Early time to recurrence predicts worse survival in patients with localized or regionally advanced cutaneous melanoma.
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ABSTRACT:
SUBMITTER: Liang C
PROVIDER: S-EPMC8459230 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We sought to develop a sentinel lymph node gene expression signature score predictive of disease recurrence in patients with cutaneous melanoma. Gene expression profiling was performed on SLN biopsies using U133A 2.0 Affymetrix gene chips. The top 25 genes associated with recurrence-free survival (RFS) were selected and a penalized regression function was used to select 12 genes with a non-zero coefficient. A proportional hazards regression model was used to evaluate the association between clinical covariates, gene signature score, and RFS. Among the 45 patients evaluated, 23 (51%) had a positive SLN. Twenty-one (46.7%) patients developed disease recurrence. For the top 25 differentially expressed genes (DEG), 12 non-zero penalized coefficients were estimated (CLGN, C1QTNF3, ADORA3, ARHGAP8, DCTN1, ASPSCR1, CHRFAM7A, ZNF223, PDE6G, CXCL3, HEXIM1, HLA-DRB). This 12-gene signature score was significantly associated with RFS (p < 0.0001) and produced a bootstrap C index of 0.888. In univariate analysis, Breslow thickness, presence of primary tumor ulceration, SLN positivity were each significantly associated with RFS. After simultaneously adjusting for these prognostic factors in relation to the gene signature, the 12-gene score remained a significant independent predictor for RFS (p < 0.0001). This SLN 12-gene signature risk score is associated with melanoma recurrence regardless of SLN status and may be used as a prognostic factor for RFS.
| S-EPMC9599365 | biostudies-literature
Project description:To identify a melanoma microRNA (miRNA) expression signature that is predictive of outcome and then evaluate its potential to improve risk stratification when added to the standard-of-care staging criteria.Total RNA was extracted from 59 formalin-fixed paraffin-embedded melanoma metastases and hybridized to miRNA arrays containing 911 probes. We then correlated miRNA expression with post-recurrence survival and other clinicopathologic criteria.We identified a signature of 18 miRNAs whose overexpression was significantly correlated with longer survival, defined as more than 18 months post-recurrence survival. Subsequent cross-validation showed that a small subset of these miRNAs can predict post-recurrence survival in metastatic melanoma with an estimated accuracy of 80.2% (95% confidence interval, 79.8-80.6%). In contrast to standard-of-care staging criteria, a six-miRNA signature significantly stratified stage III patients into "better" and "worse" prognostic categories, and a multivariate Cox regression analysis revealed the signature to be an independent predictor of survival. Furthermore, we showed that most miRNAs from the signature also showed differential expression between patients with better and worse prognoses in the corresponding paired primary melanoma.MiRNA signatures have potential as clinically relevant biomarkers of prognosis in metastatic melanoma. Our data suggest that molecularly based models of risk assessment can improve the standard staging criteria and support the incorporation of miRNAs into such models.
| S-EPMC4662869 | biostudies-literature
Project description:Locally/regionally advanced melanoma confers a major challenge in terms of surgical and medical management. Surgical treatment carries the risks of surgical morbidities and potential complications that could be lasting. In addition, these patients continue to have a high risk of relapse and death despite the use of standard adjuvant therapy. Neoadjuvant therapy has the potential to significantly improve the clinical outcome of these patients, particularly in this era of newer and effective targeted and immunotherapeutic agents. Previous neoadjuvant studies tested chemotherapy with temozolomide where the clinical activity was limited. Biochemotherapy (BCT) was tested in two studies in the neoadjuvant setting and showed high tumor response rates; however, BCT was ultimately abandoned following its failure to demonstrate survival benefits in randomized trials of metastatic disease. Success of immunotherapy and targeted therapy in prolonging the lives of patients with metastatic melanoma generated considerable interest to investigate these novel strategies in the adjuvant and neoadjuvant settings. A number of neoadjuvant targeted and immunotherapy studies have been completed in melanoma to date and have yielded promising clinical activity. Given these encouraging results, a number of studies with other molecularly targeted and immunotherapeutic agents and their combinations are ongoing in the neoadjuvant setting; long-term outcome data are eagerly awaited. Such studies also provide access to biospecimens before and during therapy, allowing for the conduct of biomarker and mechanistic studies that may have a significant impact in guiding adjuvant therapy choices and drug development.
| S-EPMC6669845 | biostudies-literature
Project description:Metabolic reprogramming is a common hallmark of tumor cells and is a crucial mediator of resistance toward anticancer therapies. The pattern of a metabolism-related signature in melanoma remains unknown. Here, we explored the role of a multi-metabolism-related gene signature in melanoma.We used the training and validation sets to develop a multi-metabolism-related gene signature. Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) method were used for constructing a model. The predictive role of the metabolic signature with clinicopathological features of melanoma was also analyzed. Functional analysis of this metabolic signature was also investigated.A ten metabolism-related gene signature was identified and can stratify melanoma into high- and low- risk groups. The signature was correlated with progressive T stage, Breslow thickness, Clark level, and worse survival (all Ps< 0.01). This metabolic signature was shown as an independent prognostic factor and was also a predictive indicator for worse survival in various clinical and molecular features of melanoma. Furthermore, the metabolic signature was implicated in immune responses such as the regulation of T cell activation and cytokine activity. The metabolic signaturewas associated with the progression and worse survival of melanoma. Our study offered a valuable metabolism-targeted therapy approach for melanoma.
| S-EPMC8291831 | biostudies-literature
Project description:Programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) targeted therapies have shown promising survival outcomes in several human neoplasms. However, it is unclear whether the expression of PD-L1 can be correlated to any clinical and pathologic variables in patients with cutaneous angiosarcoma (CA). The aim of this study was to evaluate the clinicopathological significance of PD-L1 expression in CA patients.Data from 52 patients with CA were retrospectively reviewed. PD-L1 expression, tumor proliferation determined by Ki-67 index, and immunohistochemical evaluation of tumor-infiltrating lymphocytes, CD4+ and CD8+, were used to determine correlation with clinicopathological variables.PD-L1 was positively expressed in 40% of all patients. PD-L1 expression was significantly associated with tumor cell proliferation. Multivariate analysis confirmed that high levels of CD8+ tumor-infiltrating lymphocytes were a significant predictor in patients with clinical stage I CA and the positive expression of PD-L1 was an independent prognostic factor in predicting worse outcome.PD-L1 expression is a novel pathologic marker for predicting worse outcome in patients with CA.
| S-EPMC5560454 | biostudies-other
Project description:BackgroundThe outcomes of patients with stage III cutaneous melanoma who undergo complete surgical resection can be highly variable, and estimation of individual risk of disease recurrence and mortality remains imprecise. With recent demonstrations of effective adjuvant targeted and immune checkpoint inhibitor therapy, more precise stratification of patients for costly and potentially toxic adjuvant therapy is needed. We report the utility of pre-operative circulating tumour DNA (ctDNA) in patients with high-risk stage III melanoma.Patients and methodsctDNA was analysed in blood specimens that were collected pre-operatively from 174 patients with stage III melanoma undergoing complete lymph node (LN) dissection. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for distant metastasis recurrence-free survival and melanoma-specific survival (MSS).ResultsThe detection of ctDNA in the discovery and validation cohort was 34% and 33%, respectively, and was associated with larger nodal melanoma deposit, higher number of melanoma involved LNs, more advanced stage and high lactate dehydrogenase (LDH) levels. Detectable ctDNA was significantly associated with worse MSS in the discovery [hazard ratio (HR) 2.11 P < 0.01] and validation cohort (HR 2.29, P = 0.04) and remained significant in a multivariable analysis (HR 1.85, P = 0.04). ctDNA further sub-stratified patients with AJCC stage III substage, with increasing significance observed in more advanced stage melanoma.ConclusionPre-operative ctDNA predicts MSS in high-risk stage III melanoma patients undergoing complete LN dissection, independent of stage III substage. This biomarker may have an important role in determining prognosis and stratifying patients for adjuvant treatment.
| S-EPMC6551453 | biostudies-literature
Project description:BackgroundCutaneous melanoma (CM) is one of the most aggressive cancers with highly metastatic ability. To make things worse, there are limited effective therapies to treat advanced CM. Our study aimed to investigate new biomarkers for CM prognosis and establish a novel risk score system in CM.MethodsGene expression data of CM from Gene Expression Omnibus (GEO) datasets were downloaded and analyzed to identify differentially expressed genes (DEGs). The overlapped DEGs were then verified for prognosis analysis by univariate and multivariate COX regression in The Cancer Genome Atlas (TCGA) datasets. Based on the gene signature of multiple survival associated DEGs, a risk score model was established, and its prognostic and predictive role was estimated through Kaplan-Meier (K-M) analysis and log-rank test. Furthermore, the correlations between prognosis related genes expression and immune infiltrates were analyzed via Tumor Immune Estimation Resource (TIMER) site.ResultsA total of 103 DEGs were obtained based on GEO cohorts, and four genes were verified in TCGA datasets. Subsequently, four genes (ADAMDEC1, GNLY, HSPA13, and TRIM29) model was developed by univariate and multivariate Cox regression analyses. The K-M plots showed that the high-risk group was associated with shortened survival than that in the low-risk group (P < 0.0001). Multivariate analysis suggested that the model was an independent prognostic factor (high-risk vs. low-risk, HR= 2.06, P < 0.001). Meanwhile, the high-risk group was prone to have larger breslow depth (P< 0.001) and ulceration (P< 0.001).ConclusionsThe four-gene risk score model functions well in predicting the prognosis and treatment response in CM and will be useful for guiding therapeutic strategies for CM patients. Additional clinical trials are needed to verify our findings.
| S-EPMC8024561 | biostudies-literature
Project description:Novel treatment modalities comprising immune checkpoint inhibitors and targeted therapies have revolutionized treatment of metastatic melanoma. Still, some patients suffer from rapid progression and decease within months after a diagnosis of stage IV melanoma. We aimed to assess whether genomic alterations may predict survival after the development of stage IV disease, irrespective of received therapy. We analyzed tumor samples of 79 patients with stage IV melanoma using a custom next-generation gene-sequencing panel, MelArray, designed to detect alterations in 190 melanoma-relevant genes. We classified the patients: first, as short survivors (survival ≤6 months after stage IV disease, n = 22) and long survivors (survival >6 months, n = 57); second, by using a cut-off of one year; and third, by comparing the longest surviving 20 patients to the shortest surviving 20. Among analyzed genes, no individual gene alterations, or combinations of alterations, could be dichotomously associated with survival. However, the cohort's mutational profiles closely matched three known mutational signatures curated by the Catalog of Somatic Mutations in Cancer (COSMIC): UV signature COSMIC_7 (cosine-similarity 0.932), clock-like signature COSMIC_5 (cosine-similarity 0.829), and COSMIC_30 (cosine-similarity 0.726). Patients with UV signature had longer survival compared to patients with clock-like and COSMIC 30 (p < 0.0001). Subgroup dichotomization at 6 months showed that 75% of patients with UV signature survived longer than 6 months, and about 75% of patients with clock-like signature survived less than 6 months after development of stage IV disease. In our cohort, clock-like COSMIC_5 mutational signature predicted poor survival while a UV signature COSMIC_7 predicted longer survival. The prognostic value of mutational signatures should be evaluated in prospective studies.
| S-EPMC10418148 | biostudies-literature
Project description:PurposeNeoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.Patients and methodsPatients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.ResultsA total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2-43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5-85.8], with a 43% (95% CI: 27.3-60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively).ConclusionsNeoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133.
| S-EPMC8338751 | biostudies-literature
Project description:BackgroundFerroptosis plays a vital role in hepatocellular carcinoma (HCC). CISD1 is known to regulate ferroptosis negatively. However, the correlations of CISD1 to prognosis in HCC and its potential mechanism remain unclear.AimTo investigate the expression level and prognostic value of CISD1 in HCC.MethodsGene expression and clinical data for 33 cancer types in TCGA were downloaded from the UCSC Xena platform. Pan-cancer analysis was performed to determine the expression profile and prognostic value of CISD1 in human cancers. GEO datasets and Human Protein Atlas (HPA) were used to verify the mRNA and protein expression levels. The influence of CISD1 on clinical prognosis in HCC was evaluated using a Kaplan-Meier plotter. The PPI network was constructed using the STRING database and Cytoscape. GO and KEGG pathways were constructed using the "clusterProfiler" R package with the FDR cutoff of 0.05. The methylation at the CISD1 promoter was detected using UALCAN and GEO datasets. The correlations between CISD1 and HCC immune infiltrates were investigated via TIMER.ResultsPan-cancer analysis of TCGA data showed that CISD1 is differentially expressed in multiple tumors. Data of gene expression microarrays reveal that the mRNA expression of CISD1 is higher in HCC than that in normal tissue. The protein level of CISD1, validated by the Human Protein Atlas (HPA) database, was upregulated consistently with mRNA levels in HCC samples. High CISD1 expression was associated with better overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and progression-free survival (PFS) in LGG, but with poorer OS, DFS, DSS, and PFS in LIHC. Protein-protein interaction (PPI) analysis and GO/KEGG analysis showed that the PPI network and GO term of CISD1 were mainly associated with energy and iron metabolism. Promoter hypomethylation correlated with overexpression of CISD1. CISD1 expression was positively correlated with infiltrating levels of CD8+ T cells, macrophages, neutrophils, and dendritic cells (DCs) in HCC.ConclusionsThese findings suggest that hypomethylation of the CISD1 promoter increases its expression in HCC. CISD1 is associated with prognosis and immune infiltrating levels of CD8+ T cells, macrophages, neutrophils, and DCs in HCC patients. These findings suggest that CISD1 can be used as a prognostic biomarker for determining prognosis in HCC.
| S-EPMC8933656 | biostudies-literature