Background:The mechanisms by which stress hormones impact triple-negative breast cancer (TNBC) etiology and treatment are unclear. We have previously shown that stress hormones, cortisol, and catecholamines induce rapid DNA damage and impact DNA repair in NIH 3T3 fibroblasts. This study investigates whether stress hormones increase DNA damage in breast cancer cells and if this impacts drug efficacy.Methods:We first screened a panel of 39 breast cancer cell lines for expression of adrenergic and glucocorticoid receptors and examined if stress hormones induce DNA damage and alter cell cycle regulation in vitro. A TNBC xenograft model was used to assess the impact of restraint stress on tumour growth and chemosensitivity to paclitaxel.Results:We found that stress hormones induced DNA damage, phosphorylation of ATR, which was accompanied by an up-regulation of the G1 cell kinase inhibitor p21 and a cell cycle halt of TNBCs in the G1 phase. p21 knockdown abrogated G1 arrest by stress hormones. We also demonstrated that stress significantly decreased efficacy of paclitaxel.Conclusion:We describe a novel mechanism through which stress hormones can induce drug resistance to paclitaxel, which may have profound implications for treating drug resistance in patients with TNBC.

Motor conduction studies were performed serially in 10 patients, ages 10-62 years, with clinical and electrophysiological criteria of hereditary motor and sensory neuropathy type 1 (HMSN-1) over periods of 11-19 years. Median nerve conduction velocity (MNCV) and distal motor latency showed no significant change on serial studies. Mean median compound muscle action potential (CMAP) amplitude values, however, decreased 66% in 8 patients. Observed clinical progression in HMSN-1, over prolonged periods of time, was not associated with MNCV slowing. However, CMAP amplitude reduction, reflecting progressive axonal loss, correlated with clinical deterioration.

We report a third family with six members with features of the syndrome of familial parkinsonism, depression, weight loss, and central hypoventilation. Patients with this syndrome typically die suddenly, presumably from central respiratory failure. Following multiple respiratory arrests, one affected member was successfully managed with aggressive pulmonary care, tracheostomy, and intermittent home mechanical ventilation, which, combined with carbidopa/levodopa, allowed for a functional lifestyle with improvement in apathy, mobility, and nutritional status.

Trabectedin has a low incidence of CAEs, consisting mainly of arrhythmias. This extensive data review indicates a low cardiac risk profile for trabectedin.

Purpose This analysis determined the incidence of serious rhabdomyolysis events reported during trabectedin treatment since the first phase I clinical trial in April 1996 up to September 2010. Methods Search was done in the Yondelis Ò Pharmacovigilance and Clinical Trials databases using a list of terms according to the Medical Dictionary for Regulatory Activities (MedDRA, v. 13.1), followed by a medical review of all cases retrieved. Total estimated sample was 10,841 patients: 2,789 from clinical trials; 3,926 from compassionate use programs; and 4,126 treated in the marketplace. Two groups were identified: (1) rhabdomyolysis and (2) clinically relevant creatine phosphokinase (CPK) increases without acute renal failure (ARF). Descriptive analysis included demographic, clinical/laboratory data, and contributing/confounding factors. Potential predictive factors were evaluated by multivariate stepwise logistic regression analysis. Possible changes of pharmacokinetics (PK) in patients with rhabdomyolysis were explored using a population PK model. Results The global incidence of rhabdomyolysis was 0.7 %, and most cases occurred in Cycle 2 of treatment. The incidence of fatal cases was 0.3 %. None of the variables evaluated to detect potential risk factors of rhabdomyolysis were predictive. Additionally, CPK increases (without ARF) were detected in 0.4 % of patients as an incidental finding with good prognosis. Conclusions Rhabdomyolysis is an uncommon event during trabectedin treatment. Multivariate analyses did not show any potential factor that could be predictive or represent a significantly higher risk of developing rhabdomyolysis. Nevertheless, close patient monitoring and adherence to drug administration guidelines may help to limit the incidence of this event.