Investigation of bendamustine HCL in a phase 2 study in women with resistant ovarian cancer.

We investigated the safety and efficacy of 90 mg/m(2) bendamustine HCL, administered intravenously on days 1 and 2 every 28 days in 10 women with platinum and taxane resistant epithelial ovarian cancer. There were no objective tumor responses observed; 2 patients had stable disease. Plasma samples collected at pre-treatment and end of cycle one were analyzed for changes in circulating total cytokeratin 18 and caspase cleaved cytokeratin 18 as exploratory early biomarkers of bendamustine-induced tumor cell death. All patients had measureable levels of both total and cleaved caspase 3 cytokeratin 18, but no relationship with response was possible due to the lack of clinical benefit in treated patients. Due to the high incidence of adverse events and absence of objective responses, only ten patients were treated as predefined by the Simon Two-Stage Design in the protocol. Overall, the regimen was not well tolerated and was associated with fatigue and a greater number of gastrointestinal side effects as compared to previously reported experiences in different patient populations. However, our study subjects did experience less bone marrow suppression. The lack of tolerability could reflect the degree of tumor burden within the peritoneal cavity as well as the high number of prior regimens (median of 5) received by the patients participating in this study.

High-performance liquid chromatographic analysis of lacosamide in canine serum using ultraviolet detection: application to pre-clinical pharmacokinetics in dogs.

A method for analysis of lacosamide [(R)-2-acetamido-N-benzyl-3-methoxypropionamide] is needed for both human and veterinary pharmacokinetic investigations. While lacosamide is currently used to manage partial-onset seizures in humans suffering from epilepsy, it is also presently being investigated for use in the treatment of canine epilepsy in veterinary medicine. Currently, no dosing regimen for the drug exists in dogs. A novel and simple high-performance liquid chromatography method was developed for determination of lacosamide in dog serum. Serum proteins (0.1 mL) were precipitated with -20.0°C acetonitrile after addition of the internal standard, daidzein. Separation was achieved with a Phenomenex® Luna® C18 (2) (5 µm, 250 × 4.60 mm) column with ultraviolet detection at 210 nm. The calibration curves were linear ranging from 0.5 to 25 µg/mL. Precision of the assay was <13% (RSD) and was within 12% for all points in the calibration curve. The limit of quantitation for this method was 0.5 µg/mL. The assay was applied successfully to a pre-clinical study of lacosamide pharmacokinetics in dogs.

The Grad Cohort Workshop: Evaluating an Intervention to Retain Women Graduate Students in Computing.

Women engaged in computing career tracks are vastly outnumbered by men and often must contend with negative stereotypes about their innate technical aptitude. Research suggests women's marginalized presence in computing may result in women psychologically disengaging, and ultimately dropping out, perpetuating women's underrepresentation in computing. To combat this vicious cycle, the Computing Research Association's Committee on the Status of Women in Computing Research (CRA-W) runs a multi-day mentorship workshop for women graduate students called Grad Cohort, which consists of a speaker series and networking opportunities. We studied the long-term impact of Grad Cohort on women Ph.D. students' (a) dedication to becoming well-known in one's field, and giving back to the community (professional goals), (b) the degree to which one feels computing is an important element of "who they are" (computing identity), and (c) beliefs that computing skills are innate (entity beliefs). Of note, entity beliefs are known to be demoralizing and can lead to disengagement from academic endeavors. We compared a propensity score matched sample of women and men Ph.D. students in computing programs who had never participated in Grad Cohort to a sample of past Grad Cohort participants. Grad Cohort participants reported interest in becoming well-known in their field to a greater degree than women non-participants, and to an equivalent degree as men. Also, Grad Cohort participants reported stronger interest in giving back to the community than their peers. Further, whereas women non-participants identified with computing to a lesser degree than men and held stronger entity beliefs than men, Grad Cohort participants' computing identity and entity beliefs were equivalent to men. Importantly, stronger entity beliefs predicted a weaker computing identity among students, with the exception of Grad Cohort participants. This latter finding suggests Grad Cohort may shield students' computing identity from the damaging nature of entity beliefs. Together, these findings suggest Grad Cohort may fortify women's commitment to pursuing computing research careers and move the needle toward greater gender diversity in computing.

Phase I trial of intraperitoneal pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer.

PURPOSE: This phase I trial evaluated intraperitoneal (i.p.) pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer. EXPERIMENTAL DESIGN: Dose escalation of day 1 i.p. pemetrexed accrued three patients to each of five dose levels (60-1,000 mg/m(2)), along with day 2 i.p. cisplatin (75 mg/m(2)) and day 8 i.p. paclitaxel (60 mg/m(2)). The goals were to determine maximum tolerated dose (MTD), 18-month progression-free survival (PFS), and pharmacokinetics of i.p. pemetrexed. RESULTS: Cycles, given every 21 days, had an 80% 6-cycle completion rate. There was minimal grade III toxicity in the first 4 dose levels and remarkably an almost complete absence of peripheral neuropathy and alopecia. At the highest dose level, two of three patients experienced ≥ grade III and dose-limiting toxicity (DLT; hematologic, infection, gastrointestinal). There was a pharmacokinetic advantage for i.p. pemetrexed with an intraperitoneal:plasma area under the concentration-time curve ratio of 13-fold. Neither analysis of pharmacokinetic nor homocysteine levels explains the unexpected severity of toxicity in those two patients. On the basis of plasma C(24h) levels, the 42 cycles at ≥ 500 mg/m(2) i.p. pemetrexed without DLT, the MTD appears to be 500 mg/m(2). Median PFS is 30.1 months; 18-month PFS is 78.6% (median follow-up 22.4 months). CONCLUSIONS: This i.p.-only regimen in front-line ovarian cancer is feasible with PFS in line with recent literature. We suggest phase II trials of this regimen in this population with i.p. pemetrexed at 500 mg/m(2). The favorable toxicity profile at doses <1,000 mg/m(2), which needs to be confirmed, appears to compare well with standard combination i.v./i.p. platinum/taxane chemotherapy in this disease.

Intravenous fat emulsion as treatment for ivermectin toxicosis in three dogs homozygous for the ABCB1-1Δ gene mutation.

OBJECTIVE: To describe the outcome of 3 cases of ivermectin toxicosis in dogs homozygous for the ABCB1-1Δ gene mutation treated with intravenous fat emulsion (IFE). SERIES SUMMARY: One Australian Shepherd and 2 Miniature Australian Shepherds were treated for naturally occurring ivermectin toxicosis with IFE. All 3 dogs were homozygous for the ABCB1-1Δ gene mutation. Serum ivermectin concentrations confirmed ivermectin exposure in each case. All 3 dogs exhibited tremors, ptyalism, and central nervous system depression, which progressed over several hours to stupor in 2 dogs, and to a comatose state requiring mechanical ventilation in the remaining dog. A 20% formulation of IFE(a) was administered as an IV bolus (1.5 mL/kg) followed by a slow IV infusion (7.5-15 mL/kg [0.25-0.5 mL/kg/m], over 30 minutes). No change was observed in the neurologic status of any patient. Lipemia visible upon blood sampling persisted for 36 hours in 1 dog however, no other adverse effects were noted. Flumazenil (0.01 mg/kg IV), followed by a constant rate infusion(CRI) of 0.01 mg/kg/h IV was administered in 1 case, without any apparent clinical benefit or adverse effect. NEW OR UNIQUE INFORMATION PROVIDED: IFE was ineffective in the treatment of ivermectin toxicosis in these ABCB1-1Δ homozygous mutant dogs. Further investigation is necessary to determine why IFE treatment was unsuccessful in these cases and whether its use can be optimized to yield better results.

Overexpression of tumor vascular endothelial growth factor A may portend an increased likelihood of progression in a phase II trial of bevacizumab and erlotinib in resistant ovarian cancer.

PURPOSE: This phase II trial evaluated bevacizumab plus erlotinib in platinum-resistant ovarian cancer; exploratory biomarker analyses, including that of tumor vascular endothelial growth factor A (VEGF-A), were also done. EXPERIMENTAL DESIGN: Forty heavily pretreated patients received erlotinib (150 mg/d orally) and bevacizumab (10 mg/kg i.v.) every 2 weeks until disease progression. Primary end points were objective response rate and response duration; secondary end points included progression-free survival (PFS), toxicity, and correlations between angiogenic protein levels, toxicity, and efficacy. RESULTS: Grade 3 toxicities included skin rash (n = 6), diarrhea (n = 5), fatigue (n = 4), and hypertension (n = 3). Grade 4 toxicities were myocardial infarction (n = 1) and nasal septal perforation (n = 1). Only one grade 3 fistula and one grade 2 bowel perforation were observed. Nine (23.1%) of 39 evaluable patients had a response (median duration, 36.1+ weeks; one complete response), and 10 (25.6%) patients achieved stable disease, for a disease control rate of 49%. Median PFS was 4 months, and 6-month PFS was 30.8%. Biomarker analyses identified an association between tumor cell VEGF-A expression and progression (P = 0.03); for every 100-unit increase in the VEGF-A score, there was a 3.7-fold increase in the odds of progression (95% confidence interval, 1.1-16.6). CONCLUSIONS: Bevacizumab plus erlotinib in heavily pretreated ovarian cancer patients was clinically active and well tolerated. Erlotinib did not seem to contribute to efficacy. Our study raises the intriguing possibility that high levels of tumor cell VEGF-A, capable of both autocrine and paracrine interactions, are associated with resistance to bevacizumab, emphasizing the complexity of the tumor microenvironment.