bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of Power Between Randomized Discontinuation Design and Upfront Randomization Design on Progression-Free Survival
Authors: Fu Pingfu , Dowlati Afshin , Schluchter Mark 
Published: July 2009

Purpose Enrichment based on molecular characteristics has emerged as an important inclusion criterion in phase II trials of targeted anticancer agents. In this study, we evaluate a well-described method of population enrichment by tumor growth characteristics in the early development stage of targeted cytostatic agents. Methods For some solid tumors, such as pancreatic carcinoma, using a time-to-event end point (eg, time to disease progression) to evaluate the efficacy of a cytostatic agent in a phase II trial is more relevant than clinical response by Response Evaluation Criteria in Solid Tumors. In this setting, we compared the power of the randomized discontinuation and upfront randomization designs under two previously proposed tumor growth models for treatment effect when the end point is time-to-event. Results By selecting patients with more homogeneous tumor growth characteristics, the randomized discontinuation design is more efficient than the upfront randomization design when treatment benefit is restricted to slow-growing tumors. Under a model where only a subset of patients expressing the molecular target are sensitive to the agent, the randomized discontinuation design is more powerful than the upfront randomization design when the treatment effect is small; and vice versa when the treatment effect is moderate to large. Conclusion For selected targeted agents where a bioassay to select patients expressing the specific molecular target is not available, the randomized discontinuation design is a feasible alternative patient enrichment strategy in certain disease settings and provides a reasonable platform to evaluate drugs before phase III testing.
Safety and Immunological Efficacy of a DNA Vaccine Encoding Prostatic Acid Phosphatase in Patients With Stage D0 Prostate Cancer
Authors: McNeel Douglas G. , Dunphy Edward J. , Davies James G. , Frye Thomas P. , Johnson Laura E. , Staab Mary Jane , Horvath Dorothea L. , Straus Jane , Alberti Dona , Marnocha Rebecca , Liu Glenn , Eickhoff Jens C. , Wilding George 
Published: July 2009

PurposeProstatic acid phosphatase (PAP) is a prostate tumor antigen. We have previously demonstrated that a DNA vaccine encoding PAP can elicit antigen-specific CD8+ T cells in rodents. We report here the results of a phase I/IIa trial conducted with a DNA vaccine encoding human PAP in patients with stage D0 prostate cancer.Patients and MethodsTwenty-two patients were treated in a dose-escalation trial with 100 μg, 500 μg, or 1,500 μg plasmid DNA, coadministered intradermally with 200 μg granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant, six times at 14-day intervals. All patients were observed for 1 year after treatment.ResultsNo significant adverse events were observed. Three (14%) of 22 patients developed PAP-specific IFNγ-secreting CD8+ T-cells immediately after the treatment course, as determined by enzyme-linked immunospot. Nine (41%) of 22 patients developed PAP-specific CD4+ and/or CD8+ T-cell proliferation. Antibody responses to PAP were not detected. Overall, the prostate-specific antigen (PSA) doubling time was observed to increase from a median 6.5 months pretreatment to 8.5 months on-treatment (P = .033), and 9.3 months in the 1-year post-treatment period (P = .054).ConclusionThe demonstration that a DNA vaccine encoding PAP is safe, elicits an antigen-specific T-cell response, and may be associated with an increased PSA doubling time suggests that a multi-institutional phase II trial designed to evaluate clinical efficacy is warranted.
Chronic Physical Effects and Health Care Utilization in Long-Term Ovarian Germ Cell Tumor Survivors: A Gynecologic Oncology Group Study
Authors: Matei Daniela , Miller Anna M. , Monahan Patrick , Gershenson David , Zhao Qianqian , Cella David , Champion Victoria L. , Williams Stephen D. 
Published: July 2009

Purpose This study compares late effects of treatment on physical well-being and utilization of health care resources between ovarian germ cell tumor (OGCT) survivors and age/race/education-matched controls. Patients and Methods Eligible patients had OGCT treated with surgery and chemotherapy and were disease-free for at least 2 years at time of enrollment. The matched control group was selected from acquaintances recommended by survivors. Symptoms and function were measured using previously validated scales. Health care utilization was assessed by questions regarding health insurance coverage and health services utilization. Results One hundred thirty-two survivors and 137 controls completed the study. Survivors were significantly more likely to report a diagnosis of hypertension (17% v 8%, P = .02), and marginally hypercholesterolemia (9.8% v 4.4%, P = .09), and hearing loss (5.3% v 1.5%, P = .09) compared with controls. There were no significant differences in the rates of self-reported arthritis, heart, pulmonary or kidney disease, diabetes, non-OGCT malignancies, anxiety, hearing loss, or eating disorders between groups. Among chronic functional problems, numbness, tinnitus, nausea elicited by reminders of chemotherapy (v general nausea triggers for controls), and Raynaud's symptoms were reported more frequently by survivors. Patients who received vincristine, dactinomycin, and cyclophosphamide in addition to cisplatin therapy had increased functional complaints, particularly numbness and nausea. Health care utilization was similar, but 15.9% of survivors reported being denied health insurance versus 4.4% of controls (P < .001). Conclusion Although a few sequelae of treatment persist, in general, OGCT survivors enjoy a healthy life comparable to that of controls.
Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs?
Authors: Richey Elizabeth A. , Lyons E. Alison , Nebeker Jonathan R. , Shankaran Veena , McKoy June M. , Luu Thanh Ha , Nonzee Narissa , Trifilio Steven , Sartor Oliver , Benson Al B. , Carson Kenneth R. , Edwards Beatrice J. , Gilchrist-Scott Douglas , Kuzel Timothy M. , Raisch Dennis W. , Tallman Martin S. , West Dennis P. , Hirschfeld Steven , Grillo-Lopez Antonio J. , Bennett Charles L. 
Published: July 2009

Purpose Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. Methods We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. Results Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non–orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non–orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. Conclusion AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.
Prognostic Implications of NOTCH1 and FBXW7 Mutations in Adults With T-Cell Acute Lymphoblastic Leukemia Treated on the MRC UKALLXII/ECOG E2993 Protocol
Authors: Mansour Marc R. , Sulis Maria L. , Duke Veronique , Foroni Letizia , Jenkinson Sarah , Koo Kenneth , Allen Christopher G. , Gale Rosemary E. , Buck Georgina , Richards Sue , Paietta Elisabeth , Rowe Jacob M. , Tallman Martin S. , Goldstone Anthony H. , Ferrando Adolfo A. , Linch David C. 
Published: July 2009

Purpose Notch pathway activation by mutations in either NOTCH1 and/or FBXW7 is one of the most common molecular events in T-cell acute lymphoblastic leukemia (T-ALL) and, in pediatric disease, predicts for favorable outcome. Their prognostic significance in adult T-ALL is unclear. We sought to evaluate the outcome according to mutation status of patients with adult T-ALL treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/Eastern Cooperative Oncology Group (ECOG) E2993 protocol. Methods NOTCH1 and FBXW7 were screened by a combination of denaturing high-performance liquid chromatography and sequencing in 88 adult patients with T-ALL treated on the UKALLXII/ECOG E2993 protocol and compared with clinical characteristics and outcome. Results NOTCH1 and FBXW7 mutations were common (60% and 18%, respectively) and were not associated with age or WBC count. NOTCH1 heterodimerization domain mutations were associated with FBXW7 mutations (P = .02), and NOTCH1 proline, glutamic acid, serine, threonine (PEST) rich domain and FBXW7 mutations were mutually exclusive. There were an equal number of high- and standard-risk patients in the NOTCH1 and FBXW7 mutated (MUT) groups. Patients wild type (WT) for both markers trended toward poorer event-free survival (EFS; MUT v WT, 51% v 27%, P = .10; hazard ratio, 0.6). Analysis by each marker individually was not significantly predictive of outcome (NOTCH1 MUT v WT, EFS 49% v 34%, P = .20; FBXW7 MUT v WT, EFS 53% v 41%, P.72). Conclusion NOTCH1 and FBXW7 mutant-positive patients do not fare sufficiently well to warrant an individualized treatment approach in future studies.
Phenotypic Consequences of Purine Nucleotide Imbalance inSaccharomyces cerevisiae
Authors: Saint-Marc Christelle , Pinson Benoît , Coulpier Fanny , Jourdren Laurent , Lisova Olesia , Daignan-Fornier Bertrand 
Published: July 2009

AbstractCoordinating homeostasis of multiple metabolites is a major task for living organisms, and complex interconversion pathways contribute to achieving the proper balance of metabolites. AMP deaminase (AMPD) is such an interconversion enzyme that allows IMP synthesis from AMP. In this article, we show that, under specific conditions, lack of AMPD activity impairs growth. Under these conditions, we found that the intracellular guanylic nucleotide pool was severely affected. In vivo studies of two AMPD homologs, Yjl070p and Ybr284p, indicate that these proteins have no detectable AMP, adenosine, or adenine deaminase activity; we show that overexpression of YJL070c instead mimics a loss of AMPD function. Expression of the yeast transcriptome was monitored in a AMPD-deficient mutant in a strain overexpressing YJL070c and in cells treated with the immunosuppressive drug mycophenolic acid, three conditions that lead to severe depletion of the guanylic nucleotide pool. These three conditions resulted in the up- or downregulation of multiple transcripts, 244 of which are common to at least two conditions and 71 to all three conditions. These transcriptome results, combined with specific mutant analysis, point to threonine metabolism as exquisitely sensitive to the purine nucleotide balance.
Chromosome Aberrations Resulting From Double-Strand DNA Breaks at a Naturally Occurring Yeast Fragile Site Composed of Inverted Ty Elements Are Independent of Mre11p and Sae2p
Authors: Casper Anne M , Greenwell Patricia W , Tang Wei , Petes Thomas D 
Published: July 2009

Abstract
Genetic instability at palindromes and spaced inverted repeats (IRs) leads to chromosome rearrangements. Perfect palindromes and IRs with short spacers can extrude as cruciforms or fold into hairpins on the lagging strand during replication. Cruciform resolution produces double-strand breaks (DSBs) with hairpin-capped ends, and Mre11p and Sae2p are required to cleave the hairpin tips to facilitate homologous recombination. Fragile site 2 (FS2) is a naturally occurring IR in Saccharomyces cerevisiae composed of a pair of Ty1 elements separated by ∼280 bp. Our results suggest that FS2 forms a hairpin, rather than a cruciform, during replication in cells with low levels of DNA polymerase. Cleavage of this hairpin results in a recombinogenic DSB. We show that DSB formation at FS2 does not require Mre11p, Sae2p, Rad1p, Slx4p, Pso2p, Exo1p, Mus81p, Yen1p, or Rad27p. Also, repair of DSBs by homologous recombination is efficient in mre11 and sae2 mutants. Homologous recombination is impaired at FS2 in rad52 mutants and most aberrations reflect either joining of two broken chromosomes in a “half crossover” or telomere capping of the break. In support of hairpin formation precipitating DSBs at FS2, two telomere-capped deletions had a breakpoint near the center of the IR. In summary, Mre11p and Sae2p are not required for DSB formation at FS2 or the subsequent repair of these DSBs.
β‐Receptor Selectivity of Carvedilol and Metoprolol Succinate in Patients with Heart Failure (SELECT Trial): A Randomized Dose‐Ranging Trial
Authors: Zebrack James S. , Munger Mark , MacGregor John , Lombardi William L. , Stoddard Gregory P. , Gilbert Edward M. 
Published: July 2009

Study Objective. To determine whether metoprolol succinate (a β1‐selective β‐blocker) remains β1‐selective compared with carvedilol (a nonselective β‐blocker) during upward titration of doses in patients with American College of Cardiology (ACC) stage C heart failure.Design. Prospective, randomized, parallel‐arm study.Setting. General clinical research center.Patients. Twenty‐five β‐blocker‐naïve adults with New York Heart Association functional classes II or III heart failure (i.e., ACC stage C).Intervention. Patients received either immediate‐release carvedilol 3.125 mg twice/day or controlled‐release metoprolol succinate 25 mg once/day; doses were titrated upward by doubling the dose every 2 weeks until reaching a maximum tolerated dose or a goal dose of carvedilol 25 mg twice/day and metoprolol 200 mg/day. Before each dose titration, terbutaline (a β‐receptor agonist) was infused at 6 mg/kg over 1 hour for determination of β2‐blockade.Measurements and Main Results. Patients were studied at baseline and after each dose titration of metoprolol succinate (at 25, 50, 100, and 200 mg once/day) and immediate‐release carvedilol (at 3.125, 6.25, 12.5, and 25 mg twice/day). Glucose and potassium concentrations were measured twice serially at baseline, every 10 minutes during infusion, every 15 minutes for the first hour after infusion, and every 30 minutes for the second hour after infusion. The median area under the concentration‐time curve (AUC) was calculated for changes in glucose and potassium concentrations. As assessed by glucose AUC, there was no significant difference in the degree of β2‐blockade between metoprolol 200 mg and carvedilol 25 mg. In contrast to these data, the degree of β2‐blockade as assessed by potassium AUC was greater for carvedilol compared with metoprolol across all doses.Conclusion. In this ACC stage C heart failure population, carvedilol was nonselective at all clinically relevant doses, whereas metoprolol succinate was β1‐selective at low doses and became progressively nonselective at higher doses.
Lack of Effect of Tenofovir Disoproxil Fumarate on Pharmacokinetics of Hormonal Contraceptives
Authors: Kearney Brian P. , Mathias Anita 
Published: July 2009

Study Objective. To assess the potential for a drug‐drug interaction between a representative hormonal contraceptive (norgestimate‐ethinyl estradiol) and tenofovir disoproxil fumarate (tenofovir DF), a prodrug of tenofovir, when coadministered.Design. Thirty‐day, open‐label, fixed‐sequence, pharmacokinetic drug‐drug interaction study.Setting. Single clinical phase I center.Participants. Twenty nonpregnant and nonlactating women aged 19–45 years who were taking a norgestimate‐ethinyl estradiol oral contraceptive.Intervention. Each woman received norgestimate‐ethinyl estradiol alone on study days 1–22, followed by norgestimate‐ethinyl estradiol plus tenofovir DF 300 mg once/day for 7 days during two consecutive 28‐day contraceptive cycles.Measurements and Main Results. Pharmacokinetic assessments were performed over 24 hours on study days 1 and 29 (corresponding to matching days [day 21] of the two contraceptive cycles). Serum or plasma concentrations of tenofovir, norgestimate and its active metabolite deacetyl norgestimate, and ethinyl estradiol were measured by high‐performance liquid chromatography‐tandem mass spectrometry assays. Geometric mean ratios (90% confidence intervals) for the pharmacokinetic parameters for deacetyl norgestimate and ethinyl estradiol were estimated by using analysis of variance and compared with the no‐effect criterion for bioequivalence. The tenofovir pharmacokinetic parameters were compared with historical controls. Pharmacokinetic parameters for deacetyl norgestimate and ethinyl estradiol were unaltered by coadministration of tenofovir DF. The tenofovir pharmacokinetic parameters in subjects receiving norgestimate‐ethinyl estradiol were consistent with historical control data for tenofovir.Conclusion. Tenofovir DF and norgestimate‐ethinyl estradiol are not involved in a clinically significant drug‐drug interaction; tenofovir DF did not affect the steady‐state pharmacokinetics of norgestimate or ethinyl estradiol, including the concentration at the end of the dosing interval. Both drugs were well tolerated when coadministered. Tenofovir DF is unlikely to affect the pharmacokinetics of hormonal oral contraceptives.
Pharmacokinetics of Concurrent Administration of Fosamprenavir and Atazanavir without Ritonavir in Human Immunodeficiency Virus‐Negative Subjects
Authors: McRae MaryPeace , Clay Patrick G. , Anderson Peter L. , Glaros Alan G. 
Published: July 2009

Study Objective. To quantify the pharmacokinetics of amprenavir and atazanavir (administered as the prodrug fosamprenavir) alone and in combination in human immunodeficiency virus (HIV)‐negative subjects.Design. Randomized, open‐label, three‐way crossover study.Setting. Research facility.Participants. Eleven men and 10 women who were seronegative for HIV.Intervention. Subjects were randomized to 14‐day treatment periods of fosamprenavir 1400 mg once/day, atazanavir 400 mg once/day, or fosamprenavir 1400 mg plus atazanavir 400 mg once/day; after a washout period of at least 21 days between each treatment, they received the other two treatments.Measurements and Main Results. Subjects underwent 24‐hour pharmacokinetic sampling at baseline and on day 14 of each treatment period. Primary outcome measures were area under the plasma concentration‐time curve (AUC) and maximum concentration (Cmax) for amprenavir and atazanavir. Atazanavir significantly enhanced the exposure of amprenavir. When fosamprenavir was given alone, the geometric mean of amprenavir's AUC was 20.2 μg·hour/ml (95% confidence interval [CI] 19.1–21.2 μg·hr/ml). When given in combination with atazanavir, amprenavir had an AUC of 39.8 μg·hour/ml (95% CI 38.7–40.9 μg·hr/ml). Similarly, the Cmax for amprenavir increased from 4193 ng/ml (95% CI 3927–4459 ng/ml) to 6621 ng/ml (95% CI 6427–6814 ng/ml) when given in combination with atazanavir. In contrast, AUC and Cmax for atazanavir significantly decreased when atazanavir was coadministered with fosamprenavir; AUC decreased from 17.6 μg·hour/ml (95% CI 16.6–18.7 μg·hr/ml) to 11.8 μg·hour/ml (95% CI 11.3–12.3 μg·hr/ml), and Cmax decreased from 2507 ng/ml (95% CI 2379–2635 ng/ml) to 1832 ng/ml (95% CI 1752–1911 ng/ml). Adverse events were assessed at each study visit and 1 month after the subjects completed the three treatments. Both drugs were well tolerated. One serious adverse event (grade 3 acute pancreatitis) occurred and resolved without further incident.Conclusion. Atazanavir 400 mg/day plus fosamprenavir 1400 mg/day significantly decreased concentrations of atazanavir compared with standard dosing regimens of each drug alone. This dosing scheme is not a recommended combination of dual, fully active protease inhibitors.
Frequency and Severity of Harm of Medication Errors Related to the Parenteral Nutrition Process in a Large University Teaching Hospital
Authors: Sacks Gordon S. , Rough Steve , Kudsk Kenneth A. 
Published: July 2009

Study Objective. To determine the frequency of medication errors, as well as the severity of harm resulting from these errors, related to the prescription, transcription, preparation, and administration of parenteral nutrition formulations.Design. Prospective, observational study.Setting. 471‐bed, academic teaching hospital.Patients. All adult and pediatric inpatients receiving parenteral nutrition between November 1, 2002 and May 31, 2004.Measurements and Main Results. The occurrence of incorrect prescribing practices, wrong formulation preparation, operational system errors, order entry errors related to automated technology, and incorrect administration practices were documented. In addition, the specific step in the drug process—prescription, transcription, preparation, and administration—at the time that the error occurred was noted. Harm scores, to assess the severity of the error in relation to the safety of the patient, were assigned based on the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP). The rate of errors with parenteral nutrition was then compared with the rate of errors with other high‐alert drugs, both at our institution and at a health care consortium. A total of 4730 prescriptions for parenteral nutrition were written during the study period; 74 (1.6%) were associated with a medication error. Of these errors, 1 (1%) occurred during the prescription process (and was detected before preparation), 29 (39%) occurred during the transcription process, 18 (24%) during preparation, and 26 (35%) during the administration process. Sixty‐seven (91%) of the 74 errors were considered nonharmful, as defined by NCC MERP, whereas 6 (8%) contributed to or resulted in temporary harm to a patient. The rate of errors was similar between our institution and the consortium, both for parenteral nutrition formulations and for other high‐alert drugs. The overall incidence of medication errors during the study was 15.6 errors/1000 parenteral nutrition prescriptions compounded.Conclusion. Our results demonstrate that medication errors related to the prescription, transcription, preparation, and administration of parenteral nutrition formulations occur and occasionally result in harm. Health care institutions should develop quality assurance programs to document compliance with published safe practice guidelines for parenteral nutrition.