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.

Predictors of restenosis following percutaneous coronary stent implantation: The role of trimetazidine therapy.

Aims: In-stent restenosis (ISR) is an unresolved problem following percutaneous coronary intervention (PCI), having a negative impact on clinical outcome. The main goal of this study was to find new independent predictors that may influence the development of ISR. Methods and results: In this retrospective analysis, 653 PCI patients were involved. All patients had coronary stent implantation and a follow-up coronary angiography. Based on the presence of ISR at follow-up, patients were divided into two groups: 221 in the ISR and 432 in the control group. When evaluating the medical therapy of patients, significantly more patients were on trimetazidine (TMZ) in the control compared to the ISR group (p = 0.039). TMZ was found to be an independent predictor of a lower degree of ISR development (p = 0.007). TMZ treatment was especially effective in bare metal stent (BMS)-implanted chronic coronary syndrome (CCS) patients with narrow coronary arteries. The inflammation marker neutrophil to lymphocyte ratio (NLR) was significantly elevated at baseline in the ISR group compared to controls. The reduction of post-PCI NLR was associated with improved efficacy of TMZ to prevent ISR development. Drug eluting stent implantation (p < 0.001) and increased stent diameter (p < 0.001) were the most important independent predictors of a lower degree of ISR development, while the use of longer stents (p = 0.005) was a major independent predictor of an increased ISR risk. Conclusion: TMZ reduces the occurrence of ISR following PCI, with special effectiveness in BMS-implanted patients having CCS and narrow coronary arteries. TMZ treatment may help to lower ISR formation in countries with high BMS utilization rates.

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.