Sorafenib administered using a high-dose, pulsatile regimen in patients with advanced solid malignancies: a phase I exposure escalation study.

BACKGROUND: (Pre)clinical evidence is accumulating that intermittent exposure to increased doses of protein kinase inhibitors may improve their treatment benefit. In this phase I trial, the safety of high-dose, pulsatile sorafenib was studied. PATIENTS AND METHODS: High-dose sorafenib was administered once weekly in exposure escalation cohorts according to a 3 + 3 design. Drug monitoring was performed in weeks 1-3 and doses were adjusted to achieve a predefined target plasma area under the curve (AUC)(0-12 h). The effect of low gastric pH on improving sorafenib exposure was investigated by intake of the acidic beverage cola. RESULTS: Seventeen patients with advanced malignancies without standard treatment options were included. Once weekly, high-dose sorafenib exposure was escalated up to a target AUC(0-12 h) of 125-150 mg/L/h, achieving a twofold higher Cmax compared to standard continuous dosing. Dose-limiting toxicity was observed in three patients: grade 3 duodenal perforation (2800 mg sorafenib), grade 5 multiorgan failure (2800 mg sorafenib) and grade 5 biliary tract perforation (3600 mg sorafenib). The mean difference between observed and target AUC(0-12 h) was 45% (SD ± 56%) in week 1 using a fixed starting dose of sorafenib compared to 2% (SD ± 32%) in week 3 as a result of drug monitoring (P = 0.06). Dissolving sorafenib in cola, instead of water, did not improve sorafenib exposure. Clinical benefit with stable disease as the best response was observed in two patients. CONCLUSION: Treatment with high-dose, once weekly sorafenib administration resulted in dose-limiting toxicity precluding dose escalation above the exposure cohort of 125-150 mg/L/h. Drug monitoring was a successful strategy to pursue a target exposure.

Insight in taste alterations during treatment with protein kinase inhibitors.

The role of Protein Kinase Inhibitors (PKI) in the treatment of various types of cancer is increasingly prominent. Their clinical application is accompanied by the development of side effects, among which patient-reported taste alterations. These alterations are missed frequently, but impair nutritional intake, are associated with weight loss and often result in significant morbidity, especially in the context of chronic administration. Accurate reporting of taste alterations is hampered by lack of modules for symptom objectification and inadequate understanding on the underlying mechanisms. In this review we initially describe the physiology of taste and smell and the mechanism of action of PKIs. We proceed to summarize taste related side effects as reported in major clinical trials and describe possible causal factors. Lastly, an in-depth analysis is given on potential molecular pathways responsible for the PKI-induced taste alterations. Objectification of patient-reported symptoms and universal reporting, along with a better understanding of the underlying mechanisms, will lead to early recognition and optimized treatment, ultimately improving patient adherence and quality of life.

Small cell ovarian cancer in adolescents: report of two cases and review of the literature.

Ovarian small cell carcinoma is a rare and highly malignant neoplasm carrying a poor prognosis. Although combination chemotherapy remains the cornerstone of treatment due to the rarity of these tumors, no regimen can be recommended as standard of care although in the majority of cases platinum-based regimens are used. Herein, we report two cases of small cell carcinoma of the ovaries along with a review of the relevant literature.

Metronomic vinorelbine plus bevacizumab as salvage therapy for patients with metastatic breast cancer.

PURPOSE: Continuous administration of oral vinorelbine, given 3 times a week (metronomic), is feasible and exceptionally well tolerated at doses up to 50 mg with clinical activity against refractory tumors. In this phase II study oral metronomic vinorelbine and bevacizumab were evaluated as salvage therapy in women with pretreated metastatic breast cancer (MBC). METHODS: Patients received oral vinorelbine (50 mg 3 times a week) and bevacizumab (10 mg/kg) biweekly in cycles of 28 days. The primary endpoint was objective response rate (ORR). A preplanned analysis was performed when the first 13 patients were evaluated for tumor response. RESULTS: One patient (7.7%) achieved partial response (PR) and 6 (46.1%) stable disease (SD). The combination was very well tolerated but, as per protocol, the study was closed prematurely due to lack of efficacy. CONCLUSION: The combination of oral metronomic vinorelbine and bevacizumab has good tolerance but minimal activity in terms of objective responses in pretreated patients with MBC.

Effects of vancomycin, teicoplanin, linezolid, quinupristin-dalfopristin, and telithromycin on murine gut colonization by Candida albicans.

Crl:CDI(ICR) BR adult mice were fed chow containing Candida albicans or regular chow. Both groups were subsequently given either antibiotics acting mainly against Gram-positive organisms or normal saline for 10 days. Stool cultures were performed before, at the end, and one week after discontinuation of treatment to determine the effects on the stool yeast concentration. Candida colonized mice treated with vancomycin, teicoplanin, linezolid, quinupristin-dalfopristin or telithromycin had higher colony counts of yeast in their stools than control Candida fed mice treated with saline. This increase was not statistically significant. Mice fed regular chow treated with the study drugs or saline did not have any yeasts in their stools. Dissemination of Candida was not observed in the visceral organs of any mouse.

Effects of doxycycline, metronidazole and their combination on Candida species colonization of the human oropharynx, intestinal lumen and vagina.

The present study reports about the effect of doxycycline and/or metronidazole on colonization by Candida organisms of the human gastrointestinal (GI), oropharyngeal tract and vagina. Treatment with doxycycline or metronidazole for 10 days increased, but not significantly, the GI, oropharyngeal or vaginal colonization by Candida species. The combination of doxycycline and metronidazole, used for the same period, caused a significant increase of 2.5 log10 CFU/g of stools (mean) colonization by Candida. Likewise, 2 out of 9 patients treated with the combination had substantially increased colonization of their vagina by Candida species. This effect, however, could not be expressed statistically due to the semiquantitative nature of the vaginal cultures. In contrast, the combination did not increase oropharyngeal colonization. In conclusion, doxycycline and metronidazole as monotherapies, did not increase significantly Candida colonization in the cavities examined. The combination of doxycycline and metronidazole had a substantial effect, increasing the GI and vaginal colonization by Candida organisms.

Y2O2S:Eu phosphor screens evaluation.

The x-ray luminescence of Y2O2S:Eu phosphor screens is studied both in transmission and in reflection mode observation. Detailed experimental data concerning the dependence of the absolute efficiency on the tube voltage and the screen's thickness are presented and comparisons to another rare earth phosphor material (Y2O2S:Tb) are given. With the help of theoretical calculations based on the Hamaker-Ludwig model all the experimental data are explained and the intrinsic efficiency and scattering coefficients of the phosphor are estimated.