Survival Of Cutaneous Melanoma Patients Research Articles

BRAF and NRAS Mutations and the Association with Prognosis of Acral Lentiginous and Nodular Melanomas in Indonesia.

Melanomas are rare yet the most aggressive skin cancer among Asians. Clinical presentation, risk factors, and the underlying molecular mechanisms are strikingly different from cutaneous melanoma in Caucasians. Mutation patterns of BRAF and NRAS genes were examined from DNAs derived from primary melanoma tumor tissues (fresh tissues or formalin-fixed paraffin-embedded samples) using pyrosequencing. A total of 63 patients consisting of acral lentiginous melanoma (N=22, 34.9%) and nodular melanoma (N=41, 65.1%) were included in this study. Most patients were diagnosed at Stage III-IV (N=49, 77.8%), Breslow thickness more than 4 mm (N=51, 80.9%), presence of ulceration (N=35, 55.6%), diameter larger than 6 mm (N=61, 96.8%), regional node infiltration (N=41, 77.8%). BRAF and NRAS mutations were found in 28 (44.4%) and 8 (12.7%), respectively. BRAF and NRAS mutations were significantly associated with older melanoma patients (OR = 6.075, 95%CI = 2.013-18.333 dan OR = 13.263, 95%CI = 1.518-115.901, respectively). BRAF mutations were associated with lower overall survival (Median survivals were 16.5 vs 31.4 months, Log-rank test P=0.001). NRAS mutations were not significantly associated with lower overall survival. In this study, melanoma patients are largely diagnosed at the late stages with ulceration and involvement of regional lymph nodes. BRAF mutations are associated with lower survival of cutaneous melanoma patients.

Polo-Like Kinase 4 Correlates with Aggressive Tumor Characteristics, Shortened Disease-Free Survival and Overall Survival in Patients with Cutaneous Melanoma who Undergo Surgical Resection.

Polo-like kinase 4 (PLK4) involves in tumor progression via regulating centriole duplication. This study aimed to investigate correlations of PLK4 with tumor characteristics and survival in cutaneous melanoma patients undergoing surgical resection. Tumor specimens of 43 patients were retrieved for PLK4 determination by immunohistochemistry (IHC). The IHC score was a multiplication of staining intensity and percentage of staining-positive cells. This study found the median and mean tumor PLK4 IHC score was 0.0 (interquartile range: 0.0-6.0) and 3.5 ± 3.2 (mean ± SD), respectively. Elevated tumor PLK4 IHC score correlated with lymph node metastasis (P = 0.028), higher tumor node metastasis (TNM) stage (P = 0.004), and adjuvant therapy (P =0.029). Tumor PLK4 IHC score > 0 did not relate to disease-free survival (DFS) or overall survival (OS) (both P > 0.050). Tumor PLK4 IHC score > 3 associated with decreased DFS (P = 0.027), but not OS (P = 0.098). Five-year DFS rate of patients with tumor PLK4 IHC score = 0 and > 0 was 75.0% and 53.9%, correspondingly; while the rate of patients with the score ≤ 3 and > 3 was 81.0% and 37.5%, respectively. Five-year OS rate of patients with the score = 0 and > 0 was 100.0% and 66.3%, accordingly; whereas the rate of patients with the score ≤ 3 and > 3 was 85.7% and 61.5%, correspondingly. According to forward-step multivariate analysis, neither the score > 0 nor > 3 independently related to worse DFS and OS (all P > 0.050). Further validation via THE HUMAN PROTEIN ATLAS database showed high PLK4 RNA expression associated with shortened OS in melanoma patients (P = 0.001). PLK4 correlates with lymph node metastasis, increased TNM stage, and poor DFS in cutaneous melanoma patients undergoing surgical resection.

A deep learning model based on whole slide images to predict disease-free survival in cutaneous melanoma patients

The application of deep learning on whole-slide histological images (WSIs) can reveal insights for clinical and basic tumor science investigations. Finding quantitative imaging biomarkers from WSIs directly for the prediction of disease-free survival (DFS) in stage I–III melanoma patients is crucial to optimize patient management. In this study, we designed a deep learning-based model with the aim of learning prognostic biomarkers from WSIs to predict 1-year DFS in cutaneous melanoma patients. First, WSIs referred to a cohort of 43 patients (31 DF cases, 12 non-DF cases) from the Clinical Proteomic Tumor Analysis Consortium Cutaneous Melanoma (CPTAC-CM) public database were firstly annotated by our expert pathologists and then automatically split into crops, which were later employed to train and validate the proposed model using a fivefold cross-validation scheme for 5 rounds. Then, the model was further validated on WSIs related to an independent test, i.e. a validation cohort of 11 melanoma patients (8 DF cases, 3 non-DF cases), whose data were collected from Istituto Tumori ‘Giovanni Paolo II’ in Bari, Italy. The quantitative imaging biomarkers extracted by the proposed model showed prognostic power, achieving a median AUC value of 69.5% and a median accuracy of 72.7% on the public cohort of patients. These results remained comparable on the validation cohort of patients with an AUC value of 66.7% and an accuracy value of 72.7%, respectively. This work is contributing to the recently undertaken investigation on how treat features extracted from raw WSIs to fulfil prognostic tasks involving melanoma patients. The promising results make this study as a valuable basis for future research investigation on wider cohorts of patients referred to our Institute.

Ulceration vs. Mitosis in Cutaneous Melanoma: Which Is Superior for Predicting Prognosis Across Clinical Stages?

Ulceration and high mitosis are considered among the major unfavorable prognostic factors in the survival of cutaneous melanoma patients. The aim of this study was to investigate the clinical significance of these parameters and to compare them to see which one is superior to predicting prognosis across all clinical stages of melanoma. A total of 1,074 melanomas were analyzed retrospectively. Tumor ulceration was found to be limited to the local stage for predicting survival, whereas, mitosis maintained its prognostic strength for predicting survival across all clinical stages. Furthermore, no survival differences were observed between ulceration and mitosis across clinical stages.

861P Association of genetic variants in JAK/STAT signaling pathway with cutaneous melanoma susceptibility

Janus kinase signal transducer and activator of transcription (JAK/STAT) signaling pathway is involved in cell proliferation, angiogenesis, apoptosis inhibition, metastasis, and immune suppression. Due to these multiple functions, this pathway regulates cutaneous melanoma (CM) development and progression. The JAK1, JAK2 and STAT3 proteins are encoded by polymorphic genes. This study aimed to verify whether single-nucleotide variants (SNVs) in JAK1 (c.1648+1272G>A, c.991-27C>T), JAK2 (c.-1132G>T, c.-139G>A) and STAT3 (c.*1671T>C, c.-1937C>G) altered risk, clinicopathological aspects, survival of CM patients, as well as protein activity. CM patients (N = 248) and controls (N = 274) were included in this study. Genotyping was performed by real-time polymerase chain reaction (PCR) and JAK1, JAK2 and STAT3 expression was assessed by quantitative PCR (qPCR). STAT3 c.-1937C>G SNV was investigated by luciferase, qPCR, western blot, apoptosis, and cell cycle assays in SKMEL-28 cells with CC or GG genotype. In addition, fourteen melanoma cell lines with different genotypes were used to analyze STAT3 expression with non-intervention. Individuals with STAT3 c.*1671TT and c.-1937CC genotypes, and TC haplotype of both SNVs were under 2.0-fold increased risk of CM. Specific JAK1, JAK2 and STAT3 combined genotypes were associated with up to 4.0-fold increased risk of CM. Higher luciferase activity (4,013.34 vs. 2,463.32 arbitrary unit (AU); p = 0.009), STAT3 expression by qPCR (649.20 vs. 0.04 AU; p = 0.003) and western blot (1.69 vs. 1.16 AU; p = 0.01), and percentage of cells in S phase of cell cycle (57.54 vs. 30.73 %; p = 0.04) were more frequent in SKMEL-28 with STAT3 c.-1937CC than with GG genotype. CM cell lines with CC genotype presented higher STAT3 protein levels than those with GG genotype (1.93 versus 1.27 AU, p = 0.0027). Our data present for the first-time preliminary evidence that JAK1, JAK2 and STAT3 SNVs alter risk and clinical aspects of CM patients. If validated in a further epidemiological study, our data can be used to select individuals at high-risk of CM, who should receive special attention in tumor prevention and early detection.

Association of JAK/STAT genetic variants with cutaneous melanoma.

BackgroundThe Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway regulates cutaneous melanoma (CM) development and progression. The JAK1, JAK2, and STAT3 proteins are encoded by polymorphic genes. This study aimed to verify whether single-nucleotide variants (SNVs) in JAK1 (c.1648+1272G>A, c.991-27C>T), JAK2 (c.-1132G>T, c.-139G>A), and STAT3 (c.*1671T>C, c.-1937C>G) altered the risk, clinicopathological aspects, and survival of CM patients as well as protein activity.MethodsCM patients (N = 248) and controls (N = 274) were enrolled in this study. Genotyping was performed by real-time polymerase chain reaction (PCR), and JAK1, JAK2, and STAT3 expression was assessed by quantitative PCR (qPCR). STAT3 c.-1937C>G SNV was investigated by luciferase, qPCR, western blot, apoptosis, and cell cycle assays in SKMEL-28 cells with CC or GG genotype.ResultsIndividuals with STAT3 c.*1671TT and c.-1937CC genotypes and TC haplotype of both SNVs were under about 2.0-fold increased risk of CM. Specific JAK1, JAK2, and STAT3 combined genotypes were associated with up to 4.0-fold increased risk of CM. Higher luciferase activity [4,013.34 vs. 2,463.32 arbitrary units (AU); p = 0.004], STAT3 expression by qPCR (649.20 vs. 0.03 AU; p = 0.003) and western blot (1.69 vs. 1.16 AU; p = 0.01), and percentage of cells in the S phase of the cell cycle (57.54 vs. 30.73%; p = 0.04) were more frequent in SKMEL-28 with STAT3 c.-1937CC than with GG genotype. CM cell line with CC genotype presented higher STAT3 protein levels than the one with GG genotype (1.93 versus 1.27 AU, p = 0.0027).ConclusionOur data present preliminary evidence that inherited abnormalities in the JAK/STAT pathway can be used to identify individuals at a high risk of CM, who deserve additional attention for tumor prevention and early detection.

CD206+ tumor-associated macrophages cross-present tumor antigen and drive antitumor immunity

In many solid cancers, tumor-associated macrophages (TAM) represent the predominant myeloid cell population. Antigen (Ag) cross-presentation leading to tumor Ag–directed cytotoxic CD8+ T cell responses is crucial for antitumor immunity. However, the role of recruited monocyte-derived macrophages, including TAM, as potential cross-presenting cells is not well understood. Here, we show that primary human as well as mouse CD206+ macrophages are effective in functional cross-presentation of soluble self-Ag and non–self-Ag, including tumor-associated Ag (TAA), as well as viral Ag. To confirm the presence of cross-presenting TAM in vivo, we performed phenotypic and functional analysis of TAM from B16-F10 and CT26 syngeneic tumor models and have identified CD11b+F4/80hiCD206+ TAM to effectively cross-present TAA. We show that CD11b+CD206+ TAM represent the dominant tumor-infiltrating myeloid cell population, expressing a unique cell surface repertoire, promoting Ag cross-presentation and Ag-specific CD8+ T cell activation comparable with cross-presenting CLEC9A+ DCs (cDC1). The presence of cross-presenting CD206+ TAM is associated with reduced tumor burden in mouse syngeneic tumor models and with improved overall survival in cutaneous melanoma patients. Therefore, the demonstration of effective Ag cross-presentation capabilities of CD206+ TAM, including their clinical relevance, expands our understanding of TAM phenotypic diversity and functional versatility.

Impact of a personal history of cutaneous squamous cell carcinoma in the overall survival of cutaneous melanoma patients

AbstractBackgroundThere have been previous studies on the association between cutaneous squamous cell carcinoma (cSCC) and cutaneous melanoma (CM) survival, and also the association between skin cancers and relative telomere length (RTL). In this study we analysed the overall survival (OS) of patients with CM and a positive history of cSCC to evaluate the impact of this history on survival and any possible association with RTL.Materials and MethodsA retrospective cohort study on 1613 patients with CM diagnosed between 1 January 2000 and 31 December 2015 at the Instituto Valenciano de Oncología. Contingency tables were used to analyze the association between a positive history of cSCC and other covariates. OS was evaluated using Kaplan–Meier curves and log‐rank test. Cox regression was used to determine the prognostic role of each covariate.ResultsPatients with a positive history of cSCC had a shorter OS (p < 0.001), but this was not significant at multivariate analysis. The covariates that resulted in independent predictors of shorter OS were gender, localisation, and lymphovascular invasion. Age and Breslow thickness were independent predictors only after 15 months of follow‐up; mitotic rate only between 15 and 65 months; disease stage only below 65 months, and RTL only after 65 months of follow‐up. A positive history of cSCC was not associated with RTL.ConclusionsOur results suggest that CM patients with a positive history of cSCC have a worse OS because it is related to other independent prognostic factors such as male gender and older age.

ERBB1/2/3 Expression, Prognosis, and Immune Infiltration in Cutaneous Melanoma.

BackgroundThe four ERBB tyrosine kinase family members [ERBB1 (epidermal growth factor receptor, EGFR), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4)] (ERBB receptor family) have been shown, according to previous studies, to be related to the cutaneous melanoma. ERBB3 is the only member of the ERBBs that lacks tyrosine kinase activity and thus needs to dimer with other tyrosine kinases receptors to trigger the signaling pathway, while ERBB3 may dimer with all members of the ERBB family. Melanoma progression depends on activation of ERBB signaling, especially the ERBB3/ERBB2 cascade. There are lymphocytes and T cell infiltrates in melanoma. Numerous pieces of evidences indicate that local immune status plays an important role in the formation of anti-tumor immune responses. However, the relationship between the ERBBs and prognosis and immune infiltration in cutaneous melanoma is not completely clear.MethodsThe expression of the ERBBs was analyzed through the Oncomine database, Gene Expression Profiling Interactive Analysis (GEPIA), respectively. Immunohistochemistry of ERBBs was obtained from the Human Protein Atlas is increased before HPA database. ERBBs genes expression and mutation analysis in cutaneous melanoma from the cBioPortal. Functional annotation and Kyoto Encyclopedia of Genes and Genomes is increased before KEGG pathway enrichment analysis from the Metascape. Correlations between ERBBs and 31 genes that were close to each other and frequently altered were explored by GEPIA. Using the GEPIA database, we also investigated the relationship between ERBBs and myeloid-derived suppressor cells (MDSC) in cutaneous melanoma. The disease-free survival and different tumor stages of ERBBs were evaluated by GEPIA. The correlation of ERBBs and tumor-infiltrating immune cells and prognostic(5 years survival rates) was tested by the Tumor Immune Estimation Resource (TIMER).ResultsIn general, the expression levels of ERBB1/2 in cutaneous melanoma were lower than those in normal skin tissue. By contrast, the ERBB3 expression level was higher in cutaneous melanoma than in normal skin tissue. Low expression of ERBB1/2 and high expression of ERBB3 were detrimental to the 5 years survival of cutaneous melanoma patients (ERBB1: log-rank P: 0.03; ERBB2: log-rank P: 0.008; ERBB3: log-rank P: 0.039). ERBB4 expression may not affect the prognosis of patients with cutaneous melanoma. ERBBs may not play a role in the tumor stage and disease-free survival in cutaneous melanoma patients. The relationship between the ERBB family and 31 genes that were close to each other and frequently altered is demonstrated as the genes regulated by the ERBB family being mainly concentrated in the RAS/RAF/MEK/ERK signaling pathway. ERBB2 can induce infiltration of CD8+ T cells and B cells, while ERBB3 can induce infiltration of CD4+ T cells, CD8+ T cells, and Neutrophil cells. ERBBs are more significantly associated with M1 macrophages, dendritic cells, Th1, Th2, Th17, and Treg cellular immune markers (Cor > 0.2). ERBB2/3 were related to MDSC in cutaneous melanoma, including human mononuclear myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), and may influence the progression of cutaneous melanoma through MDSC, but the conclusion needs further probing.ConclusionThis study investigated the prognosis and immune infiltration of the ERBB family in cutaneous melanoma. Our results suggest that ERBB1/2/3 may serve as early prognostic markers and potential therapeutic targets in cutaneous melanoma.

Novel Prognostic Models Predicting the Cancer-Specific Survival in Patients with Cutaneous Melanoma Based on Metastatic Lymph Node Status.

In cutaneous melanoma (CM), the present methods of lymph node (LN) staging have not sufficiently utilized the prognostic information of metastatic LNs. In this study, we aimed to construct prognostic nomograms based on the number of positive LNs (PLNs) and other clinicopathologic characteristics of CM patients. Two prognostic models were constructed in the none/single PLN (PLNnone/single) and multiple PLN (PLNmultiple) cohorts, respectively. Independent prognostic predictors associated with cancer-specific survival (CSS) in the above two cohorts were integrated to construct two nomograms for predicting the probability of 2-, 4-, and 6-year CSS in the PLNnone/single and PLNmultiple cohorts. The nomograms were evaluated by the area under the receiver operating characteristic curves (AUC), the calibration plots, and the decision curve analyses (DCAs). A total of 31,065 CM cases were included in this study. Factors included in the prognostic nomogram for patients in the PLNnone/single cohort were age, sex, race, marital status, insurance, primary tumor site, T stage, and number of PLNs, while factors included in the nomogram for cases in the PLNmultiple cohort included age, sex, marital status, insurance, primary tumor site, T stage, and number of PLNs. The AUC values for 2-, 4-, and 6-year CSS in the validation group of the PLNnone/single cohort were 0.833, 0.811, and 0.818, respectively, while in the validation group of the PLNmultiple cohort, the AUC values for 2-, 4,- and 6-year CSS were 0.720, 0.723, and 0.745, respectively. Compared with the American Joint Committee on Cancer 7th edition staging system, our two nomograms showed better predictive values. Additionally, the calibration plots and DCA curves for 2-, 4-, and 6-year CSS prediction demonstrated good coordination and net benefit in both the PLNnone/single and PLNmultiple cohorts. Our nomograms, based on the number of PLNs and other clinicopathologic characteristics, showed good predictive ability for predicting the survival of CM patients.

Web-based nomograms for predicting the prognosis of adolescent and young adult skin melanoma, a large population-based real-world analysis.

BackgroundInvasive cutaneous melanoma is one of the most common malignant diseases among adolescents and young adults (aged 15–40 years) in the United States. We aimed to develop web-based nomograms to precisely predict overall survival and cancer-specific survival in this group of patients with cutaneous melanoma.MethodsWe analyzed the overall and caner-specific death events in 19,887 patients who underwent surgical resection of cutaneous melanoma from Surveillance, Epidemiology and End Results database and developed web-based clinic-pathologic prediction models for overall survival and cancer specific survival based on Cox regression. C-statistics of Harrell and time-dependent Receiver Operating Characteristic Curve (ROC) were used to evaluate the prognostic accuracy of nomograms.ResultsMultivariate Cox regression model analysis suggested that age, sex, race, tumor location, Clark level, ulceration, thickness, and N stage were independently associated with both overall survival and cancer-specific survival in adolescent and young adult patients with cutaneous melanoma. The nomograms performed excellently in predicting overall survival and cancer-specific survival with C-index being 0.875 (95% CI: 0.847–0.903) and 0.901 (95% CI: 0.876–0.925), respectively. Time-dependent ROC verified that the prognostic accuracy of nomograms was better than that of American Joint Committee on Cancer staging system and other prognostic factors.ConclusionsThese user-friendly nomograms can precisely predict overall survival and cancer-specific survival in cutaneous melanoma patients treated with surgical resection, which may help to make individualized postoperative follow-up and therapeutic schemes.

Reconstruction of lncRNA-miRNA-mRNA network based on competitive endogenous RNA reveals functional lncRNAs in skin cutaneous melanoma

BackgroundHuman skin cutaneous melanoma is the most common and dangerous skin tumour, but its pathogenesis is still unclear. Although some progress has been made in genetic research, no molecular indicators related to the treatment and prognosis of melanoma have been found. In various diseases, dysregulation of lncRNA is common, but its role has not been fully elucidated. In recent years, the birth of the “competitive endogenous RNA” theory has promoted our understanding of lncRNAs.MethodsTo identify the key lncRNAs in melanoma, we reconstructed a global triple network based on the “competitive endogenous RNA” theory. Gene Ontology and KEGG pathway analysis were performed using DAVID (Database for Annotation, Visualization, and Integration Discovery). Our findings were validated through qRT-PCR assays. Moreover, to determine whether the identified hub gene signature is capable of predicting the survival of cutaneous melanoma patients, a multivariate Cox regression model was performed.ResultsAccording to the “competitive endogenous RNA” theory, 898 differentially expressed mRNAs, 53 differentially expressed lncRNAs and 16 differentially expressed miRNAs were selected to reconstruct the competitive endogenous RNA network. MALAT1, LINC00943, and LINC00261 were selected as hub genes and are responsible for the tumorigenesis and prognosis of cutaneous melanoma.ConclusionsMALAT1, LINC00943, and LINC00261 may be closely related to tumorigenesis in cutaneous melanoma. In addition, MALAT1 and LINC00943 may be independent risk factors for the prognosis of patients with this condition and might become predictive molecules for the long-term treatment of melanoma and potential therapeutic targets.

Analysis of disease free survival in cutaneous melanoma patients subject to sentinel lymph node biopsy.

<b>Introduction:</b> Cutaneous melanoma is estimated for 2% of malignant neoplasms occurring in humans. It is characterized by a high level of malignancy and low sensitivity to cytostatic drugs. The incidence of cutaneous melanoma is increasing in Poland. The lymphatic system is the most common route of dissemination of this neoplasm. The appearance of a sentinel node biopsy technique has made it possible to identify patients with a regionally advanced disease. It is a minimally invasive method with a small percentage of complications. <br><b>Aim: </b>Analysis of disease free survival (DFS) in cutaneous melanoma patients with sentinel lymph node biopsy. <br><b>Material and methods:</b> The analysis included 222 patients with cutaneous melanoma treated in the Department of Oncological Surgery in 2010-2015, who underwent a sentinel node biopsy. The study group consisted of 136 women and 86 men, the average age of patients was 59 years. Patients were qualified for sentinel node biopsy based on clinical evaluation and ultrasound of regional lymph nodes. The average follow-up was 25.1 months. About 2 hours before surgery, patients received a radioisotope, then lymphoscintigraphy SPECT was performed. Additionally, they were administered the Patent Blue dye in the operating room. <br><b>Results:</b> The sentinel node was identified in 217 patients (98%), and the average sentinel nodes were 2.25. Twenty-seven patients (12%) had a metastasis in sentinel nodes. In this group, the duration of symptom free survival was significantly shorter. Sentinel node status and age of the patient were independent factors affecting the prognosis of disease free survival. <br><b>Conclusions:</b> Sentinel node biopsy is a precise method to identify patients with cutaneous melanoma who have metastasis to regional lymph nodes, as well as the most important prognostic factor.

Solar Lentigines are Associated with Better Outcome in Cutaneous Melanoma.

The rising incidence of cutaneous melanoma and its stable high mortality rates despite innovative cancer care, require better prediction of the clinical outcome. In a large cutaneous melanoma population we explored whether the known clinical risk factors for melanoma susceptibility (nevus phenotype, phototype, family and personal history of melanoma and sun damage) affect melanoma outcomes. A total of 1,530 melanoma patients were included. Multivariable analysis adjusted for age, gender, melanoma stage, localization and subtype showed that familial melanoma, solar lentigines on head and neck, the back of hands, arms and shoulders were associated with a better relapse free survival. The presence of atypical naevi was associated with an increased risk of relapse. After Bonferroni correction, the correlation between presence of solar lentigines on the back of the hands and arms remained the most robust and significant prognostic factor for the relapse free survival in cutaneous melanoma patients.

Hyaluronic acid-CD44 interactions promote BMP4/7-dependent Id1/3 expression in melanoma cells

BMP4/7-dependent expression of inhibitor of differentiation/DNA binding (Id) proteins 1 and 3 has been implicated in tumor progression and poor prognosis of malignant melanoma patients. Hyaluronic acid (HA), a pericellular matrix component, supports BMP7 signalling in murine chondrocytes through its receptor CD44. However, its role in regulating BMP signalling in melanoma is not clear. In this study we found that depletion of endogenously-produced HA by hyaluronidase treatment or by inhibition of HA synthesis by 4-methylumbelliferone (4-MU) resulted in reduced BMP4/7-dependent Id1/3 protein expression in mouse melanoma B16-F10 and Ret cells. Conversely, exogenous HA treatment increased BMP4/7-dependent Id1/3 protein expression. Knockdown of CD44 reduced BMP4/7-dependent Id1/3 protein expression, and attenuated the ability of exogenous HA to stimulate Id1 and Id3 expression in response to BMP. Co-IP experiments demonstrated that CD44 can physically associate with the BMP type II receptor (BMPR) ACVR2B. Importantly, we found that coordinate expression of Id1 or Id3 with HA synthases HAS2, HAS3, and CD44 is associated with reduced overall survival of cutaneous melanoma patients. Our results suggest that HA-CD44 interactions with BMPR promote BMP4/7-dependent Id1/3 protein expression in melanoma, contributing to reduced survival in melanoma patients.

High Number of Circulating Tumor Cells Predicts Poor Survival of Cutaneous Melanoma Patients in China.

BackgroundMelanoma is an aggressive cancer with complex etiology and poor prognosis. Surgical resection is still the primary treatment of melanoma, but shows limited efficacy in late-stage patients. Additionally, reliable prognostic markers of skin melanoma patients are still lacking. Circulating tumor cells (CTCs) have shown promise in predicting prognosis of multiple cancers.Evaluating the prognostic value of CTC number in melanoma patients.Material/MethodsCTCs were isolated by immunomagnetic capture from 7.5-mL samples of blood from 100 patients with cutaneous melanoma. Baseline CTC number (pre-treatment) and post-treatment CTC number were measured. Baseline CTC number and CTC number alteration were correlated with clinicopathological features and survival.ResultsForty-three (43%) patients had more than 6 CTCs, whereas 57 (57%) had 6 cells or less. High baseline CTC count was associated with deep local invasion, lymph node metastasis, and distance metastasis, with P value of 0.003, 0.047, and 0.034, respectively. High baseline CTC count was also correlated with short overall survival time and was considered as an independent prognostic factor (P value=0.012, hazard ratio=2.262). CTC cell alteration was associated with progression-free survival and disease-specific survival (with P values of 0.012 and 0.009, respectively).ConclusionsBaseline CTC count was correlated with adverse pathological features and was predictive of survival in melanoma patients. Alteration of CTC count before and after treatment was an indicator of therapy response and prognosis. Measuring the baseline and post-treatment CTC counts is a powerful tool in monitoring melanoma progression, drug response, and survival.

Anemia in Cutaneous Malignant Melanoma: Low Blood Hemoglobin Level is Associated with Nodal Involvement, Metastatic Disease, and Worse Survival

ABSTRACTAnemia is common in cancer patients and also affects survival. However, its clinical role and prognostic significance remains unknown in cutaneous melanoma patients (CMPs). The aim of this study was to determine the clinical significance of blood hemoglobin levels in CMPs. Of 446 CMPs were enrolled into this study and were investigated retrospectively. The median value of hemoglobin levels was 13.4 g/dL (7.9–17.4 g/dL). The female patients (P < 0.001) and those with nodular histology (P = 0.040), elevated erythrocyte sedimentation rate (P < 0.001), higher serum lactate dehydrogenase (P < 0.001), lymph node involvement (P = 0.018), and metastatic disease (P < 0.001) had more likely low hemoglobin concentrations compared with other CMPs. However, serum hemoglobin levels were not significantly associated with age, anatomic localization, and various pathological features including Breslow depth, mitotic rate, and ulceration. We found that hemoglobin levels were significantly associated with outcome; the patients with low hemoglobin concentrations had worse survival than other CMPs (P < 0.001). On multivariate analyses, however, hemoglobin level lost its significance, thus, it was not found independently associated with the outcome. In conclusion, low blood hemoglobin concentration is associated with nodal involvement and metastatic disease. Although anemia in diagnosis was not an independent prognostic factor for survival in CMPs, it was associated with poor prognostic factors.

Genetic variants of PDGF signaling pathway genes predict cutaneous melanoma survival.

To investigate whether genetic variants of platelet-derived growth factor (PDGF) signaling pathway genes are associated with survival of cutaneous melanoma (CM) patients, we assessed associations of single-nucleotide polymorphisms in PDGF pathway with melanoma-specific survival in 858 CM patients of M.D. Anderson Cancer Center (MDACC). Additional data of 409 cases from Harvard University were also included for further analysis. We identified 13 SNPs in four genes (COL6A3, NCK2, COL5A1 and PRKCD) with a nominal P < 0.05 and false discovery rate (FDR) < 0.2 in MDACC dataset. Based on linkage disequilibrium, functional prediction and minor allele frequency, a representative SNP in each gene was selected. In the meta-analysis using MDACC and Harvard datasets, there were two SNPs associated with poor survival of CM patients: rs6707820 C>T in NCK2 (HR = 1.87, 95% CI = 1.35-2.59, Pmeta = 1.53E-5); and rs2306574 T>C in PRKCD (HR = 1.73, 95% CI = 1.33-2.24, Pmeta = 4.56E-6). Moreover, CM patients in MDACC with combined risk genotypes of these two loci had markedly poorer survival (HR = 2.47, 95% CI = 1.58-3.84, P < 0.001). Genetic variants of rs6707820 C>T in NCK2 and rs2306574 T>C in PRKCD of the PDGF signaling pathway may be biomarkers for melanoma survival.

Tumor Infiltrating Lymphocytes (TILs) May be Only an Independent Predictor of Nodal Involvement but not for Recurrence and Survival in Cutaneous Melanoma Patients

ABSTRACTTumor infiltrating lymphocytes (TILs) invade and disrupt melanoma cells and their clinical roles remain controversial. In this study, we aimed to determine the clinical significance of the TILs status in cutaneous melanoma patients (CMPs). Of 750 CMPs enrolled into this study 486 (64.8%) had lesions with TILs. The patients with TILs more likely had nodular histology, presence of histological regression, and absence of regional lymph node involvement. However, its presence was not associated with outcome. In conclusion, presence of TILs may be only an independent predictor for absence of nodal involvement but it is not associated with recurrence and survival in CMPs.

Genetic variants in the integrin signaling pathway genes predict cutaneous melanoma survival.

To identify genetic variants involved in prognosis of cutaneous melanoma (CM), we investigated associations of single nucleotide polymorphisms (SNPs) of genes in the integrin signaling pathway with CM survival by re-analyzing a published genome-wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center (MDACC) and then validated significant SNPs in another GWAS from Harvard University. In the MDACC study, 1,148 SNPs were significantly associated with CM-specific survival (CMSS) (p ≤ 0.050 and false-positive report probability ≤ 0.20), and nine SNPs were validated in the Harvard study (p ≤ 0.050). Among these, three independent SNPs (i.e., DOCK1 rs11018104 T > A, rs35748949 C > T and PAK2 rs1718404 C > T) showed a predictive role in CMSS, with an effect-allele attributed adjusted hazards ratio [adjHR of 1.50 (95% confidence interval (CI) = 1.18-1.90, p = 7.46E-04), 1.53 (1.18-1.97, 1.18E-03) and 0.58 (0.45-0.76, 5.60E-05), respectively]. Haplotype analysis revealed that a haplotype carrying two risk alleles A-T in DOCK1 was associated with the poorest survival in both MDACC (adjHR = 1.73, 95% CI = 1.19-2.50, p = 0.004) and Harvard (adjHR = 1.95, 95% CI = 1.14-3.33, p = 0.010) studies. In addition, patients with an increasing number of unfavorable genotypes (NUGs) for these three SNPs had a poorer survival. Incorporating NUGs with clinical variables showed a significantly improved ability to classify CMSS (AUC increased from 86.8% to 88.6%, p = 0.031). Genetic variants in the integrin signaling pathway may independently or jointly modulate the survival of CM patients. Further large, prospective studies are needed to validate these findings.