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The clinical treatment of patients with stage IV melanoma according to criteria of the American Joint Committee on Cancer (AJCC) is controversial because the 5-year survival rate is approximately 5%. Specific clinicopathologic factors are predictive of survival following curative surgery. Design: Cohort analysis of 1574 successive patients undergoing surgical resection of metastatic melanoma for a 29-year period. Patients received follow-up on a routine basis with serial examinations and radiographic studies. The median follow-up time was 19 months (range, 1-382 months). Setting: Tertiary cancer center. Patients: Surgical resection was performed in 1574 patients. The decision to perform surgery was individualized for each patient. Intervention: The technique of surgical resection was based on the site of metastasis. Main Outcome Measure: Computer-assisted database with statistical analyses using log-rank tests and Cox regression models. Results: Of the 4426 patients with AJCC stage IV melanoma, 1574 (35%) underwent surgical resection;

Purpose: Ectopic expression of GRM1 in murine melanocytes results in transformation into a form of melanoma, and more than 60% of human melanoma samples tested ectopically express GRM1. Stimulation of this receptor in vitro results in up-regulation of activated extracellular signal-regulated kinase (ERK). Furthermore, a xenograft model of melanoma treated with riluzole, an oral GRM1 blocking agent, showed decreased tumor growth compared with the untreated controls. We have now completed a phase 0 trial of riluzole in patients with melanoma. Experimental Design: Patients enrolled on this trial underwent a pretreatment biopsy, took 200 mg of oral riluzole per day for 14 days, and then underwent resection of their remaining tumor. We compared the levels of pERK and pAKT in the pretreatment and post-treatment samples and assessed the metabolic activity of pretreatment and posttreatment tumors using fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. Results: We accrued 12 patients and all expressed GRM1. We found a significant decrease in pAKT and/or pERK in post-treatment tumor samples as compared with pretreatment samples in 4 (34%) patients. These four patients had a significant decrease in FDG-PET intensity post-treatment as well. Two other patients had a clinical response with no corresponding metabolic response; five patients had similar pretreatment and post-treatment FDG-PET scan findings; and one patient had progressive disease. Conclusions: Our data show that glutamate blockade with riluzole can inhibit signaling through the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways and suppress the metabolic activity of melanoma. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma, and targeting this pathway may be an effective therapy. Recently, our group described a heretofore unknown component of melanoma pathogenesis. A transgenic murine model of melanoma was developed by the ectopic expression of metabotropic glutamate receptor 1 (GRM1) in melanocytes (1-3). These mice spontaneously develop melanocytic lesions indistinguishable from human melanoma. We have expanded these original studies and have now shown that more than 60% of human melanomas express GRM1 and that activation of this receptor results in activation of the mitogen-activated protein kinase (MAPK) pathway in a B-Raf-and N-Rasindependent fashion (1). In preclinical studies, we have shown that the ectopic expression of GRM1 in melanocytes is transforming and that inhibition of GRM1 signaling in vitro and in vivo results in cell cycle arrest and subsequent apoptosis in human melanoma (2).We have now translated our findings into the clinic and have completed a phase 0 trial of riluzole in patients with stage III and IV melanoma. Riluzole (2-amino-6-trifluoromethoxybenzothiazole) is a noncompetitive GRM1 receptor antagonist that has been shown to be safe and effective in patients with amylotropic lateral sclerosis (ALS; refs. 4-7). Rilu...

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Thicker primary and larger SN tumor size are factors that correlate best with tumor-positive NSN. Although none of these factors are absolutely predictive of residual nodal disease, these factors must be strongly considered if the SN contains metastasis, as they provide enhanced risk assessment for NSN tumor-positivity.

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Summary Objective The hypothesis of this study is that changes in fluid dynamics in subchondral bone bear a functional relationship to bone remodeling and cartilage breakdown in osteoarthritis (OA). We have utilized dynamic contrast-enhanced magnetic resonance imaging (MRI) to extract kinetic parameters of bone perfusion at various stages in the development of OA in the Dunkin-Hartley guinea pig. Design of four different ages (6, 9, 12 and 15 months), representing various stages in the development of OA, were studied. All animals underwent dynamic contrast-enhanced (DCE) MRI and perfusion data were analyzed based on the Brix two compartment pharmacokinetic model. Regions of interest were studied at the medial and lateral tibial plateaus and compared to histological/histochemical scores of articular cartilage and subchondral bone plate thickness. Results A decrease in perfusion as well as outflow obstruction was observed in animals between 6 and 9 months of age, only in the medial tibial plateau subchondral bone. The eventual cartilage and bone lesions of OA occurred also in the medial tibia. Changes in perfusion occurred in the lateral tibia but not until OA lesions were established. Kinetic parameters of inflow were unchanged in both the medial and lateral plateaus. Conclusions Dynamic contrast-enhanced MRI can be used to extract kinetic information on bone perfusion in an animal model of OA. The signal enhancement in subchondral bone temporally precedes and spatially localizes at the same site of the eventual bone and cartilage lesions. Time-intensity curves suggest outflow obstruction as an underlying mechanism.

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