Science.gov

Sample records for 90-03 phase iii

  1. Effect of education level on outcome of patients treated on Radiation Therapy Oncology Group Protocol 90-03.

    PubMed

    Konski, Andre; Berkey, Brian A; Kian Ang, K; Fu, Karen K

    2003-10-01

    It has been hypothesized that people in lower socioeconomic groups have worse outcomes because they present with advanced-stage cancers or receive inadequate treatment. The authors investigated this hypothesis by using education level as a proxy for socioeconomic status in patients treated on Radiation Therapy Oncology Group (RTOG) Protocol 90-03. RTOG 90-03 was a Phase III randomized trial investigating four different radiation fractionation schedules in the treatment of locally advanced head and neck carcinomas. Overall survival and locoregional control rates were analyzed by education level as measured by patient response on the demographic form at study entry. A significant difference was observed in the distribution of patients by education level between the standard fractionated radiation treatment arm and the hyperfractionated radiation treatment arm. More patients in the standard fractionated treatment arm had a higher education level (P = 0.018). Patients attending college had highly and significantly better overall survival and locoregional control than the other groups combined (P = 0.0056 and P = 0.025, respectively: from Cox proportional hazards models stratified by assigned treatment with educational level, T classification, N classification, Karnofsky performance status, primary site, and race). Multivariate analysis revealed that education level was significant for predicting both overall survival and locoregional control when comparing attended college/technical school compared with all other education levels. Patients attending college or technical school had improved overall survival and locoregional control. These differences cannot be explained by differences in tumor stage or treatment. Poorer overall health or lack of support systems contributing to these results needs to be investigated further. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11661

  2. Viking Phase III

    NASA Technical Reports Server (NTRS)

    1978-01-01

    VIKING PHASE III - With the incredible success of the Viking missions on Mars, mission operations have progressed though a series of phases - each being funded as mission success dictated its potential. The Viking Primary Mission phase was concluded in November, 1976, when the reins were passed on to the second phase - the Viking Extended Mission. The Extended Mission successfully carried spacecraft operations through the desired period of time needed to provided a profile of a full Martian year, but would have fallen a little short of connecting and overlapping a full Martian year of Viking operations which scientists desired as a means of determining the degree of duplicity in the red planet's seasons - at least for the summer period. Without this continuation of spacecraft data acquisitions to and beyond the seasonal points when the spacecraft actually began their Mars observations, there would be no way of knowing whether the changing environmental values - such as temperatures and winds atmospheric dynamics and water vapor, surface thermal dynamics, etc. - would match up with those acquired as the spacecraft began investigations during the summer and fall of 1976. This same broad interest can be specifically pursued at the surface - where hundreds of rocks, soil drifts and other features have become extremely familiar during long-term analysis. This picture was acquired on the 690th Martian day of Lander 1 operations - 4009th picture sequence commanded of the two Viking Landers. As such, it became the first picture acquired as the third phase of Viking operations got under way - the Viking Continuation Mission. Between the start of the Continuation Mission in April, 1978, until spacecraft operations are concluded in November, the landers will acquire an additional 200 pictures. These will be used to monitor the two landscaped for the surface changes. All four cameras, two on Lander 1 and two on Lander 2, continue to operate perfectly. Both landers will also

  3. Validation of Lysyl Oxidase As a Prognostic Marker for Metastasis and Survival in Head and Neck Squamous Cell Carcinoma: Radiation Therapy Oncology Group Trial 90-03

    PubMed Central

    Le, Quynh-Thu; Harris, Jonathan; Magliocco, Anthony M.; Kong, Christina S.; Diaz, Roman; Shin, Brian; Cao, Hongbin; Trotti, Andy; Erler, Janine T.; Chung, Christine H.; Dicker, Adam; Pajak, Thomas F.; Giaccia, Amato J.; Ang, K. Kian

    2009-01-01

    Purpose To validate lysyl oxidase (LOX), a hypoxia-related protein, as a marker for metastasis in an independent head and neck cancer (HNC) patient group enrolled onto a prospective trial. Patients and Methods We performed traditional immunohistochemical (IHC) staining and automated quantitative analysis (AQUA) for LOX expression in 66 HNC patients from one institution. We also performed AQUA staining for LOX in 306 of 1,113 patients treated on a phase III trial comparing four radiation fractionation schedules in locally advanced HNC (RTOG 90-03). Pretreatment characteristics and outcome were similar between patients with and without LOX assessment. We correlated AQUA LOX expression with time to metastasis (TTM), time to progression (TTP), and overall survival (OS). Results LOX expression from both staining methods predicted for TTM in the first 66 patients. Multivariate analysis, controlling for significant parameters including nodal stage and performance status, revealed tumor LOX expression, as a continuous variable, was an independent predictor for TTM (hazard ratio [HR], 1.21; 95% CI, 1.10 to 1.33; P = .0001), TTP (HR, 1.06; 95% CI, 1.02 to 1.10; P = .0069), and OS (HR, 1.04; 95% CI, 1.00 to 1.07; P = .0311) in RTOG 90-03 patients. This translates into a 259% increase in metastatic risk for a patient at the 75th percentile of LOX compared with one at the 25th percentile. Conclusion AQUA LOX expression was strongly associated with increased metastasis, progression, and death in RTOG 90-03 patients. This study validates that LOX is a marker for metastasis and survival in HNC. PMID:19667273

  4. Comprehensive School Transformation, Phase III. Program Evaluation.

    ERIC Educational Resources Information Center

    Prine, Donald; Wilkinson, David

    The Iowa Educational Excellence Act and its amendments provide for four types of Phase III programs: performance-based pay, supplemental pay, a combination of both, or comprehensive school transformation. In 1993, the Des Moines Phase III program, which originated as a combination of performance-based pay and supplemental pay, changed to a…

  5. Design of Training Systems Phase III Report

    DTIC Science & Technology

    1975-09-01

    as the reader is aware of this approach and relies on the T&E Report for a more detailed analysis , this summary should highlight the key T&E concerns... ANALYSIS AND EVALUATION GROUP LIBRARY TECHNICAL REPORT SECTION NAVAL POSTGRADUATE S^ MONTEREY CALliChMA TAEG REPORT NO. 28 DESIGN...EVALUATION SUMMARY I II-l IV PHASE III PRODUCTS CONCLUSIONS AND RECOMMENDATIONS IV-1 PHASE III DOCUMENTATION IV-7 11 TAE6 REPORT NO. 28

  6. Failures in Phase III: Causes and Consequences.

    PubMed

    Seruga, Bostjan; Ocana, Alberto; Amir, Eitan; Tannock, Ian F

    2015-10-15

    Phase III randomized controlled trials (RCT) in oncology fail to lead to registration of new therapies more often than RCTs in other medical disciplines. Most RCTs are sponsored by the pharmaceutical industry, which reflects industry's increasing responsibility in cancer drug development. Many preclinical models are unreliable for evaluation of new anticancer agents, and stronger evidence of biologic effect should be required before a new agent enters the clinical development pathway. Whenever possible, early-phase clinical trials should include pharmacodynamic studies to demonstrate that new agents inhibit their molecular targets and demonstrate substantial antitumor activity at tolerated doses in an enriched population of patients. Here, we review recent RCTs and found that these conditions were not met for most of the targeted anticancer agents, which failed in recent RCTs. Many recent phase III RCTs were initiated without sufficient evidence of activity from early-phase clinical trials. Because patients treated within such trials can be harmed, they should not be undertaken. The bar should also be raised when making decisions to proceed from phase II to III and from phase III to marketing approval. Many approved agents showed only better progression-free survival than standard treatment in phase III trials and were not shown to improve survival or its quality. Introduction of value-based pricing of new anticancer agents would dissuade the continued development of agents with borderline activity in early-phase clinical trials. When collaborating with industry, oncologists should be more critical and better advocates for cancer patients.

  7. Project 8 Phase III Design Concept

    NASA Astrophysics Data System (ADS)

    Ashtari Esfahani, A.; Böser, S.; Claessens, C.; de Viveiros, L.; Doe, P. J.; Doeleman, S.; Fertl, M.; Finn, E. C.; Formaggio, J. A.; Guigue, M.; Heeger, K. M.; Jones, A. M.; Kazkaz, K.; LaRoque, B. H.; Machado, E.; Monreal, B.; Nikkel, J. A.; Oblath, N. S.; Robertson, R. G. H.; Rosenberg, L. J.; Rybka, G.; Saldaña, L.; Slocum, P. L.; Tedeschi, J. R.; Thümmler, T.; VanDevender, B. A.; Wachtendonk, M.; Weintroub, J.; Young, A.; Zayas, E.

    2017-09-01

    We present a working concept for Phase III of the Project 8 experiment, aiming to achieve a neutrino mass sensitivity of 2 eV (90 % C.L.) using a large volume of molecular tritium and a phased antenna array. The detection system is discussed in detail.

  8. LM1500 Engine Marinization Contract. Phase III. Materials and Processes Development for Phase III Engine Components.

    DTIC Science & Technology

    The purpose of this report is to briefly document the principal difficulties encountered and the solutions which were effected in the course of manufacturing the modified Phase III test engine hardware. (Author)

  9. Objectives and methodology of BIOBADASER phase iii.

    PubMed

    Sanchez-Piedra, Carlos; Hernández Miguel, M Victoria; Manero, Javier; Roselló, Rosa; Sánchez-Costa, Jesús Tomás; Rodríguez-Lozano, Carlos; Campos, Cristina; Cuende, Eduardo; Fernández-Lopez, Jesús Carlos; Bustabad, Sagrario; Martín Domenech, Raquel; Pérez-Pampín, Eva; Del Pino-Montes, Javier; Millan-Arcineas, Ana Milena; Díaz-González, Federico; Gómez-Reino, Juan Jesús

    2017-09-18

    Describe the objectives, methods and results of the first year of the new version of the Spanish registry of adverse events involving biological therapies and synthetic drugs with an identifiable target in rheumatic diseases (BIOBADASER III). Multicenter prospective registry of patients with rheumatic inflammatory diseases being treated with biological drugs or synthetic drugs with an identifiable target in rheumatology departments in Spain. The main objective of BIOBADASER Phase III is the registry and analysis of adverse events; moreover, a secondary objective was added consisting of assessing the effectiveness by means of the registry of activity indexes. Patients in the registry are evaluated at least once every year and whenever they experience an adverse event or a change in treatment. The collection of data for phase iii began on 17 December 2015. During the first year, 35 centers participated. The number of patients included in this new phase in December 2016 was 2,664. The mean age was 53.7 years and the median duration of treatment was 8.1 years. In all, 40.4% of the patients were diagnosed with rheumatoid arthritis. The most frequent adverse events were infections and infestations. BIOBADASER Phase III has been launched to adapt to a changing pharmacological environment, with the introduction of biosimilars and small molecules in the treatment of rheumatic diseases. This new stage is adapted to the changes in the reporting of adverse events and now includes information related to activity scores. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  10. Laparoscopic Radiofrequency Fibroid Ablation: Phase II and Phase III Results

    PubMed Central

    Pemueller, Rodolfo Robles; Garza Leal, José Gerardo; Abbott, Karen R.; Falls, Janice L.; Macer, James

    2014-01-01

    Background and Objectives: To review phase II and phase III treatments of symptomatic uterine fibroids (myomas) using laparoscopic radiofrequency volumetric thermal ablation (RFVTA). Methods: We performed a retrospective, multicenter clinical analysis of 206 consecutive cases of ultrasound-guided laparoscopic RFVTA of symptomatic myomas conducted on an outpatient basis under two phase II studies at 2 sites (n = 69) and one phase III study at 11 sites (n = 137). Descriptive and exploratory, general trend, and matched-pair analyses were applied. Results: From baseline to 12 months in the phase II study, the mean transformed symptom severity scores improved from 53.9 to 8.8 (P < .001) (n = 57), health-related quality-of-life scores improved from 48.5 to 92.0 (P < .001) (n = 57), and mean uterine volume decreased from 204.4 cm3 to 151.4 cm3 (P = .008) (n = 58). Patients missed a median of 4 days of work (range, 2–10 days). The rate of possible device-related adverse events was 1.4% (1 of 69). In the phase III study, approximately 98% of patients were assessed at 12 months, and their transformed symptom severity scores, health-related quality-of-life scores, mean decrease in uterine volume, and mean menstrual bleeding reduction were also significant. Patients in phase III missed a median of 5 days of work (range, 1–29 days). The rate of periprocedural device-related adverse events was 3.5% (5 of 137). Despite the enrollment requirement for patients in both phases to have completed childbearing, 4 pregnancies occurred within the first year after treatment. Conclusions: RFVTA does not require any uterine incisions and provides a uterine-sparing procedure with rapid recovery, significant reduction in uterine size, significant reduction or elimination of myoma symptoms, and significant improvement in quality of life. PMID:24960480

  11. 75 FR 14575 - Voting Equipment Evaluations Phase III

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-26

    ... National Institute of Standards and Technology Voting Equipment Evaluations Phase III AGENCY: National... Phase III of the benchmark research for voting equipment used in an election in 2008 or later and/ or... Institute of Standards and Technology (NIST) will be conducting Phase III research on voting equipment...

  12. Advanced Emissions Control Development Program: Phase III

    SciTech Connect

    G.T. Amrhein; R.T. Bailey; W. Downs; M.J. Holmes; G.A. Kudlac; D.A. Madden

    1999-07-01

    The primary objective of the Advanced Emissions Control Development Program (AECDP) is to develop practical, cost-effective strategies for reducing the emissions of air toxics from coal-fired boilers. The project goal is to effectively control air toxic emissions through the use of conventional flue gas clean-up equipment such as electrostatic precipitators (ESPs), fabric filters (baghouses - BH), and wet flue gas desulfurization systems (WFGD). Development work concentrated on the capture of trace metals, fine particulate, hydrogen chloride and hydrogen fluoride, with an emphasis on the control of mercury. The AECDP project is jointly funded by the US Department of Energy's Federal Energy Technology Center (DOE), the Ohio Coal Development Office within the Ohio Department of Development (OCDO), and Babcock and Wilcox, a McDermott company (B and W). This report discusses results of all three phases of the AECDP project with an emphasis on Phase III activities. Following the construction and evaluation of a representative air toxics test facility in Phase I, Phase II focused on characterization of the emissions of mercury and other air toxics and the control of these emissions for typical operating conditions of conventional flue gas clean-up equipment. Some general comments that can be made about the control of air toxics while burning a high-sulfur bituminous coal are as follows: (1) particulate control devices such as ESP's and baghouses do a good job of removing non-volatile trace metals, (2) particulate control devices (ESPs and baghouses) effectively remove the particulate-phase mercury, but the particulate-phase mercury was only a small fraction of the total for the coals tested, (3) wet scrubbing can effectively remove hydrogen chloride and hydrogen fluoride, and (4) wet scrubbers show good potential for the removal of mercury when operated under certain conditions, however, for certain applications, system enhancements can be required to achieve high

  13. Benchmark On Sensitivity Calculation (Phase III)

    SciTech Connect

    Ivanova, Tatiana; Laville, Cedric; Dyrda, James; Mennerdahl, Dennis; Golovko, Yury; Raskach, Kirill; Tsiboulia, Anatoly; Lee, Gil Soo; Woo, Sweng-Woong; Bidaud, Adrien; Patel, Amrit; Bledsoe, Keith C; Rearden, Bradley T; Gulliford, J.

    2012-01-01

    The sensitivities of the keff eigenvalue to neutron cross sections have become commonly used in similarity studies and as part of the validation algorithm for criticality safety assessments. To test calculations of the sensitivity coefficients, a benchmark study (Phase III) has been established by the OECD-NEA/WPNCS/EG UACSA (Expert Group on Uncertainty Analysis for Criticality Safety Assessment). This paper presents some sensitivity results generated by the benchmark participants using various computational tools based upon different computational methods: SCALE/TSUNAMI-3D and -1D, MONK, APOLLO2-MORET 5, DRAGON-SUSD3D and MMKKENO. The study demonstrates the performance of the tools. It also illustrates how model simplifications impact the sensitivity results and demonstrates the importance of 'implicit' (self-shielding) sensitivities. This work has been a useful step towards verification of the existing and developed sensitivity analysis methods.

  14. [Principle and practice of clinical phase III studies].

    PubMed

    Morant, Rudolf

    2008-01-01

    Randomized phase III studies compare new treatments with standard therapy according to defined guidelines and legal rules. Large international randomized phase III studies are some of the most complex and expensive medical experiments. The results of such trials will decide about the future of new drugs and are the basis of evidence-based medicine and the development of clinical guidelines. This contribution discusses randomization, endpoints, inclusion and exclusion criteria of phase III trials as well as further challenges when developing and conducting phase III studies in oncology. Copyright 2008 S. Karger AG, Basel.

  15. CONVERSION EXTRACTION DESULFURIZATION (CED) PHASE III

    SciTech Connect

    James Boltz

    2005-03-01

    This project was undertaken to refine the Conversion Extraction Desulfurization (CED) technology to efficiently and economically remove sulfur from diesel fuel to levels below 15-ppm. CED is considered a generic term covering all desulfurization processes that involve oxidation and extraction. The CED process first extracts a fraction of the sulfur from the diesel, then selectively oxidizes the remaining sulfur compounds, and finally extracts these oxidized materials. The Department of Energy (DOE) awarded Petro Star Inc. a contract to fund Phase III of the CED process development. Phase III consisted of testing a continuous-flow process, optimization of the process steps, design of a pilot plant, and completion of a market study for licensing the process. Petro Star and the Degussa Corporation in coordination with Koch Modular Process Systems (KMPS) tested six key process steps in a 7.6-centimeter (cm) (3.0-inch) inside diameter (ID) column at gas oil feed rates of 7.8 to 93.3 liters per hour (l/h) (2.1 to 24.6 gallons per hour). The team verified the technical feasibility with respect to hydraulics for each unit operation tested and successfully demonstrated pre-extraction and solvent recovery distillation. Test operations conducted at KMPS demonstrated that the oxidation reaction converted a maximum of 97% of the thiophenes. The CED Process Development Team demonstrated that CED technology is capable of reducing the sulfur content of light atmospheric gas oil from 5,000-ppm to less than 15-ppm within the laboratory scale. In continuous flow trials, the CED process consistently produced fuel with approximately 20-ppm of sulfur. The process economics study calculated an estimated process cost of $5.70 per product barrel. The Kline Company performed a marketing study to evaluate the possibility of licensing the CED technology. Kline concluded that only 13 refineries harbored opportunity for the CED process. The Kline study and the research team's discussions with

  16. 76 FR 33589 - Standards Improvement Project-Phase III

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-08

    ...Phase III of the Standards Improvement Project (SIP-III) is the third in a series of rulemaking actions to improve and streamline OSHA standards. The Standards Improvement Project removes or revises individual requirements within rules that are confusing, outdated, duplicative, or inconsistent. OSHA identified several requirements for SIP-III (e.g., rigging, NIOSH records, and training......

  17. Separation studies of As(III), Sb(III) and Bi(III) by reversed-phase paper chromatographic technique

    SciTech Connect

    Raman, B.; Shinde, V.M.

    1987-07-01

    Reversed-phase paper chromatographic separations of As(III), Sb(III) and Bi(III) have been carried out on Whatman No 1 filter paper impregnated with triphenylphosphine oxide as stationary phase and using organic complexing agents such as sodium acetate, sodium succinate and sodium malonate solutions as active mobile phases. Results for the separation of binary and ternary mixtures are reported and the method has been successfully applied to the separation and detection of these elements present in real samples and at ppm level concentration.

  18. Phase III: Where Do We Go From Here?

    ERIC Educational Resources Information Center

    Sutton, James H.

    Iowa has implemented educational reform by providing state financing without state mandates. This paper describes the achievements of Iowa's decentralized educational reform effort. Phase I of the reform effort provided salary relief to the beginning teacher, Phase II provided salary relief for the experienced teacher, and Phase III linked future…

  19. Sample exchange/evaluation (SEE) report - Phase III

    SciTech Connect

    Winters, W.I.

    1996-01-01

    This report describes the results from Phase III of the Sample Exchange Evaluation (SEE) program. The SEE program is used to compare analytical laboratory performance on samples from the Hanford Site`s high level waste tanks.

  20. PLCO Ovarian Phase III Validation Study — EDRN Public Portal

    Cancer.gov

    Our preliminary data indicate that the performance of CA 125 as a screening test for ovarian cancer can be improved upon by additional biomarkers. With completion of one additional validation step, we will be ready to test the performance of a consensus marker panel in a phase III validation study. Given the original aims of the PLCO trial, we believe that the PLCO represents an ideal longitudinal cohort offering specimens for phase III validation of ovarian cancer biomarkers.

  1. Oxford phase III meniscal bearing fracture: case report.

    PubMed

    Lim, Hong-Chul; Shon, Won-Yong; Kim, Seung-Ju; Bae, Ji-Hoon

    2014-01-01

    Meniscal bearing fracture is a rare complication of phase III Oxford unicompartmental knee replacement (UKR). We report a case of a meniscal bearing fracture that occurred 7 years after phase III Oxford medial UKR. The meniscal bearing showed uneven delamination of the polyethylene in the thinnest articular surface and an impingement lesion. This lesion initiated a fatigue crack that propagated to cause failure of the meniscal bearing. This is the first report of a meniscal bearing fracture without a posterior marker wire.

  2. Central State University: Phase III Report

    ERIC Educational Resources Information Center

    Ohio Board of Regents, 2013

    2013-01-01

    This document is the final report on Central State University's implementation of Section 371 of Ohio Amended Substitute House Bill 153. Implementation of Phase I action items required that deliverables and timelines be shifted to give Central State the best opportunity for early success. In Phase II, Central State responded aggressively to a…

  3. Using phase II data for the analysis of phase III studies: An application in rare diseases.

    PubMed

    Wandel, Simon; Neuenschwander, Beat; Röver, Christian; Friede, Tim

    2017-06-01

    Clinical research and drug development in orphan diseases are challenging, since large-scale randomized studies are difficult to conduct. Formally synthesizing the evidence is therefore of great value, yet this is rarely done in the drug-approval process. Phase III designs that make better use of phase II data can facilitate drug development in orphan diseases. A Bayesian meta-analytic approach is used to inform the phase III study with phase II data. It is particularly attractive, since uncertainty of between-trial heterogeneity can be dealt with probabilistically, which is critical if the number of studies is small. Furthermore, it allows quantifying and discounting the phase II data through the predictive distribution relevant for phase III. A phase III design is proposed which uses the phase II data and considers approval based on a phase III interim analysis. The design is illustrated with a non-inferiority case study from a Food and Drug Administration approval in herpetic keratitis (an orphan disease). Design operating characteristics are compared to those of a traditional design, which ignores the phase II data. An analysis of the phase II data reveals good but insufficient evidence for non-inferiority, highlighting the need for a phase III study. For the phase III study supported by phase II data, the interim analysis is based on half of the patients. For this design, the meta-analytic interim results are conclusive and would justify approval. In contrast, based on the phase III data only, interim results are inconclusive and require further evidence. To accelerate drug development for orphan diseases, innovative study designs and appropriate methodology are needed. Taking advantage of randomized phase II data when analyzing phase III studies looks promising because the evidence from phase II supports informed decision-making. The implementation of the Bayesian design is straightforward with public software such as R.

  4. Sample size planning for phase II trials based on success probabilities for phase III.

    PubMed

    Götte, Heiko; Schüler, Armin; Kirchner, Marietta; Kieser, Meinhard

    2015-01-01

    In recent years, high failure rates in phase III trials were observed. One of the main reasons is overoptimistic assumptions for the planning of phase III resulting from limited phase II information and/or unawareness of realistic success probabilities. We present an approach for planning a phase II trial in a time-to-event setting that considers the whole phase II/III clinical development programme. We derive stopping boundaries after phase II that minimise the number of events under side conditions for the conditional probabilities of correct go/no-go decision after phase II as well as the conditional success probabilities for phase III. In addition, we give general recommendations for the choice of phase II sample size. Our simulations show that unconditional probabilities of go/no-go decision as well as the unconditional success probabilities for phase III are influenced by the number of events observed in phase II. However, choosing more than 150 events in phase II seems not necessary as the impact on these probabilities then becomes quite small. We recommend considering aspects like the number of compounds in phase II and the resources available when determining the sample size. The lower the number of compounds and the lower the resources are for phase III, the higher the investment for phase II should be.

  5. A Novel Bayesian Seamless Phase I/II Design

    PubMed Central

    Wang, Zuoren; Wang, Ling; Li, Chanjuan; Xia, Jielai

    2013-01-01

    This paper proposes a novel bayesian phase I/II design featuring using a hybrid mTPI method in phase I for targeting the MTD level and a randomization allocation schema for adaptively assigning patients to desirable doses in phase II. The mechanism of simultaneously escalating dose in phase I and expanding promising doses to phase II is inherited from a design proposed in literature. Extensive simulation studies indicate that our proposed design can vastly save sample size and efficiently assign more patients to optimal dose when compared to two competing designs. PMID:24023809

  6. Two-phase titration of cerium(III) by permanganate

    SciTech Connect

    Lazarev, A.I.; Lazareva, V.I.; Gerko, V.V.

    1987-02-01

    This paper presents a method for the two-phase titrimetric determination of cerium(III) with permanganate which does not require an expenditure of sugar and preliminary removal of chlorides and nitrates. The interaction of cerium(III) with permanganate at room temperature was studied as a function of the pH, the concentration of pyrophosphate, tetraphenylphosphonium (TPP), permanganate, and extraneous compounds, the rate of titration, and the time of stay of the solution in air before titration. The investigations were conducted according to the following methodology: water, solution of cerium(III) pyrophosphate, and TPP were introduced into an Erlenmeyer flask with a side branch near the bottom for clearer observation of the color of the chloroform phase. The authors established the given pH value, poured the water into a volume of 50 ml, and added chloroform. The result was titrated with permanganate solutions of various concentrations until a violet color appeared in the chloroform phase.

  7. High Voltage, Low Inductance Hydrogen Thyratron Study Program, Phase III.

    DTIC Science & Technology

    1981-12-01

    results and supporting information that bear on the progress of the Program as a whole. The Government’s Contract Monitor for Phase III was Mr. William ...ST ATTN: DRDEL-LL; -SB; -AP (IN TURN) I DRSEL-MA-MP 2800 Powder Mill Road 2 DRSEL-PA Adelphi, MD 20783 001 CINDAS 001 Cdr, ERADCOM Purdue Industrial

  8. Controversial HIV vaccine enters phase III trials amid skepticism.

    PubMed

    1998-12-01

    Clinics have begun enrolling volunteers in the first phase III trial of an HIV vaccine. Developing the vaccine has been a goal for nearly two decades, but leading scientists are skeptical about the effectiveness of a vaccine which does not use live viruses. More than 34 different candidate vaccines have been tested in phase I, and three are in phase II. The vaccine, AIDSVAX, is designed to train the immune system to protect itself against infection by creating antibodies. The scientific and political issues associated with the vaccine are presented.

  9. Phase transitions in i-butylammonium halogenoantimonate(III) and bismuthate(III) crystals

    NASA Astrophysics Data System (ADS)

    Jakubas, R.; Jóźków, J.; Bator, G.; Zaleski, J.; Baran, J.; François, P.

    1997-12-01

    Differential scanning calorimetry, dielectric, thermal expansion, infrared and preliminary X-ray diffraction studies on i-butylammonium halogenoantimonate(III) and bismuthate(III) crystals are reported. All crystals: (i-C 4H 9NH 3) 2BiCl 5, (i-C 4H 9NH 3) 2SbBr 5, (i-C 4H 9NH 3) 3BiCl 6, (i-C 4H 9NH 3) 3Bi 2Br 9, (i-C 4H 9NH 3) 3Sb 2Br 9, show one or more structural phase transitions of first order type. The values of the transition entropies suggest that the most of the phase transitions are of the order-disorder type. The infrared studies confirmed the contribution of the i-butylammonium cations in the phase transition mechanism.

  10. CHAOS III: Gas-phase Abundances in NGC 5457

    NASA Astrophysics Data System (ADS)

    Croxall, Kevin V.; Pogge, Richard W.; Berg, Danielle A.; Skillman, Evan D.; Moustakas, John

    2016-10-01

    We present Large Binocular Telescope observations of 109 H ii regions in NGC 5457 (M101) obtained with the Multi-Object Double Spectrograph. We have robust measurements of one or more temperature-sensitive auroral emission lines for 74 H ii regions, permitting the measurement of “direct” gas-phase abundances. Comparing the temperatures derived from the different ionic species, we find: (1) strong correlations of T[N ii] with T[S iii] and T[O iii], consistent with little or no intrinsic scatter; (2) a correlation of T[S iii] with T[O iii], but with significant intrinsic dispersion; (3) overall agreement between T[N ii], T[S ii], and T[O ii], as expected, but with significant outliers; (4) the correlations of T[N ii] with T[S iii] and T[O iii] match the predictions of photoionization modeling while the correlation of T[S iii] with T[O iii] is offset from the prediction of photoionization modeling. Based on these observations, which include significantly more observations of lower excitation H ii regions, missing in many analyses, we inspect the commonly used ionization correction factors (ICFs) for unobserved ionic species and propose new empirical ICFs for S and Ar. We have discovered an unexpected population of H ii regions with a significant offset to low values in Ne/O, which defies explanation. We derive radial gradients in O/H and N/O which agree with previous studies. Our large observational database allows us to examine the dispersion in abundances, and we find intrinsic dispersions of 0.074 ± 0.009 in O/H and 0.095 ± 0.009 in N/O (at a given radius). We stress that this measurement of the intrinsic dispersion comes exclusively from direct abundance measurements of H ii regions in NGC 5457.

  11. 77 FR 40936 - 60-Day Notice of Proposed Information Collection: Passport Demand Forecasting Study Phase III

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-11

    ...: Passport Demand Forecasting Study Phase III. OMB Control Number: None. Type of Request: Reinstatement of a... Notice of Proposed Information Collection: Passport Demand Forecasting Study Phase III ACTION: Notice of.... The data gathered from the Passport Demand Forecasting Study Phase III will be used to monitor, assess...

  12. Computational Analysis of the SRS Phase III Salt Disposition Alternatives

    SciTech Connect

    Dimenna, R.A.

    1999-10-07

    Completion of the Phase III evaluation and comparison of salt disposition alternatives was supported with enhanced computer models and analysis for each case on the ''short list'' of four options. SPEEDUP(TM) models and special purpose models describing mass and energy balances and flow rates were developed and used to predict performance and production characteristics for each of the options. Results from the computational analysis were a key part of the input used to select a primary and an alternate salt disposition alternative.

  13. High pressure phase transition in group III nitrides compounds

    NASA Astrophysics Data System (ADS)

    Soni, Shubhangi; Verma, S.; Kaurav, Netram; Choudhary, K. K.

    2016-05-01

    Using an effective interionic interaction potential (EIOP), the pressure induced structural phase transformation from ZnS-type (B3) to NaCl-type (B1) structure in group III Post-Transition Metal Nitrides [TMN; TM=Ga and Tl] were investigated. The long range Coulomb, van der Waals (vdW) interaction and the short-range repulsive interaction upto second-neighbor ions within the Hafemeister and Flygare approach with modified ionic charge are properly incorporated in the EIOP. The vdW coefficients are computed following the Slater-Kirkwood variational method, as both the ions are polarizable. The estimated value of the phase transition pressure (Pt) and the magnitude of the discontinuity in volume at the transition pressure are consistent as compared to the reported data.

  14. Probability of success for phase III after exploratory biomarker analysis in phase II.

    PubMed

    Götte, Heiko; Kirchner, Marietta; Sailer, Martin Oliver

    2017-02-23

    The probability of success or average power describes the potential of a future trial by weighting the power with a probability distribution of the treatment effect. The treatment effect estimate from a previous trial can be used to define such a distribution. During the development of targeted therapies, it is common practice to look for predictive biomarkers. The consequence is that the trial population for phase III is often selected on the basis of the most extreme result from phase II biomarker subgroup analyses. In such a case, there is a tendency to overestimate the treatment effect. We investigate whether the overestimation of the treatment effect estimate from phase II is transformed into a positive bias for the probability of success for phase III. We simulate a phase II/III development program for targeted therapies. This simulation allows to investigate selection probabilities and allows to compare the estimated with the true probability of success. We consider the estimated probability of success with and without subgroup selection. Depending on the true treatment effects, there is a negative bias without selection because of the weighting by the phase II distribution. In comparison, selection increases the estimated probability of success. Thus, selection does not lead to a bias in probability of success if underestimation due to the phase II distribution and overestimation due to selection cancel each other out. We recommend to perform similar simulations in practice to get the necessary information about the risk and chances associated with such subgroup selection designs.

  15. Water ice phases II, III, and V - Plastic deformation and phase relationships

    NASA Technical Reports Server (NTRS)

    Durham, W. B.; Boro, C. O.; Kirby, S. H.; Stern, L. A.; Heard, H. C.

    1988-01-01

    The ordinary water phase I was transformed to the ice phases that are known to exist in the interiors of large ice moons, such as Ganymede and Callisto for the purpose of investigating plastic deformation behavior of these ices. Ices II, III, and V were prepared using an apparatus and techniques similar to those described by Durham et al. (1983) and subsequently deformed in a gas deformation apparatus, and their deformation data were obtained. It was found that ice II was the strongest of the high-pressure phases, with a strength that was comparable to that of ice I; ice III was very weak, with the flow rate 100 to 1000 times higher than that of ice II at the same levels of stress. It was also found that ices III and V can exist metastably within the ice II field and that they may be deformed plastically within much of the metastable region without reverting to ice II. It is suggested that the weakness of the ice III phase may have profoundly influenced the evolution and the present-day behavior of the icy moons.

  16. Water ice phases II, III, and V - Plastic deformation and phase relationships

    NASA Technical Reports Server (NTRS)

    Durham, W. B.; Boro, C. O.; Kirby, S. H.; Stern, L. A.; Heard, H. C.

    1988-01-01

    The ordinary water phase I was transformed to the ice phases that are known to exist in the interiors of large ice moons, such as Ganymede and Callisto for the purpose of investigating plastic deformation behavior of these ices. Ices II, III, and V were prepared using an apparatus and techniques similar to those described by Durham et al. (1983) and subsequently deformed in a gas deformation apparatus, and their deformation data were obtained. It was found that ice II was the strongest of the high-pressure phases, with a strength that was comparable to that of ice I; ice III was very weak, with the flow rate 100 to 1000 times higher than that of ice II at the same levels of stress. It was also found that ices III and V can exist metastably within the ice II field and that they may be deformed plastically within much of the metastable region without reverting to ice II. It is suggested that the weakness of the ice III phase may have profoundly influenced the evolution and the present-day behavior of the icy moons.

  17. Reactor physics studies in the GCFR Phase III critical assembly

    SciTech Connect

    Morman, J A

    1980-03-01

    The third phase of the gas cooled fast reactor (GCFR) program, ZPR-9 Assembly 30, is based on a multi-zoned core of PuO/sub 2/-UO/sub 2/ with radial and axial blankets of UO/sub 2/. Studies performed in this assembly will be compared to the previous phases of the GCFR program and will help to define parameters in this power-flattened demonstration plant-type core. Measurements in the Phase III program included small sample reactivity worths of various materials, central reaction rates and reaction rate distributions, absorption-to-fission ratios and the central point conversion ratio and the worth of steam entry into a small central zone. The reactivity change associated with the construction of a central pin zone in the core and axial blanket was measured. Reaction rate and steam entry measurements were repeated in the pin environment. Standard analysis methods using ENDF/B-IV data are described and the results are compared to measurements performed during the program.

  18. Los Angeles International Airport Runway Incursion Studies: Phase III--Center-Taxiway Simulation

    NASA Technical Reports Server (NTRS)

    Madson, Michael D.

    2004-01-01

    Phase III of the Los Angeles International Airport Runway Incursion Studies was conducted, under an agreement with HNTB Corporation, at the NASA Ames FutureFlight Central (FFC) facility in June 2003. The objective of the study was the evaluation of a new center-taxiway concept at LAX. This study is an extension of the Phase I and Phase II studies previously conducted at FFC. This report presents results from Phase III of the study, in which a center-taxiway concept between runways 25L and 25R was simulated and evaluated. Phase III data were compared objectively against the Baseline data. Subjective evaluations by participating LAX controllers were obtained with regard to workload, efficiency, and safety criteria. To facilitate a valid comparison between Baseline and Phase III data, the same scenarios were used for Phase III that were tested during Phases I and II. This required briefing participating controllers on differences in airport and airline operations between 2001 and today.

  19. Alloy Phase Diagrams for III-P Semiconductor Crystal Growth

    NASA Astrophysics Data System (ADS)

    Gennett, Adam

    Bulk crystals of III-V ternary and quaternary semiconductors with tunable band gaps and lattice constants are attractive for numerous electronic and optoelectronic applications. In particular, the ternary GaxIn 1-xP has a band gap range of 1.351 - 2.261 eV, which corresponds to wavelengths in the near infrared to green range of the electromagnetic spectrum, and lattice constant ranging of 5.4512 - 5.8688 A. This makes it attractive for applications such as a high energy junction in multi-junction photovoltaics, terahetrtz emission, and as a substrate for yellow, amber, orange, and red AlGaInP LEDs. However, bulk growth of GaxIn1-xP ternary III-V semiconductor crystals using elemental Ga-In-P melts or pseudo-binary GaP-InP melts is significantly challenging due to the high vapor pressure of phosphorus at the typical growth temperatures, the large variation in the lattice constant of the constituent binaries, and the slow growth rates necessary in order to avoid the formation of cracks, dislocations, and multiphase inhomogeneities. Lowering the growth temperature is desirable such that the vapor pressure of phosphorus can be more easily managed. Low growth temperatures can be achieved by using gallium or indium rich solutions, as is currently used for liquid phase epitaxy. However, this approach is less attractive for growing bulk crystals due to numerous experimental difficulties such as high segregation of gallium in indium as well as sticking of the growth solution to the crucible wall and to the grown crystal, making crystal extraction without causing damage challenging. The objective of this research is to establish the conditions required for the growth of uniform composition bulk crystals of GaxIn 1-xP at any desired composition from a stoichiometric GaxIn 1-xPySb1-y quaternary melt, as well as conditions for compositional grading from a binary III-V material seed. Due to large number of conditions of melt composition and temperature that are possible, trial

  20. Final report : Phase III targeted investigation, Everest, Kansas.

    SciTech Connect

    LaFreniere, L. M.; Environmental Science Division

    2006-01-31

    The Commodity Credit Corporation (CCC), an agency of the U.S. Department of Agriculture (USDA), formerly operated grain storage facilities at two different locations at Everest, Kansas (Figure 1.1). One facility (referred to in this report as the Everest facility) was at the western edge of the city. The second facility (referred to in this report as Everest East) was about 0.5 mi northeast of the town. The CCC/USDA operated these facilities from the early 1950s until the early 1970s, at a time when commercial fumigants containing carbon tetrachloride were in common use by the CCC/USDA and private industry for the preservation of grain in storage. In 1997 the Kansas Department of Health and Environment (KDHE) sampled several domestic drinking water and non-drinking water wells in the Everest area as part of the CCC/USDA Private Well Sampling Program. All of the sampled wells were outside the Everest city limits. Carbon tetrachloride contamination was identified at a single domestic drinking water well (the Nigh well, DW06; Figure 1.1) approximately 3/8 mi northwest of the former Everest CCC/USDA grain storage facility. Subsequent KDHE investigations suggested that the contamination in DW06 could be linked to the former use of grain fumigants at the CCC/USDA facility. For this reason, the CCC/USDA is conducting a phased environmental study to determine the source and extent of the carbon tetrachloride contamination at Everest and to identify potential remedial options. The studies are being performed by the Environmental Research Division of Argonne National Laboratory. Two phases of investigation were completed previously; this report presents the findings of the targeted Phase III investigation at Everest.

  1. Evaluate fundamental approaches to longwall dust control. Phase III report

    SciTech Connect

    Babbitt, C.; Bartlett, P.; Kelly, J.; Ludlow, J.; Mangolds, A.; Rajan, S.; Ruggieri, S.; Varga, E.

    1984-03-31

    The overall objective of the contract is to evaluate the effectiveness of available dust control technology for double-drum shearer longwall sections in a coordinated, systematic program at a few longwall test sections and to make the results available to the entire coal mining industry. This program is investigating nine different dust control techniques. These nine subprograms encompass a broad range of dust control measures ranging from administrative controls to new hardware. They span not only presently employed methods but also those recently adopted in the United States and those proposed for the future. This report documents the Phase III effort on each of the subprograms. For clarity, the report is divided in sections by subprogram as follows: Section 2, Subprogram A - passive barriers/spray air movers for dust control; Section 3, Subprogram B - practical aspects of deep cutting; Section 4, Subprogram C - stage loader dust control; Section 5, Subprogram D - longwall automation technology; Section 6, Subprogram E - longwall application of ventilation curtains; Section 7, Subprogram F - reversed drum rotation; Section 8, Subprogram G - reduction of shield generated dust; Section 9, Subprogram H - air canopies for longwalls; and Section 10, Subprogram I - mining practices. 43 figures, 11 tables.

  2. Thermodynamic considerations of the vapor phase reactions in III-nitride metal organic vapor phase epitaxy

    NASA Astrophysics Data System (ADS)

    Sekiguchi, Kazuki; Shirakawa, Hiroki; Chokawa, Kenta; Araidai, Masaaki; Kangawa, Yoshihiro; Kakimoto, Koichi; Shiraishi, Kenji

    2017-04-01

    We analyzed the metal organic vapor phase epitaxial growth mechanism of the III-nitride semiconductors GaN, AlN, and InN by first-principles calculations and thermodynamic analyses. In these analyses, we investigated the decomposition processes of the group III source gases X(CH3)3 (X = Ga, Al, In) at finite temperatures and determined whether the (CH3)2GaNH2 adduct can be formed or not. The results of our calculations show that the (CH3)2GaNH2 adduct cannot be formed in the gas phase in GaN metal organic vapor phase epitaxy (MOVPE), whereas, in AlN MOVPE, the formation of the (CH3)2AlNH2 adduct in the gas phase is exclusive. In the case of GaN MOVPE, trimethylgallium (TMG, [Ga(CH3)3]) decomposition into Ga gas on the growth surface with the assistance of H2 carrier gas, instead of the formation of the (CH3)2GaNH2 adduct, occurs almost exclusively. Moreover, in the case of InN MOVPE, the formation of the (CH3)2InNH2 adduct does not occur and it is relatively easy to produce In gas even without H2 in the carrier gas.

  3. A new approach to designing phase I-II cancer trials for cytotoxic chemotherapies.

    PubMed

    Bartroff, Jay; Lai, Tze Leung; Narasimhan, Balasubramanian

    2014-07-20

    Recently, there has been much work on early phase cancer designs that incorporate both toxicity and efficacy data, called phase I-II designs because they combine elements of both phases. However, they do not explicitly address the phase II hypothesis test of H0 : p ≤ p0 , where p is the probability of efficacy at the estimated maximum tolerated dose η from phase I and p0 is the baseline efficacy rate. Standard practice for phase II remains to treat p as a fixed, unknown parameter and to use Simon's two-stage design with all patients dosed at η. We propose a phase I-II design that addresses the uncertainty in the estimate p=p(η) in H0 by using sequential generalized likelihood theory. Combining this with a phase I design that incorporates efficacy data, the phase I-II design provides a common framework that can be used all the way from the first dose of phase I through the final accept/reject decision about H0 at the end of phase II, utilizing both toxicity and efficacy data throughout. Efficient group sequential testing is used in phase II that allows for early stopping to show treatment effect or futility. The proposed phase I-II design thus removes the artificial barrier between phase I and phase II and fulfills the objectives of searching for the maximum tolerated dose and testing if the treatment has an acceptable response rate to enter into a phase III trial.

  4. EXPERIMENTAL RESULTS OF THE NEPHELINE PHASE III STUDY

    SciTech Connect

    Fox, K.; Edwards, T.

    2009-11-09

    This study is the third phase in a series of experiments designed to reduce conservatism in the model that predicts the formation of nepheline, a crystalline phase that can reduce the durability of high level waste glass. A Phase I study developed a series of glass compositions that were very durable while their nepheline discriminator values were well below the current nepheline discriminator limit of 0.62, where nepheline is predicted to crystallize upon slow cooling. A Phase II study selected glass compositions to identify any linear effects of composition on nepheline crystallization and that were restricted to regions that fell within the validation ranges of the Defense Waste Processing Facility (DWPF) Product Composition Control System (PCCS) models. However, it was not possible to identify any linear effects of composition on chemical durability performance for this set of study glasses. The results of the Phase II study alone were not sufficient to recommend modification of the current nepheline discriminator. It was recommended that the next series of experiments continue to focus not only on compositional regions where the PCCS models are considered applicable (i.e., the model validation ranges), but also be restricted to compositional regions where the only constraint limiting processing is the current nepheline discriminator. Two methods were used in selecting glasses for this Phase III nepheline study. The first was based on the relationship of the current nepheline discriminator model to the other DWPF PCCS models, and the second was based on theory of crystallization in mineral and glass melts. A series of 29 test glass compositions was selected for this study using a combination of the two approaches. The glasses were fabricated and characterized in the laboratory. After reviewing the data, the study glasses generally met the target compositions with little issue. Product Consistency Test results correlated well with the crystallization analyses in

  5. Dynamic observation of phase transformation behaviors in indium(III) selenide nanowire based phase change memory.

    PubMed

    Huang, Yu-Ting; Huang, Chun-Wei; Chen, Jui-Yuan; Ting, Yi-Hsin; Lu, Kuo-Chang; Chueh, Yu-Lun; Wu, Wen-Wei

    2014-09-23

    Phase change random access memory (PCRAM) has been extensively investigated for its potential applications in next-generation nonvolatile memory. In this study, indium(III) selenide (In2Se3) was selected due to its high resistivity ratio and lower programming current. Au/In2Se3-nanowire/Au phase change memory devices were fabricated and measured systematically in an in situ transmission electron microscope to perform a RESET/SET process under pulsed and dc voltage swept mode, respectively. During the switching, we observed the dynamic evolution of the phase transformation process. The switching behavior resulted from crystalline/amorphous change and revealed that a long pulse width would induce the amorphous or polycrystalline state by different pulse amplitudes, supporting the improvement of the writing speed, retention, and endurance of PCRAM.

  6. 76 FR 33398 - 60-Day Notice of Proposed Information Collection; Passport Demand Forecasting Study Phase III...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-08

    ... Collection: Passport Demand Forecasting Study Phase III. OMB Control Number: OMB No. 1405-0177. Type of... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF STATE 60-Day Notice of Proposed Information Collection; Passport Demand Forecasting Study Phase III, 1405-0177 ACTION...

  7. 76 FR 53704 - 30-Day Notice of Proposed Information Collection: Passport Demand Forecasting Study Phase III...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-29

    ... Notice of Proposed Information Collection: Passport Demand Forecasting Study Phase III, OMB Number 1405... of 1995. Title of Information Collection: Passport Demand Forecasting Study Phase III. OMB Control Number: OMB Number 1405-0177. Type of Request: Revision of a Currently Approved Collection. Originating...

  8. CIM5 Phase III base process development results

    SciTech Connect

    Witt, D.C.

    2000-01-06

    Integrated Demonstration Runs for the Am/Cm vitrification process were initiated in the Coupled 5-inch Cylindrical Induction Melter (CIM5) on 11/30/98 and completed on 12/9/98. Four successful runs at 60 wt% lanthanide loading were completed which met or exceeded all established criteria. The operating parameters used in these runs established the base conditions for the 5-inch Cylindrical Induction Melter (CIM5) process and were summarized in the 5-inch CIM design basis, SRT-AMC-99-OO01. (1) In subsequent tests, a total of fourteen CIM5 runs were performed using various power inputs, ramp rates and target temperatures to define the preferred processing conditions (2) Process stability and process flexibility were the key criteria used in assessing the results for each run. A preferred set of operating parameters was defined for the CIM5 batch process and these conditions were used to generate a pre-programmed, automatic processing cycle that was used for the last six CIM.5 runs (3) These operational tests were successfully completed in the January-February time frame and were summarized in SRT-AMC-99-00584. The recommended set of operating conditions defined in Runs No.1 through No.14 was used as the starting point for further pilot system runs to determine the robustness of the process, evaluate a bubbler, and investigate off-normal conditions. CIM5 Phase III Runs No.15 through No.60 were conducted utilizing the pre-programmed, automatic processing cycle to investigate system performance. This report summarizes the results of these tests and provides a recommendation for the base process as well as a processing modification for minimizing volume expansions if americium and/or curium are subject to a thermal reduction reaction like cerium. This document summarizes the results of the base process development tests conducted in the Am/Cm Pilot Facility located in Building 672-T.

  9. Phase 0 and phase III transport in various organs: combined concept of phases in xenobiotic transport and metabolism.

    PubMed

    Döring, Barbara; Petzinger, Ernst

    2014-08-01

    The historical phasing concept of drug metabolism and elimination was introduced to comprise the two phases of metabolism: phase I metabolism for oxidations, reductions and hydrolyses, and phase II metabolism for synthesis. With this concept, biological membrane barriers obstructing the accessibility of metabolism sites in the cells for drugs were not considered. The concept of two phases was extended to a concept of four phases when drug transporters were detected that guided drugs and drug metabolites in and out of the cells. In particular, water soluble or charged drugs are virtually not able to overcome the phospholipid membrane barrier. Drug transporters belong to two main clusters of transporter families: the solute carrier (SLC) families and the ATP binding cassette (ABC) carriers. The ABC transporters comprise seven families with about 20 carriers involved in drug transport. All of them operate as pumps at the expense of ATP splitting. Embedded in the former phase concept, the term "phase III" was introduced by Ishikawa in 1992 for drug export by ABC efflux pumps. SLC comprise 52 families, from which many carriers are drug uptake transporters. Later on, this uptake process was referred to as the "phase 0 transport" of drugs. Transporters for xenobiotics in man and animal are most expressed in liver, but they are also present in extra-hepatic tissues such as in the kidney, the adrenal gland and lung. This review deals with the function of drug carriers in various organs and their impact on drug metabolism and elimination.

  10. The role of technology in reducing health care costs. Phase II and phase III.

    SciTech Connect

    Cilke, John F.; Parks, Raymond C.; Funkhouser, Donald Ray; Tebo, Michael A.; Murphy, Martin D.; Hightower, Marion Michael; Gallagher, Linda K.; Craft, Richard Layne, II; Garcia, Rudy John

    2004-04-01

    In Phase I of this project, reported in SAND97-1922, Sandia National Laboratories applied a systems approach to identifying innovative biomedical technologies with the potential to reduce U.S. health care delivery costs while maintaining care quality. The effort provided roadmaps for the development and integration of technology to meet perceived care delivery requirements and an economic analysis model for development of care pathway costs for two conditions: coronary artery disease (CAD) and benign prostatic hypertrophy (BPH). Phases II and III of this project, which are presented in this report, were directed at detailing the parameters of telemedicine that influence care delivery costs and quality. These results were used to identify and field test the communication, interoperability, and security capabilities needed for cost-effective, secure, and reliable health care via telemedicine.

  11. Interdigestive gastroduodenal manometry in humans. Indication of duodenal phase III as a retroperistaltic pump.

    PubMed

    Björnsson, E S; Abrahamsson, H

    1995-03-01

    To elucidate the specific function of the three phases (I-III) of the migrating motor complex (MMC) by manometry, detailed analysis of individual pressure waves in the proximal duodenum was performed. Twenty healthy subjects (10 men and 10 women of whom 11 were tube-naive) underwent computerized manometry for 5 h during fasting followed by 45 min after a meal using an 8-channel water perfused catheter. Three recording points were in the antrum, three in the proximal duodenum (2 cm apart), one in the distal duodenum and one in the proximal jejunum. In all subjects at least one phase III (median 2) was observed during the 5-h fasting recording. In the proximal duodenum the mean proportion of retrograde pressure waves, out of all propagating waves, was significantly increased in the last part of phase III (85 +/- 9%, mean, SE), compared with early phase III (6 +/- 5%), late phase II (5 +/- 4%) and the feeding phase (10 +/- 5%), irrespective of gender or previous tube-experience. The median length of the MMCs was 108.5 min. There was no statistically significant difference between men and women or between tube-naive and tube-experienced subjects for the duodeno-jejunal motility indices of phase II and phase III, nor for duration or migration of phase III. The postprandial motility index of the small intestine was increased compared with the interdigestive late phase II, particularly in the jejunum (P < 0.02). The last part of the duodenal interdigestive phase III in healthy subjects shows the feature of a retrosperistaltic pump. This cyclic sequence of retropropagation coincides with the reported rapid alkalinization of the duodenal bulb and the gastric antrum occurring in early antral phase I.

  12. Seeking the Profile of an Elementary Educator: Phase III.

    ERIC Educational Resources Information Center

    Arth, Alfred A.; And Others

    This paper presents the third phase of a student-faculty investigation seeking the profile of the elementary school teacher. Phase I discovered an indication of different personality traits in elementary and secondary teachers. Phase II redesigned the original questionnaire and supported the findings with additional research. This third phase…

  13. National Geoscience Data Repository System -- Phase III: Implementation and Operation of the Repository

    SciTech Connect

    Keane, Christopher M.

    2002-05-28

    The National Geoscience Data Repository System, Phase III was an operational project focused on coordinating and facilitating transfers of at-risk geoscience data from the private sector to the public domain.

  14. Phase III Simplified Integrated Test (SIT) results - Space Station ECLSS testing

    NASA Technical Reports Server (NTRS)

    Roberts, Barry C.; Carrasquillo, Robyn L.; Dubiel, Melissa Y.; Ogle, Kathryn Y.; Perry, Jay L.; Whitley, Ken M.

    1990-01-01

    During 1989, phase III testing of Space Station Freedom Environmental Control and Life Support Systems (ECLSS) began at Marshall Space Flight Center (MSFC) with the Simplified Integrated Test. This test, conducted at the MSFC Core Module Integration Facility (CMIF), was the first time the four baseline air revitalization subsystems were integrated together. This paper details the results and lessons learned from the phase III SIT. Future plans for testing at the MSFC CMIF are also discussed.

  15. Sham feeding disrupts phase III of the duodenal migrating motor complex in humans.

    PubMed

    Pouderoux, P; Veyrac, M; Michel, H

    1995-09-01

    The role of the vagus nerve in the control of the intestinal migrating motor complex (MMC) is unclear. This study aimed to evaluate the effect of physiological vagal stimulation with sham feeding on phase III of the MMC. Antroduodenal motility was recorded in six healthy volunteers. The first phase III was used as a control, and sham feeding was performed during the second phase III. The MMC was disrupted within 1.5 +/- 0.4 min of sham feeding and its duration was shorter than the control phase III. Phase III propagation was inhibited in all subjects, most of them exhibiting no propagation beyond the third duodenal recording site. During sham feeding, the antrum exhibited transient phasic contractions in five out of six subjects. The duodenal motility index recorded for up to 30 min after the onset of the sham feeding was unchanged in five out of six subjects. We conclude that sham feeding consistently interrupted phase III of the duodenal MMC and induced antral contractions, but failed to provoke significant motor events in the duodenum.

  16. Biomarker-Guided Adaptive Trial Designs in Phase II and Phase III: A Methodological Review

    PubMed Central

    Antoniou, Miranta; Jorgensen, Andrea L; Kolamunnage-Dona, Ruwanthi

    2016-01-01

    Background Personalized medicine is a growing area of research which aims to tailor the treatment given to a patient according to one or more personal characteristics. These characteristics can be demographic such as age or gender, or biological such as a genetic or other biomarker. Prior to utilizing a patient’s biomarker information in clinical practice, robust testing in terms of analytical validity, clinical validity and clinical utility is necessary. A number of clinical trial designs have been proposed for testing a biomarker’s clinical utility, including Phase II and Phase III clinical trials which aim to test the effectiveness of a biomarker-guided approach to treatment; these designs can be broadly classified into adaptive and non-adaptive. While adaptive designs allow planned modifications based on accumulating information during a trial, non-adaptive designs are typically simpler but less flexible. Methods and Findings We have undertaken a comprehensive review of biomarker-guided adaptive trial designs proposed in the past decade. We have identified eight distinct biomarker-guided adaptive designs and nine variations from 107 studies. Substantial variability has been observed in terms of how trial designs are described and particularly in the terminology used by different authors. We have graphically displayed the current biomarker-guided adaptive trial designs and summarised the characteristics of each design. Conclusions Our in-depth overview provides future researchers with clarity in definition, methodology and terminology for biomarker-guided adaptive trial designs. PMID:26910238

  17. Evaluation of DCS III Transmission Alternatives. Phase 1A Report.

    DTIC Science & Technology

    1980-05-26

    Waves . . . . ... . 3-13 3.4 EHF Satellite Communicatins ... 3-15 *3.5 Optical Fibers . . . . . . . . . . . . . . . . . . . . . . 3-17 3.5.1 Optical Fiber...Defense and Space Systems Group, TRW Inc. and by TRW’s subcontractor, Page Communications Engineers, Inc., Northrop Corporation . 1.1 Purpose of the DCS III...tactical and long haul communicatins systems study have been sponsored by the U.S. Army, and the U.S. Navy also is working on submarine fiber optics

  18. The coupling of thermochemistry and phase diagrams for group III-V semiconductor systems. Final report

    SciTech Connect

    Anderson, T.J.

    1998-07-21

    The project was directed at linking the thermochemical properties of III-V compound semiconductors systems with the reported phase diagrams. The solid-liquid phase equilibrium problem was formulated and three approaches to calculating the reduced standard state chemical potential were identified and values were calculated. In addition, thermochemical values for critical properties were measured using solid state electrochemical techniques. These values, along with the standard state chemical potentials and other available thermochemical and phase diagram data, were combined with a critical assessment of selected III-V systems. This work was culminated with a comprehensive assessment of all the III-V binary systems. A novel aspect of the experimental part of this project was the demonstration of the use of a liquid encapsulate to measure component activities by a solid state emf technique in liquid III-V systems that exhibit high vapor pressures at the measurement temperature.

  19. 75 FR 38645 - Standards Improvement Project-Phase III

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-02

    ...The Occupational Safety and Health Administration (OSHA) is continuing its efforts to remove or revise outdated, duplicative, unnecessary, and inconsistent requirements in its safety and health standards. This effort builds on the success of Standards Improvement Project (SIP)--Phase I published on June 18, 1998, and SIP--Phase II published on January 5, 2005. The Agency believes that the proposed revisions will reduce compliance costs, eliminate paperwork burdens, and clarify requirements without diminishing worker protections.

  20. Phases I–III Clinical Trials Using Adult Stem Cells

    PubMed Central

    Sanz-Ruiz, Ricardo; Gutiérrez Ibañes, Enrique; Arranz, Adolfo Villa; Fernández Santos, María Eugenia; Fernández, Pedro L. Sánchez; Fernández-Avilés, Francisco

    2010-01-01

    First randomized clinical trials have demonstrated that stem cell therapy can improve cardiac recovery after the acute phase of myocardial ischemia and in patients with chronic ischemic heart disease. Nevertheless, some trials have shown that conflicting results and uncertainties remain in the case of mechanisms of action and possible ways to improve clinical impact of stem cells in cardiac repair. In this paper we will examine the evidence available, analyze the main phase I and II randomized clinical trials and their limitations, discuss the key points in the design of future trials, and depict new directions of research in this fascinating field. PMID:21076533

  1. Attrition Prevention Through Counseling Among Community College Students; NORCAL Phase III.

    ERIC Educational Resources Information Center

    Dallas, Gladys E.

    Phase III, the development and testing of experimental programs to reduce the rate of student attrition, of the Northern California Cooperative Research Project (NORCAL) on Student Attrition is reported upon. Phase I of the program was the description and identification of characteristics associated with attrition among Junior College students…

  2. 40 CFR 300.310 - Phase III-Containment, countermeasures, cleanup, and disposal.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... SUBSTANCES POLLUTION CONTINGENCY PLAN Operational Response Phases for Oil Removal § 300.310 Phase III... environment. Actions may include but are not limited to: Analyzing water samples to determine the source and... or salvage operations; placement of physical barriers to deter the spread of the oil and to protect...

  3. Local Area Network Implementation: Moving toward Phase III.

    ERIC Educational Resources Information Center

    Hoehl, Susan B.

    1989-01-01

    Describes a LAN (local area network)-based automation project which has neared completion of the first phase of implementation at the Health Sciences Library of Allegheny General Hospital (Pittsburgh, PA). Changes in the library and its objectives with increased technological experience are examined. Diagrams of the current LAN configuration and…

  4. DPI Equity Leadership Project--Phase III. Final Report.

    ERIC Educational Resources Information Center

    Riley, Linda L.

    During its third phase in 1993-94, the Wisconsin Department of Public Instruction (DPI) Gender Equity Leadership Project provided technical assistance and staff development experiences to the Wisconsin Vocational Equity Leadership Cadre (WVELC). The technical assistance/staff development component prepared the cadre to assist local districts in…

  5. Results from the Sudbury Neutrino Observatory Phase III

    SciTech Connect

    SNO Collaboration; Prior, G.

    2008-11-03

    The third and last phase of the Sudbury Neutrino Observatory (SNO) used a technique independent of previous methods, to measure the rate of neutral-current interactions in heavy water and determine precisely the total active {sup 8}B solar neutrino flux. The total flux obtained is 5.54{sub -0.31}{sup +0.33}(stat){sub -0.34}{sup +0.36}(syst) x 10{sup 6} cm{sup -2}s{sup -1}, in agreement with previous measurements and standard solar models. Results from a global analysis of solar and reactor neutrino give {Delta}m{sup 2} = 7.59{sub -0.21}{sup +0.19} x 10{sup -5} eV{sup 2} and {theta} = 34.4{sub -1.2}{sup +1.3} degrees with a reduced uncertainty on the mixing angle compared to previous phases.

  6. Summary: USA contribution to Session III, Phase 1 INTOR workshop

    SciTech Connect

    Stacey, Jr, W M; Flanagan, C A; Kulcinski, G L; Schmidt, J A; Shannon, T E

    1980-06-01

    The basic INTOR characteristics that were arrived at by the Phase-0 INTOR Workshop are summarized. These characteristics provided a point of reference for the analysis of major design issues. No requirement to change any of the suggested parameters was identified as a result of this analysis. The major design issues that were analyzed are listed. The results of these analyses and conclusions drawn therefrom are summarized.

  7. Comprehensive Evaluation of the Geothermal Resource Potential within the Pyramid Lake Paiute Reservation Phase III Report

    SciTech Connect

    Noel, Donna

    2013-12-01

    This project integrated state-of-the-art exploration technologies with a geologic framework and reservoir modeling to ultimately determine the efficacy of future geothermal production within the PLPT reservation. The information gained during this study should help the PLPT to make informed decisions regarding construction of a geothermal power plant. Additional benefits included the transfer of new technologies and geothermal data to the geothermal industry and it created and/or preserved nearly three dozen jobs accordance with the American Recovery and Reinvestment Act of 2009. A variety of tasks were conducted to achieve the above stated objectives. The following are the tasks completed within the project: 1. Permitting 2. Shallow temperature survey 3. Seismic data collection and analysis 4. Fracture stress analysis 5. Phase I reporting Permitting 7. Shallow temperature survey 8. Seismic data collection and analysis 9. Fracture stress analysis 10. Phase I reporting 11. Drilling two new wells 12. Borehole geophysics 13. Phase II reporting 14. Well testing and geochemical analysis 15. Three-dimensional geologic model 16. Three-dimensional reservoir analysis 17. Reservation wide geothermal potential analysis 18. Phase III reporting Phase I consisted of tasks 1 – 5, Phase II tasks 6 – 8, and Phase III tasks 9 – 13. This report details the results of Phase III tasks. Reports are available for Phase I, and II as separate documents.

  8. Phase transitions in tumor growth: III vascular and metastasis behavior

    NASA Astrophysics Data System (ADS)

    Llanos-Pérez, J. A.; Betancourt-Mar, J. A.; Cocho, G.; Mansilla, R.; Nieto-Villar, José Manuel

    2016-11-01

    We propose a mechanism for avascular, vascular and metastasis tumor growth based on a chemical network model. Vascular growth and metastasis, appear as a hard phase transition type, as ;first order;, through a supercritical Andronov-Hopf bifurcation, emergence of limit cycle and then through a cascade of bifurcations type saddle-foci Shilnikov's bifurcation. Finally, the thermodynamics framework developed shows that the entropy production rate, as a Lyapunov function, indicates the directional character and stability of the dynamical behavior of tumor growth according to this model.

  9. Brazing of the Tore Supra actively cooled Phase III Limiter

    SciTech Connect

    Nygren, R.E.; Walker, C.A.; Lutz, T.J.; Hosking, F.M.; McGrath, R.T.

    1993-12-31

    The head of the water-cooled Tore Supra Phase 3 Limiter is a bank of 14 round OFHC copper tubes, curved to fit the plasma radius, onto which several hundred pyrolytic graphite (PG) tiles and a lesser number of carbon fiber composite tiles are brazed. The small allowable tolerances for fitting the tiles to the tubes and mating of compound curvatures made the brazing and fabrication extremely challenging. The paper describes the fabrication process with emphasis on the procedure for brazing. In the fixturing for vacuum furnace brazing, the tiles were each independently clamped to the tube with an elaborate set of window frame clamps. Braze quality was evaluated with transient heating tests. Some rebrazing was necessary.

  10. Benzocaine polymorphism: pressure-temperature phase diagram involving forms II and III.

    PubMed

    Gana, Inès; Barrio, Maria; Do, Bernard; Tamarit, Josep-Lluís; Céolin, René; Rietveld, Ivo B

    2013-11-18

    Understanding the phase behavior of an active pharmaceutical ingredient in a drug formulation is required to avoid the occurrence of sudden phase changes resulting in decrease of bioavailability in a marketed product. Benzocaine is known to possess three crystalline polymorphs, but their stability hierarchy has so far not been determined. A topological method and direct calorimetric measurements under pressure have been used to construct the topological pressure-temperature diagram of the phase relationships between the solid phases II and III, the liquid, and the vapor phase. In the process, the transition temperature between solid phases III and II and its enthalpy change have been determined. Solid phase II, which has the highest melting point, is the more stable phase under ambient conditions in this phase diagram. Surprisingly, solid phase I has not been observed during the study, even though the scarce literature data on its thermal behavior appear to indicate that it might be the most stable one of the three solid phases. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Situational Lightning Climatologies for Central Florida: Phase III

    NASA Technical Reports Server (NTRS)

    Barrett, Joe H., III

    2008-01-01

    This report describes work done by the Applied Meteorology Unit (AMU) to add composite soundings to the Advanced Weather Interactive Processing System (AWIPS). This allows National Weather Service (NWS) forecasters to compare the current atmospheric state with climatology. In a previous phase, the AMU created composite soundings for four rawinsonde observation stations in Florida, for each of eight flow regimes. The composite soundings were delivered to the NWS Melbourne (MLB) office for display using the NSHARP software program. NWS MLB requested that the AMU make the composite soundings available for display in AWIPS. The AMU first created a procedure to customize AWIPS so composite soundings could be displayed. A unique four-character identifier was created for each of the 32 composite soundings. The AMU wrote a Tool Command Language/Tool Kit (TcVTk) software program to convert the composite soundings from NSHARP to Network Common Data Form (NetCDF) format. The NetCDF files were then displayable by AWIPS.

  12. What have we learnt from ISAAC phase III in the Asia-Pacific rim?.

    PubMed

    Fok, Annie O L; Wong, Gary W K

    2009-04-01

    International Study of Asthma and Allergies in Childhood (ISAAC) phase III had provided a worldwide map of epidemiology of asthma and allergic diseases, as well as the changes in prevalence rate of these diseases when compared to data obtained in phase I. The wide variations of environmental factors and ethnic background in Asia provide excellent opportunities for research into the environmental and genetic determinants of asthma and allergies. This review summarizes important lessons learnt from ISAAC phase III results from Asia on asthma and allergy. ISAAC phase III provided epidemiological evidence of the wide variation and increasing prevalence of asthma and allergy in many Asian countries. When compared to other regions of the world, Asia has a relatively lower prevalence of asthma and allergic diseases. Comparative studies of populations of the same ethnic group living in different environments reveal striking disparity in prevalence of asthma and allergic diseases. The established risk factors could not explain the secular trend and variations of asthma prevalence in different Asian countries. Further research is needed in this rapidly changing region of Asia in order to identify the protective or risk factors associated with the development of asthma. ISAAC phase III provides standardized data on the prevalence and burden of asthma and allergy in the Asia-Pacific region. Further research is needed to reveal the underlying factors responsible for the wide variations in disease manifestations in the region.

  13. Remedial Action Report for Operable Units 6-05 and 10-04, Phase III

    SciTech Connect

    R. P. Wells

    2007-08-15

    This Phase III remedial action report addresses the remediation of lead-contaminated soils found at the Security Training Facility STF-02 Gun Range at the Idaho National Laboratory Site. Phase I, consisting of developing and implementing institutional controls at Operble Unit 10-04 sites and developing and implementing Idaho National Laboratory Site-wide plans for both institutional controls and ecological monitoring, was addressed in a previous report. Phase II will remediate sites contaminated with trinitrotoluene and Royal Demolition Explosive. Phase IV will remediate hazards from unexploded ordnance.

  14. Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial.

    PubMed

    Lu, Charles; Lee, J Jack; Komaki, Ritsuko; Herbst, Roy S; Feng, Lei; Evans, William K; Choy, Hak; Desjardins, Pierre; Esparaz, Benjamin T; Truong, Mylene T; Saxman, Scott; Kelaghan, Joseph; Bleyer, Archie; Fisch, Michael J

    2010-06-16

    BACKGROUND AE-941 is a standardized aqueous shark cartilage extract with antiangiogenic properties that has previously been evaluated in phase I and II clinical trials. Our objective was to determine the effect of adding AE-941 to chemoradiotherapy on overall survival of patients with unresectable stage III non-small cell lung cancer (NSCLC). METHODS A randomized, double-blinded, placebo-controlled, phase III clinical trial was designed to test the efficacy of AE-941 in unresectable stage III NSCLC patients who were treated with chemoradiotherapy. Between June 5, 2000, and February 6, 2006, 379 eligible patients were enrolled in community and academic oncology centers across the United States and Canada. In February 2006, the trial was closed to new patient entry before meeting the target sample size because of insufficient accrual. All subjects received induction chemotherapy followed by concurrent chemotherapy with chest radiotherapy. Each participating center administered one of the two chemotherapy regimens, either carboplatin and paclitaxel, or cisplatin and vinorelbine. The primary endpoint was overall survival, and secondary endpoints were time to progression, progression-free survival, tumor response rate, and toxic effects. Event-time distributions were estimated by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS There was no statistically significant difference in overall survival between the chemoradiotherapy plus AE-941 group (n = 188; median survival = 14.4 months, 95% confidence interval = 12.6 to 17.9 months) and the chemoradiotherapy plus placebo group (n = 191; median survival = 15.6 months, 95% confidence interval = 13.8 to 18.1 months) (P = .73). Time to progression, progression-free survival, and tumor response rates were not statistically significantly different between the AE-941 and the placebo groups. No differences between the two groups were observed in common grade 3 or higher toxic effects attributable to

  15. Evaluation of DCS III Transmission Alternatives, Phase II, Task 2 Final Report.

    DTIC Science & Technology

    1981-11-16

    Phase IA Final Report", TRW Doc . No. 35142, May 1980 TRW, "Evaluation of DCS III Transmission Alternatives, Appendix A, Transmission Media ", TRW Doc ...of potential transmission media into the future, and to assess their comparative utility for DCS application in the years 2000 and beyond, The final...Transmission Media , AD 101360 3. Appendix B, Regulatory Barriers, AD 101361 4. Appendix C, Regional Consideration and Characterization, ’ mAD 101362 5. Phase

  16. Project NECESSITIES, Phase III. Volume IV: Teaching Materials for Kindergarten and First Grade.

    ERIC Educational Resources Information Center

    Abt Associates, Inc., Cambridge, MA.

    Phase III, Volume IV, Part A of Project NECESSITIES consists of 10 activities intended for kindergarten-aged American Indian (including Eskimo) children. Some of the supplementary materials needed to teach these activities ("Symbol Formation" and "An Animal Alphabet") are appended. The unit, entitled Learning to Communicate, begins with non-verbal…

  17. SPSP Phase III Recruiting, Selecting, and Developing Secure Power Systems Professionals. Job Profiles

    SciTech Connect

    O'Neil, Lori Ross; Conway, T. J.; Tobey, D. H.; Greitzer, Frank L.; Dalton, Angela C.; Pusey, Portia K.

    2015-03-01

    The Secure Power Systems Professional Phase III final report was released last year which an appendix of Job Profiles. This new report is that appendix broken out as a standalone document to assist utilities in recruiting and developing Secure Power Systems Professionals at their site.

  18. SPSP Phase III Recruiting, Selecting, and Developing Secure Power Systems Professionals. Individual and Team Performance Guidelines

    SciTech Connect

    O'Neil, Lori Ross; Conway, T. J.; Tobey, D. H.; Greitzer, Frank L.; Dalton, Angela C.; Pusey, Portia K.

    2015-03-01

    The Secure Power Systems Professional Phase III final report was released last year which an appendix of Individual and Team Performance Guidelines. This new report is that appendix broken out as a standalone document to assist utilities in recruiting and developing Secure Power Systems Professionals at their site.

  19. Selected Findings from Phase III-B. BTES. Beginning Teacher Evaluation Study. Supplement. Preliminary Version.

    ERIC Educational Resources Information Center

    Fisher, Charles W.; And Others

    This series of six papers concerning the Beginning Teacher Evaluation Study (BTES) starts with Teaching Behaviors, Academic Learning Time and Student Achievement: An Overview of Phase III-B of the Beginning Teacher Evaluation Study by the project director, Charles Fisher. As an introduction, it describes a model of classroom instruction based on…

  20. The Prediction of Success in Nursing Education. Phase III, 1967-1968.

    ERIC Educational Resources Information Center

    Thurston, John R.; And Others

    Specific aims of Phase III, planned as a 4-year program, included: (1) evaluating the efficiency of three instruments--Nursing Sentence Completions (NSC), Nurse Attitudes Inventory (NAI), and Luther Hospital Sentence Completions (LHSC)--for the prediction of success early in nursing school, (2) developing attitudinal area scores for the three…

  1. Acceptance test procedure, 241-SY-101 Flexible Receiver System, Phase III testing

    SciTech Connect

    Ritter, G.A.

    1994-11-21

    This Acceptance Test Procedure is for the 241-SY-101 Flexible Receiver System, Phase III Testing. This procedure will test the sealing integrity of the Flexible Receiver System to ensure that release of waste and aerosols will be minimized during the removal of the test mixer pump from tank SY-101.

  2. Effects of PECS Phase III Application Training on Independent Mands in Young Children with Autism

    ERIC Educational Resources Information Center

    Love, Jessica June

    2013-01-01

    The purpose of this study was to examine the effects of PECS phase III application training on independent mands in young children with autism. Participants were five children with autism ranging from ages 2 to 4 years old. A multiple baseline across participants was used to evaluate acquisition of independent correct mands across baseline and…

  3. Wisconsin Technical College System Equity Staff Development Workshops and Services--Phase III. Final Report.

    ERIC Educational Resources Information Center

    Baldus, Lorayne; Nelson, Orville

    The Wisconsin Technical College System (WTCS) Phase III Equity Staff Development project was conducted to determine strategies to eliminate sex bias and sex role stereotyping throughout the WTCS. The following project activities were conducted: (1) the WTCS sex equity advisory committee was formed to provide continuity and direction for state…

  4. What Works in Oklahoma Schools: A Comprehensive Needs Assessment of Oklahoma Schools. Phase III Action Steps

    ERIC Educational Resources Information Center

    Marzano Research Laboratory, 2011

    2011-01-01

    This document contains the Phase III report from the "What Works in Oklahoma Schools" study. As opposed to describing the findings from the study that was conducted, it provides a tool-kit that can be used by Oklahoma principals and teachers to determine the best courses of action for their schools and classrooms. The tools provided in…

  5. S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial)

    PubMed Central

    Yoshida, M.; Ishiguro, M.; Ikejiri, K.; Mochizuki, I.; Nakamoto, Y.; Kinugasa, Y.; Takagane, A.; Endo, T.; Shinozaki, H.; Takii, Y.; Mochizuki, H.; Kotake, K.; Kameoka, S.; Takahashi, K.; Watanabe, T.; Watanabe, M.; Boku, N.; Tomita, N.; Nakatani, E.; Sugihara, K.

    2014-01-01

    Background S-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur–uracil plus leucovorin (UFT/LV). Patients and methods Patients aged 20–80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80–120 mg/day on days 1–28 every 42 days; four courses) or UFT/LV (UFT: 300–600 mg/day and LV: 75 mg/day on days 1–28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years. Results A total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70–1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups. Conclusion Adjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer. ClinicalTrials.gov NCT00660894. PMID:24942277

  6. Novel approaches to incorporating pharmacoeconomic studies into phase III clinical trials for Alzheimer's disease.

    PubMed

    Fillit, H; Cummings, J; Neumann, P; McLaughlin, T; Salavtore, P; Leibman, C

    2010-10-01

    The societal and individual costs of Alzheimer's disease are significant, worldwide. As the world ages, these costs are increasing rapidly, while health systems face finite budgets. As a result, many regulators and payers will require or at least consider phase III cost-effectiveness data (in addition to safety and efficacy data) for drug approval and reimbursement, increasing the risks and costs of drug development. Incorporating pharmacoeconomic studies in phase III clinical trials for Alzheimer's disease presents a number of challenges. We propose several specific suggestions to improve the design of pharmacoeconomic studies in phase III clinical trials. We propose that acute episodes of care are key outcome measures for pharmacoeconomic studies. To improve the possibility of detecting a pharmacoeconomic impact in phase III, we suggest several strategies including; study designs for enrichment of pharmacoeconomic outcomes that include co-morbidity of patients; reducing variability of care that can affect pharmacoeconomic outcomes through standardized care management; employing administrative claims data to better capture meaningful pharmacoeconomic data; and extending clinical trials in open label follow-up periods in which pharmacoeconomic data are captured electronically by administrative claims. Specific aspects of power analysis for pharmacoeconomic studies are presented. The particular pharmacoeconomic challenges caused by the use of biomarkers in clinical trials, the increasing use of multinational studies, and the pharmacoeconomic challenges presented by biologicals in development for Alzheimer's disease are discussed. In summary, since we are entering an era in which pharmacoeconomic studies will be essential in drug development for supporting regulatory approval, payor reimbursement and integration of new therapies into clinical care, we must consider the design and incorporation of pharmacoeconomic studies in phase III clinical trials more seriously

  7. Two-phase treatment of patients with crossbite and tendency toward skeletal Class III malocclusion*

    PubMed Central

    Bayerl, Maria de Lourdes Machado

    2014-01-01

    Angle Class III malocclusion is characterized by an inadequate anteroposterior dental relationship which may or may not be accompanied by skeletal changes. In general, patients are distressed by a significantly compromised facial aspect which, when associated with a deficient middle third, encourages patients to seek treatment. This article reports a two-phase treatment carried out in a female patient aged six years and six months with a tendency towards a Class III skeletal pattern. This case was presented to the Brazilian Board of Orthodontics and Facial Orthopedics (BBO). It is representative of the Discrepancy Index (DI) category, and fulfills part of the requirements for obtaining BBO Diploma. PMID:25279531

  8. Phase II trial of CoQ10 for ALS finds insufficient evidence to justify Phase III

    PubMed Central

    Kaufmann, Petra; Thompson, John L.P.; Levy, Gilberto; Buchsbaum, Richard; Shefner, Jeremy; Krivickas, Lisa S.; Katz, Jonathan; Rollins, Yvonne; Barohn, Richard J.; Jackson, Carlayne E.; Tiryaki, Ezgi; Lomen-Hoerth, Catherine; Armon, Carmel; Tandan, Rup; Rudnicki, Stacy A.; Rezania, Kourosh; Sufit, Robert; Pestronk, Alan; Novella, Steven P.; Heiman-Patterson, Terry; Kasarskis, Edward J.; Pioro, Erik P.; Montes, Jacqueline; Arbing, Rachel; Vecchio, Darleen; Barsdorf, Alexandra; Mitsumoto, Hiroshi; Levin, Bruce

    2010-01-01

    Objective Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial. Methods We designed and implemented a multi-center trial with an adaptive, two-stage, bias-adjusted, randomized, placebo-controlled, double-blind, Phase II design (n=185). The primary outcome in both stages was decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700 mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo. Results Stage 1 selected the 2,700 mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an accompanying pre-specified sensitivity test, and further supplementary analyses. Pre-specified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns. Interpretation CoQ10 at 2,700 mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial. PMID:19743457

  9. A decision theoretical modeling for Phase III investments and drug licensing.

    PubMed

    Miller, Frank; Burman, Carl-Fredrik

    2017-09-18

    For a new candidate drug to become an approved medicine, several decision points have to be passed. In this article, we focus on two of them: Firstly, based on Phase II data, the commercial sponsor decides to invest (or not) in Phase III. Secondly, based on the outcome of Phase III, the regulator determines whether the drug should be granted market access. Assuming a population of candidate drugs with a distribution of true efficacy, we optimize the two stakeholders' decisions and study the inter-dependence between them. The regulator is assumed to seek to optimize the total public health benefit, resulting from the efficacy of the drug and a safety penalty. In optimizing the regulatory rules, in terms of minimal required sample size and the type I error in Phase III, we have to consider how these rules will modify the commercial optimization made by the sponsor. The results indicate that different type I errors should be used depending on the rarity of the disease.

  10. Run-In Phase III Trial Design With Pharmacodynamics Predictive Biomarkers

    PubMed Central

    2013-01-01

    Background Developments in biotechnology have stimulated the use of predictive biomarkers to identify patients who are likely to benefit from a targeted therapy. Several randomized phase III designs have been introduced for development of a targeted therapy using a diagnostic test. Most such designs require biomarkers measured before treatment. In many cases, it has been very difficult to identify such biomarkers. Promising candidate biomarkers can sometimes be effectively measured after a short run-in period on the new treatment. Methods We introduce a new design for phase III trials with a candidate predictive pharmacodynamic biomarker measured after a short run-in period. Depending on the therapy and the biomarker performance, the trial would either randomize all patients but perform a separate analysis on the biomarker-positive patients or only randomize marker-positive patients after the run-in period. We evaluate the proposed design compared with the conventional phase III design and discuss how to design a run-in trial based on phase II studies. Results The proposed design achieves a major sample size reduction compared with the conventional randomized phase III design in many cases when the biomarker has good sensitivity (≥0.7) and specificity (≥0.7). This requires that the biomarker be measured accurately and be indicative of drug activity. However, the proposed design loses some of its advantage when the proportion of potential responders is large (>50%) or the effect on survival from run-in period is substantial. Conclusions Incorporating a pharmacodynamic biomarker requires careful consideration but can expand the capacity of clinical trials to personalize treatment decisions and enhance therapeutics development. PMID:24096624

  11. Phase I-II study of isotopic immunoglobulin therapy for primary liver cancer

    SciTech Connect

    Ettinger, D.S.; Order, S.E.; Wharam, M.D.; Parker, M.K.; Klein, J.L.; Leichner, P.K.

    1982-02-01

    A phase I-II study of isotopic immunoglobulin therapy was performed in 18 patients with primary liver cancer; 14 were evaluable for toxicity. The patients received a dose of 37-157 millicuries of 131I-labeled antibody. The dose-limiting factor appears to be hematologic toxicity, especially thrombocytopenia. An objective antitumor effect was seen in six of nine patients who were evaluable for response. Present results suggest that further clinical studies with isotopic immunoglobulin are indicated.

  12. Aircrew Training Devices: Utility and Utilization of Advanced Instructional Features. Phase III. Electronic Warfare Trainers.

    DTIC Science & Technology

    1986-04-01

    Devices: Utility and Utilization of Advanced Instructional Features (Phase III- Electronic Warfare Trainers) 12 PERSONAL AUTHOR(S) Polzella . Donald J...Features, addressed a portion of this subthrust. Dr. Wayne Waag (AFHRL/OTU) was the Contract Monitor and Dr. Donald J. Polzella and Dr. David C. Hubbard...training is practicable (see Polzella , 1983, p.8). However, instructional features are expensive to implement, especially those features that require the

  13. Health-related quality of life assessment in contemporary phase III trials in advanced colorectal cancer.

    PubMed

    Adamowicz, Krzysztof; Saad, Everardo D; Jassem, Jacek

    2016-11-01

    Health-related quality of life (HRQOL) is often used as an endpoint in cancer clinical trials. We assessed the frequency and correlates of HRQOL use in phase III trials in advanced colorectal cancer. We searched PubMed for phase III trials published between January 1998 and December 2014, as well as for companion papers reporting on HRQOL separately. We excluded papers reporting on correlative biology or prognostic factors in isolation from the main trial results, as well as trials on supportive care and on local therapy. We retrieved 111 trials that enrolled a total of 61,531 patients in 241 trial arms. HRQOL was reportedly used as an endpoint in 40 trials (36%), in all but two as a secondary endpoint. There was a significant decrease in the use of HRQOL, with frequencies of 46% in trials published between 1998 and 2006, and 27% between 2007 and 2014 (P=0.04). Trials with HRQOL as endpoint were significantly larger than trials without such endpoint. Formal statistical comparisons involving HRQOL parameters were reported in 36 of 40 trials (90%) with HRQOL assessment, with a significant difference between arms found in 14 (39%), six of which favoring the experimental arm. HRQOL gains were usually accompanied by improvements in efficacy endpoints, but were not related to the number of patients or chemotherapy line. HRQOL has been formally assessed in about one-third of recent phase III trials in advanced colorectal cancer, with a significant gain in HRQOL in about 40% of cases. It is questionable whether HRQOL results may largely help select between competing treatments. This assumption may be one of the reasons for the apparent decreased use of HRQOL as an endpoint in phase III trials in this disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Phase-correlated P Cygni profile variations of the C III multiplet in UW Canis Majoris

    NASA Technical Reports Server (NTRS)

    Drechsel, H.; Kondo, Y.; Mccluskey, G. E., Jr.; Rahe, J.

    1981-01-01

    The interacting close binary system UW CMa has been observed, in the wavelength range from 1161 to 1188 A, continuously during a complete orbital cycle in 1979 with the Copernicus (OAO-3) U2 spectrometer. The C III multiplet at 1175 A, observed as a P Cygni feature, exhbits a clear dependence on the orbital phase of the binary; the radial velocity variation of this feature lags behind that of the O7 primary component by 0.1 orbital phase, which agrees with the anticipations in an earlier study by the same authors. The radiation-driven matter, flowing out of the binary, originates in the primary component.

  15. Phase-correlated P Cygni profile variations of the C III multiplet in UW Canis Majoris

    NASA Technical Reports Server (NTRS)

    Drechsel, H.; Kondo, Y.; Mccluskey, G. E., Jr.; Rahe, J.

    1981-01-01

    The interacting close binary system UW CMa has been observed, in the wavelength range from 1161 to 1188 A, continuously during a complete orbital cycle in 1979 with the Copernicus (OAO-3) U2 spectrometer. The C III multiplet at 1175 A, observed as a P Cygni feature, exhbits a clear dependence on the orbital phase of the binary; the radial velocity variation of this feature lags behind that of the O7 primary component by 0.1 orbital phase, which agrees with the anticipations in an earlier study by the same authors. The radiation-driven matter, flowing out of the binary, originates in the primary component.

  16. New Round of Studies Begin in Phase 0/I/II Cancer Prevention Clinical Trials Program | Division of Cancer Prevention

    Cancer.gov

    The NCI Division of Cancer Prevention’s Phase 0/I/II Cancer Prevention Clinical Trials Program, also known as the Consortia for Early Phase Prevention Trials, is beginning a new round of studies in the effort toward systematic early clinical development of promising preventive agents for people at increased risk of developing cancer. Infographic Highlight New Round of Studies Begin in Phase 0/I/II Cancer Prevention Clinical Trials Program |

  17. Soft recovery of polytetrafluoroethylene shocked through the crystalline phase II-III transition

    NASA Astrophysics Data System (ADS)

    Brown, E. N.; Trujillo, C. P.; Gray, G. T.; Rae, P. J.; Bourne, N. K.

    2007-01-01

    Polymers are increasingly being utilized as monolithic materials and composite matrices for structural applications historically reserved for metals. High strain-rate applications in aerospace, defense, and the automotive industries have lead to interest in the shock response of polytetrafluoroethylene (PTFE) and the ensuing changes in polymer structure due to shock prestraining. We present an experimental study of crystalline structure evolution due to pressure-induced phase transitions in a semicrystalline polymer using soft-recovery, shock loading techniques coupled with mechanical and chemical postshock analyses. Gas-launched, plate impact experiments have been performed on pedigreed PTFE 7C, mounted in momentum trapped, shock assemblies, with impact pressures above and below the phase II to phase III crystalline transition. Below the phase transition only subtle changes were observed in the crystallinity, microstructure, and mechanical response of PTFE. Shock loading of PTFE 7C above the phase II-III transition was seen to cause both an increase in crystallinity from 38% to ˜53% (by differential scanning calorimetry) and a finer crystalline microstructure, and changed the yield and flow stress behavior.

  18. Conceptual design report for environmental, safety and health phase III FY-91 line item

    SciTech Connect

    1988-09-01

    The Mound Facility (Mound), located in Miamisburg, Ohio, is a Department of Energy (DOE) development and production facility performing support work for DOE`s weapons and energy-related programs. EG&G Mound Applied Technologies (EG&G) is the Operating Contractor (OC) for this Government-Owned, Contractor-Operated (GOCO) facility. The work performed at Mound emphasizes nuclear energy and explosives technology. Mound is currently implementing an Environmental, Safety, and Health (ES&H) Program designed to protect its employees, the public, and the environment from adverse effects caused by the facility`s activities. Design has been completed, and construction is in progress for Phase I of this multiphase program. Phase II has been submitted for fiscal year (FY) 89 funding and Phase IV is being submitted as an FY 92 line item. This Conceptual Design Report (CDR) addresses Phase III of the ES&H program.

  19. A varying-stage adaptive phase II/III clinical trial design.

    PubMed

    Dong, Gaohong

    2014-04-15

    Currently, adaptive phase II/III clinical trials are typically carried out with a strict two-stage design. The first stage is a learning stage called phase II, and the second stage is a confirmatory stage called phase III. Following phase II analysis, inefficacious or harmful dose arms are dropped, then one or two promising dose arms are selected for the second stage. However, there are often situations in which researchers are in dilemma to make 'go or no-go' decision and/or to select 'best' dose arm(s), as data from the first stage may not provide sufficient information for their decision making. In this case, it is challenging to follow a strict two-stage plan. Therefore, we propose a varying-stage adaptive phase II/III clinical trial design, in which we consider whether there is a need to have an intermediate stage to obtain more data, so that a more informative decision could be made. Hence, the number of further investigational stages in our design is determined on the basis of data accumulated to the interim analysis. With respect to adaptations, we consider dropping dose arm(s), switching another plausible endpoint as the primary study endpoint, re-estimating sample size, and early stopping for futility. We use an adaptive combination test to perform final analyses. By applying closed testing procedure, we control family-wise type I error rate at the nominal level of α in the strong sense. We delineate other essential design considerations including the threshold parameters and the proportion of alpha allocated in the two-stage versus three-stage setting.

  20. On-line solid-phase extraction and multisyringe flow injection analysis of Al(III) and Fe(III) in drinking water.

    PubMed

    Vanloot, Pierre; Branger, Catherine; Margaillan, André; Brach-Papa, Christophe; Boudenne, Jean-Luc; Coulomb, Bruno

    2007-11-01

    A new analytical method was developed for on-line monitoring of residual coagulants (aluminium and iron salts) in potable water. The determination was based on a sequential procedure coupling an extraction/enrichment step of the analytes onto a modified resin and a spectrophotometric measurement of a surfactant-sensitized binary complex formed between eluted analytes and Chrome Azurol S. The optimization of the solid phase extraction was performed using factorial design and a Doehlert matrix considering six variables: sample percolation rate, sample metal concentration, flow-through sample volume (all three directly linked to the extraction step), elution flow rate, concentration and volume of eluent (all three directly linked to the elution step). A specific reagent was elaborated for sensitive and specific spectrophotometric determination of Al(III) and Fe(III), by optimizing surfactant and ligand concentrations and buffer composition. The whole procedure was automated by a multisyringe flow injection analysis (MSFIA) system. Detection limits of 4.9 and 5.6 microg L(-1) were obtained for Al(III) and Fe(III) determination , respectively, and the linear calibration graph up to 300 microg L(-1) (both for Al(III) and Fe(III)) was well adapted to the monitoring of drinking water quality. The system was successfully applied to the on-site determination of Al(III) and Fe(III) at the outlet of two water treatment units during two periods of the year (winter and summer conditions).

  1. Imprinted magnetic graphene oxide for the mini-solid phase extraction of Eu (III) from coal mine area

    NASA Astrophysics Data System (ADS)

    Patra, Santanu; Roy, Ekta; Madhuri, Rashmi; Sharma, Prashant K.

    2017-05-01

    The present work represents the preparation of imprinted magnetic reduced graphene oxide and applied it for the selective removal of Eu (III) from local coal mines area. A simple solid phase extraction method was used for this purpose. The material shows a very high adsorption as well as removal efficiency towards Eu (III), which suggest that the material have potential to be used in future for their real time applications in removal of Eu (III) from complex matrices.

  2. [Phase III clinical trial using autologous mesenchymal stem cells for stroke patients].

    PubMed

    Honmou, Osamu

    2016-04-01

    We conduct a double-blind randomized placebo-controlled clinical trial (Phase III: confirmatory trial) of intravenous infusion of autologous mesenchymal stem cells for cerebral infarction patients. The objectives of this study were to examine feasibility, safety, and efficacy of cell therapy using auto serum-expanded autologous mesenchymal stem cells derived from bone marrow in the stroke patients. Inclusion criteria is (1) Cerebral infarction onset within 40 days, (2) Supra-tentorial cerebral infarction(NINDS-III 1990) diagnosed by MRI(or CT), MRA (3D-CTA or DSA), ECG, chest X-ray etc., (3) Classified under grade 4 or 5 of mRS (modified Rankin scale), (4) Age between 20 to 80, (5) The written informed consent from subjects and legal representative is provided.

  3. Classroom Interaction in Effective and Ineffective Schools: Preliminary Results from Phase III of the Louisiana School Effectiveness Study

    ERIC Educational Resources Information Center

    Stringfield, Samuel; Teddlie, Charles; Suarez, Sandra

    2017-01-01

    A major focus in Phase III of the Louisiana School Effectiveness Study is on the relationship between classroom interaction patterns and school effectiveness. This paper presents observations on similarities and differences between prior teacher and school effectiveness studies, the LSES-III methodology, and preliminary results from one of the…

  4. Idaho Water Rental Pilot Project Probability/Coordination Study Resident Fish and Wildlife Impacts Phase III, 1997 Annual Report.

    SciTech Connect

    Leitzinger, Eric J.

    1998-10-01

    Phase III began in 1995 with the overall goal of quantifying changes in resident fish habitat in the Snake River Basin upstream of Brownlee Reservoir resulting from the release of salmon flow augmentation water.

  5. Phase III Technology for All Americans Project: Creating Assessment, Professional Development, and Program Standards for Technological Literacy.

    ERIC Educational Resources Information Center

    Dugger, William E., Jr.

    2001-01-01

    The goals of Phase III of the Technology for All Americans Project are to develop student assessment standards, professional development standards, program standards, and effective leaders. The project is based on the Standards for Technology Literacy, a NASA initiative. (JOW)

  6. Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials

    PubMed Central

    Stein, Donald G.

    2015-01-01

    Abstract Background: Despite positive preclinical studies and two positive Phase II clinical trials, two large Phase III clinical trials of progesterone treatment of acute traumatic brain injury (TBI) recently ended with negative results, so a 100% failure rate continues to plague the field of TBI trials. Methods: This paper reviews and analyses the trial structures and outcomes and discusses the implications of these failures for future drug and clinical trial development. Persistently negative trial outcomes have led to disinvestment in new drug research by companies and policy-makers and disappointment for patients and their families, failures which represent a major public health concern. The problem is not limited to TBI. Failure rates are high for trials in stroke, sepsis, cardiology, cancer and orthopaedics, among others. Results: This paper discusses some of the reasons why the Phase III trials have failed. These reasons may include faulty extrapolation from pre-clinical data in designing clinical trials and the use of subjective outcome measures that accurately reflect neither the nature of the deficits nor long-term quantitative recovery. Conclusions: Better definitions of injury and healing and better outcome measures are essential to change the embrace of failure that has dominated the field for over 30 years. This review offers suggestions to improve the situation. PMID:26274493

  7. A Phase I-II Study of Postoperative Capecitabine-Based Chemoradiotherapy in Gastric Cancer

    SciTech Connect

    Jansen, Edwin; Crosby, Tom D.L.; Dubbelman, Ria; Bartelink, Harry; Verheij, Marcel

    2007-12-01

    Background: The Intergroup 0116 randomized study showed that postoperative 5-fluorouracil-based chemoradiotherapy improved locoregional control and overall survival in patients with gastric cancer. We hypothesized that these results could be improved further by using a more effective, intensified, and convenient chemotherapy schedule. Therefore, this Phase I-II dose-escalation study was performed to determine the maximal tolerated dose and toxicity profile of postoperative radiotherapy combined with concurrent capecitabine. Patients and Methods: After recovery from surgery for adenocarcinoma of the gastroesophageal junction or stomach, all patients were treated with capecitabine monotherapy, 1,000 mg/m{sup 2} twice daily for 2 weeks. After a 1-week treatment-free interval, patients received capecitabine (650-1,000 mg/m{sup 2} orally twice daily 5 days/week) in a dose-escalation schedule combined with radiotherapy on weekdays for 5 weeks. Radiotherapy was delivered to a total dose of 45 Gy in 25 fractions to the gastric bed, anastomoses, and regional lymph nodes. Results: Sixty-six patients were treated accordingly. Two patients went off study before or shortly after the start of chemoradiotherapy because of progressive disease. Therefore, 64 patients completed treatment as planned. During the chemoradiotherapy phase, 4 patients developed four items of Grade III dose-limiting toxicity (3 patients in Dose Level II and 1 patient in Dose Level IV). The predefined highest dose of capecitabine, 1,000 mg/m{sup 2} twice daily orally, was tolerated well and, therefore, considered safe for further clinical evaluation. Conclusions: This Phase I-II study shows that intensified chemoradiotherapy with daily capecitabine is feasible in postoperative patients with gastroesophageal junction and gastric cancer.

  8. Speed of Accrual Into Phase III Oncology Trials: A Comparison Across Geographic Locations.

    PubMed

    Ruther, Nancy R; Mathiason, Michelle A; Wee, Sandra K; Emmel, Ann E; Go, Ronald S

    2015-12-01

    We sought to determine the speed at which patients were accrued into published phase III oncology trials across geographic locations and to identify the factors that may influence this process. We searched OVID-Medline and identified all phase III oncology therapeutic trials published in 2006 to 2010. The speed of accrual for each trial was calculated by dividing the number of patients enrolled by the number of months the trial was open (patients/mo). Five hundred forty-six trials were included in our study. Most of the trials were for adults (96%), late-stage cancers (78%), sponsored by either cooperative groups or academic centers (66%), and had negative results (58%). The most common trial locations were multinational (45%), United States (16%), Italy (7%), Germany (6%), Japan (6%), and France (5%). Compared with trials conducted in a single country, multinational trials accrued significantly more patients per trial, completed enrollment faster, and were published sooner (all P≤0.01). Multivariate analyses showed that multinational (P=0.001), breast cancer (P=0.001), industry sponsored (P=0.001), and equivalency trials (P=0.039) accrued significantly faster than other types of trials. Placebo-controlled and non-placebo-controlled trials accrued at similar speeds. We found no difference in speed of accrual between the United States and Europe. Speed of accrual for phase III oncology trials is fastest among multinational trials and independently influenced by the type of trial sponsor, cancer investigated, and study outcome, but not by placebo use. Trials conducted in single countries seem to accrue at similar speeds.

  9. Study of the Need for Educational Manpower for Handicapped Children and Youth: Part D - Volume III, Phase III. State Analysis Reports.

    ERIC Educational Resources Information Center

    Mintz, Raymond D.; And Others

    The document is the third of three volumes (see also EC 032 850 and EC 032 851) OF State Analysis Reports resulting from Phase III of the Study of the Need for Educational Manpower for Handicapped Children and Youth, which involved a validation study and state surveys related to the Manpower Requirements Projection Model (MRPM). Included in the…

  10. Investor Outlook: Focus on Upcoming LCA2 Gene Therapy Phase III Results.

    PubMed

    Schimmer, Joshua; Breazzano, Steven

    2015-09-01

    Investor interest in gene therapy has increased substantially over the past few years, and the next major catalyst for the field is likely to be Spark Therapeutics's phase III trial for the treatment of visual impairment caused by RPE65 gene mutations (often referred to as Leber congenital amaurosis type 2, or LCA2, but may include other retinal disorders). Analysis of the approach from the basic genetics, underlying visual mechanisms, clinical data, and commercialization considerations helps frame investor expectations and the potential implications for the broader field.

  11. Recent Developments in Cytotoxic Therapy for Advanced Gastric or Gastroesophageal Carcinoma: The Phase III Trials

    PubMed Central

    2007-01-01

    Gastric cancer remains a significant health problem around the world. It is often diagnosed in late stages and almost 50% of patients have unresectable disease. Median survival, when cancer is in advanced stages, is often less than 9 months. Once metastatic, it is an incurable condition, and in most circumstances, fewer than 10% of patients survive 24 months. Most patients with metastatic gastric or gastroesophageal cancer have baseline symptoms, some of which are quite severe. Therapy for advanced gastric or gastroesophageal cancer is palliative in nature. For a long time, the number of randomized trials conducted in patients with gastric or gastroesophageal cancer had been unacceptably low; however, in the past 10 years, the number of phase III trials has increased and it is hoped that the momentum will continue to build and more trials will be completed. Several new classes of active agents have emerged, including taxanes, camptothecins, fluoropyrimidine analogs (particularly, capecitabine and S-1), and a platinum analog (oxaliplatin). The most recent phase III data suggest that docetaxel, when added to the reference regimen of cisplatin and 5-FU (CF), results in a statistically significant prolongation of time-to-progression and overall survival, higher response rate, doubling of the 2-year survival rate, better quality of life, improved clinical benefit, and a higher rate of complicated neutropenia. Other important phase III trials demonstrate that 5-FU can be substituted with capecitabine and cisplatin can be substituted with oxaliplatin. However, in a randomized phase III trial, irinotecan plus infusional 5-FU, when compared with CF, was not superior (it was noninferior), suggesting that irinotecan may be best suited for second-line treatment of these patients. Further developments in cytotoxic therapy will be driven by the use of more sophisticated oral agents (eg, S-1) and newer clinical algorithms that will employ therapy only until maximum response is

  12. Vibrational properties of III-V semiconductor in wurtzite phase: A comparative density functional theory study

    NASA Astrophysics Data System (ADS)

    Gajaria, Trupti K.; Dabhi, Shweta D.; Baraiya, Bhumi A.; Mankad, Venu; Jha, Prafulla K.

    2017-05-01

    A First principles study of structural, vibrational and thermal properties of III-V semiconductor compounds viz. Indium Arsenide (InAs) and Gallium Arsenide (GaAs) are investigated in their wurtzite phase which is normally observed in the case of nanosystems. Phonon dispersion curve, Debye temperature and specific heat behavior for both the compounds are compared and discussed. The present work will have its implication for making devices with tunable properties using InAs and GaAs based heterojuction solar cells.

  13. INL Results for Phases I and III of the OECD/NEA MHTGR-350 Benchmark

    SciTech Connect

    Gerhard Strydom; Javier Ortensi; Sonat Sen; Hans Hammer

    2013-09-01

    The Idaho National Laboratory (INL) Very High Temperature Reactor (VHTR) Technology Development Office (TDO) Methods Core Simulation group led the construction of the Organization for Economic Cooperation and Development (OECD) Modular High Temperature Reactor (MHTGR) 350 MW benchmark for comparing and evaluating prismatic VHTR analysis codes. The benchmark is sponsored by the OECD's Nuclear Energy Agency (NEA), and the project will yield a set of reference steady-state, transient, and lattice depletion problems that can be used by the Department of Energy (DOE), the Nuclear Regulatory Commission (NRC), and vendors to assess their code suits. The Methods group is responsible for defining the benchmark specifications, leading the data collection and comparison activities, and chairing the annual technical workshops. This report summarizes the latest INL results for Phase I (steady state) and Phase III (lattice depletion) of the benchmark. The INSTANT, Pronghorn and RattleSnake codes were used for the standalone core neutronics modeling of Exercise 1, and the results obtained from these codes are compared in Section 4. Exercise 2 of Phase I requires the standalone steady-state thermal fluids modeling of the MHTGR-350 design, and the results for the systems code RELAP5-3D are discussed in Section 5. The coupled neutronics and thermal fluids steady-state solution for Exercise 3 are reported in Section 6, utilizing the newly developed Parallel and Highly Innovative Simulation for INL Code System (PHISICS)/RELAP5-3D code suit. Finally, the lattice depletion models and results obtained for Phase III are compared in Section 7. The MHTGR-350 benchmark proved to be a challenging simulation set of problems to model accurately, and even with the simplifications introduced in the benchmark specification this activity is an important step in the code-to-code verification of modern prismatic VHTR codes. A final OECD/NEA comparison report will compare the Phase I and III results

  14. ENGINEERING DEVELOPMENT OF COAL-FIRED HIGH PERFORMANCE POWER SYSTEMS PHASE II AND III

    SciTech Connect

    1998-09-30

    This report presents work carried out under contract DE-AC22-95PC95144 "Engineering Development of Coal-Fired High Performance Systems Phase II and III." The goals of the program are to develop a coal-fired high performance power generation system (HIPPS) that is capable of: à thermal efficiency (HHV) >47%; à NOx, SOx, and particulates <10% NSPS (New Source Performance Standard); à coal providing >65% of heat input; à all solid wastes benign; à cost of electricity <90% of present plants. Phase I, which began in 1992, focused on the analysis of various configurations of indirectly fired cycles and on technical assessments of alternative plant subsystems and components, including performance requirements, developmental status, design options, complexity and reliability, and capital and operating costs. Phase I also included preliminary R&D and the preparation of designs for HIPPS commercial plants approximately 300 MWe in size. This phase, Phase II, involves the development and testing of plant subsystems, refinement and updating of the HIPPS commercial plant design, and the site selection and engineering design of a HIPPS prototype plant. Work reported herein is from: à Task 2.2 HITAF Air Heaters; à Task 6 HIPPS Commercial Plant Design Update.

  15. Application of Bayesian hierarchical models for phase I/II clinical trials in oncology.

    PubMed

    Yada, Shinjo; Hamada, Chikuma

    2017-03-01

    Treatment during cancer clinical trials sometimes involves the combination of multiple drugs. In addition, in recent years there has been a trend toward phase I/II trials in which a phase I and a phase II trial are combined into a single trial to accelerate drug development. Methods for the seamless combination of phases I and II parts are currently under investigation. In the phase II part, adaptive randomization on the basis of patient efficacy outcomes allocates more patients to the dose combinations considered to have higher efficacy. Patient toxicity outcomes are used for determining admissibility to each dose combination and are not used for selection of the dose combination itself. In cases where the objective is not to find the optimum dose combination solely for efficacy but regarding both toxicity and efficacy, the need exists to allocate patients to dose combinations with consideration of the balance of existing trade-offs between toxicity and efficacy. We propose a Bayesian hierarchical model and an adaptive randomization with consideration for the relationship with toxicity and efficacy. Using the toxicity and efficacy outcomes of patients, the Bayesian hierarchical model is used to estimate the toxicity probability and efficacy probability in each of the dose combinations. Here, we use Bayesian moving-reference adaptive randomization on the basis of desirability computed from the obtained estimator. Computer simulations suggest that the proposed method will likely recommend a higher percentage of target dose combinations than a previously proposed method.

  16. Phase III Advanced Anodes and Cathodes Utilized in Energy Efficient Aluminum Production Cells

    SciTech Connect

    R.A. Christini; R.K. Dawless; S.P. Ray; D.A. Weirauch, Jr.

    2001-11-05

    During Phase I of the present program, Alcoa developed a commercial cell concept that has been estimated to save 30% of the energy required for aluminum smelting. Phase ii involved the construction of a pilot facility and operation of two pilots. Phase iii of the Advanced Anodes and Cathodes Program was aimed at bench experiments to permit the resolution of certain questions to be followed by three pilot cells. All of the milestones related to materials, in particular metal purity, were attained with distinct improvements over work in previous phases of the program. NiO additions to the ceramic phase and Ag additions to the Cu metal phase of the cermet improved corrosion resistance sufficiently that the bench scale pencil anodes met the purity milestones. Some excellent metal purity results have been obtained with anodes of the following composition: Further improvements in anode material composition appear to be dependent on a better understanding of oxide solubilities in molten cryolite. For that reason, work was commissioned with an outside consultant to model the MeO - cryolite systems. That work has led to a better understanding of which oxides can be used to substitute into the NiO-Fe2O3 ceramic phase to stabilize the ferrites and reduce their solubility in molten cryolite. An extensive number of vertical plate bench electrolysis cells were run to try to find conditions where high current efficiencies could be attained. TiB2-G plates were very inconsistent and led to poor wetting and drainage. Pure TiB2 did produce good current efficiencies at small overlaps (shadowing) between the anodes and cathodes. This bench work with vertical plate anodes and cathodes reinforced the importance of good cathode wetting to attain high current efficiencies. Because of those conclusions, new wetting work was commissioned and became a major component of the research during the third year of Phase III. While significant progress was made in several areas, much work needs to be

  17. 77 Recurrent Wheezing in Infancy: Epidemiological Changes Between EISL Phase i and iii

    PubMed Central

    Chong Neto, Herberto Jose; Rosario, Nelson; Silva, Flávia Carnieli; Melniski Bojarski, Lylia Fátima; Antonio Grasselli, Emanuel; Rosario, Cristine Secco; Rosario, Bernardo Augusto; Chong, Fernando Henrique

    2012-01-01

    Background Prevalence of allergic diseases has increased in the last years. Data on recurrent wheezing (≥3 episodes) in infancy is scarce. The aim of this study was to verify changing in prevalence of recurrent wheezing infants in the south of Brazil. Methods Cross-sectional study using a standardized and validated questionnaire (EISL: Estudio Internacional sobre Sibilancias en Lactantes) with questions: Has your baby had wheezing or whistling in the chest area or bronchitis in the first 12 months of life? Has your baby had 3 or more wheezing episodes in the first year of life? Parents of infants, ages 12 to 15 months that attended to Health Centers for routine immunization were interviewed between August 2005 to December 2006 (EISL Phase I) and September 2009 to September 2010 (EISL Phase III). Categorical variables are shown as proportion and differences verified by chi-square test, and continuous variables were expressed as mean ± SD and analyzed by Student t test. Results Three thousand three parents of infants answered questionnaire in the EISL Phase I, and 45.4% had had at least one wheezing episode; 50.7% were male, and 22.6% had recurrent wheezing episode starting at 5.5 ± 3.1 months. Five years later, in the EISL Phase III, 1003 parents participated in the survey: 40.6% had at least one wheezing episode (P = 0.46), 51.1% were male, and 19.8% had recurrent wheezing (P = 0.1) starting at 6.1 ± 3 months (P = 0.06). Conclusions Recurrent wheezing in infancy is highly prevalent and starts early in life. In our population, recurrent wheezing rates did not modify in the time period of study.

  18. TNF phase III signalling in tolerant cells is tightly controlled by A20 and CYLD.

    PubMed

    Bikker, Rolf; Christmann, Martin; Preuß, Katharina; Welz, Bastian; Friesenhagen, Judith; Dittrich-Breiholz, Oliver; Huber, René; Brand, Korbinian

    2017-09-01

    Following the acute phase of an inflammatory reaction, a strictly controlled resolution of inflammation is necessary. A dysregulation of this process leads to hyperinflammation, chronic inflammatory disease, or immune paralysis. Different mechanisms participate in the coordinated termination of the inflammatory process, e.g. the expression of antiinflammatory molecules and different forms of tolerance. To better understand the processes which mediate resolution of TNF-dependent inflammation and induce tolerance, it is necessary to characterize the signal transduction quality during TNF long-term (pre)incubation. Within a time frame from 12 to 48h, designated as phase III of the TNF response, we measured an ongoing, constitutive activation of TNFR1/NF-κB-dependent pathways in monocytic cells. Phase III signalling which was also named "constitutive signaling in TNF tolerant cells" induces the expression of low- and high-sensitive target genes including A20 which is differentially regulated by transcriptional and proteolytic events. A20 strictly controls TNF long-term constitutive signalling in an IκB kinase complex- and partially RIP-dependent manner supported by adjuvant ABIN1. In addition, CYLD proteins participate in the regulation of this late-phase signal transduction, whereas downstream molecules such as Bcl3 and p50 are not involved. A20 and CYLD are expressed with different mRNA kinetics resulting in a strong or only a modest increase in protein levels, respectively. The identification of mechanisms which contribute to the termination of inflammation will provide additional diagnostic and therapeutic aspects to specifically diagnose certain aspects of inflammation and specifically modulate them. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. A modified varying-stage adaptive phase II/III clinical trial design.

    PubMed

    Dong, Gaohong; Vandemeulebroecke, Marc

    2016-07-01

    Conventionally, adaptive phase II/III clinical trials are carried out with a strict two-stage design. Recently, a varying-stage adaptive phase II/III clinical trial design has been developed. In this design, following the first stage, an intermediate stage can be adaptively added to obtain more data, so that a more informative decision can be made. Therefore, the number of further investigational stages is determined based upon data accumulated to the interim analysis. This design considers two plausible study endpoints, with one of them initially designated as the primary endpoint. Based on interim results, another endpoint can be switched as the primary endpoint. However, in many therapeutic areas, the primary study endpoint is well established. Therefore, we modify this design to consider one study endpoint only so that it may be more readily applicable in real clinical trial designs. Our simulations show that, the same as the original design, this modified design controls the Type I error rate, and the design parameters such as the threshold probability for the two-stage setting and the alpha allocation ratio in the two-stage setting versus the three-stage setting have a great impact on the design characteristics. However, this modified design requires a larger sample size for the initial stage, and the probability of futility becomes much higher when the threshold probability for the two-stage setting gets smaller. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  20. Novel Agents for Multiple Myeloma to Overcome Resistance in Phase III Clinical Trials

    PubMed Central

    Orlowski, Robert Z.

    2013-01-01

    The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens. Also, these drugs are being increasingly used in the peri-transplant setting for transplant-eligible patients, and as part of consolidation and/or maintenance after front-line treatment, including in transplant-ineligible patients. Together, these and other strategies have contributed to a prolongation of progression-free and overall survival in myeloma patients, and an increasing proportion are able to sustain a remission for many years. Despite these improvements, however, the vast majority of patients continue to suffer relapses, which suggests a prominent role for either primary, innate drug resistance, or secondary, acquired drug resistance. As a result, there remains a strong need to develop new proteasome inhibitors and immunomodulatory agents, as well as new drug classes, which would be effective in the relapsed and/or refractory setting, and overcome drug resistance. This review will focus on novel drugs that have reached phase III trials, including carfilzomib and pomalidomide, which have recently garnered regulatory approvals. In addition, agents that are in phase II or III, potentially registration-enabling trials will be described as well, to provide an overview of the possible landscape in the relapsed and/or refractory arena over the next five years. PMID:24135408

  1. Phase III Preclinical Trials in Translational Stroke Research: Community Response on Framework and Guidelines.

    PubMed

    Boltze, Johannes; Wagner, Daniel-Christoph; Henninger, Nils; Plesnila, Nikolaus; Ayata, Cenk

    2016-08-01

    The multicenter phase III preclinical trial concept is currently discussed to enhance the predictive value of preclinical stroke research. After public announcement, we collected a community feedback on the concept with emphasis on potential design features and guidelines by an anonymous survey. Response analysis was conducted after plausibility checks by applying qualitative and quantitative measures. Most respondents supported the concept, including the implementation of a centralized steering committee. Based on received feedback, we suggest careful, stepwise implementation and to leave selected competencies and endpoint analysis at the discretion of participating centers. Strict application of quality assurance methods is accepted, but should be harmonized. However, received responses also indicate that the application of particular quality assurance models may require more attention throughout the community. Interestingly, clear and pragmatic preferences were given regarding publication and financing, suggesting the establishing of writing committees similar to large-scale clinical trials and global funding resources for financial support. The broad acceptance among research community encourages phase III preclinical trial implementation.

  2. Clinical Utility of Metrics Based on Tumor Measurements in Phase II Trials to Predict Overall Survival Outcomes in Phase III Trials by Using Resampling Methods

    PubMed Central

    An, Ming-Wen; Han, Yu; Meyers, Jeffrey P.; Bogaerts, Jan; Sargent, Daniel J.; Mandrekar, Sumithra J.

    2015-01-01

    Purpose Phase II clinical trials inform go/no-go decisions for proceeding to phase III trials, and appropriate end points in phase II trials are critical for facilitating this decision. Phase II solid tumor trials have traditionally used end points such as tumor response defined by Response Evaluation Criteria for Solid Tumors (RECIST). We previously reported that absolute and relative changes in tumor measurements demonstrated potential, but not convincing, improvement over RECIST to predict overall survival (OS). We have evaluated the metrics by using additional measures of clinical utility and data from phase III trials. Methods Resampling methods were used to assess the clinical utility of metrics to predict phase III outcomes from simulated phase II trials. In all, 2,000 phase II trials were simulated from four actual phase III trials (two positive for OS and two negative for OS). Cox models for three metrics landmarked at 12 weeks and adjusted for baseline tumor burden were fit for each phase II trial: absolute changes, relative changes, and RECIST. Clinical utility was assessed by positive predictive value and negative predictive value, that is, the probability of a positive or negative phase II trial predicting an effective or ineffective phase III conclusion, by prediction error, and by concordance index (c-index). Results Absolute and relative change metrics had higher positive predictive value and negative predictive value than RECIST in five of six treatment comparisons and lower prediction error curves in all six. However, differences were negligible. No statistically significant difference in c-index across metrics was found. Conclusion The absolute and relative change metrics are not meaningfully better than RECIST in predicting OS. PMID:26503199

  3. Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials.

    PubMed

    Falardeau, P; Champagne, P; Poyet, P; Hariton, C; Dupont, E

    2001-12-01

    more than 6 months. Two phase III clinical trials are currently underway. A phase III double-blind placebo-controlled study is being conducted to evaluate the efficacy of Neovastat in addition to induction chemotherapy/radiotherapy combined modality treatment in patients with unresectable non-small cell lung cancer stage IIIA and IIIB. A second phase III randomized, double-blind placebo-controlled study evaluates the efficacy of Neovastat as a monotherapy in metastatic renal cell carcinoma patients who have progressed following a first-line immunotherapy. Neovastat efficacy is also being evaluated in a registration phase II trial in patients with early relapse or refractory multiple myeloma.

  4. Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury.

    PubMed

    Howard, Randy B; Sayeed, Iqbal; Stein, Donald G

    2017-06-01

    To date, outcomes for all Phase III clinical trials for traumatic brain injury (TBI) have been negative. The recent disappointing results of the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) and Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SyNAPSe) Phase III trials for progesterone in TBI have triggered considerable speculation about the reasons for the negative outcomes of these two studies in particular and for those of all previous Phase III TBI clinical trials in general. Among the factors proposed to explain the ProTECT III and SyNAPSe results, the investigators themselves and others have cited: 1) the pathophysiological complexity of TBI itself; 2) issues with the quality and clinical relevance of the preclinical animal models; 3) insufficiently sensitive clinical endpoints; and 4) inappropriate clinical trial designs and strategies. This paper highlights three critical trial design factors that may have contributed substantially to the negative outcomes: 1) suboptimal doses and treatment durations in the Phase II studies; 2) the strategic decision not to perform Phase IIB studies to optimize these variables before initiating Phase III; and 3) the lack of incorporation of the preclinical and Chinese Phase II results, as well as allometric scaling principles, into the Phase III designs. Given these circumstances and the exceptional pleiotropic potential of progesterone as a TBI (and stroke) therapeutic, we are advocating a return to Phase IIB testing. We advocate the incorporation of dose and schedule optimization focused on lower doses and a longer duration of treatment, combined with the addressing of other potential trial design problems raised by the authors in the recently published trial results.

  5. Effect of phase III cardiac rehabilitation and relaxation on the quality of life in patients with cardiac syndrome X.

    PubMed

    Feizi, Aram; Ghaderi, Chiman; Dehghani, Mohammad R; Khalkhali, Hamid R; Sheikhi, Siamak

    2012-11-01

    Cardiac syndrome X is a relatively common disorder, and still not much is known about the causative factors or its pathophysiology, which makes it difficult to cure. Due to its chronic nature and debilitating symptoms, many patients have significantly reduced quality of life (QOL).The purpose of this study was to assess the impact of phase III cardiac rehabilitation (CR) and relaxation on the QOL of patients. This research is a randomized clinical trial study. Forty eligible and consenting women (age 30-65 years) were randomly assigned to four groups. In the first group (n = 11), progressive muscle relaxation (PMR); in the second group (n = 11), phase III CR; and in the third group (n = 11), PMR along with phase III CR were performed for 8 weeks at home. The fourth group (n = 7) was used as the control group. Short form of QOL questionnaire (SF-36) was used for data gathering. Data analysis was performed using χ(2), Kruskal-Wallis, and rank sum difference tests. After phase III CR, relaxation, and combination of CR and relaxation, patients demonstrated improved QOL (P < 0.001). The results of post-test multiple comparisons showed that there were statistically significant differences between control and all intervention groups (P < 0.05). There was also statistically significant difference between relaxation and combination of phase III CR and relaxation groups (P < 0.5). An 8-week phase III CR program together with relaxation improved QOL of patients with cardiac syndrome X. We suggest phase III CR program together with relaxation as an effective treatment in these patients.

  6. Effect of phase III cardiac rehabilitation and relaxation on the quality of life in patients with cardiac syndrome X

    PubMed Central

    Feizi, Aram; Ghaderi, Chiman; Dehghani, Mohammad R.; Khalkhali, Hamid R.; Sheikhi, Siamak

    2012-01-01

    Background: Cardiac syndrome X is a relatively common disorder, and still not much is known about the causative factors or its pathophysiology, which makes it difficult to cure. Due to its chronic nature and debilitating symptoms, many patients have significantly reduced quality of life (QOL).The purpose of this study was to assess the impact of phase III cardiac rehabilitation (CR) and relaxation on the QOL of patients. Materials and Methods: This research is a randomized clinical trial study. Forty eligible and consenting women (age 30-65 years) were randomly assigned to four groups. In the first group (n = 11), progressive muscle relaxation (PMR); in the second group (n = 11), phase III CR; and in the third group (n = 11), PMR along with phase III CR were performed for 8 weeks at home. The fourth group (n = 7) was used as the control group. Short form of QOL questionnaire (SF-36) was used for data gathering. Data analysis was performed using χ2, Kruskal-Wallis, and rank sum difference tests. Results: After phase III CR, relaxation, and combination of CR and relaxation, patients demonstrated improved QOL (P < 0.001). The results of post-test multiple comparisons showed that there were statistically significant differences between control and all intervention groups (P < 0.05). There was also statistically significant difference between relaxation and combination of phase III CR and relaxation groups (P < 0.5). Conclusions: An 8-week phase III CR program together with relaxation improved QOL of patients with cardiac syndrome X. We suggest phase III CR program together with relaxation as an effective treatment in these patients. PMID:23922604

  7. [Alemtuzumab for relapsing-remitting multiple sclerosis. Results of two randomized controlled phase III studies].

    PubMed

    Klotz, L; Meuth, S G; Kieseier, B; Wiendl, H

    2013-08-01

    In November 2012 the results of 2 clinical phase III trials were published which addressed the effects of alemtuzumab in patients with relapsing-remitting multiple sclerosis (MS). In the CARE-MS-I study patients with early untreated MS (EDSS ≤ 3.0, disease duration < 5 years) were included, whereas CARE-MS-II investigated the effects of alemtuzumab in patients with persisting disease activity under standard disease-modifying treatment (EDSS ≤ 5.0, disease duration < 10 years). These groups were compared to patients under treatment with frequently applied interferon β 1a (3 times  44 µg subcutaneous). Both studies clearly demonstrated a superiority of alemtuzumab compared to interferon in terms of reduction of relapse rate as well as the number of new or enlarging T2 lesions and gadolinium-enhancing lesions. Moreover, the CARE-MS-II study showed a significant delay in disease progression by alemtuzumab. The portfolio and the frequency of relevant side effects, such as infusion-related reactions, development of secondary autoimmunity or infections were within the expected range. Taken together these studies confirm the high anti-inflammatory efficacy of alemtuzumab and hence provide the first evidence of superiority of a monotherapy in direct comparison to standard disease-modifying treatment in two phase III trials in relapsing-remitting MS. These data in the context of the mode of action of alemtuzumab provide evidence for the relevance of immune cells, especially T cells, in the pathophysiology of MS. Experience with long-term effects of alemtuzumab, e.g. from the phase II extension trial as well as the side effect profile argue in favor of a sustained reprogramming of the immune system as a consequence of immune cell depletion by alemtuzumab.

  8. Effect of Carbon Ion Radiotherapy for Sacral Chordoma: Results of Phase I-II and Phase II Clinical Trials

    SciTech Connect

    Imai, Reiko; Kamada, Tadashi; Tsuji, Hiroshi; Sugawara, Shinji; Serizawa, Itsuko; Tsujii, Hirohiko; Tatezaki, Shin-ichiro

    2010-08-01

    Purpose: To summarize the results of treatment for sacral chordoma in Phase I-II and Phase II carbon ion radiotherapy trials for bone and soft-tissue sarcomas. Patients and Methods: We performed a retrospective analysis of 38 patients with medically unresectable sacral chordomas treated with the Heavy Ion Medical Accelerator in Chiba, Japan between 1996 and 2003. Of the 38 patients, 30 had not received previous treatment and 8 had locally recurrent tumor after previous resection. The applied carbon ion dose was 52.8-73.6 Gray equivalents (median, 70.4) in a total of 16 fixed fractions within 4 weeks. Results: The median patient age was 66 years. The cranial tumor extension was S2 or greater in 31 patients. The median clinical target volume was 523 cm{sup 3}. The median follow-up period was 80 months. The 5-year overall survival rate was 86%, and the 5-year local control rate was 89%. After treatment, 27 of 30 patients with primary tumor remained ambulatory with or without supportive devices. Two patients experienced severe skin or soft-tissue complications requiring skin grafts. Conclusion: Carbon ion radiotherapy appears effective and safe in the treatment of patients with sacral chordoma and offers a promising alternative to surgery.

  9. Emerging drugs for antipsychotic-induced tardive dyskinesia: investigational drugs in Phase II and Phase III clinical trials.

    PubMed

    Lockwood, Jonathan Tomas; Remington, Gary

    2015-09-01

    Antipsychotic drugs (APs) represent the mainstay of treatment for schizophrenia and other forms of psychosis. Tardive dyskinesia (TD) is a motor disorder associated with the ongoing use of APs and is characterized by involuntary, repetitive movements that are potentially irreversible. Current treatment is wanting, due in part to our limited understanding of the mechanisms underlying TD. Risk of TD associated with APs appears linked to continuous blockade of dopamine D2 receptors in the basal ganglia. Proposed mechanisms include increased dopamine activation of D2 receptors caused by supersensitivity and neurodegeneration of dopamine-producing neurons due to biochemical changes incurred by ongoing AP exposure. Existing treatments are designed to reverse or prevent the neurochemical/biological changes caused by dopamine D2 receptor blockade and include vesicular monoamine transporter (VMAT) inhibitors, antioxidants, compounds with serotonin receptor agonism as well as antagonism, GABA agonists and cholinergic agents. Randomized, controlled trials in Phase II and Phase III (ClinicalTrials.org/ClinicalTrialsRegister.eu) are summarized and discussed. Effective adjunctive treatment for the symptoms of TD will depend on gaining a better understanding of the neurological changes induced by chronic dopamine D2 receptor antagonism from APs.

  10. Comparison of futility monitoring guidelines using completed phase III oncology trials.

    PubMed

    Zhang, Qiang; Freidlin, Boris; Korn, Edward L; Halabi, Susan; Mandrekar, Sumithra; Dignam, James J

    2017-02-01

    Futility (inefficacy) interim monitoring is an important component in the conduct of phase III clinical trials, especially in life-threatening diseases. Desirable futility monitoring guidelines allow timely stopping if the new therapy is harmful or if it is unlikely to demonstrate to be sufficiently effective if the trial were to continue to its final analysis. There are a number of analytical approaches that are used to construct futility monitoring boundaries. The most common approaches are based on conditional power, sequential testing of the alternative hypothesis, or sequential confidence intervals. The resulting futility boundaries vary considerably with respect to the level of evidence required for recommending stopping the study. We evaluate the performance of commonly used methods using event histories from completed phase III clinical trials of the Radiation Therapy Oncology Group, Cancer and Leukemia Group B, and North Central Cancer Treatment Group. We considered published superiority phase III trials with survival endpoints initiated after 1990. There are 52 studies available for this analysis from different disease sites. Total sample size and maximum number of events (statistical information) for each study were calculated using protocol-specified effect size, type I and type II error rates. In addition to the common futility approaches, we considered a recently proposed linear inefficacy boundary approach with an early harm look followed by several lack-of-efficacy analyses. For each futility approach, interim test statistics were generated for three schedules with different analysis frequency, and early stopping was recommended if the interim result crossed a futility stopping boundary. For trials not demonstrating superiority, the impact of each rule is summarized as savings on sample size, study duration, and information time scales. For negative studies, our results show that the futility approaches based on testing the alternative hypothesis

  11. Lunar exploration phase III: Launch window and trajectory design for a lunar lander

    NASA Astrophysics Data System (ADS)

    Li, Jingyang; Yang, Hongwei; Baoyin, Hexi

    2015-09-01

    The lunar exploration phase III mission is a part of the China Aerospace Science and Technology Corporation's lunar exploration program that will perform a soft-landing and sample return from the Moon to test the key technologies that are required for human lunar missions. This paper focuses primarily on the trajectory design and orbital launch window generation for a lunar probe that are consistent with the constraints imposed by third phase of lunar exploration. Two categories of trajectories are explored: Earth-to-Moon and Moon-to-Earth. With the patched conic technique, the analytical and modified analytical models of the transfer trajectories are developed. The requirement of high-latitude landing for the return phase trajectory is considered in the modified model. By varying the initial input conditions and with a fast convergence iteration scheme, different characteristics of the transfer trajectory are generated. The orbital launch windows are established to study the mission sensitivities to time and fuel consumption and to provide a launch timetable that is compatible with this mission's requirements. The lunar surface stay time is analyzed for different conditions. The high-fidelity gravitational model is introduced to demonstrate the accuracy and convergence behavior of the analytical solution. The design method can also be used as a basis for the future human lunar missions.

  12. Quantification of apixaban's therapeutic utility in prevention of venous thromboembolism: selection of phase III trial dose.

    PubMed

    Leil, T A; Feng, Y; Zhang, L; Paccaly, A; Mohan, P; Pfister, M

    2010-09-01

    A model-based approach was used to integrate data from a phase II study in order to provide a quantitative rationale for selecting the apixaban dosage regimen for a phase III trial. The exposure-response models demonstrated that an increase in daily steady-state area under the plasma concentration-vs.-time curve (AUC(ss)) of 1 microg x h/ml would increase the odds ratio for major bleeding by 0.118 and decrease the odds ratio for venous thromboembolism (VTE) by 0.0499. The therapeutic utility index (TUI) was used to integrate the efficacy and safety predictions to quantify apixaban's efficacy/safety balance as a function of AUC(ss). Of the apixaban dosage regimens tested in phase II, the 2.5 mg twice-daily (b.i.d.) dosage regimen had the highest TUI (86.2%). This was also higher than the TUI for either 30 mg b.i.d. enoxaparin (82.5%) or for warfarin (71.8%). Subjects with moderate renal impairment are expected to have a 43% increase in apixaban exposure; however, apixaban's TUI suggests that dose adjustment is not needed in these subjects with renal impairment.

  13. Objective Lightning Probability Forecasting for Kennedy Space Center and Cape Canaveral Air Force Station, Phase III

    NASA Technical Reports Server (NTRS)

    Crawford, Winifred C.

    2010-01-01

    The AMU created new logistic regression equations in an effort to increase the skill of the Objective Lightning Forecast Tool developed in Phase II (Lambert 2007). One equation was created for each of five sub-seasons based on the daily lightning climatology instead of by month as was done in Phase II. The assumption was that these equations would capture the physical attributes that contribute to thunderstorm formation more so than monthly equations. However, the SS values in Section 5.3.2 showed that the Phase III equations had worse skill than the Phase II equations and, therefore, will not be transitioned into operations. The current Objective Lightning Forecast Tool developed in Phase II will continue to be used operationally in MIDDS. Three warm seasons were added to the Phase II dataset to increase the POR from 17 to 20 years (1989-2008), and data for October were included since the daily climatology showed lightning occurrence extending into that month. None of the three methods tested to determine the start of the subseason in each individual year were able to discern the start dates with consistent accuracy. Therefore, the start dates were determined by the daily climatology shown in Figure 10 and were the same in every year. The procedures used to create the predictors and develop the equations were identical to those in Phase II. The equations were made up of one to three predictors. TI and the flow regime probabilities were the top predictors followed by 1-day persistence, then VT and Ll. Each equation outperformed four other forecast methods by 7-57% using the verification dataset, but the new equations were outperformed by the Phase II equations in every sub-season. The reason for the degradation may be due to the fact that the same sub-season start dates were used in every year. It is likely there was overlap of sub-season days at the beginning and end of each defined sub-season in each individual year, which could very well affect equation

  14. Phase transitions in Group III-V and II-VI semiconductors at high pressure

    NASA Technical Reports Server (NTRS)

    Yu, S. C.; Liu, C. Y.; Spain, I. L.; Skelton, E. F.

    1979-01-01

    The structures and transition pressures of Group III-V and II-VI semiconductors and of a pseudobinary system (Ga/x/In/1-x/Sb) have been investigated. Results indicate that GaP, InSb, GaSb, GaAs and possible AlP assume Metallic structures at high pressures; a tetragonal, beta-Sn-like structure is adopted by only InSb and GaSb. The rocksalt phase is preferred in InP, InAs, AlSb, ZnO and ZnS. The model of Van Vechten (1973) gives transition pressures which are in good agreement with measured values, but must be refined to account for the occurrence of the ionic rocksalt structure in some compounds. In addition, discrepancies between the theoretical scaling values for volume changes at the semiconductor-to-metal transitions are observed.

  15. Runaway electron damage to the Tore Supra Phase III outboard pump limiter

    SciTech Connect

    Nygren, R.; Lutz, T.; Walsh, D.; Martin, G.; Chatelier, M.; Loarer, T.; Guilhem, D.

    1996-08-01

    Operation of the Phase III outboard pump limiter (OPL) in Tore Supra in 1994 was terminated prematurely when runaway electrons during the current decay following a disruption pierced leading edge tube on the electron side and caused a water leak. The location, about 20 mm outside the last closed flux surface during normal operation, and the infrared (IR) images of the limiter indicate that the runaways moved in large outward steps, i.e. tens of millimeters, in one toroidal revolution. For plasma (runaway) currents in the range of 155 to 250 kA, the drift orbits open to the outside. Basic trajectory computations suggest that such motion is possible under the conditions present for this experiment. Activation measurements made on sections of the tube to indicate the area of local damage are presented here. An understanding of this event may provide important guidance regarding the potential damage from runaways in future tokamaks.

  16. Analysis of experiments in the Phase III GCFR benchmark critical assembly

    SciTech Connect

    Hess, A.L.; Baylor, K.J.

    1980-04-01

    Experiments carried out in the third gas-cooled fast breeder reactor (GCFR) benchmark critical assembly on the Zero Power Reactor-9 at Argonne National Laboratory were analyzed using methods and computer codes employed routinely for design and performance evaluations on power-plant GCFR cores. The program for the Phase III GCFR assembly, with a 1900-liter, three-enrichment zone core, included measurements of reaction-rate profiles in a typical power-flattened design, studies of material reactivity coefficients, reaction ratio and breeding parameter determinations, and comparison of pin with plate fuel loadings. Calculated parameters to compare with all of the measured results were obtained using 10-group cross sections based on ENDF/B-4 and two-dimensional diffusion theory, with adjustments for fuel-cell heterogeneity and void-lattice streaming effects.

  17. Investor Outlook: Significance of the Positive LCA2 Gene Therapy Phase III Results.

    PubMed

    Schimmer, Joshua; Breazzano, Steven

    2015-12-01

    Spark Therapeutics recently reported positive phase III results for SPK-RPE65 targeting the treatment of visual impairment caused by RPE65 gene mutations (often referred to as Leber congenital amaurosis type 2, or LCA2, but may include other retinal disorders), marking an important inflection point for the field of gene therapy. The results highlight the ability to successfully design and execute a randomized trial of a gene therapy and also reinforce the potentially predictive nature of early preclinical and clinical data. The results are expected to pave the way for the first approved gene therapy product in the United States and should sustain investor interest and confidence in gene therapy for many approaches, including retina targeting and beyond.

  18. Production circulator fabrication and testing for core flow test loop. Final report, Phase III

    SciTech Connect

    Not Available

    1981-05-01

    The performance testing of two production helium circulators utilizing gas film lubrication is described. These two centrifugal-type circulators plus an identical circulator prototype will be arranged in series to provide the helium flow requirements for the Core Flow Test Loop which is part of the Gas-Cooled Fast Breeder Reactor Program (GCFR) at the Oak Ridge National Laboratory. This report presents the results of the Phase III performance and supplemental tests, which were carried out by MTI during the period of December 18, 1980 through March 19, 1981. Specific test procedures are outlined and described, as are individual tests for measuring the performance of the circulators. Test data and run descriptions are presented.

  19. Investigational drug tracking: phases I-III and NDA submissions--Part II.

    PubMed

    Grant, K L

    1994-10-01

    The author catalogs over 800 investigational drugs/biologicals currently in Phase I, II or III clinical trials or drugs/biologicals submitted to the FDA as new drug applications. Part I of this article appeared in the September issue of Hospital Pharmacy. The list assists in predicting when new drugs will be marketed. The entries include generic/chemical name, investigational drug number, synonyms, trade names, manufacturers, clinical trial status, predicted approval year, indications or drug class, whether the drug has been developed through biotechnology, and references. Entries were gleaned from medical journals, stock market analysis publications, and the Pharmaceutical Manufacturers Association's Medicines in Development Series. The list is alphabetized by the generic/chemical name or investigational drug number and cross-indexed by the trade name and synonyms. The list reflects those drugs which were not FDA approved as of April 15, 1994. Part I concludes with the remaining alphabetical listing by generic/chemical name or investigational drug number.

  20. Bevacizumab in ovarian cancer: A critical review of phase III studies.

    PubMed

    Rossi, Luigi; Verrico, Monica; Zaccarelli, Eleonora; Papa, Anselmo; Colonna, Maria; Strudel, Martina; Vici, Patrizia; Bianco, Vincenzo; Tomao, Federica

    2017-02-14

    Bevacizumab (BV) is a humanized monoclonal antibody targeting vascular endothelial growth factor and it is the first molecular-targeted agent to be used for the treatment of ovarian cancer (OC). Randomized Phase III trials evaluated the combination of BV plus standard chemotherapy for first-line treatment of advanced OC and for platinum-sensitive and platinum-resistant recurrent OC. These trials reported a statistically significant improvement in progression-free survival but not in overall survival. Furthermore, BV effectively improved the quality of life with regard to abdominal symptoms in recurrent OC patients. Bevacizumab is associated with adverse events such as hypertension, bleeding, thromboembolism, proteinuria, delayed wound healing, and gastrointestinal events. However, most of these events can be adequately managed. This review describes the latest evidence for BV treatment of OC and selection of patients for personalized treatment.

  1. Nonisovalent Si-III-V and Si-II-VI alloys: Covalent, ionic, and mixed phases

    DOE PAGES

    Kang, Joongoo; Park, Ji -Sang; Stradins, Pauls; ...

    2017-07-13

    In this paper, nonequilibrium growth of Si-III-V or Si-II-VI alloys is a promising approach to obtaining optically more active Si-based materials. We propose a new class of nonisovalent Si2AlP (or Si2ZnS) alloys in which the Al-P (or Zn-S) atomic chains are as densely packed as possible in the host Si matrix. As a hybrid of the lattice-matched parent phases, Si2AlP (or Si2ZnS) provides an ideal material system with tunable local chemical orders around Si atoms within the same composition and structural motif. Here, using first-principles hybrid functional calculations, we discuss how the local chemical orders affect the electronic and opticalmore » properties of the nonisovalent alloys.« less

  2. Edoxaban: Review of pharmacology and key phase I to III clinical trials.

    PubMed

    Plitt, Anna; Giugliano, Robert P

    2014-09-01

    Vitamin K antagonists (VKAs) remain the standard therapy for anticoagulation in prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in atrial fibrillation (AF). Due to numerous limitations of VKAs, target-specific oral anticoagulants have been developed. Edoxaban is a direct activated factor X inhibitor with attractive features among which are once daily dosing, no need for routine monitoring, and minimal drug-drug interactions. In patients undergoing orthopedic surgery, edoxaban was superior to enoxaparin in preventing VTE. Furthermore, a recent large-scale phase III trial in patients with symptomatic VTE demonstrated that edoxaban was noninferior to warfarin in preventing recurrent VTE and reduced bleeding. In the largest trial of anticoagulation in patients with AF to date, edoxaban was noninferior to warfarin in the prevention of stroke or systemic embolism and reduced bleeding and cardiovascular mortality. This review provides an overview of the pharmacology, clinical trial results, and potential indications for edoxaban.

  3. Nonisovalent Si-III-V and Si-II-VI alloys: Covalent, ionic, and mixed phases

    NASA Astrophysics Data System (ADS)

    Kang, Joongoo; Park, Ji-Sang; Stradins, Pauls; Wei, Su-Huai

    2017-07-01

    Nonequilibrium growth of Si-III-V or Si-II-VI alloys is a promising approach to obtaining optically more active Si-based materials. We propose a new class of nonisovalent S i2AlP (or S i2ZnS ) alloys in which the Al-P (or Zn-S) atomic chains are as densely packed as possible in the host Si matrix. As a hybrid of the lattice-matched parent phases, S i2AlP (or S i2ZnS ) provides an ideal material system with tunable local chemical orders around Si atoms within the same composition and structural motif. Here, using first-principles hybrid functional calculations, we discuss how the local chemical orders affect the electronic and optical properties of the nonisovalent alloys.

  4. Evaluating Intermittent Androgen-Deprivation Therapy Phase III Clinical Trials: The Devil Is in the Details

    PubMed Central

    Tangen, Catherine; Higano, Celestia; Vogelzang, Nicholas; Thompson, Ian

    2016-01-01

    Purpose Intermittent androgen deprivation (IAD) has been widely tested in prostate cancer. However, phase III trials testing continuous androgen deprivation (CAD) versus IAD have reached inconclusive and seemingly contradictory results. Different design and conduct issues must be critically evaluated to better interpret the results. Patients and Methods Seven published phase III trials were examined for prespecified design and outcomes. Treatment specifications; primary end point; superiority versus noninferiority design assumptions, including magnitude of assumed versus observed noninferiority margin (NIM); duration of follow-up; and quality-of-life (QOL) outcomes were considered in terms of the results and conclusions reported. Results Five trials had a superiority and three had a noninferiority primary hypothesis. Only three trials had a uniform population and overall survival (OS) end point. All trials observed better outcomes in terms of OS and progression-free survival (PFS) than assumed at time of study design, translating into prespecified NIMs or hazard ratios that reflected larger absolute differences in OS or PFS between arms. Lower-than-expected event rates also reduced statistical power for the trials. Other factors, including length of follow-up, cause of death, QOL, and primary end point, and their impact on trial interpretation are discussed. Conclusion No trial to date has demonstrated survival superiority of IAD compared with CAD. Trials concluding IAD is noninferior to CAD were based on wide NIMs that included clinically important survival differences, not likely to be considered comparable by physicians or patients. Interim analyses relying on short follow-up and including a majority of non–prostate cancer deaths will favor a noninferiority conclusion and should be interpreted cautiously. Adequate follow-up is required to ensure capture of prostate cancer deaths in both superiority and noninferiority trials. PMID:26552421

  5. Randomized phase III trial of pegfilgrastim versus filgrastim after autologus peripheral blood stem cell transplantation.

    PubMed

    Gerds, Aaron; Fox-Geiman, Mary; Dawravoo, Kevin; Rodriguez, Tulio; Toor, Amir; Smith, Scott; Kiley, Karen; Fletcher-Gonzalez, Donna; Hicks, Chindo; Stiff, Patrick

    2010-05-01

    Nonrandomized trials suggest that pegfilgrastim, a pegylated granulocyte colony-stimulating factor, could be used in lieu of filgrastim after autologus peripheral blood stem cell transplantation. This phase III, randomized, double-blinded, placebo-controlled trial compared the efficacy, costs, and safety of single-dose pegfilgrastim (single 6 mg dose) versus daily filgrastim (5 microg/kg/day) for this indication. Seventy-eight patients, matched for age, sex, underlying disease, stage, and CD34/kg transplant dose were enrolled. Cytokines were started on day +1 posttransplant and continued to an absolute neutrophil count (ANC) of 5x10(9)/L for 3 days or 10x10(9)/L for 1 day. The median time to neutrophil engraftment (ANC >1.5x10(9)/L for 3 days or 5x10(9)/L for 1 day) was the same in both groups (12 days). No differences in platelet engraftment (11 versus 13 days), number of platelet transfusions (5 versus 4), percent with positive cultures for bacterial pathogens (23% versus 15%), days of fever (1 versus 2), deaths prior to engraftment (1 versus 1), or duration of hospital stay (19 versus 19 days) were seen between the pegfilgrastim and filgrastim groups, respectively. Using the average wholesale price for doses used in this trial, there was a per-patient savings of $961 for the pegfilgrastim group (P < .001). This phase III study failed to demonstrate a difference in time to neutrophil engraftment or any clinical sequelae between pegfilgrastim and filgrastim when given post-APBSCT, with pegfilgrastim achieving a cost savings over filgrastim. Copyright 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  6. Structural and phase transformation of A{sup III}B{sup V}(100) semiconductor surface in interaction with selenium

    SciTech Connect

    Bezryadin, N. N.; Kotov, G. I. Kuzubov, S. V.

    2015-03-15

    Surfaces of GaAs(100), InAs(100), and GaP(100) substrates thermally treated in selenium vapor have been investigated by transmission electron microscopy and electron probe X-ray microanalysis. Some specific features and regularities of the formation of A{sub 3}{sup III}B{sub 4}{sup VI} (100)c(2 × 2) surface phases and thin layers of gallium or indium selenides A{sub 2}{sup III}B{sub 3}{sup VI} (100) on surfaces of different A{sup III}B{sup V}(100) semiconductors are discussed within the vacancy model of surface atomic structure.

  7. Contribution of capecitabine for therapy of patients with gastroesophageal cancer: an update of recent phase III results

    PubMed Central

    Cen, Putao; Tetzlaff, Eric D; Ajani, Jaffer A

    2008-01-01

    Background Capecitabine, an orally administered fluoropyrimidines, is widely used in the treatment of multiple malignancies. It has been extensively evaluated in patients with gastroesophageal carcinoma. Since recent reviews have discussed phase I/II trials (Cancer 107:221–231, 2006; Drugs 67:601–610, 2007), we focus on the impact of the results of the most current phase III trials using capectiabine in the treatment of advanced gastroesophageal cancers, primarily in the first-line setting. Methods To find published phase III trials, Medline was searched for English-language clinical trials published from 1996 through June 2007 along with relevant abstracts presented at the American Society of Clinical Oncology, and meetings of the European Cancer Conference and European Society of Medical Oncology. Only representative trials were chosen for this manuscript. Results The most frequently investigated combinations are capecitabine with taxanes, platinols, and camptothecins. Recent results of a large phase III trial (REAL-2) in untreated patients with gastroesophageal cancer suggest that capecitabine is a non-inferior substitute for intravenous 5-fluorouracil. These results of REAL-2 trial are substantiated by a smaller phase III trial. Previous analysis of multiple trials had suggested that capecitabine, when combined in doses lower than 1250 mg/m2 twice daily, consistently resulted in lower frequency of Grade 3 or 4 toxic effects. Conclusions Capecitabine provides much needed convenience to patients with gastroesophageal cancer. The recent data derived from two phase III trials confirm that capecitabine is a suitable substitute for intravenous 5-fluorouracil in patients whose swallowing is not greatly affected. Capecitabine remains a subject of further investigations in this group of patients with interest. PMID:18728703

  8. Stereotactic Injection of DTI-015 into Recurrent Malignant Gliomas: Phase I/II Trial

    PubMed Central

    Hassenbusch, Samuel J; Nardone, Emilio M; Levin, Victor A; Leeds, Norman; Pietronigro, Dennis

    2003-01-01

    Abstract DTI-015 (BCNU in 100% ethanol) utilizes solvent facilitated perfusion for the intratumoral treatment of gliomas. The ethanol solvent vehicle facilitates a rapid and thorough saturation of the tumor with the dissolved anticancer agent BCNU. We conducted a phase I/II dose escalation study of DTI-015 in 40 heavily pretreated patients with inoperable recurrent malignant glioma. The study goals were to establish a maximally tolerated dose (MTD) for DTI-015 and assess its safety and activity. Patients received stereotactic intratumoral injection of DTI-015 under magnetic resonance imaging guidance. Dose escalation was performed in two phases. First, DTI-015 volume was escalated at a set BCNU concentration of 12.5 mg/ml; second, BCNU mg dose was escalated by increasing BCNU concentration to 30, 45, 60, and 75 mg/ml. A MTD of 5 ml and 240 mg was established. Twenty-five of 28 DTI-015 treatments (89%) using ≤MTD were administered safely without producing high-grade drug-related adverse events. Median survival for GBM patients administered DTI-015 at ≤MTD was 55 weeks. Magnetic resonance imaging demonstrated stable disease in 72% of evaluable patients with a median of 10.5 weeks. The results suggest that DTI-015 administered at ≤MTD is well tolerated and active in patients with inoperable recurrent GBM. PMID:12659665

  9. Phase III Drilling Operations at the Long Valley Exploratory Well (LVF 51-20)

    SciTech Connect

    Finger, J.T.; Jacobson, R.D.

    1999-06-01

    During July-September, 1998, a jointly funded drilling operation deepened the Long Valley Exploratory Well from 7178 feet to 9832 feet. This was the third major drilling phase of a project that began in 1989, but had sporadic progress because of discontinuities in tiding. Support for Phase III came from the California Energy Commission (CEC), the International Continental Drilling Program (ICDP), the US Geological Survey (USGS), and DOE. Each of these agencies had a somewhat different agenda: the CEC wants to evaluate the energy potential (specifically energy extraction from magma) of Long Valley Caldera; the ICDP is studying the evolution and other characteristics of young, silicic calderas; the USGS will use this hole as an observatory in their Volcano Hazards program; and the DOE, through Sandia, has an opportunity to test new geothermal tools and techniques in a realistic field environment. This report gives a description of the equipment used in drilling and testing; a narrative of the drilling operations; compiled daily drilling reports; cost information on the project; and a brief summary of engineering results related to equipment performance and energy potential. Detailed description of the scientific results will appear in publications by the USGS and other researchers.

  10. The EORTC emotional functioning computerized adaptive test: phases I–III of a cross-cultural item bank development

    PubMed Central

    Gamper, Eva-Maria; Groenvold, Mogens; Petersen, Morten Aa; Young, Teresa; Costantini, Anna; Aaronson, Neil; Giesinger, Johannes M; Meraner, Verena; Kemmler, Georg; Holzner, Bernhard

    2014-01-01

    Background The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group is currently developing computerized adaptive testing measures for the Quality of Life Questionnaire Core-30 (QLQ-C30) scales. The work presented here describes the development of an EORTC item bank for emotional functioning (EF), which is one of the core domains of the QLQ-C30. Methods According to the EORTC guidelines on module development, the development of the EF item bank comprised four phases, of which the phases I–III are reported in the present paper. Phase I involved defining the theoretical framework for the EF item bank and a literature search. Phase II included pre-defined item selection steps and a multi-stage expert review process. In phase III, feedback from cancer patients from different countries was obtained. Results On the basis of literature search in phase I, a list of 1750 items was generated. These were reviewed and further developed in phase II with a focus on relevance, redundancy, clarity, and difficulty. The development and selection steps led to a preliminary list of 41 items. In phase III, patient interviews (N = 41; Austria, Denmark, Italy, and the UK) were conducted with the preliminary item list, resulting in some minor changes to item wording. The final list comprised 38 items. Discussion The phases I–III of the developmental process have resulted in an EF item list that was well accepted by patients in several countries. The items will be subjected to larger-scale field testing in order to establish their psychometric characteristics and their fit to an item response theory model. PMID:24217943

  11. Bottlenecks in the development of topical analgesics: molecule, formulation, dose-finding, and phase III design

    PubMed Central

    Keppel Hesselink, Jan M; Kopsky, David J; Stahl, Stephen M

    2017-01-01

    Topical analgesics can be defined as topical formulations containing analgesics or co-analgesics. Since 2000, interest in such formulations has been on the rise. There are, however, four critical issues in the research and development phases of topical analgesics: 1) The selection of the active pharmaceutical ingredient. Analgesics and co-analgesics differ greatly in their mechanism of action, and it is required to find the most optimal fit between such mechanisms of action and the pathogenesis of the targeted (neuropathic) pain. 2) Issues concerning the optimized formulation. For relevant clinical efficacy, specific characteristics for the selected vehicle (eg, cream base or gel base) are required, depending on the physicochemical characteristics of the active pharmaceutical ingredient(s) to be delivered. 3) Well-designed phase II dose-finding studies are required, and, unfortunately, such trials are missing. In fact, we will demonstrate that underdosing is one of the major hurdles to detect meaningful and statistically relevant clinical effects of topical analgesics. 4) Selection of clinical end points and innovatively designed phase III trials. End point selection can make or break a trial. For instance, to include numbness together with tingling as a composite end point for neuropathic pain seems stretching the therapeutic impact of an analgesic too far. Given the fast onset of action of topical analgesics (usually within 30 minutes), enrichment designs might enhance the chances for success, as the placebo response might decrease. Topical analgesics may become promising inroads for the treatment of neuropathic pain, once sufficient attention is given to these four key aspects. PMID:28360532

  12. Effects of Combined Phase III and Phase II Cardiac Exercise Therapy for Middle-aged Male Patients with Acute Myocardial Infarction.

    PubMed

    Lee, Chih-Wei; Wang, Ji-Hung; Hsieh, Jen-Che; Hsieh, Tsung-Cheng; Huang, Chien-Hui

    2013-11-01

    [Purpose] To investigate the effects of cardiac exercise therapy (CET) on exercise capacity and coronary risk factors (CRFs) of patients with acute myocardial infarction (AMI). [Methods] Patients who participated in an 8-week supervised, hospital-based phase II and 6-month home-based phase III CET with monthly telephone and/or home visits were defined as the exercise group (EG) (n=20), while those who did not receive phase II or phase III CET were defined as the no-exercise group (NEG) (n=10). CRFs were evaluated pre- and post-phase II and eight months after discharge. One and two-way repeated measures ANOVA were used to perform intra- and inter-group comparisons. [Results] Thirty men with AMI aged 49.3 ± 8.3 years were studied. EG increased their exercise capacity (METs) (6.8 ± 1.6 vs.10.0 ± 1.9) after phase II CET and was able to maintain it at 8-month follow-up. Both groups had significantly fewer persons who kept on smoking compared to the first examination. High density lipoprotein cholesterol (HDL-C) increased from 38.1 ± 11.0 to 43.7 ± 8.7 mg/dl at follow-up in EG while no significant difference was noted in NEG. [Conclusion] After phase III CET subjects had maintained the therapeutic effects of smoking cessation, and increasing exercise capacity obtained in phase II CET. HDL-C in EG continued to improve during phase III CET.

  13. Erythropoietin Neuroprotection in Neonatal Cardiac Surgery: A Phase I/II Safety and Efficacy Trial

    PubMed Central

    Andropoulos, Dean B.; Brady, Ken; Easley, R. Blaine; Dickerson, Heather A.; Voigt, Robert G.; Shekerdemian, Lara S.; Meador, Marcie R.; Eisenman, Carol A.; Hunter, Jill V.; Turcich, Marie; Rivera, Carlos; McKenzie, E. Dean; Heinle, Jeffrey S.; Fraser, Charles D.

    2012-01-01

    Objectives Neonates undergoing complex congenital heart surgery have a significant incidence of neurological problems. Erythropoietin has anti-apoptotic, anti-excitatory, and anti-inflammatory properties to prevent neuronal cell death in animal models, and improves neurodevelopmental outcomes in full term neonates with hypoxic ischemic encephalopathy. We designed a prospective phase I/II trial of erythropoietin neuroprotection in neonatal cardiac surgery to assess safety, and indicate efficacy. Methods Neonates undergoing surgery for D-transposition of the great vessels, hypoplastic left heart syndrome, or aortic arch reconstruction were randomized to 3 perioperative doses of erythropoietin, or placebo. Neurodevelopmental testing with Bayley Scales of Infant and Toddler Development III was performed at age 12 months. Results 59 patients received study drug. Safety profile, including MRI brain injury, clinical events, and death, was not different between groups. 3 patients in each group died. 42 patients (22 erythropoietin, 20 placebo, 79% of survivors) returned for 12-month follow-up. The mean Cognitive Scores were erythropoietin, 101.1 ± 13.6, placebo, 106.3 ± 10.8 (p=0.19); Language Scores were erythropoietin 88.5 ± 12.8, placebo 92.4 ± 12.4 (p=0.33); and Motor Scores were erythropoietin 89.9 ± 12.3, placebo 92.6 ± 14.1, (p=0.51). Conclusions Safety profile for erythropoietin administration was not different than placebo. Neurodevelopmental outcomes were not different between groups, however this pilot study was not powered to definitively address this outcome. Lessons learned from the current study suggest optimized study design features for a larger prospective trial to definitively address the utility of erythropoietin for neuroprotection in this population. PMID:23102686

  14. Erythropoietin neuroprotection in neonatal cardiac surgery: a phase I/II safety and efficacy trial.

    PubMed

    Andropoulos, Dean B; Brady, Ken; Easley, Ronald B; Dickerson, Heather A; Voigt, Robert G; Shekerdemian, Lara S; Meador, Marcie R; Eisenman, Carol A; Hunter, Jill V; Turcich, Marie; Rivera, Carlos; McKenzie, Emmett D; Heinle, Jeffrey S; Fraser, Charles D

    2013-07-01

    Neonates undergoing complex congenital heart surgery have a significant incidence of neurologic problems. Erythropoietin has antiapoptotic, antiexcitatory, and anti-inflammatory properties to prevent neuronal cell death in animal models, and improves neurodevelopmental outcomes in full-term neonates with hypoxic ischemic encephalopathy. We designed a prospective phase I/II trial of erythropoietin neuroprotection in neonatal cardiac surgery to assess safety and indicate efficacy. Neonates undergoing surgery for D-transposition of the great vessels, hypoplastic left heart syndrome, or aortic arch reconstruction were randomized to 3 perioperative doses of erythropoietin or placebo. Neurodevelopmental testing using the Bayley Scales of Infant and Toddler Development III was performed at age 12 months. Fifty-nine patients received the study drug. Safety profile, including magnetic resonance imaging brain injury, clinical events, and death, was not different between groups. Three patients in each group died. Forty-two patients (22 in the erythropoietin group and 20 in the placebo group; 79% of survivors) returned for 12-month follow-up. In the group receiving erythropoietin, mean Cognitive Scale scores were 101.1 ± 13.6, Language Scale scores were 88.5 ± 12.8, and Motor Scale scores were 89.9 ± 12.3. In the group receiving placebo, Cognitive Scale scores were 106.3 ± 10.8 (P = .19), Language Scores were 92.4 ± 12.4 (P = .33), and Motor Scale scores were 92.6 ± 14.1 (P = .51). Safety profile for erythropoietin administration was not different than placebo. Neurodevelopmental outcomes were not different between groups; however, this pilot study was not powered to definitively address this outcome. Lessons learned suggest optimized study design features for a larger prospective trial to definitively address the utility of erythropoietin for neuroprotection in this population. Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby

  15. Promising short-term clinical results of the cementless Oxford phase III medial unicondylar knee prosthesis.

    PubMed

    van Dorp, Karin B; Breugem, Stefan Jm; Bruijn, Daniël J; Driessen, Marcel Jm

    2016-04-18

    To investigate the short-term clinical results of the Oxford phase III cementless medial unicondylar knee prosthesis (UKP) compared to the cemented medial UKP. We conducted a cross-sectional study in a tertairy orthopedic centre between the period of May 2010 and September 2012. We included 99 medial UKP in 97 patients and of these UKP, 53 were cemented and 46 were cementless. Clinical outcome was measured using a questionnaire, containing a visual analogue scale (VAS) for pain, Oxford Knee score, Kujala score and SF-12 score. Knee function was tested using the American Knee Society score. Complications, reoperations and revisions were recorded. Statistical significance was defined as a P value < 0.05. In a mean follow-up time of 19.5 mo, three cemented medial UKP were revised to a total knee prosthesis. Reasons for revision were malrotation of the tibial component, aseptic loosening of the tibial component and progression of osteoarthritis in the lateral- and patellofemoral compartment. In five patients a successful reoperation was performed, because of impingement or (sub)luxation of the polyethylene bearing. Patients with a reoperation were significant younger than patients in the primary group (56.7 vs 64.0, P = 0.01) and were more likely to be male (85.7% vs 38.8%, P = 0.015). Overall the cementless medial UKP seems to perform better, but the differences in clinical outcome are not significant; a VAS pain score of 7.4 vs 11.7 (P = 0.22), an Oxford Knee score of 43.3 vs 41.7 (P = 0.27) and a Kujala score of 79.6 vs 78.0 (P = 0.63). The American Knee Society scores were slightly better in the cementless group with 94.5 vs 90.2 (P = 0.055) for the objective score and 91.2 vs 87.8 (P = 0.25) for the subjective score. The cementless Oxford phase III medial UKP shows good short-term clinical results, when used in a specialist clinic by an experienced surgeon.

  16. SPSP Phase III Recruiting, Selecting, and Developing Secure Power Systems Professionals: Behavioral Interview Guidelines by Job Roles

    SciTech Connect

    O'Neil, Lori Ross; Conway, T. J.; Tobey, D. H.; Greitzer, Frank L.; Dalton, Angela C.; Pusey, Portia K.

    2015-03-01

    The Secure Power Systems Professional Phase III final report was released last year which an appendix of Behavioral Interview Guidelines by Job Roles. This new report is that appendix broken out as a standalone document to assist utilities in recruiting and developing Secure Power Systems Professionals at their site.

  17. Study of the Need for Educational Manpower for Handicapped Children and Youth: Part A - Phase III. Final Report.

    ERIC Educational Resources Information Center

    Mintz, Raymond D.; And Others

    Phase III of the Study of the Need for Educational Manpower for Handicapped Children and Youth, in demonstrating the feasibility of the Manpower Requirements Projection Model (MRPM), gathered data in the states necessary for implementation of the model. The MRPM was developed to enable state or local administrators of special education to estimate…

  18. 78 FR 73555 - Deepwater Horizon Oil Spill; Draft Programmatic and Phase III Early Restoration Plan and Draft...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-06

    ... the Deepwater Horizon Oil Spill (Framework Agreement), the Trustees have previously selected, and BP... Deepwater Horizon Oil Spill; Draft Programmatic and Phase III Early Restoration Plan and Draft Early... as a result of the Deepwater Horizon oil spill. The restoration alternatives are comprised of early...

  19. A Sequenced Instructional Program in Physical Education for the Handicapped, Phase III. Producing and Disseminating Demonstration Packages. Final Report.

    ERIC Educational Resources Information Center

    Carr, Dorothy B.; Avance, Lyonel D.

    Presented is a sequenced instructional program in physical education which constitutes the third of a three-phase, 4-year project, funded by Title III, for handicapped children, preschool through high school levels, in the Los Angeles Unified School District. Described are the project setting and the following accomplishments: a curriculum guide…

  20. Adjudication of osteonecrosis of the jaw in phase III randomized controlled trials of denosumab: a systematic review.

    PubMed

    de Boissieu, Paul; Kanagaratnam, L; Mahmoudi, R; Morel, A; Dramé, M; Trenque, T

    2017-05-01

    Denosumab (an anti RANKL antibody) is known to be associated with an increased risk for osteonecrosis of the jaw (ONJ). Due to the variety of clinical presentation, many ONJ definitions are used. Evaluation of ONJ's frequency during phase III randomized controlled trials (RCTs) is crucial to assess benefit-risk ratio. We verified that phase III RCTs involving denosumab reported the definition of ONJ used. We systematically searched in Central, Medline, Cochrane, and Scopus, until 31 August 2015. We included original phase III RCTs, involving denosumab. Post hoc analysis and trial extension were excluded. Articles that did not mention ONJ in their methods or results were excluded. The primary outcome was the prevalence of a complete definition of ONJ. When no definition was provided, ONJ adjudication process was analyzed. Of 313 articles found, 13 RCTs were included. A definition of ONJ was detailed in two RCTs (15%). For the remaining 11 RCTs, adjudication process was mentioned for nine. In those processes, "blinded," "expert," and "independent" were the most used words. Most of the published phase III RCTs involving denosumab did not specify the definition of ONJ used to adjudicate events in the study. Instead of definition, non-scientific and non-reproducible expressions were used. Because the chosen definition could impact the ONJ estimated frequency, it should be mandatory to give the precise definition used in each RCT publication involving denosumab.

  1. Clinical phase I/II research on ultrasound thermo-chemotherapy in oral and maxillofacial-head and neck carcinoma

    NASA Astrophysics Data System (ADS)

    Shen, Guofeng; Ren, Guoxin; Guo, Wei; Chen, Yazhu

    2012-11-01

    The principle of a ultrasound thermo-chemotherapy instrument and the clinical phase I/II research on short-term and long-term therapeutic effect and main side-effect of ultrasound hyperthermia combined with chemotherapy in oral and maxillofacial-head & neck carcinoma by the instrument will be presented in this paper.

  2. Georgetown University Integrated Community Energy System (GU-ICES). Phase III, Stage I: feasibility analysis. Final report

    SciTech Connect

    Buck, Victor

    1980-10-01

    Candidate energy alternatives are analyzed in Phase III, Stage I, and the appendices are presented for the feasibility analysis. Information in eight appendices includes the following: detailed statement of work; PEPCO rate schedules; cogeneration schemes; added coal, limestone, and ash storage; hot and cold thermal storage; absorption refrigeration; high temperature heat pumps; and life cycle cost analysis. (MCW)

  3. Explorations of new phases in the Ga(III)/In(III)-Cu(II)-Se(IV)-O system.

    PubMed

    Kong, Fang; Lin, Qi-Pu; Yi, Fei-Yan; Mao, Jiang-Gao

    2009-07-20

    Four new gallium(III)/indium(III), copper(II), selenium(IV) oxides, namely, Ga(2)Cu(SeO(3))(4) (1), Ga(2)CuO(SeO(3))(3) (2), and M(2)Cu(3)(SeO(3))(6) (M = Ga 3, In 4), have been synthesized by hydrothermal or high-temperature solid-state reactions. The structure of Ga(2)Cu(SeO(3))(4) (1) features a 2D layer of corner-sharing GaO(6) and CuO(6) octahedra with the SeO(3) groups hanging on both sides of the 2D layer. Ga(2)CuO(SeO(3))(3) (2) features a pillared layered structure in which the 1D Cu(SeO(3))(3)(4-) chains act as the pillars between 2D layers formed by corner- and edge-sharing GaO(n) (n = 4, 5) polyhedra. Although the chemical compositions of M(2)Cu(3)(SeO(3))(6) (M = Ga 3, In 4) are comparable, they belong to two different structural types. Ga(2)Cu(3)(SeO(3))(6) (3) exhibits a pillared layered structure built by [Ga(2)Cu(3)(SeO(3))(4)](4+) thick layers with Se(3)O(3)(2-) groups as pillars. The structure of In(2)Cu(3)(SeO(3))(6) (4) features a 3D network composed of [In(2)(SeO(3))(2)](2+) layers and [Cu(3)(SeO(3))(4)](2-) layers interconnected through Se-O-Cu and In-O-Cu bridges, exhibiting 8-MR helical tunnels along the a-axis. Results of magnetic property measurements indicate that there are considerable antiferromagnetic interactions between copper(II) centers in Ga(2)CuO(SeO(3))(3) (2) and M(2)Cu(3)(SeO(3))(6) (M = Ga 3, In 4). Interestingly, Ga(2)Cu(3)(SeO(3))(6) (3) behaves as a weak ferromagnet below the critical temperature of T(c) = 15 K. Further magnetic studies indicate that the compound is a canted antiferromagnet with a large canting angle of about 7.1 degrees.

  4. IMPROVEMENT TO PIPELINE COMPRESSOR ENGINE RELIABILITY THROUGH RETROFIT MICRO-PILOT IGNITION SYSTEM -- PHASE III

    SciTech Connect

    Scott Chase; Daniel Olsen; Ted Bestor

    2005-03-01

    This report documents the third year's effort towards a 3-year program conducted by the Engines & Energy Conversion Laboratory (EECL) at Colorado State University (CSU) to develop micropilot ignition systems for existing pipeline compressor engines. Research activities for the overall program were conducted with the understanding that the efforts are to result in a commercial product to capture and disseminate the efficiency and environmental benefits of this new technology. Commercially-available fuel injection products were identified and applied to the program where appropriate. This approach will minimize the overall time-to-market requirements, while meeting performance and cost criteria. Two earlier phases of development precede this report. The objective for Phase I was to demonstrate the feasibility of retrofit micropilot ignition (RMI) systems for large bore, slow speed engines operating at low compression ratios under laboratory conditions at the EECL. The objective for Phase II was to further develop and optimize the micropilot ignition system at the EECL for large bore, slow speed engines operating at low compression ratios. These laboratory results were enhanced, then verified via a field demonstration project during Phase III of the Micropilot Ignition program. An Implementation Team of qualified engine retrofit service providers was assembled to install the retrofit micropilot ignition system for an engine operated by El Paso Pipeline Group at a compressor station near Window Rock, Arizona. Testing of this demonstration unit showed that the same benefits identified by laboratory testing at CSU, i.e., reduced fuel consumption and exhaust emissions (NOx, THC, CO, and CH2O). Installation efforts at Window Rock were completed towards the end of the budget period, which did not leave sufficient time to complete the durability testing. These efforts are ongoing, with funding provided by El Paso Pipeline Group, and the results will be documented in a report

  5. Phase-transformation-induced twinning of an iron(III) calix[4]pyrrolidine complex.

    PubMed

    Journot, Guillaume; Neier, Reinhard; Stoeckli-Evans, Helen

    2014-07-01

    The title compound, tetrachlorido-1κCl;2κ(3)Cl-(2,2,7,7,12,12,17,17-octamethyl-21,22,23,24-tetraazapentacyclo[16.2.1.1(3,6).1(8,11).1(13,16)]tetracosane-1κ(4)N,N',N'',N''')-μ2-oxido-diiron(III), [Fe2Cl4O(C28H52N4)], undergoes a slow phase transformation at ca 173 K from monoclinic space group P2(1)/n, denoted form (I), to the maximal non-isomorphic subgroup, triclinic space group P1, denoted form (II), which is accompanied by nonmerohedral twinning [twin fractions of 0.693 (4) and 0.307 (4)]. The transformation was found to be reversible, as on raising the temperature the crystal reverted to monoclinic form (I). In the asymmetric unit of form (I), Z' = 1, while in form (II), Z' = 2, with a very small reduction (ca 1.8%) in the unit-cell volume. The two independent molecules (A and B) in form (II) are related by a pseudo-twofold screw axis along the b axis. The molecular overlay of molecule A on molecule B has an r.m.s. deviation of 0.353 Å, with the largest distance between two equivalent atoms being 1.202 Å. The reaction of calix[4]pyrrolidine, the fully reduced form of meso-octamethylporphyrinogen, with FeCl3 gave a red-brown solid that was recrystallized from ethanol in air, resulting in the formation of the title compound. In both forms, (I) and (II), the Fe(III) atoms are coordinated to the macrocyclic ligand and have distorted octahedral FeN4OCl coordination spheres. These Fe(III) atoms lie out of the mean plane of the four N atoms, displaced towards the O atom of the [OFeCl3] unit by 0.2265 (5) Å in form (I), and by 0.2210 (14) and 0.2089 (14) Å, respectively, in the two independent molecules (A and B) of form (II). The geometry of the [OFeCl3] units are similar, with each Fe(III) atom having a tetrahedral coordination sphere. The NH H atoms are directed below the planes of the macrocycles and are hydrogen bonded to the coordinated Cl(-) ions. There are also intramolecular C-H···Cl hydrogen bonds present in both (I) and (II

  6. Solid Phase Extraction for Monitoring of Occupational Exposure to Cr (III)

    PubMed Central

    Shahtaheri, S.J.; Khadem, M.; Golbabaei, F.; Rahimi-Froushani, A.

    2007-01-01

    Chromium is an important constituent widely used in different industrial processes for production of various synthetic materials. For evaluation of workers’ exposure to trace toxic metal of Cr (III), environmental and biological monitoring are essential processes, in which, preparation of samples is one of the most time-consuming and error-prone aspects prior to analysis. The use of solid-phase extraction (SPE) has grown and is a fertile technique of sample preparation as it provides better results than those produced by liquid-liquid extraction (LLE). SPE using mini columns filled with XAD-4 resin was optimized regarding to sample pH, ligand concentration, loading flow rate, elution solvent, sample volume, elution volume, amount of resins, and sample matrix interferences. Chromium was retained on solid sorbent and was eluted with 2 M HNO3 followed by simple determination of analytes by using flame atomic absorption spectrometery. Obtained recoveries of metal ion were more than 92%. The optimized procedure was also validated with three different pools of spiked urine samples and showed a good reproducibility over six consecutive days as well as six within-day experiments. Through this study, suitable results were obtained for relative standard deviation, therefore, it is concluded that, this optimized method can be considered to be successful in simplifying sample preparation for trace residue analysis of Cr in different matrices for evaluation of occupational and environmental exposures. To evaluate occupational exposure to chromium, 16 urine samples were taken, prepared, and analyzed based on optimized procedure. PMID:19662187

  7. Epitaxial growth of three dimensionally structured III-V photonic crystal via hydride vapor phase epitaxy

    SciTech Connect

    Zheng, Qiye; Kim, Honggyu; Zhang, Runyu; Zuo, Jianmin; Braun, Paul V.; Sardela, Mauro; Balaji, Manavaimaran; Lourdudoss, Sebastian; Sun, Yan-Ting

    2015-12-14

    Three-dimensional (3D) photonic crystals are one class of materials where epitaxy, and the resultant attractive electronic properties, would enable new functionalities for optoelectronic devices. Here we utilize self-assembled colloidal templates to fabricate epitaxially grown single crystal 3D mesostructured Ga{sub x}In{sub 1−x}P (GaInP) semiconductor photonic crystals using hydride vapor phase epitaxy (HVPE). The epitaxial relationship between the 3D GaInP and the substrate is preserved during the growth through the complex geometry of the template as confirmed by X-ray diffraction (XRD) and high resolution transmission electron microscopy. XRD reciprocal space mapping of the 3D epitaxial layer further demonstrates the film to be nearly fully relaxed with a negligible strain gradient. Fourier transform infrared spectroscopy reflection measurement indicates the optical properties of the photonic crystal which agree with finite difference time domain simulations. This work extends the scope of the very few known methods for the fabrication of epitaxial III-V 3D mesostructured materials to the well-developed HVPE technique.

  8. Design of a phase III clinical trial with prospective biomarker validation: SWOG S0819.

    PubMed

    Redman, Mary W; Crowley, John J; Herbst, Roy S; Hirsch, Fred R; Gandara, David R

    2012-08-01

    The role of cetuximab in the treatment of advanced non-small cell lung cancer (NSCLC) is currently unclear. The molecular target of cetuximab, epidermal growth factor receptor (EGFR), as measured by FISH, has shown potential as a predictive biomarker for cetuximab efficacy in NSCLC. SWOG S0819 is a phase III trial evaluating both the value of cetuximab in this setting and EGFR FISH as a predictive biomarker. This work describes the decision process for determining the design and interim monitoring plan for S0819. Six possible designs were evaluated in terms of their properties and the hypotheses that can be addressed within the design constraints. A subgroup-focused, multiple-hypothesis design was selected for S0819 that incorporates coprimary endpoints to assess cetuximab in both the overall study population and among EGFR FISH-positive (FISH(+)) patients, with the sample size determined based on evaluation in the EGFR FISH(+) group. The chosen interim monitoring plan specifies interim evaluations of both efficacy and futility in the EGFR FISH(+) group alone. The futility-monitoring plan to determine early stopping in the EGFR FISH-nonpositive group is based on evaluation within the positive group, the entire study population, and the nonpositive group. SWOG S0819 uses a design that addresses both the biomarker-driven and general-efficacy objectives of this study.

  9. Reconstruction of genealogical relationships with applications to Phase III of HapMap

    PubMed Central

    Kyriazopoulou-Panagiotopoulou, Sofia; Kashef Haghighi, Dorna; Aerni, Sarah J.; Sundquist, Andreas; Bercovici, Sivan; Batzoglou, Serafim

    2011-01-01

    Motivation: Accurate inference of genealogical relationships between pairs of individuals is paramount in association studies, forensics and evolutionary analyses of wildlife populations. Current methods for relationship inference consider only a small set of close relationships and have limited to no power to distinguish between relationships with the same number of meioses separating the individuals under consideration (e.g. aunt–niece versus niece–aunt or first cousins versus great aunt–niece). Results: We present CARROT (ClAssification of Relationships with ROTations), a novel framework for relationship inference that leverages linkage information to differentiate between rotated relationships, that is, between relationships with the same number of common ancestors and the same number of meioses separating the individuals under consideration. We demonstrate that CARROT clearly outperforms existing methods on simulated data. We also applied CARROT on four populations from Phase III of the HapMap Project and detected previously unreported pairs of third- and fourth-degree relatives. Availability: Source code for CARROT is freely available at http://carrot.stanford.edu. Contact: sofiakp@stanford.edu PMID:21685089

  10. Phage idiotype vaccination: first phase I/II clinical trial in patients with multiple myeloma

    PubMed Central

    2014-01-01

    Background Multiple myeloma is characterized by clonal expansion of B cells producing monoclonal immunoglobulins or fragments thereof, which can be detected in the serum and/or urine and are ideal target antigens for patient-specific immunotherapies. Methods Using phage particles as immunological carriers, we employed a novel chemically linked idiotype vaccine in a clinical phase I/II trial including 15 patients with advanced multiple myeloma. Vaccines composed of purified paraproteins linked to phage were manufactured successfully for each patient. Patients received six intradermal immunizations with phage idiotype vaccines in three different dose groups. Results Phage idiotype was well tolerated by all study participants. A subset of patients (80% in the middle dose group) displayed a clinical response indicated by decrease or stabilization of paraprotein levels. Patients exhibiting a clinical response to phage vaccines also raised idiotype-specific immunoglobulins. Induction of a cellular immune response was demonstrated by a cytotoxicity assay and delayed type hypersensitivity tests. Conclusion We present a simple, time- and cost-efficient phage idiotype vaccination strategy, which represents a safe and feasible patient-specific therapy for patients with advanced multiple myeloma and produced promising anti-tumor activity in a subset of patients. PMID:24885819

  11. Unintentional Ga incorporation in metalorganic vapor phase epitaxy of In-containing III-nitride semiconductors

    NASA Astrophysics Data System (ADS)

    Hiroki, Masanobu; Oda, Yasuhiro; Watanabe, Noriyuki; Maeda, Narihiko; Yokoyama, Haruki; Kumakura, Kazuhide; Yamamoto, Hideki

    2013-11-01

    We prepared InAlN barrier layer films on GaN buffer layers using the metalorganic vapor phase epitaxy (MOVPE) method and investigated the InAlN/GaN heterointerfaces. Secondary ion spectroscopy experiments revealed that a quaternary alloy of InAlGaN is grown on GaN even when trimethylindium (TMIn) and trimethylaluminum (TMAl) are exclusively supplied as group-III precursors, indicating that Ga is unintentionally incorporated into the InAlN layers. This Ga incorporation is also observed in InGaN/GaN heterostructures. Our systematic investigations of the growth condition dependence, such as the TMIn flow rate, indicate that the Ga is supplied by a transmetalation reaction between TMIn and residual Ga on the flow distributor in the reactor. Here, we show that the Ga incorporation can be eliminated by adopting an elaborate growth sequence, including reactor cleaning and regrowth processes. This study provides guides for designing the MOVPE reactor configuration, as well as the growth sequences, for the growth of device structures with In-containing nitride layers.

  12. Targeting the dopamine receptor in schizophrenia: investigational drugs in Phase III trials.

    PubMed

    Rao, Naren P; Remington, Gary

    2014-02-01

    Antipsychotic drugs date back to the 1950s and chlorpromazine. Soon after, it was established that blockade of dopamine and, in particular, the D2 receptor was central to this effect. Dopamine continues to represent a critical line of investigation, although much of the work now focuses on its potential in other symptom domains. A search was carried out for investigational drugs using the key words 'dopamine', 'schizophrenia' and 'Phase III' in an American clinical trial registry (clinicaltrials.gov), published articles using the National Library of Medicine's PubMed database, and supplemented results with a manual search of cross-references and conference abstracts. Drugs were excluded that were already FDA approved. There remains interest, albeit diminished, in developing better antipsychotic compounds. The greatest enthusiasm currently centres on dopamine's role in negative and cognitive symptom domains. With theories conceptualising hypodopaminergic activity as underlying these deficits, considerable effort is focused on drug strategies that will enhance dopamine activity. Finally, a small body of research is investigating dopaminergic compounds vis-à-vis side-effect treatments. In domains beyond psychosis, however, dopamine arguably is not seen as so central, reflected in considerable research following other lines of investigation.

  13. Assessing braze quality in the actively cooled Tore Supra Phase III outboard pump limiter

    SciTech Connect

    Nygren, R.E.; Lutz, T.L.; Miller, J.D.; McGrath, R.; Dale, G.

    1994-12-31

    The quality of brazing of pyrolytic graphite armor brazed to copper tubes in Tore Supra`s Phase III Outboard Pump Limiter was assessed through pre-service qualification testing of individual copper/tile assemblies. The evaluation used non-destructive, hot water transient heating tests performed in the high-temperature, high-pressure flow loop at Sandia`s Plasma Materials Test Facility. Surface temperatures of tiles were monitored with an infrared camera as water at 120{degrees}C at about 2.07 MPa (300 psi) passed through a tube assembly initially at 30{degrees}C. For tiles with braze voids or cracks, the surface temperatures tagged behind those of adjacent well-bonded tiles. Temperature tags were correlated with flaw sizes observed during repairs based upon a detailed 2-D heat transfer analyses. {open_quotes}Bad{close_quotes} tiles, i.e., temperature tags of 10-20{degrees}C depending upon tile`s size, were easy to detect and, when removed, revealed braze voids of roughly 50% of the joint area. Eleven of the 14 tubes were rebrazed after bad tiles were detected and removed. Three tubes were rebrazed twice.

  14. Tier I ecological evaluation for phase III channel improvements to the John. F. Baldwin ship channel

    SciTech Connect

    Bienert, R.W.; Shreffler, D.K.; Word, J.Q.; Kohn, N.P.

    1994-05-01

    To assist the US Army Corps of Engineers (USACE) in determing whether the material from proposed dredging of the John F. Baldwin Ship Channel (JFBSC) is suitable for unrestricted, unconfined open-ocean disposal, Battelle/Marine Sciences Laboratory (MSL) prepared this report. Based on these findings, sediments that would be removed during Phase III improvements to the JFBSC fail to meet the three suitability criteria for open-ocean disposal. Firstly, fine-grained sediments comprise a significant fraction of the bottom material in some areas of the channel, and this material is not exposed to high current or wave energy. Dredged material from the JFBSC is not being proposed for beach nourishment; therefore the second criterion is not met. JFBSC sediments do not meet the third criterion because, although they may be substantially similar to substrates at several of the proposed disposal sites, they are from an area that historically has experienced loading of contaminants, which toxicology studies have shown have the potential to result in acute toxicity or significant bioaccumulation.

  15. Intensified Adjuvant Treatment of Prostate Carcinoma: Feasibility Analysis of a Phase I/II Trial

    PubMed Central

    Mantini, Giovanna; Fersino, Sergio; Frascino, Vincenzo; Massaccesi, Mariangela; Fionda, Bruno; Luzi, Stefano; Balducci, Mario; De Belvis, Antonio; Morganti, Alessio Giuseppe; Valentini, Vincenzo

    2014-01-01

    Purpose. To perform a preliminary feasibility acute and late toxicity evaluation of an intensified and modulated adjuvant treatment in prostate cancer (PCa) patients after radical prostatectomy. Material and Methods. A phase I/II has been designed. Eligible patients were 79 years old or younger, with an ECOG of 0–2, previously untreated, histologically proven prostate adenocarcinoma with no distant metastases, pT2–4 N0-1, and with at least one of the following risk factors: capsular perforation, positive surgical margins, and seminal vesicle invasion. All patients received a minimum dose on tumor bed of 64.8 Gy, or higher dose (70.2 Gy; 85.4%), according to the pathological stage, pelvic lymph nodes irradiation (57.7%), and/or hormonal therapy (69.1%). Results. 123 patients were enrolled and completed the planned treatment, with good tolerance. Median follow-up was 50.6 months. Grade 3 acute toxicity was only 2.4% and 3.3% for genitourinary (GU) and gastrointestinal (GI) tract, respectively. No patient had late grade 3 GI toxicity, and the GU grade 3 toxicity incidence was 5.8% at 5 years. 5-year BDSF was 90.2%. Conclusions. A modulated and intensified adjuvant treatment in PCa was feasible in this trial. A further period of observation can provide a complete assessment of late toxicity and confirm the BDSF positive results. PMID:25093169

  16. A decision-theoretic phase I-II design for ordinal outcomes in two cycles.

    PubMed

    Lee, Juhee; Thall, Peter F; Ji, Yuan; Müller, Peter

    2016-04-01

    This paper is motivated by a phase I-II clinical trial of a targeted agent for advanced solid tumors. We study a stylized version of this trial with the goal to determine optimal actions in each of two cycles of therapy. A design is presented that generalizes the decision-theoretic two-cycle design of Lee and others (2015. Bayesian dose-finding in two treatment cycles based on the joint utility of efficacy and toxicity. Journal of the American Statistical Association, to appear) to accommodate ordinal outcomes. Backward induction is used to jointly optimize the actions taken for each patient in each of the two cycles, with the second action accounting for the patient's cycle 1 dose and outcomes. A simulation study shows that simpler designs obtained by dichotomizing the ordinal outcomes either perform very similarly to the proposed design, or have much worse performance in some scenarios. We also compare the proposed design with the simpler approaches of optimizing the doses in each cycle separately, or ignoring the distinction between cycles 1 and 2.

  17. [The use of placebos in phase III clinical trials in Brazil].

    PubMed

    Rubenich, Gustavo Butzge; Heck, Stephanie Tomasi; Hellmann, Fernando; Schlemper Junior, Bruno Rodolfo

    2015-03-01

    In 2008, Brazil's Federal Council of Medicine [Conselho Federal de Medicina] (CFM)--regulatory and supervisory agency on the ethical practice of medicine--banned the participation of Brazilian doctors in studies using placebos for diseases with efficient and effective treatment. This position differs with the Helsinki Declaration, which allows the use of placebos in methodologically justified conditions. To ascertain whether the CMF's ethical regulation modified the use of placebos in phase III clinical trials in Brazil, characteristics of the records in ClinicalTrials.gov were researched in the periods from 2003 to 2007 and from 2009 to 2013. The conclusions reached were: a) the regulations issued by the CFM in 2008 were ineffective and the position adopted by the Helsinki Declaration prevails; b) there was significant sponsorship by the multinational pharmaceutical industry of trials with placebos; c) the research was predominantly on new drugs for chronic diseases, with little study done of the neglected diseases which are of great importance to Brazil.

  18. Synthesis and structural characterization of new bismuth (III) nano coordination polymer: A precursor to produce pure phase nano-sized bismuth (III) oxide

    NASA Astrophysics Data System (ADS)

    Hanifehpour, Younes; Mirtamizdoust, Babak; Hatami, Masoud; Khomami, Bamin; Joo, Sang Woo

    2015-07-01

    A novel bismuth (III) nano coordination polymer, {[Bi (pcih)(NO3)2]ṡMeOH}n (1), ("pcih" is the abbreviations of 2-pyridinecarbaldehyde isonicotinoylhydrazoneate) were synthesized by a sonochemical method. The new nano-structure was characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray powder diffraction, elemental analyses and IR spectroscopy. Single crystalline material was obtained using a heat gradient applied to a solution of the reagents. Compound 1 was structurally characterized by single crystal X-ray diffraction. The determination of the structure by single crystal X-ray crystallography shows that the complex forms a zig-zag one dimensional polymer in the solid state and the coordination number of BiIII ions is seven, (BiN3O4), with three N-donor and one O-donor atoms from two "pcih" and three O-donors from nitrate anions. It has a hemidirected coordination sphere. The supramolecular features in these complexes are guided and controlled by weak directional intermolecular interactions. The chains interact with each other through π-π stacking interactions creating a 3D framework. After thermolysis of 1 at 230 °C with oleic acid, pure phase nano-sized bismuth (III) oxide was produced. The morphology and size of the prepared Bi2O3 samples were further observed using SEM.

  19. Phase I/II Study of Nilotinib/Ruxolitinb Therapy for TKI Resistant Ph-Leukemia

    ClinicalTrials.gov

    2016-03-04

    Chronic Phase Chronic Myeloid Leukemia; Accelerated Phase Chronic Myeloid Leukemia; Blastic Phase Chronic Myeloid Leukemia; Philadelphia Positive Acute Lymphoblastic Leukemia; Resistant to Tyrosine Kinase Inhibitor Therapy

  20. Effect of low-V/III-ratio metalorganic vapor-phase epitaxy on GaAs solar cells

    NASA Astrophysics Data System (ADS)

    Xu, Hao; Toprasertpong, Kasidit; Delamarre, Amaury; Sodabanlu, Hassanet; Watanabe, Kentaroh; Nakano, Yoshiaki; Sugiyama, Masakazu

    2017-08-01

    Single-junction GaAs solar cells were grown by metalorganic vapor-phase epitaxy (MOVPE) at various input V/III ratios. All growth parameters other than V/III ratio were carefully controlled for an accurate comparison. Nearly identical cell performance characteristics including short-circuit current density (J sc) and open-circuit voltage (V oc) indicate that cell performance is independent of V/III ratio. To determine the relationship between the electrically measured V oc and V/III ratio in a more precise manner, photoluminescence (PL) was applied as a potent optical measurement tool, which does not depend on device processing and contacting issues. We also evaluated the projected cell performance under low-concentration sunlight by electroluminescence (EL) analysis. Similarly to electrical measurement, optical measurement showed no obvious degradation owing to a low V/III ratio. This study strongly demonstrates that low-cost high-efficiency GaAs solar cells can be realized by MOVPE using a low V/III ratio.

  1. Utilization of modified corn silk as a biosorbent for solid-phase extraction of Cr(III) and chromium speciation.

    PubMed

    Yu, Hongmei; Pang, Jing; Wu, Mei; Wu, Qiaoli; Huo, Cuixiu

    2014-01-01

    The ues of corn silk modified with diluted nitric acid (HNO3-MCS) as a novel biosorbent has been established for solid-phase extraction of Cr(III) and chromium speciation in water samples. The functional groups of the HNO3-MCS surface are favorable for the adsorption of Cr(III). Effective extraction conditions were optimized in both batch and column methods. At pH 3.0 - 6.0, a discrimination of Cr(III) and Cr(VI) is achieved on the HNO3-MCS surface. Cr(III) ions are retained onto the HNO3-MCS surface, however, the adsorption of Cr(VI) is negligible under the same conditions. The adsorption isotherm of HNO3-MCS for Cr(III) has been demonstrated in accordance with a linear form of the Langmuir equation, and the maximum adsorption capacity is 35.21 mg g(-1). The well fitted linear regression of the pseudo-second order model showed the indication of a chemisorption mechanism for the entire concentration range. Thermodynamic studies have shown that the adsorption process is spontaneous and endothermic. The adsorbed Cr(III) was quantitatively eluted by a nitric acid solution with detection by flame atomic absorption spectrometry (FAAS). With a sample volume of 30 mL, a detection limit (3σ) of 0.85 μg L(-1) and a precision of 2.0% RSD at the 40 μg L(-1) level were achieved. The concentration of Cr(III) could be accurately quantified within a linear range of 3 - 200 μg L(-1). After Cr(VI) has been reduced to Cr(III) with hydroxylamine hydrochloride, the total amount of chromium was obtained, and the content of Cr(VI) was given by subtraction. The procedure was validated by analyzing chromium in a certified reference material (GBW (E) 080039). It was also successfully applied for the speciation of chromium in wastewater samples.

  2. Phase III randomized trial of toremifene versus tamoxifen for Japanese postmenopausal patients with early breast cancer.

    PubMed

    Kimura, Morihiko; Tominaga, Takeshi; Kimijima, Izo; Takatsuka, Yuichi; Takashima, Shigemitsu; Nomura, Yasuo; Kasumi, Fujio; Yamaguchi, Akihiro; Masuda, Norikazu; Noguchi, Shinzaburo; Eshima, Nobuoki

    2014-05-01

    Toremifene, a selective estrogen receptor modulator, is used as adjuvant therapy for postmenopausal patients with breast cancer in Japan. For Japanese patients, however, only limited data are available on the efficacy and safety profile of toremifene. To establish the long term efficacy and safety of toremifene for Japanese patients, we conducted a prospective, multicenter, randomized phase III trial comparing toremifene and tamoxifen. The subjects were postmenopausal Japanese patients who had undergone surgery for node-negative breast cancer. Toremifene or tamoxifen was administered for 2 years. The primary endpoint was demonstration of the non-inferiority of toremifene compared with tamoxifen in respect of 5-year survival. Secondary endpoints were cumulative overall survival, cumulative disease-free survival, effects on lipid profiles, and adverse events. A total of 253 patients were enrolled. The baseline characteristics of the two treatment groups were well-balanced. Median follow-up was 66.5 months. Five-year survival was similar for toremifene and tamoxifen (97.0 vs. 96.9 %; 90 % confidence interval -3.9 to 4.1), indicating that toremifene is not inferior to tamoxifen for postmenopausal Japanese patients with early breast cancer. Cumulative overall survival and cumulative disease-free survival were also very similar for toremifene and tamoxifen (97.5 vs. 97.3 %, log-rank test P = 0.9458; 88.4 vs. 90.6 %, log-rank test P = 0.3359, respectively). Adverse events in both groups were similar and mostly mild or moderate. Thus, both are equally effective and well tolerated. Our results suggest that the efficacy and safety of toremifene and tamoxifen are equivalent for postmenopausal Japanese patients with early breast cancer.

  3. Phase III Trial of Carboplatin and Paclitaxel With or Without Sorafenib in Metastatic Melanoma

    PubMed Central

    Flaherty, Keith T.; Lee, Sandra J.; Zhao, Fengmin; Schuchter, Lynn M.; Flaherty, Lawrence; Kefford, Richard; Atkins, Michael B.; Leming, Philip; Kirkwood, John M.

    2013-01-01

    Purpose The primary objective of this study was to determine whether carboplatin, paclitaxel, and sorafenib (CPS) improve overall survival (OS) compared with carboplatin and paclitaxel (CP) in chemotherapy-naive patients with metastatic melanoma. Patients and Methods In this double-blind, randomized, placebo-controlled phase III study, all patients received carboplatin at area under the [concentration-time] curve 6 and paclitaxel 225 mg/m2 intravenously once every 21 days with random assignment to sorafenib 400 mg orally twice per day on days 2 through 19 every 21 days or placebo. The primary end point was OS, and secondary end points included progression-free survival, objective tumor response, and toxicity. Results In all, 823 patients were enrolled over 34 months. At final analysis, the median OS was 11.3 months (95% CI, 9.8 to 12.2 months) for CP and 11.1 months (95% CI, 10.3 to 12.3 months) for CPS; the difference in the OS distribution was not statistically significant by the stratified log-rank test, stratified on American Joint Committee on Cancer (AJCC) stage, Eastern Cooperative Oncology Group (ECOG) performance status, and prior therapy (P = .878). Median progression-free survival was 4.9 months for CPS and 4.2 months for CP (P = .092, stratified log-rank test). Response rate was 20% for CPS and 18% for CP (P = .427). More patients on the CPS arm had grade 3 or higher toxicities (84% v 78%; P = .027), with increased rash, hand-foot syndrome, and thrombocytopenia accounting for most of the difference. Conclusion Sorafenib does not improve OS when given in combination with CP for chemotherapy-naive patients with metastatic melanoma. This study establishes benchmark end points for the CP regimen in first-line therapy of metastatic melanoma. PMID:23248256

  4. Alemtuzumab consolidation in chronic lymphocytic leukaemia: a phase I/II multicentre trial.

    PubMed

    Al-Sawaf, Othman; Fischer, Kirsten; Herling, Carmen D; Ritgen, Matthias; Böttcher, Sebastian; Bahlo, Jasmin; Elter, Thomas; Stilgenbauer, Stephan; Eichhorst, Barbara F; Busch, Raymonde; Elberskirch, Ute; Abenhardt, Wolfgang; Kneba, Michael; Hallek, Michael; Wendtner, Clemens-Martin

    2017-03-01

    Despite high rates of long-lasting remissions in patients with chronic lymphocytic leukaemia (CLL) treated with chemoimmunotherapy, none of the current therapeutic approaches is curative with the exception of allogeneic transplantation. One strategy to extend progression-free survival and long-term survival might be the establishment of consolidation therapies. In this trial, patients with complete or partial second remission after fludarabine-based treatment received consolidation therapy with alemtuzumab. The aim of this phase I/II trial was to determine the maximal tolerable dose (MTD) of alemtuzumab consolidation and to evaluate safety and efficacy in patients who responded to second-line fludarabine-based treatment. Thirteen patients in complete (CR) or partial remission (PR) received alemtuzumab dose escalation starting with 10 mg intravenously (iv) once weekly for 8 wk and increasing in 10-mg intervals per dose level. The main dose-limiting toxicities (DLTs) were infectious complications, and the MTD was determined at 10 mg. After alemtuzumab consolidation, seven of 13 patients (53%) were in CR, and four of these patients (30.7%) achieved minimal residual disease (MRD) negativity (<1 × 10E-4). At a median follow-up of 71.5 months, four patients were progression-free, with a median progression-free survival (PFS) of 28.5 months after the end of second-line treatment. The results provide a safe and efficient schedule with weekly intravenous application of 10 mg of alemtuzumab as a consolidation regime in patients with CLL. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. A Phase III study on the efficacy of topical aloe vera gel on irradiated breast tissue.

    PubMed

    Heggie, Sue; Bryant, Guy P; Tripcony, Lee; Keller, Jacqui; Rose, Pauline; Glendenning, Mary; Heath, Jenny

    2002-12-01

    The aim of the study was to see if topical aloe vera gel would be beneficial in reducing the identified skin side-effects of radiation therapy, including erythema, pain, itching, dry desquamation, and moist desquamation, when compared with aqueous cream. The secondary aim was to assess the effect of other factors known to predict severity of radiation skin reaction, ie, breast size, smoking habit, and one or more drainages of lymphocele after surgery, on other skin side effects. A Phase III study was conducted involving 225 patients with breast cancer after lumpectomy or partial mastectomy, who required a course of radiation therapy using tangential fields. Patients were randomized to either topical aloe vera gel or topical aqueous cream to be applied 3 times per day throughout and for 2 weeks after completion of radiation treatment. Weekly skin assessments were performed by nursing staff. Aqueous cream was significantly better than aloe vera gel in reducing dry desquamation and pain related to treatment. Subjects with D cup or larger size breasts experienced significantly more erythema, regardless of treatment arm. For subjects who had undergone lymphocele drainage, the aloe vera group experienced significantly more pain than the aqueous cream group. Within the aqueous cream arm, smokers were significantly more likely to experience itching within the treatment field than were nonsmokers. Within the aloe vera arm, subjects who had undergone one or more lymphocele drainages after surgery were significantly more likely to experience erythema and itching within the treatment field than those who did not have drainage. In this study, aloe vera gel did not significantly reduce radiation-induced skin side effects. Aqueous cream was useful in reducing dry desquamation and pain related to radiation therapy.

  6. Phylodynamics of HIV-1 from a Phase-III AIDS Vaccine Trial in North America

    PubMed Central

    Pérez-Losada, Marcos; Jobes, David V.; Sinangil, Faruk; Crandall, Keith A.; Posada, David; Berman, Phillip W.

    2010-01-01

    In 2003, a phase III placebo-controlled trial (VAX004) of a candidate HIV-1 vaccine (AIDSVAX B/B) was completed in 5,403 volunteers at high risk for HIV-1 infection from North America and the Netherlands. A total of 368 individuals became infected with HIV-1 during the trial. The envelope glycoprotein gene (gp120) from the HIV-1 subtype B viruses infecting 349 patients was sequenced from clinical samples taken as close as possible to the time of diagnosis, rendering a final data set of 1,047 sequences (1,032 from North America and 15 from the Netherlands). Here, we used these data in combination with other sequences available in public databases to assess HIV-1 variation as a function of vaccination treatment, geographic region, race, risk behavior, and viral load. Viral samples did not show any phylogenetic structure for any of these factors, but individuals with different viral loads showed significant differences (P = 0.009) in genetic diversity. The estimated time of emergence of HIV-1 subtype B was 1966–1970. Despite the fact that the number of AIDS cases has decreased in North America since the early 90s, HIV-1 genetic diversity seems to have remained almost constant over time. This study represents one of the largest molecular epidemiologic surveys of viruses responsible for new HIV-1 infections in North America and could help the selection of epidemiologically representative vaccine antigens to include in the next generation of candidate HIV-1 vaccines. PMID:19864468

  7. Phylodynamics of HIV-1 from a phase III AIDS vaccine trial in Bangkok, Thailand.

    PubMed

    Pérez-Losada, Marcos; Jobes, David V; Sinangil, Faruk; Crandall, Keith A; Arenas, Miguel; Posada, David; Berman, Phillip W

    2011-03-10

    In 2003, a phase III placebo-controlled trial (VAX003) was completed in Bangkok, Thailand. Of the 2,546 individuals enrolled in the trial based on high risk for infection through injection drug use (IDU), we obtained clinical samples and HIV-1 sequence data (envelope glycoprotein gene gp120) from 215 individuals who became infected during the trial. Here, we used these data in combination with other publicly available gp120 sequences to perform a molecular surveillance and phylodynamic analysis of HIV-1 in Thailand. Phylogenetic and population genetic estimators were used to assess HIV-1 gp120 diversity as a function of vaccination treatment, viral load (VL) and CD4(+) counts, to identify transmission clusters and to investigate the timescale and demographics of HIV-1 in Thailand. Three HIV-1 subtypes were identified: CRF01_AE (85% of the infections), subtype B (13%) and CRF15_AE (2%). The Bangkok IDU cohort showed more gp120 diversity than other Asian IDU cohorts and similar diversity to that observed in sexually infected individuals. Moreover, significant differences (P<0.02) in genetic diversity were observed in CRF01_AE IDU with different VL and CD4(+) counts. No phylogenetic structure was detected regarding any of the epidemiological and clinical factors tested, although high proportions (35% to 50%) of early infections fell into clusters, which suggests that transmission chains associated with acute infection play a key role on HIV-1 spread among IDU. CRF01_AE was estimated to have emerged in Thailand in 1984.5 (1983-1986), 3-6 years before the first recognition of symptomatic patients (1989). The relative genetic diversity of the HIV-1 population has remained high despite decreasing prevalence rates since the mid 1990s. Our study and recent epidemiological reports indicate that HIV-1 is still a major threat in Thailand and suggest that HIV awareness and prevention needs to be strengthened to avoid AIDS resurgence.

  8. How Accurately Do Consecutive Cohort Audits Predict Phase III Multisite Clinical Trial Recruitment in Palliative Care?

    PubMed

    McCaffrey, Nikki; Fazekas, Belinda; Cutri, Natalie; Currow, David C

    2016-04-01

    Audits have been proposed for estimating possible recruitment rates to randomized controlled trials (RCTs), but few studies have compared audit data with subsequent recruitment rates. To compare the accuracy of estimates of potential recruitment from a retrospective consecutive cohort audit of actual participating sites and recruitment to four Phase III multisite clinical RCTs. The proportion of potentially eligible study participants estimated from an inpatient chart review of people with life-limiting illnesses referred to six Australian specialist palliative care services was compared with recruitment data extracted from study prescreening information from three sites that participated fully in four Palliative Care Clinical Studies Collaborative RCTs. The predominant reasons for ineligibility in the audit and RCTs were analyzed. The audit overestimated the proportion of people referred to the palliative care services who could participate in the RCTs (pain 17.7% vs. 1.2%, delirium 5.8% vs. 0.6%, anorexia 5.1% vs. 0.8%, and bowel obstruction 2.8% vs. 0.5%). Approximately 2% of the referral base was potentially eligible for these effectiveness studies. Ineligibility for general criteria (language, cognition, and geographic proximity) varied between studies, whereas the reasons for exclusion were similar between the audit and pain and anorexia studies but not for delirium or bowel obstruction. The retrospective consecutive case note audit in participating sites did not predict realistic recruitment rates, mostly underestimating the impact of study-specific inclusion criteria. These findings have implications for the applicability of the results of RCTs. Prospective pilot studies are more likely to predict actual recruitment. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

  9. International phase III trial of liprotamase efficacy and safety in pancreatic-insufficient cystic fibrosis patients.

    PubMed

    Borowitz, Drucy; Stevens, Christopher; Brettman, Lee R; Campion, Marilyn; Chatfield, Barbara; Cipolli, Marco

    2011-12-01

    Most cystic fibrosis (CF) patients have exocrine pancreatic insufficiency (EPI) and need supplementation with pancreatic enzyme replacement therapy (PERT). Liprotamase, a novel non-porcine PERT containing highly purified biotechnology-derived lipase, protease, and amylase, has successfully undergone initial efficacy and safety testing. In this international phase III parallel-group, randomized-withdrawal, double-blind placebo-controlled trial, CF patients with EPI 7 years and older, including nutritionally and functionally compromised individuals, underwent baseline testing for coefficients of fat and nitrogen absorption (CFA and CNA) and stool weight and frequency while off PERT. After an open-label treatment period with liprotamase, subjects were randomized 1:1 to one liprotamase or placebo capsule taken with 3 meals and 2 snacks per day. The dose was fixed and increases were not allowed. The same measurements were obtained again after treatment with double-blind study drug or placebo. 138 subjects were randomized. The adjusted least squares mean (LSM) difference between the treatment and placebo groups for change in CFA was 15.1% (p=0.001) for the subgroup with baseline CFA <40%, 8.6% (p=0.006) for subjects with baseline CFA ≥40%, and 10.6% (p<0.001) for the overall intent-to-treat population. Similar results were seen for change in CNA. Stool weight was significantly decreased although not stool frequency. Liprotamase was well tolerated with no safety concerns identified. In a CF patient population reflective of that encountered in clinical practice, this trial demonstrated that liprotamase at a fixed dose of one capsule per meal or snack (5 capsules per day) was well tolerated and significantly increased fat absorption as measured by improvement in CFA, significantly increased protein absorption as measured by improvement in CNA, and significantly decreased stool weight. Copyright © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All

  10. Diet and Respiratory Health in Children from 11 Latin American Countries: Evidence from ISAAC Phase III.

    PubMed

    Cepeda, Alfonso Mario; Thawer, Sumaiyya; Boyle, Robert J; Villalba, Sara; Jaller, Rodolfo; Tapias, Elmy; Segura, Ana María; Villegas, Rodrigo; Garcia-Larsen, Vanessa

    2017-08-28

    The burden of childhood asthma and its risk factors is an important but neglected public health challenge in Latin America. We investigated the association between allergic symptoms and dietary intake in children from this region. As part of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase III, questionnaire collected dietary intake was investigated in relation to risk of parental/child reported current wheeze (primary outcome) and rhino-conjunctivitis and eczema. Per-country adjusted logistic regressions were performed, and combined effect sizes were calculated with meta-analyses. 143,967 children from 11 countries had complete data. In children aged 6-7 years, current wheeze was negatively associated with higher fruit intake (adjusted odds ratio [aOR] 0.65; 95% CI 0.74, 0.97). Current rhino-conjunctivitis and eczema were statistically negatively associated with fruit intake (aOR 0.72; 95% CI 0.64, 0.82; and OR 0.64, 95% CI 0.56, 0.74, respectively). Vegetable intake was negatively associated with risk of symptoms in younger children, but these associations were attenuated in the 13-14 years old group. Fastfood/burger intake was positively associated with all three outcomes in the older children. A higher intake of fruits and vegetables was associated with a lower prevalence of allergic symptoms in Latin American children. Conversely, intake of fastfood was positively associated with a higher prevalence of wheeze in adolescents. Improved dietary habits in children might help reduce the epidemic of allergic symptoms in Latin America. Food interventions in asthmatic children are needed to evaluate the possible public health impact of a better diet on respiratory health.

  11. III-nitride nanopyramid light emitting diodes grown by organometallic vapor phase epitaxy

    NASA Astrophysics Data System (ADS)

    Wildeson, Isaac H.; Colby, Robert; Ewoldt, David A.; Liang, Zhiwen; Zakharov, Dmitri N.; Zaluzec, Nestor J.; García, R. Edwin; Stach, Eric A.; Sands, Timothy D.

    2010-08-01

    Nanopyramid light emitting diodes (LEDs) have been synthesized by selective area organometallic vapor phase epitaxy. Self-organized porous anodic alumina is used to pattern the dielectric growth templates via reactive ion etching, eliminating the need for lithographic processes. (In,Ga)N quantum well growth occurs primarily on the six {11¯01} semipolar facets of each of the nanopyramids, while coherent (In,Ga)N quantum dots with heights of up to ˜20 nm are incorporated at the apex by controlling growth conditions. Transmission electron microscopy (TEM) indicates that the (In,Ga)N active regions of the nanopyramid heterostructures are completely dislocation-free. Temperature-dependent continuous-wave photoluminescence of nanopyramid heterostructures yields a peak emission wavelength of 617 nm and 605 nm at 300 K and 4 K, respectively. The peak emission energy varies with increasing temperature with a double S-shaped profile, which is attributed to either the presence of two types of InN-rich features within the nanopyramids or a contribution from the commonly observed yellow defect luminescence close to 300 K. TEM cross-sections reveal continuous planar defects in the (In,Ga)N quantum wells and GaN cladding layers grown at 650-780 °C, present in 38% of the nanopyramid heterostructures. Plan-view TEM of the planar defects confirms that these defects do not terminate within the nanopyramids. During the growth of p-GaN, the structure of the nanopyramid LEDs changed from pyramidal to a partially coalesced film as the thickness requirements for an undepleted p-GaN layer result in nanopyramid impingement. Continuous-wave electroluminescence of nanopyramid LEDs reveals a 45 nm redshift in comparison to a thin-film LED, suggesting higher InN incorporation in the nanopyramid LEDs. These results strongly encourage future investigations of III-nitride nanoheteroepitaxy as an approach for creating efficient long wavelength LEDs.

  12. Differences in Funding Sources of Phase III Oncology Clinical Trials by Treatment Modality and Cancer Type.

    PubMed

    Jairam, Vikram; Yu, James B; Aneja, Sanjay; Wilson, Lynn D; Lloyd, Shane

    2017-06-01

    Given the limited resources available to conduct clinical trials, it is important to understand how trial sponsorship differs among different therapeutic modalities and cancer types and to consider the ramifications of these differences. We searched clinicaltrials.gov for a cross-sectional register of active, phase III, randomized controlled trials (RCTs) studying treatment-related endpoints such as survival and recurrence for the 24 most prevalent malignancies. We classified the RCTs into 7 categories of therapeutic modality: (1) chemotherapy/other cancer-directed drugs, (2) targeted therapy, (3) surgery, (4) radiation therapy (RT), (5) RT with other modalities, (6) multimodality therapy without RT, and (7) other. RCTs were categorized as being funded by one or more of the following groups: (1) government, (2) hospital/university, (3) industry, and (4) other. χ analysis was performed to detect differences in funding source distribution between modalities and cancer types. The percentage of multimodality trials (5%) and radiation RCTs (4%) funded by industry was less than that for chemotherapy (32%, P<0.01) or targeted therapy (48%, P<0.01). Trials studying targeted therapy were less likely to have hospital/university funding than any of the other modalities (P<0.01 in each comparison). Trials of chemotherapy were more likely to be funded by industry if they also studied targeted therapy (P<0.01). RCTs studying targeted therapies are more likely to be funded by industry than trials studying multimodality therapy or radiation. The impact of industry funding versus institutional or governmental sources of funding for cancer research is unclear and requires further study.

  13. Progressive Staging of Pilot Studies to Improve Phase III Trials for Motor Interventions

    PubMed Central

    Dobkin, Bruce H.

    2014-01-01

    Based on the suboptimal research pathways that finally led to multicenter randomized clinical trials (MRCTs) of treadmill training with partial body weight support and of robotic assistive devices, strategically planned successive stages are proposed for pilot studies of novel rehabilitation interventions Stage 1, consideration-of-concept studies, drawn from animal experiments, theories, and observations, delineate the experimental intervention in a small convenience sample of participants, so the results must be interpreted with caution. Stage 2, development-of-concept pilots, should optimize the components of the intervention, settle on most appropriate outcome measures, and examine dose-response effects. A well-designed study that reveals no efficacy should be published to counterweight the confirmation bias of positive trials. Stage 3, demonstration-of-concept pilots, can build out from what has been learned to test at least 15 participants in each arm, using random assignment and blinded outcome measures. A control group should receive an active practice intervention aimed at the same primary outcome. A third arm could receive a substantially larger dose of the experimental therapy or a combinational intervention. If only 1 site performed this trial, a different investigative group should aim to reproduce positive outcomes based on the optimal dose of motor training. Stage 3 studies ought to suggest an effect size of 0.4 or higher, so that approximately 50 participants in each arm will be the number required to test for efficacy in a stage 4, proof-of-concept MRCT. By developing a consensus around acceptable and necessary practices for each stage, similar to CONSORT recommendations for the publication of phase III clinical trials, better quality pilot studies may move quickly into better designed and more successful MRCTs of experimental interventions. PMID:19240197

  14. A phase I/II study of the protease inhibitor indinavir in children with HIV infection.

    PubMed

    Mueller, B U; Sleasman, J; Nelson, R P; Smith, S; Deutsch, P J; Ju, W; Steinberg, S M; Balis, F M; Jarosinski, P F; Brouwers, P; Mistry, G; Winchell, G; Zwerski, S; Sei, S; Wood, L V; Zeichner, S; Pizzo, P A

    1998-07-01

    Indinavir, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, is approved for the treatment of HIV infection in adults when antiretroviral therapy is indicated. We evaluated the safety and pharmacokinetic profile of the indinavir free-base liquid suspension and the sulfate salt dry-filled capsules in HIV-infected children, and studied its preliminary antiviral and clinical activity in this patient population. In addition, we evaluated the pharmacokinetic profile of a jet-milled suspension after a single dose. Previously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity were eligible for this phase I/II study. Three dose levels (250 mg/m2, 350 mg/m2, and 500 mg/m2 per dose given orally every 8 h) were evaluated in 2 age groups (<12 years and >/=12 years). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks. Fifty-four HIV-infected children (ages 3.1 to 18.9 years) were enrolled. The indinavir free-base suspension was less bioavailable than the dry-filled capsule formulation, and therapy was changed to capsules in all children. Hematuria was the most common side effect, occurring in 7 (13%) children, and associated with nephrolithiasis in 1 patient. The combination of indinavir, lamivudine, and zidovudine was well tolerated. The median CD4 cell count increased after 2 weeks of indinavir monotherapy by 64 cells/mm3, and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent way, but increased toward baseline after a few weeks of indinavir monotherapy. Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs at higher doses. Future studies need to evaluate the efficacy of indinavir when combined de novo with zidovudine and lamivudine.

  15. Combining Dosimetry & Toxicity: Analysis of two UK Phase III Clinical trials

    NASA Astrophysics Data System (ADS)

    Gulliford, Sarah L.

    2014-03-01

    There are many advantages to performing a clinical trial when implementing a novel radiotherapy technique. The clinical trials framework enables the safety and efficacy of the "experimental arm" to be tested and ensures practical support, rigorous quality control and data monitoring for participating centres. In addition to the clinical and follow-up data collected from patients within the trial, it is also possible to collect 3-D dosimetric information from the corresponding radiotherapy treatment plans. Analysing the combination of dosimetric, clinical and follow-up data enhances the understanding of the relationship between the dose delivered to both the target and normal tissue structures and reported outcomes & toxicity. Aspects of the collection, collation and analysis of data from two UK multicentre Phase III radiotherapy trials are presented here. MRC-RT01 dose-escalation prostate radiotherapy trial ISRCTN47772397 was one of the first UK multi-centre radiotherapy trials to collect 3-D dosimetric data. A number of different analysis methodologies were implemented to investigate the relationship between the dose distribution to the rectum and specific rectal toxicities. More recently data was collected from the PARSPORT trial (Parotid Sparing IMRT vs conventional head and neck radiotherapy) ISRCTN48243537. In addition to the planned analysis, dosimetric analysis was employed to investigate an unexpected finding that acute fatigue was more prevalent in the IMRT arm of the trial. It can be challenging to collect 3-D dosimetric information from multicentre radiotherapy trials. However, analysing the relationship between dosimetric and toxicity data provides invaluable information which can influence the next generation of radiotherapy techniques.

  16. Predicting Pattern Tooling and Casting Dimensions for Investment Casting, Phase III

    SciTech Connect

    Sabau, Adrian S

    2008-04-01

    Efforts during Phase III focused mainly on the shell-alloy systems. A high melting point alloy, 17-4PH stainless steel, was considered. The experimental part of the program was conducted at ORNL and commercial foundries, where wax patterns were injected, molds were invested, and alloys were poured. Shell molds made of fused-silica and alumino-silicates were considered. A literature review was conducted on thermophysical and thermomechanical properties alumino-silicates. Material property data, which were not available from material suppliers, was obtained. For all the properties of 17-4PH stainless steel, the experimental data available in the literature did not cover the entire temperature range necessary for process simulation. Thus, some material properties were evaluated using ProCAST, based on CompuTherm database. A comparison between the predicted material property data and measured property data was made. It was found that most material properties were accurately predicted only over several temperature ranges. No experimental data for plastic modulus were found. Thus, several assumptions were made and ProCAST recommendations were followed in order to obtain a complete set of mechanical property data at high temperatures. Thermal expansion measurements for the 17-4PH alloy were conducted during heating and cooling. As a function of temperature, the thermal expansion for both the alloy and shell mold materials showed different evolution on heating and cooling. Numerical simulations were performed using ProCAST for the investment casting of 17-4PH stainless steel parts in fused silica molds using the thermal expansion obtained on heating and another one with thermal expansion obtained on cooling. Since the fused silica shells had the lowest thermal expansion properties in the industry, the dewaxing phase, including the coupling between wax-shell systems, was neglected. The shell mold was considered to be a pure elastic material. The alloy dimensions were

  17. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3.

    PubMed

    Van Cutsem, Eric; Labianca, Roberto; Bodoky, György; Barone, Carlo; Aranda, Enrique; Nordlinger, Bernard; Topham, Claire; Tabernero, Josep; André, Thierry; Sobrero, Alberto F; Mini, Enrico; Greil, Richard; Di Costanzo, Francesco; Collette, Laurence; Cisar, Laura; Zhang, Xiaoxi; Khayat, David; Bokemeyer, Carsten; Roth, Arnaud D; Cunningham, David

    2009-07-01

    PURPOSE The primary objective of this randomized, multicenter, phase III trial was to investigate whether the addition of irinotecan to the de Gramont infusional fluorouracil (FU)/leucovorin (LV) adjuvant regimen (LV5FU2) would improve disease-free survival (DFS) in patients with stage III colon cancer. PATIENTS AND METHODS After curatively intentioned surgery, patients with stage II and III colon cancer were randomly allocated surgery to receive LV5FU2 (LV 200 mg/m(2) as a 2-hour infusion, followed by FU; as a 400 mg/m(2) bolus and then a 600 mg/m(2) continuous infusion over 22 hours, days 1 and 2, every 2 weeks for 12 cycles: de Gramont regimen) with or without irinotecan (180 mg/m(2) as a 30- to 90-minute infusion, day 1, every 2 weeks). In total, 260 (7.9%) of 3,278 patients received an alternative high-dose infusional FU/LV regimen (Arbeitsgemeinschaft Internische Onkologie regimen) with or without irinotecan. Results The principal efficacy analysis was based on 2,094 treated patients with stage III disease, randomly allocated in the LV5FU2 strata. After a median follow-up of 66.3 months, the 5-year DFS rate was 56.7% with irinotecan/LV5FU2 and 54.3% with LV5FU2 alone (primary end point: log-rank P = .106). Combining irinotecan with LV5FU2 did not significantly improve overall survival in this patient group compared with LV5FU2 alone (5-year rate 73.6% v 71.3%, respectively; log-rank P = .094). The addition of irinotecan to LV5FU2 was associated with an increased incidence of grade 3 to 4 GI events and neutropenia. CONCLUSION Irinotecan added to LV5FU2 as adjuvant therapy did not confer a statistically significant improvement in DFS or overall survival in patients with stage III colon cancer compared with LV5FU2 alone.

  18. Remedial Design/Remedial Action Work Plan for Operable Units 6-05 and 10-04, Phase III

    SciTech Connect

    R. P. Wells

    2006-09-19

    The remedial design/remedial action for Operable Unit 6-05 (Waste Area Group 6) and Operable Unit 10-04 (Waste Area Group 10) - collectively called Operable Unit 10-04 has been divided into four phases. Phase I consists of developing and implementing institutional controls at Operable Unit 10-04 sites and developing and implementing Idaho National Laboratory-wide plans for both institutional controls and ecological monitoring. Phase II will remediate sites contaminated with trinitrotoluene and Royal Demolition Explosive. Phase III will remediate lead contamination at a gun range, and Phase IV will remediate hazards from unexploded ordnance. This Phase III remedial Design/Remedial Action Work Plan addresses the remediation of lead-contaminated soils found at the Security Training Facility (STF)-02 Gun Range located at the Idaho National Laboratory. Remediation of the STF-02 Gun Range will include excavating contaminated soils; physically separating copper and lead for recycling; returning separated soils below the remediation goal to the site; stabilizing contaminated soils, as required, and disposing of the separated soils that exceed the remediation goal; encapsulating and disposing of creosote-contaminated railroad ties and power poles; removing and disposing of the wooden building and asphalt pads found at the STF-02 Gun Range; sampling and analyzing soil to determine the excavation requirements; and when the remediation goals have been met, backfilling and contouring excavated areas and revegetating the affected area.

  19. TAILORING INORGANIC SORBENTS FOR SRS STRONTIUM AND ACTINIDE SEPARATIONS: MODIFIED MONOSODIUM TITANATE PHASE III FINAL REPORT

    SciTech Connect

    Taylor-Pashow, K.; Hobbs, D.

    2010-09-01

    This document provides a final report of Phase III testing activities for the development of modified monosodium titanate (mMST), which exhibits improved strontium and actinide removal characteristics compared to the baseline MST material. The activities included characterization of the crystalline phases present at varying temperatures, solids settling characteristics, quantification of the peroxide content; evaluation of the post-synthesis gas release under different conditions; the extent of desorption of {sup 85}Sr, Np, and Pu under washing conditions; and the effects of age and radiation on the performance of the mMST. Key findings and conclusions include the following. The peroxide content of several mMST samples was determined using iodometric titration. The peroxide content was found to decrease with age or upon extended exposure to elevated temperature. A loss of peroxide was also measured after exposure of the material to an alkaline salt solution similar in composition to the simulated waste solution. To determine if the loss of peroxide with age affects the performance of the material, Sr and actinide removal tests were conducted with samples of varying age. The oldest sample (4 years and 8 months) did show lower Sr and Pu removal performance. When compared to the youngest sample tested (1 month), the oldest sample retained only 15% of the DF for Pu. Previous testing with this sample indicated no decrease in Pu removal performance up to an age of 30 months. No loss in Np removal performance was observed for any of the aged samples, and no uptake of uranium occurred at the typical sorbent loading of 0.2 g/L. Additional testing with a uranium only simulant and higher mMST loading (3.0 g/L) indicated a 10% increase of uranium uptake for a sample aged 3 years and 8 months when compared to the results of the same sample measured at an age of 1 year and 5 months. Performance testing with both baseline-MST and mMST that had been irradiated in a gamma source to

  20. Design and analysis of phase III trials with ordered outcome scales: the concept of the sliding dichotomy.

    PubMed

    Murray, Gordon D; Barer, David; Choi, Sung; Fernandes, Helen; Gregson, Barbara; Lees, Kennedy R; Maas, Andrew I R; Marmarou, Anthony; Mendelow, A David; Steyerberg, Ewout W; Taylor, Gillian S; Teasdale, Graham M; Weir, Christopher J

    2005-05-01

    The conventional approach to the analysis of a Phase III trial in head injury or stroke takes an ordered scale measuring functional outcome and collapses the scale to a binary outcome of favorable versus unfavorable. This discards potentially relevant information which limits statistical power and moreover is not in accord with clinical practice. We propose an alternative approach where a favorable outcome is defined as better than would be expected, taking account of each individual patient's baseline prognosis. This is illustrated through a worked example based on data from a Phase III trial in head injury. The approach is also compared with the proportional odds model, which is another statistical approach that can exploit an ordered outcome scale. The approach raises issues of clinical, statistical, and regulatory importance, and we initiate what we believe needs to become a widespread debate amongst the community involved in clinical research in head injury and stroke.

  1. Mono- and polynucleation, atomistic growth, and crystal phase of III-V nanowires under varying group V flow

    SciTech Connect

    Dubrovskii, V. G.

    2015-05-28

    We present a refined model for the vapor-liquid-solid growth and crystal structure of Au-catalyzed III-V nanowires, which revisits several assumptions used so far and is capable of describing the transition from mononuclear to polynuclear regime and ultimately to regular atomistic growth. We construct the crystal phase diagrams and calculate the wurtzite percentages, elongation rates, critical sizes, and polynucleation thresholds of Au-catalyzed GaAs nanowires depending on the As flow. We find a non-monotonic dependence of the crystal phase on the group V flow, with the zincblende structure being preferred at low and high group V flows and the wurtzite structure forming at intermediate group V flows. This correlates with most of the available experimental data. Finally, we discuss the atomistic growth picture which yields zincblende crystal structure and should be very advantageous for fabrication of ternary III-V nanowires with well-controlled composition and heterointerfaces.

  2. Novel concepts for the compression of large volumes of carbon dioxide-phase III

    SciTech Connect

    Moore, J. Jeffrey; Allison, Timothy C.; Evans, Neal D.; Moreland, Brian; Hernandez, Augusto J.; Day, Meera; Ridens, Brandon L.

    2014-06-30

    and tested in a closed loop compressor facility using CO2 . Both test programs successfully demonstrated good performance and mechanical behavior. In Phase III, a pilot compression plant consisting of a multi-stage centrifugal compressor with cooled diaphragm technology has been designed, constructed, and tested. Comparative testing of adiabatic and cooled tests at equivalent inlet conditions shows that the cooled diaphragms reduce power consumption by 3-8% when the compressor is operated as a back-to-back unit and by up to 9% when operated as a straight-though compressor with no intercooler. The power savings, heat exchanger effectiveness, and temperature drops for the cooled diaphragm were all slightly higher than predicted values but showed the same trends.

  3. Phase fluctuation spectra: New radio science information to become available in the DSN tracking system Mark III-77

    NASA Technical Reports Server (NTRS)

    Berman, A. L.

    1977-01-01

    An algorithm was developed for the continuous and automatic computation of Doppler noise concurrently at four sample rate intervals, evenly spanning three orders of magnitude. Average temporal Doppler phase fluctuation spectra will be routinely available in the DSN tracking system Mark III-77 and require little additional processing. The basic (noise) data will be extracted from the archival tracking data file (ATDF) of the tracking data management system.

  4. Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials.

    PubMed

    Hughes, Derralynn A; Gonzalez, Derlis E; Lukina, Elena A; Mehta, Atul; Kabra, Madhulika; Elstein, Deborah; Kisinovsky, Isaac; Giraldo, Pilar; Bavdekar, Ashish; Hangartner, Thomas N; Wang, Nan; Crombez, Eric; Zimran, Ari

    2015-07-01

    Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities, and, additionally in children, growth failure. Fifty-seven patients aged 3-62 years at the baseline of two phase III trials for velaglucerase alfa treatment were enrolled in the single extension study. In the extension, they received every-other-week velaglucerase alfa intravenous infusions for 1.2-4.8 years at 60 U/kg, although 10 patients experienced dose reduction. No patient experienced a drug-related serious adverse event or withdrew due to an adverse event. One patient died following a convulsion that was reported as unrelated to the study drug. Only one patient tested positive for anti-velaglucerase alfa antibodies. Combining the experience of the initial phase III trials and the extension study, significant improvements were observed in the first 24 months from baseline in hematology variables, organ volumes, plasma biomarkers, and, in adults, the lumbar spine bone mineral density Z-score. Improvements were maintained over longer-term treatment. Velaglucerase alfa had a good long-term safety and tolerability profile, and patients continued to respond clinically, which is consistent with the results of the extension study to the phase I/II trial of velaglucerase alfa. EudraCT number 2008-001965-27; www.clinicaltrials.gov identifier NCT00635427.

  5. Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials

    PubMed Central

    Hughes, Derralynn A; Gonzalez, Derlis E; Lukina, Elena A; Mehta, Atul; Kabra, Madhulika; Elstein, Deborah; Kisinovsky, Isaac; Giraldo, Pilar; Bavdekar, Ashish; Hangartner, Thomas N; Wang, Nan; Crombez, Eric; Zimran, Ari

    2015-01-01

    Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities, and, additionally in children, growth failure. Fifty-seven patients aged 3–62 years at the baseline of two phase III trials for velaglucerase alfa treatment were enrolled in the single extension study. In the extension, they received every-other-week velaglucerase alfa intravenous infusions for 1.2–4.8 years at 60 U/kg, although 10 patients experienced dose reduction. No patient experienced a drug-related serious adverse event or withdrew due to an adverse event. One patient died following a convulsion that was reported as unrelated to the study drug. Only one patient tested positive for anti-velaglucerase alfa antibodies. Combining the experience of the initial phase III trials and the extension study, significant improvements were observed in the first 24 months from baseline in hematology variables, organ volumes, plasma biomarkers, and, in adults, the lumbar spine bone mineral density Z-score. Improvements were maintained over longer-term treatment. Velaglucerase alfa had a good long-term safety and tolerability profile, and patients continued to respond clinically, which is consistent with the results of the extension study to the phase I/II trial of velaglucerase alfa. EudraCT number 2008-001965-27; http://www.clinicaltrials.gov identifier NCT00635427. Am. J. Hematol. 90:584–591, 2015. © 2015 Wiley Periodicals, Inc. PMID:25801797

  6. Fe(II)-Fe(III)-bearing phases as a mineralogical control on the heterogeneity of arsenic in Southeast Asian groundwater.

    PubMed

    Burnol, Andre; Charlet, Laurent

    2010-10-01

    Although groundwater arsenic constitutes a major hazard to the health of the people of Southeast Asia, the exact mineralogical origin of the arsenic in these fluvial aquifers is still under debate. Fe(III) oxides are the dominant hosts of mobilizable arsenic in the sediments, with the role of secondary Fe(II)-bearing phases like mackinawite, siderite, vivianite, magnetite, and carbonate green rust (fougerite) still unclear. Based on published field data from Chakdaha (India), the importance of the phases for arsenic mobility is evaluated quantitatively using models of growing complexity. Arsenic heterogeneity can be explained by the presence of two contrasted redox zones in the aquifers, with Fe(III) oxides being the dominant sorbent for arsenic in the less reduced zones and Fe(II) sulfides and/or Fe(II) carbonates being the solid-phase hosts for arsenic under more reduced conditions below impermeable soils or close to rivers where sulfate is reduced. A 1D reactive transport model which simulates the transition between the two environments has been developed and compared to field data. The results show that microbial sulfate reduction followed by abiotic and/or biotic reduction of As(III)-bearing iron oxides accounts for the spatial heterogeneity of arsenic in such reduced aquifers.

  7. Underground Test Area Subproject Phase I Data Analysis Task. Volume III - Groundwater Recharge and Discharge Data Documentation Package

    SciTech Connect

    1996-10-01

    Volume III of the documentation for the Phase I Data Analysis Task performed in support of the current Regional Flow Model, Transport Model, and Risk Assessment for the Nevada Test Site Underground Test Area Subproject contains the data covering groundwater recharge and discharge. Because of the size and complexity of the model area, a considerable quantity of data was collected and analyzed in support of the modeling efforts. The data analysis task was consequently broken into eight subtasks, and descriptions of each subtask's activities are contained in one of the eight volumes that comprise the Phase I Data Analysis Documentation.

  8. Characterisation of stationary phases in subcritical fluid chromatography with the solvation parameter model. III. Polar stationary phases.

    PubMed

    West, C; Lesellier, E

    2006-03-31

    In this third paper, varied types of polar stationary phases, namely silica gel (SI), cyano (CN)- and amino-propyl (NH2)-bonded silica, propanediol-bonded silica (DIOL), poly(ethylene glycol) (PEG) and poly(vinyl alcohol) (PVA), were investigated in subcritical fluid mobile phase. This study was performed to provide a greater knowledge of the properties of these phases in SFC, and to allow a more rapid and efficient choice of polar stationary phase in regard of the chemical nature of the solutes to be separated. The effect of the nature of the stationary phase on interactions between solute and stationary phases and between solute and carbon dioxide-modifier mobile phases was studied by the use of a linear solvation energy relationship (LSER), the solvation parameter model. The retention behaviour observed with sub/supercritical fluid with carbon dioxide-methanol is close to the one reported in normal-phase liquid chromatography with hexane. The hydrogen bond acidity and basicity, and the polarity/polarizability favour the solute retention when the molar volume of the solute reduces it. As with non-polar phases, the absence of water in the subcritical fluid allows the solute/stationary phase interactions to play a greater part in the retention behaviour. As expected, the DIOL phase and the bare silica display a similar behaviour towards acidic and basic solutes, when interactions with basic compounds are lower with the NH2 phase. On the CN phase, all interactions (hydrogen bonding, dipole-dipole and charge transfer) have a nearly equivalent weight on the retention. The polymeric phases, PEG and PVA, provide the most accurate models, possibly due to their better surface homogeneity.

  9. Lapatinib-Related Rash and Breast Cancer Outcome in the ALTTO Phase III Randomized Trial

    PubMed Central

    Sonnenblick, Amir; de Azambuja, Evandro; Agbor-tarh, Dominique; Bradbury, Ian; Campbell, Christine; Huang, Yingjie; Dueck, Amylou C.; Pritchard, Kathleen I.; Wolff, Antonio C.; Jackisch, Christian; Lang, Istvan; Untch, Michael; Smith, Ian; Boyle, Frances; Xu, Binghe; Gomez, Henry; Perez, Edith A.; Piccart, Martine

    2016-01-01

    Background: Previously we have shown that early development of rash is associated with a higher chance of achieving pathological complete response to neoadjuvant lapatinib. In the current analysis, we investigate its impact on survival in the ALTTO phase III adjuvant trial. Methods: In ALTTO, patients with human epidermal growth factor receptor 2 (HER2)–positive early breast cancer were randomly assigned to adjuvant trastuzumab, lapatinib, their sequence, or their combination for a total duration of one year. We evaluated whether the development of early lapatinib-related rash (ie, within 6 weeks) is associated with disease-free (DFS) and overall survival (OS). Landmark analysis at eight weeks and time-dependent analysis were tested in a multivariable model stratifying on trial’s stratification factors. All statistical tests were two-sided. Results: Out of 6098 lapatinib-treated patients, 3973(65.2%) were included in the landmark analysis, of whom 1389 (35.0%) had developed early rash. After median follow-up of 4.5 years, the development of early rash was associated with a trend of improved DFS (multivariable: hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.73 to 1.03, P = .10) and statistically significantly improved OS (multivariable: HR = 0.63, 95% CI = 0.48 to 0.82, P < .001) compared with subjects without early rash. Compared with patients randomly assigned to trastuzumab (n = 2051), patients who were randomly assigned to trastuzumab/lapatinib combination and developed early rash (n = 692) had superior DFS (multivariable: HR = 0.72, 95% CI = 0.55 to 0.92, P = .01) and OS (multivariable: HR = 0.59, 95% CI = 0.39 to 0.90, P = .01). Time-dependent analysis suggests that the occurrence of rash is predictive of lapatinib benefit, both when given in combination or sequential to trastuzumab. Conclusions: Our results indicate that early development of rash identifies patients who derive superior benefit from lapatinib

  10. Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1.

    PubMed

    Smith, Matthew; De Bono, Johann; Sternberg, Cora; Le Moulec, Sylvestre; Oudard, Stéphane; De Giorgi, Ugo; Krainer, Michael; Bergman, Andries; Hoelzer, Wolfgang; De Wit, Ronald; Bögemann, Martin; Saad, Fred; Cruciani, Giorgio; Thiery-Vuillemin, Antoine; Feyerabend, Susan; Miller, Kurt; Houédé, Nadine; Hussain, Syed; Lam, Elaine; Polikoff, Jonathan; Stenzl, Arnulf; Mainwaring, Paul; Ramies, David; Hessel, Colin; Weitzman, Aaron; Fizazi, Karim

    2016-09-01

    Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC. Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments. A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post-random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively). Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes. © 2016 by

  11. Safety with Ocrelizumab in Rheumatoid Arthritis: Results from the Ocrelizumab Phase III Program

    PubMed Central

    Emery, Paul; Rigby, William; Tak, Paul P.; Dörner, Thomas; Olech, Ewa; Martin, Carmen; Millar, Laurie; Travers, Helen; Fisheleva, Elena

    2014-01-01

    Objective The objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA). Methods This was an analysis of the double-blind, placebo-controlled periods and long-term follow-up of 4 OCR phase III trials in RA (SCRIPT, STAGE, FILM and FEATURE). Safety data per study and the results of a meta-analysis of serious infectious events (SIEs) are presented. Results Overall, 868 patients received placebo, 1064 patients OCR 200 mg×2 (or 400 mg×1) (OCR200), and 827 patients OCR 500 mg×2 (OCR500) plus background methotrexate (MTX) at baseline and 24 weeks. During the double-blind, placebo-controlled periods, the incidence of adverse events and serious adverse events was comparable between the OCR+MTX and placebo +MTX groups. Infusion-related reactions were more common with OCR+MTX and decreased in frequency with subsequent infusions. Serious infusion-related reactions were rare (0.1%). Serious infections occurred more frequently with OCR500+MTX. In the meta-analysis, a statistically significant difference from placebo +MTX in incidence of SIEs per 100 patient-years of 2.4 (95% CI, 0.3–4.5) was observed with OCR500+MTX, but not with OCR200+MTX (0.6; 95% CI, −1.3 to 2.4). Patients recruited in Asia exhibited a higher risk of serious infections (hazard ratio, 1.78; 95% CI, 1.03–3.06). The incidence of human anti-human antibodies was <5%. Long-term follow-up indicated no differences in malignancy rates between the treatment groups. There was no apparent difference in time to B-cell repletion between the OCR dose groups. Conclusions In placebo-controlled clinical trials of RA, OCR500+MTX was associated with a higher risk of serious infections compared with placebo +MTX. The safety profile of OCR 200+MTX was comparable with placebo+MTX. Trial Registration STAGE Clinical Trials.gov NCT00406419 SCRIPT Clinical Trials.gov NCT00476996 FILM Clinical Trials.gov NCT00485589 FEATURE Clinical Trials.gov NCT00673920 PMID:24498318

  12. A new phase diagram of water under negative pressure: The rise of the lowest-density clathrate s-III.

    PubMed

    Huang, Yingying; Zhu, Chongqin; Wang, Lu; Cao, Xiaoxiao; Su, Yan; Jiang, Xue; Meng, Sheng; Zhao, Jijun; Zeng, Xiao Cheng

    2016-02-01

    Ice and ice clathrate are not only omnipresent across polar regions of Earth or under terrestrial oceans but also ubiquitous in the solar system such as on comets, asteroids, or icy moons of the giant planets. Depending on the surrounding environment (temperature and pressure), ice alone exhibits an exceptionally rich and complicated phase diagram with 17 known crystalline polymorphs. Water molecules also form clathrate compounds with inclusion of guest molecules, such as cubic structure I (s-I), cubic structure II (s-II), hexagonal structure H (s-H), tetragonal structure T (s-T), and tetragonal structure K (s-K). Recently, guest-free clathrate structure II (s-II), also known as ice XVI located in the negative-pressure region of the phase diagram of water, is synthesized in the laboratory and motivates scientists to reexamine other ice clathrates with low density. Using extensive Monte Carlo packing algorithm and dispersion-corrected density functional theory optimization, we predict a crystalline clathrate of cubic structure III (s-III) composed of two large icosihexahedral cavities (8(6)6(8)4(12)) and six small decahedral cavities (8(2)4(8)) per unit cell, which is dynamically stable by itself and can be fully stabilized by encapsulating an appropriate guest molecule in the large cavity. A new phase diagram of water ice with TIP4P/2005 (four-point transferable intermolecular potential/2005) model potential is constructed by considering a variety of candidate phases. The guest-free s-III clathrate with ultralow density overtakes s-II and s-H phases and emerges as the most stable ice polymorph in the pressure region below -5834 bar at 0 K and below -3411 bar at 300 K.

  13. Can high pressure I-II transitions in semiconductors be affected by plastic flow and nanocrystal precipitation in phase I?

    NASA Astrophysics Data System (ADS)

    Weinstein, B. A.; Lindberg, G. P.

    Pressure-Raman spectroscopy in ZnSe and ZnTe single crystals reveals that Se and Te nano-crystals (NCs) precipitate in these II-VI hosts for pressures far below their I-II phase transitions. The inclusions are evident from the appearance and negative pressure-shift of the A1 Raman peaks of Se and Te (trigonal phase). The Se and Te NCs nucleate at dislocations and grain boundaries that arise from pressure-induced plastic flow. This produces chemical and structural inhomogeneities in the zincblende phase of the host. At substantially higher pressures, the I-II transition proceeds in the presence of these inhomogenities. This can affect the transition's onset pressure Pt and width ΔPt, and the occurrence of metastable phases along the transition path. Precipitation models in metals show that nucleation of inclusions depends on the Peierls stress τp and a parameter α related to the net free energy gained on nucleation. For favorable values of τp and α, NC precipitation at pressures below the I-II transition could occur in other compounds. We propose criteria to judge whether this is likely based on the observed ranges of τp in the hosts, and estimates of α derived from the cohesive energy densities of the NC materials. One finds trends that can serve as a useful guide, both to test the proposed criteria, and to decide when closer scrutiny of phase transition experiments is warranted, e.g., in powders where high dislocation densities are initially created

  14. A new phase diagram of water under negative pressure: The rise of the lowest-density clathrate s-III

    PubMed Central

    Huang, Yingying; Zhu, Chongqin; Wang, Lu; Cao, Xiaoxiao; Su, Yan; Jiang, Xue; Meng, Sheng; Zhao, Jijun; Zeng, Xiao Cheng

    2016-01-01

    Ice and ice clathrate are not only omnipresent across polar regions of Earth or under terrestrial oceans but also ubiquitous in the solar system such as on comets, asteroids, or icy moons of the giant planets. Depending on the surrounding environment (temperature and pressure), ice alone exhibits an exceptionally rich and complicated phase diagram with 17 known crystalline polymorphs. Water molecules also form clathrate compounds with inclusion of guest molecules, such as cubic structure I (s-I), cubic structure II (s-II), hexagonal structure H (s-H), tetragonal structure T (s-T), and tetragonal structure K (s-K). Recently, guest-free clathrate structure II (s-II), also known as ice XVI located in the negative-pressure region of the phase diagram of water, is synthesized in the laboratory and motivates scientists to reexamine other ice clathrates with low density. Using extensive Monte Carlo packing algorithm and dispersion-corrected density functional theory optimization, we predict a crystalline clathrate of cubic structure III (s-III) composed of two large icosihexahedral cavities (8668412) and six small decahedral cavities (8248) per unit cell, which is dynamically stable by itself and can be fully stabilized by encapsulating an appropriate guest molecule in the large cavity. A new phase diagram of water ice with TIP4P/2005 (four-point transferable intermolecular potential/2005) model potential is constructed by considering a variety of candidate phases. The guest-free s-III clathrate with ultralow density overtakes s-II and s-H phases and emerges as the most stable ice polymorph in the pressure region below −5834 bar at 0 K and below −3411 bar at 300 K. PMID:26933681

  15. How to improve the clinical development paradigm and its division into phases I, II and III.

    PubMed

    Bamberger, Marion; Moore, Nicholas; Lechat, Philippe

    2011-01-01

    of improvement of the medical benefit (ASMR) [level II/III or IV/V]. Such requests mainly concern uncertainties regarding the transposability, the patient profile or correct usage in real life. Among the studies whose results were provided, in 15 cases the results were in line with expectations, in 6 cases they resulted in downward re-evaluations and the final 3 cases were inconclusive. The final recommendations of the round table were: Defining the medical need that is not covered by working in consultation (Industry and Health Authorities); Providing a Complementary Investigations Plan (PIC) after the MA at a very early stage to reinforce the early MA, and/or HTA (health technology assessment) preparation and monitoring (possible constraining actions); Enhanced use of modelling techniques and their transposability; "Intussusception" of phases to optimise the development of a complete dossier; Early "scientific opinions" (EMA, French Health Products Safety Agency [Afssaps], French Health Authority [HAS]); Raising the awareness of the authorities, industry, doctors and patients with regard to controlled observational studies; Developing the use of public data bases.

  16. A Phase I/II Radiation Dose Escalation Study with Concurrent Chemotherapy for Patients with Inoperable Stages I-III Non-Small Cell Lung Cancer: The Phase I Results of RTOG 0117

    PubMed Central

    Bradley, Jeffrey D.; Moughan, Jennifer; Graham, Mary V.; Byhardt, Roger; Govindan, Ramaswamy; Fowler, Jack; Purdy, James A.; Michalski, Jeff M; Gore, Elizabeth; Choy, Hak

    2009-01-01

    Background In preparation for a Phase III comparison of high-dose versus standard dose radiation therapy, this Phase I/II study was initiated to establish the maximum tolerated dose (MTD) of radiation therapy, in the setting of concurrent chemotherapy, using 3DCRT for NSCLC. Methods Eligibility included patients with histologically proven, unresectable Stages I-III NSCLC. Concurrent chemotherapy consisted of paclitaxel 50 mg/m2 and carboplatin AUC=2 given weekly. Radiation dose was to be sequentially intensified by increasing the daily fraction size starting from 75.25 Gy/35 fractions. Results The Phase I portion of this study accrued 17 patients from 10 institutions and was closed in January 2004. After the initial eight patients were accrued to Cohort 1, the trial closed temporarily on September 26, 2002 due to reported toxicity. Two acute treatment-related DLTs were reported at the time: a grade 5 and a grade 3 radiation pneumonitis. The protocol, therefore, was revised to de-escalate the RT dose (74 Gy/37 fractions). Patients in Cohort 1 continued to develop toxicity with 6/8 (75%) eventually developing ≥ grade 3 events. Cohort 2 accrued 9 patients. There was one DLT, a grade 3 esophagitis, in Cohort 2 in the first 5 patients (1/5) and no DLTs for the next 2 patients (0/2). Conclusions The MTD was determined to be 74 Gy/37 fractions (2.0 Gy per fraction) using 3DCRT with concurrent paclitaxel and carboplatin. This dose level, in the Phase II portion, has been well tolerated with low rates of acute and late lung toxicities. PMID:20457350

  17. A Phase I/II Radiation Dose Escalation Study With Concurrent Chemotherapy for Patients With Inoperable Stages I to III Non-Small-Cell Lung Cancer: Phase I Results of RTOG 0117

    SciTech Connect

    Bradley, Jeffrey D.; Moughan, Jennifer; Graham, Mary V.; Byhardt, Roger; Govindan, Ramaswamy; Fowler, Jack; Purdy, James A.; Michalski, Jeff M.; Gore, Elizabeth; Choy, Hak

    2010-06-01

    Purpose: In preparation for a Phase III comparison of high-dose versus standard-dose radiation therapy, this Phase I/II study was initiated to establish the maximum tolerated dose of radiation therapy in the setting of concurrent chemotherapy, using three-dimensional conformal radiation therapy for non-small-cell lung cancer. Methods and Materials: Eligibility included patients with histologically proven, unresectable Stages I to III non-small-cell lung cancer. Concurrent chemotherapy consisted of paclitaxel, 50 mg/m{sup 2}, and carboplatin, AUC of 2, given weekly. The radiation dose was to be sequentially intensified by increasing the daily fraction size, starting from 75.25 Gy/35 fractions. Results: The Phase I portion of this study accrued 17 patients from 10 institutions and was closed in January 2004. After the initial 8 patients were accrued to cohort 1, the trial closed temporarily on September 26, 2002, due to reported toxicity. Two acute treatment-related dose-limiting toxicities (DLTs) were reported at the time: a case of grade 5 and grade 3 radiation pneumonitis. The protocol, therefore, was revised to de-escalate the radiation therapy dose (74 Gy/37 fractions). Patients in cohort 1 continued to develop toxicity, with 6/8 (75%) patients eventually developing grade >=3 events. Cohort 2 accrued 9 patients. There was one DLT, a grade 3 esophagitis, in cohort 2 in the first 5 patients (1/5 patients) and no DLTs for the next 2 patients (0/2 patients). Conclusions: The maximum tolerated dose was determined to be 74 Gy/37 fractions (2.0 Gy per fraction) using three-dimensional conformal radiation therapy with concurrent paclitaxel and carboplatin therapy. This dose level in the Phase II portion has been well tolerated, with low rates of acute and late lung toxicities.

  18. Self-reported conflicts of interest of authors, trial sponsorship, and the interpretation of editorials and related phase III trials in oncology.

    PubMed

    Bariani, Giovanni M; de Celis Ferrari, Anezka C R; Hoff, Paulo M; Krzyzanowska, Monika K; Riechelmann, Rachel P

    2013-06-20

    Growing participation by industry in cancer research has resulted in increased reporting of conflicts of interest (COI). We aimed to test any association between authors' conclusions and self-reported COI or trial sponsorship in cancer studies. Editorials and related phase III trials published in six clinical oncology journals in the last 3.5 years were analyzed independently by two investigators who classified study conclusions according to authors' endorsement of the experimental therapy. Logistic regression multivariable models were used to assess predictors of favorable conclusions of editorialists and of phase III authors. From January 2008 to October 2011, 1,485 articles were retrieved: 150 phase III trials and 150 editorials were eligible. Among the phase III trials, 82 (54.7%) had positive results, and 78 (52.0%) were entirely or partially funded by industry. Any COI were disclosed in 103 phase III trials (68.7%) and in 71 editorials (47.3%). Multivariable analysis showed that phase III trial results were the only significant predictor for a positive conclusion by trial authors (odds ratio [OR], 92.2; 95% CI, 19.7 to 431.6; P < .001). Sponsorship did not predict for positive conclusion by phase III authors (OR, 0.86; 95% CI, 0.3 to 2.5; P = .788). The only factor associated with positive conclusions by editorial authors was a positive conclusion by phase III trial authors (OR, 36.3; 95% CI, 6.8 to 194.2; P < .001). The interpretation of recently published phase III cancer trials by their authors or by editorialists was not influenced by financial relationships or industry sponsorship. Increased awareness of COI policies may have led to more integrity in cancer research reporting.

  19. ABE Phase III: Progress and Problems. September 1, 1969-April 1, 1970.

    ERIC Educational Resources Information Center

    Southwestern Cooperative Educational Lab., Albuquerque, NM.

    Interim information concerning the ABE III grants is provided in the three parts of this report. Part 1 (outline) describes the goals and objectives of each component; Part 2 describes accomplishments and problems to date; and Part 3 deals with coordination and supervision activities undertaken by the Lab. The components of the program are: (1)…

  20. Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders

    ClinicalTrials.gov

    2017-06-02

    Hurler Syndrome (MPS I); Hurler-Scheie Syndrome With Early Neurologic Involvement and/or Sensitization to Enzyme Replacement Therapy (ERT); Hunter Syndrome (MPS II); Sanfilippo Syndrome (MPS III); Krabbe Disease (Globoid Leukodystrophy); Metachromatic Leukodystrophy (MLD); Adrenoleukodystrophy (ALD and AMN); Sandhoff Disease; Tay Sachs Disease; Pelizaeus Merzbacher (PMD); Niemann-Pick Disease; Alpha-mannosidosis

  1. Project NECESSITIES, Phase III. Volume V: Teaching Materials for Second and Third Grades.

    ERIC Educational Resources Information Center

    Abt Associates, Inc., Cambridge, MA.

    Part III, Volume V, Part A of Project NECESSITIES consists of 6 units intended for 2nd-grade American Indian (including Eskimo) children. Activities include music, pantomime, and drama to allow the student and teacher to develop their own classroom version of the story of creation so that the student learns the difference between fact and truth.…

  2. The costs and effectiveness of large Phase III pre-licensure vaccine clinical trials.

    PubMed

    Black, Steven

    2015-01-01

    Prior to the 1980s, most vaccines were licensed based upon safety and effectiveness studies in several hundred individuals. Beginning with the evaluation of Haemophilus influenzae type b conjugate vaccines, much larger pre-licensure trials became common. The pre-licensure trial for Haemophilus influenzae oligosaccharide conjugate vaccine had more than 60,000 children and that of the seven-valent pneumococcal conjugate vaccine included almost 38,000 children. Although trial sizes for both of these studies were driven by the sample size required to demonstrate efficacy, the sample size requirements for safety evaluations of other vaccines have subsequently increased. With the demonstration of an increased risk of intussusception following the Rotashield brand rotavirus vaccine, this trend has continued. However, routinely requiring safety studies of 20,000-50,000 or more participants has two major downsides. First, the cost of performing large safety trials routinely prior to licensure of a vaccine is very large, with some estimates as high at US$200 million euros for one vaccine. This high financial cost engenders an opportunity cost whereby the number of vaccines that a company is willing or able to develop to meet public health needs becomes limited by this financial barrier. The second downside is that in the pre-licensure setting, such studies are very time consuming and delay the availability of a beneficial vaccine substantially. One might argue that in some situations, this financial commitment is warranted such as for evaluations of the risk of intussusception following newer rotavirus vaccines. However, it must be noted that while an increased risk of intussusception was not identified in large pre-licensure studies, in post marketing evaluations an increased risk of this outcome has been identified. Thus, even the extensive pre-licensure evaluations conducted did not identify an associated risk. The limitations of large Phase III trials have also been

  3. Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: updated overall survival and biomarker analyses.

    PubMed

    Mitchell, P; Thatcher, N; Socinski, M A; Wasilewska-Tesluk, E; Horwood, K; Szczesna, A; Martín, C; Ragulin, Y; Zukin, M; Helwig, C; Falk, M; Butts, C; Shepherd, F A

    2015-06-01

    Tecemotide is a MUC1-antigen-specific cancer immunotherapy. The phase III START study did not meet its primary end point but reported notable survival benefit with tecemotide versus placebo in an exploratory analysis of the predefined patient subgroup treated with concurrent chemoradiotherapy. Here, we attempted to gain further insight into the effects of tecemotide in START. START recruited patients who did not progress following frontline chemoradiotherapy for unresectable stage III non-small-cell lung cancer. We present updated overall survival (OS) data and exploratory analyses of OS for baseline biomarkers: soluble MUC1 (sMUC1), antinuclear antibodies (ANA), neutrophil/lymphocyte ratio (NLR), lymphocyte count, and HLA type. Updated OS data are consistent with the primary analysis: median 25.8 months (tecemotide) versus 22.4 months (placebo) (HR 0.89, 95% CI 0.77-1.03, P = 0.111), with ∼20 months additional median follow-up time compared with the primary analysis. Exploratory analysis of the predefined subgroup treated with concurrent chemoradiotherapy revealed clinically relevant prolonged OS with tecemotide versus placebo (29.4 versus 20.8 months; HR 0.81, 95% CI 0.68-0.98, P = 0.026). No improvement was seen with sequential chemoradiotherapy. High sMUC1 and ANA correlated with a possible survival benefit with tecemotide (interaction P = 0.0085 and 0.0022) and might have future value as biomarkers. Interactions between lymphocyte count, NLR, or prespecified HLA alleles and treatment effect were not observed. Updated OS data support potential treatment benefit with tecemotide in patients treated with concurrent chemoradiotherapy. Exploratory biomarker analyses suggest that elevated sMUC1 or ANA levels correlate with tecemotide benefit. NCT00409188. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  4. Phase I/II Study of Temozolomide Plus Nimustine Chemotherapy for Recurrent Malignant Gliomas: Kyoto Neuro-oncology Group

    PubMed Central

    AOKI, Tomokazu; ARAKAWA, Yoshiki; UEBA, Tetsuya; ODA, Masashi; NISHIDA, Namiko; AKIYAMA, Yukinori; TSUKAHARA, Tetsuya; IWASAKI, Koichi; MIKUNI, Nobuhiro; MIYAMOTO, Susumu

    2017-01-01

    The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemo-regimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m2/day) (Day 1–5) plus various doses of ACNU (30, 35, 40, 45 mg/m2/day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70–100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m2) plus ACNU (40 mg/m2). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12–35%) and 8% (95% CI, 4–15%). Median PFS was 13 months (95% CI, 9.2–17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67–89%) and 49% (95% CI, 33–57%). Median OS was 11.8 months (95% CI, 8.2–14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS. PMID:27725524

  5. Systems Description; Sperry Low Temperature Geothermal Conversion System - Phase I and Phase II; Final Report, Volume III

    SciTech Connect

    Matthews, Hugh B.

    1982-01-01

    This Volume should be considered the introductory volume to the series of six volumes even though numbered out of sequence. Volumes I and II were completed first and released in 1981 while a staff member was available to do the work. Volumes III through VI are being written and released some two years later as DOE funding became available for the purpose. They are as complete as possible considering that almost all the people involved in the program are now unavailable. This Volume III is an overview of the entire program, and many of the items presented herein briefly will be found in expanded form in one of the other five volumes. It will be noticed that assumptions and parameters such as well flow, well temperature, wet bulb temperatures, etc., involved in the several different performance calculations in the volume vary somewhat. These calculations were made at different times for different purposes and no attempt has been made to bring them into exact agreement.

  6. Once-daily USL255 as adjunctive treatment of partial-onset seizures: Randomized phase III study

    PubMed Central

    Chung, Steve S; Fakhoury, Toufic A; Hogan, R Edward; Nagaraddi, Venkatesh N; Blatt, Ilan; Lawson, Balduin; Arnold, Stephan; Anders, Bob; Clark, Annie M; Laine, Dawn; Meadows, R Shawn; Halvorsen, Mark B

    2014-01-01

    Objective To evaluate the efficacy and safety of USL255, Qudexy™ XR (topiramate) extended-release capsules, as an adjunctive treatment for refractory partial-onset seizures (POS) in adults taking one to three concomitant antiepileptic drugs. Methods In this global phase III study (PREVAIL; NCT01142193), 249 adults with POS were randomized 1:1 to once-daily USL255 (200 mg/day) or placebo. The primary and key secondary efficacy endpoints were median percent reduction in weekly POS frequency and responder rate (proportion of patients with ≥50% reduction in seizure frequency). Seizure freedom was also assessed. Safety (adverse events, clinical and laboratory findings), as well as treatment effects on quality of life (QOLIE-31-P) and clinical global impression of change (CGI-C), were evaluated. Results Across the entire 11-week treatment phase, USL255 significantly reduced the median percent seizure frequency and significantly improved responder rate compared with placebo. Efficacy over placebo was observed early in treatment, in patients with highly refractory POS, and in those with the most debilitating seizure types (i.e., complex partial, partial secondarily generalized). USL255 was safe and generally well tolerated with a low incidence of neurocognitive adverse events. USL255 was associated with significant clinical improvement without adversely affecting quality of life. Significance The PREVAIL phase III clinical study demonstrated that once-daily USL255 (200 mg/day) significantly improved seizure control and was safe and generally well tolerated with few neurocognitive side effects. PMID:24902983

  7. Integrated low emissions cleanup system for coal fueled turbines Phase III bench-scale testing and evaluation

    SciTech Connect

    Newby, R.A.; Alvin, M.A.; Bachovchin, D.M.

    1995-08-01

    The United States Department of Energy, Morgantown Energy Research Center (DOE/METC), is sponsoring the development of coal-fired turbine technologies such as Pressurized Fluidized Bed Combustion (PFBC), coal Gasification Combined Cycles (GCC), and Direct Coal-Fired Turbines (DCFT). A major technical development challenge remaining for coal-fired turbine systems is high-temperature gas cleaning to meet environmental emissions standards, as well as to ensure acceptable turbine life. The Westinghouse Electric Corporation, Science & Technology Center, has evaluated an Integrated Low Emissions Cleanup (ILEC) concept that has been configured to meet this technical challenge. This ceramic hot gas filter (HGF), ILEC concept controls particulate emissions, while simultaneously contributing to the control of sulfur and alkali vapor contaminants in high-temperature, high-pressure, fuel gases or combustion gases. This document reports on the results of Phase III of the ILEC evaluation program, the final phase of the program. In Phase III, a bench-scale ILEC facility has been tested to (1) confirm the feasibility of the ILEC concept, and (2) to resolve some major filter cake behavior issues identified in PFBC, HGF applications.

  8. Preliminary results of a phase I/II study of sodium pentosanpolysulfate in the treatment of chronic radiation-induced proctitis

    SciTech Connect

    Grigsby, P.W.; Pilepich, M.V.; Parsons, C.L. )

    1990-02-01

    This is a report of a phase I/II study of 13 patients treated with sodium pentosanpolysulfate (PPS) for chronic radiation-induced proctitis. A complete response was obtained in 82%, a partial response occurred in 9%, and 9% failed to respond to therapy. No significant toxicity was observed. It is concluded that PPS is an effective treatment for chronic radiation-induced proctitis and a phase III randomized, double-blind study of PPS versus placebo is planned.

  9. Antiangiogenic Therapy in Advanced Non-small-cell Lung Cancer: A Meta-analysis of Phase III Randomized Trials.

    PubMed

    Raphael, Jacques; Chan, Kelvin; Karim, Safiya; Kerbel, Robert; Lam, Henry; Santos, Keemo Delos; Saluja, Ronak; Verma, Sunil

    2017-01-12

    We conducted a meta-analysis to evaluate the efficacy of adding any antiangiogenic therapy (AT) to the standard of care in advanced non-small-cell lung cancer (NSCLC). The electronic databases Ovid PubMed, Cochrane Central Register of Controlled Trials, and Embase were searched to identify eligible trials. We included all phase III randomized trials with any line and type of treatment, histology. and AT dose. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for overall response rates (RR) were calculated. We divided the population into 2 subgroups based on the bevacizumab dose. Data of 19,098 patients from 25 phase III trials were analyzed. Compared with the standard of care, the addition of AT did not prolong OS (HR 0.98; 95% confidence interval [CI], 0.96-1.00; P = .1 and HR 0.97; 95% CI, 0.94-1.00; P = .06 for groups 1 and 2, respectively). However, there was a significant improvement in PFS with the addition of AT (HR 0.85; 95% CI, 0.79-0.91; P < .00001 and HR 0.81; 95% CI, 0.75-0.88; P < .00001 for groups 1 and 2, respectively) and overall RR (OR 1.61; 95% CI, 1.30-2.01; P < .0001 and OR 1.72; 95% CI, 1.39-2.14; P < .00001 for groups 1 and 2, respectively). This is the first meta-analysis including only all phase III trials with AT in NSCLC showing no significant effect on OS and an improvement in PFS and RR only. The role of AT in advanced NSCLC is still questionable; strong validated biomarkers are eagerly needed to predict which subgroup might benefit the most from such therapy.

  10. Phase I/II Trial of Single Session Stereotactic Body Radiotherapy for Previously Un-irradiated Spinal Metastases

    PubMed Central

    Garg, Amit K.; Shiu, Almon S.; Yang, James; Wang, Xin-Shelley; Allen, Pamela; Brown, Barry W.; Grossman, Patricia; Frija, Erik K.; McAleer, Mary Frances; Azeem, Syed; Brown, Paul D.; Rhines, Laurence D.; Chang, Eric L.

    2013-01-01

    Background This Phase I/II study tests the hypothesis that single-fraction SBRT for previously un-irradiated spinal metastases is a safe, feasible, and efficacious treatment approach. Methods All patients were evaluated by a multidisciplinary team. Spinal MRI was performed before treatment and at regular intervals to both define target volume and response to treatment. SBRT was delivered to a peripheral dose of 16–24 Gy in 1 fraction while limiting dose to the spinal cord. Higher doses were used for renal cell histology. The NCI Common Toxicity Criteria 2.0 and McCormick neurological function score were used as toxicity assessment tools. Results A total of 61 patients harboring 63 tumors of the non-cervical spine were enrolled and treated with SBRT between 2005 and 2010 on a prospective Phase I/II trial at the University of Texas M. D. Anderson Cancer Center. Mean follow-up was 20 months. Actuarial 18-month imaging local control for all patients was 88%. Actuarial 18-month overall survival for all patients was 64%. Median survival for all patients was 30 months. No significant differences in outcomes were noted with respect to tumor histology and SBRT dose. Two patients experienced radiation adverse events (Grade 3 or higher). Actuarial 18-month freedom from neurologic deterioration from any cause as was 82%. Conclusions This Phase I/II data support an expanded indication for SBRT as first-line treatment of selected spinal metastases patients. Additional studies that can prospectively identify predictive factors for spinal cord toxicity after SBRT are warranted to minimize the incidence of this serious yet rare complication. PMID:22511344

  11. THE PHASES DIFFERENTIAL ASTROMETRY DATA ARCHIVE. III. LIMITS TO TERTIARY COMPANIONS

    SciTech Connect

    Muterspaugh, Matthew W.; Lane, Benjamin F.; Kulkarni, S. R.; Konacki, Maciej; Burke, Bernard F.; Colavita, M. M.; Shao, M. E-mail: blane@draper.co

    2010-12-15

    The Palomar High-precision Astrometric Search for Exoplanet Systems (PHASES) monitored 51 subarcsecond binary systems to evaluate whether tertiary companions as small as Jovian planets orbited either the primary or secondary stars, perturbing their otherwise smooth Keplerian motions. Twenty-one of those systems were observed 10 or more times and show no evidence of additional companions. A new algorithm is presented for identifying astrometric companions and establishing the (companion mass)-(orbital period) combinations that can be excluded from existence with high confidence based on the PHASES observations, and the regions of mass-period phase space being excluded are presented for 21 PHASES binaries.

  12. NCI will no longer support investigator-initiated phase III clinical trials through R01 and P01s grants | Division of Cancer Prevention

    Cancer.gov

    The NCI has traditionally provided support for all phases of clinical trials and interventions via grants and cooperative agreements (including the R03, R21, R01, P01, U01, U10, and UM1 mechanisms). Historically, the majority of early phase trials have been conducted under R03, R21, R01, P01, U01, and UM1 activity codes, whereas most Phase III clinical trials have been conducted under the U10 activity code, with a limited number of Phase III clinical trials performed under the R01, P01, and U01 activity codes... |

  13. Whole Brain Radiotherapy and RRx-001: Two Partial Responses in Radioresistant Melanoma Brain Metastases from a Phase I/II Clinical Trial: A TITE-CRM Phase I/II Clinical Trial.

    PubMed

    Kim, Michelle M; Parmar, Hemant; Cao, Yue; Pramanik, Priyanka; Schipper, Matthew; Hayman, James; Junck, Larry; Mammoser, Aaron; Heth, Jason; Carter, Corey A; Oronsky, Arnold; Knox, Susan J; Caroen, Scott; Oronsky, Bryan; Scicinski, Jan; Lawrence, Theodore S; Lao, Christopher D

    2016-04-01

    Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with RRx-001 and whole brain radiotherapy (WBRT) without neurologic or systemic toxicity in the context of a phase I/II clinical trial. RRx-001 is an reactive oxygen and reactive nitrogen species (ROS/RNS)-dependent systemically nontoxic hypoxic cell radiosensitizer with vascular normalizing properties under investigation in patients with various solid tumors including those with brain metastases. Metastatic melanoma to the brain is historically associated with poor outcomes and a median survival of 4 to 5 months. WBRT is a mainstay of treatment for patients with multiple brain metastases, but no significant therapeutic advances for these patients have been described in the literature. To date, candidate radiosensitizing agents have failed to demonstrate a survival benefit in patients with brain metastases, and in particular, no agent has demonstrated improved outcome in patients with metastatic melanoma. Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with novel radiosensitizing agent RRx-001 and WBRT without neurologic or systemic toxicity in the context of a phase I/II clinical trial. Published by Elsevier Inc.

  14. North Dakota Statewide Nursing Study, Phase III. Final Report and Recommendations.

    ERIC Educational Resources Information Center

    Clark, Neil; Smith, David

    The process, outcomes, and recommendations resulting from a project to develop a statewide nursing resource planning system are examined. Phase 1 of the project investigated nursing manpower demands for 1984 and 1986, while phase 2 studied the current scope of nursing practice. In addition to summarizing the findings of these investigations,…

  15. Lafayette Parish Cooperative Jail Project--LPCJP. Phase III Final Report.

    ERIC Educational Resources Information Center

    Lafayette Parish School Board, LA.

    A three-phase project was conducted to further the education of inmates in the Lafayette (Louisiana) Parish Correctional Center. Phase I of the project was designed to prepare inmates to be eligible to take the General Educational Development (GED) test, and/or to teach life-coping skills so that they would better function in society upon their…

  16. North Dakota Statewide Nursing Study, Phase III. Final Report and Recommendations.

    ERIC Educational Resources Information Center

    Clark, Neil; Smith, David

    The process, outcomes, and recommendations resulting from a project to develop a statewide nursing resource planning system are examined. Phase 1 of the project investigated nursing manpower demands for 1984 and 1986, while phase 2 studied the current scope of nursing practice. In addition to summarizing the findings of these investigations,…

  17. In-plant demonstration of optimization of energy utilization in beck dyeing of carpet. Proposed Part III, Phase III extension of DOE contract

    SciTech Connect

    1981-01-01

    A proposal to demonstrate on a commercial scale an optimized procedure for beck dyeing of carpet to improve energy utilization is discussed. The proposal is for Phase III. A number of energy conserving procedural and equipment modification including lower dyeing temperature, lower liquor ratio, lower air exhaust flows, and recycle of hot spent dyebaths will be demonstrated in the plant dyeings. Pilot-scale experiments suggest that these modifications will reduce direct energy consumption in carpet dyeing by 400 Btu per pound of carpet processed. Adoption of the modified process by only 50% of the carpet industry would yield an annual reduction in energy consumption of 1 x 10/sup 12/ Btu's (1.7 x 10/sup 5/ BOE). The pilot-scale experiments also indicate that a cost savings of approximately 2 cents per pound of carpet dyed can be achieved with the suggested modifications. The demonstrated technology will have application in other types of nylon and polyester fiber dyeing. The Salem Carpet Mills carpet dyeing facility at Chickamauga, Georgia, will be the site of the demonstration.

  18. Identification of high-pressure phases III and IV in hydrogen: Simulating Raman spectra using molecular dynamics

    NASA Astrophysics Data System (ADS)

    Magdău, Ioan B.; Ackland, Graeme J.

    2013-05-01

    We present a technique for extracting Raman intensities from ab initio molecular dynamics (MD) simulations at high temperature. The method is applied to the highly anharmonic case of dense hydrogen up to 500 K for pressures ranging from 180 to 300 GPa. On heating or pressurizing we find first-order phase transitions under the experimental conditions of the phase III-IV boundary. At even higher pressures, close to 350 GPa, we find a second phase transformation to the previously proposed Cmca-4. Our method enables, for the first time, a direct comparison of Raman vibrons between theory and experiment at finite temperature. This turns out to provide excellent discrimination between subtly different structures found in MD. We find candidate structures whose Raman spectra are in good agreement with experiment. The new phase obtained in high-temperature simulations adopts a dynamic, simple hexagonal structure with three layer types: freely rotating hydrogen molecules, static hexagonal trimers, and rotating hexagonal trimers. We show that previously calculated structures for phase IV are inconsistent with experiment, and their appearance in simulation is due to finite-size effects.

  19. ReACT Phase II trial: a critical evaluation of the use of rindopepimut plus bevacizumab to treat EGFRvIII-positive recurrent glioblastoma.

    PubMed

    Gatson, Na Tosha N; Weathers, Shiao-Pei S; de Groot, John F

    2016-01-01

    Glioblastoma is the most deadly primary brain tumor in adults and has long represented a therapeutic challenge. Disease recurrence is inevitable, and the management of recurrent disease is complicated by spontaneous or induced tumor heterogeneity which confers resistance to therapy and increased oncogenicity. EGFR and the tumor-specific mutation EGFRvIII is commonly altered in glioblastoma making it an appealing therapeutic target. Immunotherapy is an emerging and promising therapeutic approach to glioma and the EGFRvIII vaccine, rindopepimut, is the first immunotherapeutic drug to enter Phase III clinical trials for glioblastoma. Rindopepimut activates a specific immune response against tumor cells harboring the EGFRvIII protein. This review evaluates the recently completed ReACT Phase II trial using rindopepimut plus bevacizumab in the setting of EGFRvIII-positive recurrent glioblastoma (Clinical Trials identifier: NCT01498328).

  20. A Phase I/II adaptive design for heterogeneous groups with application to a stereotactic body radiation therapy trial.

    PubMed

    Wages, Nolan A; Read, Paul W; Petroni, Gina R

    2015-01-01

    Dose-finding studies that aim to evaluate the safety of single agents are becoming less common, and advances in clinical research have complicated the paradigm of dose finding in oncology. A class of more complex problems, such as targeted agents, combination therapies and stratification of patients by clinical or genetic characteristics, has created the need to adapt early-phase trial design to the specific type of drug being investigated and the corresponding endpoints. In this article, we describe the implementation of an adaptive design based on a continual reassessment method for heterogeneous groups, modified to coincide with the objectives of a Phase I/II trial of stereotactic body radiation therapy in patients with painful osseous metastatic disease. Operating characteristics of the Institutional Review Board approved design are demonstrated under various possible true scenarios via simulation studies. Copyright © 2015 John Wiley & Sons, Ltd.

  1. Motivation, recruitment, and screening of volunteers for a phase I/II HIV preventive vaccine trial in Thailand.

    PubMed

    Jenkins, R A; Chinaworapong, S; Morgan, P A; Ruangyuttikarn, C; Sontirat, A; Chiu, J; Michael, R A; Nitayaphan, S; Khamboonruang, C

    1998-06-01

    Data from recruitment and screening for a phase I/II preventive HIV-1 vaccine trial in Thailand were evaluated with respect to correlates of participation at each phase. Correlates included demographic variables, motivation for interest in the trial, and factors related to communication and contact. Participants were recruited at two sites through varied methods. The majority of prescreenees reported altruistic motives for interest in the trial and blood donors emerged as a group that may have been particularly altruistic. Findings indicated site differences in attrition during recruitment and screening, but not in enrollment into the vaccine trial. Blood donation and willingness to be contacted by phone at home were significantly related to making and keeping screening appointments.

  2. Value of DNA Ploidy and S-Phase Fraction as Prognostic Factors in Stage III Cutaneous Melanoma

    PubMed Central

    Martin, Ginette; Halwani, Fawaz; Shibata, Henry; Meterissian, Sarkis

    2000-01-01

    Objective To determine the prognostic value of flow cytometric analysis (S-phase fraction and DNA index) performed on lymph-node metastases of patients with stage III melanoma. Design A retrospective chart review with flow cytometric analysis of paraffin-embedded tissues. Setting A university teaching hospital. Patients Among 332 patients with cutaneous melanoma, 33 with stage III were identified. Distant metastases developed in 16 patients; 17 had no further recurrence. Charts were reviewed to obtain clinicopathologic parameters such as sex, age, location of the primary tumour, histologic features, presence or absence of ulceration, and Clark’s and Breslow’s levels. Intervention DNA ploidy and S-phase fraction were determined on the paraffin-embedded nodes. Main outcome measures The groups with or without recurrence were compared in terms of disease-free survival (DFS) and overall survival (OS). These survival parameters were correlated with DNA ploidy and S-phase fraction. Results By univariate analysis, clinicopathologic factors did not predict OS. A higher Clark’s level of invasion and more than 3 positive lymph nodes were associated with shorter DFS (p < 0.05). Tumour thickness and S-phase fraction did not correlate with either DFS or OS. Patients with diploid lymph-node metastases had an 87% 12-month survival compared with 41% for those with aneuploid tumours. Conclusions DNA ploidy may be used as a prognostic index in patients with lymph-node metastases. This could be particularly useful in the context of sentinel lymph-node mapping by which more patients are being identified with single microscopic lymph-node involvement. PMID:10714254

  3. Afghanistan Security Forces Fund Phase III-U.S. Army Corps of Engineers Real Property Accountability

    DTIC Science & Technology

    2009-04-14

    None A.1., B.1. Commander, U.S. Army Corps of Engineers, Afghanistan Engineer District None A.1., A.2., B.1., B.2., B.3. ii Table of Contents...requirement for an oxygen supply system at NMH. The NMH phase II contract, awarded on August 1, 2006, included option 0016 to replace the oxygen supply...Proposals (RFP). The Kabul NMH phase II contract file did not document that this planning coordination took place. AED exercised this contract

  4. Methodological quality of animal studies of neuroprotective agents currently in phase II/III acute ischemic stroke trials.

    PubMed

    Philip, Maria; Benatar, Michael; Fisher, Marc; Savitz, Sean I

    2009-02-01

    Numerous neuroprotective agents have proven effective in animal stroke studies, but every drug has failed to achieve its primary outcome when brought forward to clinical trials. We analyzed the quality and adequacy of animal studies supporting the efficacy of NXY-059 and other neuroprotective agents that are currently being investigated in phase II/III trials. We conducted a systematic search of all neuroprotective drugs in Phase II or III trials and collected data from animal studies of focal cerebral ischemia testing agents systemically administered within 24 hours of occlusion. The methodological rigor of each individual study was evaluated using 5 criteria derived from the STAIR guidelines. The adequacy of the preclinical "package" for each drug was then evaluated by combining the results of all studies for each drug to determine which of a further 5 STAIR criteria were met before moving forward from animal to human studies. Our search yielded 13 agents of which 10 had published data in peer-reviewed journals. There is substantial within-drug variability in the quality of preclinical studies as well as substantial variation in the completeness of the collective preclinical literature for different drugs. There has been little or no improvement in the quality of animal studies since NXY-059, and current agents have not been subjected to a more complete preclinical evaluation. There is significant heterogeneity in the quality of animal testing for neuroprotective agents in stroke. Drugs in the post-SAINT era have not been subjected to more thorough preclinical evaluation.

  5. A robust two-stage design identifying the optimal biological dose for phase I/II clinical trials.

    PubMed

    Zang, Yong; Lee, J Jack

    2017-01-15

    We propose a robust two-stage design to identify the optimal biological dose for phase I/II clinical trials evaluating both toxicity and efficacy outcomes. In the first stage of dose finding, we use the Bayesian model averaging continual reassessment method to monitor the toxicity outcomes and adopt an isotonic regression method based on the efficacy outcomes to guide dose escalation. When the first stage ends, we use the Dirichlet-multinomial distribution to jointly model the toxicity and efficacy outcomes and pick the candidate doses based on a three-dimensional volume ratio. The selected candidate doses are then seamlessly advanced to the second stage for dose validation. Both toxicity and efficacy outcomes are continuously monitored so that any overly toxic and/or less efficacious dose can be dropped from the study as the trial continues. When the phase I/II trial ends, we select the optimal biological dose as the dose obtaining the minimal value of the volume ratio within the candidate set. An advantage of the proposed design is that it does not impose a monotonically increasing assumption on the shape of the dose-efficacy curve. We conduct extensive simulation studies to examine the operating characteristics of the proposed design. The simulation results show that the proposed design has desirable operating characteristics across different shapes of the underlying true dose-toxicity and dose-efficacy curves. The software to implement the proposed design is available upon request. Copyright © 2016 John Wiley & Sons, Ltd.

  6. Phase I/II trial evaluating carbon ion radiotherapy for the treatment of recurrent rectal cancer: the PANDORA-01 trial.

    PubMed

    Combs, Stephanie E; Kieser, Meinhard; Habermehl, Daniel; Weitz, Jürgen; Jäger, Dirk; Fossati, Piero; Orrechia, Roberto; Engenhart-Cabillic, Rita; Pötter, Richard; Dosanjh, Manjit; Jäkel, Oliver; Büchler, Markus W; Debus, Jürgen

    2012-04-03

    Treatment standard for patients with rectal cancer depends on the initial staging and includes surgical resection, radiotherapy as well as chemotherapy. For stage II and III tumors, radiochemotherapy should be performed in addition to surgery, preferentially as preoperative radiochemotherapy or as short-course hypofractionated radiation. Advances in surgical approaches, especially the establishment of the total mesorectal excision (TME) in combination with sophisticated radiation and chemotherapy have reduced local recurrence rates to only few percent. However, due to the high incidence of rectal cancer, still a high absolute number of patients present with recurrent rectal carcinomas, and effective treatment is therefore needed.Carbon ions offer physical and biological advantages. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increase relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the cell line as well as the endpoint analyzed.Japanese data on the treatment of patients with recurrent rectal cancer previously not treated with radiation therapy have shown local control rates of carbon ion treatment superior to those of surgery. Therefore, this treatment concept should also be evaluated for recurrences after radiotherapy, when dose application using conventional photons is limited. Moreover, these patients are likely to benefit from the enhanced biological efficacy of carbon ions. In the current Phase I/II-PANDORA-01-Study the recommended dose of carbon ion radiotherapy for recurrent rectal cancer will be determined in the Phase I part, and feasibilty and progression-free survival will be assessed in the Phase II part of the study.Within the Phase I part, increasing doses from 12 × 3 Gy E to 18 × 3 Gy E will be applied.The primary endpoint in the Phase

  7. Thymostimulin versus placebo for palliative treatment of locally advanced or metastasised hepatocellular carcinoma: a phase III clinical trial

    PubMed Central

    2010-01-01

    Background Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independent phase II trials. The aim of this study was to assess the efficacy of thymostimulin in a phase III trial. Methods The study was designed as a prospective randomised, placebo-controlled, double-blind, multicenter clinical phase III trial. Between 10/2002 and 03/2005, 135 patients with locally advanced or metastasised HCC (Karnofsky ≥60%/Child-Pugh ≤ 12) were randomised to receive thymostimulin 75 mg s.c. 5×/week or placebo stratified according to liver function. Primary endpoint was twelve-month survival, secondary endpoints overall survival (OS), time to progression (TTP), tumor response, safety and quality of life. A subgroup analysis according to liver function, KPS and tumor stage (Okuda, CLIP and BCLC) formed part of the protocol. Results Twelve-month survival was 28% [95%CI 17-41; treatment] and 32% [95%CI 19-44; control] with no significant differences in median OS (5.0 [95% CI 3.7-6.3] vs. 5.2 [95% CI 3.5-6.9] months; p = 0.87, HR = 1.04 [95% CI 0.7-1.6]) or TTP (5.3 [95%CI 2.0-8.6] vs. 2.9 [95%CI 2.6-3.1] months; p = 0.60, HR = 1.13 [95% CI 0.7-1.8]). Adjustment for liver function, Karnofsky status or tumor stage did not affect results. While quality of life was similar in both groups, fewer patients on thymostimulin suffered from accumulating ascites and renal failure. Conclusions In our phase III trial, we found no evidence of any benefit to thymostimulin in the treatment of advanced HCC and there is therefore no justification for its use as single-agent treatment. The effect of thymostimulin on hepato-renal function requires further confirmation. Trial Registration Current Controlled Trials ISRCTN64487365. PMID:20735834

  8. Thymostimulin versus placebo for palliative treatment of locally advanced or metastasised hepatocellular carcinoma: a phase III clinical trial.

    PubMed

    Dollinger, Matthias M; Lautenschlaeger, Christine; Lesske, Joachim; Tannapfel, Andrea; Wagner, Anna-Dorothea; Schoppmeyer, Konrad; Nehls, Oliver; Welker, Martin-Walter; Wiest, Reiner; Fleig, Wolfgang E

    2010-08-24

    Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independent phase II trials. The aim of this study was to assess the efficacy of thymostimulin in a phase III trial. The study was designed as a prospective randomised, placebo-controlled, double-blind, multicenter clinical phase III trial. Between 10/2002 and 03/2005, 135 patients with locally advanced or metastasised HCC (Karnofsky >or=60%/Child-Pugh phase III trial, we found no evidence of any benefit to thymostimulin in the treatment of advanced HCC and there is therefore no justification for its use as single-agent treatment. The effect of thymostimulin on hepato-renal function requires further confirmation. Current Controlled Trials ISRCTN64487365.

  9. Magnetic antenna excitation of whistler modes. III. Group and phase velocities of wave packets

    NASA Astrophysics Data System (ADS)

    Urrutia, J. M.; Stenzel, R. L.

    2015-07-01

    The properties of whistler modes excited by single and multiple magnetic loop antennas have been investigated in a large laboratory plasma. A single loop excites a wavepacket, but an array of loops across the ambient magnetic field B0 excites approximate plane whistler modes. The single loop data are measured. The array patterns are obtained by linear superposition of experimental data shifted in space and time, which is valid in a uniform plasma and magnetic field for small amplitude waves. Phasing the array changes the angle of wave propagation. The antennas are excited by an rf tone burst whose propagating envelope and oscillations yield group and phase velocities. A single loop antenna with dipole moment across B0 excites wave packets whose topology resembles m = 1 helicon modes, but without radial boundaries. The phase surfaces are conical with propagation characteristics of Gendrin modes. The cones form near the antenna with comparable parallel and perpendicular phase velocities. A physical model for the wave excitation is given. When a wave burst is applied to a phased antenna array, the wave front propagates both along the array and into the plasma forming a "whistler wing" at the front. These laboratory observations may be relevant for excitation and detection of whistler modes in space plasmas.

  10. Garrison-Taft 500 KV Transmission Project : Phase III Hunter Survey, Final Report.

    SciTech Connect

    Allen, Stewart D.

    1989-07-01

    This report presents the results of the Phase 3 survey of hunters conducted to assess the impacts of Bonneville Power Administration's 500-kV transmission line on elk hunting opportunities in western Montana. This survey is the final in a series of three (Allen, 1983; 1988). These three surveys are the social component of the Elk Monitoring and Mitigation Project being conducted by several state and federal agencies. A report prepared by the Montana Department of Fish, Wildlife and Parks contains a description of the entire monitoring effort, a description of the two study areas, and progress on the biological component of the study (Canfield, 1988). The primary concern is that the line and associated access roads could decrease hunters' perceptions of the quality of the setting, potentially leading to less satisfaction. Hunters could continue to hunt in the areas but with less enjoyment, they could discontinue hunting in the area, or they could continue to use the area, but differently than before. The study also was designed to identify positive effects of the line. The Phase 3 hunter survey asked a sample of hunters interviewed at check stations during Phase 2 about their use of the DeBorgia (western) study area and the Harvey Creek-Eightmile (eastern) study area during the Fall, 1987 hunting season. Before presenting the methods and results, it may be helpful to summarize the findings from the Phase 1 and 2 hunter surveys, to provide a context for interpreting Phase 3 data. 5 refs., 11 tabs.

  11. A post hoc analysis of subgroup outcomes and creatinine in the phase III clinical trial (EMPOWER) of dexpramipexole in ALS.

    PubMed

    Bozik, Michael E; Mitsumoto, Hiroshi; Brooks, Benjamin R; Rudnicki, Stacy A; Moore, Dan H; Zhang, Bing; Ludolph, Albert; Cudkowicz, Merit E; van den Berg, Leonard H; Mather, James; Petzinger, Thomas; Archibald, Donald

    2014-09-01

    Our objective was to compare the phase II and phase III (EMPOWER) studies of dexpramipexole in ALS and evaluate potential EMPOWER responder subgroups and biomarkers based on significant inter-study population differences. In a post hoc analysis, we compared the baseline population characteristics of both dexpramipexole studies and analyzed EMPOWER efficacy outcomes and laboratory measures in subgroups defined by significant inter-study differences. Results showed that, compared with phase II, the proportion of El Escorial criteria (EEC) definite participants decreased (p = 0.005), riluzole use increased (p = 0.002), and mean symptom duration increased (p = 0.037) significantly in EMPOWER. Baseline creatinine (p < 0.001) and on-study creatinine change (p < 0.001) correlated significantly with ALSFRS-R in EMPOWER. In the EMPOWER subgroup defined by EEC-definite ALS, riluzole use, and < median symptom duration (15.3 months), dexpramipexole-treated participants had reduced ALSFRS-R slope decline (p = 0.015), decreased mortality (p = 0.011), and reduced creatinine loss (p = 0.003). In conclusion, significant differences existed between the phase II and EMPOWER study populations in ALS clinical trials of dexpramipexole. In a post hoc analysis of EMPOWER subgroups defined by these differences, potential clinical benefits of dexpramipexole were identified in the subgroup of riluzole-treated, short-symptom duration, EEC-definite ALS participants. Creatinine loss correlated with disease progression and was reduced in dexpramipexole-treated participants, suggesting it as a candidate biomarker.

  12. CHEMKIN-III: A FORTRAN chemical kinetics package for the analysis of gas-phase chemical and plasma kinetics

    SciTech Connect

    Kee, R.J.; Rupley, F.M.; Meeks, E.; Miller, J.A.

    1996-05-01

    This document is the user`s manual for the third-generation CHEMKIN package. CHEMKIN is a software package whose purpose is to facilitate the formation, solution, and interpretation of problems involving elementary gas-phase chemical kinetics. It provides a flexible and powerful tool for incorporating complex chemical kinetics into simulations of fluid dynamics. The package consists of two major software components: an Interpreter and a Gas-Phase Subroutine Library. The Interpreter is a program that reads a symbolic description of an elementary, user-specified chemical reaction mechanism. One output from the Interpreter is a data file that forms a link to the Gas-Phase Subroutine Library. This library is a collection of about 100 highly modular FORTRAN subroutines that may be called to return information on equations of state, thermodynamic properties, and chemical production rates. CHEMKIN-III includes capabilities for treating multi-fluid plasma systems, that are not in thermal equilibrium. These new capabilities allow researchers to describe chemistry systems that are characterized by more than one temperature, in which reactions may depend on temperatures associated with different species; i.e. reactions may be driven by collisions with electrons, ions, or charge-neutral species. These new features have been implemented in such a way as to require little or no changes to CHEMKIN implementation for systems in thermal equilibrium, where all species share the same gas temperature. CHEMKIN-III now has the capability to handle weakly ionized plasma chemistry, especially for application related to advanced semiconductor processing.

  13. Treatment of primary glioblastoma multiforme with cetuximab, radiotherapy and temozolomide (GERT) – phase I/II trial: study protocol

    PubMed Central

    Combs, Stephanie E; Heeger, Steffen; Haselmann, Renate; Edler, Lutz; Debus, Jürgen; Schulz-Ertner, Daniela

    2006-01-01

    Background The implementation of combined radiochemotherapy (RCHT) with temozolomide (TMZ) has lead to a significant increase in overall survival times in patients with Glioblastoma multiforme (GBM), however, outcome still remains unsatisfactory. The majority of GBMs show an overexpression and/or amplification of the epidermal growth factor receptor (EGFR). Therefore, addition of EGFR-inhibition with cetuximab to the current standard treatment approach with radiotherapy and TMZ seems promising. Methods/design GERT is a one-armed single-center phase I/II trial. In a first step, dose-escalation of TMZ from 50 mg/m2 to 75 mg/m2 together with radiotherapy and cetuximab will be performed. Should safety be proven, the phase II trial will be initiated with the standard dose of 75 mg/m2 of TMZ. Cetuximab will be applied in the standard application dose of 400 mg/m2 in week 1, thereafter at a dose of 250 mg/m2 weekly. A total of 46 patients will be included into this phase I/II trial. Primary endpoints are feasibility and toxicity, secondary endpoints are overall and progression-free survival. An interim analysis will be performed after inclusion of 15 patients into the main study. Patients' enrolment will be performed over a period of 2 years. The observation time will end 2 years after inclusion of the last patient. Discussion The goal of this study is to evaluate the safety and efficacy of combined RCHT-immunotherapy with TMZ and cetuximab as first-line treatment for patients with primary GBM. PMID:16709245

  14. Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing's disease: results from a Phase III study.

    PubMed

    Pivonello, Rosario; Petersenn, Stephan; Newell-Price, John; Findling, James W; Gu, Feng; Maldonado, Mario; Trovato, Andrew; Hughes, Gareth; Salgado, Luiz R; Lacroix, André; Schopohl, Jochen; Biller, Beverly M K

    2014-09-01

    Signs and symptoms of Cushing's disease are associated with high burden of illness. In this analysis, we evaluated the effect of pasireotide treatment on signs and symptoms in patients with Cushing's disease. Phase III study with double-blind randomization of two pasireotide doses. Patients (n = 162) with persistent/recurrent or de novo Cushing's disease and urinary free cortisol (UFC) levels ≥1·5× upper limit of normal (ULN) were randomized to receive subcutaneous pasireotide (600/900 μg bid). At month 3, patients with UFC ≤2 × ULN and not exceeding the baseline value continued their randomized dose; all others received 300 μg bid uptitration. At month 6, patients could enter an open-label phase until month 12 with a maximal dose of 1200 μg bid. Changes in signs and symptoms of hypercortisolism over 12 months' treatment in patients still enroled in the study and with evaluable measurements were assessed in relation to degree of UFC control. Reductions in blood pressure were observed even without full UFC control and were greatest in patients who did not receive antihypertensive medications during the study. Significant reductions in total cholesterol and low-density lipoprotein (LDL)-cholesterol were observed in patients who achieved UFC control. Reductions in BMI, weight and waist circumference occurred during the study even without full UFC control. Adverse effects were typical of somatostatin analogues except for hyperglycaemia-related events, which were experienced by 72·8% of patients. In the largest Phase III study of medical therapy in Cushing's disease, significant improvements in signs and symptoms were seen during 12 months of pasireotide treatment, as UFC levels decreased. © 2014 John Wiley & Sons Ltd.

  15. Microbial Reduction of Al-Substituted Fe(III) (Hydr)oxides: Redefining the Reducing Capacity of Fe Phases in Natural Soils

    NASA Astrophysics Data System (ADS)

    Ekstrom, E. B.; Hansel, C. M.

    2008-12-01

    Aluminum, one of the most abundant elements in soils and sediments, is also commonly found co- precipitated with Fe in natural Fe (III) (hydr)oxides. Although significant progress has been made elucidating the rates and solid-phase products of Fe(III) reduction by dissimilatory iron-reducing bacteria (DIRB) grown on pure, synthetic iron (hydr)oxides, relatively little is known about the impact of Al co-precipitation within Fe(III) (hydr)oxides on growth and bacterial Fe reduction by DIRB. Two previous studies investigating bacterial Fe reduction of Al-containing goethite minerals found contrasting results. To better understand the role of Al-substitution in controlling the rate, extent, and products of bacterial Fe(III) reduction, we have performed Fe(III) reduction experiments with the model DIRB, Shewanella putrefaciens CN32 grown on synthetic ferrihydrite, lepidocrocite, and goethite containing between 0 and 13 mole % Al. These experiments reveal that the impact of Al varies among Fe(III) (hydr)oxide minerals. Increasing Al-substitution in ferrihydrite results in a decrease of bacterial growth and Fe(III) reduction, while increasing Al content within lepidocrocite causes increased bacterial growth and Fe(III) reduction. For goethite, no change in Fe(III) reduction or growth is observed when growth on goethite containing increasing Al-substitution. Given the prevalence of Al-substitution in natural Fe(III) (hydr)oxides, our results bring into question the conventional assumptions about Fe(III) oxide bioavailability and suggest a more prominent role of natural lepidocrocite phases in impacting DIRB activity in soils and sediments.

  16. Engineering development of coal-fired high performance power systems, Phase II and III

    SciTech Connect

    1999-01-01

    The goals of the program are to develop a coal-fired high performance power generation system (HIPPS) that is capable of: thermal efficiency (HHV) {ge} 47%; NOx, SOx, and particulates {le} 10% NSPS (New Source Performance Standard) coal providing {ge} 65% of heat input; all solid wastes benign; cost of electricity {le} 90% of present plants. Phase 1, which began in 1992, focused on the analysis of various configurations of indirectly fired cycles and on technical assessments of alternative plant subsystems and components, including performance requirements, developmental status, design options, complexity and reliability, and capital and operating costs. Phase 1 also included preliminary R and D and the preparation of designs for HIPPS commercial plants approximately 300 MWe in size. This phase, Phase 2, involves the development and testing of plant subsystems, refinement and updating of the HIPPS commercial plant design, and the site selection and engineering design of a HIPPS prototype plant. Work reported herein is from: Task 2.1 HITAC Combustors; Task 2.2 HITAF Air Heaters; Task 6 HIPPS Commercial Plant Design Update.

  17. Engineering development of coal-fired high performance power systems, Phase II and III

    SciTech Connect

    1999-04-01

    The goals of the program are to develop a coal-fired high performance power generation system (HIPPS) that is capable of: thermal efficiency (HHV) {ge} 47%, NOx, SOx, and particulates {le} 10% NSPS (New Source Performance Standard) coal providing {ge} 65% of heat input, all solid wastes benign, and cost of electricity {le} 90% of present plants. Phase 1, which began in 1992, focused on the analysis of various configurations of indirectly fired cycles and on technical assessments of alternative plant subsystems and components, including performance requirements, developmental status, design options, complexity and reliability, and capital and operating costs. Phase 1 also included preliminary R and D and the preparation of designs for HIPPS commercial plants approximately 300 MWe in size. This phase, Phase 2, involves the development and testing of plant subsystems, refinement and updating of the HIPPS commercial plant design, and the site selection and engineering design of a HIPPS prototype plant. Work reported herein is from: Task 2.1 HITAC Combustors; Task 2.2 HITAF Air Heaters; Task 6 HIPPS Commercial Plant Design Update.

  18. Engineering development of coal-fired high performance power systems, Phase II and III

    SciTech Connect

    1998-07-01

    The goals of the program are to develop a coal-fired high performance power generation system (HIPPS) that is capable of: thermal efficiency (HHV) {ge} 47%, NOx, SOx, and particulates {le} 10% NSPS (New Source Performance Standard), coal providing {ge} 65% of heat input, all solid wastes benign cost of electricity {le} 90% of present plants. Phase 1, which began in 1992, focused on the analysis of various configurations of indirectly fired cycles and on technical assessments of alternative plant subsystems and components, including performance requirements, developmental status, design options, complexity and reliability, and capital and operating costs. Phase 1 also included preliminary R and D and the preparation of designs for HIPPS commercial plants approximately 300 MWe in size. This phase, Phase 2, involves the development and testing of plant subsystems, refinement and updating of the HIPPS commercial plant design, and the site selection and engineering design of a HIPPS prototype plant. Work reported herein is from: Task 2.1 HITAF Combustor; Task 2.2 HITAF Air Heaters; Task 6 HIPPS Commercial Plant Design Update.

  19. Absence of Liver Toxicity in Perampanel-Treated Subjects: Pooled results from partial seizure phase III perampanel clinical studies.

    PubMed

    Laurenza, Antonio; Yang, Haichen; Williams, Betsy; Zhou, Sharon; Ferry, Jim

    2015-07-01

    The liver plays a major role in the metabolism and elimination of many antiepileptic drugs (AEDs), including perampanel. Some of the metabolites identified for perampanel are likely formed via reactive intermediates, which have the potential to covalently bind to protein and cause idiosyncratic toxicities, including hepatotoxicity. The approved AED perampanel is a selective, noncompetitive AMPA receptor antagonist. The safety and tolerability of perampanel have been well documented in 3 double-blind, randomized, placebo-controlled, phase III studies. Here we report the effects of perampanel on liver function in patients from the phase III studies to assess the potential for liver toxicity. Following 6-week baseline, patients (≥12 years old) with drug-resistant partial seizures were randomized to once-daily double-blind treatment (6-week titration, 13-week maintenance) with 2, 4, 8, or 12mg perampanel (n=1038) or with placebo (n=442). Clinical laboratory tests for hepatobiliary laboratory parameters were evaluated at baseline and at end of treatment. These included alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and total bilirubin. Treatment-emergent markedly abnormal values (an increase in NCI-CTC grade relative to baseline and a grade ≥2) and treatment-emergent adverse events (TEAEs) related to hepatobiliary parameters were also recorded. Mean hepatobiliary values were within normal ranges at baseline and end of treatment for all perampanel groups and placebo. Mean changes from baseline to end of treatment were small. The incidence of markedly abnormal results was very low for perampanel and placebo. TEAEs related to hepatobiliary parameters occurred in 0.4% of perampanel patients and 0% of placebo patients. Hepatobiliary disorders included cholelithiasis (n=3 in perampanel) and abnormal hepatic function (n=1 in perampanel). None of the events were serious or led to perampanel discontinuation. No

  20. Hysteroscopic Essure Inserts for Permanent Contraception: Extended Follow-Up Results of a Phase III Multicenter International Study.

    PubMed

    Chudnoff, Scott G; Nichols, John E; Levie, Mark

    2015-01-01

    To describe safety, tolerability, and effectiveness results through 5 years of follow-up of a Phase III trial with Essure inserts. Multicenter, nonrandomized, single-arm international study (Canadian Task Force classification II-3). Thirteen clinical study centers in the United States, Europe, and Australia. A total of 518 previously fertile women seeking permanent contraception. The objective of the hysteroscopic sterilization procedure was bilateral Essure insert placement (ESS205 model) and tubal occlusion. Women with satisfactory device location and tube occlusion (based on modified hysterosalpingography [HSG]) were instructed to discontinue alternative contraception and to rely on Essure inserts for permanent contraception. The primary endpoint for the Phase III study was the rate of pregnancies occurring during the first year of relying (i.e., HSG-confirmed occlusion) on the Essure inserts for permanent contraception (i.e., 12 months after HSG). For the full 5 years of follow-up (5 years total of relying on the Essure inserts for contraception), the endpoints of interest were safety, prevention of pregnancy, and satisfaction. No pregnancies were reported among women relying on the Essure inserts who completed the full 5 years of follow-up. As of December 5, 2007, 449 women with successful bilateral placement relying on the Essure inserts contributed a total 24 942 woman-months of follow-up for assessing effectiveness. Overall, the Essure inserts were generally well tolerated, with participant comfort rated as "good" to "excellent" by 99% of women (382 of 385) after 5 years of use. Similarly, overall satisfaction was rated as "somewhat" to "very satisfied" by 98% of women (376 of 384) after 5 years of use. The majority of adverse events reported during the 5 years of follow-up were rated as either "mild" or "moderate" in severity. Three severe events (abdominal pain with very heavy periods and irregular menstrual bleeding) were reported in 2 subjects during

  1. 7Li and 14N NMR studies of phase II-III transition in LiNH4SO4 single crystals

    NASA Astrophysics Data System (ADS)

    Lim, Ae Ran

    2016-12-01

    The NMR spectra of 7Li and 14N nuclei in LiNH4SO4 crystals were obtained near the phase transition temperature TC2=284.5 K. Below TC2, the two physically inequivalent Li groups in phase III were distinguished in 7Li NMR spectra. Meanwhile, the 14N NMR spectra in phase II above TC2 showed four pairs of lines, where as those in phase III showed eight pairs. These changes in the resonance frequencies near TC2 were attributed to the structural phase transition. The 7Li and 14N nuclei in the structure are coordinated through the Li-O-H-N skeleton. Therefore, changes in their NMR spectra with temperature are correlated. The displacements of 7Li and 14N in LiNH4SO4 crystals play important roles in the phase transition near TC2.

  2. Evaluation of hydrothermal resources of North Dakota. Phase III final technical report

    SciTech Connect

    Harris, K.L.; Howell, F.L.; Wartman, B.L.; Anderson, S.B.

    1982-08-01

    The hydrothermal resources of North Dakota were evaluated. This evaluation was based on existing data on file with the North Dakota Geological Survey (NDGS) and other state and federal agencies, and field and laboratory studies conducted. The principal sources of data used during the study were WELLFILE, the computer library of oil and gas well data developed during the Phase I study, and WATERCAT, a computer library system of water well data assembled during the Phase II study. A field survey of the shallow geothermal gradients present in selected groundwater observation holes was conducted. Laboratory determinations of the thermal conductivity of core samples were done to facilitate heat-flow calculations on those holes-of-convenience cased.

  3. Microwave Landing System (MLS). Phase III (Basic Narrow and Small Community Configurations). Volume II.

    DTIC Science & Technology

    1978-01-01

    How many inputs should be simultaneously excited to generate a beam? (c) With that amplitudes and phases should the inputs be excited? IIn addition to...probes would be orthogonal. Beams generated by simultaneously exciting several probes with different amplitudes would be the superposition of several...orthogonal sinc (x) beams of different amplitudes . A set of weiqhts was also derived which would fine scan the beam in tenth beamwidth £ncrements

  4. Development of a Semi-Autonomous Underwater Vehicle for Intervention Missions (SAUVIM Phase III-C)

    DTIC Science & Technology

    2010-01-28

    Program Officer for the SAUVIM project. The Advisory Committee ( AdCom ) was formed to provide technical advice and direction by reviewing research...directions and progress, and to provide advice and assistance in exploring potential applications and users. The six-member AdCom consists of Mr. Fred...year was submitted in July 1999. The next two ONR and AdCom site visits were on May 11, 2000 and November 14, 2000. A Final Report for Phase I was

  5. Phase 0/I/II Cancer Prevention Clinical Trials Program (Consortia) | Division of Cancer Prevention

    Cancer.gov

    Five cancer research centers lead multiple collaborative networks to assess potential cancer preventive agents and to conduct early clinical development of promising preventive agents. Also called the Consortia for Early Phase Prevention Trials, the studies require extensive biomarker analysis, investigation of the biologic effects of the cancer preventive agents on their intended molecular targets and on multiple endpoints associated with carcinogenesis, and correlation with clinically relevant endpoints. | Systematic early clinical development of promising preventive agents through five major medical research centers.

  6. High-pressure single-crystal elasticity study of CO{sub 2} across phase I-III transition

    SciTech Connect

    Zhang, Jin S. Bass, Jay D.; Shieh, Sean R.; Dera, Przemyslaw; Prakapenka, Vitali

    2014-04-07

    Sound velocities and elastic moduli of solid single-crystal CO{sub 2} were measured at pressures up to 11.7(3) GPa by Brillouin spectroscopy. The aggregate adiabatic bulk modulus (K{sub S}), shear modulus (G), and their pressure derivatives for CO{sub 2} Phase I are K{sub S0} = 3.4(6) GPa, G{sub 0} = 1.8(2) GPa, (dK{sub S}/dP){sub 0} = 7.8(3), (dG/dP){sub 0} = 2.5(1), (d{sup 2}K{sub S}/dP{sup 2}){sub 0} = −0.23(3) GPa{sup −1}, and (d{sup 2}G/dP{sup 2}){sub 0} = −0.10(1) GPa{sup −1}. A small increase of elastic properties was observed between 9.8(1) and 10.5(3) GPa, in agreement with the CO{sub 2} I-III transition pressure determined from previous x-ray diffraction experiments. Above the transition pressure P{sub T}, we observed a mixture dominated by CO{sub 2}-I, with minor CO{sub 2}-III. The CO{sub 2}-I + III mixture shows slightly increased sound velocities compared to pure CO{sub 2}-I. Elastic anisotropy calculated from the single-crystal elasticity tensor exhibits a decrease with pressure beginning at 7.9(1) GPa, which is lower than P{sub T}. Our results coincide with recent X-ray Raman observations, suggesting that a pressure-induced electronic transition is related to local structural and optical changes.

  7. Low-density nanoporous phases of group-III nitrides built from sodalite cage clusters.

    PubMed

    Liu, Zhifeng; Wang, Xinqiang; Liu, Gaobin; Zhou, Ping; Sui, Jian; Wang, Xuefang; Zhu, Hengjiang; Hou, Zhilin

    2013-06-07

    We report a new family of M12N12 (M = Al and Ga) cluster-assembled low-density materials with distinguished structures and properties based on state-of-the-art first-principles calculations. Specifically, the thermodynamic stability of the sodalite cage M12N12, with Th symmetry and a large HOMO-LUMO gap, is firstly proved using a first-principles molecular dynamics (FPMD) study. We consider this novel structure as a building block to construct new cluster-assembled materials. On the basis of the interaction of the cages with each other, eight new low-density nanoporous phases have been characterized, some of which with high stability are even more stable than experimentally synthesized MN phases. The intrinsic higher flexibilities (lower bulk moduli) and porous characteristics (the pore size: from 0.360 to 0.952 nm for AlN, 0.381 to 0.982 nm for GaN) of these phases should make them extremely promising for molecular sieving, gas storage, and particularly, atomic transport, control and purification applications. Furthermore, these new materials can not only retain the structural characteristics of the building block, but also preserve its electronic properties of wide-energy gap, with an indirect or a direct band gap of 1.038-2.640 eV. Our results may be feasible for extending the range of properties and applications of the corresponding MN compound.

  8. A phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC)

    PubMed Central

    Pal, Sumanta; Azad, Arun; Bhatia, Shailender; Drabkin, Harry; Costello, Brian; Sarantopoulos, John; Kanesvaran, Ravindran; Lauer, Richard; Starodub, Alexander; Hauke, Ralph; Sweeney, Christopher J.; Hahn, Noah M.; Sonpavde, Guru; Richey, Stephen; Breen, Timothy; Kremmidiotis, Gabriel; Leske, Annabell; Doolin, Elizabeth; Bibby, David C.; Simpson, Jeremy; Iglesias, Jose; Hutson, Thomas

    2015-01-01

    Purpose BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). Experimental Design A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3+3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and 1-2 prior therapies (including ≥1 VEGF-TKI) were randomized to BNC105P with everolimus (Arm A) or everolimus alone (Arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival (OS) and exploratory biomarker analyses. Results In the phase I study (n=15), a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in Arms A and B, respectively. 6MPFS was similar in the treatment arms (Arm A: 33.82% v Arm B: 30.30%, P=0.66) and no difference in median PFS was observed (Arm A: 4.7 mos v Arm B: 4.1 mos; P=0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone binding globulin and serum amyloid A protein were associated with clinical outcome with BNC105P. Conclusions Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. PMID:25788492

  9. Phase Coupling Between Spectral Components of Collapsing Langmuir Solitons in Solar Type III Radio Bursts

    NASA Technical Reports Server (NTRS)

    Thejappa, G.; MacDowall, R. J.; Bergamo, M.

    2012-01-01

    We present the high time resolution observations of one of the Langmuir wave packets obtained in the source region of a solar type III radio burst. This wave packet satisfies the threshold condition of the supersonic modulational instability, as well as the criterion of a collapsing Langmuir soliton, i.e., the spatial scale derived from its peak intensity is less than that derived from its short time scale. The spectrum of t his wave packet contains an intense spectral peak at local electron plasma frequency, f(sub pe) and relatively weaker peaks at 2f(sub pe) and 3f(sub pe). We apply the wavelet based bispectral analysis technique on this wave packet and compute the bicoherence between its spectral components. It is found that the bicoherence exhibits two peaks at (approximately f(sub pe), approximately f(sub pe)) and (approximately f(sub pe) approximately 2f(sub pe)), which strongly suggest that the spectral peak at 2f(sub pe) probably corresponds to the second harmonic radio emission, generated as a result of the merging of antiparallel propagating Langmuir waves trapped in the collapsing Langmuir soliton, and, the spectral peak at 3f(sub pe) probably corresponds to the third harmonic radio emission, generated as a result of merging of a trapped Langmuir wave and a second harmonic electromagnetic wave.

  10. Electron diffraction based analysis of phase fractions and texture in nanocrystalline thin films, part III: application examples.

    PubMed

    Lábár, J L; Adamik, M; Barna, B P; Czigány, Zs; Fogarassy, Zs; Horváth, Z E; Geszti, O; Misják, F; Morgiel, J; Radnóczi, G; Sáfrán, G; Székely, L; Szüts, T

    2012-04-01

    In this series of articles, a method is presented that performs (semi)quantitative phase analysis for nanocrystalline transmission electron microscope samples from selected area electron diffraction (SAED) patterns. Volume fractions and degree of fiber texture are determined for the nanocrystalline components. The effect of the amorphous component is minimized by empirical background interpolation. First, the two-dimensional SAED pattern is converted into a one-dimensional distribution similar to X-ray diffraction. Volume fractions of the nanocrystalline components are determined by fitting the spectral components, calculated for the previously identified phases with a priori known structures. These Markers are calculated not only for kinematic conditions, but the Blackwell correction is also applied to take into account dynamic effects for medium thicknesses. Peak shapes and experimental parameters (camera length, etc.) are refined during the fitting iterations. Parameter space is explored with the help of the Downhill-SIMPLEX. The method is implemented in a computer program that runs under the Windows operating system. Part I presented the principles, while part II elaborated current implementation. The present part III demonstrates the usage and efficiency of the computer program by numerous examples. The suggested experimental protocol should be of benefit in experiments aimed at phase analysis using electron diffraction methods.

  11. Modulation of 5-fluorouracil as adjuvant systemic chemotherapy in colorectal cancer: the IGCS-COL multicentre, randomised, phase III study

    PubMed Central

    De Placido, S; Lopez, M; Carlomagno, C; Paoletti, G; Palazzo, S; Manzione, L; Iannace, C; Ianniello, G P; De Vita, F; Ficorella, C; Farris, A; Pistillucci, G; Gemini, M; Cortesi, E; Adamo, V; Gebbia, N; Palmeri, S; Gallo, C; Perrone, F; Persico, G; Bianco, A R

    2005-01-01

    The aims of this multicentre, randomised phase III trial were to evaluate: (1) the role of levamisol (LEV); and (2) the role of folinic acid (FA), added to 5-fluorouracil (5FU) in the adjuvant treatment of colorectal cancer. Patients with histologically proven, radically resected stage II or III colon or rectal cancer were eligible. The study had a 2 × 2 factorial design with four treatment arms: (a) 5FU alone, (b) 5FU+LEV, (c) 5FU+FA, (d) 5FU+LEV+FA, and two planned comparisons, testing the role of LEV and of FA, respectively. From March 1991, to September 1998, 1327 patients were randomised. None of the two comparisons resulted in a significant disease-free (DFS) or overall (OAS) survival advantage. The hazard ratio (HR) of relapse was 0.89 (95% confidence intervals (CI): 0.73–1.09) for patients receiving FA and 0.99 (95% CI 0.80–1.21) for those receiving LEV; corresponding HRs of death were 1.02 (95% CI: 0.80–1.30) and 0.94 (95% CI 0.73–1.20). Nonhaematological toxicity (all grade vomiting, diarrhoea, mucositis, congiuntivitis, skin, fever and fatigue) was significantly worse with FA, while all other toxicities were similar. In the present trial, there was no evidence that the addition of FA or LEV significantly prolongs DFS and OAS of radically resected colorectal cancer patients. PMID:16222322

  12. A phase I/II trial of Erlotinib in higher risk myelodysplastic syndromes and acute myeloid leukemia after azacitidine failure.

    PubMed

    Thepot, Sylvain; Boehrer, Simone; Seegers, Valérie; Prebet, Thomas; Beyne-Rauzy, Odile; Wattel, Eric; Delaunay, Jacques; Raffoux, Emmanuel; Hunault, Mathilde; Jourdan, Eric; Chermat, Fatiha; Sebert, Marie; Kroemer, Guido; Fenaux, Pierre; Adès, Lionel

    2014-12-01

    Survival after azacitidine (AZA) failure in higher-risk myelodysplastic syndromes (MDS) is poor and new treatment options are needed. Erlotinib, an oral inhibitor of the epidermal-growth-factor-receptor (EGFR), has shown in preclinical models some efficacy in higher risk MDS and acute myeloid leukemia (AML). In this phase I/II trial, 30 patients received 100mg/day (n=5) or 150mg/day (n=25) of Erlotinib orally after primary or secondary resistance to AZA treatment. Eighteen MDS and 12 AML patients were treated. This outpatient treatment was well tolerated with limited grade III-IV extra hematological toxicities (skin (n=1), and diarrhea (n=3). Response was observed in 6 patients (20%) including 1 complete remission (CR), 1 marrow CR and 4 hematological improvement (2 erythroid and 2 on platelets). Median duration of response was 5 months. Erlotinib appears to induce a significant number of responses in higher risk MDS/AML having failed AZA treatment. Given the good safety profile of Erlotinib, its combination with other drugs could be tested in the future in MDS and AML.

  13. Dependence of polarity inversion on V/III ratio in -c-GaN growth by oxide vapor phase epitaxy

    NASA Astrophysics Data System (ADS)

    Taniyama, Yuki; Yamaguchi, Yohei; Takatsu, Hiroaki; Sumi, Tomoaki; Kitamoto, Akira; Imade, Mamoru; Yoshimura, Masashi; Isemura, Masashi; Mori, Yusuke

    2016-05-01

    One of the issues in bulk c-GaN growth is the decrease in the diameter of crystals with an increase in thickness owing to the appearance of inclined \\{ 10\\bar{1}1\\} and \\{ 10\\bar{1}2\\} facets. In this study, we performed -c-GaN growth by oxide vapor phase epitaxy (OVPE). As a result, truncated-inverted-pyramidal crystals were successfully grown on dot-patterned -c-GaN substrates. The diameter of the top surface of crystals was larger than that of windows. We further investigated the dependence of the ratio of inversion-domain area to growth area (R ID) on growth temperature, V/III ratio, and growth rate. The remained results revealed that R ID decreased with increasing growth temperature and V/III ratio, and kept constant for growth rate. Additionally, an epitaxial layer on -c-GaN substrates with a growth rate of 12.4 µm/h and an R ID as low as 3.8% was obtained under an NH3 partial pressure (P NH3) of 83 kPa at 1200 °C.

  14. Phase III trial comparing two low dose rates in brachytherapy of cervix carcinoma: Report at two years

    SciTech Connect

    Lambin, P.; Gerbaulet, A.; Kramer, A.; Haie-Meder, C.; Malaise, E.P.; Chassagne, D. ); Scalliet, P. )

    1993-02-15

    This Phase III randomized trial examined the effect of two low dose rates (0.73 or 0.38 Gy[center dot]h[sup [minus]1]) on the local control, survival, relapse-free survival, complications, and secondary effects in the treatment of cervical cancers. A total of 204 Stage Ib or II cervical carcinoma patients were included between January 1985 and September 1988. Treatment consisted of uterovaginal [sup 137]Cs irradiation followed by surgery. The two groups were similar for age, tumor stage and medical or surgical history. Their brachytherapy parameters were also similar (60 Gy pear dimensions, dose to critical organs, total kerma, etc....). There were no differences in the short-term effects or therapeutic outcome. However, overall complications and side effects observed after 6 months were significantly more frequent (p < 0.01) in the higher dose rate group. 40 refs., 4 figs., 6 tabs.

  15. OECD/NEA expert group on uncertainty analysis for criticality safety assessment: Results of benchmark on sensitivity calculation (phase III)

    SciTech Connect

    Ivanova, T.; Laville, C.; Dyrda, J.; Mennerdahl, D.; Golovko, Y.; Raskach, K.; Tsiboulia, A.; Lee, G. S.; Woo, S. W.; Bidaud, A.; Sabouri, P.; Bledsoe, K.; Rearden, B.; Gulliford, J.; Michel-Sendis, F.

    2012-07-01

    The sensitivities of the k{sub eff} eigenvalue to neutron cross sections have become commonly used in similarity studies and as part of the validation algorithm for criticality safety assessments. To test calculations of the sensitivity coefficients, a benchmark study (Phase III) has been established by the OECD-NEA/WPNCS/EG UACSA (Expert Group on Uncertainty Analysis for Criticality Safety Assessment). This paper presents some sensitivity results generated by the benchmark participants using various computational tools based upon different computational methods: SCALE/TSUNAMI-3D and -1D, MONK, APOLLO2-MORET 5, DRAGON-SUSD3D and MMKKENO. The study demonstrates the performance of the tools. It also illustrates how model simplifications impact the sensitivity results and demonstrates the importance of 'implicit' (self-shielding) sensitivities. This work has been a useful step towards verification of the existing and developed sensitivity analysis methods. (authors)

  16. The effects of PECS teaching to Phase III on the communicative interactions between children with autism and their teachers.

    PubMed

    Carr, Deborah; Felce, Janet

    2007-04-01

    The study investigated the impact of mastery of the Picture Exchange Communication System (PECS) to Phase III, on the communications of children with autism. Children aged between 3 and 7 years, formed a PECS intervention group and a non-intervention control group. The intervention group received 15 h of PECS teaching over 5 weeks. Three 2-h classroom observations recorded communications between the children and their teachers. These occurred: 6 weeks before teaching; during the week immediately prior to teaching; during the week immediately following teaching. For the control group, two 2-h observations were separated by a 5-week interval without PECS teaching. Communicative initiations and dyadic interactions increased significantly between the children and teachers in the PECS group but not for the control group.

  17. Idaho Water Rental Pilot Project probability/coordination study resident fish and wildlife impacts, Phase III. Annual report

    SciTech Connect

    Leitzinger, E.

    1996-09-01

    Phase III began in 1995 with the overall goal of quantifying changes in resident fish habitat in the Snake River basin upstream of Brownlee Reservoir resulting from the release of salmon flow augmentation water. Existing data, in the form of weighted usable area versus flow relationships, were used to estimate habitat changes for white sturgeon (Acipenser transmontanus) and rainbow trout (Oncorhynchus mykiss)in the Snake River between C.J. Strike Dam and Brownlee pool. The increased flows resulted in increased white sturgeon habitat for most life stages. Rainbow trout adult and spawning habitat increased while juvenile and fry habitat generally decreased. Whether or not these short term increases in habitat result in long term benefits to the fish populations has yet to be determined.

  18. Idaho Water Rental Pilot Project Probability/Coordination Study Resident Fish and Wildlife Impact Phase III, 1995 Annual Report.

    SciTech Connect

    Leitzinger, Eric J.

    1996-09-01

    Phase III began in 1995 with the overall goal of quantifying changes in resident fish habitat in the Snake River basin upstream of Brownlee Reservoir resulting from the release of salmon flow augmentation water. Existing data, in the form of weighted usable area versus flow relationships, were used to estimate habitat changes for white sturgeon (Acipenser transmontanus) and rainbow trout (Oncorhynchus mykiss) in the Snake River between C.J. Strike Dam and Brownlee pool. The increased flows resulted in increased white sturgeon habitat for most life stages. Rainbow trout adult and spawning habitat increased while juvenile and fry habitat generally decreased. Whether or not these short term increases in habitat result in long term benefits to the fish populations has yet to be determined.

  19. Immunogenicity of a protective whole cell mycobacterial vaccine in HIV-infected adults: a phase III study in Tanzania.

    PubMed

    Lahey, Timothy; Arbeit, Robert D; Bakari, Muhammad; Horsburgh, C Robert; Matee, Mecky; Waddell, Richard; Mtei, Lillian; Vuola, Jenni M; Pallangyo, Kisali; von Reyn, C Fordham

    2010-11-10

    Preventive immunization with whole inactivated Mycobacterium vaccae (MV) confers protection against HIV-associated tuberculosis (TB) in BCG-immunized adults with CD4 counts ≥200 cells/μl. We evaluated the immunogenicity of MV in the 2013 subjects of the phase III DarDarTrial using an interferon gamma (IFN-γ) enzyme linked immunosorbent assay (ELISA), tritiated thymidine lymphocyte proliferation assay (LPA) and an ELISA for antibodies to the TB glycolipid lipoarabinomannan (LAM). MV immunization boosts IFN-γ and LPA responses to MV sonicate, and antibody responses to LAM. Post-immunization immune responses to MV correlated with baseline clinical factors, but the responses did not predict protection from HIV-associated TB.

  20. Design of a Phase III cluster randomized trial to assess the efficacy and safety of a malaria transmission blocking vaccine.

    PubMed

    Delrieu, Isabelle; Leboulleux, Didier; Ivinson, Karen; Gessner, Bradford D

    2015-03-24

    Vaccines interrupting Plasmodium falciparum malaria transmission targeting sexual, sporogonic, or mosquito-stage antigens (SSM-VIMT) are currently under development to reduce malaria transmission. An international group of malaria experts was established to evaluate the feasibility and optimal design of a Phase III cluster randomized trial (CRT) that could support regulatory review and approval of an SSM-VIMT. The consensus design is a CRT with a sentinel population randomly selected from defined inner and buffer zones in each cluster, a cluster size sufficient to assess true vaccine efficacy in the inner zone, and inclusion of ongoing assessment of vaccine impact stratified by distance of residence from the cluster edge. Trials should be conducted first in areas of moderate transmission, where SSM-VIMT impact should be greatest. Sample size estimates suggest that such a trial is feasible, and within the range of previously supported trials of malaria interventions, although substantial issues to implementation exist.

  1. From research to phase III: preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine.

    PubMed

    Guy, Bruno; Barrere, Beatrice; Malinowski, Claire; Saville, Melanie; Teyssou, Remy; Lang, Jean

    2011-09-23

    Dengue vaccine development has reached a major milestone with the initiation, in 2010, of the first phase III clinical trial to investigate the Sanofi Pasteur CYD tetravalent dengue vaccine (TDV). The CYD TDV candidate is composed of four recombinant, live, attenuated vaccines (CYD-1-4) based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the pre-membrane and envelope genes of one of the four dengue virus serotypes. The vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YFV 17D, and does not infect mosquitoes by the oral route. In vitro and in vivo preclinical studies showed that CYD TDV induces controlled stimulation of human dendritic cells, and significant immune responses in monkeys. Scale up and industrialization are being conducted in parallel with preclinical and clinical development to fulfill the needs of phase II/III trials, and to anticipate and facilitate supply and access to vaccine in the countries where the dengue disease burden makes it an urgent public health priority. The vaccine has now been administered to more than 6000 children and adults from dengue endemic and non-endemic areas and no safety concerns have arisen in any of the completed or ongoing trials. A three-dose vaccination regimen induces an immune response against all four serotypes in the large majority of vaccinees. Preexisting flavivirus immunity favors quicker and higher immune responses to CYD TDV, without adversely effecting clinical safety or increasing vaccine viremia. The observed level and nature of the cellular immune responses in humans are consistent with the good safety and immunogenicity profile of the vaccine. Preliminary results of an ongoing, proof-of-concept efficacy and large scale safety study in Thai children are expected by the end of 2012. Here we discuss the different steps and challenges of developing CYD TDV, from research to industrialization, and summarize some of the challenges to the successful

  2. Comprehensive safety assessment of a human inactivated diploid enterovirus 71 vaccine based on a phase III clinical trial

    PubMed Central

    Zhang, Wei; Kong, Yujia; Jiang, Zhiwei; Li, Chanjuan; Wang, Ling; Xia, Jielai

    2016-01-01

    abstract Human enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease (HFMD). In a previous phase III trial in children, a human diploid cell-based inactivated EV71 vaccine elicited EV71 specific immune responses and protection against EV71 associated HFMD. This study aimed to assess the factors influencing the severity of adverse events observed in this previous trial. This was a randomized, double-blinded, placebo-controlled, phase III clinical trial of a human diploid vaccine carried out in 12,000 children in Guangxi Zhuang Autonomous Region, China (ClinicalTrials.gov: NCT01569581). Solicited events were recorded for 7 days and unsolicited events were reported for 28 days after each injection. Age trend analysis of adverse reaction was conducted in each treatment group. Multiple logistic regression models were built to identify factors influencing the severity of adverse reactions. Fewer solicited adverse reactions were observed in older participants within the first 7 days after vaccination (P < 0.0001), except local pain and pruritus. More severe adverse reactions were observed after the initial injection than after the booster injection. Serious cold or respiratory tract infections (RTI) were observed more often in children aged 6–36 months than in older children. Only the severity of local swelling was associated with body mass index. Children with throat discomfort before injection had a higher risk of serious cold or RTI. These results indicated that the human diploid cell-based vaccine achieved a satisfactory safety profile. PMID:26837471

  3. Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma

    PubMed Central

    Ribas, Antoni; Kefford, Richard; Marshall, Margaret A.; Punt, Cornelis J.A.; Haanen, John B.; Marmol, Maribel; Garbe, Claus; Gogas, Helen; Schachter, Jacob; Linette, Gerald; Lorigan, Paul; Kendra, Kari L.; Maio, Michele; Trefzer, Uwe; Smylie, Michael; McArthur, Grant A.; Dreno, Brigitte; Nathan, Paul D.; Mackiewicz, Jacek; Kirkwood, John M.; Gomez-Navarro, Jesus; Huang, Bo; Pavlov, Dmitri; Hauschild, Axel

    2013-01-01

    Purpose In phase I/II trials, the cytotoxic T lymphocyte–associated antigen-4–blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy. Patients and Methods Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine). Results In all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88; P = .127). Objective response rates were similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the chemotherapy arm. However, response duration (measured from date of random assignment) was significantly longer after tremelimumab (35.8 v 13.7 months; P = .0011). Diarrhea, pruritus, and rash were the most common treatment-related adverse events in the tremelimumab arm; 7.4% had endocrine toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy arm were considered treatment related by either investigators or sponsor. Conclusion This study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma. PMID:23295794

  4. Vapor phase growth technique of III-V compounds utilizing a preheating step

    NASA Technical Reports Server (NTRS)

    Olsen, Gregory Hammond (Inventor); Zamerowski, Thomas Joseph (Inventor); Buiocchi, Charles Joseph (Inventor)

    1978-01-01

    In the vapor phase epitaxy fabrication of semiconductor devices and in particular semiconductor lasers, the deposition body on which a particular layer of the laser is to be grown is preheated to a temperature about 40.degree. to 60.degree. C. lower than the temperature at which deposition occurs. It has been discovered that by preheating at this lower temperature there is reduced thermal decomposition at the deposition surface, especially for semiconductor materials such as indium gallium phosphide and gallium arsenide phosphide. A reduction in thermal decomposition reduces imperfections in the deposition body in the vicinity of the deposition surface, thereby providing a device with higher efficiency and longer lifetime.

  5. Theory of nematic systems of semiflexible polymers. III. Phase equilibria in solutions

    NASA Astrophysics Data System (ADS)

    Ronca, G.; Yoon, D. Y.

    1985-07-01

    Biphasic equilibria of lyotropic solutions of semiflexible polymers are calculated using the worm-like chain model with limiting curvature. The threshold concentration at incipient phase separation varies gradually with molecular weight to reach a finite value at infinite chain length. This limiting concentration is found to depend on the axial ratio of the persistence length and on the temperature. The theory is then applied specifically to poly(n-hexyl isocyanate) (PHIC) solutions. Deriving the configurational parameters from measurements on chain dimensions in dilute solutions, theoretical calculations are found to satisfactorily match recent experimental results on the molecular weight dependence of the threshold concentration of PHIC in toluene.

  6. Fluid flow through a vertical to horizontal 90 elbow bend III three phase flow

    SciTech Connect

    Spedding, P.L.; Benard, E.; Crawford, N.M.

    2008-01-15

    Three phase water/oil/air flow was studied around a vertical upward to horizontal 90 elbow bend of R/d = 0.654. The results were more complex than corresponding two phase data. The pressure drop recorded for the two tangent legs sometimes showed significant variations to the straight pipe data. In most cases this variation was caused by differences in the flow regimes between the two systems. The elbow bend tended to constrict the flow presented by the vertical inlet tangent leg while sometimes acting as a wave and droplet generator for the horizontal outlet tangent leg. It could be argued that the inclusion of the elbow bend altered the flow regime map transitional boundaries but it also is possible that insufficient settling length was provided in the apparatus design. The elbow bend pressure drop was best presented as l{sub e}/d the equivalent length to diameter ratio using the actual total pressure drop in the vertical inlet tangent leg. Generally l{sub e}/d values rose with gas rate, but exhibited an increasingly complex relation with f{sub o} the oil to liquid volumetric ratio as liquid rate was increased. A significant maximum in l{sub e}/d was in evidence around the inversion from water dominated to oil dominated flows. Several models are presented to predict the data. (author)

  7. Targeting radioimmunotherapy of hepatocellular carcinoma with iodine ({sup 131}I) metuximab injection: Clinical Phase I/II trials

    SciTech Connect

    Chen Zhinan . E-mail: chcerc2@fmmu.edu.cn; Mi Li; Xu Jing

    2006-06-01

    Purpose: HAb18G/CD147 is a hepatocellular carcinoma (HCC)-associated antigen. We developed iodine ({sup 131}I) metuximab injection (Licartin), a novel {sup 131}I-labeled HAb18G/CD147-specific monoclonal antibody F(ab'){sub 2} fragment, and evaluated its safety, pharmacokinetics, and clinical efficacy on HCC in Phase I/II trials. Methods and Materials: In a Phase I trial, 28 patients were randomly assigned to receive the injection in 9.25-, 18.5-, 27.75-, or 37-MBq/kg doses by hepatic artery infusion. In a multicenter Phase II trial, 106 patients received the injection (27.75 MBq/kg) on Day 1 of a 28-day cycle. Response rate and survival rate were the endpoints. Results: No life-threatening toxic effects were found. The safe dosage was 27.75 MBq/kg. The blood clearance fitted a biphasic model, and its half-life was 90.56-63.93 h. In the Phase II trial, the injection was found to be targeted and concentrated to tumor tissues. Of the 73 patients completing two cycles, 6 (8.22%) had a partial response, 14 (19.18%) minor response, and 43 (58.90%) stable disease. The 21-month survival rate was 44.54%. The survival rate of progression-free patients was significantly higher than that of patients with progressive disease after either one or two cycles (p < 0.0001 or p 0.0019). Conclusion: Iodine ({sup 131}I) metuximab injection is safe and active for HCC patients.

  8. A phase I-II trial of fludarabine, bendamustine and rituximab (FBR) in previously treated patients with CLL.

    PubMed

    Jain, Nitin; Balakrishnan, Kumudha; Ferrajoli, Alessandra; O'Brien, Susan M; Burger, Jan A; Kadia, Tapan M; Cortes, Jorge E; Ayres, Mary L; Tambaro, Francesco Paolo; Keating, Michael J; Gandhi, Varsha; Wierda, William G

    2016-09-15

    Chemoimmunotherapy regimens have been the standard first-line therapy for patients with chronic lymphocytic leukemia (CLL). For young, fit patients the standard of care is combination of fludarabine, cyclophosphamide, and rituximab (FCR). Based on the preclinical work demonstrating that bendamustine combined with fludarabine resulted in increased DNA damage, we designed a phase I-II clinical trial with fludarabine, bendamustine, and rituximab (FBR) for patients with relapsed/refractory CLL. Treatment consisted of fludarabine 20 mg/m2 daily x 3 days and rituximab 375-500 mg/m2 x 1 day. Phase I included bendamustine at increasing doses of 20, 30, 40, or 50 mg/m2 daily x 3 days; phase II was with FR, and B at the selected dose. DNA damage response (H2AX phosphorylation) was evaluated in a subset of patients. Fifty-one patients were enrolled. The median age was 62 years; median number of prior therapies was 2; 40% had del(11q); and 41 patients had received prior FCR-based therapies. Hematologic toxicity was more common in ≥40 mg/m2 dose cohorts. Maximum tolerated dose (MTD) was not identified. Bendamustine-elicited H2AX phosphorylation was not dose-dependent, but markedly increased after fludarabine. We identified bendamustine 30 mg/m2 as the safe dose for phase II. The overall response rate (ORR) was 67% with 36% complete response (CR) / CR with incomplete count recovery (CRi). Younger patients (<65 years) had significantly higher ORR (81% vs. 50%; p=0.038). The median progression-free survival was 19 months, and the median overall survival was 52.5 months. FBR is an effective and tolerable CIT regimen for patients with relapsed CLL.

  9. Subcutaneous Progesterone Is Effective and Safe for Luteal Phase Support in IVF: An Individual Patient Data Meta-Analysis of the Phase III Trials

    PubMed Central

    Doblinger, Jakob; Cometti, Barbara; Trevisan, Silvia; Griesinger, Georg

    2016-01-01

    Objective To summarize efficacy and safety data on a new progesterone compound which is available for subcutaneous administration as compared to vaginally administered progesterone for luteal phase support in patients undergoing IVF treatment. Design Data from two randomized phase III trials (07EU/Prg06 and 07USA/Prg05) performed according to GCP standards with a total sample size of 1435 per-protocol patients were meta-analyzed on an individual patient data level. Setting University affiliated reproductive medicine unit. Patients Subcutaneous progesterone was administered to a total of 714 subjects and vaginal progesterone was administered to a total of 721 subjects who underwent fresh embryo transfer after ovarian stimulation followed by IVF or ICSI. The subjects were between 18 and 42 years old and had a BMI <30kg/m2. Interventions Subcutaneous progesterone 25 mg daily vs. either progesterone vaginal gel 90 mg daily (07EU/Prg06) or 100 mg intravaginal twice a day (07USA/Prg05) for luteal phase support in IVF patients. Main outcome measures Ongoing pregnancy rate beyond 10 gestational weeks, live birth rate and OHSS risk. Results The administration of subcutaneous progesterone versus intra-vaginal progesterone had no impact on ongoing pregnancy likelihood (OR = 0.865, 95% CI 0.694 to 1.077; P = n.s.), live birth likelihood (OR = 0.889, 95% CI 0.714 to 1.106; P = n.s.) or OHSS risk (OR = 0.995, 95% CI 0.565 to 1.754; P = n.s.) in regression analyses accounting for clustering of patients within trials, while adjusting for important confounders. Only female age and number of oocytes retrieved were significant predictors of live birth likelihood and OHSS risk. Conclusion No statistical significant or clinical significant differences exist between subcutaneous and vaginal progesterone for luteal phase support. PMID:26991890

  10. Structural transition of PETN-I to ferroelastic orthorhombic phase PETN-III at elevated pressures.

    PubMed

    Tschauner, O; Kiefer, B; Lee, Y; Pravica, M; Nicol, M; Kim, E

    2007-09-07

    Using powder x-ray diffraction and first-principles calculations, we provide evidence for a structural transition of PETN-I below 6 GPa to an orthorhombic phase of space group P2(1)2(1)2. The transition can be rationalized as shear-stress induced and ferroelastic, which involves a slight static displacement of the molecules that breaks the fourfold symmetry of PETN-I. Previously reported changes in the optical spectra reflect a lifting of the twofold degeneracy of modes in tetragonal PETN-I. The observed transition is expected to induce soft shear compliances along specific directions in PETN crystallites that may relate to the observed dependence of detonation pressure on crystal orientation.

  11. Structural Transition of PETN-I to Ferroelastic Orthorhombic Phase PETN-III at Elevated Pressures

    SciTech Connect

    Tschauner,O.; Kiefer, B.; Lee, Y.; Pravica, M.; Nicol, M.; Kim, E.

    2007-01-01

    Using powder x-ray diffraction and first-principles calculations, we provide evidence for a structural transition of PETN-I below 6 GPa to an orthorhombic phase of space group P2{sub 1}2{sub 1}2. The transition can be rationalized as shear-stress induced and ferroelastic, which involves a slight static displacement of the molecules that breaks the fourfold symmetry of PETN-I. Previously reported changes in the optical spectra reflect a lifting of the twofold degeneracy of modes in tetragonal PETN-I. The observed transition is expected to induce soft shear compliances along specific directions in PETN crystallites that may relate to the observed dependence of detonation pressure on crystal orientation.

  12. Microwave Landing System (MLS). Phase III. (Basic Narrow & Small Community Configurations). Volume I.

    DTIC Science & Technology

    1978-06-01

    Type N Female Power - AMP 201298-3 Female The TWT amplifier will output a fault signal when the TWT is over temperature, when the helix current is...Control Section 3-24 3.2.1.5.2 Monitor Section 3-26 3.2.1.6 TWT Amplifier 3-28 3.2.1.7 RF Unit 3-29 3.2.1.7.1 C-Band Exciter 3-29 3.2.1.7.2 Bi-Phase...3-60 3.2.2.5.1 Control Section 3-66 3.2.2.5.2 Monitor Section 3-66 3.2.2.6 TWT Amplifier 3-66 3.2.2.7 RF Unit 3-66 3.2.2.8 Local Control/Status 3-66

  13. Intrapleural administration of interleukin 2 in pleural mesothelioma: a phase I-II study.

    PubMed Central

    Goey, S. H.; Eggermont, A. M.; Punt, C. J.; Slingerland, R.; Gratama, J. W.; Oosterom, R.; Oskam, R.; Bolhuis, R. L.; Stoter, G.

    1995-01-01

    mesothelioma. A formal phase II study is warranted. Based on the observed toxicity, the lack of dose-response relationship and the immunomodulatory effects seen at relatively low-dose IL-2, the recommended dose for a phase II study is 3 x 10(6) IU day-1 using the present treatment schedule. Images Figure 1 PMID:7577483

  14. Liposomal cisplatin combined with gemcitabine in pretreated advanced pancreatic cancer patients: a phase I-II study.

    PubMed

    Stathopoulos, George P; Boulikas, Teni; Vougiouka, Maria; Rigatos, Sotirios K; Stathopoulos, John G

    2006-05-01

    The present trial is a phase I-II study based on a new liposomal cisplatin (lipoplatin). Previous preclinical and clinical data (phase I pharmacokinetics) led to the investigation of a combined treatment modality involving lipoplatin and gemcitabine. The gemcitabine dose was kept standard at 1000 mg/m2 and the lipoplatin dose was escalated from 25 mg/m2 to 125 mg/m2. The treatment was administered to advanced pretreated pancreatic cancer patients who were refractory to previous chemotherapy which included gemcitabine. Lipoplatin at 125 mg/m2 was defined as dose limiting toxicity (DLT) and 100 mg/m2 as the maximum tolerated dose (MTD) in combination with 1000 mg/m2 of gemcitabine. Preliminary objective response rate data showed a partial response in 2/24 patients (8.3%), disease stability in 14 patients (58.3%) for a median duration of 3 months (range 2-7 months) and clinical benefit in 8 patients (33.3%). Liposomal cisplatin is a non-toxic alternative agent to bare cisplatin. In combination with gemcitabine, it has an MTD of 100 mg/m2 and shows promising efficacy in refractory pancreatic cancer.

  15. Geologic model of San Andres reservoir, Roberts Unit CO sub 2 Phase III area, Wasson field, Yoakum County, Texas

    SciTech Connect

    Bent, J.V. Jr. )

    1992-04-01

    Roberts unit is a mature San Andres waterflood project located in Wasson field, Yoakum County, Texas. Texaco, as operator, has evaluated the reservoir for CO{sub 2} flooding, and a four-phased CO{sub 2} project has been designed for the unit. A critical aspect of CO{sub 2} flood design is the development of geologic reservoir management, such as flood monitoring and evaluation of infill drilling. The geologic reservoir model established for the southeastern part of the unit (the CO{sub 2} Phase III area) is an example of this design. The reservoir consists of stacked carbonate depositional sequences. The cyclic nature of these depositional sequences is reflected in both core-defined lithofacies and porosity log character. Sequences consist of basal mudstones, restricted-shelf skeletal wackestones, open-shelf skeletal wackestones and packstones, solution and brecciated zones, and peloidal packstone caps. Intertidal mudstones and wackestones occur at the top of the reservoir and in the overlying reservoir seal. Porosity distribution is controlled by diagenetic events, but these events are closely related to depositional facies. Reservoir geometry and reservoir quality are interpreted from study of carbonate lithofacies, porosity and permeability relationships, and injection characteristics. Depositional sequences are subdivided into layers (flow units) for use in reservoir simulation. Log normalization, core description, porosity interpretation, reservoir mapping, three-dimensional modeling, and joint effort between project geologists and engineers contributed to development of the reservoir model.

  16. A phase I/II trial of TAC-101, an oral synthetic retinoid, in patients with advanced hepatocellular carcinoma.

    PubMed

    Higginbotham, Kimberly B; Lozano, Richard; Brown, Thomas; Patt, Yehuda Z; Arima, Takashi; Abbruzzese, James L; Thomas, Melanie B

    2008-12-01

    Preclinical models showed TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid), an oral synthetic retinoid, has anti-tumor activity in hepatocellular carcinoma (HCC). A phase I/II study was performed in advanced HCC patients (pts). Thirty-three patients were enrolled. During Phase I, pts received 40 mg daily for 14 days q3 weeks; 2 of 5 patients developed DLT so dose was reduced to 20 mg/day. Twenty-eight patients received 20 mg/day. No pt had a CR or PR, but 12 of 21 (57%) had SD. Two pts (9.5%) had late PR after discontinuing TAC-101. Median survival (MS) for all 28 pts treated with 20 mg/day was 12.7 months (95% CI 8.8-22.7); MS for 21 evaluable pts was 19.2 months (95% CI 10.4-27.6). 20 mg of TAC- was well tolerated. Significant disease stabilization (12/21 pts, 57%), 2 late PRs, and prolonged MS (19.2 months) suggest that TAC-101 provides meaningful patient benefit.

  17. Phase IIB/III Trial of Tenecteplase in Acute Ischemic Stroke: Results of a Prematurely Terminated Randomized Clinical Trial

    PubMed Central

    Haley, E. Clarke; Thompson, John L.P.; Grotta, James C.; Lyden, Patrick D.; Hemmen, Thomas G.; Brown, Devin L.; Fanale, Christopher; Libman, Richard; Kwiatkowski, Thomas G.; Llinas, Rafael H.; Levine, Steven R.; Johnston, Karen C.; Buchsbaum, Richard; Levy, Gilberto; Levin, Bruce

    2010-01-01

    Background: Intravenous alteplase (rt-PA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to a) choose a best dose of tenecteplase to carry forward, and b) to provide evidence for either promise or futility of further testing of tenecteplase versus rt-PA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rt-PA. Methods: The trial began as a small, multi-center, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rt-PA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24 hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage (ICH) to choose a “best” dose of tenecteplase to carry forward. Once a “best” dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rt-PA could be compared by 3 month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III. Results: The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4 mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3 month outcomes between the remaining tenecteplase groups and rt-PA. Symptomatic ICH rates were highest in the

  18. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial.

    PubMed

    Haley, E Clarke; Thompson, John L P; Grotta, James C; Lyden, Patrick D; Hemmen, Thomas G; Brown, Devin L; Fanale, Christopher; Libman, Richard; Kwiatkowski, Thomas G; Llinas, Rafael H; Levine, Steven R; Johnston, Karen C; Buchsbaum, Richard; Levy, Gilberto; Levin, Bruce

    2010-04-01

    Intravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA. The trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a "best" dose of tenecteplase to carry forward. Once a "best" dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III. The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg

  19. Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of ledipasvir/sofosbuvir.

    PubMed

    Wyles, David; Dvory-Sobol, Hadas; Svarovskaia, Evguenia S; Doehle, Brian P; Martin, Ross; Afdhal, Nezam H; Kowdley, Kris V; Lawitz, Eric; Brainard, Diana M; Miller, Michael D; Mo, Hongmei; Gane, Edward J

    2017-04-01

    Ledipasvir/sofosbuvir combination treatment in phase III clinical trials resulted in sustained viral suppression in 94-99% of patients. This study characterized drug resistance in treatment failures, which may help to inform retreatment options. We performed NS5A and NS5B deep sequencing of hepatitis C virus (HCV) from patients infected with genotype (GT) 1 who participated in ledipasvir/sofosbuvir phase II and III clinical trials. Fifty-one of 2144 (2.4%) (42 GT1a and 9 GT1b) treated patients met the criteria for resistance analysis due to virologic failure following the end of treatment. The majority of patients with virologic failure (38 of 51; 74.5%) had detectable ledipasvir-specific resistance-associated substitutions (RASs) at the time of virologic failure (1% deep sequencing cut-off). The percent of patients with NS5A RASs at virologic failure were 37.5%, 66.7%, 94.7% and 100% in patients treated for 6, 8, 12 and 24weeks, respectively. The common substitutions detected at failure were Q30R/H, and/or Y93H/N in GT1a and Y93H in GT1b. At failure, 35.3% (18/51) of virologic failure patients' viruses had two or more NS5A RASs and the majority of patients harbored NS5A RASs conferring a 100-1000-fold (n=10) or >1000-fold (n=23) reduced susceptibility to ledipasvir. One patient in a phase II study with a known ledipasvir RAS at baseline (L31M) developed the S282T sofosbuvir (NS5B) RAS at failure. In GT1 HCV-infected patients treated with ledipasvir/sofosbuvir±ribavirin, virologic failure was rare. Ledipasvir resistance in NS5A was selected or enhanced in most patients with virologic failure, one of whom also developed resistance to sofosbuvir. Clinical studies have shown that combination treatment with ledipasvir/sofosbuvir efficiently cures most patients with genotype 1 hepatitis C infection. For the few patients failing treatment, we show that resistance to ledipasvir was observed in most patients, whereas resistance to sofosbuvir was less common. This has

  20. The EORTC module for quality of life in patients with thyroid cancer: phase III.

    PubMed

    Singer, Susanne; Jordan, Susan; Locati, Laura D; Pinto, Monica; Tomaszewska, Iwona M; Araújo, Cláudia; Hammerlid, Eva; Vidhubala, E; Husson, Olga; Kiyota, Naomi; Brannan, Christine; Salem, Dina; Gamper, Eva M; Arraras, Juan Ignacio; Ioannidis, Georgios; Andry, Guy; Inhestern, Johanna; Grégoire, Vincent; Licitra, Lisa

    2017-04-01

    The purpose of the study was to pilot-test a questionnaire measuring health-related quality of life (QoL) in thyroid cancer patients to be used with the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire EORTC QLQ-C30. A provisional questionnaire with 47 items was administered to patients treated for thyroid cancer within the last 2 years. Patients were interviewed about time and help needed to complete the questionnaire, and whether they found the items understandable, confusing or annoying. Items were kept in the questionnaire if they fulfilled pre-defined criteria: relevant to the patients, easy to understand, not confusing, few missing values, neither floor nor ceiling effects, and high variance. A total of 182 thyroid cancer patients in 15 countries participated (n = 115 with papillary, n = 31 with follicular, n = 22 with medullary, n = 6 with anaplastic, and n = 8 with other types of thyroid cancer). Sixty-six percent of the patients needed 15 min or less to complete the questionnaire. Of the 47 items, 31 fulfilled the predefined criteria and were kept unchanged, 14 were removed, and 2 were changed. Shoulder dysfunction was mentioned by 5 patients as missing and an item covering this issue was added. To conclude, the EORTC quality of life module for thyroid cancer (EORTC QLQ-THY34) is ready for the final validation phase IV. © 2017 Society for Endocrinology.

  1. ASSESSMENT OF SUBSURFACE FATE OF MONOETHANOLAMINE AT SOUR GAS PROCESSING PLANT SITES-PHASE III

    SciTech Connect

    James A. Sorensen

    1999-02-01

    Alkanolamines are commonly used by the natural gas industry to remove hydrogen sulfide, carbon dioxide, and other acid gases from the natural gas in which they occur (''sour'' gas if hydrogen sulfide is present). At sour gas-processing plants, as at all plants that use alkanolamines for acid gas removal (AGR), spills and on-site management of wastes containing alkanolamines and associated reaction products have occasionally resulted in subsurface contamination that is presently the focus of some environmental concern. In 1994, the Energy and Environmental Research Center (EERC) initiated a three-phase program to investigate the natural attenuation processes that control the subsurface transport and fate of the most commonly used alkanolamine in Canada, monoethanolamine (MEA). Funding for the MEA research program was provided by the U.S. Department of Energy (DOE), Canadian Association of Petroleum Producers (CAPP), Canadian Occidental Petroleum Ltd. (CanOxy), Gas Research Institute (GRI), Environment Canada, and the National Energy Board of Canada. The MEA research program focused primarily on examining the biodegradability of MEA and MEA-related waste materials in soils and soil-slurries under a variety of environmentally relevant conditions, evaluating the mobility of MEA in soil and groundwater and the effectiveness of bioremediation techniques for removing contaminants and toxicity from MEA-contaminated soil. The presently inactive Okotoks sour gas-processing plant, owned by CanOxy in Alberta, Canada, was the source of samples and field data for much of the laboratory-based experimental work and was selected to be the location for the field-based efforts to evaluate remediation techniques. The objective of the research program is to provide the natural gas industry with ''real world'' data and insights developed under laboratory and field conditions regarding the effective and environmentally sound use of biological methods for the remediation of soil

  2. Thermal Soret Diffusion in the Liquid Phase Epitaxial Growth of Binary Iii-V Compounds

    NASA Astrophysics Data System (ADS)

    Chien, Chung-Ping

    The conditions necessary for stable nucleation and growth in the liquid phase epitaxial growth of GaAs and InP are analytically established and, in the former, experimentally confirmed in this research. A transient thermodynamic transport treatment of supersaturated to undersaturated melts, which includes the coupling between solute and heat transport(thermal Soret diffusion), has been solved in closed form. The thermal Soret diffusion effect has been found to be a very important factor for the stabilization of solute transport. For steady-state LPE growth, the thermal Soret diffusion will give rise to a separation effect that forces the steady -state solute concentration to exceed the equilibrium liquidus concentration at a noninteracting interface. This increased concentration, near the growth interface, can cause localized nonuniformities in the melt which leads to terrace, miniscus -line and/or hillock growth morphologies. When nucleation and growth are initiated at near equilibrium liquidus conditions, at the substrate interface with a temperature gradient, meltback and spontaneous nucleation are minimized. To enhance stable uniform growth, the substrate should be brought into contact with the melt at a very critical time, during melt saturation, when the equilibrium liquidus concentration is reached at the noninteracting interface of the slider. The critical melt saturation time for the transient concentration to reach the liquidus concentration at this interface has been analytically determined and experimentally confirmed. In this analysis, the Soret thermal diffusion coefficient has also been evaluated in terms of the solute and solvent masses and the temperature dependence of the solute diffusion coefficient. The critical time determined in this analysis appears to be in close agreement with the experimental results for LPE GaAs. When near steady-state solute transport is achieved at the initiation of growth on the substrate, i.e., the liquidus solute

  3. Treatment of Geographic Atrophy With Subconjunctival Sirolimus: Results of a Phase I/II Clinical Trial

    PubMed Central

    Wong, Wai T.; Dresner, Samuel; Forooghian, Farzin; Glaser, Tanya; Doss, Lauren; Zhou, Mei; Cunningham, Denise; Shimel, Katherine; Harrington, Molly; Hammel, Keri; Cukras, Catherine A.; Ferris, Frederick L.; Chew, Emily Y.

    2013-01-01

    Purpose. To investigate the safety and effects of subconjunctival sirolimus, an mTOR inhibitor and immunosuppressive agent, for the treatment of geographic atrophy (GA). Methods. The study was a single-center, open-label phase II trial, enrolling 11 participants with bilateral GA; eight participants completed 24 months of follow-up. Sirolimus (440 μg) was administered every 3 months as a subconjunctival injection in only one randomly assigned eye in each participant for 24 months. Fellow eyes served as untreated controls. The primary efficacy outcome measure was the change in the total GA area at 24 months. Secondary outcomes included changes in visual acuity, macular sensitivity, central retinal thickness, and total drusen area. Results. The study drug was well tolerated with few symptoms and related adverse events. Study treatment in study eyes was not associated with structural or functional benefits relative to the control fellow eyes. At month 24, mean GA area increased by 54.5% and 39.7% in study and fellow eyes, respectively (P = 0.41), whereas mean visual acuity decreased by 21.0 letters and 3.0 letters in study and fellow eyes, respectively (P = 0.03). Substantial differences in mean changes in drusen area, central retinal thickness, and macular sensitivity were not detected for all analysis time points up to 24 months. Conclusions. Repeated subconjunctival sirolimus was well-tolerated in patients with GA, although no positive anatomic or functional effects were identified. Subconjunctival sirolimus may not be beneficial in the prevention of GA progression, and may potentially be associated with effects detrimental to visual acuity. (ClinicalTrials.gov number, NCT00766649.) PMID:23548622

  4. NOVEL CONCEPTS RESEARCH IN GEOLOGIC STORAGE OF CO2 PHASE III

    SciTech Connect

    Neeraj Gupta

    2005-11-04

    As part of the Department of Energy's (DOE) initiative on developing new technologies for storage of carbon dioxide in geologic reservoirs, Battelle has been investigating the feasibility of CO{sub 2} sequestration in the deep saline reservoirs in the Ohio River Valley region. In addition to the DOE, the project is being sponsored by American Electric Power (AEP), BP, The Ohio Coal Development Office (OCDO) of the Ohio Air Quality Development Authority, and Schlumberger. The main objective of the project is to demonstrate that CO{sub 2} sequestration in deep formations is feasible from engineering and economic perspectives, as well as being an inherently safe practice and one that will be acceptable to the public. In addition, the project is designed to evaluate the geology of deep formations in the Ohio River Valley region in general and in the vicinity of AEP's Mountaineer Power Plant in particular, in order to determine their potential use for conducting a long-term test of CO{sub 2} disposal in deep saline formations. The current technical progress report summarizes activities completed for the July through September 2005 period of the project. As discussed in the report, the field activities focused on preparations for reservoir testing in the Copper Ridge ''B-zone'' in the AEP No.1 well. In addition work continued on development of injection well design options, engineering assessment of CO{sub 2} capture systems, reservoir simulations, work on a Class V Underground Injection Control permit, and assessment of monitoring technologies as they apply to the project site. Overall, the current design feasibility phase project is proceeding according to plans.

  5. A phase 0 trial of riluzole in patients with resectable stage III and IV melanoma.

    PubMed

    Yip, Dana; Le, Maithao N; Chan, Joseph L-K; Lee, Jonathan H; Mehnert, Janice A; Yudd, Anthony; Kempf, Jeffery; Shih, Weichung J; Chen, Suzie; Goydos, James S

    2009-06-01

    Ectopic expression of GRM1 in murine melanocytes results in transformation into a form of melanoma, and more than 60% of human melanoma samples tested ectopically express GRM1. Stimulation of this receptor in vitro results in up-regulation of activated extracellular signal-regulated kinase (ERK). Furthermore, a xenograft model of melanoma treated with riluzole, an oral GRM1 blocking agent, showed decreased tumor growth compared with the untreated controls. We have now completed a phase 0 trial of riluzole in patients with melanoma. Patients enrolled on this trial underwent a pretreatment biopsy, took 200 mg of oral riluzole per day for 14 days, and then underwent resection of their remaining tumor. We compared the levels of pERK and pAKT in the pretreatment and post-treatment samples and assessed the metabolic activity of pretreatment and post-treatment tumors using fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. We accrued 12 patients and all expressed GRM1. We found a significant decrease in pAKT and/or pERK in post-treatment tumor samples as compared with pretreatment samples in 4 (34%) patients. These four patients had a significant decrease in FDG-PET intensity post-treatment as well. Two other patients had a clinical response with no corresponding metabolic response; five patients had similar pretreatment and post-treatment FDG-PET scan findings; and one patient had progressive disease. Our data show that glutamate blockade with riluzole can inhibit signaling through the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways and suppress the metabolic activity of melanoma. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma, and targeting this pathway may be an effective therapy.

  6. A Phase 0 Trial of Riluzole in Patients with Resectable Stage III and IV Melanoma

    PubMed Central

    Yip, Dana; Le, Maithao N.; Chan, Joseph L.-K.; Lee, Jonathan H.; Mehnert, Janice A.; Yudd, Anthony; Kempf, Jeffery; Shih, Weichung J.; Chen, Suzie; Goydos, James S.

    2010-01-01

    Purpose Ectopic expression of GRM1 in murine melanocytes results in transformation into a form of melanoma, and more than 60% of human melanoma samples tested ectopically express GRM1. Stimulation of this receptor in vitro results in up-regulation of activated extracellular signal–regulated kinase (ERK). Furthermore, a xenograft model of melanoma treated with riluzole, an oral GRM1 blocking agent, showed decreased tumor growth compared with the untreated controls. We have now completed a phase 0 trial of riluzole in patients with melanoma. Experimental Design Patients enrolled on this trial underwent a pretreatment biopsy, took 200 mg of oral riluzole per day for 14 days, and then underwent resection of their remaining tumor. We compared the levels of pERK and pAKT in the pretreatment and post-treatment samples and assessed the metabolic activity of pretreatment and post-treatment tumors using fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. Results We accrued 12 patients and all expressed GRM1. We found a significant decrease in pAKT and/or pERK in post-treatment tumor samples as compared with pretreatment samples in 4 (34%) patients. These four patients had a significant decrease in FDG-PET intensity post-treatment as well. Two other patients had a clinical response with no corresponding metabolic response; five patients had similar pretreatment and post-treatment FDG-PET scan findings; and one patient had progressive disease. Conclusions Our data show that glutamate blockade with riluzole can inhibit signaling through the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways and suppress the metabolic activity of melanoma. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma, and targeting this pathway may be an effective therapy. PMID:19458050

  7. Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study.

    PubMed

    Yamaue, Hiroki; Tsunoda, Takuya; Tani, Masaji; Miyazawa, Motoki; Yamao, Kenji; Mizuno, Nobumasa; Okusaka, Takuji; Ueno, Hideki; Boku, Narikazu; Fukutomi, Akira; Ishii, Hiroshi; Ohkawa, Shinichi; Furukawa, Masayuki; Maguchi, Hiroyuki; Ikeda, Masafumi; Togashi, Yosuke; Nishio, Kazuto; Ohashi, Yasuo

    2015-07-01

    Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36 months (95% CI, 7.46-10.18) for the Active group and 8.54 months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival.

  8. Advanced heat pump for recovery of volatile organic compounds, Phase III - demonstration of BCSRHP mobile regenerator. Final report

    SciTech Connect

    Not Available

    1994-11-01

    Under Phase I of the subject contract, feasibility studies and basic engineering studies were performed for a Brayton Cycle Solvent Recovery Heat Pump (BCSRBP) system to prevent pollution from small source emitters. It was determined that the cost of a complete system, including adsorbers and regeneration process, would be far too much for the small emission source in most cases. This {open_quotes}integrated{close_quotes} approach was therefore not feasible. However, it was concluded that the expensive portion of the Brayton cycle process, the regenerator, could be shared by mounting it on a trailer that could be transported to different sites to regenerate an adsorber. Under Phase II of the project a mobile regenerator (BCSRI-IP) was designed and built to serve a large number of sites. Adsorbers were designed to control emissions for a week or more between regenerations. The purpose of phase III was to demonstrate the cost effectiveness and efficiency of the shared (decoupled) BRAYSORB{reg_sign} solvent recovery system in energy use and emission control compared to other control technologies through a performance testing program at representative industrial and commercial host sites in Southern California. NUCON was the prime contractor for the demonstration portion of this project. Support and funding were received from Southern California Edison Company, South Coast Air Quality Management District, and the U.S. Department of Energy in addition to the contribution by NUCON. Contractual arrangements were completed with each of the host sites and permits for both the stationary and mobile equipment were acquired. The adsorbers were installed at each host site and the appropriate interface connections were made. The mobile regenerator was transported to Southern California for the demonstration.

  9. Phase I/II study of metastatic melanoma patients treated with nivolumab who had progressed after ipilimumab

    PubMed Central

    Weber, Jeffrey; Gibney, Geoffrey; Kudchadkar, Ragini; Yu, Bin; Cheng, PingYan; Martinez, Alberto J.; Kroeger, Jodie; Richards, Allison; McCormick, Lori; Moberg, Valerie; Cronin, Heather; Zhao, Xiuhua; Schell, Michael; Chen, Yian Ann

    2016-01-01

    The checkpoint inhibitor nivolumab is active in metastatic melanoma patients who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3-4 drug related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. Response rate for ipilimumab-refractory patients was 30% (95%CI: 21% - 41%). Median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when followed up a median of 16 months. One and two year survivals were 68.4% and 31.2%, respectively. Ipilimumab-naïve and -refractory patients showed no significant difference in survival. The 21 patients with prior grade 3–4 toxicity to ipilimumab that was managed with steroids, tolerated nivolumab well, with 62% (95%CI: 38% - 82%) having complete or partial remissions or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSCs) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3-4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab. PMID:26873574

  10. A phase I/II study of neoadjuvant liposomal doxorubicin, paclitaxel, and hyperthermia in locally advanced breast cancer.

    PubMed

    Vujaskovic, Zeljko; Kim, Dong W; Jones, Ellen; Lan, Lan; McCall, Linda; Dewhirst, Mark W; Craciunescu, Oana; Stauffer, Paul; Liotcheva, Vlayka; Betof, Allison; Blackwell, Kimberly

    2010-01-01

    The prognosis for locally advanced breast cancer (LABC) patients continues to be poor, with an estimated five-year survival of only 50-60%. Preclinical data demonstrates enhanced therapeutic efficacy with liposomal encapsulation of doxorubicin combined with hyperthermia (HT). Therefore this phase I/II study was designed to evaluate the safety and efficacy of a novel neoadjuvant combination treatment of paclitaxel, liposomal doxorubicin, and hyperthermia. Eligible patients received four cycles of neoadjuvant liposomal doxorubicin (30-75 mg/m(2)), paclitaxel (100-175 mg/m(2)), and hyperthermia. They subsequently underwent either a modified radical mastectomy or lumpectomy with axillary node dissection followed by radiation therapy and then eight cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy. Forty-seven patients with stage IIB-III LABC were enrolled and 43 patients were evaluable. Fourteen patients (33%) had inflammatory breast cancer. Combined (partial + complete) clinical response rate was 72% and combined pathological response rate was 60%. Four patients achieved a pathologically complete response. Sixteen patients were eligible for breast-conserving surgery. The cumulative equivalent minutes (CEM 43) at T90 (tenth percentile of temperature distribution) was significantly greater for those with a pathological response. Four-year disease-free survival was 63% (95% CI, 46%-76%) and the four-year overall survival was 75% (95% CI, 58-86%). Neoadjuvant therapy using paclitaxel, liposomal doxorubicin and hyperthermia is a feasible and well tolerated treatment strategy in patients with LABC. The thermal dose parameter CEM 43 T90 was significantly correlated with attaining a pathological response.

  11. A phase I/II study of neoadjuvant liposomal doxorubicin, paclitaxel, and hyperthermia in locally advanced breast cancer

    PubMed Central

    Vujaskovic, Zeljko; Kim, Dong W.; Jones, Ellen; Lan, Lan; McCall, Linda; Dewhirst, Mark W.; Craciunescu, Oana; Stauffer, Paul; Liotcheva, Vlayka; Betof, Allison; Blackwell, Kimberly

    2010-01-01

    Purpose The prognosis for locally advanced breast cancer (LABC) patients continues to be poor, with an estimated five-year survival of only 50–60%. Preclinical data demonstrates enhanced therapeutic efficacy with liposomal encapsulation of doxorubicin combined with hyperthermia (HT). Therefore this phase I/II study was designed to evaluate the safety and efficacy of a novel neoadjuvant combination treatment of paclitaxel, liposomal doxorubicin, and hyperthermia. Materials and methods Eligible patients received four cycles of neoadjuvant liposomal doxorubicin (30–75 mg/m2), paclitaxel (100–175 mg/m2), and hyperthermia. They subsequently underwent either a modified radical mastectomy or lumpectomy with axillary node dissection followed by radiation therapy and then eight cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy. Results Forty-seven patients with stage IIB-III LABC were enrolled and 43 patients were evaluable. Fourteen patients (33%) had inflammatory breast cancer. Combined (partial + complete) clinical response rate was 72% and combined pathological response rate was 60%. Four patients achieved a pathologically complete response. Sixteen patients were eligible for breast-conserving surgery. The cumulative equivalent minutes (CEM 43) at T90 (tenth percentile of temperature distribution) was significantly greater for those with a pathological response. Four-year disease-free survival was 63% (95% CI, 46%–76%) and the four-year overall survival was 75% (95% CI, 58–86%). Conclusions Neoadjuvant therapy using paclitaxel, liposomal doxorubicin and hyperthermia is a feasible and well tolerated treatment strategy in patients with LABC. The thermal dose parameter CEM 43 T90 was significantly correlated with attaining a pathological response. PMID:20377362

  12. Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab.

    PubMed

    Weber, Jeffrey; Gibney, Geoffrey; Kudchadkar, Ragini; Yu, Bin; Cheng, Pingyan; Martinez, Alberto J; Kroeger, Jodie; Richards, Allison; McCormick, Lori; Moberg, Valerie; Cronin, Heather; Zhao, Xiuhua; Schell, Michael; Chen, Yian Ann

    2016-04-01

    The checkpoint inhibitor nivolumab is active in patients with metastatic melanoma who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab-refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3-4 drug-related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. The response rate for ipilimumab-refractory patients was 30% (95% CI, 21%-41%). The median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when patients were followed up for a median of 16 months. One- and 2-year survival rates were 68.4% and 31.2%, respectively. Ipilimumab-naïve and ipilimumab-refractory patients showed no significant difference in survival. The 21 patients with prior grade 3-4 toxicity to ipilimumab that was managed with steroids tolerated nivolumab well, with 62% (95% CI, 38%-82%) having complete or partial responses or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSC) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3-4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab.

  13. Methadone induction in primary care (ANRS-Methaville): a phase III randomized intervention trial

    PubMed Central

    2012-01-01

    Background In France, the rapid scale-up of buprenorphine, an opioid maintenance treatment (OMT), in primary care for drug users has led to an impressive reduction in HIV prevalence among injecting drug users (IDU) but has had no major effect on Hepatitis C incidence. To date, patients willing to start methadone can only do so in a methadone clinic (a medical centre for drug and alcohol dependence (CSAPA) or a hospital setting) and are referred to primary care physicians after dose stabilization. This study aims to assess the effectiveness of methadone in patients who initiated treatment in primary care compared with those who initiated it in a CSAPA, by measuring abstinence from street opioid use after one year of treatment. Methods/Design The ANRS-Methaville study is a randomized multicenter non-inferiority control trial comparing methadone induction (lasting approximately 2 weeks) in primary care and in CSAPA. The model of care chosen for methadone induction in primary care was based on study-specific pre-training of all physicians, exclusion criteria and daily supervision of methadone during the initiation phase. Between January 2009 and January 2011, 10 sites each having one CSAPA and several primary care physicians, were identified to recruit patients to be randomized into two groups, one starting methadone in primary care (n = 147), the other in CSAPA (n = 48). The primary outcome of the study is the proportion of participants abstinent from street opioids after 1 year of treatment i.e. non-inferiority of primary care model in terms of the proportion of patients not using street opioids compared with the proportion observed in those starting methadone in a CSAPA. Discussion The ANRS-Methaville study is the first in France to use an interventional trial to improve access to OMT for drug users. Once the non-inferiority results become available, the Ministry of Health and agency for the safety of health products may change the the New Drug Application

  14. Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of a multicenter phase I/II trial

    PubMed Central

    Palumbo, Antonio; Larocca, Alessandra; Genuardi, Mariella; Kotwica, Katarzyna; Gay, Francesca; Rossi, Davide; Benevolo, Giulia; Magarotto, Valeria; Cavallo, Federica; Bringhen, Sara; Rus, Cecilia; Masini, Luciano; Iacobelli, Massimo; Gaidano, Gianluca; Mitsiades, Constantine; Anderson, Kenneth; Boccadoro, Mario; Richardson, Paul

    2010-01-01

    Background Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen. Design and Methods This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1–4, prednisone at a dose of 1.5 mg/kg also on days 1–4 and thalidomide at a dose of 50–100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1–4 and 1.6, 3.2, or 4.8 g on days 5–35. Results Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3–4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient. Conclusions This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1–4 followed by 4.8 g p.o. on days 5–35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs (ClinicalTrials.gov Identifier: NCT00406978). PMID:20053869

  15. Motivations to participate in a Phase I/II HIV vaccine trial: A descriptive study from Dar es Salaam, Tanzania.

    PubMed

    Tarimo, E A M; Bakari, M; Kakoko, D C V; Kohi, T W; Mhalu, F; Sandstrom, E; Kulane, A

    2016-02-24

    The search for an efficacious HIV vaccine is a global priority. To date only one HIV vaccine trial (RV144) has shown modest efficacy in a phase III trial. With existing different HIV-1 subtypes and frequent mutations, multiple trials are needed from different geographical sites particularly in sub-Saharan Africa where most HIV infections occur. Thus, motivations to participate in HIV vaccine trials among Tanzanians need to be assessed. This paper describes the motives of Police Officers who showed great interest to volunteer in HIVIS-03 in Dar es Salaam, Tanzania. A descriptive cross-sectional study was conducted among Police Officers who showed interest to participate in the HIVIS-03, a phase I/II HIV vaccine trial in Dar es Salaam. Prior to detailed training sessions about HIV vaccine trials, the potential participants narrated their individual motives to participate in the trial on a piece of paper. Descriptive analysis using content approach and frequency distributions were performed. Of the 265 respondents, 242 (91.3%) provided their socio-demographic characteristics as well as reasons that would make them take part in the proposed trial. Majority, (39.7%), cited altruism as the main motive. Women were more likely to volunteer due to altruism compared to men (P < 0.01). Researchers' explanations about HIV/AIDS vaccine studies motivated 15.3%. More men (19.6%) than women (1.7%) were motivated to volunteer due to researchers' explanations (P < 0.001). Also, compared to other groups, those unmarried and educated up to secondary level of education were motivated to volunteer due to researchers' explanation (P < 0.05). Other reasons were: desire to become a role model (18.6%); to get knowledge for educating others (14.0%); to cooperate with researchers in developing an HIV vaccine (9.5%); to get protection against HIV infection (7.0%), and severity of the disease within families (6.2%). These results were supported by testimonies from both men and women

  16. Use of concomitant inhaled corticosteroids: pooled data from two phase III studies of aclidinium plus formoterol in COPD.

    PubMed

    D'Urzo, Anthony; Singh, Dave; Garcia Gil, Esther

    2017-12-01

    Bronchodilator therapy is the backbone of the management of chronic obstructive pulmonary disease. In some patients, inhaled corticosteroids can be prescribed in combination with bronchodilators. Through a subgroup analysis of pooled data from two large phase III clinical trials of bronchodilator therapy according to concomitant inhaled corticosteroid use (user vs. non-user), we sought to evaluate the clinical benefit of adding inhaled corticosteroids to dual bronchodilator therapy in chronic obstructive pulmonary disease. The primary focus of this analysis of pooled data from the phase III ACLIFORM and AUGMENT studies was to evaluate the efficacy of aclidinium/formoterol on lung function stratified by inhaled corticosteroid use. We found that lung-function end points were significantly improved regardless of concomitant inhaled corticosteroid use among patients treated with the dual bronchodilator aclidinium/formoterol 400/12 µg twice daily compared with placebo and both monotherapies. Together with the previously reported observations that aclidinium/formoterol 400/12 µg reduces exacerbations vs. placebo in inhaled corticosteroid users and improves dyspnoea compared to monotherapy in inhaled corticosteroid non-users, these data suggest that both groups achieve lung function improvements, which translates to different clinical benefits depending on whether or not a patient is receiving concomitant inhaled corticosteroids.CHRONIC LUNG DISEASE: 'TRIPLE' THERAPY COULD PROVE BENEFICIAL: A dual bronchodilator therapy taken together with corticosteroid inhalers may benefit patients with severe chronic lung disease. Bronchodilator drugs relax the lungs and widen airways in patients with chronic obstructive pulmonary disease (COPD). While recent studies have shown that a dual bronchodilator therapy containing aclidinium and formoterol significantly improves lung function in COPD, little is known about combining the dual therapy with inhaled corticosteroids (ICSs

  17. Recurrence-free survival as a putative surrogate for overall survival in phase III trials of curative-intent treatment of colorectal liver metastases: Systematic review.

    PubMed

    Araujo, Raphael L C; Herman, Paulo; Riechelmann, Rachel P

    2017-06-10

    To verify whether recurrence-free survival (RFS) surrogates overall survival (OS) in phase III trials for resectable colorectal liver metastases (CRLM). MEDLINE, EMBASE, and Scopus databases were consulted. Eligible studies were phase III trials testing any type of systemic therapy (neoadjuvant, adjuvant or perioperative) added to surgery in patients with resectable CRLM. A linear regression model based on hazard ratios (HR) of OS and RFS was performed. Of 3059 studies, 5 phase III trials (1162 patients) were included for analyses. A linear regression weighted by each trial was used to estimate the association between each HR and RFS. The originated formula was: OS HR = (0.93 × RFS HR) + 0.14; with RFS 95%CI (0.48-1.38), with P = 0.007. This association suggests that RFS could work as a putative surrogate endpoint of OS in this population, avoiding bigger, longer and more resource-consuming trials. The OS could be assumed based on RFS and our model could be useful to better estimate sample size calculations of phase III trials of CRLM aiming for OS.

  18. Study of the Need for Educational Manpower for Handicapped Children and Youth: Part D - Volume I, Phase III. State Analysis Reports.

    ERIC Educational Resources Information Center

    Mintz, Raymond D.; And Others

    The document is the first of three volumes (see also EC 032 851 and EC 032 852) of State Analysis Reports resulting from Phase III of the Study of the Need for Educational Manpower for Handicapped Children and Youth, which involved a validation study and state surveys related to the Manpower Requirements Projection Model (MRPM). Included in the…

  19. Study of the Need for Educational Manpower for Handicapped Children and Youth Part D - Volume II, Phase III. State Analysis Reports.

    ERIC Educational Resources Information Center

    Mintz, Raymond D.; And Others

    The document is the second of three volumes (see also EC 032 850 and EC 032 852) of State Analysis Reports resulting from Phase III of the Study of the Need for Educational Manpower for Handicapped Children and Youth, which involved a validation study and state surveys related to the Manpower Requirements Projection Model (MRPM). Included in this…

  20. Preclinical Rationale for the Phase III Trials in Metastatic Pancreatic Cancer: Is Wishful Thinking Clouding Successful Drug Development for Pancreatic Cancer?

    PubMed

    Thota, Ramya; Maitra, Anirban; Berlin, Jordan D

    2017-02-01

    Prior phase III trials in advanced pancreatic cancer have been predominantly unsuccessful. In this review, we attempt to understand how past preclinical data were translated into phase III clinical trials in metastatic pancreatic cancer as described in the article. A systematic literature review conducted through the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases, from January 1997 to June 2015 using key words-phase III clinical trials, metastatic/advanced pancreatic adenocarcinoma or pancreatic cancer identified 30 randomized controlled trials (RCTs) that met criteria. The trials were limited to RCTs in the first-line treatment of patients with metastatic pancreatic cancer. The success rate of first-line phase III studies in advanced pancreatic cancer was only 13%. In 60% of the RCTs, no preclinical experiments were referenced in biologically cognate pancreatic models. Nine (30%) of the RCTs were designed based on preclinical evidence from in vitro cell lines alone without additional in vivo validation in xenograft models. It remains uncertain how strongly the preclinical data influence the development of clinical regimens but so far the studies developed based on more solid preclinical evidence have been successful.

  1. EVALUATION OF DEMONSTRATED AND EMERGING TECHNOLOGIES FOR THE TREATMENT OF CONTAMINATED LAND AND GROUNDWATER (PHASE III) - 1999 SPECIAL SESSION ON MONITORED NATURAL ATTENUATION

    EPA Science Inventory

    This report includes the papers presented at the NATO/CCMS Pilot Study Meeting in Angers, France, May 9-14, 1999, for the special session on Monitored Natural Attenuation (MNA). This is the Phase III of the Evaluation of Demonstrated and Emerging Technologies for the Treatment a...

  2. A National Study of Internal Medicine--Phase III. Analysis of 1976-1977 Resident Cohort Currently in Practice. Final Report.

    ERIC Educational Resources Information Center

    Schleiter, Mary Kay; Tarlov, Alvin R.

    The different practice styles of young internists and the relationship between training and practice were studied as part of the National Study of Internal Medicine Manpower, Phase III. The practices of four groups of physicians were compared: general internists with traditional residencies, general internists who received their residency training…

  3. EVALUATION OF DEMONSTRATED AND EMERGING TECHNOLOGIES FOR THE TREATMENT OF CONTAMINATED LAND AND GROUNDWATER (PHASE III) - 1999 SPECIAL SESSION ON MONITORED NATURAL ATTENUATION

    EPA Science Inventory

    This report includes the papers presented at the NATO/CCMS Pilot Study Meeting in Angers, France, May 9-14, 1999, for the special session on Monitored Natural Attenuation (MNA). This is the Phase III of the Evaluation of Demonstrated and Emerging Technologies for the Treatment a...

  4. Topical report on subsurface fracture mapping from geothermal wellbores. Phase I. Pulsed radar techniques. Phase II. Conventional logging methods. Phase III. Magnetic borehole ranging

    SciTech Connect

    Hartenbaum, B.A.; Rawson, G.

    1980-09-01

    To advance the state-of-the-art in Hot Dry Rock technology, an evaluation is made of (i) the use of radar to map far-field fractures, (ii) the use of more than twenty different conventional well logging tools to map borehole-fracture intercepts, and (iii) the use of magnetic dipole ranging to determine the relative positions of the injection well and the production well within the fractured zone. It is found that according to calculations, VHF backscatter radar has the potential for mapping fractures within a distance of 50 +- 20 meters from the wellbore. A new technique for improving fracture identification is presented. Analyses of extant data indicate that when used synergistically the (1) caliper, (2) resistivity dipmeter, (3) televiewer, (4) television, (5) impression packer, and (6) acoustic transmission are useful for mapping borehole-fracture intercepts. Improvements in both data interpretation techniques and high temperature operation are required. The surveying of one borehole from another appears feasible at ranges of up to 200 to 500 meters by using a low frequency magnetic field generated by a moderately strong dipole source (a solenoid) located in one borehole, a sensitive B field detector that traverses part of the second borehole, narrow band filtering, and special data inversion techniques.

  5. Theoretical study of metal-ligand interaction in Sm(III), Eu(III), and Tb(III) complexes of coumarin-3-carboxylic acid in the gas phase and solution.

    PubMed

    Georgieva, Ivelina; Trendafilova, Natasha; Aquino, Adélia J A; Lischka, Hans

    2007-12-10

    The interaction of lanthanide(III) cations (Ln(III) = Sm(III), Eu(III), and Tb(III)) with the deprotonated form of the coumarin-3-carboxylic acid (cca-) has been investigated by density functional theory (DFT/B3LYP) and confirmed by reference MP2 and CCSD(T) computations. Solvent effects on the geometries and stabilities of the Ln(III) complexes were computed using a combination of water clusters and a continuum solvation model. The following two series of systems were considered: (i) Ln(cca)2+, Ln(cca)2+, Ln(cca)3 and (ii) Ln(cca)(H2O)2Cl2, Ln(cca)2(H2O)2Cl, Ln(cca)3. The strength and character of the Ln(III)-cca- bidentate bonding were characterized by calculated Ln-O bond lengths, binding energies, ligand deformation energies, energy partitioning analysis, sigma-donation contributions, and natural population analyses. The energy decomposition calculations predicted predominant electrostatic interaction terms to the Ln-cca bonding (ionic character) and showed variations of the orbital interaction term (covalent contributions) for the Ln-cca complexes studied. Electron distribution analysis suggested that the covalent contribution comes mainly from the interaction with the carboxylate moiety of cca-.

  6. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab.

    PubMed

    Koren, Michael J; Lundqvist, Pernille; Bolognese, Michael; Neutel, Joel M; Monsalvo, Maria Laura; Yang, Jingyuan; Kim, Jae B; Scott, Rob; Wasserman, Scott M; Bays, Harold

    2014-06-17

    The aim of this study was to compare biweekly and monthly evolocumab with placebo and oral ezetimibe in patients with hypercholesterolemia in a phase III trial. Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced LDL-C in phase II trials. Patients 18 to 80 years of age with fasting low-density lipoprotein cholesterol (LDL-C) ≥100 and <190 mg/dl and Framingham risk scores ≤10% were randomized (1:1:1:1:2:2) to oral placebo and subcutaneous (SC) placebo biweekly; oral placebo and SC placebo monthly; ezetimibe and SC placebo biweekly; ezetimibe and SC placebo monthly; oral placebo and evolocumab 140 mg biweekly; or oral placebo and evolocumab 420 mg monthly. A total of 614 patients were randomized and administered doses. Evolocumab treatment reduced LDL-C from baseline, on average, by 55% to 57% more than placebo and 38% to 40% more than ezetimibe (p < 0.001 for all comparisons). Evolocumab treatment also favorably altered other lipoprotein levels. Treatment-emergent adverse events (AEs), muscle-related AEs, and laboratory abnormalities were comparable across treatment groups. In the largest monotherapy trial using a PCSK9 inhibitor to date, evolocumab yielded significant LDL-C reductions compared with placebo or ezetimibe and was well tolerated in patients with hypercholesterolemia. (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2 [MENDEL-2]; NCT01763827). Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  7. A Phase I/II Trial of Gefitinib Given Concurrently With Radiotherapy in Patients With Nonmetastatic Prostate Cancer

    SciTech Connect

    Joensuu, Greetta; Joensuu, Timo; Nokisalmi, Petri

    2010-09-01

    Purpose: To estimate the safety and tolerability of daily administration of 250 mg of gefitinib given concurrently with three-dimensional conformal radiotherapy for patients with nonmetastatic prostate cancer. Methods and Materials: A total of 42 patients with T2-T3N0M0 tumors were treated in a nonrandomized single-center study. A prostate-specific antigen (PSA) level of <20 and a good performance status (WHO, 0-1) were required. Adjuvant or neoadjuvant hormone treatments were not allowed. A daily regimen of 250 mg of gefitinib was started 1 week before radiation therapy began and lasted for the duration of radiation therapy. A dose of 50.4 Gy (1.8 Gy/day) was administered to the tumor, prostate, and seminal vesicles, followed by a 22-Gy booster (2 Gy/day) for a total dose of 72.4 Gy. Correlative studies included analysis of epidermal growth factor receptor (EGFR), EGFRvIII, and phosphorylated EGFR in tumors and tumor necrosis factor, interleukin-1{alpha} (IL-1{alpha}), and IL-6 in serum. Results: Maximum tolerated dose was not reached in phase I (12 patients), and 30 additional patients were treated in phase II. Thirty (71.4%) patients completed trial medication. Dose-limiting toxicities were recorded for 16 (38.1%) patients, the most common of which was a grade 3 to 4 increase in transaminase (6 patients). After a median follow-up of 38 months, there were no deaths due to prostate cancer. The estimated PSA relapse-free survival rate at 4 years (Kaplan-Meier) was 97%, the salvage therapy-free survival rate was 91%, and the overall survival rate was 87%. These figures compared favorably with those of matched patients treated with radiation only at higher doses. Conclusions: The combination of gefitinib and radiation is reasonably well tolerated and has promising activity against nonmetastatic prostate cancer.

  8. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study.

    PubMed

    Ohtsu, Atsushi; Ajani, Jaffer A; Bai, Yu-Xian; Bang, Yung-Jue; Chung, Hyun-Cheol; Pan, Hong-Ming; Sahmoud, Tarek; Shen, Lin; Yeh, Kun-Huei; Chin, Keisho; Muro, Kei; Kim, Yeul Hong; Ferry, David; Tebbutt, Niall C; Al-Batran, Salah-Eddin; Smith, Heind; Costantini, Chiara; Rizvi, Syed; Lebwohl, David; Van Cutsem, Eric

    2013-11-01

    The oral mammalian target of rapamycin inhibitor everolimus demonstrated promising efficacy in a phase II study of pretreated advanced gastric cancer. This international, double-blind, phase III study compared everolimus efficacy and safety with that of best supportive care (BSC) in previously treated advanced gastric cancer. Patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were randomly assigned to everolimus 10 mg/d (assignment schedule: 2:1) or matching placebo, both given with BSC. Randomization was stratified by previous chemotherapy lines (one v two) and region (Asia v rest of the world [ROW]). Treatment continued until disease progression or intolerable toxicity. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), overall response rate, and safety. Six hundred fifty-six patients (median age, 62.0 years; 73.6% male) were enrolled. Median OS was 5.4 months with everolimus and 4.3 months with placebo (hazard ratio, 0.90; 95% CI, 0.75 to 1.08; P = .124). Median PFS was 1.7 months and 1.4 months in the everolimus and placebo arms, respectively (hazard ratio, 0.66; 95% CI, 0.56 to 0.78). Common grade 3/4 adverse events included anemia, decreased appetite, and fatigue. The safety profile was similar in patients enrolled in Asia versus ROW. Compared with BSC, everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy. The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers.

  9. Current Practices in the Treatment of Alzheimer Disease: Where is the Evidence After the Phase III Trials?

    PubMed

    Ehret, Megan J; Chamberlin, Kevin W

    2015-08-01

    The purpose of this systematic review was to review the current place in therapy of the 4 medications, donepezil, rivastigmine, galantamine, and memantine, approved for the treatment of Alzheimer disease (AD) since the publication of Phase III trials. A systematic literature search of MEDLINE and EMBASE was conducted for articles published in the past 10 years. The search was performed using the following Medical Subject Headings and text key words: Alzheimer's disease, treatment, donepezil, galantamine, rivastigmine, memantine, dementia of the Alzheimer's type, and dementia. Studies that evaluated new doses, indications, and dose formulations remain a large part of the current literature. Donepezil gained approval for the treatment of severe AD and became available in a 23-mg/d dose formulation. Rivastigmine became available in a patch formulation. Memantine became available as an extended-release capsule. Use of a combination product formulation was recently approved, memantine extended release/donepezil. Controversy among clinicians remains regarding when to initiate therapy, appropriate duration of therapy, and how and when to discontinue the treatment of AD. Only drugs that affect cholinergic function have shown consistent, but modest, clinical effects, even in late-phase trials. There is a need for a better appreciation of the various risk factors and drug targets for the treatment of AD. The wide range of targets makes it unlikely that affecting only 1 of those targets (eg, cholinergic function or N-methyl-d-aspartate) will lead to a more than minimally effective treatment option, regardless of when a treatment is started and discontinued. There is substantial opportunity for the continued growth and development of drugs and clinical trial expansion for the treatment of AD. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

  10. Optical studies of blue phase III, twist-bend and bent-core nematic liquid crystals in high magnetic fields

    NASA Astrophysics Data System (ADS)

    Challa, Pavan Kumar

    This dissertation is mainly divided into three parts. First, the dynamic light scattering measurements on both calamitic and bent-core nematic liquid crystals, carried out in the new split-helix resistive magnet at the National High Magnetic Field Laboratory, Tallahassee is discussed. In a nematic liquid crystal the molecules tend to be aligned along a constant direction, labeled by a unit vector (or "director") n. However, there are fluctuations from this average configuration. These fluctuations are very large for long wavelengths and give rise to a strong scattering of light. The magnetic field reduces the fluctuations of liquid crystal director n. Scattered light was detected at each scattering angle ranging from 0° to 40°. The relaxation rate and inverse scattered intensity of director fluctuations exhibit a linear dependence on field-squared up to 25 Tesla. We also observe evidence of field dependence of certain nematic material parameters. In the second part of the dissertation, magneto-optical measurements on two liquid crystals that exhibit a wide temperature-range amorphous blue phase (BPIII) are discussed. Blue phase III is one of the phases that occur between chiral nematic and isotropic liquid phases. Samples were illuminated with light from blue laser; the incident polarization direction of the light was parallel to the magnetic field. The transmitted light was passed through another polarizer oriented at 90° with respect to the first polarizer and was detected by a photo-detector. Magnetic fields up to 25Tesla are found to suppress the onset of BPIII in both materials by almost 1 degree celcius. This effect appears to increase non-linearly with the field strength. The effect of high fields on established BPIII's is also discussed, in which we find significant hysteresis and very slow dynamics. Possible explanations of these results are discussed. In the third part of the dissertation, magneto-optic measurements on two odd-numbered dimer molecules

  11. The dynamics of the internal phonons tris(quinolin-8-olato) aluminum(III) in crystalline β-phase

    NASA Astrophysics Data System (ADS)

    Degli Esposti, Alessandra; Brinkmann, Martin; Ruani, Giampiero

    2002-01-01

    A new approach to the analysis of the internal phonons of tris(quinolin-8-olato) aluminum(III) is presented, which enlightens the role played by the ligands in determining the vibrational properties of the organometallic compound and evidences the importance of the contributions arising from the coupling terms among the three quinolinato fragments. An accurate exam of the normal modes of the meridianal isomer evidences the role of the interactions among the fragments in the vibrational dynamics of the ground state. Due to the special attention paid to the quinolinato fragments, a preliminary investigation on the vibrational properties of 8-hydroxyquinoline, taken as a model fragment, was also performed. The vibrational properties of the polymorph species β of the organometallic molecule were obtained refining the calculated frequencies, the dipole moment derivative matrix, and the polarizability derivative tensor derived by the hybrid density functional B3LYP/6-31G* comparing with the frequencies and intensities recorded by the infrared and the Raman spectroscopies performed on a polycrystalline sample. One thus obtains the most accurate intramolecular force constants up to date for the meridianal isomer in a crystalline phase.

  12. Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma

    SciTech Connect

    Safran, Howard . E-mail: hsafran@lifespan.org; Di Petrillo, Thomas; Akerman, Paul; Ng, Thomas; Evans, Devon; Steinhoff, Margaret; Benton, David; Purviance, John; Goldstein, Lisa; Tantravahi, Umadevi; Kennedy, Teresa R.N.

    2007-02-01

    Purpose: To determine the overall survival for patients with locally advanced, HER2 overexpressing, esophageal adenocarcinoma receiving trastuzumab, paclitaxel, cisplatin, and radiation on a Phase I-II study. Methods and Materials: Patients with adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 overexpression by immunohistochemistry (IHC) were eligible. All patients received cisplatin 25 mg/m{sup 2} and paclitaxel 50 mg/m{sup 2} weekly for 6 weeks with radiation therapy (RT) 50.4 Gy. Patients received trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg. Results: Nineteen patients were entered: 7 (37%) had celiac adenopathy, and 7 (37%) had retroperitoneal, portal adenopathy, or scalene adenopathy. Fourteen of 19 patients (74%) had either 3+ HER2 expression by immunohistochemistry, or an increase in HER2 gene copy number by HER2 gene amplification or high polysomy by fluorescence in situ hybridization. The median survival of all patients was 24 months and the 2-year survival was 50%. Conclusions: Assessment of the effect of trastuzumab in the treatment of patients with esophageal adenocarcinoma overexpressing HER2 is limited by the small number of patients in this study. Overall survival, however, was similar to prior studies without an increase in toxicity. Evaluation of HER2 status should be performed in future trials for patients with adenocarcinoma of the esophagus that investigate therapies targeting the HER family.

  13. Acoustic Detection of Faults and Degradation in a High-Bypass Turbofan Engine during VIPR Phase III Testing

    NASA Technical Reports Server (NTRS)

    Boyle, Devin K.

    2017-01-01

    The Vehicle Integrated Propulsion Research (VIPR) Phase III project was executed at Edwards Air Force Base, California, by the National Aeronautics and Space Administration and several industry, academic, and government partners in the summer of 2015. One of the research objectives was to use external radial acoustic microphone arrays to detect changes in the noise characteristics produced by the research engine during volcanic ash ingestion and seeded fault insertion scenarios involving bleed air valves. Preliminary results indicate the successful acoustic detection of suspected degradation as a result of cumulative exposure to volcanic ash. This detection is shown through progressive changes, particularly in the high-frequency content, as a function of exposure to greater cumulative quantities of ash. Additionally, detection of the simulated failure of the 14th stage stability bleed valve and, to a lesser extent, the station 2.5 stability bleed valve, to their fully-open fail-safe positions was achieved by means of spectral comparisons between nominal (normal valve operation) and seeded fault scenarios.

  14. Ethical issues in pediatric oncology phase I-II trials based on a mother's point of view.

    PubMed

    Oppenheim, D; Geoerger, B; Hartmann, O

    2005-11-01

    Phase I-II trials are developing in Pediatrics and raise many complex relational, psychological and ethical issues. We present and discuss these based on an interview in a pediatric oncology setting, with a mother who accepted that her daughter be included in such trials and who expressed why she accepted with great sensitivity and profoundness. She explained that after many years of inefficient treatments she had lost all her landmarks and was ready to accept any proposition, even those she would have considered unacceptable earlier. She did not know whether there is a limit to what is acceptable. Her only objective was to gain any time possible in order to continue living with her daughter. She found it important that the research doctor be different from the doctor involved in patient care, and that the latter remains the major decision-maker and correspondent: thus the child's best interests take precedence over that of research. Interviews with the psycho-oncologist can help the parents and the doctors gain a better insight into the various aspects, rational and irrational, conscious and unconscious, involved in the proposition to participate in a clinical trial and in the parents' or the child's acceptance or refusal.

  15. Tank vapor sampling and analysis data package for tank 241-C-106 waste retrieval sluicing system process test phase III

    SciTech Connect

    LOCKREM, L.L.

    1999-08-13

    This data package presents sampling data and analytical results from the March 28, 1999, vapor sampling of Hanford Site single-shell tank 241-C-106 during active sluicing. Samples were obtained from the 296-C-006 ventilation system stack and ambient air at several locations. Characterization Project Operations (CPO) was responsible for the collection of all SUMMATM canister samples. The Special Analytical Support (SAS) vapor team was responsible for the collection of all triple sorbent trap (TST), sorbent tube train (STT), polyurethane foam (PUF), and particulate filter samples collected at the 296-C-006 stack. The SAS vapor team used the non-electrical vapor sampling (NEVS) system to collect samples of the air, gases, and vapors from the 296-C-006 stack. The SAS vapor team collected and analyzed these samples for Lockheed Martin Hanford Corporation (LMHC) and Tank Waste Remediation System (TWRS) in accordance with the sampling and analytical requirements specified in the Waste Retrieval Sluicing System Vapor Sampling and Analysis Plan (SAP) for Evaluation of Organic Emissions, Process Test Phase III, HNF-4212, Rev. 0-A, (LMHC, 1999). All samples were stored in a secured Radioactive Materials Area (RMA) until the samples were radiologically released and received by SAS for analysis. The Waste Sampling and Characterization Facility (WSCF) performed the radiological analyses. The samples were received on April 5, 1999.

  16. Phase I-II study of plitidepsin and dacarbazine as first-line therapy for advanced melanoma.

    PubMed

    Plummer, R; Lorigan, P; Brown, E; Zaucha, R; Moiseyenko, V; Demidov, L; Soriano, V; Chmielowska, E; Andrés, R; Kudryavtseva, G; Kahatt, C; Szyldergemajn, S; Extremera, S; de Miguel, B; Cullell-Young, M; Calvert, H

    2013-09-17

    This phase I-II trial compared plitidepsin 1-h infusion alone or combined with dacarbazine (DTIC) 1-h infusion as front-line therapy for advanced melanoma. The recommended dose (RD) for plitidepsin/DTIC was defined in the first stage. In the second stage, patients were randomised to receive single-agent plitidepsin 3.2 mg m(-2) (n = 20) on days 1, 8 and 15 every 4 weeks (q4wk) or plitidepsin 2.4 mg m(-2) on days 1, 8 and 15 q4wk combined with DTIC 800 mg m(-2) q4wk (n = 38). The overall response rate with plitidepsin/DTIC was 21.4%; all responders had normal serum lactate dehydrogenase (LDH) levels and performance status ≤ 1 at baseline. Median progression-free survival (PFS) with plitidepsin/DTIC was 3.3 months in all patients, and 4.3 months in those with baseline normal LDH. No responses occurred with single-agent plitidepsin and median PFS was 1.5 months. Both regimens were well tolerated. Haematological abnormalities were more common and transaminase increases more severe with plitidepsin/DTIC. Treatment-related transaminase increases leading to infusion omission on day 8 were relatively common. No drug-drug pharmacokinetic interactions were found. This plitidepsin/DTIC schedule has antitumour activity and manageable toxicity in advanced melanoma. Further evaluation of plitidepsin 2.4 mg m(-2) fortnightly and DTIC 800 mg m(-2) q4wk is recommended.

  17. Impact of ixekizumab on psoriasis itch severity and other psoriasis symptoms: Results from 3 phase III psoriasis clinical trials.

    PubMed

    Kimball, Alexandra B; Luger, Thomas; Gottlieb, Alice; Puig, Luis; Kaufmann, Roland; Nikaï, Enkeleida; Zhu, Baojin; Edson-Heredia, Emily; Carlier, Hilde; Lin, Chen-Yen; Goldblum, Orin; Yosipovitch, Gil

    2016-12-01

    Itch is a prevalent symptom of psoriasis that impacts quality of life. We sought to describe improvements in itch severity, skin pain, and bothersomeness of skin appearance caused by psoriasis among patients who received ixekizumab, etanercept, or placebo in three 12-week, phase III clinical trials (UNCOVER-1, -2, and -3). The itch numeric rating scale evaluated psoriasis itch severity in all 3 trials. Skin pain was assessed by skin pain visual analog scale. Bothersomeness because of redness/discoloration, thickness, and scaling/flaking was assessed with the Psoriasis Skin Appearance Bothersomeness instrument. Psoriasis skin appearance bothersomeness and skin pain were assessed at baseline and week 12; itch numeric rating scale score was assessed at baseline and weeks 1, 2, 4, 8, and 12. Patients who received ixekizumab demonstrated statistically significant improvements (P < .001) in itch severity, reduction in skin pain, and degree of bothersomeness compared with those who received etanercept or placebo. Clinically meaningful improvements in itch severity were achieved as early as week 1. Longer-term evaluations of psoriasis symptom improvement with ixekizumab treatment are needed. After treatment with ixekizumab, patients reported fast, significant, and clinically meaningful improvements in itch severity and other psoriasis-related symptoms such as skin pain and skin appearance bothersomeness. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  18. Analysis and reporting of sex differences in phase III medical device clinical trials-how are we doing?

    PubMed

    Nolan, Martha R; Nguyen, Thuy-Linh

    2013-05-01

    Over the past decade, the scientific community has begun to recognize the importance of biological sex differences in disease pathology, diagnosis, prevention, and treatment; however, the practice of sex-specific analysis and reporting is not integrated as standard practice by either our federal health agencies or by major medical journals. Despite the reforms of 20 years ago and the general inclusion of women in drug clinical trials, we have yet to see data routinely analyzed and reported by sex. Major journals are not requiring it, and large, publicly available datasets, such as ClinicalTrials.gov , are not systematically collecting and pointing to it. However, federal health databases and medical journals have the potential to impact progress in sex-specific analysis and reporting. We conducted a search on ClinicalTrials.gov for phase III device clinical trials and assessed their practice of sex differences evaluation. Reporting of clinical trial results by sex will maximize scientific value of research investments, significantly impact clinical decision-making, and transform medical care.

  19. Genetic epidemiology of dengue viruses in phase III trials of the CYD tetravalent dengue vaccine and implications for efficacy.

    PubMed

    Rabaa, Maia A; Girerd-Chambaz, Yves; Duong Thi Hue, Kien; Vu Tuan, Trung; Wills, Bridget; Bonaparte, Matthew; van der Vliet, Diane; Langevin, Edith; Cortes, Margarita; Zambrano, Betzana; Dunod, Corinne; Wartel-Tram, Anh; Jackson, Nicholas; Simmons, Cameron P

    2017-09-05

    This study defined the genetic epidemiology of dengue viruses (DENV) in two pivotal phase III trials of the tetravalent dengue vaccine, CYD-TDV, and thereby enabled virus genotype-specific estimates of vaccine efficacy (VE). Envelope gene sequences (n = 661) from 11 DENV genotypes in 10 endemic countries provided a contemporaneous global snapshot of DENV population genetics and revealed high amino acid identity between the E genes of vaccine strains and wild-type viruses from trial participants, including at epitope sites targeted by virus neutralising human monoclonal antibodies. Post-hoc analysis of all CYD14/15 trial participants revealed a statistically significant genotype-level VE association within DENV-4, where efficacy was lowest against genotype I. In subgroup analysis of trial participants age 9-16 years, VE estimates appeared more balanced within each serotype, suggesting that genotype-level heterogeneity may be limited in older children. Post-licensure surveillance is needed to monitor vaccine performance against the backdrop of DENV sequence diversity and evolution.

  20. Lessons learned from the development of oral calcitonin: the first tablet formulation of a protein in phase III clinical trials.

    PubMed

    Karsdal, M A; Henriksen, K; Bay-Jensen, A C; Molloy, B; Arnold, M; John, M R; Byrjalsen, I; Azria, M; Riis, B J; Qvist, P; Christiansen, C

    2011-04-01

    Oral delivery of proteins has been hampered by an array of difficulties. However, promising novel oral delivery systems have been developed. 5-CNAC, formulated with the peptide salmon calcitonin, is in phase III clinical trials for the treatment of osteoporosis or osteoarthritis and could become the first marketed oral peptide. This article reviews key findings and implications from studies undertaken to date with this oral formulation. Findings include these: (1) the optimal calcitonin tablet dose is 0.8 mg; (2) 0.8 mg of oral calcitonin is rapidly absorbed, reaching maximum concentration in 15 to 30 minutes, and is eliminated from plasma with a short half-life-9 to 15 minutes; (3) the 0.8-mg tablet is more highly absorbed than the marketed nasal formulation, with biomarker levels indicating significantly greater efficacy in suppression of bone resorption; (4) drug absorption is increased with dosing at least 10 minutes before a meal rather than postprandially and also with 50 mL of water; (5) the optimal timing of dosing for osteoporosis therapy is in the evening to mitigate the circadian peak in bone resorption; and (6) the oral formulations of synthetic and recombinant calcitonin have similar pharmacokinetic and pharmacodynamic properties. These key findings may aid researchers in the development of other oral formulations.

  1. Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial.

    PubMed

    de Lima, M; McMannis, J; Gee, A; Komanduri, K; Couriel, D; Andersson, B S; Hosing, C; Khouri, I; Jones, R; Champlin, R; Karandish, S; Sadeghi, T; Peled, T; Grynspan, F; Daniely, Y; Nagler, A; Shpall, E J

    2008-05-01

    The copper chelator tetraethylenepentamine (TEPA; StemEx) was shown to attenuate the differentiation of ex vivo cultured hematopoietic cells resulting in preferential expansion of early progenitors. A phase I/II trial was performed to test the feasibility and safety of transplantation of CD133+ cord blood (CB) hematopoietic progenitors cultured in media containing stem cell factor, FLT-3 ligand, interleukin-6, thrombopoietin and TEPA. Ten patients with advanced hematological malignancies were transplanted with a CB unit originally frozen in two fractions. The smaller fraction was cultured ex vivo for 21 days and transplanted 24 h after infusion of the larger unmanipulated fraction. All but two units contained <2 x 10(7) total nucleated cells (TNCs) per kilogram pre-expansion. All donor-recipient pairs were mismatched for one or two HLA loci. Nine patients were beyond first remission; median age and weight were 21 years and 68.5 kg. The average TNCs fold expansion was 219 (range, 2-620). Mean increase of CD34+ cell count was 6 (over the CD34+ cell content in the entire unit). Despite the low TNCs per kilogram infused (median=1.8 x 10(7)/kg), nine patients engrafted. Median time to neutrophil and platelet engraftment was 30 (range, 16-46) and 48 (range, 35-105) days. There were no cases of grades 3-4 acute graft-versus-host disease (GVHD) and 100-day survival was 90%. This strategy is feasible.

  2. A phase III randomised controlled trial of single-dose triple therapy in COPD: the IMPACT protocol.

    PubMed

    Pascoe, Steven J; Lipson, David A; Locantore, Nicholas; Barnacle, Helen; Brealey, Noushin; Mohindra, Rajat; Dransfield, Mark T; Pavord, Ian; Barnes, Neil

    2016-08-01

    Patients with symptomatic advanced chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations are particularly at risk of poor outcomes and present a significant burden on healthcare systems. The relative merits of treating with different inhaled combination therapies e.g. inhaled corticosteroids (ICS)/long-acting β2-agonist (LABA), LABA/long-acting muscarinic antagonists (LAMA), ICS/LABA/LAMA, in this patient group are poorly understood, as is reflected in current guidelines. The InforMing the PAthway of COPD Treatment (IMPACT) study will evaluate the efficacy and safety of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus FF/VI or UMEC/VI over a 52-week treatment period. The study has been designed with a focus on understanding the comparative merits of each treatment modality in different phenotypes/endotypes.This is a phase III, randomised, double-blind, three-arm, parallel-group, global multicentre study comparing the rate of moderate and severe exacerbations between FF/UMEC/VI and FF/VI or UMEC/VI over a 52-week treatment period. The study aims to recruit 10 000 patients from approximately 1070 centres. Eligible patients are aged ≥40 years, with symptomatic advanced COPD (Global initiative for chronic Obstructive Lung Disease (GOLD) group D) and an exacerbation in the previous 12 months.The first patients were recruited to the IMPACT study (ClinicalTrials.gov: NCT02164513) in June 2014 and the anticipated completion date is July 2017.

  3. Flexible selection of a single treatment incorporating short-term endpoint information in a phase II/III clinical trial.

    PubMed

    Stallard, Nigel; Kunz, Cornelia Ursula; Todd, Susan; Parsons, Nicholas; Friede, Tim

    2015-10-15

    Seamless phase II/III clinical trials in which an experimental treatment is selected at an interim analysis have been the focus of much recent research interest. Many of the methods proposed are based on the group sequential approach. This paper considers designs of this type in which the treatment selection can be based on short-term endpoint information for more patients than have primary endpoint data available. We show that in such a case, the familywise type I error rate may be inflated if previously proposed group sequential methods are used and the treatment selection rule is not specified in advance. A method is proposed to avoid this inflation by considering the treatment selection that maximises the conditional error given the data available at the interim analysis. A simulation study is reported that illustrates the type I error rate inflation and compares the power of the new approach with two other methods: a combination testing approach and a group sequential method that does not use the short-term endpoint data, both of which also strongly control the type I error rate. The new method is also illustrated through application to a study in Alzheimer's disease. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

  4. Ovarian Transcriptome Analysis of Portunus trituberculatus Provides Insights into Genes Expressed during Phase III and IV Development

    PubMed Central

    Han, Tao; Liu, Tao; Wang, Chunlin; Xiao, Jia; Mu, Changkao; Li, Ronghua; Yu, Fangping; Shi, Huilai

    2015-01-01

    Enhancing the production of aquatic animals is crucial for fishery management and aquaculture applications. Ovaries are specialized tissues that play critical roles in producing oocytes and hormones. Significant biochemical changes take place during the sexual maturation of Portunus trituberculatus, but the genetics of this process has not been extensively studied. Transcriptome sequencing can be used to determine gene expression changes within specific periods. In the current study, we used transcriptome sequencing to produce a comprehensive transcript dataset for the ovarian development of P. trituberculatus. Approximately 100 million sequencing reads were generated, and 126,075 transcripts were assembled. Functional annotation of the obtained transcripts revealed important pathways in ovarian development, such as those involving the vitellogenin gene. Also, we performed deep sequencing of ovaries in phases III and IV of sexual maturation in P. trituberculatus. Differential analysis of gene expression identified 506 significantly differentially expressed genes, which belong to 20 pathway, transporters, development, transcription factors, metabolism of other amino acids, carbohydrate and lipid, solute carrier family members, and enzymes. Taken together, our study provides the first comprehensive transcriptomic resource for P. trituberculatus ovaries, which will strengthen understanding of the molecular mechanisms underlying the sexual maturation process and advance molecular nutritional studies of P. trituberculatus. PMID:26431399

  5. Conversion From Twice-Daily Tacrolimus to Once-Daily Extended Release Tacrolimus (LCPT): The Phase III Randomized MELT Trial

    PubMed Central

    Bunnapradist, S; Ciechanowski, K; West-Thielke, P; Mulgaonkar, S; Rostaing, L; Vasudev, B; Budde, K

    2013-01-01

    Phase III noninferiority trial examining efficacy and safety of converting stable renal transplant recipients from twice-daily tacrolimus to a novel extended-release once-daily tacrolimus formulation (LCPT) with a controlled agglomeration technology. Controls maintained tacrolimus twice daily. The primary efficacy endpoint was proportion of patients with efficacy failures (death, graft failure, locally read biopsy-proven acute rejection [BPAR], or loss to follow-up) within 12 months. Starting LCPT dose was 30% lower (15% for blacks) than preconversion tacrolimus dose; target trough levels were 4–15 ng/mL. A total of 326 patients were randomized; the mITT population (n = 162 each group) was similar demographically in the two groups. Mean daily dose of LCPT was significantly (p < 0.0001) lower than preconversion tacrolimus dose at each visit; mean trough levels between groups were similar. There were four efficacy failures in each group; safety outcomes were similar between groups. Frequency of premature study drug discontinuation was LCPT: 12% versus tacrolimus twice daily: 5% (p = 0.028). LCPT demonstrated noninferiority to tacrolimus twice daily in efficacy failure rates. LCPT may offer a safe and effective alternative for converting patients to a once-daily formulation. Compared to currently available tacrolimus formulation, LCPT requires lower doses to achieve target trough levels. PMID:23279614

  6. Intravenous amifostine during chemoradiotherapy for head-and-neck cancer: A randomized placebo-controlled phase III study

    SciTech Connect

    Buentzel, Jens . E-mail: jens.buentzel@shk-ndh.de; Micke, Oliver; Adamietz, Irenaus A.; Monnier, Alain; Glatzel, Michael; Vries, Alexander de

    2006-03-01

    Purpose: Clinical trials demonstrated the efficacy and safety of intravenous (i.v.) or subcutaneous (s.c.) amifostine for reducing xerostomia and mucositis after radiotherapy or radiochemotherapy for head-and-neck cancer. This randomized, double-blinded, placebo-controlled, phase III study evaluated the efficacy and safety of i.v. amifostine during radiochemotherapy for head-and-neck cancer. Methods and Materials: Patients from European and American study centers received i.v. amifostine 300 mg/m{sup 2} (n = 67) or placebo (n = 65) before carboplatin 70 mg/m{sup 2} and radiotherapy on Days 1 to 5 and 21 to 25, and i.v. amifostine 200 mg/m{sup 2} or placebo before radiotherapy on other days. Results: Toxicity incidences were (amifostine, placebo, p value): Grade 2 or higher acute xerostomia (39%, 34%, 0.715), Grade 3 or higher acute mucositis (39%, 22%, 0.055), Grade 2 or higher late xerostomia (37%, 24%, 0.235), and Grade 3 or higher treatment-related adverse events (42%, 20%, 0.008). One-year rates of locoregional failure, progression-free survival, and overall survival were not significantly different between treatments. Conclusions: The used amifostine doses were not able to reduce the toxicity of simultaneous radiochemotherapy for head-and-neck cancer. The safety of amifostine and the lack of tumor protection were consistent with previous studies.

  7. High intensity focused ultrasound (HIFU) treatment of BPH: results of a multi-center phase III study

    NASA Astrophysics Data System (ADS)

    Sanghvi, N.; Gardner, T.; Koch, M.; Bihrle, R.; Foster, R.; Resnick, M.; Seftel, A.; Grunberger, I.; Stiedle, C.; Corchan, J.

    2003-04-01

    The five centers phase III trial was to show that HIFU can treat prostate tissue thermally for symptomatic relief of BPH and improve flow rates. At five sites, 68 BPH patients were treated with the Sonablate device (Focus Surgery, Inc. Indianapolis, IN). A urethral Foley catheter was inserted into the urethra to aid in positioning and was kept in-situ during the treatment. A cooling device was used to cool the rectal wall. The patients returned home within a few hours after the procedure. The Foley catheter was kept electively to avoid any incidence of acute urinary retention following the therapy. The catheter was removed after 4-5 days. The average treatment time was 38 minutes. The patients were treated without pain, blood loss or complications. At 90 days post treatment, average Qmax and AUA Symptom Scores improved from 8.7 ml/s to 12.66 ml/s (48%) and 23.06 to 11.62 (52%), respectively. Significant prostate tissue changes took place before and after the treatment. 80% of the patients had cavity formation at the site of treatment at the bladder neck and prostate. Nonsurgical HIFU therapy is safe and effective for providing symptomatic relief of BPH symptoms and the treatment can be performed as an outpatient procedure.

  8. Phase I/II Trial Evaluating Carbon Ion Radiotherapy for Salvaging Treatment of Locally Recurrent Nasopharyngeal Carcinoma

    PubMed Central

    Kong, Lin; Hu, Jiyi; Guan, Xiyin; Gao, Jing; Lu, Rong; Lu, Jiade J.

    2016-01-01

    Background: Radiation therapy is the mainstay strategy for the treatment of nasopharyngeal cancer (NPC). Intensity-modulated X-ray therapy (IMXT) alone is the current standard for stage I and II NPC. For stage III and IV A/B diseases, concurrent chemotherapy should be provided in addition to IMXT. However, optimal treatment for locally recurrent NPC after previous definitive dose of radiotherapy is lacking. Various techniques including brachytherapy, IMXT, stereotactic radiosurgery or radiotherapy (SRS or SBRT) have been used in the management of locally recurrent NPC. Due to the inherent limitation of these techniques, i.e., limited range of irradiation or over-irradiation to surrounding normal tissues, moderate efficacy has been observed at the cost of severe toxicities. Carbon ion radiotherapy (CIRT) offers potential physical and biological advantages over photon and proton radiotherapy. Due to the inverted dose profile of particle beams and their greater energy deposition within the Bragg peak, precise dose delivery to the target volume(s) without exposing the surrounding organs at risk to extra doses is possible. In addition, CIRT provides an increased relative biological effectiveness (RBE) as compared to photon and proton radiotherapy. Such advantages may translate to improved outcomes after irradiation in terms of disease control in radio-resistant and previously treated, recurrent malignancies. It is therefore reasonable to postulate that recurrent NPC after high-dose radiotherapy could be more resistant to re-irradiation using photons. Reports on the treatment of radio-resistant malignancies in the head and neck region such as melanoma, sarcoma, and adenoid cystic carcinoma (ACC) have demonstrated superior local control rates from CIRT as compared to photon irradiation. Thus patients with recurrent NPC are likely to benefit from the enhanced biological effectiveness of carbon ions. As effective retreatment strategy is lacking for locally recurrent NPC

  9. Phase I/II Trial Evaluating Carbon Ion Radiotherapy for Salvaging Treatment of Locally Recurrent Nasopharyngeal Carcinoma.

    PubMed

    Kong, Lin; Hu, Jiyi; Guan, Xiyin; Gao, Jing; Lu, Rong; Lu, Jiade J

    2016-01-01

    Radiation therapy is the mainstay strategy for the treatment of nasopharyngeal cancer (NPC). Intensity-modulated X-ray therapy (IMXT) alone is the current standard for stage I and II NPC. For stage III and IV A/B diseases, concurrent chemotherapy should be provided in addition to IMXT. However, optimal treatment for locally recurrent NPC after previous definitive dose of radiotherapy is lacking. Various techniques including brachytherapy, IMXT, stereotactic radiosurgery or radiotherapy (SRS or SBRT) have been used in the management of locally recurrent NPC. Due to the inherent limitation of these techniques, i.e., limited range of irradiation or over-irradiation to surrounding normal tissues, moderate efficacy has been observed at the cost of severe toxicities. Carbon ion radiotherapy (CIRT) offers potential physical and biological advantages over photon and proton radiotherapy. Due to the inverted dose profile of particle beams and their greater energy deposition within the Bragg peak, precise dose delivery to the target volume(s) without exposing the surrounding organs at risk to extra doses is possible. In addition, CIRT provides an increased relative biological effectiveness (RBE) as compared to photon and proton radiotherapy. Such advantages may translate to improved outcomes after irradiation in terms of disease control in radio-resistant and previously treated, recurrent malignancies. It is therefore reasonable to postulate that recurrent NPC after high-dose radiotherapy could be more resistant to re-irradiation using photons. Reports on the treatment of radio-resistant malignancies in the head and neck region such as melanoma, sarcoma, and adenoid cystic carcinoma (ACC) have demonstrated superior local control rates from CIRT as compared to photon irradiation. Thus patients with recurrent NPC are likely to benefit from the enhanced biological effectiveness of carbon ions. As effective retreatment strategy is lacking for locally recurrent NPC, carbon ion

  10. Epitaxial growth of III-V nitrides and phase separation and ordering in indium gallium nitride alloys

    NASA Astrophysics Data System (ADS)

    Doppalapudi, Dharanipal

    The family of III-V nitrides are wide band-gap semiconductors with a broad range of opto-electronic applications in LEDs, laser diodes, UV detectors as well as high temperature/high frequency devices. Due to the lack of good quality native substrates, GaN is grown on foreign substrates that have a lattice and thermal mismatch with GaN. This results in a material with a high density of defects, which in turn adversely affects the opto-electronic properties of the epilayer. In this study, GaN films were epitaxially grown on various substrates (C-plane sapphire, A-plane sapphire, SiC and ZnO) by molecular beam epitaxy. Additionally, GaN homoepitaxy onto laterally overgrown thick GaN substrates was investigated. It was demonstrated that the polarity of the GaN film plays a major role in determining the properties of the films. The growth parameters were optimized to eliminate inversion domain boundaries, which result in domains of opposite polarity in the GaN lattice. For growth on A-plane sapphire, it was found that substrate nitridation and low temperature buffer deposition are critical in order to obtain good epitaxial growth, in spite of the relatively small mismatch between the film and substrate. A crystallographic model was developed to explain this observation. By optimizing growth parameters, GaN films with excellent structural, transport, optical and device properties were grown. The second part of this research involves growth of ternary alloys and superlattice structures, which are essential in the fabrication of many devices. It was found that the InN-GaN pseudo-binary system is not homogeneous over the entire composition range. Due to the mismatch between the tetrahedral radii of GaN and InN, InGaN alloys exhibited phase separation and long-range atomic ordering. Investigations of InxGa1-xN films grown over a wide range of compositions by XRD and TEM showed that the predominant strain relieving mechanism was phase separation in films with x > 0.2, and

  11. Observation Targeting for the Tehachapi Pass and Mid-Columbia Basin: WindSENSE Phase III Project Summary Report

    SciTech Connect

    Hanley, D

    2011-10-22

    The overall goal of this multi-phased research project known as WindSENSE is to develop an observation system deployment strategy that would improve wind power generation forecasts. The objective of the deployment strategy is to produce the maximum benefit for 1- to 6-hour ahead forecasts of wind speed at hub-height ({approx}80 m). In Phase III of the project, the focus was on the Mid-Columbia Basin region which encompasses the Bonneville Power Administration (BPA) wind generation area shown in Figure 1 that includes Klondike, Stateline, and Hopkins Ridge wind plants. The typical hub height of a wind turbine is approximately 80-m above ground level (AGL). So it would seem that building meteorological towers in the region upwind of a wind generation facility would provide data necessary to improve the short-term forecasts for the 80-m AGL wind speed. However, this additional meteorological information typically does not significantly improve the accuracy of the 0- to 6-hour ahead wind power forecasts because processes controlling wind variability change from day-to-day and, at times, from hour-to-hour. It is also important to note that some processes causing significant changes in wind power production function principally in the vertical direction. These processes will not be detected by meteorological towers at off-site locations. For these reasons, it is quite challenging to determine the best type of sensors and deployment locations. To address the measurement deployment problem, Ensemble Sensitivity Analysis (ESA) was applied in the Phase I portion of the WindSENSE project. The ESA approach was initially designed to produce spatial fields that depict the sensitivity of a forecast metric to a set of prior state variables selected by the user. The best combination of variables and locations to improve the forecast was determined using the Multiple Observation Optimization Algorithm (MOOA) developed in Phase I. In Zack et al. (2010a), the ESA-MOOA approach was

  12. NOVEL CONCEPTS RESEARCH IN GEOLOGIC STORAGE OF CO2 PHASE III THE OHIO RIVER VALLEY CO2 STORAGE PROJECT

    SciTech Connect

    Neeraj Gupta

    2005-05-26

    As part of the Department of Energy's (DOE) initiation on developing new technologies for storage of carbon dioxide in geologic reservoir, Battelle has been awarded a project to investigate the feasibility of CO{sub 2} sequestration in the deep saline reservoirs in the Ohio River Valley region. This project is the Phase III of Battelle's work under the Novel Concepts in Greenhouse Gas Management grant. The main objective of the project is to demonstrate that CO{sub 2} sequestration in deep formations is feasible from engineering and economic perspectives, as well as being an inherently safe practice and one that will be acceptable to the public. In addition, the project is designed to evaluate the geology of deep formations in the Ohio River Valley region in general and in the vicinity of AEP's Mountaineer Power Plant in particular, in order to determine their potential use for conducting a long-term test of CO{sub 2} disposal in deep saline formations and potentially in nearby deep coal seams. The current technical progress report summarizes activities completed for the January through March 2005 period of the project. As discussed in the report, the technical activities focused on development of injection well design, preparing a Class V Underground Injection Control permit, assessment of monitoring technologies, analysis of coal samples for testing the capture system by Mitsubishi Heavy Industry, and presentation of project progress at several venues. In addition, related work has progressed on a collaborative risk assessment project with Japan research institute CREIPI and technical application for the Midwest Regional Carbon Sequestration Partnership.

  13. Difluprednate 0.05% Versus Prednisolone Acetate 1% for Endogenous Anterior Uveitis: A Phase III, Multicenter, Randomized Study

    PubMed Central

    Sheppard, John D.; Toyos, Melissa M.; Kempen, John H.; Kaur, Paramjit; Foster, C. Stephen

    2014-01-01

    Purpose. Endogenous anterior uveitis (AU), when untreated, may lead to vision loss. This study compared the safety and efficacy of difluprednate versus prednisolone acetate for the treatment of this condition. Methods. This phase III, double-masked, noninferiority study randomized patients with mild to moderate endogenous AU to receive difluprednate 0.05% (n = 56) four times daily, alternating with vehicle four times daily, or prednisolone acetate 1% (n = 54) eight times daily. The 14-day treatment period was followed by a 14-day dose-tapering period and a 14-day observation period. The primary efficacy end point was change in anterior chamber cell grade (range, 0 for ≤1 cell to 4 for >50 cells) from baseline to day 14. Results. At day 14, the mean change in anterior chamber cell grade with difluprednate was noninferior to that with prednisolone acetate (−2.2 vs. −2.0, P = 0.16). The proportions of difluprednate-treated patients versus prednisolone acetate–treated patients demonstrating complete clearing of anterior chamber cells at day 3 were 13.0% vs. 2.1% (P = 0.046) and at day 21 were 73.9% vs. 63.8% (P = 0.013). A significant between-group difference in the mean IOP increase was seen at day 3 (2.5 mm Hg for difluprednate-treated patients and 0.1 mm Hg for prednisolone acetate–treated patients, P = 0.0013) but not at other time points. The mean IOP values in both groups remained less than 21 mm Hg throughout the study. Conclusions. Difluprednate 0.05% four times daily is well tolerated and is noninferior to prednisolone acetate 1% eight times daily for the treatment of endogenous AU. (ClinicalTrials.gov number, NCT01201798.) PMID:24677110

  14. Evaluation of Angiopoietin-2 as a biomarker in gastric cancer: results from the randomised phase III AVAGAST trial

    PubMed Central

    Hacker, Ulrich T; Escalona-Espinosa, Laura; Consalvo, Nicola; Goede, Valentin; Schiffmann, Lars; Scherer, Stefan J; Hedge, Priti; Van Cutsem, Eric; Coutelle, Oliver; Büning, Hildegard

    2016-01-01

    Background: In the phase III AVAGAST trial, the addition of bevacizumab to chemotherapy improved progression-free survival (PFS) but not overall survival (OS) in patients with advanced gastric cancer. We studied the role of Angiopoietin-2 (Ang-2), a key driver of tumour angiogenesis, metastasis and resistance to antiangiogenic treatment, as a biomarker. Methods: Previously untreated, advanced gastric cancer patients were randomly assigned to receive bevacizumab (n=387) or placebo (n=387) in combination with chemotherapy. Plasma collected at baseline and at progression was analysed by ELISA. The role of Ang-2 as a prognostic and a predictive biomarker of bevacizumab efficacy was studied using a Cox proportional hazards model. Logistic regression analysis was applied for correlations with metastasis. Results: Median baseline plasma Ang-2 levels were lower in Asian (2143 pg ml−1) vs non-Asian patients (3193 pg ml−1), P<0.0001. Baseline plasma Ang-2 was identified as an independent prognostic marker for OS but did not predict bevacizumab efficacy alone or in combination with baseline VEGF. Baseline plasma Ang-2 correlated with the frequency of liver metastasis (LM) at any time: Odds ratio per 1000 pg ml−1 increase: 1.19; 95% CI 1.10–1.29; P<0.0001 (non-Asians) and 1.37; 95% CI 1.13–1.64; P=0.0010 (Asians). Conclusions: Baseline plasma Ang-2 is a novel prognostic biomarker for OS in advanced gastric cancer strongly associated with LM. Differences in Ang-2 mediated vascular response may, in part, account for outcome differences between Asian and non-Asian patients; however, data have to be further validated. Ang-2 is a promising drug target in gastric cancer. PMID:27031850

  15. Bitopertin in Negative Symptoms of Schizophrenia-Results From the Phase III FlashLyte and DayLyte Studies.

    PubMed

    Bugarski-Kirola, Dragana; Blaettler, Thomas; Arango, Celso; Fleischhacker, Wolfgang W; Garibaldi, George; Wang, Alice; Dixon, Mark; Bressan, Rodrigo A; Nasrallah, Henry; Lawrie, Stephen; Napieralski, Julie; Ochi-Lohmann, Tania; Reid, Carol; Marder, Stephen R

    2017-07-01

    There is currently no standard of care for treatment of negative symptoms of schizophrenia, although some previous results with glutamatergic agonists have been promising. Three (SunLyte [WN25308], DayLyte [WN25309], and FlashLyte [NN25310]) phase III, multicenter, randomized, 24-week, double-blind, parallel-group, placebo-controlled studies evaluated the efficacy and safety of adjunctive bitopertin in stable patients with persistent predominant negative symptoms of schizophrenia treated with antipsychotics. SunLyte met the prespecified criteria for lack of efficacy and was declared futile. Key inclusion criteria were age ≥18 years, DSM-IV-TR diagnosis of schizophrenia, score ≥40 on the sum of the 14 Positive and Negative Syndrome Scale negative symptoms and disorganized thought factors, unaltered antipsychotic treatment, and clinical stability. Following a 4-week prospective stabilization period, patients were randomly assigned 1:1:1 to bitopertin (5 mg and 10 mg [DayLyte] and 10 mg and 20 mg [FlashLyte]) or placebo once daily for 24 weeks. The primary efficacy end point was mean change from baseline in Positive and Negative Syndrome Scale negative symptom factor score at week 24. The intent-to-treat population in DayLyte and FlashLyte included 605 and 594 patients, respectively. At week 24, mean change from baseline showed improvement in all treatment arms but no statistically significant separation from placebo in Positive and Negative Syndrome Scale negative symptom factor score and all other end points. Bitopertin was well tolerated. These studies provide no evidence for superior efficacy of adjunctive bitopertin in any of the doses tested over placebo in patients with persistent predominant negative symptoms of schizophrenia. Copyright © 2017. Published by Elsevier Inc.

  16. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer.

    PubMed

    Oettle, H; Richards, D; Ramanathan, R K; van Laethem, J L; Peeters, M; Fuchs, M; Zimmermann, A; John, W; Von Hoff, D; Arning, M; Kindler, H L

    2005-10-01

    This randomized phase III study compared the overall survival (OS) of pemetrexed plus gemcitabine (PG) versus standard gemcitabine (G) in patients with advanced pancreatic cancer. Patients with unresectable locally advanced or metastatic pancreatic cancer and no prior systemic therapy (including 5-fluorouracil as a radiosensitizer) were randomized to receive either 1,250 mg/m(2) gemcitabine on days 1 and 8 plus pemetrexed 500 mg/m(2) after gemcitabine on day 8 (PG arm) of each 21-day cycle, or gemcitabine 1,000 mg/m(2) on days 1, 8 and 15 of each 28-day cycle (G arm). Five hundred and sixty-five patients with well-balanced baseline characteristics were randomly assigned (283 PG, 282 G). OS was not improved on the PG arm (6.2 months) compared with the G arm (6.3 months) (P=0.8477). Progression-free survival (3.9 versus 3.3 months; P=0.1109) and time to treatment failure (3 versus 2.2 months; P=0.2680) results were similar. Tumor response rate (14.8% versus 7.1%; P=0.004) was significantly better on the PG arm. Grade 3 or 4 neutropenia (45.1% versus 12.8%), thrombocytopenia (17.9% versus 6.2%), anemia (13.9% versus 2.9%), febrile neutropenia (9.9% versus 0.4%; all P <0.001) and fatigue (15% versus 6.6%; P=0.002) were significantly more common on the PG arm. Four treatment-related deaths occurred on the PG arm and none in the G arm. Pemetrexed plus gemcitabine therapy did not improve OS. Single-agent gemcitabine remains the standard of care for advanced pancreatic cancer.

  17. A New Viscous Cysteamine Eye Drops Treatment for Ophthalmic Cystinosis: An Open-Label Randomized Comparative Phase III Pivotal Study.

    PubMed

    Liang, Hong; Labbé, Antoine; Le Mouhaër, Jeannie; Plisson, Céline; Baudouin, Christophe

    2017-04-01

    The purpose of this study was to evaluate the efficacy of new viscous cysteamine hydrochloride (CH) eye drops (vCH 0.55%) compared with standard CH 0.10% drops treatment. This was an open-label, phase III, randomized, two-arm multicenter trial conducted at two centers in France. Cystinosis patients ≥2 years old were randomized 1:1 to receive eye drops, four times per day for 90 days in both eyes. We compared the superiority in reducing corneal cystine crystal density as assessed by in vivo confocal microscopy (IVCM). We also evaluated photophobia, corneal cystine crystal scores (CCCSs), and cystine crystal depth measured by optical coherence tomography. Safety objectives were to assess adverse events (AEs), local adverse drug reactions, and ocular safety parameters. We included 15 patients with vCH 0.55% and 16 patients with CH 0.10% drops for 90 days. The mean absolute change in IVCM total score at day 90 in the vCH 0.55% drops group (-4.6 ± 3.1) was significantly greater than and superior to the mean absolute change in the CH 0.10% drops group (-0.46 ± 3.38; P < 0.0001). Photophobia, CCCS, and corneal cystine crystal depth were significantly more improved in the vCH 0.55% drops group than in the CH 0.10% group. The most frequent local adverse drug reactions in both groups were stinging, burning, redness, and blurred vision. vCH 0.55% was effective in reducing corneal cystine crystal density and superior to treatment with CH 0.10% drops, which offer advantages over hospital pharmacy formulations and is a more preferable and convenient treatment option.

  18. Genetic Predictors of Taxane-induced Neurotoxicity in a SWOG Phase III Intergroup Adjuvant Breast Cancer Treatment Trial (S0221)

    PubMed Central

    Sucheston, Lara E.; Zhao, Hua; Yao, Song; Zirpoli, Gary; Liu, Song; Barlow, William E.; Budd, G. Thomas; Hershman, Dawn L.; Davis, Warren; Ciupak, Gregory L.; Stewart, James A.; Isaacs, Claudine; Hobday, Timothy J.; Salim, Muhammad; Hortobagyi, Gabriel N.; Gralow, Julie R.; Livingston, Robert B.; Albain, Kathy S.; Hayes, Daniel F.; Ambrosone, Christine B.

    2012-01-01

    Purpose We assessed SNPS in the Fanconi Anemia (FA)/BRCA pathway in women being was taxanes for breast cancer in an effort to find a prognostic biomarker for neurological toxicities, which while improve survival remain a debilitating outcome. Patients and Methods We used data and samples (n=888) from SWOG0221, a phase III adjuvant trial of 4 dose/schedules of cyclophosphamide (C), doxorubicin (A) and paclitaxel (T) for high risk breast cancer. The relationship of SNPs in the (FA)/BRCA pathway with risk grade 3/4 neurotoxicities. In a separate cohort we measured the correlation of significant SNPs in this pathway with corresponding gene expression. Results No associations between SNPs in BRCA1 and taxane-induced neuropathy was found. For FANCD2, significant associations between 4 (out of 20) SNPs and neurological toxicities, with risk estimates approaching 2. Two FANCD2 haplotypes were also found to be significantly associated with neurological toxicity, increasing the odds in the overall population 1.8 (95% confidence interval (CI) 1.3–2.5) and 1.7 (95% CI, 1.2–2.4) fold. Although numbers were small, there appeared to be a specific African-American haplotype that was associated with an almost 3-fold increase in risk of neurological toxicity. Expression analyses revealed that significant FANCD2 SNPs were associated with FANCD2 expression levels (p=0.03) Conclusion SNPs in FANCD2, were associated with a 70 to 80% increase in the odds of grade 3/4 neurological toxicities and increased expression of the gene. If replicated, women with these genotypes should be closely monitored for toxicities, and could be targeted for preventive measures or alternative therapeutic approaches. PMID:21766209

  19. Efficacy and tolerability of fesoterodine in men with overactive bladder: a pooled analysis of 2 phase III studies.

    PubMed

    Herschorn, Sender; Jones, J Stephen; Oelke, Matthias; MacDiarmid, Scott; Wang, Joseph T; Guan, Zhonghong

    2010-05-01

    To assess the efficacy, safety, and tolerability of fesoterodine 4 and 8 mg in men with overactive bladder. This was a subanalysis of pooled data from 358 men enrolled in 2 double-blind, placebo-controlled phase III trials. Subjects with frequency and urgency or urgency urinary incontinence (UUI) were randomized to fesoterodine 4 mg, fesoterodine 8 mg, or placebo for 12 weeks. Efficacy endpoints included bladder diary variables and subject-reported treatment response. By week 12, men treated with fesoterodine 4 or 8 mg had significantly greater median percentage improvements in micturition frequency, urgency episodes, and UUI episodes versus placebo and significantly greater percentages reported a treatment response versus placebo. Significant increases in mean voided volume (MVV) per micturition versus placebo occurred with fesoterodine 8 mg only. At week 12, fesoterodine 8 mg was significantly more efficacious than fesoterodine 4 mg in improving UUI episodes and MVV per micturition. The most commonly reported adverse events with fesoterodine 4 and 8 mg were dry mouth (12.5% and 37.7% vs 5.6% with placebo) and constipation (2.5% and 8.8% vs 0.8% with placebo). Symptoms suggestive of urinary retention were reported in 0.8%, 0.8%, and 5.3% of men in the placebo, fesoterodine 4 mg, and fesoterodine 8 mg groups, respectively; only 1 subject, in the fesoterodine 8 mg group, was catheterized. Fesoterodine 4 and 8 mg are generally safe, efficacious, and well tolerated for the treatment of overactive bladder symptoms in men. The 8 mg dose provides additional benefit and allows for treatment individualization. Copyright 2010 Elsevier Inc. All rights reserved.

  20. Evaluation of Angiopoietin-2 as a biomarker in gastric cancer: results from the randomised phase III AVAGAST trial.

    PubMed

    Hacker, Ulrich T; Escalona-Espinosa, Laura; Consalvo, Nicola; Goede, Valentin; Schiffmann, Lars; Scherer, Stefan J; Hedge, Priti; Van Cutsem, Eric; Coutelle, Oliver; Büning, Hildegard

    2016-04-12

    In the phase III AVAGAST trial, the addition of bevacizumab to chemotherapy improved progression-free survival (PFS) but not overall survival (OS) in patients with advanced gastric cancer. We studied the role of Angiopoietin-2 (Ang-2), a key driver of tumour angiogenesis, metastasis and resistance to antiangiogenic treatment, as a biomarker. Previously untreated, advanced gastric cancer patients were randomly assigned to receive bevacizumab (n=387) or placebo (n=387) in combination with chemotherapy. Plasma collected at baseline and at progression was analysed by ELISA. The role of Ang-2 as a prognostic and a predictive biomarker of bevacizumab efficacy was studied using a Cox proportional hazards model. Logistic regression analysis was applied for correlations with metastasis. Median baseline plasma Ang-2 levels were lower in Asian (2143 pg ml(-1)) vs non-Asian patients (3193 pg ml(-1)), P<0.0001. Baseline plasma Ang-2 was identified as an independent prognostic marker for OS but did not predict bevacizumab efficacy alone or in combination with baseline VEGF. Baseline plasma Ang-2 correlated with the frequency of liver metastasis (LM) at any time: Odds ratio per 1000 pg ml(-1) increase: 1.19; 95% CI 1.10-1.29; P<0.0001 (non-Asians) and 1.37; 95% CI 1.13-1.64; P=0.0010 (Asians). Baseline plasma Ang-2 is a novel prognostic biomarker for OS in advanced gastric cancer strongly associated with LM. Differences in Ang-2 mediated vascular response may, in part, account for outcome differences between Asian and non-Asian patients; however, data have to be further validated. Ang-2 is a promising drug target in gastric cancer.

  1. Phase III study of combined chemohormonal therapy in metastatic prostate cancer (ECOG 3882): an Eastern Cooperative Oncology Group study.

    PubMed

    Leaf, Andrea N; Propert, Kathleen; Corcoran, Chris; Catalano, Paul J; Trump, Donald L; Harris, Jules E; Davis, Thomas E

    2003-01-01

    This study, a phase III multicenter randomized trial opened by ECOG in April 1983 and closed in June 1986 was designed to evaluate whether a combination of doxorubicin and an intravenous formulation of diethylstilbestrol diphosphate (DES) was superior to doxorubicin alone in men with hormone refractory prostate cancer. All patients received doxorubicin at a dose of 50 mg/m2 iv every 3 wk either alone or with 1 g DES iv daily for 5 d followed by 1 g iv twice weekly for four cycles (12 wk). The 51 evaluable patients with visceral metastases displayed a significantly increased response rate (27% vs 63%) on the combined therapy arm (p = 0.04). However, the 111 evaluable patients with osseous disease exhibited no difference in response rate between either arm with a p-value of >0.99. Similarly, clinical response rates revealed no difference between the two arms. Cases of cardiac toxicity graded as severe, life threatening, or lethal in the combined therapy arm were 10 times more frequent in the combined-therapy arm than in the doxorubicin-alone group (6.75% compared to 0.7%). This difference was statistically significant (p = 0.0041). All of the cases of superficial and deep venous thrombosis occurred on the combined-therapy arm. There were no other significant differences in the numbers of grade 3 or 4 toxic events. The most common toxicity was hematologic. Failure-free survival duration did reach statistical significance in the combined-therapy group (p = 0.012), although the actual durations were short (2.6-3.2 mo). There was no difference in overall survival between the two groups.

  2. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial.

    PubMed

    Pujade-Lauraine, Eric; Hilpert, Felix; Weber, Béatrice; Reuss, Alexander; Poveda, Andres; Kristensen, Gunnar; Sorio, Roberto; Vergote, Ignace; Witteveen, Petronella; Bamias, Aristotelis; Pereira, Deolinda; Wimberger, Pauline; Oaknin, Ana; Mirza, Mansoor Raza; Follana, Philippe; Bollag, David; Ray-Coquard, Isabelle

    2014-05-01

    In platinum-resistant ovarian cancer (OC), single-agent chemotherapy is standard. Bevacizumab is active alone and in combination. AURELIA is the first randomized phase III trial to our knowledge combining bevacizumab with chemotherapy in platinum-resistant OC. Eligible patients had measurable/assessable OC that had progressed < 6 months after completing platinum-based therapy. Patients with refractory disease, history of bowel obstruction, or > two prior anticancer regimens were ineligible. After investigators selected chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan), patients were randomly assigned to single-agent chemotherapy alone or with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) until progression, unacceptable toxicity, or consent withdrawal. Crossover to single-agent bevacizumab was permitted after progression with chemotherapy alone. The primary end point was progression-free survival (PFS) by RECIST. Secondary end points included objective response rate (ORR), overall survival (OS), safety, and patient-reported outcomes. The PFS hazard ratio (HR) after PFS events in 301 of 361 patients was 0.48 (95% CI, 0.38 to 0.60; unstratified log-rank P < .001). Median PFS was 3.4 months with chemotherapy alone versus 6.7 months with bevacizumab-containing therapy. RECIST ORR was 11.8% versus 27.3%, respectively (P = .001). The OS HR was 0.85 (95% CI, 0.66 to 1.08; P < .174; median OS, 13.3 v 16.6 months, respectively). Grade ≥ 2 hypertension and proteinuria were more common with bevacizumab. GI perforation occurred in 2.2% of bevacizumab-treated patients. Adding bevacizumab to chemotherapy statistically significantly improved PFS and ORR; the OS trend was not significant. No new safety signals were observed.

  3. Predictors of post-treatment relapse to smoking in successful quitters: Pooled data from two phase III varenicline trials

    PubMed Central

    Heffner, Jaimee L.; Lee, Theodore C.; Arteaga, Carmen; Anthenelli, Robert M.

    2010-01-01

    Background Identifying predictors of smoking relapse helps to elucidate the challenges of long-term smoking cessation and provides direction for improved treatment development. Methods In this post hoc data analysis, we examined predictors of relapse from end-of-treatment (week 13) through 1-year follow-up (week 52) for treatment-responding participants who achieved the primary efficacy endpoint of 4-week continuous abstinence (weeks 9–12), during two phase III varenicline trials. Results Of 626 smokers classified as treatment responders for all treatment groups across both trials, 301 (48%) relapsed during follow-up (weeks 13–52). The odds of relapsing were almost 5 times greater (odds ratio [OR]=4.92, 95% confidence interval [CI]: 2.77–8.97; p<.001) for treatment responders who did not initiate continuous abstinence until the final 4 weeks of the treatment period compared with those who initiated continuous abstinence by their quit date. Participants who reported >30 days of abstinence during the year prior to study entry were significantly more likely to relapse than those who reported 0 days of abstinence (OR=2.38, 95% CI: 1.17–5.04; p=.013). Conclusion Results of these analyses suggest that the ability to quit smoking on the initial quit date and maintain abstinence throughout the treatment period is a good prognostic indicator for long-term abstinence. The relationship between post-treatment relapse and longer pretreatment periods of abstinence is counterintuitive, yet not without precedence in the literature. PMID:20071105

  4. Randomized Phase III Clinical Trial of Five Different Arms of Treatment in 332 Patients with Cancer Cachexia

    PubMed Central

    Macciò, Antonio; Madeddu, Clelia; Serpe, Roberto; Massa, Elena; Dessì, Mariele; Panzone, Filomena; Contu, Paolo

    2010-01-01

    Purpose. A phase III, randomized study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia—lean body mass (LBM), resting energy expenditure (REE), and fatigue—and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines. Patients and Methods. Three hundred thirty-two assessable patients with cancer-related anorexia/cachexia syndrome were randomly assigned to one of five treatment arms: arm 1, medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day); arm 2, oral supplementation with eicosapentaenoic acid; arm 3, L-carnitine (4 g/day); arm 4, thalidomide (200 mg/day); and arm 5, a combination of the above. Treatment duration was 4 months. Results. Analysis of variance showed a significant difference between treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5; interleukin (IL)-6 decreased significantly in arm 5 and arm 4; GPS and Eastern Cooperative Oncology Group performance status (ECOG PS) score decreased significantly in arm 5, arm 4, and arm 3. Toxicity was quite negligible, and was comparable between arms. Conclusion. The most effective treatment in terms of all three primary efficacy endpoints and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents. PMID:20156909

  5. Tolerance and Acceptance Results of a Palladium-103 Permanent Breast Seed Implant Phase I/II Study

    SciTech Connect

    Pignol, Jean-Philippe Rakovitch, Eileen; Keller, Brian M.; Sankreacha, Raxa; Chartier, Carole

    2009-04-01

    Purpose: To test, in a prospective Phase I/II trial, a partial breast irradiation technique using a {sup 103}Pd permanent breast seed implant (PBSI) realized in a single 1-h procedure under sedation and local freezing. Methods and Materials: Eligible patients had infiltrating ductal carcinoma {<=}3 cm in diameter, surgical margin {>=}2 mm, no extensive intraductal component, no lymphovascular invasion, and negative lymph nodes. Patients received a permanent seed implant, and a minimal peripheral dose of 90 Gy was prescribed to the clinical target volume, with a margin of 1.5 cm. Results: From May 2004 to April 2007, 67 patients received the PBSI treatment. The procedure was well tolerated, with 17% of patients having significant pain after the procedure. Only 1 patient (1.5%) had an acute skin reaction (Grade 3 according to the National Cancer Institute Common Toxicity Criteria). The rates of acute moist desquamation, erythema, and indurations were 10.4%, 42%, and 27%, respectively. At 1 year the rate of Grade 1 telangiectasia was 14%. The rate of skin reaction decreased from 65% to 28% when skin received less than the 85% isodose. According to a Radiation Therapy Oncology Group questionnaire, 80-90% of patients were very satisfied with their treatment, and the remainder were satisfied. One patient (1.5%) developed an abscess, which resolved after the use of antibiotics. There was no recurrence after a median follow-up of 32 months (range, 11-49 months). Conclusions: The feasibility, safety, and tolerability of PBSI compares favorably with that of external beam and other partial breast irradiation techniques.

  6. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial.

    PubMed

    Knauf, Wolfgang U; Lissitchkov, Toshko; Aldaoud, Ali; Liberati, Anna M; Loscertales, Javier; Herbrecht, Raoul; Juliusson, Gunnar; Postner, Gerhard; Gercheva, Liana; Goranov, Stefan; Becker, Martin; Fricke, Hans-Joerg; Huguet, Francoise; Del Giudice, Ilaria; Klein, Peter; Merkle, Karlheinz; Montillo, Marco

    2012-10-01

    The efficacy of bendamustine versus chlorambucil in a phase III trial of previously untreated patients with Binet stage B/C chronic lymphocytic leukaemia (CLL) was re-evaluated after a median observation time of 54 months in May 2010. Overall survival (OS) was analysed for the first time. At follow-up, investigator-assessed complete response (CR) rate (21·0% vs 10·8%), median progression-free survival (21·2 vs 8·8 months; P < 0·0001; hazard ratio 2·83) and time to next treatment (31·7 vs 10·1 months; P < 0·0001) were improved for bendamustine over chlorambucil. OS was not different between groups for all patients or those ≤65 years, >65 years, responders and non-responders. However, patients with objective response or a CR experienced a significantly longer OS than non-responders or those without a CR. Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78·3% vs 63·6%; P = 0·004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated CLL patients, with the achievement of a CR or objective response appearing to prolong OS. Bendamustine should be considered as a preferred first-line option over chlorambucil for CLL patients ineligible for fludarabine, cyclophosphamide and rituximab. © 2012 Blackwell Publishing Ltd.

  7. Tai Chi as an adjunct physical activity for adults aged 45 years and older enrolled in phase III cardiac rehabilitation.

    PubMed

    Taylor-Piliae, Ruth E; Silva, Edna; Sheremeta, Sharon Peachey

    2012-03-01

    Cardiac rehabilitation improves physical, cognitive and psychosocial functioning, yet services are greatly underutilized with increasing patterns of attrition over time. Tai Chi has been suggested as a possible adjunct to cardiac rehabilitation exercise training. To describe differences in physical, cognitive and psychosocial functioning among adults ≥ 45 years old attending phase III cardiac rehabilitation, who have or have not self-selected Tai Chi exercise as an adjunct physical activity. A cross-sectional design compared subjects attending group-based Wu style Tai Chi classes plus cardiac rehabilitation, with cardiac rehabilitation only. Subjects had a battery of physical and cognitive functioning tests administered to examine aerobic endurance, balance, strength, and flexibility, verbal retrieval/recall, attention, concentration and tracking. Subjects completed a health survey to ascertain cardiac event information, medical history, and psychosocial functioning (i.e. health-related quality of life, stress, depressive symptoms, social support, and Tai Chi self-efficacy). A total of 51 subjects (75% married, 84% college-educated, 96% White/European-American) participated. Subjects were on average 70 (± 8) years old and had attended cardiac rehabilitation for 45 (± 37) months. Approximately 45% (n = 23) attended Tai Chi classes plus cardiac rehabilitation, while 55% (n = 28) attended cardiac rehabilitation only. Subjects attending Tai Chi plus cardiac rehabilitation had better balance, perceived physical health, and Tai Chi self-efficacy compared to those attending cardiac rehabilitation only (p ≤ 0.03). Tai Chi can be easily implemented in any community/cardiac rehabilitation facility, and may offer adults additional options after a cardiac event.

  8. Phase I-II trial of weekly bicalutamide in men with elevated prostate-specific antigen and negative prostate biopsies.

    PubMed

    Zanardi, Silvia; Puntoni, Matteo; Maffezzini, Massimo; Bandelloni, Roberto; Mori, Marco; Argusti, Alessandra; Campodonico, Fabio; Turbino, Laura; Branchi, Daniela; Montironi, Rodolfo; Decensi, Andrea

    2009-04-01

    Men with elevated prostate-specific antigen (PSA) and negative prostate biopsies are at risk for prostate cancer. The antiandrogen bicalutamide has a prolonged half-life, thus potentially allowing an intermittent administration to retain activity while reducing toxicity. We conducted a phase I-II trial of weekly bicalutamide in men with PSA >4 ng/mL and negative biopsies. Eighty subjects were nonrandomly assigned to a three-arm trial to either bicalutamide 50 mg/wk (n = 26) or 100 mg/wk (n = 28) or no treatment (n = 26) for 6 months. Blood samples were obtained at 0, 3, and 6 months, and prostate biopsies were repeated after 6 months. The outcome measures were 6-month changes of tissue Ki-67 (primary end point), high-grade prostatic intraepithelial neoplasia (HG-PIN), proliferative inflammatory atrophy, circulating PSA, and sex hormones. Ki-67 expression was higher in HG-PIN than in normal tissue (10% versus 3%; P < 0.01) but was not modulated by bicalutamide in normal luminal cells. A trend toward an improvement of HG-PIN status was found in treated subjects (26% improved, 60% had no change, 15% worsened) as compared with the no-treatment arm (4% improved, 83% had no change, 13% worsened; P = 0.07). Proliferative inflammatory atrophy prevalence was not reduced by bicalutamide. Bicalutamide reduced PSA by 50% in both arms and raised testosterone and estradiol levels. Asymptomatic breast swelling was noted in 40% of the treated cases. A weekly administration of bicalutamide seems to be reasonably safe and shows an encouraging signal of activity on HG-PIN prevalence, supporting further studies of this schedule in men at high risk despite the negative primary end-point findings on Ki-67.

  9. Phase I/II Study of Pre-operative Docetaxel and Mitoxantrone for High-risk Prostate Cancer

    PubMed Central

    Garzotto, Mark; Higano, Celestia S.; O’Brien, Catherine; Rademacher, Brooks L.S.; Janeba, Nicole; Fazli, Ladan; Lange, Paul H.; Lieberman, Stephen; Beer, Tomasz M.

    2009-01-01

    Background To determine the 5-year recurrence-free survival in patients with high-risk prostate cancer after neoadjuvant combination chemotherapy followed by surgery. Secondary endpoints included safety, pathologic effects of chemotherapy and predictors of disease recurrence. Patients and Methods Fifty seven patients were enrolled in a Phase I/II study of weekly docetaxel 35 mg/m2 and escalating mitoxantrone to 4 mg/m2 prior to prostatectomy. Patients were treated with 16 weeks of chemotherapy administered weekly on a 3 of every 4 week schedule. A tissue micro-array, constructed from the prostatectomy specimens served to facilitate the exploratory evaluation of biomarkers. The primary end point was relapse-free survival. Relapse was defined as a confirmed serum prostate-specific antigen (PSA) > 0.4 ng/ml. Results Of the 57 patients, 54 received 4 cycles of docetaxel and mitoxantrone prior to radical prostatectomy. Grade 4 toxicities were limited to leucopenia, neutropenia and hyperglycemia. Serum testosterone levels remained stable after chemotherapy. Negative surgical margins were attained in 67% of cases. Lymph node involvement was detected in 18.5% of cases. With a median follow-up of 63 months, 27 of 57 (47.4%) patients recurred. The Kaplan-Meier relapse-free survival at 2 years was 65.5% (95%CI 53.0% to 78.0%) and 49.8% at 5 years (95%CI 35.5% to 64.1%). Pretreatment serum PSA, lymph node involvement, and post-chemotherapy tissue VEGF expression were independent predictors of early relapse. Conclusions Preoperative chemotherapy with docetaxel and mitoxantrone is feasible. Approximately half of the high risk patients remain relapse free at 5 years and clinical and molecular predictors of early relapse were identified. PMID:20143429

  10. Anticoagulation Control in Swiss Primary Care: Time in Therapeutic Range Percentages Exceed Benchmarks of Phase III Trials.

    PubMed

    Djalali, Sima; Valeri, Fabio; Gerber, Bernhard; Meli, Damian N; Senn, Oliver

    2017-09-01

    In randomized controlled trials, non-vitamin K antagonist oral anticoagulants (NOACs) demonstrated noninferiority to vitamin K antagonists (VKAs) in patients who spent limited time in therapeutic range (TTR). In real-life patients, TTR is known to vary significantly across countries and health-care settings. We aim to evaluate the quality of VKA treatment in Swiss primary care (PC) by comparing patients' median TTR to levels achieved in the phase III NOAC trials RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF-TIMI 48. Patient characteristics affecting TTR control shall be estimated. This is a retrospective longitudinal study in Swiss PC patients receiving VKA for ≥6 months. We identified patients from the PC research database FIRE (Family medicine International Classification of Primary Care Research using Electronic medical records) and calculated TTR according to Rosendaal formula. Comparative data from NOAC trials were retrieved from medical literature. Linear regression models were used to assess predictors of TTR. Primary care encounters of 215 patients were analyzed. Like in the NOAC trials, median observation period was 2.2 years, but patients were older (67.9% vs 38% ≥75 years) and differed in terms of concomitant diseases and drugs. Median TTR was 75% (65% in the NOAC trials). Female sex was independently associated with a lower TTR and significantly modified by increasing age. Practitioners should consider that patients in NOAC trials are only partly representative of PC patients, particularly in terms of TTR control. Only a minority of the observed patients would require a therapy switch to NOACs due to inadequate TTR. Further research is needed in order to identify specific features of care management that are associated with these outcomes.

  11. SCORE2 Report 1: Techniques to Optimize Recruitment in Phase III Clinical Trials of Patients With Central Retinal Vein Occlusion.

    PubMed

    Scott, Ingrid U; VanVeldhuisen, Paul C; Ip, Michael S; Blodi, Barbara A; Oden, Neal L; Figueroa, Maria

    2016-10-01

    To investigate recruitment rates of patients with central retinal vein occlusion (CRVO) into phase III clinical trials evaluating intravitreal pharmacotherapy for treatment of macular edema in the United States, describe recruitment techniques in the Study of COmparative Treatments for REtinal Vein Occlusion 2 (SCORE2), and assess which SCORE2 recruitment techniques were most useful to principal investigators and clinical coordinators. Retrospective survey within a randomized clinical trial. Recruitment rates of the Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE)-CRVO trial, CRUISE Study, and SCORE2 were calculated. Techniques employed to facilitate recruitment in SCORE2 are described, and a survey was sent to the principal investigator and primary clinical coordinator of each SCORE2 site to assess the usefulness of recruitment techniques. In SCORE2, the recruitment rate of 0.39 participants/month/site was higher than in SCORE-CRVO (0.10 participants/month/site) and CRUISE (0.23 participants/month/site). For study design factors in SCORE2, investigators and coordinators rated provision of standard-of-care treatments to all study participants as having a major positive impact on recruitment. A monthly e-newsletter to site staff and communication by physician members of the SCORE2 Executive Committee to sites upon each randomization were perceived as effective means to help site staff focus on recruitment. The SCORE2 recruitment rate compares favorably to previous clinical trials investigating intravitreal pharmacotherapy for treatment of CRVO-associated macular edema. Study design factors, methods of communication with sites, and recruitment techniques implemented in SCORE2 were well received by investigators and coordinators and may be helpful in future clinical trials. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial.

    PubMed

    Hankins, Jane S; McCarville, Mary Beth; Rankine-Mullings, Angela; Reid, Marvin E; Lobo, Clarisse L C; Moura, Patricia G; Ali, Susanna; Soares, Deanne P; Aldred, Karen; Jay, Dennis W; Aygun, Banu; Bennett, John; Kang, Guolian; Goldsmith, Jonathan C; Smeltzer, Matthew P; Boyett, James M; Ware, Russell E

    2015-12-01

    Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170-199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was a National Heart, Lung, and Blood Institute-funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSβ(0) -thalassemia (1), and HbSD (1), median age = 5.4 years (range, 2.7-9.8)]. Because of the slow patient accrual and administrative delays, SCATE was terminated early. In an intention-to-treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI = 0-35%) in the hydroxyurea arm and 47% (95% CI = 6-81%) in observation arm at 15 months (P = 0.16). In post hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities when compared with observation (0% vs. 50%, P = 0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (-15.5 vs. +10.2 cm/sec, P = 0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities.

  13. Dermatological side-effects of telaprevir-based triple therapy for chronic hepatitis C in phase III trials in Japan.

    PubMed

    Torii, Hideshi; Sueki, Hirohiko; Kumada, Hiromitsu; Sakurai, Yuko; Aoki, Keiji; Yamada, Ichimaro; Ohtsuki, Mamitaro

    2013-08-01

    Telaprevir-based triple therapy is highly effective for chronic hepatitis C. However, concern has been expressed over the high frequency and severity of its dermatological side-effects compared with those associated with peginterferon (PEG-IFN) and ribavirin (RBV) therapy. Thus, here, we evaluated the dermatological adverse reactions of telaprevir-based triple therapy in Japanese multicenter phase III clinical trials in an attempt to characterize the dermatological side-effects and establish appropriate management plans. In these trials, 126 treatment-naïve patients and 141 treatment-failure patients were administrated telaprevir, PEG-IFN-α-2b and RBV for 12 weeks followed by PEG-IFN-α-2b and RBV for another 12 weeks (T12/PR24 group), and 63 treatment-naïve patients were administrated PEG-IFN-α-2b and RBV for 48 weeks (PR48 group). Dermatological adverse reactions developed in over 80% patients in both groups, and most of them were grade 1 or 2. In the T12/PR24 group, there were more grade 2 or grade 3 events, and the time to onset was earlier than that in the PR48 group. Most reactions could be managed with topical corticosteroids and oral antihistamines, and the rates of discontinuation due to dermatological reactions were not high even in the T12/PR24 group. In the T12/PR24 group, however, two cases of Stevens-Johnson syndrome and one case of drug rash with eosinophilia and systemic symptoms, which corresponds to drug-induced hypersensitivity syndrome in Japan, were reported. For appropriate treatments of individual dermatological adverse reactions, the judgment of discontinuation of antiviral drugs and treatment based on the severity are extremely important in this triple therapy.

  14. Ren Shen Yangrong Tang for Fatigue in Cancer Survivors: A Phase I/II Open-Label Study

    PubMed Central

    Xu, Yichen; Chen, Yanzhi

    2015-01-01

    Abstract Objectives: This open-label, prospective, phase I/II trial was performed to establish the safety and efficacy of Traditional Chinese Medicine (TCM) herbal products for treating non–anemia-related fatigue in patients with cancer. Although this practice is widespread in China, it has not been confirmed in a prospective clinical study. Design: Thirty-three patients who had completed cancer treatment, had stable disease and no anemia, and reported moderate to severe fatigue (rated ≥4 on a 0–10 scale) were enrolled in a TCM outpatient clinic. Patients took Ren Shen Yangrong Tang (RSYRT) decoction, a soup containing 12 TCM herbs, twice a day for 6 weeks. RSYRT aims to correct qi deficiency. Fatigue was assessed before and after RSYRT therapy, which all patients completed. Results: No discomfort or toxicity was observed. Before the study, all patients had had fatigue for at least 4 months. Fatigue severity decreased significantly from before therapy to 6 weeks after therapy: from 7.06 to 3.30 on a 0–10 scale (p<0.001). Fatigue category (mild, moderate, severe) shifted significantly (p=0.024): Of 22 patients with severe fatigue (rated ≥7) before therapy, 11 had mild fatigue and 11 had moderate fatigue after TCM treatment. The time-to-fatigue-alleviation was 2–3 weeks. Conclusion: RSYRT therapy was safe and was associated with fatigue improvement in nonanemic cancer survivors, consistent with historical TCM clinical practice experience. Because of a possible placebo effect in this open-label study, decoction RSYRT warrants further study in randomized clinical trials to confirm its effectiveness for managing moderate to severe fatigue. PMID:25918996

  15. Disclosure of funding sources and conflicts of interest in phase III surgical trials: survey of ten general surgery journals.

    PubMed

    Bridoux, Valérie; Moutel, Grégoire; Schwarz, Lilian; Michot, Francis; Herve, Christian; Tuech, Jean-Jacques

    2014-10-01

    Discussions regarding disclosure of funding sources and conflicts of interest (COI) in published peer-reviewed journal articles are becoming increasingly more common and intense. The aim of the present study was to examine whether randomized controlled trials (RCTs) published in leading surgery journals report funding sources and COI. All articles reporting randomized controlled phase III trials published January 2005 through December 2010 were chosen for review from ten international journals. We evaluated the number of disclosed funding sources and COI, and the factors associated with such disclosures. From a review of 657 RCT from the ten journals, we discovered that presence or absence of a funding source and COI was disclosed by 47 % (309) and 25.1 % (165), respectively. Most articles in "International Committee of Medical Journal Editors (ICMJE)-affiliated journals" did not disclose COI. Disclosure of funding was associated with a journal impact factor >3 (51.7 vs 41.6 %; p < 0.01), statistician/epidemiologist involvement (64.2 vs 43.7 %; p < 0.001), publication after 2008 (52.9 vs 41.1 %; p < 0.01), and the journal being ICMJE-affiliated (49.3 vs 40 %; p < 0.05). Conflict of interest disclosure was associated with publication after 2008 (38.7 vs 11.3 %; p < 0.001), and with the journal not being affiliated with ICMJE (36.9 vs 21.3 %; p < 0.001). Of the published studies we investigated, over half did not disclose funding sources (i.e., whether or not there was a funding source), and almost three quarters did not disclose whether COI existed. Our findings suggest the need to adopt best current practices regarding disclosure of competing interests to fulfill responsibilities to readers and, ultimately, to patients.

  16. Timing of first-line cancer treatments - early versus late - a systematic review of phase III randomized trials.

    PubMed

    Mhaskar, A R; Quinn, G; Vadaparampil, S; Djulbegovic, B; Gwede, C K; Kumar, A

    2010-12-01

    To conduct a systematic review and meta-analysis of all phase III randomized controlled trials comparing efficacy of early versus late first-line or initial treatments for cancer. A comprehensive literature search of MEDLINE and Cochrane library databases was performed (1966-2008). Data was extracted and pooled as per the methods recommended by the Cochrane Collaboration. Of the 570 identified studies, 10 (3811 patients) met inclusion criteria: three each in prostate cancer and multiple myeloma (MM), two in chronic lymphocytic leukemia (CLL), and one each in lung cancer, and follicular lymphoma. The analyses showed no survival benefit with early treatment except in prostate cancer (hazard ratio [HR]=1.23, 95% CI 1.11-1.37 p<0.001). There was no survival difference in MM (HR=0.92, 95% CI 0.56-1.52 p=0.74), CLL (HR=0.76, 95% CI 0.56-1.04 p=0.09), lung cancer (HR=0.95, 95% CI 0.72-1.24 p=0.71), or follicular lymphoma (HR=1, 95% CI 0.55-1.83 p=0.99). No statistically significant difference in response rate between early and late treatment was detected in any cancer type. Data shows that delaying cancer treatments does not necessarily compromise therapeutic outcomes except possibly in locally advanced prostate cancer. These findings provide a unique window to oncologists and patients to address time-sensitive issues if desired by patients. Copyright © 2010 Elsevier Ltd. All rights reserved.

  17. Phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate in dogs with naturally occurring malignant tumors.

    PubMed

    Cai, Shuang; Zhang, Ti; Forrest, W C; Yang, Qiuhong; Groer, Chad; Mohr, Eva; Aires, Daniel J; Axiak-Bechtel, Sandra M; Flesner, Brian K; Henry, Carolyn J; Selting, Kimberly A; Tate, Deborah; Swarz, Jeffrey A; Bryan, Jeffrey N; Forrest, M Laird

    2016-09-01

    OBJECTIVE To conduct a phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate (HA-Pt) in dogs with naturally occurring malignant tumors. ANIMALS 18 healthy rats, 9 healthy mice, and 16 dogs with cancer. PROCEDURES HA-Pt was prepared and tested by inductively coupled plasma mass spectrometry; DNA-platinum adduct formation and antiproliferation effects of cisplatin and HA-Pt were compared in vitro. Effects of cisplatin (IV) and HA-Pt (SC) in rodents were tested by clinicopathologic assays. In the clinical trial, dogs with cancer received 1 to 4 injections of HA-Pt (10 to 30 mg/m(2), intratumoral or peritumoral, q 3 wk). Blood samples were collected for pharmacokinetic analysis; CBC, serum BUN and creatinine concentration measurement, and urinalysis were conducted before and 1 week after each treatment. Some dogs underwent hepatic enzyme testing. Tumors were measured before the first treatment and 3 weeks after each treatment to assess response. RESULTS No adverse drug effects were detected in pretrial assessments in rodents. Seven of 16 dogs completed the study; 3 had complete tumor responses, 3 had stable disease, and 1 had progressive disease. Three of 7 dogs with oral and nasal squamous cell carcinoma (SCC) that completed the study had complete responses. Myelosuppression and cardiotoxicosis were identified in 6 and 2 dogs, respectively; none had nephrotoxicosis. Four of 5 dogs with hepatic enzymes assessed had increased ALT activities, attributed to diaquated cisplatin products in the HA-Pt. Pharmacokinetic data fit a 3-compartment model. CONCLUSIONS AND CLINICAL RELEVANCE HA-Pt treatment resulted in positive tumor responses in some dogs, primarily those with SCC. The adverse effect rate was high. IMPACT FOR HUMAN MEDICINE Oral SCC in dogs has characteristics similar to human head and neck SCC; these results could be useful in developing human treatments.

  18. Tivozanib Versus Sorafenib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma: Results From a Phase III Trial

    PubMed Central

    Motzer, Robert J.; Nosov, Dmitry; Eisen, Timothy; Bondarenko, Igor; Lesovoy, Vladimir; Lipatov, Oleg; Tomczak, Piotr; Lyulko, Oleksiy; Alyasova, Anna; Harza, Mihai; Kogan, Mikhail; Alekseev, Boris Y.; Sternberg, Cora N.; Szczylik, Cezary; Cella, David; Ivanescu, Cristina; Krivoshik, Andrew; Strahs, Andrew; Esteves, Brooke; Berkenblit, Anna; Hutson, Thomas E.

    2013-01-01

    Purpose Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. This phase III trial compared tivozanib with sorafenib as initial targeted therapy in patients with metastatic renal cell carcinoma (RCC). Patients and Methods Patients with metastatic RCC, with a clear cell component, prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic RCC were randomly assigned to tivozanib or sorafenib. Prior VEGF-targeted therapy and mammalian target of rapamycin inhibitor were not permitted. The primary end point was progression-free survival (PFS) by independent review. Results A total of 517 patients were randomly assigned to tivozanib (n = 260) or sorafenib (n = 257). PFS was longer with tivozanib than with sorafenib in the overall population (median, 11.9 v 9.1 months; hazard ratio [HR], 0.797; 95% CI, 0.639 to 0.993; P = .042). One hundred fifty-six patients (61%) who progressed on sorafenib crossed over to receive tivozanib. The final overall survival (OS) analysis showed a trend toward longer survival on the sorafenib arm than on the tivozanib arm (median, 29.3 v 28.8 months; HR, 1.245; 95% CI, 0.954 to 1.624; P = .105). Adverse events (AEs) more common with tivozanib than with sorafenib were hypertension (44% v 34%) and dysphonia (21% v 5%). AEs more common with sorafenib than with tivozanib were hand-foot skin reaction (54% v 14%) and diarrhea (33% v 23%). Conclusion Tivozanib demonstrated improved PFS, but not OS, and a differentiated safety profile, compared with sorafenib, as initial targeted therapy for metastatic RCC. PMID:24019545

  19. Active surveillance for intussusception in a phase III efficacy trial of an oral monovalent rotavirus vaccine in India.

    PubMed

    John, Jacob; Kawade, Anand; Rongsen-Chandola, Temsunaro; Bavdekar, Ashish; Bhandari, Nita; Taneja, Sunita; Antony, Kalpana; Bhatnagar, Veereshwar; Gupta, Arun; Kabra, Madhulika; Kang, Gagandeep

    2014-08-11

    Post licensure studies have identified an increased risk of intussusception following vaccination with currently licensed rotavirus vaccines, raising safety concerns generic to all rotavirus vaccines. We describe the surveillance for intussusception in a phase III clinical trial with an oral monovalent rotavirus vaccine developed from the neonatal 116E strain. Using broad screening criteria and active surveillance, the incidence of intussusception between 6 weeks and 2 years of age was measured in 4532 children who received three doses of vaccine and 2267 children who received a placebo in the clinical trial. Possible intussusceptions were evaluated with a screening ultrasonogram. An independent intussusception case adjudication committee reviewed all intussusceptions and graded them on Brighton Collaboration criteria for diagnostic certainty. We identified twenty-three intussusceptions on ultrasound from 1361 evaluated sentinel events. Eleven were of level 1 diagnostic certainty as determined by the independent intussusception case adjudication committee. None required surgical intervention, and the earliest identified intussusception was at 36 days following the third dose in a placebo recipient. Among vaccine recipients the first event of intussusception occurred 112 days after the third dose. The incidence of ultrasound-diagnosed intussusception was 200/100,000 child-years (95% CI, 120, 320) among those receiving the vaccine and 141/100,000 child-years (95% CI, 50, 310) among those receiving the placebo. The incidence rate of confirmed intussusception among vaccine recipients was 94/100,000 child-years (95% CI, 41, 185) and 71/100,000 child-years (95% CI, 15, 206) among those receiving the placebo. In this licensure study, 23 cases of intussusception were identified through an active surveillance system, but there was no temporal association with rotavirus vaccination. The use of active surveillance with broad criteria intended for ensuring safety of children

  20. Safety Profile of the 9-Valent HPV Vaccine: A Combined Analysis of 7 Phase III Clinical Trials.

    PubMed

    Moreira, Edson D; Block, Stan L; Ferris, Daron; Giuliano, Anna R; Iversen, Ole-Erik; Joura, Elmar A; Kosalaraksa, Pope; Schilling, Andrea; Van Damme, Pierre; Bornstein, Jacob; Bosch, F Xavier; Pils, Sophie; Cuzick, Jack; Garland, Suzanne M; Huh, Warner; Kjaer, Susanne K; Qi, Hong; Hyatt, Donna; Martin, Jason; Moeller, Erin; Ritter, Michael; Baudin, Martine; Luxembourg, Alain

    2016-08-01

    The overall safety profile of the 9-valent human papillomavirus (9vHPV) vaccine was evaluated across 7 Phase III studies, conducted in males and females (nonpregnant at entry), 9 to 26 years of age. Vaccination was administered as a 3-dose regimen at day 1, and months 2 and 6. More than 15 000 subjects received ≥1 dose of 9vHPV vaccine. In 2 of the studies, >7000 control subjects received ≥1 dose of quadrivalent HPV (qHPV) vaccine. Serious and nonserious adverse events (AEs) and new medical conditions were recorded throughout the study. Subjects testing positive for pregnancy at day 1 were not vaccinated; those who became pregnant after day 1 were discontinued from further vaccination until resolution of the pregnancy. Pregnancies detected after study start (n = 2950) were followed to outcome. The most common AEs (≥5%) experienced by 9vHPV vaccine recipients were injection-site AEs (pain, swelling, erythema) and vaccine-related systemic AEs (headache, pyrexia). Injection-site AEs were more common in 9vHPV vaccine than qHPV vaccine recipients; most were mild-to-moderate in intensity. Discontinuations and vaccine-related serious AEs were rare (0.1% and <0.1%, respectively). Seven deaths were reported; none were considered vaccine related. The proportions of pregnancies with adverse outcome were within ranges reported in the general population. The 9vHPV vaccine was generally well tolerated in subjects aged 9 to 26 years with an AE profile similar to that of the qHPV vaccine; injection-site AEs were more common with 9vHPV vaccine. Its additional coverage and safety profile support widespread 9vHPV vaccination. Copyright © 2016 by the American Academy of Pediatrics.

  1. The influence of industry sponsorship on the reporting of subgroup analyses within phase III randomised controlled trials in gastrointestinal oncology.

    PubMed

    Barton, Sarah; Peckitt, Clare; Sclafani, Francesco; Cunningham, David; Chau, Ian

    2015-12-01

    Correct interpretation of subgroup analyses (SGA) is important as it influences selection of therapeutic interventions for patient subsets. The primary aim of our study was to compare reporting of SGA between industry and non-industry sponsored trials. We performed a systematic literature review and extracted data from journal articles (JA) and conference abstracts (CA) published over a decade reporting SGA results of phase III randomised controlled gastrointestinal (GI) oncology trials with patient participants of ≥150. In JA, SGA was reported in 100/145 (69%) trials: 41/54 industry sponsored (76%; 95% confidence interval [CI]: 63-86%) and 59/91 non-industry sponsored (65%; 95% CI: 55-74%) trials (p = 0.16). In CA, SGA was reported in 86/204 (42%) trials: 43/83 industry sponsored (52%; 95% CI: 41-62%) and 43/121 non-industry sponsored (36%; 95% CI: 28-44%) trials (p = 0.02). Number of SGA performed per trial was significantly larger for industry compared to non-industry sponsored trials in both JA (median 6 versus 2, p = 0.003) and CA (median 1 versus 0, p = 0.023). Claims of subgroup effect were made in 52% of trials in JA and 50% in CA, with significant test of interaction evident in only 25% of JA and 16% of CA, with no difference between industry and non-industry trials. Industry sponsored trials with a significant primary end-point reported more SGA (p < 0.001 JA; p = 0.046 CA). Industry sponsored trials reported more SGA. Claimed subgroup effects were often not accompanied by significant interaction test; thus circumspection should be adopted when using SGA to deviate from standard therapeutic decision-making in GI oncology. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Noninvasive diagnosis of hypolactasia with 4-Galactosylxylose (Gaxilose): a multicentre, open-label, phase IIB-III nonrandomized trial.

    PubMed

    Aragón, Juan J; Hermida, Carmen; Martínez-Costa, Oscar H; Sánchez, Valentina; Martín, Igor; Sánchez, José J; Codoceo, Rosa; Cano, José M; Cano, Ana; Crespo, Laura; Torres, Yolanda; García, Francisco J; Fernández-Mayoralas, Alfonso; Solera, Jesús; Martínez, Pilar

    2014-01-01

    Hypolactasia affects over half of the world population. Diagnosis remains problematic as currently available tests, such as the hydrogen breath test, have low reliability and lactose intolerance symptoms are unspecific. We evaluated the diagnostic performance and safety of a new noninvasive diagnostic test based on urine or serum measurement of D-xylose after lactase cleavage of orally administered 4-galactosylxylose (gaxilose). In a multicentre, open-label, nonrandomized, phase IIb-III study, consecutive patients with symptoms suggestive of lactose intolerance sequentially underwent intestinal biopsy for direct measurement of lactase activity (reference standard), hydrogen breath test, and blood glucose test after lactose challenge, 4- and 5-hour urine-based gaxilose test, and blood-based gaxilose test. For the gaxilose tests, 0 to 4 and 4 to 5 hours urine samples were taken after a 0.45 g gaxilose dose, whereas serum samples were taken 90 minutes after a 2.7 g dose for D-xylose determination. Genetic testing of hypolactasia was also assessed. Of the 222 patients enrolled, 203 completed all diagnostic tests; 108 were hypolactasic according to biopsy. The sensitivities and specificities and positive and negative predictive values of the gaxilose tests were all >90% versus 69% to 85% for the hydrogen breath test and the blood glucose test. The area under the ROC curve was significantly higher for the gaxilose tests (>0.9, P≤0.007). These tests also had higher sensitivity than genetic testing for hypolactasia and were well tolerated. The diagnostic performance of the gaxilose tests is excellent and can substantially improve the diagnosis of hypolactasia.

  3. Efficacy and Safety of Cariprazine in Acute Exacerbation of Schizophrenia: Results From an International, Phase III Clinical Trial.

    PubMed

    Kane, John M; Zukin, Stephen; Wang, Yao; Lu, Kaifeng; Ruth, Adam; Nagy, Krisztián; Laszlovszky, István; Durgam, Suresh

    2015-08-01

    This phase III study evaluated the efficacy and safety of cariprazine, a dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors, in patients with acute exacerbation of schizophrenia. Patients were randomized to 6-week double-blind treatment with placebo, cariprazine 3 to 6 mg/d, or cariprazine 6 to 9 mg/d. Primary and secondary efficacy: change from baseline to week 6 in Positive and Negative Syndrome Scale total and Clinical Global Impressions-Severity scores, respectively, analyzed using a mixed-effects model for repeated measures adjusting for multiple comparisons. Safety included treatment-emergent adverse events, clinical laboratory values, vital signs, electrocardiograms, ophthalmologic examination, Columbia-Suicide Severity Rating Scale, and extrapyramidal symptom scales. In the Safety Population (placebo, n = 147; cariprazine 3-6 mg/d, n = 151; cariprazine 6-9 mg/d, n = 148), 60.5% of patients completed the study. At week 6, statistically significant least squares mean differences in favor of cariprazine versus placebo were observed for Positive and Negative Syndrome Scale total score (3-6 mg/d: -6.8, P = 0.003; 6-9 mg/d: -9.9, P < 0.001) and Clinical Global Impressions-Severity (3-6 mg/d: -0.3, P = 0.012; 6-9 mg/d: -0.5, P < 0.001). Common treatment-emergent adverse events (≥5% and twice the rate of placebo) in both cariprazine groups were akathisia, extrapyramidal disorder, and tremor; most were mild to moderate in severity. Mean changes in metabolic parameters were generally small and similar between groups. Prolactin levels decreased in all groups. In conclusion, cariprazine 3 to 6 and 6 to 9 mg/d versus placebo demonstrated significant improvement on primary and secondary efficacy parameters. Cariprazine was generally well tolerated. These results suggest that cariprazine may be a new and effective treatment for schizophrenia.

  4. Long-term safety of sorafenib in advanced renal cell carcinoma: follow-up of patients from phase III TARGET.

    PubMed

    Hutson, Thomas E; Bellmunt, Joaquim; Porta, Camillo; Szczylik, Cezary; Staehler, Michael; Nadel, Andrea; Anderson, Sibyl; Bukowski, Ronald; Eisen, Tim; Escudier, Bernard

    2010-09-01

    The phase III Treatment Approaches in Renal cancer Global Evaluation Trial (TARGET) indicated that sorafenib is effective and well tolerated in advanced renal cell carcinoma patients. However, few data have been published on the safety of long-term sorafenib treatment. A retrospective subgroup analysis was performed to evaluate the efficacy and safety of sorafenib in patients in TARGET who received treatment for >1 year. The present subgroup analysis (based on the September 2006 database with updated safety analysis) evaluated the efficacy and safety of sorafenib in all patients in the sorafenib arm of TARGET who were treated for >1 year. The assessments included the overall survival, progression-free survival (PFS), disease control rate (DCR), and safety. The patients remained on therapy post-progression at the discretion of the investigator. In TARGET, 169 patients received treatment with sorafenib for >1 year. The median PFS of patients in this subpopulation was 10.9 months from the date of randomisation, with a DCR of 92%. The most commonly reported treatment-related adverse events of any grade were diarrhoea (74%), rash/desquamation (51%), hand-foot skin reaction (49%), alopecia (39%), and fatigue (38%). Adverse events were mild to moderate, and presented early in the course of the treatment; there were no unexpected toxicities associated with the long-term administration of sorafenib. Results of this subgroup analysis of patients enrolled in TARGET who received treatment for >1 year indicate that long-term treatment with sorafenib is associated with continued efficacy and a well-tolerated safety profile. Copyright 2010. Published by Elsevier Ltd.

  5. Tai Chi as an adjunct physical activity for adults aged 45 years and older enrolled in phase III cardiac rehabilitation

    PubMed Central

    Taylor-Piliae, Ruth E; Silva, Edna; Sheremeta, Sharon Peachey

    2015-01-01

    Background Cardiac rehabilitation improves physical, cognitive and psychosocial functioning, yet services are greatly underutilized with increasing patterns of attrition over time. Tai Chi has been suggested as a possible adjunct to cardiac rehabilitation exercise training. Aim To describe differences in physical, cognitive and psychosocial functioning among adults ≥ 45 years old attending phase III cardiac rehabilitation, who have or have not self-selected Tai Chi exercise as an adjunct physical activity. Methods A cross-sectional design compared subjects attending group-based Wu style Tai Chi classes plus cardiac rehabilitation, with cardiac rehabilitation only. Subjects had a battery of physical and cognitive functioning tests administered to examine aerobic endurance, balance, strength, and flexibility, verbal retrieval/recall, attention, concentration and tracking. Subjects completed a health survey to ascertain cardiac event information, medical history, and psychosocial functioning (i.e. health-related quality of life, stress, depressive symptoms, social support, and Tai Chi self-efficacy). Results A total of 51 subjects (75% married, 84% college-educated, 96% White/European-American) participated. Subjects were on average 70 (± 8) years old and had attended cardiac rehabilitation for 45 (± 37) months. Approximately 45% (n = 23) attended Tai Chi classes plus cardiac rehabilitation, while 55% (n = 28) attended cardiac rehabilitation only. Subjects attending Tai Chi plus cardiac rehabilitation had better balance, perceived physical health, and Tai Chi self-efficacy compared to those attending cardiac rehabilitation only (p ≤ 0.03). Conclusion Tai Chi can be easily implemented in any community/cardiac rehabilitation facility, and may offer adults additional options after a cardiac event. PMID:21095159

  6. Phase I/II Trial of the Anti-HIV Activity of Mifepristone in HIV-Infected Subjects ACTG 5200

    PubMed Central

    Para, Michael F.; Schouten, Jeff; Rosenkranz, Susan L.; Yu, Song; Weiner, David; Tebas, Pablo; White, C. Jo; Reeds, Dominic; Lertora, Juan; Patterson, Kristine B.; Daar, Eric S.; Cavert, Wintson; Brizz, Barbara

    2012-01-01

    Background Mifepristone is a glucocorticoid receptor inhibitor shown in vitro to have anti-HIV activity and anti-simian immunodeficiency virus activity in a macaque model. A phase I/II trial was performed to assess the drug’s safety and anti-HIV activity. Methods A 28-day double-blind, placebo-controlled trial of mifepristone at doses of 75 mg, 150 mg, and 225 mg given daily was conducted in HIV+ persons with CD4+ lymphocyte counts ≥350 cells per cubic millimeter who had no recent antiretroviral therapy. Results Fifty-six male and 1 female subjects with a median entry CD4+ lymphocyte count of 555 cells per cubic millimeter and plasma HIV-1 RNA of 15,623 copies per milliliter were accrued. Forty-five subjects (78.9%) were available for endpoint analysis. In each arm, changes from baseline to day 28 in plasma HIV-1 RNA and CD4+ lymphocyte count were not significantly different from zero (no change). There was no relationship between mifepristone trough concentrations and plasma HIV-1 RNA. Day 28 morning plasma cortisol levels were significantly higher in the 150 mg and 225 mg arms compared with placebo, confirming biologic activity, and returned to baseline by day 56. Serum lipids did not change during the trial. Fasting blood sugar was 2.5 mg/dL higher on day 28 in the mifepristone arms, but the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) did not change. Three subjects (7.3%) receiving mifepristone developed a grade 2 rash. Conclusions Mifepristone at doses of 75–225 mg daily was safe and well-tolerated, but did not show significant anti-HIV activity. PMID:20130470

  7. Phase I/II trial of HIV-1 hyperimmune globulin for the prevention of HIV-1 vertical transmission in Uganda.

    PubMed

    Guay, Laura A; Musoke, Philippa; Hom, David L; Nakabiito, Clemensia; Bagenda, Danstan; Fletcher, Courtney V; Marum, Lawrence H; Fowler, Mary Glenn; Falksveden, Lars G; Wahren, Britta; Kataaha, Peter; Wigzell, Hans; Mmiro, Francis A; Jackson, J Brooks

    2002-07-05

    To assess the safety, tolerance, pharmacokinetics, and virologic and immunologic changes associated with the use of Ugandan HIV hyperimmune globulin (HIVIGLOB) in HIV infected pregnant Ugandan women and their infants. A prospective, phase I/II, three-arm dose escalation trial of HIVIGLOB. HIVIGLOB was prepared from discarded HIV infected units of blood collected from the National Blood Bank in Kampala. From June 1996 to April 1997, 31 HIV positive pregnant women were enrolled with HIVIGLOB infusions given at 37 weeks gestation and within 16 h of birth for infants. The first 10 mother-infant pairs were infused at a dose of 50 mg/kg, followed by 11 pairs at 200 mg/kg, and 10 pairs at 400 mg/kg. Study participants were followed for 30 months. Thirty-one women and 29 infants were infused with HIVIGLOB. The infusions were safe and well tolerated by the women and their infants at all doses. There were no significant changes in virologic or immunologic parameters after HIVIGLOB infusion. Pharmacokinetic properties of this product were similar to other immune globulin products with a median half-life of 28 days in women and 30 days in infants. An HIV immune globulin product derived from HIV infected Ugandan donors is safe, well tolerated, and has pharmacokinetic properties consistent with other immunoglobulin products. Data suggest that a 400 mg/kg dose of HIVIGLOB would be the most appropriate dose for a subsequent efficacy trial of HIVIGLOB for the prevention of mother to child HIV transmission.

  8. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer

    PubMed Central

    Liu, Mei-Ching; Lee, Soo Chin; Vanlemmens, Laurence; Ferrero, Jean-Marc; Tabei, Toshio; Pivot, Xavier; Iwata, Hiroji; Aogi, Kenjiro; Lugo-Quintana, Roberto; Harbeck, Nadia; Brickman, Marla J.; Zhang, Ke; Kern, Kenneth A.; Martin, Miguel

    2010-01-01

    This multicenter, randomized, open-label phase III trial (planned enrollment: 700 patients) was conducted to test the hypothesis that single-agent sunitinib improves progression-free survival (PFS) compared with capecitabine as treatment for advanced breast cancer (ABC). Patients with HER2-negative ABC that recurred after anthracycline and taxane therapy were randomized (1:1) to sunitinib 37.5 mg/day or capecitabine 1,250 mg/m2 (1,000 mg/m2 in patients >65 years) BID on days 1–14 q3w. The independent data-monitoring committee (DMC) determined during the first interim analysis (238 patients randomized to sunitinib, 244 to capecitabine) that the trial be terminated due to futility in reaching the primary endpoint. No statistical evidence supported the hypothesis that sunitinib improved PFS compared with capecitabine (one-sided P = 0.999). The data indicated that PFS was shorter with sunitinib than capecitabine (median 2.8 vs. 4.2 months, respectively; HR, 1.47; 95% CI, 1.16–1.87; two-sided P = 0.002). Median overall survival (15.3 vs. 24.6 months; HR, 1.17; two-sided P = 0.350) and objective response rates (11 vs. 16%; odds ratio, 0.65; P = 0.109) were numerically inferior with sunitinib versus capecitabine. While no new or unexpected safety findings were reported, sunitinib treatment was associated with higher frequencies and greater severities of many common adverse events (AEs) compared with capecitabine, resulting in more temporary discontinuations due to AEs with sunitinib (66 vs. 51%). The relative dose intensity was lower with sunitinib than capecitabine (73 vs. 95%). Based on these efficacy and safety results, sunitinib should not be used as monotherapy for patients with ABC. PMID:20339913

  9. Monitoring safety in a phase III real‐world effectiveness trial: use of novel methodology in the Salford Lung Study

    PubMed Central

    Harvey, Catherine; Brewster, Jill; Bakerly, Nawar Diar; Elkhenini, Hanaa F.; Stanciu, Roxana; Williams, Claire; Brereton, Jacqui; New, John P.; McCrae, John; McCorkindale, Sheila; Leather, David

    2016-01-01

    Abstract Background The Salford Lung Study (SLS) programme, encompassing two phase III pragmatic randomised controlled trials, was designed to generate evidence on the effectiveness of a once‐daily treatment for asthma and chronic obstructive pulmonary disease in routine primary care using electronic health records. Objective The objective of this study was to describe and discuss the safety monitoring methodology and the challenges associated with ensuring patient safety in the SLS. Refinements to safety monitoring processes and infrastructure are also discussed. The study results are outside the remit of this paper. The results of the COPD study were published recently and a more in‐depth exploration of the safety results will be the subject of future publications. Achievements The SLS used a linked database system to capture relevant data from primary care practices in Salford and South Manchester, two university hospitals and other national databases. Patient data were collated and analysed to create daily summaries that were used to alert a specialist safety team to potential safety events. Clinical research teams at participating general practitioner sites and pharmacies also captured safety events during routine consultations. Confidence in the safety monitoring processes over time allowed the methodology to be refined and streamlined without compromising patient safety or the timely collection of data. The information technology infrastructure also allowed additional details of safety information to be collected. Conclusion Integration of multiple data sources in the SLS may provide more comprehensive safety information than usually collected in standard randomised controlled trials. Application of the principles of safety monitoring methodology from the SLS could facilitate safety monitoring processes for future pragmatic randomised controlled trials and yield important complementary safety and effectiveness data. © 2016 The Authors

  10. Third phase formation in the extraction of Nd(III) by octyl(phenyl)-N,N-diisobutyl carbamoyl methyl phosphine oxide (O{Phi}CMPO)

    SciTech Connect

    Suresh, A.; Brahmmananda Rao, C.V.S.; Sabharwal, K.N.; Srinivasan, T.G.; Vasudeva Rao, P.R.

    1999-01-01

    Third phase formation in the extraction of Nd(III) by 0.2 M Octyl(Phenyl)-N,N-Diisobutyl Carbamoyl methyl phosphine oxide (O{Phi}CMPO) in n-dodecane has been studied with tri-n-butyl phosphate (TBP) and tri-n-amyl phosphate (TAP) as modifiers to provide a comparison between these two modifier systems. The effect of concentration of TAP as modifier for the extraction of Nd(III) by 0.2 M O{Phi}CMPO has been studied. The extraction of Nd(III) by TAP/n-dodecane in the absence of O{Phi}CMPO has also been studied and the results are reported here.

  11. Effect of aclidinium bromide on cough and sputum symptoms in moderate-to-severe COPD in three phase III trials

    PubMed Central

    McGarvey, Lorcan; Morice, Alyn H; Smith, Jaclyn A; Birring, Surinder S; Chuecos, Ferran; Seoane, Beatriz; Jarreta, Diana

    2016-01-01

    Background Cough and sputum are troublesome symptoms in chronic obstructive pulmonary disease (COPD) and are associated with adverse outcomes. The efficacy of aclidinium bromide 400 µg twice daily in patients with stable COPD has been established in two phase III studies (ACCORD COPD I and ATTAIN) and a phase IIIb active-comparator study. This analysis evaluated cough-related symptoms across these studies. Method Patients were randomised to placebo, aclidinium 200 µg or 400 µg twice daily in ACCORD (12 weeks) and ATTAIN (24 weeks), or to placebo, aclidinium 400 µg twice daily or tiotropium 18 µg once daily (6-week active-comparator study). Analysed end points included changes from baseline in Evaluating Respiratory Symptoms (E-RS; formerly known as EXAcerbations of Chronic pulmonary disease Tool), total and cough/sputum scores and frequency/severity of morning and night-time cough and sputum symptoms. Results Data for 1792 patients were evaluated. E-RS cough/sputum domain scores were significantly reduced with aclidinium 400 µg versus placebo in ATTAIN (−0.7 vs −0.3, respectively; p<0.01) and the active-comparator study (−0.6 vs −0.2, respectively; p<0.01). In the active-comparator study, significantly greater improvements were observed with aclidinium versus placebo for severity of morning cough (−0.19 vs −0.02; p<0.01) and phlegm (−0.19 vs −0.02; p<0.05). In ACCORD, aclidinium reduced night-time cough frequency (−0.36 vs 0.1 for placebo; p<0.001) and severity (−0.24 vs −0.1 for placebo; p<0.05), and frequency of night-time sputum production (−0.37 vs 0.05 for placebo; p<0.001). Conclusions Aclidinium 400 µg twice daily improves cough and sputum expectoration versus placebo in stable COPD. Trial registration numbers NCT00891462; NCT01001494; NCT01462929. PMID:28074135

  12. Energetics and Dynamics of Electron Transfer and Proton Transfer in Dissociation of Metal III (salen)-Peptide Complexes in the Gas Phase

    SciTech Connect

    Laskin, Julia; Yang, Zhibo; Chu, Ivan K.

    2008-03-12

    Time- and collision energy-resolved surface-induced dissociation (SID) of ternary complexes of CoIII(salen)+, FeIII(salen)+, and MnIII(salen)+ with several angiotensin peptide analogs was studied using a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR MS) specially equipped to perform SID experiments. Time-resolved fragmentation efficiency curves (TFECs) were modeled using an RRKM-based approach developed in our laboratory. The approach utilizes a very flexible analytical expression for the internal energy deposition function that is capable of reproducing both single-collision and multiple-collision activation in the gas phase and excitation by collisions with a surface. The energetics and dynamics of competing dissociation pathways obtained from the modeling provides important insight on the competition between proton transfer, electron transfer, loss of neutral peptide ligand, and other processes that determine gas-phase fragmentation of these model systems. Similar fragmentation behavior was obtained for various CoIII(salen)-peptide systems of different angiotensin analogs. In contrast, dissociation pathways and relative stabilities of the complexes changed dramatically when cobalt was replaced with trivalent iron or manganese. We demonstrate that the electron transfer efficiency is correlated with redox properties of the metalIII(salen) complexes (Co > Fe > Mn), while differences in the types of fragments formed from the complexes reflect differences in the modes of binding between the metal-salen complex and the peptide ligand. RRKM modeling of time- and collision energy-resolved SID data suggests that the competition between proton transfer and electron transfer during dissociation of CoIII(salen)-peptide complexes is mainly determined by differences in entropy effects while the energetics of these two pathways are very similar.

  13. Integrated Fast Neutron Flux at the End of Phases I, II, III, and IV-1B of the MOX Zr-cladding Tube

    SciTech Connect

    Gray Chang

    2004-03-01

    This report using the detailed ATR quarter core model calculated neutronic tallies, the MCWO-calculated Zr-cladding fast neutron fluence (E > 0.1 MeV and E > 1.0 MeV) distributions at the end of Phase-I, -II, -III, and -IV Irradiation are tabulated in Table 1, 2, 3, and 4. At the end of the Phase-I irradiation, the MCWO-calculated Zr-cladding fast neutron fluences of the removed MOX capsules 1 and 8 are 2.68 and 2.68 x 1020 n/cm2, respectively. At the end of Phase-II Irradiation are tabulated in Table 2. At the end of the Phase-II irradiation, the MCWO-calculated Zr-cladding fast neutron fluences of the removed MOX capsules 9 and 2 are 6.78 and 6.79 x 1020 n/cm2, respectively. At the end of the Phase-III irradiation, the MCWO-calculated Zr-cladding fast neutron fluences of the removed MOX capsules 10 and 3 are 9.82 and 9.70 x 1020 n/cm2, respectively. And, at the end of the Phase-IV part 1B irradiation, the MCWO-calculated Zr-cladding fast neutron fluences of the removed MOX capsules 4 and 13 are 1.41 and 1.39 x 1021 n/cm2, respectively.

  14. Magnetic solid-phase extraction combined with graphite furnace atomic absorption spectrometry for speciation of Cr(III) and Cr(VI) in environmental waters.

    PubMed

    Jiang, Hong-mei; Yang, Ting; Wang, Yan-hong; Lian, Hong-zhen; Hu, Xin

    2013-11-15

    A new approach of magnetic solid phase extraction (MSPE) coupled with graphite furnace atomic absorption spectrometry (GFAAS) has been developed for the speciation of Cr(III) and Cr(VI) using zincon-immobilized silica-coated magnetic Fe3O4 nanoparticles (Zincon-Si-MNPs) as the MSPE absorbent. Cr(III) was quantitatively reserved on the absorbent at pH 9.1 while total Cr was reserved at pH 6.5. The absorbed Cr species were eluted by using 2 mol/L HCl and detected by GFAAS. The concentration of Cr(VI) could be calculated by subtracting Cr(III) from total Cr. All the parameters affecting the separation and extraction efficiency of Cr species such as pH, extraction time, concentration and volume of eluent, sample volume and influence of co-existing ions were systematically examined and the optimized conditions were established accordingly. The detection limit (LOD) of the method was 0.016 and 0.011 ng mL(-1) for Cr(III) and Cr(VI), respectively, with the enrichment factor of 100 and 150. The precisions of this method (Relative standard deviation, RSD, n=7) for Cr(III) and Cr(VI) at 0.1 ng mL(-1) were 6.0% and 6.2%, respectively. In order to validate the proposed method, a certified reference material of environmental water was analyzed, and the result of Cr speciation was in good agreement with the certified value. This MSPE-GFAAS method has been successfully applied for the speciation of Cr(III) and Cr(VI) in lake and tap waters with the recoveries of 88-109% for the spiked samples. Moreover, the MSPE separation mechanism of Cr(III) and Cr(VI) based on their adsorption-desorption on Zincon-Si-MNPs has been explained through various spectroscopic characterization.

  15. Kinetics and Mechanisms of Cr(VI) Formation via the Oxidation of Cr(III) Solid Phases by Chlorine in Drinking Water.

    PubMed

    Chebeir, Michelle; Liu, Haizhou

    2016-01-19

    Hexavalent chromium Cr(VI), typically existing as the oxyanion form of CrO4(2-), is being considered for more stringent drinking water standards by regulatory agencies. Cr(VI) can be inadvertently produced via the oxidation of trivalent chromium Cr(III) solids. This study investigated the kinetics and mechanisms of Cr(III) solids oxidation by chlorine in drinking water and associated Cr(VI) formation. Batch experiments were carried out with three Cr(III) solids of environmental relevance, i.e., chromium hydroxide Cr(OH)3(s), chromium oxide Cr2O3(s), and copper chromite Cu2Cr2O5(s). Impacts of water chemical parameters including pH (6.0-8.5) and bromide concentration (0-5 mg/L) were examined. Results showed that the rapid oxidation of Cr(III) solid phases by chlorine was accompanied by Cr(VI) formation and an unexpected production of dissolved oxygen. Analysis of reaction stoichiometry indicated the existence of Cr intermediate species that promoted the autocatalytic decay of chlorine. An increase in pH modestly enhanced Cr(VI) formation due to changes of reactive Cr(III) surface hydroxo species. Bromide, a trace chemical constituent in source waters, exhibited a catalytic effect on Cr(VI) formation due to an electron shuttle mechanism between Cr(III) and chlorine and the bypass of Cr intermediate formation. The kinetics data obtained from this study suggest that the oxidation of Cr(III) solids by chlorine in water distribution systems can contribute to Cr(VI) occurrence in tap water, especially in the presence of a trace level of bromide.

  16. Direct speciation analysis of thallium based on solid phase extraction and specific retention of a Tl(III) complex on alumina coated with sodium dodecyl sulfate.

    PubMed

    Biaduń, Ewa; Sadowska, Monika; Ospina-Alvarez, Natalia; Krasnodębska-Ostręga, Beata

    Alumina (Al2O3) with an average particle size of 63 μm was modified with the anionic surfactant sodium dodecyl sulfate (SDS) and then applied to (i) solid phase extraction and separation of both thallium(I) and thallium(III), and (ii) preconcentration of Tl(III) from waste water samples. Only Tl(III), in the form of its complex with diethylenetriaminepentaacetate (DTPA), was retained on the sorbent, from where it can be eluted with 40 % nitric acid. Thallium species were then quantified by ICP MS. The method was characterized by a LOD of 25 pg of Tl(I) and 160 pg of Tl(III) in 10 mL samples. A large excesses of Tl(I) over Tl(III) was tolerated, and relatively high levels of other metal ions, such as a 500-fold excess of Pb(II) and Cd(II), and a 2000-fold excess of Zn(II), respectively, do not interfere. The sorbent was easily prepared and possesses a high loading capacity, and these properties make it an attractive material for rapid and efficient extraction and speciation of Tl. Graphical abstract:Schematic of the SPE procedure for separation (with preconcentration) of Tl(III) from Tl(I) was developed and applied to direct speciation analysis of thallium in wastewater. Self-made columns packed with alumina coated with SDS were used. The method is resistant to interferences from Pb, Cd, Zn and tolerates a large excess of Tl(I) over Tl(III).

  17. Adjuvant regional chemotherapy and systemic chemotherapy versus systemic chemotherapy alone in patients with stage II-III colorectal cancer: a multicentre randomised controlled phase III trial.

    PubMed

    Nordlinger, Bernard; Rougier, Philippe; Arnaud, Jean-Pierre; Debois, Muriel; Wils, Jaques; Ollier, Jean-Claude; Grobost, Olivier; Lasser, Philippe; Wals, Jacob; Lacourt, Jerome; Seitz, Jean-François; Guimares dos Santos, Jose; Bleiberg, Harry; Mackiewickz, Rémy; Conroy, Thierry; Bouché, Olivier; Morin, Thierry; Baila, Liliana; van Cutsem, Eric; Bedenne, Laurent

    2005-07-01

    Systemic adjuvant chemotherapy can improve overall survival and reduce the incidence of distant metastases for patients with advanced colon cancer. This study aimed to investigate whether regional chemotherapy (given by intraperitoneal or intraportal methods) combined with systemic chemotherapy was more effective than was systemic chemotherapy alone in terms of survival and recurrence for patients with stage II-III colorectal cancer. The study also compared systemic chemotherapy with fluorouracil and folinic acid with that of fluorouracil and levamisole. During surgery, 753 patients with stage II-III colorectal cancer were randomly assigned to systemic chemotherapy alone (379 with fluorouracil and folinic acid, and 374 with fluorouracil and levamisole), and 748 to postoperative regional chemotherapy with fluorouracil followed by systemic chemotherapy with fluorouracil and folinic acid (n=368) or with fluorouracil and levamisole (n=380). Regional chemotherapy was given intraperitoneally (n=415) or intraportally (n=235) according to institution. The primary endpoint was 5-year overall survival. Secondary endpoints were 5-year disease-free survival and toxic effects. Analyses were by intention to treat. Median follow-up was 6.8 years (range 0.0-10.1). 5-year overall survival was 72.3% (95% CI 69.0-75.6) for patients assigned regional and systemic chemotherapy, compared with 72.0% (68.7-75.3) for those assigned systemic chemotherapy alone (hazard ratio [HR] 0.97 [0.81-1.15], p=0.69). 5-year overall survival for all patients assigned fluorouracil and levamisole was 72.0% (68.7-75.2) compared with 72.3% (69.0-75.6) for all those assigned fluorouracil and folinic acid (HR 0.98 [0.82-1.17], p=0.81). The hazard ratios for 5-year disease-free survival were 0.94 (0.80-1.10) for regional versus non-regional treatment, and 0.92 (0.79-1.08) for all fluorouracil and levamisole versus fluorouracil and folinic acid. Grade 3-4 toxic effects were low in all groups. Fluorouracil

  18. Position-controlled III-V compound semiconductor nanowire solar cells by selective-area metal-organic vapor phase epitaxy.

    PubMed

    Fukui, Takashi; Yoshimura, Masatoshi; Nakai, Eiji; Tomioka, Katsuhiro

    2012-01-01

    We demonstrate position-controlled III-V semiconductor nanowires (NWs) by using selective-area metal-organic vapor phase epitaxy and their application to solar cells. Efficiency of 4.23% is achieved for InP core-shell NW solar cells. We form a 'flexible NW array' without a substrate, which has the advantage of saving natural resources over conventional thin film photovoltaic devices. Four junction NW solar cells with over 50% efficiency are proposed and discussed.

  19. Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results.

    PubMed

    Yang, Xiaohong; Lee, Sang-Rok; Choi, Yun-Seok; Alexander, Veronica J; Digenio, Andres; Yang, Qingqing; Miller, Yury I; Witztum, Joseph L; Tsimikas, Sotirios

    2016-04-01

    Elevated apoC-III levels predict increased cardiovascular risk when present on LDL and HDL particles. We developed novel high-throughput chemiluminescent ELISAs that capture apoB, lipoprotein (a) [Lp(a)], and apoA-I in plasma and then detect apoC-III on these individual lipoproteins as apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoAI complexes, respectively. We assessed the effects on these complexes of placebo or 100-300 mg volanesorsen, a generation 2.0+ antisense drug that targets apoC3 mRNA in patients with hypertriglyceridemia, including familial chylomicronemia syndrome (n = 3), volanesorsen monotherapy (n = 51), and as add-on to fibrate (n = 26), treated for 85 days and followed for 176 days. Compared with placebo, volanesorsen was associated with an 82.3 ± 11.7%, 81.3 ± 15.7%, and 80.8 ± 13.6% reduction in apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoA-I, respectively (300 mg dose;P< 0.001 for all), at day 92. Strong correlations in all assay measures were noted with total plasma apoC-III, chylomicron-apoC-III, and VLDL-apoC-III. In conclusion, novel high-throughput ELISAs were developed to detect lipoprotein-associated apoC-III, including for the first time on Lp(a). Volanesorsen uniformly lowers apoC-III on apoB-100, Lp(a), and apoA-I lipoproteins, and may be a potent agent to reduce triglycerides and cardiovascular risk mediated by apoC-III.

  20. Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results1

    PubMed Central

    Yang, Xiaohong; Lee, Sang-Rok; Choi, Yun-Seok; Alexander, Veronica J.; Digenio, Andres; Yang, Qingqing; Miller, Yury I.; Witztum, Joseph L.; Tsimikas, Sotirios

    2016-01-01

    Elevated apoC-III levels predict increased cardiovascular risk when present on LDL and HDL particles. We developed novel high-throughput chemiluminescent ELISAs that capture apoB, lipoprotein (a) [Lp(a)], and apoA-I in plasma and then detect apoC-III on these individual lipoproteins as apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoAI complexes, respectively. We assessed the effects on these complexes of placebo or 100–300 mg volanesorsen, a generation 2.0+ antisense drug that targets apoC3 mRNA in patients with hypertriglyceridemia, including familial chylomicronemia syndrome (n = 3), volanesorsen monotherapy (n = 51), and as add-on to fibrate (n = 26), treated for 85 days and followed for 176 days. Compared with placebo, volanesorsen was associated with an 82.3 ± 11.7%, 81.3 ± 15.7%, and 80.8 ± 13.6% reduction in apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoA-I, respectively (300 mg dose; P < 0.001 for all), at day 92. Strong correlations in all assay measures were noted with total plasma apoC-III, chylomicron-apoC-III, and VLDL-apoC-III. In conclusion, novel high-throughput ELISAs were developed to detect lipoprotein-associated apoC-III, including for the first time on Lp(a). Volanesorsen uniformly lowers apoC-III on apoB-100, Lp(a), and apoA-I lipoproteins, and may be a potent agent to reduce triglycerides and cardiovascular risk mediated by apoC-III. PMID:26848137

  1. Exploratory analysis of a phase III trial of pirfenidone identifies a subpopulation of patients with idiopathic pulmonary fibrosis as benefiting from treatment.

    PubMed

    Azuma, Arata; Taguchi, Yoshio; Ogura, Takashi; Ebina, Masahito; Taniguchi, Hiroyuki; Kondoh, Yasuhiro; Suga, Moritaka; Takahashi, Hiroki; Nakata, Koichiro; Sato, Atsuhiko; Kudoh, Shoji; Nukiwa, Toshihiro

    2011-10-28

    A phase III trial in Japan showed that pirfenidone is effective for idiopathic pulmonary fibrosis (IPF). To find out which patients specifically benefit from pirfenidone, we analyzed in an exploratory manner the data from the phase III trial. The patients in the phase III trial were stratified by baseline percentage predicted vital capacity (%VC), arterial oxygen partial pressure (PaO(2)), and the lowest oxygen saturation by pulse oximetry (SpO(2)) during the 6-minute steady-state exercise test (6MET). In the subpopulations, changes in VC and subjective symptoms (cough and dyspnea on the Fletcher, Hugh-Jones [F, H-J] Classification scale) were evaluated in patients treated with high-dose (1800 mg/day) pirfenidone, low-dose (1200 mg/day) pirfenidone, and placebo at week 52. Significant efficacy of pirfenidone in reducing the decline in VC could be seen in a subpopulation having %VC ≥ 70% and SpO(2) < 90% at baseline. This favorable effect was accompanied by categorical change in VC and progression-free survival time. In the subpopulation, pirfenidone significantly suppressed cough and dyspnea. IPF patients having %VC ≥ 70% and SpO(2) < 90% at baseline will most likely benefit from pirfenidone when evaluated using changes in VC (and %VC), and cough and dyspnea symptoms. This subpopulation could expect to benefit most from pirfenidone treatment. This clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13th, 2005 (REGISTRATION NUMBER: JAPICCTI-050121).

  2. Lack of effect of perampanel on QT interval duration: Results from a thorough QT analysis and pooled partial seizure Phase III clinical trials.

    PubMed

    Yang, Haichen; Laurenza, Antonio; Williams, Betsy; Patten, Anna; Hussein, Ziad; Ferry, Jim

    2015-08-01

    Perampanel is a selective, noncompetitive AMPA receptor antagonist approved as adjunctive treatment for partial seizures. To assess potential for delayed cardiac repolarization, a Phase I thorough QT study was performed, supplemented by plasma concentration-QT data modeled from 3 pooled Phase III studies. The Phase I thorough QT study (double-blind, combined fixed-sequence, parallel-group) quantified the effect of perampanel (6 mg once daily for 7 days, followed by dose escalation to a single 8-mg dose, a single 10-mg dose, then 12 mg once daily for 7 days), moxifloxacin positive control (single 400-mg dose on Day 16), and placebo on QT interval duration in healthy subjects (N = 261). Electrocardiograms were recorded at baseline, Day 7 (post 6 mg dose), and Day 16 (post 12 mg dose). Statistical comparisons were between the highest approved perampanel dose (12 mg) versus placebo, a "mid-therapeutic" dose (6 mg) versus placebo, and moxifloxacin versus placebo. Acknowledging that the Phase I thorough QT study could not incorporate a true "supratherapeutic" dose due to length of titration and tolerability concerns in healthy subjects, Phase III studies of perampanel included expanded electrocardiogram safety evaluations specifically intended to support concentration-QT response modeling. The lack of effect of perampanel on the QT interval is shown from pooled analysis of 3 double-blind, placebo-controlled, 19-week, Phase III studies with perampanel doses ≤ 12 mg (N = 1038, total perampanel; and N=442, placebo) in patients with partial seizures. QT measures were corrected for heart rate using Fridericia's (QTcF; the primary endpoint) and Bazett's (QTcB) formulas. In the Phase I thorough QT study, the positive control moxifloxacin caused peak time-matched, baseline-adjusted, placebo-corrected (ΔΔ) QTcF of 12.15 ms at 4h postdose, confirming a drug effect on QTc interval and study assessment sensitivity. Mean baseline-adjusted (Δ) QTcF versus nominal time curves were

  3. Hospital resource use of patients receiving isavuconazole vs voriconazole for invasive mold infections in the phase III SECURE trial.

    PubMed

    Horn, David; Goff, Debra; Khandelwal, Nikhil; Spalding, James; Azie, Nkechi; Shi, Fei; Franks, Billy; Shorr, Andrew F

    2016-07-01

    In the phase III SECURE trial, isavuconazole was non-inferior to voriconazole for all-cause mortality for the primary treatment of invasive mold disease (IMD) caused by Aspergillus spp. and other filamentous fungi. This analysis assessed whether hospital resource utilization was different between patients treated with isavuconazole vs voriconazole in SECURE. The analysis population comprised adults with proven/probable/possible IMD enrolled in SECURE. The primary endpoint was hospital length of stay (LOS) in the overall trial population. Patients were also stratified by estimated glomerular filtration rate-modification of diet in renal disease category (< 60 mL/min/1.73 m(2) [moderate-to-severe impairment] and ≥60 mL/min/1.73 m(2) [mild or no impairment]), body mass index (BMI; <25, ≥25-<30, and ≥30 kg/m(2)), and age (≤45, >45-≤65, and >65 years). Data from 516 patients (258 per arm) were evaluated. Overall, median LOS was not statistically significantly different between the isavuconazole (15.0 days) and voriconazole (16.0 days; p = 0.607) arms. Median LOS was statistically significantly shorter in patients with moderate-to-severe renal impairment treated with isavuconazole (9.0 days) vs voriconazole (19.0 days; hazard ratio [HR]: 3.44; 95% confidence interval [CI] = 1.51-7.83). Median LOS was shorter, but not significantly, in patients with a BMI ≥30 kg/m(2) (isavuconazole 13.5 days vs voriconazole 22 days; HR = 1.57; 95% CI = 0.70-3.52) or aged >65 years (isavuconazole 15.0 days vs voriconazole 20.0 days; HR = 1.37; 95% CI = 0.87-2.16). As the patient subgroups analyzed were small, sub-group findings should be interpreted with caution in light of the lack of statistical significance for each sub-group-by-treatment interaction. Isavuconazole may reduce hospital LOS in certain subgroups of patients with IMD, especially those with moderate-to-severe renal impairment.

  4. GASTRICHIP: D2 resection and hyperthermic intraperitoneal chemotherapy in locally advanced gastric carcinoma: a randomized and multicenter phase III study

    PubMed Central

    2014-01-01

    Background In Europe, gastric cancer remains diagnosed at advanced stage (serosal and/or lymph node involvement). Despite curative management combining perioperative systemic chemotherapy and gastrectomy with D1-D2 lymph node dissection, 5-year survival rates of T3 and/or N + patients remain under 30%. More than 50% of recurrences are peritoneal and/or locoregional. The use of adjuvant hyperthermic intraperitoneal chemotherapy that eliminates free cancer cells that can be released into peritoneal cavity during the gastrectomy and prevents peritoneal carcinomatosis recurrences, was extensively evaluated by several randomized trials conducted in Asia. Two meta-analysis reported that adjuvant hyperthermic intraperitoneal chemotherapy significantly reduces the peritoneal recurrences and significantly improves the overall survival. As it was previously done for the evaluation of the extension of lymph node dissection, it seems very important to validate on European or caucasian patients the results observed in trials performed in Asia. Methods/design GASTRICHIP is a prospective, open, randomized multicenter phase III clinical study with two arms that aims to evaluate the effects of hyperthermic intraperitoneal chemotherapy with oxaliplatin on patients with gastric cancer involving the serosa and/or lymph node involvement and/or with positive cytology at peritoneal washing, treated with perioperative systemic chemotherapy and D1-D2 curative gastrectomy. Peroperatively, at the end of curative surgery, patients will be randomized after preoperatively written consent has been given for participation. Primary endpoint will be overall survival from the date of surgery to the date of death or to the end of follow-up (5 years). Secondary endpoint will be 3- and 5-year recurrence-free survival, site of recurrence, morbidity, and quality of life. An ancillary study will compare the incidence of positive peritoneal cytology pre- and post-gastrectomy in two arms of the study

  5. Taking Personalized Medicine Seriously: Biomarker Approaches in Phase IIb/III Studies in Major Depression and Schizophrenia

    PubMed Central

    Laughren, Thomas; Lamers, Femke; Picard, Rosalind; Walther, Sebastian; Goff, Donald; Sainati, Stephen

    2015-01-01

    and integration of such markers into clinical research is both required and feasible in order to meet the benefit of personalized medicine. This article is based on proceedings from the “Taking Personalized Medicine Seriously—Biomarker Approaches in Phase IIb/III Studies in Major Depression and Schizophrenia” session, which was held during the 10th Annual Scientific Meeting of the International Society for Clinical Trials Meeting (ISCTM) in Washington, DC, February 18 to 20, 2014. PMID:25977838

  6. Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer.

    PubMed

    Katakami, Nobuyuki; Harada, Toshiyuki; Murata, Toru; Shinozaki, Katsunori; Tsutsumi, Masakazu; Yokota, Takaaki; Arai, Masatsugu; Tada, Yukio; Narabayashi, Masaru; Boku, Narikazu

    2017-10-02

    Purpose Opioid-induced constipation (OIC) is a frequent and debilitating adverse effect (AE) of opioids-common analgesics for cancer pain. We investigated the efficacy and safety of a peripherally acting μ-opioid receptor antagonist, naldemedine (S-297995), for OIC, specifically in patients with cancer. Patients and Methods This phase III trial consisted of a 2-week, randomized, double-blind, placebo-controlled study (COMPOSE-4) and an open-label, 12-week extension study (COMPOSE-5). In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned on a 1:1 basis to receive once-daily oral naldemedine 0.2 mg or placebo. The primary end point was the proportion of spontaneous bowel movement (SBM) responders (≥ 3 SBMs/week and an increase of ≥ 1 SBM/week from baseline). The primary end point of COMPOSE-5 was safety. Results In COMPOSE-4, 193 eligible patients were randomly assigned to naldemedine (n = 97) or placebo (n = 96). The proportion of SBM responders in COMPOSE-4 was significantly greater with naldemedine than with placebo (71.1% [69 of 97 patients] v 34.4% [33 of 96 patients]; P < .0001). A greater change from baseline was observed with naldemedine than with placebo in the frequency of SBMs/week (5.16 v 1.54; P < .0001), SBMs with complete bowel evacuation/week (2.76 v 0.71; P < .0001), and SBMs without straining/week (3.85 v 1.17; P = .0005). In COMPOSE-4, more patients treated with naldemedine than with placebo reported treatment-emergent AEs (TEAEs) (44.3% [43 of 97 patients] v 26.0% [25 of 96 patients]; P = .01); in COMPOSE-5, 105 (80.2%) of 131 of patients reported TEAEs. Diarrhea was the most frequently reported TEAE in COMPOSE-4 (19.6% [19 of 97 patients] v 7.3% [seven of 96 patients] with naldemedine v placebo) and COMPOSE-5 (18.3% [24 of 131 patients] with naldemedine). Naldemedine was not associated with signs or symptoms of opioid withdrawal and had no notable impact on opioid-mediated analgesia. Conclusion Once-daily oral naldemedine

  7. A Phase III Study of Balugrastim Versus Pegfilgrastim in Breast Cancer Patients Receiving Chemotherapy With Doxorubicin and Docetaxel.

    PubMed

    Gladkov, Oleg; Moiseyenko, Vladimir; Bondarenko, Igor N; Shparyk, Yaroslav; Barash, Steve; Adar, Liat; Avisar, Noa

    2016-01-01

    This study aimed to evaluate the efficacy and safety of once-per-cycle balugrastim versus pegfilgrastim for neutrophil support in breast cancer patients receiving myelosuppressive chemotherapy. Breast cancer patients (n = 256) were randomized to 40 or 50 mg of subcutaneous balugrastim or 6 mg of pegfilgrastim ≈24 hours after chemotherapy (60 mg/m(2) doxorubicin and 75 mg/m(2) docetaxel, every 21 days for up to 4 cycles). The primary efficacy parameter was the duration of severe neutropenia (DSN) in cycle 1. Secondary parameters included DSN (cycles 2-4), absolute neutrophil count (ANC) nadir, febrile neutropenia rates, and time to ANC recovery (cycles 1-4). Safety, pharmacokinetics, and immunogenicity were assessed. Mean cycle 1 DSN was 1.0 day with 40 mg of balugrastim, 1.3 with 50 mg of balugrastim, and 1.2 with pegfilgrastim (upper limit of 95% confidence intervals for between-group DSN differences was <1.0 day for both balugrastim doses versus pegfilgrastim). Between-group efficacy parameters were comparable except for time to ANC recovery in cycle 1 (40 mg of balugrastim, 2.0 days; 50 mg of balugrastim, 2.1; pegfilgrastim, 2.6). Median terminal elimination half-life was ≈37 hours for 40 mg of balugrastim, ≈36 for 50 mg of balugrastim, and ≈45 for pegfilgrastim. Antibody response to balugrastim was low and transient, with no neutralizing effect. Once-per-cycle balugrastim is not inferior to pegfilgrastim in reducing cycle 1 DSN in breast cancer patients receiving chemotherapy; both drugs have comparable safety profiles. This paper provides efficacy and safety data for a new, once-per-cycle granulocyte colony-stimulating factor, balugrastim, for the prevention of chemotherapy-induced neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. In this phase III trial, balugrastim was shown to be not inferior to pegfilgrastim in the duration of severe neutropenia in cycle 1 of doxorubicin/docetaxel chemotherapy, and the safety

  8. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial.

    PubMed

    Ellis, Paul; Barrett-Lee, Peter; Johnson, Lindsay; Cameron, David; Wardley, Andrew; O'Reilly, Susan; Verrill, Mark; Smith, Ian; Yarnold, John; Coleman, Robert; Earl, Helena; Canney, Peter; Twelves, Chris; Poole, Christopher; Bloomfield, David; Hopwood, Penelope; Johnston, Stephen; Dowsett, Mitchell; Bartlett, John M S; Ellis, Ian; Peckitt, Clare; Hall, Emma; Bliss, Judith M

    2009-05-16

    Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration. In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m(2), epirubicin 60 mg/m(2), cyclophosphamide 600 mg/m(2) at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m(2) at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m(2) at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493. All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0.95, 95% CI 0.85-1.08; p=0.44). 75.6% (95% CI 73.7-77.5) of patients in the experimental group and 74.3% (72.3-76.2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0.0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and

  9. Phase I Trial of Erlotinib-Based Multimodality Therapy for Inoperable Stage III Non-small Cell Lung Cancer

    PubMed Central

    Choong, Nicholas W.; Mauer, Ann M.; Haraf, Daniel J.; Lester, Eric; Hoffman, Philip C.; Kozloff, Mark; Lin, Shang; Dancey, Janet E.; Szeto, Livia; Grushko, Tatyana; Olopade, Olufunmilayo I.; Salgia, Ravi; Vokes, Everett E.

    2015-01-01

    Introduction This Phase I trial aimed to determine the maximum-tolerated-dose of erlotinib administered with two standard chemoradiotherapy regimens for non-small cell lung cancer. Methods Unresectable stage III non-small cell lung cancer patients were enrolled in this 2-arm dose-escalation study. Erlotinib, given only during chemoradiotherapy, was escalated from 50 to 150 mg/d in 3 to 6 patient cohorts. Arm A: erlotinib with cisplatin (50 mg/m2 IV days 1, 8, 29, 36), etoposide (50 mg/m2 IV days 1–5, 29–33) and chest radiotherapy (66 Gy, 2 Gy/d) followed by docetaxel (75 mg/m2 IV Q21 d) for 3 cycles. Arm B: induction carboplatin (AUC 6) and paclitaxel (200 mg/m2) for two 21-d cycles then radiotherapy with erlotinib, carboplatin (AUC = 2/wk) and paclitaxel (50 mg/m2/wk). Results Seventeen patients were treated in each arm. Patient characteristics: performance status 0 to 24 patients, 1 to 10 patients, median age 63 years, adenocarcinoma 21% and female 14 patients. Dose-escalation of erlotinib to 150 mg/d was possible on both chemoradiotherapy regimens. Grade 3/4 leukopenia and neutropenia were predominant toxicities in both arms. Grade 3 chemoradiotherapy toxicities in arm A were esophagitis (3 patients), vomiting (1), ototoxicity (1), diarrhea (2), dehydration (3), pneumonitis (1); and arm B was esophagitis (6). Seven patients (21%) developed rash (all grade 1/2). Median survival times for patients on Arm A and B were 10.2 and 13.7 months, respectively. Three-year overall survival in patients with and without rash were 53% and 10%, respectively (log-rank P = 0.0807). Epidermal growth factor receptor IHC or FISH positive patients showed no significant overall survival difference. Conclusion Addition of standard-dose erlotinib to chemoradiotherapy is feasible without evident increase in toxicities. However, the survival data are disappointing in this unselected patient population and does not support further investigation of this approach. PMID:18758303

  10. Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial

    PubMed Central

    Shaw, E; Miró, J M; Puig-Asensio, M; Pigrau, C; Barcenilla, F; Murillas, J; Garcia-Pardo, G; Espejo, E; Padilla, B; Garcia-Reyne, A; Pasquau, J; Rodriguez-Baño, J; López-Contreras, J; Montero, M; de la Calle, C; Pintado, V; Calbo, E; Gasch, O; Montejo, M; Salavert, M; Garcia-Pais, M J; Carratalà, J; Pujol, M

    2015-01-01

    Introduction Despite the availability of new antibiotics such as daptomycin, methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia continues to be associated with high clinical failure rates. Combination therapy has been proposed as an alternative to improve outcomes but there is a lack of clinical studies. The study aims to demonstrate that combination of daptomycin plus fosfomycin achieves higher clinical success rates in the treatment of MRSA bacteraemia than daptomycin alone. Methods and analysis A multicentre open-label, randomised phase III study. Adult patients hospitalised with MRSA bacteraemia will be randomly assigned (1:1) to group 1: daptomycin 10 mg/kg/24 h intravenous; or group 2: daptomycin 10 mg/kg/24 h intravenous plus fosfomycin 2 gr/6 g intravenous. The main outcome will be treatment response at week 6 after stopping therapy (test-of-cure (TOC) visit). This is a composite variable with two values: Treatment success: resolution of clinical signs and symptoms (clinical success) and negative blood cultures (microbiological success) at the TOC visit. Treatment failure: if any of the following conditions apply: (1) lack of clinical improvement at 72 h or more after starting therapy; (2) persistent bacteraemia (positive blood cultures on day 7); (3) therapy is discontinued early due to adverse effects or for some other reason based on clinical judgement; (4) relapse of MRSA bacteraemia before the TOC visit; (5) death for any reason before the TOC visit. Assuming a 60% cure rate with daptomycin and a 20% difference in cure rates between the two groups, 103 patients will be needed for each group (α:0.05, ß: 0.2). Statistical analysis will be based on intention to treat, as well as per protocol and safety analysis. Ethics and dissemination The protocol was approved by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS). The sponsor commits itself to publishing the data in first quartile peer-review journals

  11. Postoperative opioid sparing with injectable hydroxypropyl-β-cyclodextrin-diclofenac: pooled analysis of data from two Phase III clinical trials

    PubMed Central

    Gan, Tong J; Singla, Neil; Daniels, Stephen E; Hamilton, Douglas A; Lacouture, Peter G; Reyes, Christian RD; Carr, Daniel B

    2017-01-01

    Purpose Use of nonopioid analgesics (including nonsteroidal anti-inflammatory drugs) for postoperative pain management can reduce opioid consumption and potentially prevent opioid-related adverse events. This study examined the postoperative opioid-sparing effect of repeated-dose injectable diclofenac formulated with hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac. Patients and methods Pooled data from two double-blind, randomized, placebo- and active comparator-controlled Phase III trials were analyzed. Patients received HPβCD-diclofenac, placebo, or ketorolac by intravenous injection every 6 hours for up to 5 days following abdominal/pelvic or orthopedic surgery. Rescue opioid use was evaluated from the time of first study drug administration to up to 120 hours following the first dose in the overall study population and in subgroups defined by baseline pain severity, age, and HPβCD-diclofenac dose. Results Overall, 608 patients received ≥1 dose of study medication and were included in the analysis. While 93.2% of patients receiving placebo required opioids, the proportion of patients requiring opioids was significantly lower for patients receiving HPβCD-diclofenac (18.75, 37.5, or 50 mg) or ketorolac (P<0.005 for all comparisons). Mean cumulative opioid dose and number of doses were significantly lower among patients receiving HPβCD-diclofenac versus placebo for the 0–24 through 0–120 hour time periods (P<0.0001), as well as versus ketorolac for the 0–72 through 0–120 hour time periods (P<0.05). HPβCD-diclofenac significantly reduced opioid consumption versus placebo in subgroups based on baseline pain severity (moderate, severe) and age (<65 years, ≥65 years) from the 0–24 hour period onward. When compared to ketorolac, HPβCD-diclofenac also significantly reduced cumulative opioid consumption among patients with moderate baseline pain (0–72 through 0–120 hours) and opioid dose number among patients ≥65 years old (0–24 through 0

  12. Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas.

    PubMed

    Galanis, E; Okuno, S H; Nascimento, A G; Lewis, B D; Lee, R A; Oliveira, A M; Sloan, J A; Atherton, P; Edmonson, J H; Erlichman, C; Randlev, B; Wang, Q; Freeman, S; Rubin, J

    2005-03-01

    ONYX-015 is a provisionally replication competent adenovirus with oncolytic activity in cells with malfunctioning p53. Sarcomas represent a rational target for this approach given the high frequency of p53 mutations (40-75%) and MDM-2 amplification (10-30%). We, therefore, undertook a phase I/II study of ONYX-015, days 1-5 every month administered intratumorally under radiographic guidance, in combination with MAP (mitomycin-C, doxorubicin, cisplatin) chemotherapy in patients with advanced sarcoma. Six patients were treated. Injected lesions included liver metastases in four patients and chest wall metastases in two patients. Sarcoma histologies were gastrointestinal stromal tumors (GIST, two patients), leiomyosarcoma (two patients), liposarcoma (one patient), and malignant peripheral nerve sheath tumor (1 patient). Dose escalation was performed from 10(9) plaque forming units (PFU)/dose (total dose of 5 x 10(9) PFU/cycle) to 10(10) PFU/dose (total dose of 5 x 10(10) PFU/cycle) without dose-limiting toxicity being encountered. Immunohistochemistry of the metastatic lesions prior to treatment showed that five out of six patients were positive for p53, while two patients also had mdm-2 overexpression. Adenoviral replication was detected in two out of six patient biopsies on day 5 of the first cycle, by in situ hybridization (ISH). Both patients were treated at the highest dose level. ONYX-015 viral DNA was detected by quantitative PCR in the plasma of 5/6 patients on day 5 of the first cycle, and up to day 12 (7 days after the last viral dose) in one patient who had extended sampling for viral kinetics performed, suggesting viral replication in sarcoma tissue. One patient with p53 mutation and MDM-2 amplification achieved a partial response to treatment that lasted 11 months. In conclusion, intratumoral administration of ONYX-015 in combination with MAP chemotherapy is well tolerated with no significant toxicity due to ONYX-015 being encountered. Detection of viral

  13. Phase III Study of the Efficacy and Safety of Subcutaneous Versus Intravenous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis

    PubMed Central

    Ogata, Atsushi; Tanimura, Kazuhide; Sugimoto, Toyohiko; Inoue, Hiroshi; Urata, Yukitomo; Matsubara, Tsukasa; Kondo, Masakazu; Ueki, Yukitaka; Iwahashi, Mitsuhiro; Tohma, Shigeto; Ohta, Shuji; Saeki, Yukihiko; Tanaka, Toshio

    2014-01-01

    Objective To evaluate the efficacious noninferiority of subcutaneous tocilizumab injection (TCZ-SC) monotherapy to intravenous TCZ infusion (TCZ-IV) monotherapy in Japanese patients with rheumatoid arthritis (RA) with an inadequate response to synthetic and/or biologic disease-modifying antirheumatic drugs (DMARDs). Methods This study had a double-blind, parallel-group, double-dummy, comparative phase III design. Patients were randomized to receive TCZ-SC 162 mg every 2 weeks or TCZ-IV 8 mg/kg every 4 weeks; no DMARDs were allowed during the study. The primary end point was to evaluate the noninferiority of TCZ-SC to TCZ-IV regarding the American College of Rheumatology criteria for 20% improvement in disease activity (ACR20) response rates at week 24 using an 18% noninferiority margin. Additional efficacy, safety, pharmacokinetic, and immunogenicity parameters were assessed. Results At week 24, ACR20 response was achieved in 79.2% (95% confidence interval [95% CI] 72.9, 85.5) of the TCZ-SC group and in 88.5% (95% CI 83.4, 93.5) of the TCZ-IV group; the weighted difference was −9.4% (95% CI −17.6, −1.2), confirming the noninferiority of TCZ-SC to TCZ-IV. Remission rates of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate and the Clinical Disease Activity Index at week 24 were 49.7% and 16.4% in the TCZ-SC group and 62.2% and 23.1% in the TCZ-IV group, respectively. Serum trough TCZ concentrations were similar between the groups over time. Incidences of all adverse events and serious adverse events were 89.0% and 7.5% in the TCZ-SC group and 90.8% and 5.8% in the TCZ-IV group, respectively. Anti-TCZ antibodies were detected in 3.5% of the TCZ-SC group; no serious hypersensitivity was reported in these patients. Conclusion TCZ-SC monotherapy demonstrated comparable efficacy and safety to TCZ-IV monotherapy. TCZ-SC could provide additional treatment options for patients with RA. PMID:23983039

  14. A phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for prostate cancer.

    PubMed

    Newton, Robert U; Taaffe, Dennis R; Spry, Nigel; Gardiner, Robert A; Levin, Gregory; Wall, Bradley; Joseph, David; Chambers, Suzanne K; Galvão, Daniel A

    2009-06-29

    targeting bone density, cardiovascular function, lean and fat mass, physical function and falls risk as primary study endpoints. In terms of advancement of prostate cancer care, we expect dissemination of the knowledge gained from this project to reduce fracture risk, improve physical and functional ability, quality of life and ultimately survival rate in this population. A Phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for prostate cancer; ACTRN12609000200280.

  15. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial

    PubMed Central

    Ellis, Paul; Barrett-Lee, Peter; Johnson, Lindsay; Cameron, David; Wardley, Andrew; O'Reilly, Susan; Verrill, Mark; Smith, Ian; Yarnold, John; Coleman, Robert; Earl, Helena; Canney, Peter; Twelves, Chris; Poole, Christopher; Bloomfield, David; Hopwood, Penelope; Johnston, Stephen; Dowsett, Mitchell; Bartlett, John MS; Ellis, Ian; Peckitt, Clare; Hall, Emma; Bliss, Judith M

    2009-01-01

    Summary Background Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration. Methods In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2 at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m2 at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m2 at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493. Findings All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0·95, 95% CI 0·85–1·08; p=0·44). 75·6% (95% CI 73·7–77·5) of patients in the experimental group and 74·3% (72·3–76·2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0·0001); the most frequent events were neutropenia (937 events vs 797 events

  16. Open-label, randomized, comparative, phase III study on effects of reducing steroid use in combination with Palonosetron

    PubMed Central

    Komatsu, Yoshito; Okita, Kenji; Yuki, Satoshi; Furuhata, Tomohisa; Fukushima, Hiraku; Masuko, Hiroyuki; Kawamoto, Yasuyuki; Isobe, Hiroshi; Miyagishima, Takuto; Sasaki, Kazuaki; Nakamura, Michio; Ohsaki, Yoshinobu; Nakajima, Junta; Tateyama, Miki; Eto, Kazunori; Minami, Shinya; Yokoyama, Ryoji; Iwanaga, Ichiro; Shibuya, Hitoshi; Kudo, Mineo; Oba, Koji; Takahashi, Yasuo

    2015-01-01

    The purpose of this study is to compare the efficacy of a single administration of dexamethasone (DEX) on day 1 against DEX administration on days 1–3 in combination with palonosetron (PALO), a second-generation 5-HT3 receptor antagonist, for chemotherapy-induced nausea and vomiting (CINV) in non-anthracycline and cyclophosphamide (AC) moderately-emetogenic chemotherapy (MEC). This phase III trial was conducted with a multi-center, randomized, open-label, non-inferiority design. Patients who received non-AC MEC as an initial chemotherapy were randomly assigned to either a group administered PALO (0.75 mg, i.v.) and DEX (9.9 mg, i.v.) prior to chemotherapy (study treatment group), or a group administered additional DEX (8 mg, i.v. or p.o.) on days 2–3 (control group). The primary endpoint was complete response (CR) rate. The CR rate difference was estimated by logistic regression with allocation factors as covariates. The non-inferiority margin was set at −15% (study treatment group − control group). From April 2011 to March 2013, 305 patients who received non-AC MEC were randomly allocated to one of two study groups. Overall, the CR rate was 66.2% in the study treatment group (N = 151) and 63.6% in the control group (N = 154). PALO plus DEX day 1 was non-inferior to PALO plus DEX days 1–3 (difference, 2.5%; 95% confidence interval [CI]: −7.8%–12.8%; P-value for non-inferiority test = 0.0004). There were no differences between the two groups in terms of complete control rate (64.9 vs 61.7%) and total control rate (49.7% vs 47.4%). Anti-emetic DEX administration on days 2–3 may be eliminated when used in combination with PALO in patients receiving non-AC MEC. PMID:25872578

  17. A randomized, double-blind, placebo-controlled phase III trial of duloxetine in Japanese fibromyalgia patients.

    PubMed

    Murakami, Masato; Osada, Kenichi; Mizuno, Hiromichi; Ochiai, Toshimitsu; Alev, Levent; Nishioka, Kusuki

    2015-08-22

    Fibromyalgia is characterized by widespread pain and is often accompanied by accessory symptoms. There are limited treatment options for this condition in Japan. Therefore, we conducted a phase III study to assess the efficacy and safety of duloxetine in Japanese patients with fibromyalgia. This randomized, double-blind, placebo-controlled, parallel-group trial was conducted in Japan. Outpatients who met the American College of Rheumatology 1990 criteria for fibromyalgia and whose Brief Pain Inventory (BPI) average pain score was ≥4 were randomized to duloxetine 60 mg or placebo once daily for 14 weeks. The primary efficacy measure was the change in the BPI average pain score from baseline. Secondary efficacy, quality of life (QoL), and safety outcomes were also evaluated. Mixed-effects model repeated-measures (MMRM) analysis and last observation carried forward (LOCF) analysis of covariance were used to evaluate the primary efficacy measure. Overall, 393 patients were randomized to receive either duloxetine (n = 196) or placebo (n = 197). The MMRM analysis revealed no significant difference between duloxetine and placebo regarding the change in BPI average pain scores at week 14. Based on LOCF analysis, a statistically significant improvement in the change in BPI average pain scores at week 14 was observed for patients treated with duloxetine compared with placebo. Duloxetine treatment was associated with improved outcomes in nearly all secondary and post hoc analyses. The treatment was generally well tolerated. Somnolence, nausea, and constipation were the most common treatment-emergent adverse events in the duloxetine group. The discontinuation rates due to treatment-emergent adverse events were similar in both groups. Although the MMRM analysis did not demonstrate superiority of duloxetine over placebo, duloxetine treatment was associated with improved outcomes in secondary and post hoc analyses of the mean change in the BPI average pain score and

  18. Survival Outcomes of Sipuleucel-T Phase III Studies: Impact of Control-Arm Cross-Over to Salvage Immunotherapy.

    PubMed

    George, Daniel J; Nabhan, Chadi; DeVries, Todd; Whitmore, James B; Gomella, Leonard G

    2015-09-01

    Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic/minimally symptomatic metastatic castrate-resistant prostate cancer (CRPC). After disease progression, control-arm patients on three double-blind, randomized phase III sipuleucel-T trials were offered, in nonrandomized open-label protocols, APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control manufacture. These exploratory analyses evaluated potential effects on survival outcomes associated with such treatment. Of 249 control-treated patients, 165 (66.3%) received APC8015F. We explored the effects of APC8015F on the overall survival (OS; Cox regression) of control-arm patients and treatment effects of sipuleucel-T versus control adjusted for APC8015F treatment [iterative parameter estimation model (IPE)]. The median time to first APC8015F infusion was 5.2 months (range, 1.8-33.1) after randomization and 2.2 months (0.5-14.6) after progression. After disease progression, median survival was longer for APC8015F-treated versus control-only treated patients [20.0 vs. 9.8 months; HR, 0.53; 95% confidence interval (CI), 0.38-0.74; P < 0.001]; however, baseline characteristics were more favorable for APC8015F-treated patients. Multivariate regression analyses identified lactate dehydrogenase, alkaline phosphatase, hemoglobin, ECOG status, age, and number of bone metastases as potential (P < 0.1) independent predictors of postprogression survival. After adjusting for these predictors, APC8015F (HR, 0.78; 95% CI, 0.54-1.11; P = 0.17) treatment trended toward improved survival. Estimated median OS benefit for sipuleucel-T versus control adjusted for APC8015F treatment was 3.9 months if APC8015F had no effect and was 8.1 months if APC8015F was equally as effective as sipuleucel-T. Exploratory analyses indicate that APC8015F treatment may have extended patient survival, suggesting the sipuleucel-T OS advantage in CRPC may be more robust than previously estimated.

  19. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide.

    PubMed

    Wick, Wolfgang; Hartmann, Christian; Engel, Corinna; Stoffels, Mandy; Felsberg, Jörg; Stockhammer, Florian; Sabel, Michael C; Koeppen, Susanne; Ketter, Ralf; Meyermann, Richard; Rapp, Marion; Meisner, Christof; Kortmann, Rolf D; Pietsch, Torsten; Wiestler, Otmar D; Ernemann, Ulrike; Bamberg, Michael; Reifenberger, Guido; von Deimling, Andreas; Weller, Michael

    2009-12-10

    The standard of care for anaplastic gliomas is surgery followed by radiotherapy. The NOA-04 phase III trial compared efficacy and safety of radiotherapy followed by chemotherapy at progression with the reverse sequence in patients with newly diagnosed anaplastic gliomas. Patients (N = 318) were randomly assigned 2:1:1 (A:B1:B2) to receive conventional radiotherapy (arm A); procarbazine, lomustine (CCNU), and vincristine (PCV; arm B1); or temozolomide (arm B2) at diagnosis. At occurrence of unacceptable toxicity or disease progression, patients in arm A were treated with PCV or temozolomide (1:1 random assignment), whereas patients in arms B1 or B2 received radiotherapy. The primary end point was time to treatment failure (TTF), defined as progression after radiotherapy and one chemotherapy in either sequence. Patient characteristics in the intention-to-treat population (n = 274) were balanced between arms. All histologic diagnoses were centrally confirmed. Median TTF (hazard ratio [HR] = 1.2; 95% CI, 0.8 to 1.8), progression-free survival (PFS; HR = 1.0; 95% CI, 0.7 to 1.3, and overall survival (HR = 1.2; 95% CI, 0.8 to 1.9) were similar for arms A and B1/B2. Extent of resection was an important prognosticator. Anaplastic oligodendrogliomas and oligoastrocytomas share the same, better prognosis than anaplastic astrocytomas. Hypermethylation of the O(6)-methylguanine DNA-methyltransferase (MGMT) promoter (HR = 0.59; 95% CI, 0.36 to 1.0), mutations of the isocitrate dehydrogenase (IDH1) gene (HR = 0.48; 95% CI, 0.29 to 0.77), and oligodendroglial histology (HR = 0.33; 95% CI, 0.2 to 0.55) reduced the risk of progression. Hypermethylation of the MGMT promoter was associated with prolonged PFS in the chemotherapy and radiotherapy arm. Initial radiotherapy or chemotherapy achieved comparable results in patients with anaplastic gliomas. IDH1 mutations are a novel positive prognostic factor in anaplastic gliomas, with a favorable impact stronger than that of 1p/19q

  20. Bimatoprost Sustained-Release Implants for Glaucoma Therapy: 6-Month Results From a Phase I/II Clinical Trial.

    PubMed

    Lewis, Richard A; Christie, William C; Day, Douglas G; Craven, E Randy; Walters, Thomas; Bejanian, Marina; Lee, Susan S; Goodkin, Margot L; Zhang, Jane; Whitcup, Scott M; Robinson, Michael R

    2017-03-01

    To evaluate the safety and intraocular pressure (IOP)-lowering effect of a biodegradable bimatoprost sustained-release implant (Bimatoprost SR). Phase I/II, prospective, 24-month, dose-ranging, paired-eye controlled clinical trial. At baseline following washout, open-angle glaucoma patients (n = 75) were administered Bimatoprost SR (6 μg, 10 μg, 15 μg, or 20 μg) intracamerally in the study eye; the fellow eye began topical bimatoprost 0.03% once daily. Rescue topical IOP-lowering medication or a single repeat treatment with implant was allowed. The primary endpoint was IOP change from baseline. The main safety measure was adverse events. Results through month 6 are reported. Bimatoprost SR provided rapid, sustained IOP lowering. Overall mean IOP reduction from baseline through week 16 in study eyes was 7.2, 7.4, 8.1, and 9.5 mm Hg with the 6-μg, 10-μg, 15-μg, and 20-μg dose strengths of implant, respectively, vs 8.4 mm Hg in topical bimatoprost-treated pooled fellow eyes (data censored at rescue/retreatment). Rescue/retreatment was not required in 91% and 71% of study eyes up to week 16 and month 6, respectively. Adverse events in study eyes usually occurred within 2 days after the injection procedure and were transient. Conjunctival hyperemia with onset later than 2 days after the injection procedure was more common with topical bimatoprost than Bimatoprost SR (17.3% vs 6.7% of eyes). Bimatoprost SR demonstrated favorable efficacy and safety through 6 months. All dose strengths were comparable to topical bimatoprost in overall IOP reduction through week 16. A single administration controlled IOP in the majority of patients for up to 6 months. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  1. A Phase III Study of Balugrastim Versus Pegfilgrastim in Breast Cancer Patients Receiving Chemotherapy With Doxorubicin and Docetaxel

    PubMed Central

    Gladkov, Oleg; Moiseyenko, Vladimir; Bondarenko, Igor N.; Shparyk, Yaroslav; Barash, Steve; Adar, Liat

    2016-01-01

    Objectives. This study aimed to evaluate the efficacy and safety of once-per-cycle balugrastim versus pegfilgrastim for neutrophil support in breast cancer patients receiving myelosuppressive chemotherapy. Methods. Breast cancer patients (n = 256) were randomized to 40 or 50 mg of subcutaneous balugrastim or 6 mg of pegfilgrastim ≈24 hours after chemotherapy (60 mg/m2 doxorubicin and 75 mg/m2 docetaxel, every 21 days for up to 4 cycles). The primary efficacy parameter was the duration of severe neutropenia (DSN) in cycle 1. Secondary parameters included DSN (cycles 2–4), absolute neutrophil count (ANC) nadir, febrile neutropenia rates, and time to ANC recovery (cycles 1–4). Safety, pharmacokinetics, and immunogenicity were assessed. Results. Mean cycle 1 DSN was 1.0 day with 40 mg of balugrastim, 1.3 with 50 mg of balugrastim, and 1.2 with pegfilgrastim (upper limit of 95% confidence intervals for between-group DSN differences was <1.0 day for both balugrastim doses versus pegfilgrastim). Between-group efficacy parameters were comparable except for time to ANC recovery in cycle 1 (40 mg of balugrastim, 2.0 days; 50 mg of balugrastim, 2.1; pegfilgrastim, 2.6). Median terminal elimination half-life was ≈37 hours for 40 mg of balugrastim, ≈36 for 50 mg of balugrastim, and ≈45 for pegfilgrastim. Antibody response to balugrastim was low and transient, with no neutralizing effect. Conclusion. Once-per-cycle balugrastim is not inferior to pegfilgrastim in reducing cycle 1 DSN in breast cancer patients receiving chemotherapy; both drugs have comparable safety profiles. Implications for Practice: This paper provides efficacy and safety data for a new, once-per-cycle granulocyte colony-stimulating factor, balugrastim, for the prevention of chemotherapy-induced neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. In this phase III trial, balugrastim was shown to be not inferior to pegfilgrastim in the duration of severe neutropenia

  2. Tofacitinib versus methotrexate in rheumatoid arthritis: patient-reported outcomes from the randomised phase III ORAL Start trial

    PubMed Central

    Strand, Vibeke; Lee, Eun Bong; Fleischmann, Roy; Koncz, Tamas; Zwillich, Samuel H; Gruben, David; Wilkinson, Bethanie; Krishnaswami, Sriram; Wallenstein, Gene

    2016-01-01

    Objectives To compare patient-reported outcomes (PROs) in methotrexate (MTX)-naive patients (defined as no prior treatment or ≤3 doses) receiving tofacitinib versus MTX. Methods In the 24-month, phase III, randomised, controlled, ORAL Start trial (NCT01039688), patients were randomised 2:2:1 to receive tofacitinib 5 mg two times per day (n=373), tofacitinib 10 mg two times per day (n=397) or MTX (n=186). PROs assessed included Patient Global Assessment of disease (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and health-related quality of life (Short Form-36 [SF-36]). Results PROs improved following tofacitinib and MTX treatment: benefits were sustained over 24 months. Patients receiving tofacitinib reported earlier responses which were significantly different between each tofacitinib dose and MTX at month 3 through month 24. At month 6 (primary end point), significant improvements versus MTX were observed in PtGA, pain, HAQ-DI, SF-36 Physical Component Summary (PCS), 5/8 domain scores and FACIT-F with tofacitinib 5 mg two times per day; all PROs, except SF-36 Mental Component Summary Score and Medical Outcomes Survey-Sleep, with tofacitinib 10 mg two times per day. At month 6, the proportion of patients reporting improvements ≥minimum clinically important difference were significant versus MTX with tofacitinib 5 mg two times per day in PtGA and 3/8 SF-36 domains; and with tofacitinib 10 mg two times per day in PtGA, pain, HAQ-DI, SF-36 PCS, 4/8 domains and FACIT-F. Conclusions Patients with rheumatoid arthritis receiving tofacitinib 5 and 10 mg two times per day monotherapy versus MTX reported statistically significant and clinically meaningful improvements in multiple PROs over 24 months; onset of benefit with tofacitinib treatment occurred earlier. Trial registration number NCT01039688. PMID:27752357

  3. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial.

    PubMed

    Goldstein, David; El-Maraghi, Robert Hassan; Hammel, Pascal; Heinemann, Volker; Kunzmann, Volker; Sastre, Javier; Scheithauer, Werner; Siena, Salvatore; Tabernero, Josep; Teixeira, Luis; Tortora, Giampaolo; Van Laethem, Jean-Luc; Young, Rosemary; Penenberg, Darryl Neil; Lu, Brian; Romano, Alfredo; Von Hoff, Daniel D

    2015-02-01

    Positive findings from the phase III MPACT trial led to the regulatory approval of nab-paclitaxel plus gemcitabine as a treatment option for patients with metastatic pancreatic cancer. This report is an update of overall survival (OS) based on longer follow-up. Patients (n = 861) with metastatic pancreatic cancer and a Karnofsky performance status of 70 or greater were randomly assigned one to one to receive nab-paclitaxel + gemcitabine or gemcitabine alone. Efficacy data for this post hoc analysis were collected through May 9, 2013. Exploratory analyses of carbohydrate antigen 19-9 (CA19-9) and neutrophil-to-lymphocyte ratio (NLR) were conducted. The primary efficacy endpoint was OS, which was analyzed for all randomly assigned patients by the Kaplan-Meier method. All statistical tests were two-sided. The median OS was statistically significantly longer for nab-paclitaxel plus gemcitabine vs gemcitabine alone (8.7 vs 6.6 months, hazard ratio [HR] = 0.72, 95% confidence interval [CI] = 0.62 to 0.83, P < .001). Long-term (>three-year) survivors were identified in the nab-paclitaxel plus gemcitabine arm only (4%). In pooled treatment arm analyses, higher CA19-9 level and NLR at baseline were statistically significantly associated with worse OS. There appeared to be a treatment effect for OS favoring nab-paclitaxel plus gemcitabine over gemcitabine alone in poor-prognosis subgroups defined by these factors (HR = 0.612, P < .001 for CA19-9 level ≥ median and HR = 0.81, P = .079 for NLR > 5). These data confirm and extend the primary report of OS, supporting the superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone. Subgroup analyses support the relevance of CA 19-9 and NLR as prognostic markers in metastatic pancreatic cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  4. A randomised phase III study comparing high-dose chemotherapy to conventionally dosed chemotherapy for stage III ovarian cancer: the Finnish Ovarian Cancer (FINOVA) study.

    PubMed

    Grénman, Seija; Wiklund, Tom; Jalkanen, Jyrki; Kuoppala, Tapio; Mäenpää, Johanna; Kuronen, Arja; Leminen, Arto; Puistola, Ulla; Vuolo-Merilä, Päivi; Salmi, Tuula; Vuento, Maarit; Yliskoski, Merja; Itälä, Maija; Helenius, Hans; Joensuu, Heikki; Lehtovirta, Pentti

    2006-09-01

    Women with stage III ovarian cancer and with < or = 2 cm residual tumour were randomly assigned to receive either conventionally dosed chemotherapy (group A) or HDCT (group B). Patients allocated to group A received 6 cycles of paclitaxel (T) 135 mg/m2 and cisplatin (P) 75 mg/m2 every 3 weeks, and those allocated to HDCT received 3 TP cycles followed by peripheral blood stem cell mobilisation with cyclophosphamide (C) 3000 mg/m2 and T 175 mg/m2, and subsequently HDCT with carboplatin 1500 mg/m2, C 120 mg/kg, and mitoxantrone 75 mg/m2. The trial was closed early after 42 patients were entered due to slow accrual. The median follow-up time of patients who were alive was 81 months. The median progression-free survival time was 15.9 and 16.6 months (hazard ratio, HR 0.83; 95% CI 0.41-1.69, P = 0.61) and the median overall survival time was 43.7 and 64.3 months (HR, 0.74; 95% CI 0.34-1.61, P = 0.44) in groups A and B, respectively. Although one patient died of HDCT-related toxicity, the regimen was otherwise relatively well tolerated. We conclude that the HDCT regimen used was feasible, but did not result in significantly improved survival in this prematurely closed trial. A clinically important survival benefit cannot be excluded due to the small sample size.

  5. PICASSO III: A Phase III, Placebo-Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft Tissue Sarcoma.

    PubMed

    Ryan, Christopher W; Merimsky, Ofer; Agulnik, Mark; Blay, Jean-Yves; Schuetze, Scott M; Van Tine, Brian A; Jones, Robin L; Elias, Anthony D; Choy, Edwin; Alcindor, Thierry; Keedy, Vicki L; Reed, Damon R; Taub, Robert N; Italiano, Antoine; Garcia Del Muro, Xavier; Judson, Ian R; Buck, Jill Y; Lebel, Francois; Lewis, Jonathan J; Maki, Robert G; Schöffski, Patrick

    2016-09-12

    Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, thereby avoiding the generation of toxic metabolites. The PICASSO III trial compared doxorubicin plus palifosfamide with doxorubicin plus placebo in patients who had received no prior systemic therapy for metastatic soft tissue sarcoma. Patients were randomly assigned 1:1 to receive doxorubicin 75 mg/m(2) intravenously day 1 plus palifosfamide 150 mg/m(2)/d intravenously days 1 to 3 or doxorubicin plus placebo once every 21 days for up to six cycles. The primary end point was progression-free survival (PFS) by independent radiologic review. In all, 447 patients were randomly assigned to receive doxorubicin plus palifosfamide (n = 226) or doxorubicin plus placebo (n = 221). Median PFS was 6.0 months for doxorubicin plus palifosfamide and 5.2 months for doxorubicin plus placebo (hazard ratio, 0.86; 95% CI, 0.68 to 1.08; P = .19). Median overall survival was 15.9 months for doxorubicin plus palifosfamide and 16.9 months for doxorubicin plus placebo (hazard ratio, 1.05; 95% CI, 0.79 to 1.39; P = .74). There was a higher incidence of grade 3 to 4 adverse events in the doxorubicin plus palifosfamide arm (63.6% v 50.9%) including a higher rate of febrile neutropenia (21.4% v 12.6%). No significant difference in PFS was observed in patients receiving doxorubicin plus palifosfamide compared with those receiving doxorubicin plus placebo. The observed median PFS and overall survival in this large, international study can serve as a benchmark for future studies of doxorubicin in metastatic soft tissue sarcoma. © 2016 by American Society of Clinical Oncology.

  6. Selective determination of gold(III) ion using CuO microsheets as a solid phase adsorbent prior by ICP-OES measurement.

    PubMed

    Rahman, Mohammed M; Khan, Sher Bahadar; Marwani, Hadi M; Asiri, Abdullah M; Alamry, Khalid A; Al-Youbi, Abdulrahman O

    2013-01-30

    We have prepared calcined CuO microsheets (MSs) by a wet-chemical process using reducing agents in alkaline medium and characterized by UV/vis., fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffraction (XRD), and field-emission scanning electron microscopy (FESEM) etc. The detailed structural, compositional, and optical characterizations of the MSs were evaluated by XRD pattern, FT-IR, X-ray photoelectron spectroscopy (XPS), and UV-vis spectroscopy, respectively which confirmed that the obtained MSs are well-crystalline CuO and possessed good optical properties. The CuO MSs morphology was investigated by FESEM, which confirmed that the calcined nanomaterials were sheet-shaped and grown in large-quantity. Here, the efficiency of the CuO MS was applied for a selective adsorption of gold(III) ion prior to its detection by inductively coupled plasma-optical emission spectrometry (ICP-OES). The selectivity of CuO MSs towards various metal ions, including Au(III), Cd(II), Co(II), Cr(III), Fe(III), Pd(II), and Zn(II) was analyzed. Based on the adsorption isotherm study, it was confirmed that the selectivity of MSs phase was mostly towards Au(III) ion. The static adsorption capacity for Au(III) was calculated to be 57.0 mg g(-1). From Langmuir adsorption isotherm, it was confirmed that the adsorption process was mainly monolayer-adsorption onto a surface containing a finite number of adsorption sites.

  7. The Systems Approach to Functional Job Analysis. Task Analysis of the Physician's Assistant: Volume II--Curriculum and Phase I Basic Core Courses and Volume III--Phases II and III--Clinical Clerkships and Assignments.

    ERIC Educational Resources Information Center

    Wake Forest Univ., Winston Salem, NC. Bowman Gray School of Medicine.

    This publication contains a curriculum developed through functional job analyses for a 24-month physician's assistant training program. Phase 1 of the 3-phase program is a 6-month basic course program in clinical and bioscience principles and is required of all students regardless of their specialty interest. Phase 2 is a 6 to 10 month period of…

  8. Effect of Protein Incorporation on the Nanostructure of the Bicontinuous Microemulsion Phase of Winsor-III Systems: A Small-Angle Neutron Scattering Study

    SciTech Connect

    Hayes, Douglas G.; Gomez del Rio, Javier A.; Ye, Ran; Urban, Volker S.; Pingali, Sai Venkatesh; O’Neill, Hugh M.

    2015-01-20

    Small-angle neutron scattering (SANS) analysis using the Teubner₋Strey model has been employed to evaluate the effect of protein incorporation into the middle, bicontinuous microemulsion (BμE) phase of Winsor-III (WIII) systems formed by an aerosol-OT (AOT)/alkyl ethoxylate mixed surfactant system to understand better the extraction of proteins into and out of BμEs and to study the effect of proteins on a system that serves as a biomimetic analog of cell membranes. Under conditions of high salinity, the incorporation of positively charged proteins cytochrome c, lysozyme, and α-chymotrypsin, near their solubilization limit in the BμEs promoted the release of water and oil from the BμEs, a decrease in the quasi-periodic repeat distance (d), an increase in ordering (a decrease in the amphiphilicity factor, fa) for the surfactant monolayers, and a decrease in the surface area per surfactant headgroup, suggesting that the proteins affected the self-assembly of components in the BμE phase and produced Debye shielding of AOTs sulfonate headgroup. For WIII systems possessing lower salinity, cytochrome c reduced the efficiency of surfactant in the BμE phase, noted by increases in d and fa, suggesting that the enzyme and AOT underwent ion pairing. We find that the results of this study demonstrate the importance of ionic strength to modulate proteinsurfactant interactions, which in turn will control the release of proteins encapsulated in the BμEs, relevant to WIII-based protein extraction and controlled release from BμE delivery systems, and demonstrate the utility of BμEs as a model system to understand the effect of proteins on biomembranes.

  9. Selenium catalyzed Fe(III)-EDTA reduction by Na2SO3: a reaction-controlled phase transfer catalysis.

    PubMed

    Xiang, Kaisong; Liu, Hui; Yang, Bentao; Zhang, Cong; Yang, Shu; Liu, Zhilou; Liu, Cao; Xie, Xiaofeng; Chai, Liyuan; Min, Xiaobo

    2016-04-01

    Fe(II)-EDTA, a typical chelated iron, is able to coordinate with nitric oxide (NO) which accelerates the rates and kinetics of the absorption of flue gas. However, Fe(II)-EDTA can be easily oxidized to Fe(III)-EDTA which is unable to absorb NO. Therefore, the regeneration of fresh Fe(II)-EDTA, which actually is the reduction of Fe(III)-EDTA to Fe(II)-EDTA, becomes a crucial step in the denitrification process. To enhance the reduction rate of Fe(III)-EDTA, selenium was introduced into the SO3 (2-)/Fe(III)-EDTA system as catalyst for the first time. By comparison, the reduction rate was enhanced by four times after adding selenium even at room temperature (25 °C). Encouragingly, elemental Se could precipitate out when SO3 (2-) was consumed up by oxidation to achieve self-separation. A catalysis mechanism was proposed with the aid of ultraviolet-visible (UV-Vis) spectroscopy, Tyndall scattering, horizontal attenuated total reflection Fourier transform infrared (HATR-FTIR) spectroscopy, and X-ray diffraction (XRD). In the catalysis process, the interconversion between SeSO3 (2-) and nascent Se formed a catalysis circle for Fe(III)-EDTA reduction in SO3 (2-) circumstance.

  10. Accelerating clinical development of HIV vaccine strategies: methodological challenges and considerations in constructing an optimised multi-arm phase I/II trial design.

    PubMed

    Richert, Laura; Doussau, Adélaïde; Lelièvre, Jean-Daniel; Arnold, Vincent; Rieux, Véronique; Bouakane, Amel; Lévy, Yves; Chêne, Geneviève; Thiébaut, Rodolphe

    2014-02-26

    Many candidate vaccine strategies against human immunodeficiency virus (HIV) infection are under study, but their clinical development is lengthy and iterative. To accelerate HIV vaccine development optimised trial designs are needed. We propose a randomised multi-arm phase I/II design for early stage development of several vaccine strategies, aiming at rapidly discarding those that are unsafe or non-immunogenic. We explored early stage designs to evaluate both the safety and the immunogenicity of four heterologous prime-boost HIV vaccine strategies in parallel. One of the vaccines used as a prime and boost in the different strategies (vaccine 1) has yet to be tested in humans, thus requiring a phase I safety evaluation. However, its toxicity risk is considered minimal based on data from similar vaccines. We newly adapted a randomised phase II trial by integrating an early safety decision rule, emulating that of a phase I study. We evaluated the operating characteristics of the proposed design in simulation studies with either a fixed-sample frequentist or a continuous Bayesian safety decision rule and projected timelines for the trial. We propose a randomised four-arm phase I/II design with two independent binary endpoints for safety and immunogenicity. Immunogenicity evaluation at trial end is based on a single-stage Fleming design per arm, comparing the observed proportion of responders in an immunogenicity screening assay to an unacceptably low proportion, without direct comparisons between arms. Randomisation limits heterogeneity in volunteer characteristics between arms. To avoid exposure of additional participants to an unsafe vaccine during the vaccine boost phase, an early safety decision rule is imposed on the arm starting with vaccine 1 injections. In simulations of the design with either decision rule, the risks of erroneous conclusions were controlled <15%. Flexibility in trial conduct is greater with the continuous Bayesian rule. A 12-month gain in

  11. SURFACE CHEMKIN-III: A Fortran package for analyzing heterogeneous chemical kinetics at a solid-surface - gas-phase interface

    SciTech Connect

    Coltrin, M.E.; Kee, R.J.; Rupley, F.M.; Meeks, E.

    1996-05-01

    This document is the user`s manual for the SURFACE CHEMKIN-III package. Together with CHEMKIN-III, this software facilitates the formation, solution, and interpretation of problems involving elementary heterogeneous and gas-phase chemical kinetics in the presence of a solid surface. The package consists of two major software components: an Interpreter and a Surface Subroutine Library. The Interpreter is a program that reads a symbolic description of a user-specified chemical reaction mechanism. One output from the Interpreter is a data file that forms a link to the Surface Subroutine Library, which is a collection of about seventy modular Fortran subroutines that may be called from a user`s application code to return information on chemical production rates and thermodynamic properties. This version of SURFACE CHEMKIN-III includes many modifications to allow treatment of multi-fluid plasma systems, for example modeling the reactions of highly energetic ionic species with a surface. Optional rate expressions allow reaction rates to depend upon ion energy rather than a single thermodynamic temperature. In addition, subroutines treat temperature as an array, allowing an application code to define a different temperature for each species. This version of SURFACE CHEMKIN-III allows use of real (non-integer) stoichiometric coefficients; the reaction order with respect to species concentrations can also be specified independent of the reaction`s stoichiometric coefficients. Several different reaction mechanisms can be specified in the Interpreter input file through the new construct of multiple materials.

  12. Liquid phase epitaxy of binary III-V nanocrystals in thin Si layers triggered by ion implantation and flash lamp annealing

    NASA Astrophysics Data System (ADS)

    Wutzler, Rene; Rebohle, Lars; Prucnal, Slawomir; Bregolin, Felipe L.; Hübner, Rene; Voelskow, Matthias; Helm, Manfred; Skorupa, Wolfgang

    2015-05-01

    The integration of III-V compound semiconductors in Si is a crucial step towards faster and smaller devices in future technologies. In this work, we investigate the formation process of III-V compound semiconductor nanocrystals, namely, GaAs, GaSb, and InP, by ion implantation and sub-second flash lamp annealing in a SiO2/Si/SiO2 layer stack on Si grown by plasma-enhanced chemical vapor deposition. Raman spectroscopy, Rutherford Backscattering spectrometry, and transmission electron microscopy were performed to identify the structural and optical properties of these structures. Raman spectra of the nanocomposites show typical phonon modes of the compound semiconductors. The formation process of the III-V compounds is found to be based on liquid phase epitaxy, and the model is extended to the case of an amorphous matrix without an epitaxial template from a Si substrate. It is shown that the particular segregation and diffusion coefficients of the implanted group-III and group-V ions in molten Si significantly determine the final appearance of the nanostructure and thus their suitability for potential applications.

  13. SCOPE1: a randomised phase II/III multicentre clinical trial of definitive chemoradiation, with or without cetuximab, in carcinoma of the oesophagus

    PubMed Central

    2011-01-01

    Background Chemoradiotherapy is the standard of care for patients with oesophageal cancer unsuitable for surgery due to the presence of co-morbidity or extent of disease, and is a standard treatment option for patients with squamous cell carcinoma of the oesophagus. Modern regimens of chemoradiotherapy can lead to significant long-term survival. However the majority of patients will die of their disease, most commonly with local progression/recurrence of their tumours. Cetuximab may overcome one of the principal mechanisms of tumour radio-resistance, namely tumour repopulation, in patients treated with chemoradiotherapy. The purpose of this research is first to determine whether the addition of cetuximab to definitive chemoradiotherapy for treatment of patients with non-metastatic carcinoma of the oesophagus is active (in terms of failure-free rate), safe, and feasible within the context of a multi-centre randomised controlled trial in the UK. If the first stage is successful then the trial will continue to accrue sufficient patients to establish whether the addition of cetuximab to the standard treatment improves overall survival. Methods/Design SCOPE1 is a two arm, open, randomised multicentre Phase II/III trial. Eligible patients will have histologically confirmed carcinoma of the oesophagus and have been chosen to receive definitive chemoradiotherapy by an accredited multidisciplinary team including a specialist Upper GI surgeon. 420 patients will be randomised to receive definitive chemoradiotherapy with or without cetuximab using a 1:1 allocation ratio. During Phase II of the study, the trial will assess safety (toxicity), activity (failure-free rate) and feasibility (recruitment rate and protocol dose modifications/delays) in 90 patients in the experimental arm. If the experimental arm is found to be active, safe, and feasible by the Independent Data Monitoring Committee then recruitment will continue into Phase III. This second stage will recruit a further

  14. Polymorphism of Alprazolam (Xanax): a review of its crystalline phases and identification, crystallographic characterization, and crystal structure of a new polymorph (form III).

    PubMed

    de Armas, Héctor Novoa; Peeters, Oswald M; Van den Mooter, Guy; Blaton, Norbert

    2007-05-01

    A new polymorphic form of Alprazolam (Xanax), 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo-[4,3-alpha][1,4]benzodiazepine, C(17)H(13)ClN(4), has been investigated by means of X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and differential scanning calorimetry (DSC). This polymorphic form (form III) was obtained during DSC experiments after the exothermic recrystallization of the melt of form I. The crystal unit cell dimensions for form III were determined from diffractometer methods. The monoclinic unit cell found for this polymorph using XRPD after indexing the powder diffractogram was confirmed by the cell parameters obtained from single crystal X-ray diffractometry on a crystal isolated from the DSC pans. The single crystal unit cell parameters are: a = 28.929(9), b = 13.844(8), c = 7.361(3) angstroms, beta = 92.82(3) degrees , V = 2944(2) angstroms(3), Z = 8, space group P2(1) (No.4), Dx = 1.393 Mg/m(3). The structure obtained from single crystal X-ray diffraction was used as initial model for Rietveld refinement on the powder diffraction data of form III. The temperature phase transformations of alprazolam were also studied using high temperature XRPD. A review of the different phases available in the Powder Diffraction File (PDF) database for this drug is described bringing some clarification and corrections. (c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association.

  15. Synthesis of nano-pore samarium (III)-imprinted polymer for preconcentrative separation of samarium ions from other lanthanide ions via solid phase extraction.

    PubMed

    Shirvani-Arani, Simindokht; Ahmadi, Seyed Javad; Bahrami-Samani, Ali; Ghannadi-Maragheh, Mohammad

    2008-08-08

    A batch process was developed to separate samarium ions from some lanthanide ions by a novel solid phase which was prepared via the ion-imprinting technique. The samarium (III) ion-imprinted polymer (IIP) particles were synthesized by preparing the ternary complex of samarium ions with 5,7-dichloroquinoline-8-ol (DCQ) and 4-vinylpyridine (VP). Then, thermally copolymerization with styrene (functional monomer, STY) and divinylbenzene (cross-linking monomer, DVB) followed in the presence of 2-methoxy ethanol (porogen) and 2,2'-azobisisobutyronitrile (initiator, AIBN). The imprinted ion was removed by stirring the above particles with 50% (v/v) HCl to obtain the leached IIP particles. Moreover, control polymer (CP) particles were similarly prepared without the samarium ions. The unleached and leached IIP particles were characterized by X-ray diffraction (XRD), infra-red spectroscopy (IR), thermo gravimetric analysis (TGA) and scanning electron microscopy (SEM). Finally, preconcentration and selectivity studies for samarium and the other lanthanide ions were carried out. The preconcentration of the samarium (III) traces was studied during rebinding with the leached IIP particles as a function of pH, the weight of the polymer material, the preconcentration and the elution times, the eluent volume and the aqueous phase volume. These studies indicated that the samarium (III) amount as low as 1 microg, present in 200 mL, could be preconcentrated into 25 mL of 1.0 M HCl.

  16. Interfacial Area and Interfacial Transfer in Two-Phase Flow Systems (Volume III. Chapters 11-14)

    SciTech Connect

    Guo, T.; Park, J.; Kojasoy, G.

    2003-03-15

    Experiments were performed on horizontal air-water bubbly two-phase flow, axial flow, stratified wavy flow, and annular flow. Theoretical studies were also undertaken on interfacial parameters for a horizontal two-phase flow.

  17. Results of a phase I-II study of fenretinide and rituximab for patients with indolent B-cell lymphoma and mantle cell lymphoma.

    PubMed

    Cowan, Andrew J; Stevenson, Phillip A; Gooley, Ted A; Frayo, Shani L; Oliveira, George R; Smith, Stephen D; Green, Damian J; Roden, Jennifer E; Pagel, John M; Wood, Brent L; Press, Oliver W; Gopal, Ajay K

    2017-02-01

    Fenretinide, a synthetic retinoid, induces apoptotic cell death in B-cell non-Hodgkin lymphoma (B-NHL) and acts synergistically with rituximab in preclinical models. We report results from a phase I-II study of fenretinide with rituximab for B-NHLs. Eligible diagnoses included indolent B-NHL or mantle cell lymphoma. The phase I design de-escalated from fenretinide at 900 mg/m(2) PO BID for days 1-5 of a 7-day cycle. The phase II portion added 375 mg/m(2) IV rituximab weekly on weeks 5-9 then every 3 months. Fenretinide was continued until progression or intolerance. Thirty-two patients were treated: 7 in phase I, and 25 in phase II of the trial. No dose-limiting toxicities were observed. The phase II component utilized fenretinide 900 mg/m(2) twice daily with rituximab. The most common treatment-related adverse events of grade 3 or higher were rash (n = 3) and neutropenia (n = 3). Responses were seen in 6 (24%) patients on the phase II study, with a median duration of response of 47 months (95% confidence interval, 2-56). The combination of fenretinide and rituximab was well tolerated, yielded a modest overall response rate, but with prolonged remission durations. Further study should focus on identifying the responsive subset of B-NHL. © 2017 John Wiley & Sons Ltd.

  18. Improving access to preparatory information for children undergoing general anaesthesia for tooth extraction and their families: study protocol for a Phase III randomized controlled trial

    PubMed Central

    2014-01-01

    Background Children can find anaesthesia induction especially distressing and postoperative psychological and physical morbidity are common. Preparation programmes for general anaesthesia (GA) are highly effective in reducing this distress. A Phase II study has already verified the effectiveness of a prototype preoperative GA-coping computer game to help children cope with induction in a dental GA setting. The biggest patient users of pediatric GA services in the UK are children who need to have teeth removed (estimated to be 100,000 yearly). Tooth decay is the most common disease in children worldwide. This study is a Phase III randomized controlled trial (RCT) and will evaluate the effectiveness of the new internet version of this game. Methods/design The Phase III RCT will use a double-blind three-armed design. The clinical trial will recruit up to 210 children and will compare the web-based game against standard care and another non-medical game. At least 53 patients in each group will be required for 90% statistical power. Distress will be assessed through an evaluation of the child’s behaviour during the visit and later parental reports of physical and psychological morbidity. The satisfaction of parents and children will be measured; the mode of usage of the web-based game will be automatically recorded and the impact on the service (for example, recovery time and throughput) will be reported. The Phase III study primary outcome will measure: (1) patient experience: acceptance of anaesthetic induction, child cooperation and distress, reduction of peri- and postoperative morbidity, child and family satisfaction, and (2) service improvement: anaesthetic time and improvement in throughput. Measures will be administered at baseline, at the time of the GA treatment visit, and at 48 hours and one week postoperatively. Discussion This study aims to determine the effectiveness of an online GA-coping game for children and families undergoing tooth extraction under

  19. Lattice Dynamical Properties of Group-III Nitrides AN (A = B, Al, Ga and In) in Zinc-Blende Phase

    NASA Astrophysics Data System (ADS)

    Kushwaha, A. K.

    2016-03-01

    In the present paper, we have calculated the phonon dispersion relations, phonon density of states, Debye characteristic temperature and the zone boundary phonons for group-III nitrides AN (A = B, Al, Ga and In) using eleven-parameter three-body shell model with both the ions being polarizable. Our calculated results are in good agreement with experimental results available in the literature.

  20. A Phase I/II Study of Oblimersen Plus Cisplatin and Fluorouracil in Gastric & Esophageal Junction Cancer

    ClinicalTrials.gov

    2015-06-10

    Adenocarcinoma of the Esophagus; Adenocarcinoma of the Gastroesophageal Junction; Diffuse Adenocarcinoma of the Stomach; Intestinal Adenocarcinoma of the Stomach; Mixed Adenocarcinoma of the Stomach; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Squamous Cell Carcinoma of the Esophagus; Stage III Esophageal Cancer; Stage IIIA Gastric Cancer; Stage IIIB Gastric Cancer; Stage IIIC Gastric Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer

  1. Primary Analysis of the Phase II Component of a Phase I/II Dose Intensification Study Using Three-Dimensional Conformal Radiation Therapy and Concurrent Chemotherapy for Patients With Inoperable Non–Small-Cell Lung Cancer: RTOG 0117

    PubMed Central

    Bradley, Jeffrey D.; Bae, Kyounghwa; Graham, Mary V.; Byhardt, Roger; Govindan, Ramaswamy; Fowler, Jack; Purdy, James A.; Michalski, Jeff M.; Gore, Elizabeth; Choy, Hak

    2010-01-01

    Purpose Phase I of Radiation Therapy Oncology Group (RTOG) 0117 determined that 74 Gy was the maximum-tolerated dose with concurrent weekly carboplatin/paclitaxel chemotherapy for inoperable non–small-cell lung cancer (NSCLC). Phase II results are reported here. Patients and Methods Patients with unresectable stages I-III NSCLC were eligible. Chemotherapy consisted of weekly paclitaxel at 50 mg/m2 and carboplatin at area under the curve 2 mg/m2. The radiation dose was 74 Gy given in 37 fractions. Radiation therapy volumes included those of the gross tumor and involved nodes. The volume of lung at or exceeding 20 Gy (V20) was mandated to be ≤ 30%. Results Of the combined phase I/II enrollment, a total of 55 patients received 74 Gy, of whom 53 were evaluable. The median follow-up was 19.3 months (range, 0.9 to 57.9 months) for all patients and 25.4 months (range, 13.1 to 57.9 months) for those still alive. The median survival for all patients was 25.9 months. The percentage surviving at least 12 months was 75.5% (95% CI, 65.7% to 85.2%). The median overall survival (OS) and progression-free survival (PFS) times for stage III patients (n = 44) were 21.6 months and 10.8 months, respectively. OS and PFS rates at 12 months were 72.7% and 50.0%, respectively. Twelve patients experienced grade ≥ 3 lung toxicity (two patients had grade 5 lung toxicity). Conclusion The median survival time and OS rate at 12 months for this regimen are encouraging. These results serve as projection expectations for the high-dose radiation arms of the current RTOG 0617 phase III intergroup trial. PMID:20368547

  2. A randomized Phase III trial of thoracoscopic versus open esophagectomy for thoracic esophageal cancer: Japan Clinical Oncology Group Study JCOG1409.

    PubMed

    Kataoka, Kozo; Takeuchi, Hiroya; Mizusawa, Junki; Ando, Masahiko; Tsubosa, Yasuhiro; Koyanagi, Kazuo; Daiko, Hiroyuki; Matsuda, Satoru; Nakamura, Kenichi; Kato, Ken; Kitagawa, Yuko

    2016-02-01

    A randomized Phase III study was commenced in May 2015 to confirm the non-inferiority of thoracoscopic esophagectomy to open esophagectomy in terms of overall survival for clinical Stage I-III esophageal cancer. A total of 300 patients will be accrued from Japanese institutions over 6 years. The primary endpoint is overall survival. The secondary endpoints are relapse-free survival, proportion of patients with R0 resection, proportion of patients who underwent re-operation, adverse events, postoperative respiratory function change, postoperative quality-of-life score (EORTC QLQ-C30), and proportion of patients who need conversion from thoracoscopic surgery to open surgery. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000017628.

  3. Oxidation of chromium(III) by free chlorine in tap water during the chlorination process studied by an improved solid-phase spectrometry.

    PubMed

    Saputro, Sulistyo; Yoshimura, Kazuhisa; Takehara, Kô; Matsuoka, Shiro; Narsito

    2011-01-01

    The oxidation of Cr(III) at naturally-occurring concentration levels, i.e., µg dm(-3) or lower levels, by free chlorine during the chlorination process of tap water was studied using an improved solid-phase spectrophotometric method, which can be directly applicable to the specific determination of Cr(VI) at µg dm(-3) or lower levels. The effect of the pH on the oxidation kinetics was investigated under three different pH conditions. The results showed that free chlorine oxidized the Cr(III) to Cr(VI), following the pseudo-first-order kinetics with half lifetimes of 3.0, 3.3 and 14.4 h at pH 5.0, 7.0 and 8.0, respectively, if the hypochlorite concentration was maintained at 4 mg Cl dm(-3).

  4. The PACOVAR-trial: A phase I/II study of pazopanib (GW786034) and cyclophosphamide in patients with platinum-resistant recurrent, pre-treated ovarian cancer

    PubMed Central

    2011-01-01

    Background The prognosis of patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC) is poor. There is no standard treatment available. Emerging evidence suggests a major role for antiangiogenic treatment modalities in EOC, in particular in combination with the metronomic application of low dose chemotherapy. The novel, investigational oral antiangiogenic agent pazopanib targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit is currently being studied in different tumour types and is already used as first line therapy in recurrent renal cell carcinoma. A combined therapy consisting of pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent, pretreated EOC. Methods/design This study is designed as a multicenter phase I/II trial evaluating the optimal dose for pazopanib (phase I) as well as activity and tolerability of a combination regimen consisting of pazopanib and metronomic cyclophosphamide in the palliative treatment of patients with recurrent, platinum-resistant, pre-treated ovarian cancer (phase II). The patient population includes patients with histologically or cytologically confirmed diagnosis of EOC, cancer of the fallopian tube or peritoneal cancer which is platinumresistant or -refractory. Patients must have measurable disease according to RECIST criteria and must have failed available standard chemotherapy. Primary objectives are determination of the optimal doses for pazopanib (phase I) and the overall response rate according to RECIST criteria (phase II). Secondary objectives are time to progression, overall survival, safety and tolerability. The treatment duration is until disease progression or intolerability of study drug regimen (with a maximum of 13 cycles up to 52 weeks per subject). Discussion The current phase I/II trial shall clarify the potential of the multitargeting antiangiogenic

  5. Correct usage, ease of use, and preference of two dry powder inhalers in patients with COPD: analysis of five phase III, randomized trials

    PubMed Central

    Riley, John H; Tabberer, Maggie; Richard, Nathalie; Donald, Alison; Church, Alison; Harris, Stephanie S

    2016-01-01

    Background Handheld inhalers are used to deliver treatment for COPD. Incorrect usage leads to suboptimal disease control. Complex treatment regimens and use of multiple inhalers may reduce patient compliance. The Anoro Ellipta™ dry powder inhaler (DPI) simultaneously delivers umeclidinium bromide (UMEC) and vilanterol (VI) without coformulation being required. Aim To assess the correct usage and ease of use of the Ellipta™ DPI administering UMEC/VI and to compare patient preference for Ellipta™ with the HandiHaler® through exploratory analyses of patient and observer questionnaires in five Phase III studies. Methods Two Phase III, 3-month double-blind, placebo-controlled studies assessed the correct usage of the Ellipta™ DPI at Day 1 and after 6 weeks, and ease of use of the Ellipta™ DPI using a nonvalidated patient questionnaire after 6 weeks or early withdrawal. In three 6-month, blinded double-dummy, active comparator studies (two Phase IIIa and one Phase IIIb), patients completed a COPD device preference questionnaire between the Ellipta™ DPI and the Handi-Haler® at Day 168 (Week 24) or early withdrawal. Results In the 3-month placebo-controlled studies, ≥98% of patients used the Ellipta™ DPI correctly and 99% of patients found the inhaler easy/very easy-to-use and the dose counter easy/very easy to read. Across the two Phase IIIa active comparator studies, patients consistently stated a preference for the Ellipta™ DPI over HandiHaler® regarding the number of steps to use (59% vs 17%), time taken to use (62% vs 14%), and ease of use (63% vs 15%) regardless of which inhaler contained active drug. Results were consistent in the Phase IIIb active comparator study. Conclusion Delivery of UMEC/VI via the Ellipta™ DPI was considered easy-to-use, and patients with COPD demonstrated clear preference for this inhaler compared with HandiHaler®. PMID:27578968

  6. The PACOVAR-trial: a phase I/II study of pazopanib (GW786034) and cyclophosphamide in patients with platinum-resistant recurrent, pre-treated ovarian cancer.

    PubMed

    Eichbaum, Michael; Mayer, Christine; Eickhoff, Regina; Bischofs, Esther; Gebauer, Gerhard; Fehm, Tanja; Lenz, Florian; Fricke, Hans-Christian; Solomayer, Erich; Fersis, Nikos; Schmidt, Marcus; Wallwiener, Markus; Schneeweiss, Andreas; Sohn, Christof

    2011-10-20

    The prognosis of patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC) is poor. There is no standard treatment available. Emerging evidence suggests a major role for antiangiogenic treatment modalities in EOC, in particular in combination with the metronomic application of low dose chemotherapy. The novel, investigational oral antiangiogenic agent pazopanib targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit is currently being studied in different tumour types and is already used as first line therapy in recurrent renal cell carcinoma. A combined therapy consisting of pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent, pretreated EOC. This study is designed as a multicenter phase I/II trial evaluating the optimal dose for pazopanib (phase I) as well as activity and tolerability of a combination regimen consisting of pazopanib and metronomic cyclophosphamide in the palliative treatment of patients with recurrent, platinum-resistant, pre-treated ovarian cancer (phase II). The patient population includes patients with histologically or cytologically confirmed diagnosis of EOC, cancer of the fallopian tube or peritoneal cancer which is platinumresistant or -refractory. Patients must have measurable disease according to RECIST criteria and must have failed available standard chemotherapy. Primary objectives are determination of the optimal doses for pazopanib (phase I) and the overall response rate according to RECIST criteria (phase II). Secondary objectives are time to progression, overall survival, safety and tolerability. The treatment duration is until disease progression or intolerability of study drug regimen (with a maximum of 13 cycles up to 52 weeks per subject). The current phase I/II trial shall clarify the potential of the multitargeting antiangiogenic tyrosinkinaseinhibitor GW 786034 (pazopanib) in

  7. Water-soluble oxoglaucine-Y(III), Dy(III) complexes: in vitro and in vivo anticancer activities by triggering DNA damage, leading to S phase arrest and apoptosis.

    PubMed

    Wei, Jian-Hua; Chen, Zhen-Feng; Qin, Jiao-Lan; Liu, Yan-Cheng; Li, Zhu-Quan; Khan, Taj-Malook; Wang, Meng; Jiang, Yan-Hua; Shen, Wen-Ying; Liang, Hong

    2015-07-07

    Complexes of yttrium(III) and dysprosium(III) with the traditional Chinese medicine active ingredient oxoglaucine (OG), namely [Y(OG)2(NO3)3]·CH3OH (1) and [Dy(OG)2(NO3)3]·H2O (2), were synthesized and characterized by elemental analysis, IR, ESI-MS, (1)H and (13)C NMR as well as single-crystal X-ray diffraction analysis. In vitro the complexes exhibited higher anticancer activity than the free ligand OG against the tested cancer cell lines. Among the tested cell lines, HepG2 is the most sensitive to the complexes. Complex 2 can trigger DNA damage in HepG2 cells, resulting in cell cycle arrest in the S phase and leading to cell apoptosis. The S phase cell-cycle arrest is caused via the ATM (ataxia-telangiectasia mutated)-Chk2-Cdc25A pathway. Chk2 is phosphorylated and activated in an ATM-dependent manner. It, in turn, phosphorylates Cdc25A phosphatise on serine124, causing the inactivation of Cdc25A in ubiquitin-mediated proteolytic degradation. The cyclin-Cdk complexes of the S phase could also be inhibited by limited supply of cyclins A and E. This irreversible cell cycle arrest process ultimately induces mitochondria-involved apoptotic cell death via the activation of Bcl-2 protein. Complex e2 ffectively inhibited tumour growth in the BEL-7402 xenograft mouse model and exhibited higher safety in vivo than cisplatin.

  8. Adsorption of As(III), As(V) and Cu(II) on zirconium oxide immobilized alginate beads in aqueous phase.

    PubMed

    Kwon, Oh-Hun; Kim, Jong-Oh; Cho, Dong-Wan; Kumar, Rahul; Baek, Seung Han; Kurade, Mayur B; Jeon, Byong-Hun

    2016-10-01

    A composite adsorbent to remove arsenite [As(III)], arsenate [As(V)], and copper [Cu(II)] from aqueous phase was synthesized by immobilizing zirconium oxide on alginate beads (ZOAB). The composition (wt%) of ZOAB (Zr-34.0; O-32.7; C-21.3; Ca-1.0) was confirmed by energy dispersive X-ray (EDX) analysis. Sorption studies were conducted on single and binary sorbate systems, and the effects of contact time, initial adsorbate concentration, and pH on the adsorption performance of ZOAB (pHPZC = 4.3) were monitored. The sorption process for As(III)/As(V) and Cu(II) reached an equilibrium state within 240 h and 24 h, respectively, with maximum sorption capacities of 32.3, 28.5, and 69.9 mg g(-1), respectively. The addition of Cu(II) was favorable for As(V) sorption in contrast to As(III). In the presence of 48.6 mg L(-1) Cu(II), the sorption capacity of As(V) increased from 1.5 to 3.8 mg g(-1) after 240 h. The sorption data for As(III)/As(V) and Cu(II) conformed the Freundlich and Langmuir isotherm models, respectively. The adsorption of As(III), As(V), and Cu(II) followed pseudo second order kinetics. The effect of arsenic species on Cu(II) sorption was insignificant. The results of present study demonstrated that the synthesized sorbent could be useful for the simultaneous removal of both anionic and cationic contaminants from wastewaters.

  9. A Phase I/II adaptive design to determine the optimal treatment regimen from a set of combination immunotherapies in high-risk melanoma.

    PubMed

    Wages, Nolan A; Slingluff, Craig L; Petroni, Gina R

    2015-03-01

    In oncology, vaccine-based immunotherapy often investigates regimens that demonstrate minimal toxicity overall and higher doses may not correlate with greater immune response. Rather than determining the maximum tolerated dose, the goal of the study becomes locating the optimal biological dose, which is defined as a safe dose demonstrating the greatest immunogenicity, based on some predefined measure of immune response. Incorporation of adjuvants, new or optimized peptide vaccines, and combining vaccines with immune modulators may enhance immune response, with the aim of improving clinical response. Innovative dose escalation strategies are needed to establish the safety and immunogenicity of new immunologic combinations. We describe the implementation of an adaptive design for identifying the optimal treatment strategy in a multi-site, FDA-approved, phase I/II trial of a novel vaccination approach using long-peptides plus TLR agonists for resected stage IIB-IV melanoma. Operating characteristics of the design are demonstrated under various possible true scenarios via simulation studies. Overall performance indicates that the design is a practical Phase I/II adaptive method for use with combined immunotherapy agents. The simulation results demonstrate the method's ability to effectively recommend optimal regimens in a high percentage of trials with manageable sample sizes. The numerical results presented in this work include the type of simulation information that aid review boards in understanding design performance, such as average sample size and frequency of early trial termination, which we hope will augment early-phase trial design in cancer immunotherapy.

  10. Phase I/II trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: AIO KRK 0205

    PubMed Central

    Hoehler, T; von Wichert, G; Schimanski, C; Kanzler, S; Moehler, M H; Hinke, A; Seufferlein, T; Siebler, J; Hochhaus, A; Arnold, D; Hallek, M; Hofheinz, R; Hacker, U T

    2013-01-01

    Background: Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer. Methods: Two dose levels (I/II) were defined: capecitabine 850/1000 mg m−2 twice daily on days 1–14; oxaliplatin 100/130 mg m−2 on day 1; bevacizumab 7.5 mg kg−1 on day 1; imatinib 300 mg day−1 on days 1–21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS). Results: Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities. Conclusion: The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy. PMID:23963139

  11. Effect of Teduglutide, a Glucagon-like Peptide 2 Analog, on Citrulline Levels in Patients With Short Bowel Syndrome in Two Phase III Randomized Trials

    PubMed Central

    Seidner, Douglas L; Joly, Francisca; Youssef, Nader N

    2015-01-01

    Objectives: In clinical trials, treatment with the glucagon-like peptide 2 analog teduglutide was associated with improved fluid and nutrient absorption and increased intestinal villus height and crypt depth in patients with short bowel syndrome (SBS). Plasma citrulline, an amino acid produced by enterocytes, is considered a measure of enterocyte mass. This analysis assessed changes in plasma citrulline levels in patients with SBS in 2 phase III clinical studies of teduglutide. Methods: Both teduglutide studies (0.05 or 0.10 mg/kg/day in CL0600-004 and 0.05 mg/kg/day in CL0600-020) were phase III, 24-week, double-blind, and placebo controlled. Plasma citrulline levels were analyzed and validated by liquid chromatography coupled to tandem mass spectrometry. Results: In both the CL0600-004 and CL0600-020 studies, change in mean plasma citrulline concentrations at Week 24 vs. baseline was significantly greater with teduglutide compared with placebo (10.9 (0.05-mg/kg/day dose) and 15.7 (0.10-mg/kg/day dose) vs. 2.0 μmol/L and 20.6 vs. 0.7 μmol/L, respectively, for each study (P≤0.0001 for each comparison with placebo)). Teduglutide treatment was associated with reductions from baseline in PS (parenteral support) volume requirements; however, a significant correlation between PS reduction and increase in plasma citrulline at Week 24 was observed in only one out of the three teduglutide treatment groups. Conclusions: In 2 phase III studies, patients receiving teduglutide had significant increases in plasma citrulline at Week 24 compared with patients receiving placebo. Increases in plasma citrulline concentrations likely reflect enterocyte mass expansion, but no clear correlation was detected between change in plasma citrulline and change in weekly PS volume. PMID:26111125

  12. Dosing considerations for rufinamide in patients with Lennox-Gastaut syndrome: Phase III trial results and real-world clinical data.

    PubMed

    Kothare, Sanjeev; Kluger, Gerhard; Sachdeo, Rajesh; Williams, Betsy; Olhaye, Omar; Perdomo, Carlos; Bibbiani, Francesco

    2017-04-01

    Lennox-Gastaut syndrome (LGS), a rare, severe form of childhood-onset epilepsy, is difficult to control. Rufinamide is indicated for adjunctive treatment of seizures associated with LGS in adults and pediatric patients aged ≥1 year. In clinical practice, rufinamide dosing and titration may differ from the trial setting. Here, rufinamide clinical trial data are compared with real-world experience to provide insight into optimal dosing and titration strategies. Rufinamide Phase III and open-label extension (OLE) studies were reviewed; effect of titration and dose on adverse events (AEs) and concomitant AED use were analyzed. Real-world studies of rufinamide in LGS were identified via PubMed search. Clinical data were extracted and compared. Results demonstrated that a rapid titration schedule (7 or 14 days) of rufinamide was tolerable for most patients and resulted in highly significant reductions in total and tonic-atonic seizures, with efficacy and tolerability sustained over 3 years. The most common AEs during the Phase III study - somnolence, vomiting, and pyrexia - occurred during the first 3 weeks of treatment, and a small subset of patients were unable to reach target dose in that time. Use of concomitant AEDs had no clinically significant effect on plasma concentrations of rufinamide. Data from real-world clinical studies are consistent with the Phase III and OLE study results. However, relative to those used in clinical trials, lower doses and slower titration schedules were commonly employed in real-world settings. A lower dose and slower titration schedule ("low and slow") may reduce incidence of AEs without compromising efficacy of rufinamide in LGS. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  13. Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer

    PubMed Central

    Mochiki, E; Ohno, T; Kamiyama, Y; Aihara, R; Haga, N; Ojima, H; Nakamura, J; Ohsawa, H; Nakabayashi, T; Takeuchi, K; Asao, T; Kuwano, H

    2006-01-01

    Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80 mg m−2 day−1 from days 1 to 14 of a 28-day cycle. Paclitaxel was given intravenously on days 1, 8, and 15, starting with a dose of 40 mg m−2 day−1. The dose was increased in a stepwise manner to 70 mg m−2. Treatment was repeated every 4 weeks unless disease progression was confirmed. In the phase I portion, 17 patients were enrolled. The MTD of paclitaxel was estimated to be 70 mg m−2 because 40% of the patients given this dose level (two of five) had DLT. The RD was determined to be 60 mg m−2. In the phase II portion, 24 patients, including five with assessable disease who received the RD in the phase I portion, were evaluated. The median number of treatment courses was six (range: 1–17). The incidence of the worst-grade toxicity in patients given the RD was 28 and 8%, respectively. All toxic effects were manageable. The response rate was 54.1%, and the median survival time was 15.5 months. Our phase I/II trial showed that S-1 combined with paclitaxel is effective and well tolerated in patients with advanced gastric cancer. PMID:17133268

  14. Phase Coupling in Langmuir Wave Packets: Evidence for Four Wave Interactions in Solar Type III Radio Bursts

    NASA Technical Reports Server (NTRS)

    Thejappa, G.; MacDowall, R. J.; Bergamo, M.

    2012-01-01

    The four wave interaction process, known as the oscillating two stream instability (OTSI) is considered as one of the mechanisms responsible for stabilizing the electron beams associated with solar type III radio bursts. It has been reported that (1) an intense localized Langmuir wave packet associated with a type III burst contains the spectral characteristics of the OTSI: (a) a resonant peak at the local electron plasma frequency, f(sub pe), (b) a Stokes peak at a frequency slightly lower than f(sub pe), (c) anti-Stokes peak at a frequency slightly higher than f(sub pe), and (d) a low frequency enhancement below a few hundred Hz, (2) the frequencies and wave numbers of these spectral components satisfy the resonance conditions of the OTSI, and (3) the peak intensity of the wave packet is well above the thresholds for the OTSI as well as spatial collapse of envelope solitons. Here, for the first time, applying the trispectral analysis on this wave packet, we show that the tricoherence, which measures the degree of coherent four-wave coupling amongst the observed spectral components exhibits a peak. This provides an additional evidence for the OTSI and related spatial collapse of Langmuir envelope solitons in type III burst sources.

  15. Chitosan film loaded with silver nanoparticles-sorbent for solid phase extraction of Al(III), Cd(II), Cu(II), Co(II), Fe(III), Ni(II), Pb(II) and Zn(II).

    PubMed

    Djerahov, Lubomir; Vasileva, Penka; Karadjova, Irina; Kurakalva, Rama Mohan; Aradhi, Keshav Krishna

    2016-08-20

    The present study describes the ecofriendly method for the preparation of chitosan film loaded with silver nanoparticles (CS-AgNPs) and application of this film as efficient sorbent for separation and enrichment of Al(III), Cd(II), Cu(II), Co(II), Fe(III), Ni(II), Pb(II) and Zn(II). The stable CS-AgNPs colloid was prepared by dispersing the AgNPs sol in chitosan solution at appropriate ratio and further used to obtain a cast film with very good stability under storage and good mechanical strength for easy handling in aqueous medium. The incorporation of AgNPs in the structure of CS film and interaction between the polymer matrix and nanoparticles were confirmed by UV-vis and FTIR spectroscopy. The homogeneously embedded AgNPs (average diameter 29nm, TEM analysis) were clearly observed throughout the film by SEM. The CS-AgNPs nanocomposite film shows high sorption activity toward trace metals under optimized chemical conditions. The results suggest that the CS-AgNPs nanocomposite film can be feasibly used as a novel sorbent material for solid-phase extraction of metal pollutants from surface waters.

  16. DEMONSTRATION OF FUEL CELLS TO RECOVER ENERGY FROM LANDFILL GAS - PHASE III. DEMONSTRATION TESTS - PHASE IV. GUIDELINES AND DEMONSTRATIONS - VOLUME 2. APPENDICES

    EPA Science Inventory

    The report summarizes the results of a four-phase program to demonstrate that fuel cell energy recovery using a commercial phosphoric acid fuel cell is both environmentally sound and commercially feasible. Phase I, a conceptual design and evaluation study, addressed the technical...

  17. DEMONSTRATION OF FUEL CELLS TO RECOVER ENERGY FROM LANDFILL GAS - PHASE III. DEMONSTRATION TESTS - PHASE IV. GUIDELINES AND RECOMMENDATIONS- VOLUME 1. TECHNICAL REPORT

    EPA Science Inventory

    The report summarizes the results of a four-phase program to demonstrate that fuel cell energy recovery using a commercial phosphoric acid fuel cell is both environmentally sound and commercially feasible. Phase I, a conceptual design and evaluation study, addressed the technical...

  18. DEMONSTRATION OF FUEL CELLS TO RECOVER ENERGY FROM LANDFILL GAS - PHASE III. DEMONSTRATION TESTS - PHASE IV. GUIDELINES AND DEMONSTRATIONS - VOLUME 2. APPENDICES

    EPA Science Inventory

    The report summarizes the results of a four-phase program to demonstrate that fuel cell energy recovery using a commercial phosphoric acid fuel cell is both environmentally sound and commercially feasible. Phase I, a conceptual design and evaluation study, addressed the technical...

  19. DEMONSTRATION OF FUEL CELLS TO RECOVER ENERGY FROM LANDFILL GAS - PHASE III. DEMONSTRATION TESTS - PHASE IV. GUIDELINES AND RECOMMENDATIONS- VOLUME 1. TECHNICAL REPORT

    EPA Science Inventory

    The report summarizes the results of a four-phase program to demonstrate that fuel cell energy recovery using a commercial phosphoric acid fuel cell is both environmentally sound and commercially feasible. Phase I, a conceptual design and evaluation study, addressed the technical...

  20. Use of vancomycin silica stationary phase in packed capillary electrochromatography: III. enantiomeric separation of basic compounds with the polar organic mobile phase.

    PubMed

    Fanali, Salvatore; Catarcini, Paolo; Quaglia, Maria Giovanna

    2002-02-01

    The separation of basic compounds into their enantiomers was achieved using capillary electrochromatography in 50 or 75 microm inner diameter (ID) fused-silica capillaries packed with silica a stationary phase derivatized with vancomycin and mobile phases composed of mixtures of polar organic solvents containing 13 mM ammonium acetate. Enantiomer resolution, electroosmotic flow, and the number of theoretical plates were strongly influenced by the type and concentration of the organic solvent. Mobile phases composed of 13 mM ammonium acetate dissolved in mixtures of acetonitrile/methanol, ethanol, n-propanol, or isopropanol were tested and the highest enantioresolutions were achieved using the first mobile phase, allowing the separation of almost all investigated enantiomers (9 from 11 basic compounds). The use of capillaries with different ID (50 and 75 microm ID) packed with the same chiral stationary phase revealed that a higher number of theoretical plates and higher enantioresolution was achieved with the tube with lowest ID.

  1. Phase I/II Study of Erlotinib Combined With Cisplatin and Radiotherapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

    SciTech Connect

    Herchenhorn, Daniel; Dias, Fernando L.; Viegas, Celia M.P.; Federico, Miriam H.; Araujo, Carlos Manoel M.; Small, Isabelle; Bezerra, Marcos; Fontao, Karina M.D.; Knust, Renata E.; Ferreira, Carlos G.; Martins, Renato G.

    2010-11-01

    Purpose: Erlotinib, an oral tyrosine kinase inhibitor, is active against head-and-neck squamous cell carcinoma (HNSCC) and possibly has a synergistic interaction with chemotherapy and radiotherapy. We investigated the safety and efficacy of erlotinib added to cisplatin and radiotherapy in locally advanced HNSCC. Methods and Materials: In this Phase I/II trial 100 mg/m{sup 2} of cisplatin was administered on Days 8, 29, and 50, and radiotherapy at 70 Gy was started on Day 8. During Phase I, the erlotinib dose was escalated (50 mg, 100 mg, and 150 mg) in consecutive cohorts of 3 patients, starting on Day 1 and continuing during radiotherapy. Dose-limiting toxicity was defined as any Grade 4 event requiring radiotherapy interruptions. Phase II was initiated 8 weeks after the last Phase I enrollment. Results: The study accrued 9 patients in Phase I and 28 in Phase II; all were evaluable for efficacy and safety. No dose-limiting toxicity occurred in Phase I, and the recommended Phase II dose was 150 mg. The most frequent nonhematologic toxicities were nausea/vomiting, dysphagia, stomatitis, xerostomia and in-field dermatitis, acneiform rash, and diarrhea. Of the 31 patients receiving a 150-mg daily dose of erlotinib, 23 (74%; 95% confidence interval, 56.8%-86.3%) had a complete response, 3 were disease free after salvage surgery, 4 had inoperable residual disease, and 1 died of sepsis during treatment. With a median 37 months' follow-up, the 3-year progression-free and overall survival rates were 61% and 72%, respectively. Conclusions: This combination appears safe, has encouraging activity, and deserves further studies in locally advanced HNSCC.

  2. Project 8, Phase III Design: Placing an eV-Scale Limit on the Neutrino Mass using Cyclotron Radiation Emission Spectroscopy

    NASA Astrophysics Data System (ADS)

    Oblath, Noah; Project 8 Collaboration

    2016-09-01

    We report on the design concept for Phase III of the Project 8 experiment. In the third phase of Project 8 we aim to place a limit on the neutrino mass that is similar to the current limits set by tritium beta-decay experiments, mν < 2eV . From the first two phases of Project 8 we move to a novel design consisting of a 100cm3 cylindrical volume of tritium gas instrumented with two 30-element rings of inward-facing antennas. Beam-forming techniques similar to those used in radioastronomy will be employed to search for and track electron signals in the fiducial volume. This talk will present the quantitative design concept for the phased-array receiver, and illustrate how we are progressing towards the Phase IV experiment, which will have sensitivity to the neutrino mass scale allowed by the inverted mass hierarchy. This work is supported by the DOE Office of Science Early Career Research Program, and the Laboratory Directed Research and Development Program at Pacific Northwest National Laboratory.

  3. Eight Cycles of ABVD Versus Four Cycles of BEACOPPescalated Plus Four Cycles of BEACOPPbaseline in Stage III to IV, International Prognostic Score ≥ 3, High-Risk Hodgkin Lymphoma: First Results of the Phase III EORTC 20012 Intergroup Trial.

    PubMed

    Carde, Patrice; Karrasch, Matthias; Fortpied, Catherine; Brice, Pauline; Khaled, Hussein; Casasnovas, Olivier; Caillot, Denis; Gaillard, Isabelle; Bologna, Serge; Ferme, Christophe; Lugtenburg, Pieternella Johanna; Morschhauser, Frank; Aurer, Igor; Coiffier, Bertrand; Meyer, Ralph; Seftel, Matthew; Wolf, Max; Glimelius, Bengt; Sureda, Anna; Mounier, Nicolas

    2016-06-10

    To compare patients with high-ris