Dataset Information

The Expression of CD74-Regulated Inflammatory Markers in Stage IV Melanoma: Risk of CNS Metastasis and Patient Survival.

ABSTRACT: Innate inflammatory features have been found in melanoma tumors from patients at all stages, and molecular analysis has identified definitive inflammatory proteins expressed by tumors cells in patients who presents the worst prognosis. We have previously observed weakened outcomes in patients with constitutive expression of inducible nitric oxide synthase (iNOS), macrophage migration inhibitory factor (MIF) and improved outcomes with CD74 expression in stage III melanoma. In our current study, we tested our hypothesis on CD74-regulated inflammatory markers' expression in stage IV melanoma tumors whether the signature is associated with survival outcome and/or risk of developing CNS metastasis. We retrospectively identified 315 patients with stage IV melanoma. In a tissue microarray (TMA), we examined the expression of cells with CD74, its receptor MIF, and downstream inflammatory markers iNOS, nitrotyrosine (NT), cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES1). We analyzed the association of those inflammatory markers with overall survival time (OS) and time to CNS metastasis using Kaplan-Meier survival analyses. Our data validates CD74 as a useful prognostic tumor cell protein marker associated with favorable OS as in stage III melanomas, while the tumor NT expression strongly predicts an increased risk of developing CNS metastasis (p = 0.0008) in those patients.

SUBMITTER: Ogata D

PROVIDER: S-EPMC7764866 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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The Expression of CD74-Regulated Inflammatory Markers in Stage IV Melanoma: Risk of CNS Metastasis and Patient Survival.

Ogata Dai D Roszik Jason J Oba Junna J Kim Sun-Hee SH Bassett Roland L RL Haydu Lauren E LE Tanese Keiji K Grimm Elizabeth A EA Ekmekcioglu Suhendan S

Cancers 20201214 12

Innate inflammatory features have been found in melanoma tumors from patients at all stages, and molecular analysis has identified definitive inflammatory proteins expressed by tumors cells in patients who presents the worst prognosis. We have previously observed weakened outcomes in patients with constitutive expression of inducible nitric oxide synthase (iNOS), macrophage migration inhibitory factor (MIF) and improved outcomes with CD74 expression in stage III melanoma. In our current study, w ...[more]

PMID: 33327409

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Project description:BackgroundThe clinical course of cutaneous melanoma (CM) can differ significantly for patients with identical stages of disease, defined clinico-pathologically, and no molecular markers differentiate patients with such a diverse prognosis. This study aimed to define the prognostic value of whole genome DNA methylation profiles in stage III CM.MethodsGenome-wide methylation profiles were evaluated by the Illumina Human Methylation 27 BeadChip assay in short-term neoplastic cell cultures from 45 stage IIIC CM patients. Unsupervised K-means partitioning clustering was exploited to sort patients into 2 groups based on their methylation profiles. Methylation patterns related to the discovered groups were determined using the nearest shrunken centroid classification algorithm. The impact of genome-wide methylation patterns on overall survival (OS) was assessed using Cox regression and Kaplan-Meier analyses.ResultsUnsupervised K-means partitioning by whole genome methylation profiles identified classes with significantly different OS in stage IIIC CM patients. Patients with a "favorable" methylation profile had increased OS (P = 0.001, log-rank = 10.2) by Kaplan-Meier analysis. Median OS of stage IIIC patients with a "favorable" vs. "unfavorable" methylation profile were 31.5 and 10.4 months, respectively. The 5 year OS for stage IIIC patients with a "favorable" methylation profile was 41.2% as compared to 0% for patients with an "unfavorable" methylation profile. Among the variables examined by multivariate Cox regression analysis, classification defined by methylation profile was the only predictor of OS (Hazard Ratio = 2.41, for "unfavorable" methylation profile; 95% Confidence Interval: 1.02-5.70; P = 0.045). A 17 gene methylation signature able to correctly assign prognosis (overall error rate = 0) in stage IIIC patients on the basis of distinct methylation-defined groups was also identified.ConclusionsA discrete whole-genome methylation signature has been identified as molecular marker of prognosis for stage IIIC CM patients. Its use in daily practice is foreseeable, and promises to refine the comprehensive clinical management of stage III CM patients.

Project description:BackgroundSeveral therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial.MethodsPatients with resected stage IIIB-C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from >3-12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups.ResultsFrom the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm.ConclusionResults of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident.Trial registration numberNCT02388906.

Dataset Information

The Expression of CD74-Regulated Inflammatory Markers in Stage IV Melanoma: Risk of CNS Metastasis and Patient Survival.

Publications

The Expression of CD74-Regulated Inflammatory Markers in Stage IV Melanoma: Risk of CNS Metastasis and Patient Survival.

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