The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R.

Imatinib mesylate (IM), a small molecule that is a selective inhibitor of the ABL, platelet derived growth factor receptor (PDGFR-R) and stem cell ligand receptor (c-kit) tyrosine kinases (TK). IM was also found to inhibit the TK activity of BCR/ABL fusion protein produced in chronic myelogenous leukemia, with marked clinical activity against the disease. Since both PDGF-R and c-kit both having a putative role in tumorigenesis, we investigated the efficacy and safety of the use of IM in patients with endocrine tumors unresponsive to conventional therapies that expressed c-kit and/or PDGF-R (within the framework of a comprehensive phase II multi-center study of IM in patients with solid tumors). IM was initiated at a dose of 400 mg/day, with possible dose escalation within 1 week to 600 mg/day and an option to raise the dose to 800 mg/day in the event of progression and in the absence of safety concerns for a period of up to 12 months. Between September 2002 and July 2003, 15 adult patients with disseminated endocrine tumors were recruited as follows: medullary thyroid carcinoma (MTC, n = 6); adrenocortical carcinoma (ACC, n = 4); malignant pheochromocytoma (pheo, n = 2); carcinoid (non-secreting, n = 2), neuroendocrine tumor (NET, n = 1). No objective responses were observed. MTC--disease progression in 4 patients, and treatment discontinuation in 2 patients due to adverse events; ACC--disease progression in 3 patients, and treatment discontinuation in 1 patient due to severe psychiatric adverse event; Pheo--disease progression in 2 patients; Carcinoid--stable disease in 1 patient (6.5 months), and disease progression in 1 patient; NET--disease progression in 1 patient. IM does not appear to be useful for treatment of malignant endocrine tumors, also causing significant toxicity in this patient population.

Cancer disease predictive diagnosis: BAT/CD3-positive lymphocytes in cancer patients.

BAT is an immune-activating monoclonal antibody produced against Daudi cell membranes and selected for stimulating lymphocyte proliferation. The anti-tumor activity of BAT is related to its immunostimulatory properties. Both T and NK cells mediate the anti-tumor activity of BAT. CD4-positive T cells respond to BAT activation by proliferation and INF-gamma production. The aim of the study was to assess the probability that the BAT monoclonal antibody binding capacity to T cells is a marker for different cancers. Human peripheral blood T cells from colon, breast and prostate cancer patients, as well as healthy volunteer donors, were tested for the percentage of binding to BAT mAb (BAT/CD3 cells) by FACS analysis. All patients were tested before undergoing surgery or treatment, and their diagnosis was confirmed by histology. The results showed that the percentage of BAT monoclonal antibody binding to CD3-positive T cells in the peripheral blood was different in cancer patients with diverse tumor types. We found that lymphocytes from the blood of healthy donors contained 25% BAT/CD3 cells. In colon and breast cancer patients, a significant decrease to 13 and 11% of BAT/CD3 cells was found. In contrast, these cells increased ><50% in patients with prostate cancer. These findings may have a potential diagnostic significance and also assist in the evaluation of strategies for the therapeutic use of BAT for different cancer patients.

Prediction of extravesical disease by preoperative serum markers in patients with clinically organ confined invasive bladder cancer.

PURPOSE: We assessed the value of preoperative levels of CEA, CA-125 or CA 19-9 in patients with clinically organ confined bladder cancer to predict pathological extravesical and/or node positive disease. MATERIALS AND METHODS: Serum levels of CEA, CA-125 and CA 19-9 were measured prospectively in all patients scheduled for cystectomy for clinically organ confined bladder cancer between September 1999 and May 2004. Biomarker expression was compared between patients with pathologically organ confined disease (pT2 or less, pN0) and patients with extravesical disease (greater than pT2, or pN1 or greater), and between patients with pathologically node negative (any pT, pN0) and node positive disease (any pT, pN1 or greater). RESULTS: Of the 91 patients enrolled, 46 had (51%) pathologically organ confined tumors, 45 (49%) had extravesical disease and 17 (19%) had positive lymph nodes. Preoperative serum levels of all markers were significantly higher in cases of extravesical disease than in organ confined disease. On multivariate analysis CEA with an odds ratio of 8.6 (95% CI 1.51-48.6) and CA-125 with an OR of 29.5 (95% CI 3.6-242.6) proved independent predictors of extravesical disease. CA-125 and CA 19-9 levels were significantly higher in patients with node positive disease than in those with node negative disease. On multivariate analysis CA-125 with an OR of 22.2 (95% CI 3.8-129) and CA 19-9 with an OR of 5.2 (95% CI 1.09-24.76) proved independent predictors of node positive disease. CONCLUSIONS: Increase in serum tumor markers before cystectomy in patients with clinically organ confined muscle invasive bladder cancer is a strong indicator of the presence of extravesical and node positive disease.