Cellular effects of imatinib on medullary thyroid cancer cells harboring multiple endocrine neoplasia Type 2A and 2B associated RET mutations.

BACKGROUND: Activating mutations in the RET gene, which encodes a tyrosine kinase receptor, often cause medullary thyroid carcinoma (MTC). Surgical resection is the only curative treatment; no effective systemic treatment is available. We evaluated imatinib, a tyrosine kinase inhibitor currently used to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, as a potential drug for systemic treatment of MTC, in 2 MTC-derived cell lines expressing multiple endocrine neoplasia-associated mutant RET receptors. METHODS: We determined RET expression and Y1062 phosphorylation using Western blot analysis and quantitative polymerase chain reaction. We determined the effects on cell proliferation by a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, and we used fluorescence-activated cell sorter analysis with annexin V/propidium iodide staining to study imatinib-induced cell-cycle arrest, apoptosis, and cell death. RESULTS: Imatinib inhibited RET Y1062 phosphorylation in a dose-dependent manner after 1.5 hours of exposure. After 16 hours both RET Y1062 phosphorylation and protein expression levels were affected. Dose-dependent decreases in cell proliferation of both cell lines after exposure to imatinib with inhibitory concentration of 50% levels of 23 +/- 2 micromol/L and 25 +/- 4 micromol/L were seen. These values are high, compared with those for chronic myelogenous leukemia and gastrointestinal stromal tumors. We further could show that imatinib induced cell-cycle arrest, and apoptotic and nonapoptotic cell death. CONCLUSIONS: Imatinib inhibits RET-mediated MTC cell growth affecting RET protein levels in vitro in a dose-dependent manner. The concentration of imatinib necessary to inhibit RET in vitro, however, makes it impossible to conclude that imatinib monotherapy will be a good option for systemic therapy of MTC.

Acceptable age for prophylactic surgery in children with multiple endocrine neoplasia type 2a.

AIMS: Germline mutated RET proto-oncogene, causing multiple endocrine neoplasia (MEN)-2a syndrome is the indication for prophylactic total thyroidectomy. Literature regarding the risk and the extent of early surgical intervention is scarce and the optimum age for surgery is still controversial. To optimize management in these young children we evaluate our experience and results. PATIENTS AND METHODS: From 1990 to 2001 preventive total thyroidectomy was performed in 13 MEN-2a gene carriers (4 boys and 9 girls; median age 7 (4-14) years). Preoperative assessment, surgical procedure, pathological examination, postoperative complications and treatment results were studied. RESULTS: Surgery existed of a total thyroidectomy alone (n=3) in children with normal basal calcitonin and in combination with tracheo-esophageal exploration (n=6) or central compartment dissection (n=4) in case of abnormal calcitonin levels. Eight children presented with medullary thyroid cancer (MTC), three (median: 5 (4-12) years) with microscopic MTC and five (median 6 (4-14) years) with frank invasive MTC. Four of these five patients were younger than 6 years. Except for long-lasting hypoparathyroidism in one patient there were no complications. At a median follow-up of 6.5 years all patients are disease free. CONCLUSION: MTC in RET mutated MEN-2a gene carriers in childhood are found at the age of 4 years. Therefore, DNA testing should be done preferably before that age. Preventive surgery can be performed safely at that age and may be limited to total thyroidectomy when baseline calcitonin levels are normal.

Impact of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in patients with biochemical evidence of recurrent or residual medullary thyroid cancer.

BACKGROUND: Conventional imaging such as with (99m)Tc(V)dimercaptosunnic acid (DMSA), (111)In-octreotide scintigraphy, computed tomography (CT), and magnetic resonance imaging (MRI) rarely localizes occult medullary thyroid cancer (MTC). The role of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is not well defined. The aim of this study was to examine the usefulness of postoperative FDG-PET in localizing MTC metastases. METHODS: FDG-PET was performed in 26 patients with elevated serum tumor markers after total thyroidectomy with central compartment dissection and additional neck dissection on indication. Patient- and lesion-based results were compared with the findings of conventional nuclear imaging and validated by morphological imaging (CT, MRI, ultrasonography), including bone scintigraphy and pathology when possible. Clinical impact was evaluated. RESULTS: FDG-PET detected foci in 50% of patients with lesion-based sensitivity of 96%. (111)In-octreotide detected foci in 19% with sensitivity of 41%, and (99m)Tc(V)DMSA scintigraphy and morphological imaging detected foci in 21% and 40%, respectively, with sensitivity of 57% and 87%. No lesions were found in 11 patients (42%). Positive FDG-PET findings led to surgical intervention in nine patients (35%). They all underwent surgery for removal of residual tumor or metastases. One patient achieved disease-free status. In all patients who underwent surgery, serum calcitonin levels were reduced by an average of 58 +/- 31%. CONCLUSIONS: For detection of occult MTC lesions, FDG-PET is superior to conventional nuclear imaging and is the best detection method yet available. FDG-PET in postoperative follow-up has clinical value and may be used for guiding reoperation and additional morphological imaging preoperatively.