Identification of Plasma Lipid Alterations Associated with Melanoma Metastasis.

The aim of this study was to apply a state-of-the-art quantitative lipidomic profiling platform to uncover lipid alterations predictive of melanoma progression. Our study included 151 melanoma patients; of these, 83 were without metastasis and 68 with metastases. Plasma samples were analyzed using a targeted Lipidyzer™ platform, covering 13 lipid classes and over 1100 lipid species. Following quality control filters, 802 lipid species were included in the subsequent analyses. Total plasma lipid contents were significantly reduced in patients with metastasis. Specifically, levels of two out of the thirteen lipid classes (free fatty acids (FFAs) and lactosylceramides (LCERs)) were significantly decreased in patients with metastasis. Three lipids (CE(12:0), FFA(24:1), and TAG47:2-FA16:1) were identified as more effective predictors of melanoma metastasis than the well-known markers LDH and S100B. Furthermore, the predictive value substantially improved upon combining the lipid markers. We observed an increase in the cumulative levels of five lysophosphatidylcholines (LPC(16:0); LPC(18:0); LPC(18:1); LPC(18:2); LPC(20:4)), each individually associated with an elevated risk of lymph node metastasis but not cutaneous or distant metastasis. Additionally, seventeen lipid molecules were linked to patient survival, four of which (CE(12:0), CE(14:0), CE(15:0), SM(14:0)) overlapped with the lipid panel predicting metastasis. This study represents the first comprehensive investigation of the plasma lipidome of melanoma patients to date. Our findings suggest that plasma lipid profiles may serve as important biomarkers for predicting clinical outcomes of melanoma patients, including the presence of metastasis, and may also serve as indicators of patient survival.

Prognostic Role of Clinicopathological Characteristics and Serum Markers in Metastatic Melanoma Patients Treated with BRAF and MEK Inhibitors.

Prognostic studies can provide important information about disease biology and improve the use of biomarkers to optimize treatment decisions. METHODS: A total of 199 patients with advanced melanoma treated with BRAF + MEK inhibitors were included in our single-center retrospective study. We analyzed the risk of progression and death using multivariate Cox proportional hazard models. The predictive effect of prognostic factors on progression-free survival (PFS) was evaluated in ROC analysis. RESULTS: We found that primary tumor localization, Clark level, pT category, baseline M stage and baseline serum S100B are independent and significant prognostic factors for PFS. The discriminative power of the combination of these factors was excellent for predicting 18 month PFS (AUC 0.822 [95% CI 0.727; 0.916], p < 0.001). Primary tumor localization on the extremities, Clark level V, baseline M1c stage or M1d stage, and elevated baseline serum S100B and LDH levels were independently and significantly associated with unfavorable overall survival (OS). CONCLUSION: Baseline M stage and serum S100B appear to be independent prognostic factors for both PFS and OS in melanoma patients treated with BRAF + MEK inhibitors. We newly identified significant and independent prognostic effects of primary tumor localization and Clark level on survival that warrant further investigation.

Primary tumour category, site of metastasis, and baseline serum S100B and LDH are independent prognostic factors for survival in metastatic melanoma patients treated with anti-PD-1.

Background: Prognostic classification of metastatic melanoma patients treated with anti-PD-1 is of great interest to clinicians. Objective: We aimed to determine the anti-PD-1 treatment related prognostic performance of demographics, clinical and histological prognostic markers and baseline serum S100B and LDH levels in advanced melanoma. Methods: A total of 200 patients with unresectable metastatic melanoma were included in this retrospective study. 34.5% had stage M1c disease and 11.5% had stage M1d disease at the start of therapy. 30% had pT4b primary melanoma. 55.5% had elevated baseline serum S100B levels and 62.5% had elevated baseline serum LDH levels. We analysed the risk of death using univariate and multivariate Cox proportional-hazards models and the median overall (OS) and progression-free (PFS) survival using the Kaplan-Meier estimator. Results: The median follow-up time from the start of anti-PD-1 treatment in patients who were alive at the end of the study (N=81) was 37 months (range: 6.1-95.9). The multivariate Cox regression analysis showed that M1c stage (vs. M1a, p=0.005) or M1d stage at the start of therapy (vs. M1a, p=0.001), pT4b category (vs. pT1a, p=0.036), elevated baseline serum S100B levels (vs. normal S100B, p=0.008) and elevated LDH levels (vs. normal LDH, p=0.049) were independently associated with poor survival. The combination of M1d stage, elevated baseline serum S100B and LDH levels and pT4b category was associated with a very high risk of death (HR 4.72 [1.81; 12.33]). In the subgroup of patients with pT4b primary melanoma, the median OS of patients with normal serum S100B levels was 37.25 months [95% CI 11.04; 63.46]), while the median OS of patients with elevated serum S100B levels was 8.00 months [95% CI 3.49; 12.51]) (p<0.001); the median OS of patients with normal serum LDH levels was 41.82 months [95% CI 11.33; 72.32]), while the median OS of patients with elevated serum LDH levels was 12.29 months [95% CI 4.35; 20.23]) (p=0.002). Conclusion: Our real-world study indicates that the prognostic role of primary melanoma parameters is preserved in anti-PD-1 treated stage IV patients. Furthermore, there seems to be perspective in combining clinical, histological and serum prognostic markers in a prognostic model.

Combining Biomarkers for the Diagnosis of Metastatic Melanoma.

The early detection of melanoma relapse can improve patient survival; thus, there is a great need for easily accessible biomarkers that facilitate the diagnosis of metastatic disease. We investigated the diagnostic effect of blood biomarkers such as lactate dehydrogenase (LDH), S100B, and osteopontin in the detection of metastases. Clinical data and peripheral blood samples of 206 melanoma patients were collected (no metastasis, N = 120; metastasis, N = 86). The discriminative power of blood biomarkers, patient demographics, and clinicopathological parameters of primary melanomas were evaluated using univariate and multivariate logistic regression models and receiver operating characteristic (ROC) analysis to determine the area under the curve (AUC). Plasma osteopontin levels showed a significant and independent effect on the probability of metastasis, similar to serum S100B levels. In addition, the location of the primary tumor on the lower extremities and the American Joint Committee on Cancer (AJCC) categories pT2b-3a, pT3b-4a, and pT4b were associated with the diagnosis of metastasis. Importantly, the combination of the three blood biomarkers and primary tumor localization and AJCC pT category yielded excellent discrimination (AUC: training set: 0.803; validation set: 0.822). In conclusion, plasma osteopontin can be classified as a melanoma biomarker; moreover, by combining clinicopathological prognostic variables, the diagnostic effect of blood biomarkers in the detection of metastatic melanoma can be improved.

Cutaneous metastases at the sites of pembrolizumab-induced bullous pemphigoid lesions in a patient with melanoma.

The authors report a case of bullous pemphigoid (BP) that occurred during pembrolizumab therapy in a 67-year-old male patient with advanced melanoma. Following regression of BP blisters, they reintroduced anti-PD-1 treatment. Due to the flare-up of BP, immunotherapy was discontinued again and corticosteroid was restarted. As the BP lesions regressed, interestingly, new skin metastases developed, exactly where the blisters were. One year after discontinuation of anti-PD-1 treatment, considering the significant tumor progression, pembrolizumab was restarted. This induced tumor remission, while the added low-dose corticosteroid was able to prevent the recurrence of BP. The patient carries the BP-predisposing HLA-DQB1*03:01 allele. In conclusion, anti-PD-1 rechallenge may be considered in metastatic melanoma, even if restarting anti-PD-1 has previously caused the flare-up of BP symptoms.

Immune checkpoint inhibitors prolong the survival of patients with metastatic melanoma. Bullous pemphigoid (BP) is a rare, cutaneous, immune-related adverse event. The authors report a case of BP that occurred during pembrolizumab therapy in a 67-year-old male patient with advanced melanoma who responded to anti-PD-1 treatment with a partial response. Following the resolution of BP symptoms, pembrolizumab treatment was restarted after discontinuation of systemic corticosteroid therapy. Due to the flare-up of BP, anti-PD-1 treatment was discontinued and steroid therapy was restarted; however, skin metastases soon developed, exactly where the BP blisters were. Pembrolizumab rechallenge was successful in inducing the complete regression of skin metastases, while the added low-dose corticosteroid was able to prevent the recurrence of BP.

Regional variability of melanoma incidence and prevalence in Hungary. Epidemiological impact of ambient UV radiation and socioeconomic factors.

BACKGROUND: The incidence of cutaneous melanoma has risen faster than almost any other type of cancer in the last 50 years. Ultraviolet (UV) radiation and genetic susceptibility are the most important risk factors. OBJECTIVE: We aimed to determine the epidemiologic indicators of melanoma in Hungary, a country with an estimated population of 9.8 million and an area of 93 030 km2. METHODS: Anonymized patient records from the National Health Insurance Fund Management covering the entire population were used to determine the incidence and prevalence of melanoma in the counties of Hungary from 2013 to 2017. Altogether 20 030 melanoma cases were identified for inclusion in this study. RESULTS: The prevalence of melanoma increased over the investigated period and was significantly higher among women than men. The incidence of melanoma stagnated during this period and the incidence rate was the highest among the elderly. Interestingly, the incidence was higher in males in the elderly population, while the incidence was higher in females in the younger (<60 years) population. Geographical variations in ambient UV radiation did not show statistically significant correlation with the regional variability of epidemiologic indicators, probably due to small differences in the number of bright sunshine hours per year between regions. Although Hungary is a relatively small country, we observed regional heterogeneity in socioeconomic factors. Notably, a significant and strong negative correlation was found between single-person household rates and melanoma prevalence. CONCLUSION: In addition to ambient UV radiation, melanoma incidence and prevalence appear to be related to age, gender and socioeconomic factors.

Predictive Performance of Serum S100B Versus LDH in Melanoma Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Currently, no consensus on the use of blood tests for monitoring disease recurrence in patients with resected melanoma exists. The only meta-analysis conducted in 2008 found that elevated serum S100B levels were associated with significantly worse survival in melanoma patients. Serum LDH is an established prognostic factor in patients with advanced melanoma. OBJECTIVE: To compare the discriminative and prognostic ability of serum S100B with that of serum LDH in patients with melanoma. METHODS: This systematic review and meta-analysis were reported in accordance with the PRISMA Statement. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42019137138). RESULTS: A quantitative analysis of data from 6 eligible studies included 1,033 patients with cutaneous melanoma. The discriminative ability of serum S100B at identifying disease relapse [pooled Area Under the ROC (AUROC) 78.64 (95% CI 70.28; 87.01)] was significantly greater than the discriminative ability of serum LDH [AUROC 64.41 (95% CI 56.05; 7278)] (p=0.013). Ten eligible studies with 1,987 patients were included in the risk of death analysis. The prognostic performance of serum S100B [pooled estimate of adjusted hazard ratio (HR) 1.78 (95% CI 1.38; 2.29)] was independent but not superior to that of serum LDH [HR 1.60 (95% CI 1.36; 2.29)]. LIMITATIONS: A relatively small number of articles were eligible and there was considerable heterogeneity across the included studies. CONCLUSIONS: Serum biomarkers may provide relevant information on melanoma patient status and should be further researched. Serum S100B is a valid marker for diagnosis of melanoma recurrence. SYSTEMATIC REVIEW REGISTRATION: The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42019137138).

Increasing melanoma incidence in the elderly in North-East Hungary: is this a more serious problem than we thought?

There is a great need for efficient and cost-effective melanoma screening, but this is not yet solved. Epidemiological studies on trends in melanoma incidence by tumour thickness, anatomical site and demographical data can help to improve public health efforts regarding earlier melanoma diagnosis. We aimed to study the trends in the incidence and characteristics of patients and their melanoma in North-East Hungary from 2000 to 2014. Data were obtained from a university hospital-based registry. A total of 1509 cutaneous invasive melanomas of 1464 patients were included in the study. A moderate but significant increase in incidence was observed in the region [average annual percentage change: 3.04 (0.07; 6.11); P = 0.045], with a breakpoint in 2007. From 2001 to 2007, the trend was increasing [APC: 9.84 (3.52; 16.55); P=0.006], but it stalled from 2007 [APC: -2.45 (-5.99; 1.23); P = 0.164]. However, in the age groups over the age of 60 years, where the standardised incidence was the highest, the incidence continued to rise. Furthermore, older age, male sex and trunk or lower extremity localization were found to be associated with thicker melanomas. Our results support that regular screening examination for melanoma would be desirable for people over the age of 60 years.