Survival In Malignant Melanoma Patients Research Articles

Association between weight loss and death in patients with malignant melanoma: A retrospective study of 28 cases.

Malignant melanoma (MM) is often associated with a poor prognosis due to metastasis and cancer death. The monitoring of prognostic factors is of vital importance, and among these factors, elevated lactate dehydrogenase (LDH) should be closely observed during the disease course. Important factors for predicting the survival of MM patients include tumor thickness, ulceration, the number of lymph node metastases, metastatic lesions, and the sites of metastasis. Weight loss is not generally included in the prognostic factors of MM, but it is monitored in other cancers, such as lung cancer and gastrointestinal cancer. The objective of this study was to investigate the association between weight loss and MM prognosis. Using data from MM patients who had been treated at our institution, we assessed the prognoses of two groups: weight loss of at least 5% body weight or weight loss not exceeding 5% body weight within a 12-month period. As a result, a higher mortality rate was found for the former group. Furthermore, the loss of at least 5% of body weight within a month was found to almost always adversely affect the patient's prognosis. The present study indicates that there may be an association between MM prognosis and weight loss of at least 5% within a year, and body weight could potentially serve as an informative factor for MM survival.

Bioinformatics analysis identifies PSMB8 as a key gene in the cutaneous malignant melanoma tumor microenvironment.

Cutaneous tumors are commonly seen in clinical practice, and malignant melanoma (MM) is the leading cause of cutaneous tumor-induced death. The tumor microenvironment (TME), a critical part of tumorigenesis, has been a research hotspot in recent years. However, the effects of the MM microenvironment components remain elusive. This study aimed to analyze the various components in the TME of MM to identify factors affecting the tumorigenesis, progression, and metastasis of MM and the survival of MM patients. We also aimed to identify biomarkers related to TME rehabilitation to provide a new direction for MM treatment. We used bioinformatics to analyze the RNA-seq and somatic mutation data of 473 MM patients from The Cancer Genome Atlas database. Firstly, the patients' immunity and stroma were separately scored by the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) method. According to the median score, the participants were split into high- and low-score groups. Then, Gene Set Enrichment Analysis (GSEA) was performed, showing that high-expression genes were highly abundant in biological and metabolic activities associated with the immune system. Differentially expressed genes (DEGs) and differentially mutated genes (DMGs) were identified and intersected to obtain the key immune-related genes PSMB8, FAM216B, DYSF, and FAM131C. PSMB8 was finally selected as the preferred immune-related prognostic marker; it was positively associated with overall survival and therefore considered a protective gene for MM patients. The GSEA analysis showed that PSMB8 with high expression had greater gene abundance in biological and metabolic processes related to immune system. In addition, CIBERSORT analysis showed an association between the proportion of tumor-infiltrating immune cells and PSMB8 expression. Our results suggest that PSMB8 might be associated with tumorigenesis and MM progression and could serve as a biomarker for the TME rehabilitation of MM. Our findings provide a new perspective and direction for the treatment of MM.

Improving care of melanoma patients through efficient, integrated cellular-molecular pathology workflows using tissue samples with low tumour nuclear content

AimsThe aim of this quality improvement project was to improve the turnaround time of B-raf proto-oncogene (BRAF) mutation testing in patients with malignant melanoma to support oncologists in making timely...

Expression of SEC62 Oncogene in Benign, Malignant and Borderline Melanocytic Tumors-Unmasking the Wolf in Sheep's Clothing?

Simple SummaryAmplification and overexpression of the SEC62 oncogene was reported in a variety of human cancers and was associated with poor prognosis as well as lymph node and distant metastases. In this study, SEC62 expression was analyzed in benign, borderline, and malignant melanocytic lesions of 209 patients. We found the highest expression in Spitz nevi, followed by melanoma metastases, primary melanoma, congenital nevi, and blue nevi. In melanoma patients, high Sec62 levels correlated with shorter overall and progression-free survival. Significantly higher Sec62 levels were found in melanomas with lymph node and distant metastases compared with those without. Taken together, these data suggest a relevant role of SEC62 as a metastasis-stimulating oncogene in melanoma development, which represents a promising therapeutic target.SEC62 oncogene located at chromosomal region 3q26 encodes for a transmembrane protein of the endoplasmic reticulum (ER) and is expressed at high levels in numerous human malignancies. SEC62 overexpression has been associated with worse prognosis and high risk for lymphatic and distant metastases in head and neck cancer, cervical cancer, hepatocellular cancer, and lung cancer. However, its role in the development and tumor biology of melanocytic lesions has not been investigated so far. An immunohistochemical study including 209 patients with melanocytic lesions (malignant melanoma (MM), n = 93; melanoma metastases (MET), n = 28; Spitz nevi (SN), n = 29; blue nevi (BN), n = 21; congenital nevi (CN), n = 38) was conducted and SEC62 expression was correlated with clinical data including patient survival and histopathological characteristics. SN showed the highest SEC62 expression levels followed by MET, MM, CN, and BN. High SEC62 expression correlated with a shorter overall and progression-free survival in MM patients. Additionally, high Sec62 levels correlated significantly with higher tumor size (T stage), the presence of tumor ulceration, and the presence of lymph node as well as distant metastases. Strikingly, SEC62 expression showed a strong correlation with Clark level. Taken together, these data demonstrate that SEC62 is a promising prognostic marker in MM and has the potential to predict biological behavior and clinical aggressiveness of melanocytic lesions.

Protein tyrosine phosphatase 1B(PTP1B) promotes melanoma cells progression through Src activation

ABSTRACT Previous studies have demonstrated that protein tyrosine phosphatase 1B (PTP1B) can promote tumor progression in breast cancer, colon cancer and prostate cancer. Additionally, PTP1B also acts as a tumor suppressor in esophageal cancer and lymphoma. These findings suggest that PTP1B functions as a double-faceted molecule in tumors. However, the role of PTP1B in malignant melanoma (MM) is still unknown. PTP1B expression in normal and melanoma tissues was evaluated by GEO analysis and immunohistochemistry. The effects of PTP1B on cell migration and invasion were evaluated in melanoma cells with up – and downregulated PTP1B expression. In this study, we initially demonstrated that the expression of PTP1B in malignant melanoma tissue is significantly higher than its expression in benign nevus tissue and indicated poor survival of malignant melanoma patients. In vitro studies have demonstrated that inhibition of PTP1B suppresses and overexpression of PTP1B promotes migration and invasion of melanoma cells. Moreover, we found that PTP1B could interact with Src via coimmunoprecipitation and dephosphorylation of the Src at Tyr530 site. Collectively, our study revealed that PTP1B can promote melanoma cell metastasis by interacting with Src and provides a theoretical basis for future applications of PTP1B inhibitors in the treatment of malignant melanoma.

The programmed cell death protein-1/programmed cell death ligand 1 expression, CD3+ T cell infiltration, NY-ESO-1 expression, and microsatellite instability phenotype in primary cutaneous melanoma and mucosal melanoma and their clinical significance and prognostic value: a study of 89 consecutive cases.

We evaluated the expression of programmed cell death protein-1 (PD-1), programmed cell death ligand 1 (PD-L1), and NY-ESO-1 antigen; the infiltration of CD3+ T cells; and the microsatellite instability (MSI) phenotype, as well as the relationship of each factor to survival in malignant melanoma patients. Malignant melanoma samples from 89 patients were stained by immunohistochemistry to evaluate PD-1, PD-L1, CD3+ tumor-infiltrating lymphocytes (TILs), NY-ESO-1, and MSI. PD-1 and PD-L1 were expressed in 19.1 and 32.6% of the 89 samples, respectively. There was a significant correlation between PD-1 and PD-L1 expression (r = 0.207, P = 0.046). High infiltration of CD3+ T cells was observed in 41.6% of the samples, and increased cell infiltration was associated with increased PD-1 expression (P = 0.001). NY-ESO-1 antigen was detected in 13.5% of all samples, and the expression of NY-ESO-1 was positively correlated with the expression of PD-1 (P < 0.001). In our research, MSI was detected in 18 samples (20.2%). Survival analysis showed that a high infiltration of CD3+ T cells was related to longer progression-free survival (PFS) [24.0 months, 95% confidence interval (CI): 7.4-40.6 vs. 11.0 months, 95% CI: 7.1-12.9, P = 0.031], similarly, the median overall survival (OS) of the CD3+ T cell high-infiltration patients was also longer (53.0 vs. 38.0 months), but with no statistical significance (P = 0.200). The results for the immune markers mentioned above provide a theoretical basis for the prognosis and immunotherapy selection of malignant melanoma patients.

Overexpression of mRNA-decapping enzyme 1a predicts disease-specific survival in malignant melanoma.

Our previous study identified that rs11551405 A allele located at the 3' UTR of mRNA-decapping enzyme 1a (DCP1A) was associated with an increased risk for malignant melanoma (MM). The aim of this study was to investigate whether that association is manifested at the DCP1A expression and whether an altered DCP1A expression can predict disease-specific survival (DSS) of MM patients. The DCP1A expression in specimens of 56 cases of primary MM (23 cases at TNM stage I-II and 33 cases at TNM stage III-IV) and 43 cases of benign nevi (BN) was measured by quantitative RT-PCR (qRT-PCR), immunohistochemistry, and western blotting. The levels of DCP1A expression and the clinical characteristics of the patients were recorded and compared, along with the DSS within the 3 years of follow-up. The average relative mRNA level of DCP1A was significantly (P=0.002) higher in the MM tissues (0.159±0.007) than that shown in the BN tissues (0.122±0.009). The DCP1A immunohistochemistry scores of MM samples (5.55±2.56) were significantly (P<0.001) higher than those of the BN samples (3.58±3.66). Tissue protein levels of DCP1A in MM (0.378±0.021) were much (P<0.05) higher than those in BN tissues (0.265±0.017). Higher DCP1A expression was significantly correlated with shorter DSS time in patients with MM (P<0.05). The multivariate Cox regression analysis revealed that DCP1A expression was an independent prognostic factor for DSS (hazard ratio=1.648, P=0.021). Elevation of DCP1A expression may be an epigenetic contributing factor for oncogenesis of MM, and high DCP1A level may predict an unfavorable prognosis for MM.

Clinical and prognostic factors in 98 patients with malignant melanoma in China.

ObjectiveTo investigate clinical and prognostic factors in patients with malignant melanoma (MM) in China.MethodsA total of 98 MM patients were enrolled in the study. Enumeration data were analyzed using Fisher’s exact probability tests or χ2 tests. Survival rates were calculated using log-rank tests. A Cox multivariate regression analysis was performed to determine independent prognostic factors.ResultsThe male: female incidence ratio was 1.88:1. The highest incidence rate was seen in the 45–65 year age group. Primary lesion ulceration was seen in 60.2% of patients. The 1-year, 3-year and 5-year survival rates were 85.7%, 34.7% and 13.3%, respectively. In univariate analyses, the 5-year survival rate in patients was significantly associated with ulceration (P < 0.01), clinical stage (P < 0.01) and surgical excision of the tumor (P < 0.01). Cox multivariate regression analysis confirmed that ulceration and clinical stage were independent prognostic factors.ConclusionsSome clinical characteristics of MM patients in China are significantly different from those of patients in Western countries. Ulceration and clinical stage are independent risk factors for poor survival in MM patients.

Oncolytic virotherapy including Rigvir and standard therapies in malignant melanoma.

The treatment of metastatic melanoma has evolved from an era where interferon and chemotherapy were the mainstay of treatments to an era where immunotherapy has become the frontline. Ipilimumab (IgG1 CTLA-4 inhibitor), nivolumab (IgG4 PD-1 inhibitor), pembrolizumab (IgG4 PD-1 inhibitor) and nivolumab combined with ipilimumab have become first-line therapies in patients with metastatic melanoma. In addition, the high prevalence of BRAF mutations in melanoma has led to the discovery and approval of targeted molecules, such as vemurafenib (BRAF kinase inhibitor) and trametinib (MEK inhibitor), as they yielded improved responses and survival in malignant melanoma patients. This is certainly a burgeoning time in immunotherapy drug development, and the aforementioned efforts along with the recent US Food and Drug Administration approval of talimogene laherparepvec (T-VEC), a recombinant oncolytic herpes virus, have paved the way to exploring the role of additional oncolytic viruses, such as the echovirus Rigvir, as new and innovative treatment modalities in patients with melanoma. Herein, we discuss the current standard of care treatment in melanoma with an emphasis on immunotherapy and oncolytic viruses in development.

Dinitrophenyl hapten with laser immunotherapy for advanced malignant melanoma: A clinical study.

The present study aimed to evaluate the efficacy and safety of in situ immunotherapy with dinitrophenyl (DNP) hapten in combination with laser therapy for patients with malignant melanoma (MM). Between February 2008 and March 2012, 72 patients with stage III or IV MM were enrolled. Patients received in situ DNP alone (n=32) or in combination with laser therapy (n=32), and each group received dacarbazine chemotherapy. The levels of peripheral cluster of differentiation (CD)4+CD25+ regulatory T cells (Tregs), interleukin (IL)-10 and tumor growth factor (TGF)-β were detected by ELISA. The association between delayed-type hypersensitivity (DTH) and survival time was evaluated. Although peripheral Treg levels significantly decreased over time in the two groups (P<0.001), there was no significant difference between the treatment groups (P=0.098). Patients receiving the combination treatment exhibited significantly higher interferon-γ production by CD8+ and CD4+ T cells (both P<0.001), as well as significantly reduced levels of IL-10, TGF-β1 and TGF-β2. In addition, patients in the combination treatment group experienced significantly longer overall survival (OS; P=0.024) and disease-free survival (DFS; P=0.007) times; a DTH response of ≥15 mm was also associated with increased OS time and DFS time (P≤0.001). Finally, no severe adverse events were observed in either treatment group. Overall, in situ immunization with DNP in combination with laser immunotherapy may activate focal T cells, producing a regional antitumor immune response that increases cell-mediated immunity and improves survival in MM patients. Thus, this may represent a novel therapeutic strategy for patients with unresectable, advanced MM.

Complex Formation between S100B Protein and the p90 Ribosomal S6 Kinase (RSK) in Malignant Melanoma Is Calcium-dependent and Inhibits Extracellular Signal-regulated Kinase (ERK)-mediated Phosphorylation of RSK

S100B is a prognostic marker for malignant melanoma. Increasing S100B levels are predictive of advancing disease stage, increased recurrence, and low overall survival in malignant melanoma patients. Using S100B overexpression and shRNA(S100B) knockdown studies in melanoma cell lines, elevated S100B was found to enhance cell viability and modulate MAPK signaling by binding directly to the p90 ribosomal S6 kinase (RSK). S100B-RSK complex formation was shown to be Ca(2+)-dependent and to block ERK-dependent phosphorylation of RSK, at Thr-573, in its C-terminal kinase domain. Additionally, the overexpression of S100B sequesters RSK into the cytosol and prevents it from acting on nuclear targets. Thus, elevated S100B contributes to abnormal ERK/RSK signaling and increased cell survival in malignant melanoma.

Serum CEACAM1 Correlates with Disease Progression and Survival in Malignant Melanoma Patients

The search for melanoma biomarkers is crucial, as the incidence of melanoma continues to rise. We have previously demonstrated that serum CEACAM1 (sCEACAM1) is secreted from melanoma cells and correlates with disease progression in metastatic melanoma patients. Here, we have used a different cohort of melanoma patients with regional or metastatic disease (N = 49), treated with autologous vaccination. By monitoring sCEACAM1 in serum samples obtained prior to and after vaccination, we show that sCEACAM1 correlates with disease state, overall survival, and S100B. The trend of change in sCEACAM1 following vaccination (increase/decrease) inversely correlates with overall survival. DTH skin test is used to evaluate patients' anti-melanoma immune response and to predict response to vaccination. Importantly, sCEACAM1 had a stronger prognostic value than that of DTH, and when sCEACAM1 decreased following treatment, this was the dominant predictor of increased survival. Collectively, our results point out the relevance of sCEACAM1 in monitoring melanoma patients.

Increased Expression of the Tumor Suppressor PLZF Is a Continuous Predictor of Long-Term Survival in Malignant Melanoma Patients

Promyelocytic leukemia zinc finger (PLZF) is a transcriptional repressor and tumor suppressor inhibiting melanoma cell growth in vitro and in vivo in animal models. In this study, we analyzed the impact of in vivo primary tumor gene expression of PLZF on the long-term survival of malignant melanoma patients. PLZF expression was assessed by using DNA microarray and real-time polymerase chain reaction analysis of 41 primary malignant melanomas from patients with a defined histology and a close to 20-year clinical follow-up, of 29 melanoma metastases, and of 6 different melanoma cell lines. Kaplan-Meier survival analyses, log-rank statistics and Cox regression analysis were employed to identify the impact of PLZF expression on long-term survival. We detected PLZF expression in 92% of primary melanoma tumors in vivo but not in melanoma cell lines in vitro. By univariate analysis, we identified: (1) PLZF mRNA expression < or = 10,000 mRNA copies/mug total tumor RNA, (2) Breslow tumor thickness >4 mm, and (3) American Joint Committee on Cancer stages IIC, IIIB, IIIC, and IV as statistically significant pretreatment risk factors. We defined a continuous prognostic index (i.e., risk score) for primary melanoma patients based on the regression coefficient of PLZF mRNA expression. Applying a cutpoint to the prognostic index at - 1.65, patients were assigned to one of two risk groups: low-risk patients (n = 28) with a median overall survival of 79 months (5-year survival of 61%) and high-risk patients (n = 13) with a median overall survival of 32 months (5-year survival of 23%) (p < 0.05). This is the first time that PLZF mRNA expression has been linked to a prognostic model for primary malignant melanoma patients to derive prognostic groups for clinical purposes (e.g., improved melanoma immunotherapies).

A Graphical Method for Assessing Goodness of Fit in Cox's Proportional Hazards Model

Abstract Suggested here is a simple graphical method for studying the goodness of fit in Cox's regression model for survival data. The method is easy to use, as it does not require the estimation of alternative models and only involves quantities similar to those already appearing in the partial likelihood expression that is needed in the parameter estimation. The rationale behind the graphs is very intuitive: They make a direct comparison between observed and expected failure frequencies, as estimated from the model. In a correctly specified model one anticipates an approximate balance between such frequencies; otherwise there will typically be groups of individuals for which the expected frequencies are systematically too high or too low to match with the data, and this shows in the graphs introduced here. In the concrete applications of the method the individuals are stratified in a way that depends on what aspect of the model is being checked against data. There is always one graph for each stratum. Simulated and real data are used to illustrate the method. In the simulations two types of defect that can come up in a Cox's model are considered: (a) an influential covariate has been deleted from the model, and (b) a common baseline hazard for all individuals has been assumed in a case in which the individuals should be stratified according to baseline hazard. Serious defects in the model are relatively easy to detect from the diagnostic graphs. As concrete applications of the method, studied briefly are the fitting of Cox's model to the well-known Stanford heart transplant data and to a data set describing the survival of malignant melanoma patients after operation. The article concludes with some general observations concerning the randomness in the graphs.