Lapatinib: clinical benefit in patients with HER 2-positive advanced breast cancer.

BACKGROUND: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor 2 (HER2), has shown activity in combination with capecitabine in patients with HER2-positive advanced breast cancer progressive on standard treatment regimens. We present results on preapproval drug access for this combination in such patients occurring in the general oncology practice in the Netherlands. METHODS: Patients with HER2-positive advanced breast cancer progressive on schedules containing anthracyclines, taxanes, and trastuzumab were eligible. Brain metastases were allowed if stable. Lapatinib 1250 mg÷day was given continuously in combination with capecitabine 1000 mg÷m2 twice daily for two weeks in a three-week cycle. Efficacy was assessed by use of response evaluation criteria in solid tumours version 1.0. Progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS: Eighty-three patients were enrolled from January 2007 until July 2008. The combination was generally well tolerated and the most common drug-related serious adverse events were nausea and÷or vomiting (5%) and diarrhoea (2%). Seventy-eight patients were evaluable for response. Clinical benefit (response or stable disease for at least 12 weeks) was observed in 50 patients (64%) of whom 15 had a partial response and 35 stable disease. The median PFS and OS were 17 weeks (95% CI: 13 to 21) and 39 weeks (95% CI: 24 to 54), respectively. For OS, higher Eastern Cooperative Oncology Group (ECOG) status (p=0.016), brain metastases at study entry (p=0.010) and higher number of metastatic sites (p=0.012) were significantly negative predictive factors. CONCLUSION: In a patient population with heavily pretreated HER2-positive advanced breast cancer lapatinib plus capecitabine was well tolerated and offered clinical benefit.

Gas chromatographic-mass spectrometric (GC-MS) analysis of gonadal steroids in plasma of the male African catfish, Clarias gariepinus: effects of castration or treatment with gonadotropin releasing hormone analogue.

To identify testicular steroids that may be involved in the feedback mechanisms of the hypothalamus-pituitary-gonad axis in African catfish, Clarias gariepinus, steroids, which are known to be produced by the testis in vitro, were identified and quantified in blood plasma before and after castration using gas chromatography followed by mass spectrometry. Before castration 20 testicular steroids were detected. Quantitatively dominant steroids were testosterone (16.9 +/- 4.3 ng/ml), androstenedione (12.0 +/- 3.9 ng/ml), and 11-ketotestosterone (6.7 +/- 1.8 ng/ml). After castration, only these steroids showed a strong decrease in plasma, indicating that they are of testicular origin. Assuming that steroids involved in the feedback to the pituitary are under gonadotropic control, fish were injected with two doses of a salmon gonadotropin releasing hormone analogue (sGnRHa). The lower sGnRHa dose (0.25 microgram/kg body weight) increased plasma GTH-II levels in the same range as those induced by castration, resulting in a significant increase in plasma levels of testosterone, androstenedione, and 11-ketotestosterone. After injection of a higher dose of sGnRHa (5.0 micrograms/kg body weight), there was a greater increase in plasma GTH-II level, as well as a significant increase in most of the other steroids studied. The decreased levels of testosterone, androstenedione, and 11-ketotestosterone after castration and the significant increase in these steroids following moderate GTH stimulation, suggest that one or more of these steroids plays a role in the feedback mechanism within the hypothalamus-pituitary-gonad axis.

Steroid hormone secretion by testicular tissue from African catfish, Clarias gariepinus, in primary culture: identification and quantification by gas chromatography - mass spectrometry.

With the final aim of identifying the testicular steroids involved in the feedback mechanism of the hypothalamus-pituitary-gonad axis, steroid secretion by the testis of African catfish, Clarias gariepinus, was studied in vitro, by means of gas chromatography followed by mass spectrometry. Testicular fragments of sexually mature catfish raised in captivity were incubated in L-15 medium with and without catfish pituitary extract (cfPE). Without adding cfPE, 22 steroids could be identified, amongst which 11ß-hydroxyandrostenedione, 11ß-hydroxytestosterone, 11-ketotestosterone and 11-ketoandrostenedione were dominating. After incubation in the presence of cfPE, the concentrations of the four 11-oxygenated steroids were increased about 4-fold. The amounts of pregnane derivatives in the incubation medium showed the largest increases in the presence of cfPE. 5ß-Pregnane-triol levels, for example, were 60-fold higher than in the medium from control incubations. The secretion of 5α- and 5ß-androstanes was also stimulated by cfPE.The stimulation was not equal for all steroids, indicating that cfPE not only stimulates total steroidogenesis by increasing the availability of cholesterol, but also by influencing specific steroid converting enzyme activities.