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 III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy.

PURPOSE: To determine whether weekly epoetin alfa could improve hemoglobin (HgB) levels, reduce RBC transfusions, and improve quality of life (QOL) in patients with advanced cancer and with anemia after receiving myelosuppressive chemotherapy. PATIENTS AND METHODS: This double-blind, placebo-controlled study randomly assigned patients to placebo or epoetin alfa (Ortho Biotech, Bridgewater, NJ) 40,000 U subcutaneous weekly for 16 weeks. QOL, HgB, and RBC transfusions were measured pretreatment and monthly. RESULTS: The study accrued 344 patients; 330 were assessable for efficacy and 305 were assessable for QOL. Placebo-treated patients had a mean increase in HgB of 0.9 g/dL (range, -3.8 to +5.3) compared with 2.8 g/dL (range, -2.2 to +7.5) for epoetin-treated patients (P < .0001). During the study, 31.7% of placebo-treated patients achieved a > or = 2 g/dL HgB increase compared with 72.7% of epoetin-treated patients (P < .0001). The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6% and 25.3% (P = .005), respectively. The placebo group received 256 units of RBCs compared with 127 units in the epoetin group (P < .0001). The incidence of toxicity in the groups was similar. Changes in the average QOL scores from baseline to the end of the study were similar in the two groups (P = not significant). The HgB responders (irrespective of treatment arm) had a mean change in Functional Assessment of Cancer Therapy (FACT) fatigue score from a baseline of +5.1 compared with -2.1 for the nonresponders (P = .006). CONCLUSION: Epoetin alfa significantly improved HgB and reduced transfusions in this patient population. These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia.     

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.     

Evaluation of the Heart Truth Professional Education Campaign on Provider Knowledge of Women and Heart Disease

BackgroundThe Heart Truth Professional Education Campaign was developed to facilitate education of health care providers in evidence-based strategies to prevent cardiovascular disease (CVD) in women.MethodsAs part of the 3-year campaign, lectures based on the American Heart Association's evidence-based guidelines for CVD prevention in women were presented by local speakers to healthcare providers and students in three high-risk states: Delaware, Ohio, and New York. Participants' responses to pretest and posttest questions about CVD in women are presented. We performed t-test and multivariable linear regression to assess the influence of provider characteristics on baseline knowledge and knowledge change after the lecture.ResultsBetween 2008 and 2011, 2,995 healthcare providers, students, and other participants completed the baseline assessment. Knowledge scores at baseline were highest for physicians, with obstetrician/gynecologists scoring lowest (63%) and cardiologists highest (76%). Nurses had intermediate total knowledge (56%) and students had the lowest total knowledge (49%) at baseline. Pre- and post-lecture assessments were completed by 1,893 (63%) of attendees. Scores were significantly higher after the educational lecture (p ≤ .001), with greater increase for those with lower baseline scores. Baseline knowledge of the use of statins, hormone therapy, and antioxidants, as well as approaches to smoking cessation and treatment of hypertension, differed by provider type.ConclusionTailoring of lectures for non-physician audiences may be beneficial given differences in baseline knowledge. More emphasis is needed on statin use for all providers and on smoking cessation and treatment of hypertension for nurses, students, and other healthcare professionals.     

An Investigation of Nonlexical Reading Impairments

Word and nonword reading ability was tested in a group of 11 patients with varying levels of language impairments. For the least impaired patients, the probability of grapheme-phoneme association affected nonword reading ability. An advantage reading nonwords that sound like words (pseudohomophones) was found for six patients, and was unrelated to the severity of patients' nonlexical reading impairments. All patients showed evidence of impairment to all three processing components hypothesised to be necessary for nonlexical reading. A focused study of the phonological processing abilities of the five subjects with mildest impairment uncovered differential influences of segment size and lexicality on patients' ability to combine aurally-presented sound segments. Results are interpreted as indicating multiple sources of impairment to a number of cognitive operations that are specialised to support nonlexical reading.     

IMPAIRED ENCODING OF ABSTRACT LETTER ORDER: SEVERE ALEXIA IN A MILDLY APHASIC PATIENT

We describe the single word reading impairment of a patient with severe acquired alexia in the context of largely spared auditory-verbal language. DES shows strong effects of lexical variables when reading words; she is completely unable to read nonwords. Her “visual” reading errors (orthographically related word substitutions) reflect a strong positional bias to differ from targets toward their right sides; this positional bias was evident across several different topographic transformations of the stimuli and was present in her spelling errors. Such a pattern of positional letter retention is commonly associated with right “neglect dyslexia” and has been interpreted as indicating damage to a spatially encoded word representation. However, DES shows no sign of spatial impairment in nonlanguage tasks, fails to demonstrate several of the characteristics thought to be diagnostic of “neglect dyslexia,” and shows no evidence of neglect in sentence reading. In contrast to the spatial account, we interpret DES's primary impairment as one involving a prelexical, transient level of representation in which letter order is coded abstractly (i.e. neither spatially nor serially).     

Cognitive treatments of sentence processing disorders: What have we learned?

Several cognitive neuropsychological studies describing treatments of sentence processing disorders have been reported in recent years. We review the outcome of 10 studies that describe treatment outcomes for 17 aphasic patients. Although the studies used different approaches to intervention, they shared the goal of improving reversible sentence comprehension, and they targeted a hypothesised deficit of “thematic mapping”. Several trends in treatment outcomes were observed. In most cases, there was strong evidence that the treatments induced a change in the pattern of sentence processing. Moreover, the outcomes indicated that impaired reversible sentence comprehension can arise from a range of impairments, only some of which directly implicate structural and/or lexical deficits assumed to be the source of poor thematic mapping abilities. Patterns of post-therapy generalisation within and across processing modalities appeared to be related, among other things, to the therapy approach and to the selection of treatment materials. These findings are discussed with regard to the theoretical implications of sentence processing treatment data.     

Understanding Population-Based Site-Specific Cancer Incidence Rates in the USA

As compared with conventionally reported national population-based incidence rates, incidence rates better represent the ??burden?? of disease if they remove prevalent cases from the denominator. In order to reflect the ??risk?? in a disease-free population, rates should both exclude prevalent cases from the denominator and second or later diagnosed cases at the same site from the numerator. Five common cancers were evaluated through a correction method using 2005?C2007 Surveillance, Epidemiology, and End Results Program data to determine the extent of difference between conventional and corrected incidence rates. These corrections lowered the incidence rates 4.0?C5.8% for female breast cancer, 4.6?C7.6% for melanoma, 3.0?C4.0% for colorectal cancer, and 2.1?C2.5% for lung and bronchus cancer. Corrected incidence rates for prostate cancer were 9.9?C13.7% higher. In cancers with either high prevalence and/or high occurrence of multiple primaries at the same site, corrected population-based incidence rates are warranted.