Role of vandetanib in the management of medullary thyroid cancer

Traditionally available treatments, like cytotoxic chemotherapy and external-beam radiation therapy, are limited and essentially ineffective for metastatic medullary thyroid carcinoma (MTC). In the last decade, small-molecule tyrosine kinase inhibitors (TKI) have been introduced in the field of thyroid cancer, after having been shown effective in a wide variety of other tumors. This review focuses on vandetanib (ZD6474, Zactima™; AstraZeneca) and its role in the treatment of MTC. Vandetanib is an oral TKI that targets VEGF receptors 2 and 3, RET, and at higher concentrations, the epidermal growth factor (EGF) receptor. This drug has been tested in two important phase II studies which demonstrated that both the 100 and 300 mg/day dosage of vandetanib have antitumor activity on advanced MTC. A phase III trial (ZETA trial) evaluating vandetanib in 331 patients with locally advanced or metastatic MTC showed a significant prolongation of PFS for patients receiving vandetanib compared with placebo. Toxicity surveillance in all studies reported high rates of adverse effects with diarrhea, rash, fatigue and nausea being the most commonly experienced by patients. Vandetanib is currently approved in the United States for unresectable locally advanced or metastatic MTC and has become a new standard of care in this rare and indolent pathology

Receptor binding and degradation of urokinase-type plasminogen activator by human mesangial cells

Receptor binding and degradation of urokinase-type plasminogen activator by human mesangial cells. The binding of [125I] labeled urokinase-type plasminogen activator (u-PA) was studied on human mesangial cells (MC) in culture. The binding of active [125I]u-PA at 37°C reached a plateau after 30 minutes of incubation and remained stable for at least four hours. When the supernatant was analyzed with trichloracetic acid (TCA), TCA soluble radioactive material could be detected after a lag phase of 30 minutes, and then increased linearly for four hours. Analysis by electrophoresis on SDS PAGE and autoradiography of the cell associated radioactivity and of the intracellular content showed that active u-PA and u-PA complexed to plasminogen activator inhibitor type-1 (PAI-1) were bound to the cell surface, but only u-PA/PAI-1 complexes were internalized and degraded. Therefore, the Kd and the number of binding sites were determined by competitive inhibition curves at 4°C using diisopropyl-fluorophosphate (DFP) u-PA. Scatchard plots showed a Kd = 400 ± 30 pM, and Bmax = 240,000 ± 25,000 sites/cell. Excess of the amino terminal fragment of u-PA (ATF) completely blocked the specific binding of [125I]u-PA, confirming that the binding of u-PA was independent of the presence of the active site and/or of the formation of complexes with PAI-1. 3H thymidine incorporation by mesangial cells after stimulation with 100nM active u-PA showed that u-PA had a moderate but significant mitogenic effect, in contrast to inactive u-PA and ATF. However, this mitogenic effect was not accompanied by a proliferative effect. Pretreatment of mesangial cell with a phosphoinositol-specific phospholipase C decreased the binding of [125I]u-PA by 60%, indicating that the majority of the u-PA receptor is anchored in the membrane by a phosphatidylinositol group. These results, together with a positive labeling of MC with monoclonal antibodies to the receptor of U937 cells, and the positive RNA hybridization with the cDNA probe for the human receptor cloned from U937 cells, indicate that the u-PA receptor on mesangial cells is identical to the one of U937 cells. In conclusion, human mesangial cells in culture express a specific receptor for u-PA, which could play a major role in the regulation of u-PA activity by degrading u-PA complexed to PAI-1

Serum calcitonin nadirs to undetectable levels within 1 month of curative surgery in medullary thyroid cancer

ABSTRACT Objective: Because serum calcitonin (CT) is a reliable marker of the presence, volume, and extent of disease in medullary thyroid cancer (MTC), both the ATA and NCCN guidelines use the 2-3 month post-operative CT value as the primary response to therapy variable that determines the type and intensity of follow up evaluations. We hypothesized that the calcitonin would nadir to undetectable levels within 1 month of a curative surgical procedure. Subjects and methods: This retrospective review identified 105 patients with hereditary and sporadic MTC who had at least two serial basal CT measurements done in the first three months after primary surgery. Results: When evaluated one year after initial surgery, 42 patients (42/105, 40%) achieved an undetectable basal calcitonin level without additional therapies and 56 patients (56/84, 67%) demonstrated a CEA within the normal reference range. In patients destined to have an undetectable CT as the best response to initial therapy, the calcitonin was undetectable by 1 month after surgery in 97% (41/42 patients). Similarly, in patients destined to have a normalize their CEA, the CEA was within the reference range by 1 month post-operatively in 63% and by 6 months in 98%. By 6 months after curative initial surgery, 100% of patients had achieved a nadir undetectable calcitonin, 98% had reached the CEA nadir, and 97% had achieved normalization of both the calcitonin and CEA. Conclusion: The 1 month CT value is a reliable marker of response to therapy that allows earlier risk stratification than the currently recommended 2-3 month CT measurement

Determinants of smoking cessation attempts among HIV-infected patients results from a hospital-based prospective cohort.

Non-acquired immune-deficiency syndrome (AIDS) defining malignancies (especially lung cancer) and bacterial infections as well as cardiovascular diseases now account for almost one third of deaths and morbid events in treated patients infected by the Human Immunodeficiency Virus (HIV). Tobacco smoking is a major modifiable risk factor of these emergent conditions and almost half of these patients are regular smokers in resource-rich countries. To estimate the effect of HIV infection characteristics on smoking cessation attempts among HIV-infected smokers. All smokers of the ANRS CO3 Aquitaine Cohort with at least two visits between 2000 and 2005 were included in this analysis. The probability of smoking cessation attempts was estimated using survival analyses for recurrent events (frailty model). Covariates were CD4 cell count, gender, age, HIV transmission categories, duration since HIV-diagnosis, AIDS stage, antiretroviral therapy, and cardiovascular history. Among 2223 smokers, 743 attempted to quit smoking at least once. The incidence of smoking cessation attempt was lower among patients infected through injection drug use (IDU) and was higher among patients aged 50 or older (HR=1.4), those with a known duration of HIV infection >15 years (HR=1.5), and those who had already tried to quit smoking once (HR=4.2) or more (HR=5.8). Traditional characteristics associated with smoking cessation attempts are the most important to explain smoking cessation attempts in HIV-infected patients. These results indicate that strategies successfully implemented in other populations should be reinforced to fit the needs of HIV-infected patients

Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy

OBJECTIVE: To assess whether immunodeficiency is associated with the most frequent non-AIDS-defining causes of death in the era of combination antiretroviral therapy (cART). DESIGN: Observational multicentre cohorts. METHODS: Twenty-three cohorts of adults with estimated dates of human immunodeficiency virus (HIV) seroconversion were considered. Patients were seroconverters followed within the cART era. Measurements were latest CD4, nadir CD4 and time spent with CD4 cell count less than 350 cells/microl. Outcomes were specific causes of death using a standardized classification. RESULTS: Among 9858 patients (71 230 person-years follow-up), 597 died, 333 (55.7%) from non-AIDS-defining causes. Non-AIDS-defining infection, liver disease, non-AIDS-defining malignancy and cardiovascular disease accounted for 53% of non-AIDS deaths. For each 100 cells/microl increment in the latest CD4 cell count, we found a 64% (95% confidence interval 58-69%) reduction in risk of death from AIDS-defining causes and significant reductions in death from non-AIDS infections (32, 18-44%), end-stage liver disease (33, 18-46%) and non-AIDS malignancies (34, 21-45%). Non-AIDS-defining causes of death were also associated with nadir CD4 while being cART-naive or duration of exposure to immunosuppression. No relationship between risk of death from cardiovascular disease and CD4 cell count was found though there was a raised risk associated with elevated HIV RNA. CONCLUSION: In the cART era, the most frequent non-AIDS-defining causes of death are associated with immunodeficiency, only cardiovascular disease was associated with high viral replication. Avoiding profound and mild immunodeficiency, through earlier initiation of cART, may impact on morbidity and mortality of HIV-infected patients

Child custody issues and co-occurrence of intimate partner violence and child maltreatment: controversies and points of agreement amongst practitioners

The situation of families undergoing separation in a context of co-occurrence of intimate partner violence (IPV) and child maltreatment raises certain issues related to child custody. The results presented in this paper were collected and analysed within the framework of a qualitative study aiming to identify the principal points of agreement and the main controversies amongst practitioners in several different types of organizations. Focus groups were held with a total of 43 practitioners from six different settings concerned with child custody in cases of co-occurrence of IPV and child maltreatment. Although they agreed on the importance of ensuring the safety of victims of violence, their views diverged on three points: (1) the importance of preserving the father–child relationship; (2) collaboration between voluntary organizations and semi-voluntary or legal agencies; and (3) consideration of cultural differences