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01-07-2010 | Melanomas

Isolated Hepatic Perfusion with High-Dose Melphalan Results in Immediate Alterations in Tumor Gene Expression in Patients with Metastatic Ocular Melanoma

Authors: Sheelu Varghese, PhD, Hui Xu, BS, David Bartlett, MD, Marybeth Hughes, MD, James F. Pingpank, MD, Tatiana Beresnev, MD, H. Richard Alexander Jr., MD

Published in: Annals of Surgical Oncology | Issue 7/2010

Abstract

Background

Patients with ocular melanoma liver metastases have a poor prognosis, treatment options are limited, and median survival is less than 1 year. In this study, we characterized the early molecular changes that occur in tumors immediately after vascular isolation perfusion with melphalan with hyperthermia in patients with hepatic metastases from ocular melanoma.

Methods

Patients underwent treatment on a clinical trial using a 60-min hyperthermic isolated hepatic perfusion (IHP) with melphalan. Microarray analysis was performed in 28 tumor samples obtained intraoperatively of which 12 were pre- and 16 were post-IHP. Various statistical analyses were performed to identify differentially expressed genes and gene categories between the groups.

Results

Median survival of 17 treated patients was 11.9 months. Unsupervised hierarchical clustering of all tumors resulted in separation of pre and post-IHP samples into two distinct groups. Analysis of genes showed that the Ras GTPase activator, ecotropic viral integration site 5 (EVI5), and several other melanoma-associated genes were overexpressed in pre-IHP tumors. In post-IHP samples the overexpression of a DNA replication associated gene, replication factor C (RFC5), was significantly associated with shortened survival (P < 0.003). Other major gene ontology categories identified in the post-IHP tumor samples were DNA-directed RNA polymerase activity and chromatin remodeling, both important categories involved in DNA replication and repair.

Conclusions

These results demonstrate that acute changes in gene expression patterns occur in tumors immediately after treatment with melphalan administered via hyperthermic IHP. Rapid activation of DNA synthesis and repair pathways may be a mechanism of acquired tumor resistance in patients with ocular melanoma.

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Title: Isolated Hepatic Perfusion with High-Dose Melphalan Results in Immediate Alterations in Tumor Gene Expression in Patients with Metastatic Ocular Melanoma
Authors: Sheelu Varghese, PhD
Hui Xu, BS
David Bartlett, MD
Marybeth Hughes, MD
James F. Pingpank, MD
Tatiana Beresnev, MD
H. Richard Alexander Jr., MD
Publication date: 01-07-2010
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 7/2010
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-010-0998-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Isolated Hepatic Perfusion with High-Dose Melphalan Results in Immediate Alterations in Tumor Gene Expression in Patients with Metastatic Ocular Melanoma

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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