Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer.

PURPOSE: We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. PATIENTS AND METHODS: An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. RESULTS: Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m(2) were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t(1/2)) of 17-AAG were 11.6 L/h/m(2) and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t(1/2) of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. CONCLUSION: The MTD of weekly 17-AAG is 308 mg/m(2). 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.     

Phase I and pharmacologic study of infusional topotecan and Carboplatin in relapsed and refractory acute leukemia.

PURPOSE: To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias. EXPERIMENTAL DESIGN: Patients received topotecan and carboplatin by 5-day continuous infusion at nine dose levels. Patients achieving a complete remission received up to two additional courses for consolidation. Plasma topotecan and ultrafilterable platinum were assayed on days 1 to 5. In addition, pretreatment levels of various polypeptides in leukemic cells were examined by immunoblotting to assess possible correlations with response. RESULTS: Fifty-one patients received a total of 69 courses of therapy. Dose-limiting toxicity consisted of grade 4/5 typhlitis and grade 3/4 mucositis after one course of therapy or grade 4 neutropenia and thrombocytopenia lasting >50 days when a second course was administered on day 21. Among 45 evaluable patients, there were 7 complete remissions, 2 partial remissions, 1 incomplete complete remission, and 1 reversion to chronic-phase chronic myelogenous leukemia. Topotecan steady-state plasma concentrations increased with dose. No accumulation of topotecan or ultrafilterable platinum occurred between days 1 and 5 of therapy. Leukemic cell levels of topoisomerase I, checkpoint kinase 1, checkpoint kinase 2, and Mcl-1 correlated with proliferating cell nuclear antigen but not with response. In contrast, low Bcl-2 expression correlated with response (P = 0.014, Mann-Whitney U test). CONCLUSIONS: The maximum tolerated dose was 1.6 mg/m(2)/d topotecan plus 150 mg/m(2)/d carboplatin. The complete remission rate in a heavily pretreated population was 16% (33% at the highest three dose levels). Responses seem to correlate with low pretreatment blast cell Bcl-2 expression.     

The Role of Self-Beliefs in Predicting Postschool Outcomes for Deaf Young Adults

The aim of this study was to explore the role of self-beliefs in predicting postschool outcomes for deaf young adults in transition from secondary settings. Three self-level constructs were explored: self-concept, self-determination, and expectations about the future. This study utilized data from the National Longitudinal Transition Study-2 (NLTS2) that collected longitudinal data from youths with disabilities across the nation, 550 of which were deaf or hard of hearing and met the selection criteria in this study. This study examined the relationships between these deaf adolescents’ self-beliefs and actual future achievements that were reached as they transitioned to adult life, in three domains: life, employment, and education. Despite the generally positive self-beliefs of deaf individuals, which were, in some cases, related to postschool outcomes, the self-beliefs assessed in this study did not emerge as comprehensive predictors of postschool attainments. Findings suggest that for deaf individuals, successfully navigating transitions to adult life involves dimensions beyond individual agency. Positive self-beliefs are clearly a part of successfully attaining postschool outcomes, but deaf individuals may not have full access to equitable opportunities to capitalize on these beliefs.     

Cochrane systematic reviews are useful to map research gaps for decreasing maternal mortality

ObjectivesTo use an “evidence-mapping” approach to assess the usefulness of Cochrane reviews in identifying research gaps in the maternal health.Study Design and SettingThe article describes the general mapping, prioritizing, reconciling, and updating approach: (1) identifying gaps in the maternal health research using published systematic reviews and formulating research questions, (2) prioritizing questions using Delphi method, (3) reconciling identified research priorities with the existing literature (i.e., searching of ongoing trials in trials registries), (4) updating the process. A comprehensive search of Cochrane systematic reviews published or updated from January 2006 to March 2011 was performed. We evaluated the “Implications for Research” section to identify gaps in the research.ResultsOur search strategy identified 695 references; 178 systematic reviews identifying at least one research gap were used. We formulated 319 research questions, which were classified into 11 different categories based on the direct and indirect causes of maternal mortality: postpartum hemorrhage, abortion, hypertensive disorders, infection/sepsis, caesarean section, diabetes, pregnancy prevention, preterm labor, other direct causes, indirect causes, and health policies and systems. Most research questions concerned the effectiveness of clinical interventions, including drugs (42.6%), nonpharmacologic interventions (16.3%), and health system (14.7%).ConclusionIt is possible to identify gaps in the maternal health research by using this approach.     

“Flipped classrooms” in training in maxillofacial surgery: preparation before the traditional didactic lecture?

While virtual learning environments (VLE) can be used in medical education as stand-alone educational interventions, they can also be used in preparation for traditional “face-to-face” training sessions as part of a “flipped classroom” model. We sought to evaluate the introduction of this model in a single module on maxillofacial radiology from a course on trauma skills. Course delegates were randomised into two groups: one was given access to an e-learning resource (test group) and the other attended a traditional didactic lecture (control group). Knowledge and confidence were assessed before and after the course with a 20-question single-best-answer paper and a 10-situation 100 mm visual analogue scale (VAS) paper, respectively. All participants were then given free access to the VLE for 30 days and were invited to take part in an e-survey. Neither group showed improvements in the single-best-answer scores, but both groups showed comparable improvements in VAS (control: median (range) values improved from 40.8 (17.7–82.5) mm to 62.8 (35.3–88.7) mm, p = 0.001; test group: from 47.7 (10.9–58.1) mm to 60.5 (32.4–75.6) mm, p = 0.005). Half of the respondents stated that they preferred the “flipped classroom” approach, and 22/22 stated that they would be “likely” or “very likely” to use an e-learning resource with expanded content. The “flipped classroom” approach was well received and there were comparable improvements in confidence. As maxillofacial radiology lends itself to online instruction with its reliance on the recognition of patterns, and problem-based approach to learning, a piloted e-learning resource could be developed in this area.