A phase II and pharmacokinetic study of weekly 72-h topotecan infusion in patients with platinum-resistant and paclitaxel-resistant ovarian carcinoma

BACKGROUND: As suggested by preclinical trials, prolonged administration of topotecan, a reversible inhibitor of topoisomerase-I, may have a therapeutic advantage. Following a phase I trial of weekly 72-h topotecan infusion, we performed a phase II trial utilizing this schedule in ovarian carcinoma. METHODS: Eligibility included platinum-/paclitaxel-resistant ovarian carcinoma, measurable disease, and adequate hematologic, renal, and hepatic function. A dose of 2.0 mg/m(2) of topotecan was administered as a 72-h infusion weekly via an ambulatory pump. Plasma topotecan concentrations were determined prior to and at the completion of each weekly course. RESULTS: Twenty-four patients were entered and 23 patients were evaluable for toxicity and response. Two hundred eighteen weekly courses of therapy were administered (median 7 weeks, range 4-46 weeks). Toxicity was mild with grade 3 leukopenia, neutropenia, and anemia occurring in 13, 13, and 17% of patients, respectively. Two of 23 patients (9.1%) (CI 1-28%) had partial responses of 2 and 3 months' duration and 6 had stable disease. Steady state plasma topotecan lactone concentrations were a median of 1.2 ng/ml (range 0.4-8.00 ng/ml) following the first week of infusion. Steady state topotecan lactone concentrations after the first week of infusion were highest in 2 patients with partial responses. Mean steady state plasma topotecan lactone concentrations after the first week of infusion were 4.6, 2.0, and 1.3 ng/ml for partial response, stable disease, and progressive disease, respectively. An analysis of variance of steady state plasma topotecan concentrations after the first week of infusion over all administered cycles demonstrated a significant difference in steady state plasma topotecan lactone concentrations between patients with partial response and stable disease and between partial response and no response (significant at the 0.05 level after adjustment for multiple comparisons). Controlling for cycle number, steady state topotecan lactone concentrations are significantly greater for patients with responding or stable disease than those with progressive disease (P = 0.0003) and have a lower bound of > or = 1.9 ng/ml (95% confidence level). CONCLUSION: Steady state topotecan lactone concentrations are associated with responding or stable disease in platinum- and paclitaxel-resistant ovarian cancer. Steady state topotecan concentrations could potentially be utilized to modify tumor exposure and response.     

Patient knowledge and attitudes toward cervical cancer screening after the 2012 screening guidelines

Objective

To assess women’s attitudes and preferences related to recent changes in cervical cancer screening guidelines.

Creatine kinase from the bovine myometrium: purification and characterization

Summary Creatine kinase from the smooth muscle of the cow uterus was extracted and purified by procedures involving precipitation of the enzyme in the presence of ethanol, cation exchange chromatography on phosphocellulose, gel filtration in Sephadex G-150 and anion exchange chromatography on DEAE-cellulose. The purified enzyme eluted as a single active peak after rechromatography on Sephadex G-150 with a molecular weight of about 82 000. Electrophoresis in polyacrylamide gels in tris-glycine buffer (pH 8.6) under non-denaturing conditions revealed a single enzymatically active protein band. In the presence of sodium dodecyl sulphate, the enzyme migrated as a single band in polyacrylamide gels at a mobility corresponding to a molecular weight of about 40 000 per subunit. Reaction with iodoacetamide indicated the presence of sulphydryl groups of differing susceptibility to alkylation. The purified enzyme was optimally active over a wide pH range (6.5–8.0). The Michaelis constants (K _m) of the enzyme for MgADP and phosphoryl creatine (PCr) are 0.12mm and 0.7mm respectively, which are significantly lower than those for skeletal muscle CK. MgADP lowered the dissociation constant of the enzyme for PCr (from about 3.6mm to 0.7mm). Evidence is presented that the high affinity of the smooth muscle CK to MgADP and the MgADP-mediated facilitation of PCr binding might be key factors in the role of this enzyme in harnessing the energy reserves of the cell.     

Criminal recidivism in three models of mandatory drug treatment

Although research has generally been supportive of compulsory treatment programs for drug abusers, findings remain mixed, and few studies have assessed the impacts of different coercive program elements. This study compared criminal recidivism outcomes of 350 clients mandated to the same long-term residential treatment facilities from three different legal sources. On several measures of recidivism, including long-term re-arrest rates that controlled for time at risk, clients mandated from two highly structured programs were found to recidivate at less than half the rate of comparison group clients. This group effect was upheld in multivariate models that controlled for pre-treatment differences and other factors related to recidivism. Combined with results of a previous retention study involving these clients, the findings provide support for the use of structured protocols for informing clients in mandatory programs about legal contingencies of participation and enforcing contingencies through frequent contact between legal agents and treatment staff.