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Pro-inflammatory cytokines predict relapse-free survival after one month of interferon-α but not observation in intermediate risk melanoma patients

Tarhini, AA and Lin, Y and Zahoor, H and Shuai, Y and Butterfield, LH and Ringquist, S and Gogas, H and Sander, C and Lee, S and Agarwala, SS and Kirwood, JM (2015) Pro-inflammatory cytokines predict relapse-free survival after one month of interferon-α but not observation in intermediate risk melanoma patients. PLoS ONE, 10 (7).

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Copyright: © 2015 Tarhini et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: E1697 was a phase III trial of adjuvant interferon (IFN)-α2b for one month (Arm B) versus observation (Arm A) in patients with resected melanoma at intermediate risk. We evaluated the levels of candidate serum cytokines, the HLA genotype, polymorphisms of CTLA4 and FOXP3 genes and the development of autoantibodies for their association with relapse free survival (RFS) in Arm A and Arm B among 268 patients with banked biospecimens. Methods: ELISA was used to test 5 autoantibodies. Luminex/One Lambda LABTypeRSSO was used for HLA Genotyping. Selected CTLA4 and FOXP3 Single nucleotide polymorphisms (SNPs) and microsatellites were tested for by polymerase chain reaction (PCR). Sixteen serum cytokines were tested at baseline and one month by Luminex xMAP multiplex technology. Cox Proportional Hazards model was applied and the Wald test was used to test the marginal association of each individual marker and RFS. We used the Lasso approach to select the markers to be included in a multi-marker Cox Proportional Hazards model. The ability of the resulting models to predict one year RFS was evaluated by the time-dependent ROC curve. The leave-one-out method of cross validation (LOOCV) was used to avoid over-fitting of the data. Results: In the multi-marker modeling analysis conducted in Arm B, one month serum IL2Rα, IL- 12p40 and IFNα levels predicted one year RFS with LOOCV AUC = 82%. Among the three markers selected, IL2Rα and IFNα were the most stable (selected in all the cross validation cycles). The risk score (linear combination of the 3 markers) separated the RFS curves of low and high risk groups well (p = 0.05). This model did not hold for Arm A, indicating a differential marker profile in Arm B linked to the intervention (adjuvant therapy). Conclusions: Early on-treatment proinflammatory serum markers (IL2Rα, IL-12p40, IFNα) significantly predict RFS in our cohort of patients treated with adjuvant IFN-α2b and warrant further study.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Tarhini, AA
Lin, Yyal14@pitt.eduYAL14
Zahoor, Hhaz42@pitt.eduHAZ42
Shuai, Yshuai@pitt.eduSHUAI
Butterfield, LHlhb3@pitt.eduLHB3
Ringquist, S
Gogas, H
Sander, Ccas32@pitt.eduCAS32
Lee, S
Agarwala, SS
Kirwood, JM
ContributionContributors NameEmailPitt UsernameORCID
Centers: Other Centers, Institutes, or Units > Pittsburgh Cancer Institute
Date: 20 July 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 7
DOI or Unique Handle: 10.1371/journal.pone.0132745
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Biostatistics
Refereed: Yes
Date Deposited: 23 Aug 2016 14:25
Last Modified: 05 Feb 2019 05:55


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