Signal regulatory protein γ is associated with an exhaustion-prone immune microenvironment in metastatic melanoma.

Autophagy meets tissue-resident memory: Emerging crosstalk and therapeutic opportunities in cutaneous melanoma.

Sentinel lymph node biopsy (SLNB) is the standard staging procedure in cutaneous melanoma of the head and neck, but current guidelines are extrapolated from non-head and neck studies. Existing risk models lack specificity for this region. Using the National Cancer Database, we developed and internally validated a nomogram and web-based calculator to estimate SLNB positivity specifically in head and neck cutaneous melanoma. We conducted a retrospective cohort study using the NCDB, including patients with cutaneous melanoma of the head and neck. The inclusion criteria were patients with clinical node-negative, early-stage melanoma who underwent SLNB between 2004 and 2021. Demographic, clinical, and pathologic features were compared using chi-squared testing, and multivariable logistic regression identified independent predictors of SLNB positivity. Significant factors were incorporated into a nomogram and interactive risk calculator. We included 14,058 clinical N0, M0 cutaneous head and neck melanoma patients who underwent SLNB. Of these, 2182 (15.5%) had a positive SLNB. In multivariable analysis, age, head and neck sublocation, histologic subtype, mitotic rate, Breslow thickness, lymphovascular invasion, and ulceration were identified as independent predictors of SLNB positivity. A nomogram based on these variables was developed. The model demonstrated good discrimination with a C-index of 0.724 (95% CI, 0.712-0.735). This study provides a predictive tool that allows head and neck surgeons to estimate the risk of SLNB positivity in individual patients, enabling more personalized surgical decision-making in early-stage head and neck melanoma.

ACR Appropriateness Criteria® Staging and Follow-Up of Melanoma.

Giant thick melanomas (GTMs) are rare tumors characterized by extreme size and depth. We aimed to describe their clinical features and outcomes. We retrospectively reviewed eleven patients diagnosed with GTMs at a tertiary dermatology center. GTMs were defined as primary cutaneous melanomas with diameter > 5cm and Breslow thickness > 4mm. Tumor size was measured clinically, and all histopathology was reviewed by two dermatopathologists. Clinical, pathological, treatment, and outcome data were extracted from electronic records. Eleven patients (median age 69years) presented with large tumors (median diameter 55mm; median Breslow thickness 12mm), most often on the trunk or extremities. Over half (54.5%) had stage III-IV disease at diagnosis, and treatments included surgery and systemic therapy. Median overall survival was 13months, with two long-term survivors. GTMs are aggressive and frequently diagnosed at advanced stages. Early recognition and multidisciplinary management are essential. Giant thick melanoma (GTM) is a rare entity characterized by aggressive behavior and poor prognosis. We conducted a retrospective descriptive study defining GTM as lesions with a diameter > 5cm and Breslow thickness > 4mm. Eleven cases were analyzed (mean age: 68.5years), with a female predominance and predominant localization on the trunk. The main reasons for consultation were tumor growth, bleeding, and neurological symptoms. At diagnosis, AJCC stages ranged from IIB to IV. During follow-up, seven patients died -five due to melanoma and two from other causes-, while two remain alive and under active follow-up. Median follow-up was 1year (range 0-15years; mean 3.5years). These findings confirm the severity of GTM and highlight the persistence of diagnostic delay. The main limitation of this study is the small sample size.

The elevated incidence of second primary tumors (SPTs) has been reported in certain subtypes of cutaneous T-cell lymphomas (CTCLs) and cutaneous B-cell lymphomas (CBCLs), but remains unclear for overall primary cutaneous lymphomas (PCLs). Using Surveillance, Epidemiology and End Results (SEER) data, we analyzed 20,970 patients with PCLs and evaluated standardized incidence ratios (SIRs) and survival outcomes of SPTs stratified by lymphoma subtype (indolent vs. aggressive). A total of 2,589 SPTs were identified (SIR = 1.40, 95% CI 1.35-1.45), with significantly elevated risks across sex, ethnicity, stage, latency, year of diagnosis, and treatment. Both indolent and aggressive CTCLs were associated with increased SPT risk, with SIRs of 1.27 (1.16-1.39) and 1.38 (1.11-1.69), respectively. Lymphatic and hematopoietic malignancies predominated in indolent CTCLs, along with thyroid cancer, whereas aggressive CTCLs were mainly associated with extranodal non-Hodgkin lymphoma and myeloma. Increased SPT incidence was also observed in indolent and aggressive CBCLs (SIR = 1.49 and 1.38), with indolent CBCLs showing a broad SPT spectrum including lung cancer and cutaneous melanoma. Patients younger than 30 years, with stage I disease or aggressive PCLs, had decreased age-adjusted overall and disease-specific survival, indicating a need for more intensive surveillance.

Cutaneous and mucosal melanoma are biologically and clinically distinct malignancies whose epidemiology varies markedly across populations and skin phototypes. In Arab and other Eastern Mediterranean populations, melanoma is comparatively uncommon but is frequently diagnosed at an advanced stage and shows a relatively high proportion of acral and mucosal subtypes. Data describing melanoma in the Palestinian population are scarce. We characterised the clinicopathological profile of cutaneous and mucosal melanoma diagnosed at a large Palestinian diagnostic pathology service and placed the findings in a comparative regional context. We performed a retrospective review of all histopathologically confirmed cases of cutaneous and mucosal melanoma reported at Medicare Diagnostic Laboratories, West Bank, Palestine, between May 2008 and May 2026. Demographic variables (age, sex), anatomical site, melanoma subtype, depth of invasion (Clark level), and, where recorded, Breslow thickness and American Joint Committee on Cancer (AJCC) stage were abstracted from pathology records. Diagnoses were confirmed on haematoxylin-eosin sections supported by immunohistochemistry (S100, SOX10, HMB-45, Melan-A). Repeat specimens were consolidated to the patient level, and findings were compared with published series from neighbouring countries. Fifty-seven patients with primary melanoma were identified, comprising 47 cutaneous (82.5%) and 10 mucosal (17.5%) tumours. The mean age at diagnosis was 59.5 +/- 17.0 years (range 10-87), and there was a slight female predominance (30 women, 52.6%; male-to-female ratio 0.90:1). Acral sites (sole, heel, plantar, and subungual regions) accounted for 15 of 47 cutaneous melanomas (31.9%), the most common single location, followed by the head and neck (14, 29.8%). Among mucosal tumours, the anorectum was the predominant site (6 of 10, 60%). A histological subtype was explicitly recorded in only 19 of 57 cases; within this limited subset the nodular pattern predominated (18 of 19), although the large proportion of cases without a stated subtype precludes firm conclusions about the true distribution of melanoma subtypes in this cohort. The Clark level was documented in 27 patients, of whom 26 (96.3%) had level IV-V (deep) invasion. A further 17 patients presented with metastatic melanoma deposits without a primary tumour in the archive. Melanoma in this Palestinian cohort was characterised by a slight female predominance, a high proportion of acral (31.9% of cutaneous) and mucosal (17.5% of all primary) tumours, a predominantly nodular phenotype among the subset of cases with a recorded subtype, and deep invasion at diagnosis. This profile mirrors patterns reported in neighbouring Arab and Eastern Mediterranean populations and contrasts with more lightly pigmented (Fitzpatrick I-II) Western populations. The findings underline the need for improved melanoma awareness, routine examination of acral and mucosal sites, and strengthened cancer registration in Palestine.

Melanoma is an aggressive malignancy with rising global incidence. While early surgical intervention improves survival in localized cases, treatment resistance and recurrence remain a challenge. This underscores the critical need to identify prognostic biomarkers for early diagnosis, personalized treatment, and novel therapeutic development. The GSE126076 and melanoma dataset (Skin Cutaneous Melanoma, TCGA, PanCancer Atlas) were analyzed using an information-theoretical method to identify prognostic factors. Survival analysis was performed via Kaplan-Meier curves and log-rank tests to compare high- and low-mRNA expression groups. In vitro, A375 cells and A2058 cells were treated with the GGT inhibitor 6-diazo-5-oxo-L-norleucin (DON). Cell viability was assessed using the CCK-8 assay and intracellular GSH levels were measured following treatment. Through information-theoretic analysis and survival analysis, we identified GGT6 as a prognostic gene in melanoma. Survival analysis revealed that high GGT6 expression was significantly associated with shorter disease-specific survival across all disease stages. In vitro, 10 μM DON for 72 h reduced A375 cell proliferation by 90.72% versus control (p<0.0001), with an IC50 of 5.14 μM; and reduced A2058 cell proliferation by 60.93% (p<0.0001), with an IC50 of 7.93 μM. Measurement of GSH levels of A375 and A2058 cells revealed that melanoma cells treated with 10 μM DON exhibited lower GSH levels compared with the respective control groups (p<0.0001 and p=0.0042, respectively). Our study is the first to demonstrate the association between GGT6 expression levels and melanoma prognosis, and reveals that GGT inhibition suppresses melanoma cell viability. These findings provide new insights into the mechanisms of melanoma development and progression, and suggest GGT as a potential therapeutic target for clinical treatment.

Oral melanoma in the immunotherapy era: Immune evasion, resistance, and therapeutic opportunities.

Optimising personalised melanoma care: A national e-Delphi consensus survey exploring expert perspectives on the use of a novel prognostic biomarker for early-stage cutaneous malignant melanoma.

AI-based histopathology analysis predicts checkpoint inhibitor response in advanced melanoma and identifies patterns associated with response.

Cutaneous melanoma accounts for 5% of new cancer diagnoses in the United States. Despite advancements in treatment of melanoma, marked racial, ethnic, and socioeconomic disparities persist. To determine if there are racial and ethnic disparities in melanoma survival and to highlight opportunities for interventions to improve melanoma patient outcomes. The databases PubMed/Medline, EMBASE, and Web of Science were searched from inception to February 9, 2021. Original publications reporting mortality statistics by race/ethnicity for patients with cutaneous melanoma, vulvar melanoma, or melanoma metastases were selected. Only experimental studies, observational studies, and research letters, with a study population in the United States were included. This investigation was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Authors performed title and abstract screening, followed by full text review in duplicate. We hypothesized that racial and ethnic minority groups would have worse melanoma mortality outcomes when compared to White patients. Five representative studies with dates ranging from 1992-2015 were selected. The overall hazard ratio (HR) for Black patients vs. White patients was 1.31 (95% confidence interval (CI): 1.09-1.57), indicating that Black patients had a 31% increase in the risk of death as compared to White patients. Asian/Pacific Islander patients also had a 31% increase in the risk of death as compared to White patients (HR 1.31, 95% CI: 1.17-1.46). Hispanic patients had a 9% increase in the risk of death as compared to Non-Hispanic White (HR 1.09, 95% CI: 1.03-1.16). There was no significant difference in risk between American Indian/Alaskan Native and White patients (HR 0.94, 95% CI: 0.57-1.55). Worse melanoma survival outcomes in racial and ethnic minority groups are evidenced by multiple studies. More current investigations of melanoma outcomes in racial and ethnic minorities are necessary to identify and implement measures to narrow the gap in health outcomes. Question: Are there racial and ethnic disparities in melanoma mortality outcomes? The pooled meta-analysis revealed that there are significantly worse melanoma survival outcomes in racial and ethnic minority groups when compared to White patients. The overall HR for Black, Asian/Pacific Islander, and Hispanic patients compared to White patients were 1.31, 1.31, and 1.09, respectively. Meaning: Worse melanoma survival outcomes in racial and ethnic minority groups are evidenced by these meta-analyses.

The RAC1 GTPase hotspot mutation P29S (RAC1P29S) is among the top driver oncogenes of cutaneous melanoma, which is known to develop resistance to MAPK pathway inhibitors including those targeting BRAF and MEK. Isoprenylcysteine carboxylmethyltransferase (ICMT) is the enzyme catalyzing the last step of post-translational prenylation of RAC1, which is among its substrates. We demonstrate that RAC1P29S/C189S, which lacks C-terminal prenylation site, has lost the ability to induce resistance toward MAPK-pathway-inhibitors in BRAFV600E melanoma cells. Furthermore, the combination of vemurafenib with cysmethynil, a proof-of-concept ICMT inhibitor, showed efficacy in combating RAC1P29S-driven resistance of BRAFV600E melanoma cells in both in vitro and in vivo settings. Concurrent treatment with cysmethynil and the MAPK pathway inhibitors efficiently inhibited proliferation and tumor formation of RAC1P29S cells that are resistant to MAPK pathway inhibitors alone. Mechanistically, we found that the combined treatment impaired the nuclear translocation of TAZ, whose transcriptional activity is shown to account for resistance to MAPK pathway inhibitors in RAC1P29S melanoma. We further validated the role of TAZ in RAC1P29S-driven resistance by demonstrating that introducing a constitutively-active TAZ mutant enhanced the resistance to MAPK pathway inhibitors in native cells, phenocopying the effect of RAC1P29S. The novel application of MAPK pathway inhibitors and cysmethynil combination in RAC1P29S-driven MAPK-pathway-inhibitor-resistant melanoma cells extends the potential utility of ICMT inhibitors, and also provides a new mechanism for targeting ICMT in cancer.

Alpine regions exhibit high incidence rates of cutaneous melanoma due to increased ultraviolet radiation at higher altitudes. In 2022, the "Montagna SÌ, Melanoma NO" (Mountain YES, Melanoma NO) public health campaign began promoting sun-protective behaviors in these areas. This study aims to evaluate an intervention's effectiveness 3 years after its launch and assess improvements in sun safety practices. A before-and-after comparative study was conducted by surveying a random sample of 229 Belluno residents in the Veneto Region, Italy, in 2022, and 115 of those same individuals in 2025 using a standardized questionnaire. Data on sociodemographics, phenotypic characteristics, sun exposure habits, sunscreen use, protective clothing/eyewear usage, and campaign awareness were collected. In 2025, 43% of respondents (95% CI: 33.44%-52.17%) reported being aware of the health promotion efforts. A significant increase in sunscreen application during outdoor activities lasting more than 1 hour and during skiing was detected. Nevertheless, other protective measures, such as the use of caps and sunglasses, did not demonstrate any significant improvement. The campaign was effective. It reached its target population and improved sun-protective behaviors, confirming the value of community-engaged, tailored health promotion strategies. Further initiatives are necessary to address the remaining gaps in melanoma prevention adherence.

JAAD Game Changers: "Histopathologic regression in patients with primary cutaneous melanoma undergoing sentinel lymph node biopsy is associated with favorable survival and, after metastasis, with improved progression-free survival on immune checkpoint inhibitor therapy: A single-institutional cohort study".

Sentinel lymph node biopsy (SLNB) for cutaneous melanoma (CM) provides essential prognostic information and is a component of the American Joint Committee on Cancer (AJCC) staging; however, up to 88% of SLNBs performed are negative. This means most patients who undergo the procedure do not benefit but are exposed to additional costs and surgery-associated morbidities. Improved tools are needed to identify patients at low risk of sentinel lymph node (SLN) positivity for whom the procedure is unnecessary and can be avoided. Here, we compared the sentinel lymph node positivity predictive accuracy of the integrated 31-gene expression profile (GEP) for sentinel lymph node biopsy (i31-SLNB) and the Melanoma Institute Australia (MIA) nomogram in patients with CM enrolled in the prospective DECIDE study who underwent SLNB. Data from patients with T1-T4 tumors and i31-SLNB test results from a prospective, multicenter study were evaluated. Area under the curve (AUC) was used to compare the discriminative performance of the i31-SLNB and MIA nomogram in predicting SLN positivity. Observed SLN positivity rates in patients with conflicting risk predictions were examined. The analysis included 912 patients, of whom 430 were SLN-assessed. The i31-SLNB predicted < 5% risk of SLN positivity more often than the MIA nomogram and observed positivity was below 5% for the i31-SLNB (2.6%, negative predictive value [NPV] = 97.4%, 95% CI 94.2-100.0%) but not the MIA nomogram (5.8%, NPV = 94.2%, 95% CI 88.1-98.7%). The AUC for the i31-SLNB was 0.74, significantly higher than that of the MIA nomogram (0.61; p = 0.001), demonstrating better discriminative performance. At 5% and 10% risk thresholds, when the tools conflicted in their risk predictions, the i31-SLNB was accurate, with observed SLN positivity rates of 1.9% and 2.8% below each threshold and 11.5% and 25.8% above each threshold. The i31-SLNB more accurately stratifies patients under consideration for SLNB into groups based on risk of SLN positivity than the clinicopathologic-only MIA nomogram.

This report presents a case of amelanotic metastatic cutaneous melanoma to the vitreous masquerading as a fungal endophthalmitis. A 74-year-old immunocompromised man with a history of Stage 4 metastatic cutaneous melanoma presented with 1+ vitreous cell and a fluffy white peripheral infiltrate in the left eye. Following subsequent vitrectomy for a vitreous hemorrhage, this patient developed preretinal macular deposits that continued to increase in size while undergoing treatment for a presumed fungal endophthalmitis. The patient went on to develop a total retinal detachment with a diffuse hemorrhagic retinopathy. Cytopathologic analysis revealed necrotic melanoma cells from the preretinal surface and within the vitreous cavity. This case highlights the importance of including vitreous metastasis in the differential of vitritis in the setting of cutaneous melanoma. Optical coherence tomography can be used to monitor the progression of preretinal deposits, with an increase in size of the deposits prompting reevaluation of treatment options.

Shared genetic architecture of Parkinson's disease and cutaneous melanoma: Heterogeneous pleiotropy and Colocalization at the SOX6 locus.

Immune checkpoint blockade (ICB) often fails in cutaneous melanoma due to an incomplete understanding of the spatially organized tumor microenvironment (TME). This study aims to define the spatial architecture of the melanoma TME and identify key molecular regulators that determine anti-tumor immunity and ICB response. We employed an integrative analysis of single-cell and spatial transcriptomics to map the TME. We defined spatial domains and deconvoluted their cellular composition. Cell-cell communication and risk modeling were performed. Functional roles of candidate genes were assessed using in vitro co-culture with anti-PD-1 and in vivo knockdown in a humanized mouse model. We delineated two prognostically significant spatial domains: an Immune region and a Melanocyte region. Multi-omics convergence nominated CORO1A as a key regulator within the immune niche. Its knockdown synergized with anti-PD-1 to suppress tumor growth in vivo, and anti-PD-1 downregulated its expression in vitro. We further identified APP-CD74 and FN1-CD44 as key inter-domain communication axes. Our study provides a spatially resolved blueprint of the melanoma TME and identifies CORO1A as a functional regulator within the immune niche, where its modulation enhances T-cell activity and synergizes with ICB. These findings reveal spatial organization as a critical determinant of immunotherapy efficacy and nominate CORO1A as a promising target for combination therapy.

Second Primary Malignancies Incur Significant Mortality Penalty in Patients With Cutaneous Melanoma.