Faculty Bibliography

PURPOSE: To evaluate whole-body positron emission tomography (PET)/computed tomography in staging of patients with metastatic choroidal melanoma. DESIGN: Interventional non-randomized clinical study. METHODS: Twenty patients were referred for whole-body 18-fluoro-2-deoxy-D-glucose (FDG) PET/computed tomography imaging because of suspected metastatic choroidal melanoma. PET/computed tomography images were studied for the presence and distribution of metastatic melanoma. Subsequent biopsies were performed to confirm the presence of metastatic disease. RESULTS: Twenty patients underwent PET/computed tomography. Eighteen were imaged because of abnormal clinical, hematologic, or radiographic screening studies during the course of their follow-up after plaque brachytherapy or enucleation. Two were imaged before treatment of their primary tumor. PET/computed tomography revealed or confirmed metastatic melanoma in eight (40%) of these 20 patients. The mean time from initial diagnosis to metastasis was 47 months (range 0 to 154). The most common sites for metastases were the liver (100%), bone (50%), lung (25%), lymph nodes (25%), and subcutaneous tissue (25%). Cardiac, brain, thyroid, and posterior abdominal wall lesions (12.5%) were also noted. Six patients (75%) had multiple organ involvement. No false positives were noted. PET/computed tomography imaging also detected benign lesions of the bone and lymph nodes in three patients (15%). All patients had hepatic metastases and liver enzyme assays were abnormal in only one (12.5%) of eight patients. CONCLUSIONS: PET/computed tomography imaging is a sensitive tool for the detection and localization of hepatic and extra-hepatic (particularly osseous) metastatic choroidal melanoma

PURPOSE: Inactivation of the tumor suppressor gene, phosphatase and tensin homologue (PTEN), is a major alteration in preclinical melanoma models. We investigated the clinical relevance of PTEN expression in the primary melanoma patients with extended follow-up. EXPERIMENTAL DESIGN: We correlated PTEN expression with clinicopathologic variables and outcome in 127 primary melanomas (median follow-up, 12.8 years). We evaluated the associations between PTEN expression and proliferation and resistance to apoptosis (assessed by Ki-67 and Bcl-2, respectively). We also examined the effect of a favorable phenotype, defined as retained PTEN, low proliferative index, and low expression of Bcl-2 on disease-free survival and overall survival. RESULTS: Altered PTEN, Bcl-2, and Ki-67 expressions were observed in 55 of 127 (43.3%), 61 of 127 (48%), and 43 of 114 (37.7%) of cases, respectively. Decreased PTEN expression correlated significantly with the ulceration (P = 0.01). Rates of disease-free survival and overall survival in patients with favorable phenotype were 72% and 74% at 5 years versus 64% and 64% in patients with an unfavorable phenotype. At 10 years, the rates of disease-free survival and overall survival were 72% and 68% for patients with a favorable phenotype but declined to 60% and 55% in patients with an unfavorable phenotype. However, relationships between both PTEN and Bcl2 and patient survival were not significant as well as the associations between PTEN and Bcl-2 or Ki-67. CONCLUSIONS: Our data suggest that altered PTEN expression is common in primary melanomas and is associated with aggressive tumor behavior. However, PTEN alone provided limited prognostic value. Our findings show the need to examine molecular alterations identified in preclinical studies using an adequately large cohort of patients with extended follow-up to better assess the magnitude of their clinical relevance

The purpose of this study was (i) to determine the maximum tolerated dose (MTD) of docetaxel that can be administered in combination with Doxil, given without and with granulocyte colony stimulating factor (G-CSF), (ii) to define the pharmacokinetics (PK) of docetaxel when used in combination with Doxil, and (iii) to make preliminary observations on the anti-tumor activity of this combination in patients with metastatic solid tumors. Thirty-seven patients with metastatic cancer were enrolled. Courses were repeated every 3 weeks. Patients received a fixed dose of Doxil 30 mg/m(2) in combination with escalating doses of docetaxel ranging from 40 to 100 mg/m(2). After encountering dose-limiting febrile neutropenia, subsequent escalation was accomplished with G-CSF support. Selected patients at the recommended phase II dose underwent PK evaluation. The most common toxicity observed was neutropenia. Dose-limiting toxicity (30 mg/m(2) Doxil + 80 mg/m(2) docetaxel) was febrile neutropenia in three of six patients treated without G-CSF. Major non-hematological toxicities included alopecia, mucositis and hand-foot syndrome, and were observed after cumulative doses of chemotherapy. Objective responses (complete/partial) were documented in eight of 37 patients (four with breast cancer) and stable disease was seen in 17 patients. PK studies showed an increased tissue retention (decreased clearance) of docetaxel when given with Doxil. The recommended phase II dose of Doxil/docetaxel is 30/60 mg/m(2), q3 weeks, without G-CSF. Further dose escalation to 30/80 mg/m(2) is safe with G-CSF support. Anti-tumor activity, particularly against breast cancer, was observed at various dose levels. Our observations should provide evidence for phase II studies of this combination in patients with breast cancer and other anthracycline/taxane-sensitive cancers

Malignant melanoma presents a therapeutic challenge. Patients at high risk for recurrence (stage III) are eligible for adjuvant treatment with IFN-alpha or may enrol in a clinical trial. Both options offer no meaningful survival advantage. Patients with metastatic disease (stage IV) have a 5-year survival of < 10% and have no effective treatment options. Despite aggressive investigations into vaccine therapy, no vaccine has yet received FDA approval. Biological therapies with IFN-alpha and IL-2 have demonstrated a real but minimal effect. Chemotherapeutic options are even more dismal. Single-agent chemotherapy yields a 15-20% response rate of short lived duration. Combination chemotherapy alone or with immunological adjuvants yields response rates of 35-45% but with significant toxicity and no significant improvement in survival. Novel treatment agents that target metabolic pathways, angiogenesis inhibitors, antisense therapies, gene therapies and innovative vaccines may offer hope for an otherwise grave disease

Our objective was to evaluate the role of amifostine as a cytoprotector in patients with solid tumors receiving the myelosuppressive regimen of gemcitabine/cisplatin combination. Patients with advanced solid tumors were randomized to gemcitabine-amifostine-cisplatin (GAP) or gemcitabine-cisplatin (GP) in Cycle 1 (C1) and then were crossed over to the other treatment in Cycle 2 (C2). Amifostine at 740 mg/m2, followed by gemcitabine and cisplatin, were given for 2 consecutive weeks, every 4 weeks. Two GP combinations were studied: G 1000 mg/m2 and P 40 mg/m2 days 1, 8 (high dose), and G 800 mg/m2 and P 30 mg/m2 days 1, 8 (low dose). Forty patients were enrolled. Of the 19 patients treated with high-dose GP, 11 (nine patients GP in C1 and GAP in C2, two patients GAP in C1 and GP in C2) completed 2 cycles of therapy. Of the eight non-evaluable patients, five patients dropped out due to toxicity or refusal after treatment with amifostine in C1. Of the 21 patients treated with low-dose GP, 15 (eight patients GP in C1 and GAP in C2, seven patients GAP in C1 and GP in C2) were likewise evaluable. The incidence of grade 3 or 4 hematologic toxicities was similar for GP and GAP during the first 2 cycles of treatment, and there were no statistically significant differences in mean absolute neutrophil count, hemoglobin level and platelet levels between the cycles in each arm. We conclude that amifostine, at 740 mg/m2, does not lead to less myelosuppression when combined with gemcitabine/cisplatin chemotherapy regimens and may possibly contribute to subjective intolerance