Please cite this article as: Mariani P., Piperno-Neumann S., Servois V., Berry M.G., Dorval T., Plancher C., Couturier J., Levy-Gabriel C., Lumbroso-Le Rouic L., Desjardins L., Salmon R.J. Surgical management of liver metastases from uveal melanoma:16 years'experience at the Institut Curie., European Journal of Surgical Oncology (2009Oncology ( ), doi: 10.1016Oncology ( /j.ejso.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Purpose: Uveal melanoma is the most common primary intraocular malignant tumor in adults and is defined by a poor natural outcome, as 50% of patients die from metastases. The aim of this study was to develop and characterize a panel of human uveal melanoma xenografts transplanted into immunodeficient mice.Experimental Design: Ninety tumor specimens were grafted into severe combined immunodeficient mice, and 25 transplantable xenografts were then established (28%). Relationship between tumor graft and clinical, biological, and therapeutic features of the patients included were investigated. Characterization of 16 xenografts included histology, molecular analyses by immunohistochemistry, genetic alteration analysis (single-nucleotide polymorphism), and specific tumor antigen expression by quantitative reverse transcription-PCR. Pharmacologic characterization (chemosensitivity) was also done in four models using two drugs, temozolomide and fotemustine, currently used in the clinical management of uveal melanoma.Results: Take rate of human uveal melanoma was 28% (25 of 90). Tumor take was independent of size, histologic parameters, or chromosome 3 monosomy but was significantly higher in metastatic tumors. Interestingly, in vivo tumor growth was prognostic for a lower metastasis-free survival in patients with primary tumors. A high concordance between the patients' tumors and their corresponding xenografts was found for all parameters tested (histology, genetic profile, and tumor antigen expression). Finally, the four xenografts studied displayed different response profiles to chemotherapeutic agents.Conclusions: Based on these results, this panel of 16 uveal melanoma xenografts represents a useful preclinical tool for both pharmacologic and biological assessments. Clin Cancer Res; 16(8); 2352-62. ©2010 AACR.Uveal melanoma is the most common primary intraocular malignant tumor in adults. Despite the increased diagnostic accuracy and the development of conservative and effective treatments on primary tumor sites, such as plaque radiotherapy and photon beam therapy, the mortality remains stable and 50% of patients die from metastases that frequently involve the liver. Chemotherapy, such as oral temozolomide and intra-arterial fotemustine used at the metastatic stage, induces very low response rates, 14.3% and 36%, respectively, and a median survival time of 6.7 and 15 months (1-3). No postoperative adjuvant therapies are currently available to decrease the risk of metastases. Several prognostic factors of disseminated relapse after initial ophthalmologic treatment have been determined, including location with respect to the equator, monosomy 3, and retinal detachment (4). However, no effect of these prognostic markers on patient care can be envisaged in the absence of effective systemic therapies.The growing body of knowledge about molecular and genetics events involved in oncogenesis and tumor progression has led to the identification of new therapeutic targets and therapeutic agents. Preclinical investigatio...

A high percentage of uveal melanoma patients develop metastatic tumors predominantly in the liver. We studied the molecular profiles derived from gene expression microarrays and comparative genomic hybridization microarrays, to identify genes associated with metastasis in this aggressive cancer. We compared 28 uveal melanomas from patients who developed liver metastases within three years of enucleation with 35 tumors from patients without metastases or who developed metastases more than 3 years after enucleation. Protein tyrosine phosphatase type IV A member 3 (PTP4A3/PRL3), was identified as a strong predictor of metastasis occurrence. We demonstrated that the differential expression of this gene, which maps to 8q24.3, was not merely a consequence of 8q chromosome overrepresentation. PTP4A3 overexpression in uveal melanoma cell lines significantly increased cell migration and invasiveness in vivo, suggesting a direct role for this protein in metastasis. Our findings suggest that PTP4A3 or its cellular substrates could constitute attractive therapeutic targets to treat metastatic uveal melanomas. Cancer Res; 71(3); 666-74. Ó2010 AACR.