate in selected patients and can be considered within the context of a multidisciplinary evaluation.

As a highly aggressive skin cancer, melanoma presents substantial clinical challenges stemming from its metastatic potential and therapy resistance, primarily driven by epithelial-mesenchymal transition (EMT). This review examines EMT's central role in melanoma progression. Molecular mechanisms are detailed, encompassing transcription factors (ZEB1, Snail, Twist), signaling pathways (transforming growth factor beta/Smad, Wnt/β-catenin, phosphatidylinositol 3-kinase/protein kinase B, mitogen-activated protein kinase/extracellular signal-regulated kinase), plus epigenetic and noncoding RNA regulators. Through extracellular matrix remodeling and phenotypic plasticity, EMT potentiates melanoma cell invasion. This facilitation enables key metastatic cascade steps: intravasation and distant colonization. EMT further drives resistance to both targeted therapies (BRAF/MEK inhibitors) and immunotherapies. Mechanisms include T-cell exclusion, PD-L1 upregulation, and immunosuppressive tumor microenvironment remodeling. Tumor progression is amplified via EMT interactions with stromal components, including cancer-associated fibroblasts and immune cells. Prognostically valuable biomarkers are emerging, particularly EMT gene signatures detectable in circulating tumor cells and tissue samples. Preclinical studies suggest therapeutic potential for strategies targeting EMT transcription factors, signaling pathways, and combination approaches. Despite progress, limitations endure: EMT heterogeneity and inadequate preclinical models. Future work will leverage single-cell analysis and spatial transcriptomics to decipher EMT dynamics. Such advances could enable personalized melanoma treatments. EMTs' multifaceted role is underscored herein, along with the urgent requirement for innovative therapeutics to enhance patient outcomes.

Uveal melanoma is the most common intraocular malignancy in adults. Prognostic markers such as monosomy 3 and chromosome 8q gain are well validated in Western cohorts but remain unproven in Indian patients. We retrospectively analysed 30 tumours (17 metastatic, 13 nonmetastatic) using the OncoScan FFPE Assay Kit. Loss of chromosome 6q was strongly associated with metastasis (odds ratios, 23.2; 95% confidence intervals, 2.5-214; P  < 0.001), compared to monosomy 3 and 8q gain. Multivariate analysis confirmed 6q loss as the dominant independent predictor. These findings support population-specific prognostic models and highlight the clinical value of integrating 6q status into risk assessment.

The exact role of nevi in the development of melanoma is not yet completely understood, and it remains unknown whether de novo and nevus-associated melanoma (NAM) constitute distinct biological entities. A few studies have documented differences in histological and clinical characteristics between de novo and NAMs; however, data from Southern Europe are lacking. This study examined epidemiological and clinical data of patients who were followed up at the Melanoma Reference Center of the General Hospital of Athens G. Gennimatas from 2022 to 2024 and had been diagnosed with primary skin melanoma from 1999 to 2024. In a total of 509 primary melanomas 289 (56.8%) were nevus-associated and 220 (43.2%) de novo. NAMs were more likely to be diagnosed in patients <40 and 40-65 years old compared to de novo melanomas (P < 0.001). NAMs were more likely to develop on the trunk and the extremities compared to de novo tumors, which predominated on the head (P < 0.001). Superficial spreading melanomas were more likely to be nevus-associated, while nodular, acral lentiginous, and lentigo maligna melanomas were more likely to develop de novo (P < 0.001). NAMs were more likely to be diagnosed at earlier stages and be thinner compared to de novo tumors (P < 0.001). NAMs were also more likely not to present ulceration (P = 0.002) and to have a low mitotic rate (<3/mm2) (P < 0.001). Patients with de novo melanomas more often experienced disease progression compared to those with NAM. NAMs seem to have less aggressive behavior compared to de novo melanomas. This study highlights the differences between de novo and NAMs, adding novel information about features such as the presence of dysplastic nevi, the mitotic rate, and the disease progression that had not been investigated in previous studies.

This retrospective cohort study evaluated disparities across insurance types, racial groups, and socioeconomic status (SES) in acral lentiginous melanoma (ALM). We analyzed adults diagnosed with ALM in the National Cancer Database from 2016-2020. Cox proportional hazards model assessed associations between demographic and clinical variables with ALM-specific survival. Kaplan-Meier curves analyzed 1-, 3-, and 5-year survival. A total of 3446 patients with ALM were identified. Uninsured patients presented with advanced-stage cancers, experienced longer time to treatment, and were more likely to undergo major amputations compared with privately insured patients ( P  < 0.001). Survival analysis indicated lower probabilities for uninsured patients at 1, 3, and 5 years, although the differences did not reach statistical significance. Black patients were more likely uninsured, had higher Charlson-Deyo comorbidity scores, resided in areas of lower income and education, experienced longer time to treatment ( P  < 0.001), and had significantly lower survival at 3 and 5 years compared with White patients ( P  < 0.01). Patients in SES Q1 traveled further for care, had longer time to treatment, were less likely to be treated with Mohs surgery ( P  < 0.001), and had worse survival at 1, 3, and 5 years compared with patients in SES Q4 ( P  < 0.001). In conclusion, significant disparities in disease presentation, access to care, and health outcomes in patients with ALM exist based on insurance status, race, and SES, emphasizing the need for targeted interventions to enhance early diagnosis and equitable treatment.

Pathogenic variants in the CDKN2A gene are the most common genetic cause of hereditary melanoma, significantly increasing the risk of multiple melanomas at an early age and the incidence of noncutaneous tumors, particularly pancreatic cancer. Similarly, the MITF p.E318K variant is associated with an elevated risk of cutaneous melanoma, renal cell carcinoma, and pancreatic cancer. This study investigates the incidence of cutaneous and noncutaneous cancers among first- and second-degree relatives of patients with cutaneous melanoma who carry the same CDKN2A or MITF p.E318K germline variants as their corresponding index case. Among 62 relatives of patients with cutaneous melanoma, 48 (77.4%) carried CDKN2A variants, while 14 (22.6%) carried the MITF p.E318K variant. Of the 39 CDKN2A carriers with follow-up data (mean duration: 60.87 months), 31 were cancer-free at the time of genetic diagnosis, while eight had a prior cancer history, including seven with cutaneous melanoma. During follow-up, five carriers developed a new cancer. In CDKN2A families, additional cutaneous melanoma and pancreatic cancer cases were observed in 43.75 and 21.87% families, respectively. In the MITF cohort, none of the 12 cancer-free carriers developed cutaneous melanoma during a mean follow-up of 24.64 months, although two developed basal cell carcinoma. Among the three index cases, two had invasive cutaneous melanoma, and all three families had pancreatic cancer cases. This study highlights the heightened elevated cancer risk for CDKN2A and MITF p.E318K variant emphasizing the need for ongoing surveillance.

Compound 48/80 (Com 48/80), a mast cell degranulator, triggers allergic reactions and has been linked to a reduced risk of skin cancer. This study investigated the potential anticancer effects of Com 48/80 using in vitro and in vivo melanoma models. In vitro, Com 48/80 significantly induced apoptosis in melanocytes through caspase activation. In the melanoma animal model experiment, Com 48/80 enhanced survival, reduced tumor volume, and downregulated melanoma-specific genes (Dct2 and Gp100), while increasing the activities of caspase-3, -8, and -9. Additionally, Com 48/80 elevated allergy-related and immune-enhancing mediators, including immunoglobulin E, histamine, interleukin (IL)-2, IL-4, IL-5, IL-6, IL-12, IL-13, IL-33, tumor necrosis factor-α, thymic stromal lymphopoietin, and interferon-γ. In the immunodeficient mice, Com 48/80 improved survival, suppressed melanoma growth, reduced immobility time, and enhanced the expression of immune mediators. Moreover, Com 48/80 significantly lowered tissue damage indicators compared to tumor control mice. These results suggest that Com 48/80 inhibits melanoma progression by inducing apoptosis and enhancing immune responses, highlighting the potential of Com 48/80 as a novel therapeutic strategy for melanoma treatment and prevention.

Metastatic melanoma is characterized by high rates of treatment resistance. While various factors have been studied for their prognostic significance, this study evaluated the potential prognostic value of the intrinsic disorder of T-cell receptor beta (TRB) polypeptides. TRB recombination sequencing reads were extracted from tumor RNA-seq files representing The Cancer Genome Atlas, Skin Cutaneous Melanoma dataset, and genomics files representing the National Institutes of Health, phs002683 dataset. Intrinsic disorder values were computed for the TRB V-complementarity determining region 3 (CDR3)-J amino acid sequences for all cases. Survival analyses assessed overall survival and disease-specific survival for case sets based on assigning cases to upper or lower 50 th percentile groups, based in turn on intrinsic disorder values. For the phs002683 dataset, intrinsic disorder values were compared between cases representing resistance to immune checkpoint inhibitors (ICIs) and cases representing no observed resistance. The results indicated that the upper 50 th percentile of the range of intrinsic disorder values was linked to better outcomes. This was obtained for two TRB datasets representing different RNA-seq file, recombination read extraction algorithms, and was observed for two different intrinsic disorder models. Furthermore, low minimum various long-3 and various short-long 2 values correlated with ICI treatment resistance. The findings of this study suggest that the diversity of intrinsic disorder values representing TRB V-CDR3-J assemblies may represent a novel prognostic biomarker for metastatic melanoma cases and a potential biomarker for indicating different personalized treatments.