Prognostic Factor In Melanoma Research Articles

Volume tumor impact on melanoma survival assessed using Breslow density

Volume tumor impact on melanoma survival assessed using Breslow density

Evaluation of 2-methoxyestradiol serum levels as a potential prognostic marker in malignant melanoma.

Experimental findings indicated that 2-methoxyestradiol (2-ME), an endogenous metabolite of 17β-estradiol, may exhibit anti-tumorigenic properties in various types of tumour, such as melanoma and endometrial carcinoma. In patients with endometrial cancer, the serum levels of 2-ME are decreased compared with those in healthy controls, and this finding has been associated with a poor outcome. The aim of the present study was to examine whether the serum levels of 2-ME are decreased in patients with melanoma, and whether this decrease may be correlated with disease stage and, therefore, serve as a prognostic indicator. ELISA was used to detect serum levels of 2-ME in patients with stage I-IV malignant melanoma (MM). A cohort of 78 patients with MM was analysed, along with 25 healthy controls, among whom 15 were women in the second trimester of pregnancy (positive control). As expected, significantly elevated levels of serum 2-ME were observed in pregnant control patients compared with those in patients with MM and healthy controls. There was no observed correlation between 2-ME serum levels in patients with MM and disease stage, tumour thickness, lactate dehydrogenase or S100 calcium-binding protein B levels. In addition, the 2-ME levels of patients with MM did not differ significantly from those of normal healthy controls. Overall, the findings of the present study indicated that the 2-ME serum levels in patients with MM were not decreased, and there was no correlation with early- or advanced-stage disease. Therefore, in contrast to published results on endometrial cancer, endogenous serum 2-ME levels in MM were not found to be correlated with tumour stage and did not appear to be a suitable prognostic factor in MM.

523 ANRIL inherited variants associated with primary melanoma TIL grade

Genome-wide association studies have reported an association between genetic variants in or near the ANRIL (CDKN2B-AS1) gene and age-related diseases. Despite these variants’ proximity to CDKN2A, which encodes melanoma tumor suppressor genes, their associations with melanoma prognostic factors are unknown. Here we investigated the associations of these variants with primary melanoma Breslow thickness, ulceration, and tumor-infiltrating lymphocyte (TIL) grade. Our analysis included 3,285 European-origin participants in the Genes, Environment and Melanoma (GEM) Study with incident invasive primary melanoma.

Role of vitamin D serum levels in prevention of primary and recurrent melanoma

Patients afflicted with melanoma show lower vitamin D serum levels (VDSL) than the healthy population. This hypothesis agrees with its well-known antiproliferative features. An observational study was carried out to collect VDSL in patients suffering from melanoma. Our aim was to identify a potential connection between low VDSL and the risk to incur melanoma. Furthermore, we studied the association between VDSL at the diagnosis of melanoma and other germane prognostic factors. The population held in regard was composed of 154 patients with a diagnosis of melanoma between 2016 and 2019. These patients were retrospectively collected from our follow-up storage. We compared VDSL to clinical and pathological parameters (age, sex, tumour location, Breslow’s depth, Clark’s level, histological subtype, ulceration, et aliqua). Moreover, we recruited a control group with negative melanoma history. Mean and median of VDSL were significantly lower in the melanoma group. Instead, we found a negative association between melanoma and VDSL > 30 ng/L (OR 0.11; p < 0.0001). No correlation between VDSL and both Breslow’s depth and Clark’s level was discovered, but the VDSL comparison between thin (depth ≤ 1 mm) and thick tumours (depth > 1 mm) revealed a statistically significant difference (21.1 ± 8.2 ng/L vs 17.8 ± 8.1; p = 0.01). Moreover, VDSL were significantly lower in melanomas with mitotic rate ≥ 1/mm2 (22.1 ± 8.3 ng/L; p < 0007). Nevertheless, no connection was found between VDSL and both ulceration and positive sentinel nodes (p = 0.76; p = 0.74). Besides, our study revealed no association between VDSL and histological subtype (p = 0.161). Lower VDSL correlate with thick and high mitotic rate tumours. Future prospective studies would investigate if appropriate upkeep of suitable VDSL can decrease the risk of primary and recurrent melanoma diagnosis.

The Relationship Between Epidermal Mitotic Density, Atypical Mitotic FigureDensity, Breslow Depth, Ulceration, and Dermal Mitotic Rate in Cutaneous Melanoma: A Retrospective Cohort Study.

Prognostic factors for melanoma include Breslow depth (BD), ulceration, and dermal mitotic rate (DMR). No studies have queried the effect of epidermal mitotic density (EMD) or atypical mitotic figure density (AMD) in an outcome-based assessment. Our objective was to determine if there is a relationship between EMD, AMD, BD, DMR, and ulceration and patient outcomes. This was a retrospective cohort study of 185 cases of thick and thin melanomas. Univariate and multivariate cause-specific regression analysis was performed. There was a positive correlation between EMD and BD (P = .0001). The difference between AMD in thick and thin melanomas was statistically significant. For every unit increase in EMD, patients had a 2.8-fold increase in the risk of distant metastasis; however, statistical significance was lost in the multivariate analysis. In adjusted analyses, ulceration, DMR, and BD were associated with outcomes. There were no statistically significant correlations between AMD and outcomes. This study is limited by its small sample size, diminution of the epidermis in some thick melanomas preventing EMD estimates, and reproducibility of mitotic figure counting. EMD and AMD do not seem to have any independent value in multivariate analyses for melanoma. Ulceration, BD, and DMR were significantly associated with outcomes and further solidify these known predictors of prognosis.

Expression of lncRNA FGD5-AS1 correlates with poor prognosis in melanoma patients.

Growing evidence demonstrates that long non-coding RNAs (lncRNAs) play an important role in cancer origination and progression. A novel identified lncRNA, FGD5 antisense RNA 1 (FGD5-AS1), was reported to be overexpressed in several tumors. The present study aimed to investigate the expression of FGD5-AS1 in melanoma and its associations with clinical prognosis in melanoma patients. The expression levels of FGD5-AS1 in 188 pairs of melanoma specimens and matched non-tumor specimens were determined using a real-time polymerase chain reaction. A chi-squared test was performed to determine the relationship between FGD5-AS1 levels and clinicopathological features. The overall survival rates of melanoma patients based on the expression of FGD5-AS1 were calculated by the Kaplan-Meier method with a log-rank test. Finally, univariate and multivariate assays were carried out to determine whether FGD5-AS1 was a prognostic factor in melanoma patients. We observed that FGD5-AS1 in melanoma specimens was distinctly up-regulated compared to adjacent non-tumor specimens (p < 0.01). In malignant cases, higher expression of FGD5-AS1 was prominently associated with tumor thickness (p = 0.024) and advanced tumor stage (p = 0.039). The data from our clinical study revealed that patients with high FGD5-AS1 expression had a distinctly shorter overall survival (p = 0.0034) and disease-free survival (p < 0.0001) than those with low FGD5-AS1 expression. Multivariate analysis demonstrated that high FGD5-AS1 expression may serve as a potential independent prognostic factor in melanoma. FGD5-AS1 may act as a prognostic predictor and a possible drug-target for melanoma patients.

The prognostic significance of VISTA and CD33-positive myeloid cells in cutaneous melanoma and their relationship with PD-1 expression

V-domain Ig suppressor of T-cell activation (VISTA), which mediates immune evasion in cancer, is mainly expressed on hematopoietic cells and myeloid cells in the tumor. We evaluated correlations among the expression of VISTA, the myeloid-derived suppressor cell marker CD33, and programmed death-1 (PD-1), and determined their relationships with clinicopathological characteristics and disease outcomes in melanoma. Diagnostic tissue from 136 cases of melanoma was evaluated by immunohistochemistry for CD33, VISTA, and PD-1 expression. Dual immunofluorescence using CD33 and VISTA antibodies was performed. VISTA expression positively correlated with CD33 expression in melanoma tissue. Dual immunofluorescence staining revealed that VISTA was expressed by CD33-positive myeloid cells. PD-1 expression correlated with CD33 and VISTA expression. CD33 and VISTA expression were significantly associated with negative prognostic factors, including a deeper Breslow thickness and an advanced stage of disease. High expression of either CD33 or VISTA was associated with worse survival. Positivity for both VISTA and PD-1 predicted worse survival. Multivariate analysis showed that both CD33 and VISTA expression were independent prognostic factors in cutaneous melanoma. VISTA and CD33 expression are independent unfavourable prognostic factors in melanoma, which suggests their potential as therapeutic targets.

Clinical significance of lncRNA MIR31HG in melanoma.

The aim of this study was to explore the expression of long non-coding RNA (lncRNA) MIR31HG in malignant melanoma (MM), and to investigate its clinical significance. The quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to detect the expression of lncRNA MIR31HG in MM tissues and cells. The relationship between lncRNA MIR31HG expression and the clinicopathological characteristics was analyzed. Furthermore, the cell counting kit-8 (CCK-8) and the transwell assays were performed to assess the effect of MIR31HG on cell proliferation and metastasis in vitro, respectively. The expression of MIR31HG was significantly upregulated in MM tissues and cells. To explore the relationship between MIR31HG expression and clinical features, the patients were divided into two groups according to the mean expression of MIR31HG, including high expression group and low expression group. The subsequent results indicated that MIR31HG expression was correlated with lymph nodes metastasis, distal metastasis, and TNM stage. The multivariate analysis indicated that a high expression of MIR31HG could be used as an independent prognostic factor for MM. MIR31HG low-expression cells were constructed in vitro. Compared with the control cells, the cells with low expression of MIR31HG showed significantly low malignancy, including decreased cell proliferation rate and migration and invasion rates. LncRNA MIR31HG was a novel factor involved in MM progression, which could be used as a potential biomarker and therapeutic target for MM.

Nevi and Breslow thickness in melanoma: sex differences?

A large body of evidence in the scientific literature suggests that the numbers of common and atypical nevi are strong, independent risk factors for the occurrence of cutaneous malignant melanoma. Furthermore, some studies recently found an association between high nevus counts and an improved melanoma prognosis. The aim of this study was to investigate a possible relationship between the number of common and atypical nevi and melanoma prognostic factors. We carried out a retrospective analysis of patients with a histopathologically confirmed diagnosis of melanoma. These patients were treated at the Dermatology Clinic of the University of Florence from January 2000 to December 2013. The main analysis investigated the association of common and atypical nevi with Breslow thickness and ulceration. The number of nevi was investigated as a continuous variable and a categorical variable considering the median number of common nevi, given the skewness of the distribution of common nevi. We analyzed 818 melanoma patients treated from January 2000 to December 2013. We found a sex and nevi interaction: among women, thick melanomas occur more frequently in patients with a low common nevi count (<10); no association was found in men. This sex and nevi interaction was also found considering the association with very thick melanomas (Breslow > 4 mm). Moreover, the presence of an increasing number of atypical nevi was associated with increased risk of ulceration in both sexes. These data provide new perspectives in the differential sex-related biological behavior of melanoma among females and males.

Anti-angiogenic role of microRNA-23b in melanoma by disturbing NF-κB signaling pathway via targeted inhibition of NAMPT.

Aim: Melanoma is the major cause of death in patients inflicting skin cancer. We identify miR-23b plays an anti-angiogenic role in melanoma. Materials & methods: We collected tumor tissues from melanoma patients. Experiments in vivo and in vitro were designed to evaluate the role of miR-23b in melanoma. Results & conclusion: miR-23b was found to be downregulated in melanoma tissues, and associated with poor patient survival. Elevating miR-23b inhibited cell viability and colony formation, reduced pro-angiogenetic ability, and accelerated apoptosis in SK-MEL-28 cells. miR-23b targeted NAMPT. Disturbing NF-κB signaling pathway with ammonium pyrrolidinedithiocarbamate (an inhibitor of NF-kB signaling pathway) impeded acquired pro-angiogenetic ability of nicotinamide phosphoribosyl transferase-overexpressed SK-MEL-28 cells. MiR-23b is a prognostic factor in melanoma. This study provides an enhanced understanding of microRNA-based targets for melanoma treatment.

Progressive Disease in Sentinel-negative Melanoma Patients: Biological Differences and Importance of Sentinel Lymph Node Biopsy.

Among the most important prognostic factors in melanoma is the sentinel lymph node (SLN) status. Using our electronic database we identified 109 of 890 SLN-negative patients with progressive disease (PD). These patients were characterized for melanoma type, molecular type, sequence and extent of metastatic spread. A total of 61 of 109 SLN-negative patients had PD in the SLN-basin indicating false-negative SLN (group-1). Forty eight of 109 patients had PD at distant sites and were therefore impossible to be identified using SLN biopsy (group-2). Despite distant spread these patients had significantly more single organ metastasis (p<0.001) and significantly longer disease-free-survival (p=0.001) compared to group-1. Additionally, to significant differences on a molecular basis between the two groups (p=0.01), all lentigo maligna and spindle-cell-melanomas belonged to group-2 and all, except one lentigo maligna melanoma, had single visceral metastasis. Two different biological groups among SLN-negative patients with PD were demonstrated. Extravascular-migratory-metastasis, rather than hematogenous spread, might be responsible for the observed PD with single organ involvement.

Late recurrence of melanoma after 10years - Is the course of the disease different from early recurrences?

It is known that melanoma can metastasize and recur many years after the first diagnosis. Although predictive and prognostic factors for melanoma are well defined, there is still insufficient information about the factors affecting the recurrence period and the effect of the recurrence time to survival. This study investigates the course of melanoma to show prognostic factors comparing early and late recurrence patients. The main objective is to uncover the effect of the recurrence time on the progression of the disease. In this retrospective study, late recurrence (LR) was defined as melanoma recurrence 10years after the first diagnosis and early recurrence (ER) was defined as recurrence within 10years. Gender, age, localization of primary tumour, time to first metastasis, survival rates, histological subtype, stage, tumour thickness, invasion level, ulceration and regression of the primary melanoma were documented. Survival curves were evaluated using the Kaplan-Meier and compared with the log-rank test. Multivariate Cox proportional hazard models were used to identify significant independent prognostic factors for melanoma-specific survival (MSS). A total of 1537 melanoma patients were analysed. Early metastasis was developed in 1438 patients (93.6%), and 99 patients (6.4%) developed late metastasis. Late recurrence patients were younger (P<0.001) and had fewer ulcerated (P=0.005), fewer head/neck localized (P=0.009) and thinner (P<0.001) melanomas than ER patients. The MSS time (mean±SD) was nearly identical for LR (31±4.4months 95% CI [22.3-39.7]) and ER (32±1.9months [28.3-35.7]). Multivariate regression analysis revealed male gender (hazard ratio [HR=1.4, P<0.001), truncal tumour localization (HR=1.7, P<0.001), tumour thickness (HR=1.4, P<0.045) and ulceration (HR=1.3, P<0.008) as significant independent prognostic factors for MSS. Although ER and LR patients are found to have different clinicopathologic features, the time of the first recurrence after diagnosis do not seem to have an effect on the survival.

Aryl Hydrocarbon Receptor Modulates Carcinogenesis and Maintenance of Skin Cancers.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that responds to a wide range of chemicals, including chemical carcinogens such as dioxins and carcinogenic polyaromatic hydrocarbons, and induces a battery of genes associated with detoxification, proliferation, and immune regulation. Recent reports suggest that AHR plays an important role in carcinogenesis and maintenance of various types of skin cancers. Indeed, AHR is a susceptibility gene for squamous cell carcinoma and a prognostic factor for melanoma and Merkel cell carcinoma. In addition, the carcinogenic effects of ultraviolet (UV) and chemical carcinogens, both of which are major environmental carcinogenetic factors of skin, are at least partly mediated by AHR, which regulates UV-induced inflammation and apoptosis, the DNA repair system, and metabolic activation of chemical carcinogens. Furthermore, AHR modulates the efficacy of key therapeutic agents in melanoma. AHR activation induces the expression of resistance genes against the inhibitors of V600E mutated B-Raf proto-oncogene, serine/threonine kinase (BRAF) in melanoma and upregulation of programmed cell death protein 1 (PD-1) in tumor-infiltrating T cells surrounding melanoma. Taken together, these findings underscore the importance of AHR in the biology of skin cancers. Development of therapeutic agents that modulate AHR activity is a promising strategy to advance chemoprevention and chemotherapy for skin cancers.

An 18-year Study of Malignant Melanoma in Childhood and Adolescence.

Background:Malignant melanoma is rare in childhood and adolescence. Diagnostic uncertainty and misdiagnosis often lead to delayed treatment.Methods:We evaluated children and adolescents under 20 years of age presenting with malignant melanoma at our institution over an 18-year period. Data were collected, analyzed, and interpreted, following which findings were compared with the existing literature.Results:Twenty-four patients were included in the study with mean follow-up of 61.8 months. Males comprised 54% of cases. On presentation, 33% of children had melanoma of s thickness 2–4 mm and 34% had stage III disease. Younger children presented with thicker melanomas, differing subtypes, and more advanced stage disease compared with older children. Extremities were the most common sites affected (42%). Dissection of the draining lymph node basins was undertaken in 38% of cases. Overall survival was 92%.Conclusions:Tumor subtype, biology, hormonal influence, and lymph node status are all important prognostic factors in malignant melanoma in childhood and adolescence. Compared with adults, children presenting with thicker melanomas and more advanced stage disease generally have more favorable outcomes and a better survival. Plastic surgeons, commonly encountering skin lesion in children, must maintain a high index of suspicion so that early excision and sentinel lymph node biopsy may be promptly offered to patients with melanoma.

Abstract 2779: miR-142-3p as a regulator of RAC1 and a prognostic factor in melanoma

Abstract In order to identify miRNAs able to distinguish melanoma patients with good or poor prognosis, the expression profile of a panel of miRNAs evaluated in primary melanoma samples from 65 patients was compared to clinicopathological data from these patients (Breslow’s depth, mitotic counts, metastasis progression and survival). The miR-142-3p was identified as presenting at least 2-fold reduced expression in melanoma samples from patients with poor prognosis for 3 of 4 clinical parameters analyzed compared to melanoma samples from patients with good prognosis. The miR-142-3p expression was validated by RT-qPCR in primary human melanoma samples, confirming a significant lower expression in melanoma patients with poor prognosis compared to those with good prognosis. Searching for miR-142-3p mRNA targets in melanoma, the gene expression profile was analyzed by gene microarrays in a wild type and miR-142-3p overexpressing melanoma cell line. RAC1, ITGB8 e GNB2 were found as potential targets of this miRNA. Protein expression analyses in melanoma cell lines overexpressing the miR-142-3p reinforced the regulation of RAC1 by this miRNA. Functional assays showed that the overexpression of miR-142-3p leads to a reduced migratory ability compared to control cells, indicating its role in cell migration process. Finally, multivariate COX analyses demonstrated that high levels of RAC1 and reduced levels of miR-142-3p predict poor progression-free survival of melanoma patients, revealing these molecules as potential prognostic biomarkers for melanoma patients. Supported by FAPESP, CNPQ and CAPES Short title: miR-142-3p as a prognostic factor in melanoma Note: This abstract was not presented at the meeting. Citation Format: Adriana T. Cruz, Júlia A. Morata, Ana C. Monteiro, Ana Luísa P. Ayub, Roseli S. Soares, André Fujita, Fernando Andrade, Victor Tron, Miriam G. Jasiulionis. miR-142-3p as a regulator of RAC1 and a prognostic factor in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2779.

Tropomyosin-Related Kinase Receptor and Neurotrophin Expression in Cutaneous Melanoma Is Associated with a Poor Prognosis and Decreased Survival

Objective: Normally, activation of tropomyosin-related kinase (TRK) receptors by neurotrophins (NTs) stimulates intracellular pathways involved in cell survival and proliferation. Dysregulation of NT/TRK signaling may affect neoplasm prognosis. Data on NT and TRK expression in melanomas are limited, and it is unclear whether NT/TRK signaling pathways are involved in the origin and progression of this neoplasm. Methods: We examined whether NT/TRK expression differs across different cutaneous melanoma grades and subtypes, and whether it is associated with melanoma prognosis and survival. A cross-sectional study was performed in which the expression of TrkA, TrkB, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) was analyzed by immunohistochemistry of 154 melanoma samples. We investigated NT/TRK expression associations with prognostic factors for melanoma, relapse-free survival (RFS), and overall survival (OS). Results: Of the 154 melanoma samples, 77 (55.4%) were TrkA immunopositive, 81 (58.3%) were TrkB immunopositive, 113 (81.3%) were BDNF immunopositive, and 104 (75.4%) were NGF immunopositive. We found NT/TRK expression associated strongly with several clinical prognostic factors, including the tumor-node-metastasis stage (p < 0.001), histological subtype (p < 0.001), and Clark level (p < 0.05), as well as with a worse OS (p < 0.05 for all, except TrkB) and RFS (p < 0.05 for all). Conclusions: Our results show strong associations of NT/TRK expression with melanoma stage progression and a poor prognosis.

Evaluation of Cyclooxygenase-2 Expression in Association with Clinical-Pathological Factors in Malignant Melanoma.

Background and Objective:The primary goal of this study is to develop a rigorous understanding of the correlation between COX-2 expression and malignant melanoma prognostic factors. Material and Methods:In this cross-sectional study, we analyzed 60 cases of cutaneous malignant melanoma. The related stained slides were reviewed by two pathologists. The results were interpreted according to the COX2 staining index (SI), tumor thickness (Breslow, Clark), number of mitoses per 10 hpf, and melanoma types. Gender, lymph node involvement, metastasis, and survival were considered as evaluation factors as well. Results:The expression of the COX-2 protein was evident in 98.4% of cases. A strong Staining Index(SI) was reported in 60% of all melanomas, moderate staining was detected in 20.8% and weak staining in 10%; 1.6% of studied cases showed no staining. Benign nevus specimens showed no staining for the COX-2 enzyme.Conclusion:We have demonstrated that COX-2 is strongly expressed in the majority of malignant melanomas and that the SI score of COX-2 is related to the number of mitoses, tumor thickness (based on Clark level and Breslow), melanoma sub-type, lymph node involvement, and metastases; No association was noted between the anatomic site, gender, and survival. COX-2 can be applied as a prognostic factor in malignant melanoma and a promising candidate for future target therapies.

Does Wide Excisional Biopsy in Skin Cancer Prevent Finding The Real Sentinel Lymph Node?

Purpose/Aim: The presence of nodal metastasis is an important prognostic factor for malignant melanoma and causes a 50% decrease in survival. Patients found not to have lymph node metastasis as a result of sentinel lymph node biopsy but develop regional lymph node metastasis in the follow-up period are called false negative sentinel. The hypothesis of this study was that excisional biopsy in patients with large lesions may change the lymphatic pathway and therefore cause false negative results. Materials & Methods: A total of 40 Sprague-Dawley rats were divided into 4 groups: the control group, Group 1 (10 mm excision), Group 2 (15 mm lesion excision), and Group 3 (20 mm excision). Sentinel lymph nodes were found via imaging with nanocolloidal albumin including 99mTc and indocyanine green (ICG) before the excision and at 3 weeks after the excision. Evaluations were performed to determine whether or not they were the same nodes. Results: The false sentinel node detection rate in Group 3 was significantly higher than in both the control group and Group 1 (p < 0.05). No significant difference was detected between Group 2 and 3 according to false sentinel node detection rate. There were differences between preoperative and postoperative detection of sentinel lymph nodes found by radioactive and ICG methods but no significant difference was detected in the Kappa agreement coefficient. Conclusion: It can be suggested that incisional biopsy is performed on large lesions initially, followed by wide excision combined with SLNB at the second stage. This can help to prevent changes in the lymphatic pathway and therefore to decrease false negativity rates caused by the previous surgery.

Prognostic and predictive role of elevated lactate dehydrogenase in patients with melanoma treated with immunotherapy and BRAF inhibitors: a systematic review and meta-analysis.

Levels of serum lactate dehydrogenase (LDH) are a recognized prognostic factor in malignant melanoma (MM). It is relevant to confirm its prognostic role in patients treated with targeted therapies [BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi)] and immunotherapy (IT). Furthermore, its role as a predictive marker in patients treated with these drugs had still not been investigated. We performed an electronic search for studies reporting information on overall survival (OS) or progression-free survival (PFS) according to LDH levels and on their predictive effect in patients treated with targeted therapies (BRAFi and MEKi) and IT. Data were pooled using hazard ratios (HRs) for OS and HRs for PFS according to a fixed-effect or a random-effect model. For predictive analysys, effect of new agents versus standard therapy was evaluated in LDH high population. A total of 71 publications were retrieved for a total of 16 159 patients. Overall, elevated LDH levels were associated with an HR for OS of 1.72 [95% confidence interval (CI): 1.6-1.85; P<0.0001]. Similarly, HR for PFS was 1.83 (95% CI: 1.53-2.2; P<0.0001). In the LDH elevated subgroup, new agents improved OS significantly (HR: 0.71; 95% CI: 0.62-0.82; P<0.0001) and PFS (HR: 0.63; 95% CI: 0.55-0.72; P<0.0001). In advanced MM treated with IT or BRAFi±MEKi, elevated LDH level at baseline represents a poor prognostic factor. However, patients with increased LDH levels and treated with these drugs gain significant benefits in terms of PFS and OS.

Tumour-infiltrating lymphocytes, programmed death ligand 1 and cyclooxygenase-2 expression in skin melanoma of elderly patients: clinicopathological correlations.

Age is an important prognostic factor in melanoma; notably, elderly patients tend to present with advanced stage skin melanoma (SM) and worse outcome. Moreover, SM is an immunogenic cancer, and its interaction with the aging immune system could have an effect on biologic behaviour of this disease. Tumour-infiltrating lymphocytes (TILs) could represent the host response in SM; it has been shown that higher grade of TILs is associated with better survival. Moreover, programmed death ligand 1 (PD-L1) and cyclooxygenase-2 (COX-2) are potential markers of host immune response and inflammation. We retrospectively reviewed 113 consecutive cases of early-stage SM that occurred in patients aged greater than or equal to 65 years at the time of diagnosis, followed between January 2010 and March 2014 at the University and General Hospital of Udine, Italy. The aim of this study was to evaluate TILs grade, PD-L1 expression on TILs and tumour expression of PD-L1 and COX-2 and their prognostic value in elderly patients with early SM. A better disease-free survival as well as melanoma-specific survival (MSS) was significantly associated with TILs [hazard ratios (HR): 0.41, 95% confidence interval (CI): 0.20-0.84, P=0.02 and HR: 0.37, 95% CI: 0.17-0.82, P=0.01, respectively]. PD-L1 positivity on TILs was associated with a better MSS (HR: 0.41, 95% CI: 0.17-0.97, P=0.04). Moreover, among patients with TILs, those showing COX-2 positivity on tumour cells and no PD-L1 expression on TILs had a worse disease-free survival and MSS (HR: 5.18, 95% CI: 1.33-20.23, P=0.018; HR: 6.21, 95% CI: 1.20-32.24, P=0.03; respectively). Immune and inflammatory markers deserve further investigation in aging patients with melanoma.