Science.gov

Sample records for patients phase iii

  1. 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

  2. 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

  3. Magnetic Resonance–Guided Focused Ultrasound for Patients With Painful Bone Metastases: Phase III Trial Results

    PubMed Central

    Ghanouni, Pejman; Kanaev, Sergey V.; Iozeffi, Dmitri; Gianfelice, David; Fennessy, Fiona Mary; Kuten, Abraham; Meyer, Joshua E.; LeBlang, Suzanne D.; Roberts, Ann; Choi, Junsung; Larner, James M.; Napoli, Alessandro; Turkevich, Vladimir G.; Inbar, Yael; Tempany, Clare Mary C.; Pfeffer, Raphael M.

    2014-01-01

    Background Pain due to bone metastases is a common cause of cancer-related morbidity, with few options available for patients refractory to medical therapies and who do not respond to radiation therapy. This study assessed the safety and efficacy of magnetic resonance-guided focused ultrasound surgery (MRgFUS), a noninvasive method of thermal tissue ablation for palliation of pain due to bone metastases. Methods Patients with painful bone metastases were randomly assigned 3:1 to receive MRgFUS sonication or placebo. The primary endpoint was improvement in self-reported pain score without increase of pain medication 3 months after treatment and was analyzed by Fisher’s exact test. Components of the response composite, Numerical Rating Scale for pain (NRS) and morphine equivalent daily dose intake, were analyzed by t test and Wilcoxon rank-sum test, respectively. Brief Pain Inventory (BPI-QoL), a measure of functional interference of pain on quality of life, was compared between MRgFUS and placebo by t test. Statistical tests were two-sided. Results One hundred forty-seven subjects were enrolled, with 112 and 35 randomly assigned to MRgFUS and placebo treatments, respectively. Response rate for the primary endpoint was 64.3% in the MRgFUS arm and 20.0% in the placebo arm (P < .001). MRgFUS was also superior to placebo at 3 months on the secondary endpoints assessing worst score NRS (P < .001) and the BPI-QoL (P < .001). The most common treatment-related adverse event (AE) was sonication pain, which occurred in 32.1% of MRgFUS patients. Two patients had pathological fractures, one patient had third-degree skin burn, and one patient suffered from neuropathy. Overall 60.3% of all AEs resolved on the treatment day. Conclusions This multicenter phase III trial demonstrated that MRgFUS is a safe and effective, noninvasive treatment for alleviating pain resulting from bone metastases in patients that have failed standard treatments. PMID:24760791

  4. 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

  5. A Phase I/II Trial of Topotecan and Radiation Therapy for Brain Metastases in Patients With Solid Tumors

    SciTech Connect

    Hedde, Jan-Peter; Neuhaus, Thomas . E-mail: t.neuhaus@jk-bonn.de; Schueller, Heinrich; Metzler, Ute; Schmidt-Wolf, Ingo G.H.; Kleinschmidt, Rolf; Losem, Christoph; Lange, Oliver; Grohe, Christian; Stier, Sebastian; Ko, Yon-Dschun

    2007-07-01

    Purpose: Outcomes in patients with brain metastases undergoing whole-brain radiotherapy (WBRT) are hardly encouraging, and an improvement in results is therefore needed. One possible approach is the addition of chemotherapeutics. However the data presented thus far are also disappointing. A promising substance in this setting could become topotecan, which is known to cross the blood-brain barrier and additionally offers radiosensitizing effects. Therefore we performed a phase I/II trial to evaluate the feasibility of a concurrent radiochemotherapy regimen. Methods and Materials: From January 1999 to July 2001, a total of 75 patients (10 in phase I and 65 in phase II) were included. The WBRT was applied with a fraction size of 2 Gy/day for a total of 40 Gy. Topotecan was administered as a 30-min infusion with 0.2 to 0.5 mg/m{sup 2}/day for 5 days over 4 weeks within 2 h to radiation therapy. Results: Because of the higher toxic rates seen in patients receiving 0.5 mg/m{sup 2}/day, the recommended dosage for phase II was 0.4 mg/m{sup 2}/day. In this group Grade 3/4 hematologic and nonhematologic side effects occurred in 19% and 21% of the patients, respectively. The overall response rate was 72% with an overall survival of 17 weeks and 30 weeks among the responders. Conclusions: Based on the moderate toxicity profile presented here we recommend to perform a phase III trial to confirm the promising phase I/II data.

  6. A Phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma

    PubMed Central

    Larkin, J M G; Hughes, S A; Beirne, D A; Patel, P M; Gibbens, I M; Bate, S C; Thomas, K; Eisen, T G; Gore, M E

    2006-01-01

    Temozolomide is an alkylating agent with activity in the treatment of melanoma metastatic to the brain. Lomustine is a nitrosurea that crosses the blood brain barrier and there is evidence to suggest that temozolomide may reverse resistance to lomustine. A multicentre phase I/II study was conducted to assess the maximum-tolerated dose (MTD), safety and efficacy of the combination of temozolomide and lomustine in melanoma metastatic to the brain. Increasing doses of temozolomide and lomustine were administered in phase I of the study to determine the MTD. Patients were treated at the MTD in phase II of the study to six cycles, disease progression or unacceptable toxicity. Twenty-six patients were enrolled in the study. In phase I of the study, the MTD was defined as temozolomide 150 mg m−2 days 1–5 every 28 days and lomustine 60 mg m–2 on day 5 every 56 days. Dose-limiting neutropaenia and thrombocytopaenia were observed at higher doses. Twenty patients were treated at this dose in phase II of the study. No responses to therapy were observed. Median survival from starting chemotherapy was 2 months. The combination of temozolomide and lomustine in patients with brain metastases from melanoma does not demonstrate activity. The further evaluation of this combination therefore is not warranted. PMID:17146474

  7. A phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma.

    PubMed

    Larkin, J M G; Hughes, S A; Beirne, D A; Patel, P M; Gibbens, I M; Bate, S C; Thomas, K; Eisen, T G; Gore, M E

    2007-01-15

    Temozolomide is an alkylating agent with activity in the treatment of melanoma metastatic to the brain. Lomustine is a nitrosurea that crosses the blood brain barrier and there is evidence to suggest that temozolomide may reverse resistance to lomustine. A multicentre phase I/II study was conducted to assess the maximum-tolerated dose (MTD), safety and efficacy of the combination of temozolomide and lomustine in melanoma metastatic to the brain. Increasing doses of temozolomide and lomustine were administered in phase I of the study to determine the MTD. Patients were treated at the MTD in phase II of the study to six cycles, disease progression or unacceptable toxicity. Twenty-six patients were enrolled in the study. In phase I of the study, the MTD was defined as temozolomide 150 mg m(-2) days 1-5 every 28 days and lomustine 60 mg m(-2) on day 5 every 56 days. Dose-limiting neutropaenia and thrombocytopaenia were observed at higher doses. Twenty patients were treated at this dose in phase II of the study. No responses to therapy were observed. Median survival from starting chemotherapy was 2 months. The combination of temozolomide and lomustine in patients with brain metastases from melanoma does not demonstrate activity. The further evaluation of this combination therefore is not warranted. PMID:17146474

  8. 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.

  9. 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.

  10. A Multicenter Phase I/II Study of the BCNU Implant (Gliadel ® Wafer) for Japanese Patients with Malignant Gliomas

    PubMed Central

    AOKI, Tomokazu; NISHIKAWA, Ryo; SUGIYAMA, Kazuhiko; NONOGUCHI, Naosuke; KAWABATA, Noriyuki; MISHIMA, Kazuhiko; ADACHI, Jun-ichi; KURISU, Kaoru; YAMASAKI, Fumiyuki; TOMINAGA, Teiji; KUMABE, Toshihiro; UEKI, Keisuke; HIGUCHI, Fumi; YAMAMOTO, Tetsuya; ISHIKAWA, Eiichi; TAKESHIMA, Hideo; YAMASHITA, Shinji; ARITA, Kazunori; HIRANO, Hirofumi; YAMADA, Shinobu; MATSUTANI, Masao

    2014-01-01

    Carmustine (BCNU) implants (Gliadel® Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent MGs. After the insertion of BCNU implants (8 sheets maximum, 61.6 mg BCNU) into the removal cavity, various chemotherapies (including temozolomide) and radiotherapies were applied. After placement, overall and progression-free survival rates and whole blood BCNU levels were evaluated. In patients with newly diagnosed MGs, the overall survival rates at 12 months and 24 months were 100.0% and 68.8%, and the progression-free survival rate at 12 months was 62.5%. In patients with recurrent MGs, the progression-free survival rate at 6 months was 37.5%. There were no grade 4 or higher adverse events noted due to BCNU implants, and grade 3 events were observed in 5 of 24 patients (20.8%). Whole blood BCNU levels reached a peak of 19.4 ng/mL approximately 3 hours after insertion, which was lower than 1/600 of the peak BCNU level recorded after intravenous injections. These levels decreased to less than the detection limit (2.00 ng/mL) after 24 hours. The results of this study involving Japanese patients are comparable to those of previous studies in the United States and Europe. PMID:24739422

  11. 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

  12. 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

  13. Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study

    PubMed Central

    Nilsson, S.; Cislo, P.; Sartor, O.; Vogelzang, N. J.; Coleman, R. E.; O'Sullivan, J. M.; Reuning-Scherer, J.; Shan, M.; Zhan, L.; Parker, C.

    2016-01-01

    Background Radium-223 dichloride (radium-223), a first-in-class α-emitting radiopharmaceutical, is recommended in both pre- and post-docetaxel settings in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases based on overall survival benefit demonstrated in the phase III ALSYMPCA study. ALSYMPCA included prospective measurements of health-related quality of life (QOL) using two validated instruments: the general EuroQoL 5D (EQ-5D) and the disease-specific Functional Assessment of Cancer Therapy-Prostate (FACT-P). Patients and methods Analyses were conducted to determine treatment effects of radium-223 plus standard of care (SOC) versus placebo plus SOC on QOL using FACT-P and EQ-5D. Outcomes assessed were percentage of patients experiencing improvement, percentage of patients experiencing worsening, and mean QOL scores during the study. Results Analyses were carried out on the intent-to-treat population of patients randomized to receive radium-223 (n = 614) or placebo (n = 307). The mean baseline EQ-5D utility and FACT-P total scores were similar between treatment groups. A significantly higher percentage of patients receiving radium-223 experienced meaningful improvement in EQ-5D utility score on treatment versus placebo {29.2% versus 18.5%, respectively; P = 0.004; odds ratio (OR) = 1.82 [95% confidence interval (CI) 1.21–2.74]}. Findings were similar for FACT-P total score [24.6% versus 16.1%, respectively; P = 0.020; OR = 1.70 (95% CI 1.08–2.65)]. A lower percentage of patients receiving radium-223 experienced meaningful worsening versus placebo measured by EQ-5D utility score and FACT-P total score. Prior docetaxel use and current bisphosphonate use did not affect these findings. Treatment was a significant predictor of EQ-5D utility score, with radium-223 associated with higher scores versus placebo (0.56 versus 0.50, respectively; P = 0.002). Findings were similar for FACT-P total score (99.08 versus 95

  14. Confirmation of model-based dose selection for a Japanese phase III study of rivaroxaban in non-valvular atrial fibrillation patients.

    PubMed

    Kaneko, Masato; Tanigawa, Takahiko; Hashizume, Kensei; Kajikawa, Mariko; Tajiri, Masahiro; Mueck, Wolfgang

    2013-01-01

    This study was designed to confirm the appropriateness of the dose setting for a Japanese phase III study of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF), which had been based on model simulation employing phase II study data. The previously developed mixed-effects pharmacokinetic/pharmacodynamic (PK-PD) model, which consisted of an oral one-compartment model parameterized in terms of clearance, volume and a first-order absorption rate, was rebuilt and optimized using the data for 597 subjects from the Japanese phase III study, J-ROCKET AF. A mixed-effects modeling technique in NONMEM was used to quantify both unexplained inter-individual variability and inter-occasion variability, which are random effect parameters. The final PK and PK-PD models were evaluated to identify influential covariates. The empirical Bayes estimates of AUC and C(max) from the final PK model were consistent with the simulated results from the Japanese phase II study. There was no clear relationship between individual estimated exposures and safety-related events, and the estimated exposure levels were consistent with the global phase III data. Therefore, it was concluded that the dose selected for the phase III study with Japanese NVAF patients by means of model simulation employing phase II study data had been appropriate from the PK-PD perspective. PMID:23337693

  15. 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

  16. Blueberry Improves the Therapeutic Effect of Etanercept on Patients with Juvenile Idiopathic Arthritis: Phase III Study.

    PubMed

    Zhong, Yingjie; Wang, Ye; Guo, Jun; Chu, Haifeng; Gao, Yong; Pang, Limin

    2015-01-01

    Juvenile idiopathic arthritis (JIA) is the most common arthritis in the adolescents under the age of 16. Etanercept, an inhibitor of tumor necrosis factor, is often used to treat JIA despite its significant side effects. Homeopathic remedies, such as blueberries, have anti-inflammatory properties with fewer unwanted effects and should be considered as a primary treatment. We aimed to explore the efficacy and safety of combination therapy of blueberry and etanercept for JIA. Two hundred and one JIA patients were selected, and randomly and evenly assigned to three groups: ETA (50 mg of etanercept twice weekly), ETABJ (matched etanercept and 50 ml blueberry juice daily) and ETAPJ (matched etanercept and placebo juice). The severity of JIA was measured using American College of Rheumatology scales (ACR) 20, 50 and 70. The levels of pro-inflammatory cytokines, interleukin-1 (IL1) alpha and IL1 beta, and interleukin-1 receptor antagonist (IL1RA) were measured by qRT-PCR and ELISA. After a 6-month follow-up, the ACR20, ACR50 and ACR70 in an ETABJ group were higher than those in other two groups (P < 0.05), suggesting clinically meaningful improvement in JIA. Meanwhile, the symptoms and side effects were reduced significantly or absent in an ETABJ group, including mental diseases, retrobulbar optic neuritis, gaining weight, infection, cutaneous vasculitis, diarrhea, uveitis and pancytopenia. Blueberries reduced the levels of IL1 alpha and beta, and increased the level of IL1RA. Thus, a combination therapy of blueberry and etanercept can reduce the severity of JIA and should be developed as a new method for JIA therapy. PMID:26477692

  17. Blueberry Improves the Therapeutic Effect of Etanercept on Patients with Juvenile Idiopathic Arthritis: Phase III Study.

    PubMed

    Zhong, Yingjie; Wang, Ye; Guo, Jun; Chu, Haifeng; Gao, Yong; Pang, Limin

    2015-01-01

    Juvenile idiopathic arthritis (JIA) is the most common arthritis in the adolescents under the age of 16. Etanercept, an inhibitor of tumor necrosis factor, is often used to treat JIA despite its significant side effects. Homeopathic remedies, such as blueberries, have anti-inflammatory properties with fewer unwanted effects and should be considered as a primary treatment. We aimed to explore the efficacy and safety of combination therapy of blueberry and etanercept for JIA. Two hundred and one JIA patients were selected, and randomly and evenly assigned to three groups: ETA (50 mg of etanercept twice weekly), ETABJ (matched etanercept and 50 ml blueberry juice daily) and ETAPJ (matched etanercept and placebo juice). The severity of JIA was measured using American College of Rheumatology scales (ACR) 20, 50 and 70. The levels of pro-inflammatory cytokines, interleukin-1 (IL1) alpha and IL1 beta, and interleukin-1 receptor antagonist (IL1RA) were measured by qRT-PCR and ELISA. After a 6-month follow-up, the ACR20, ACR50 and ACR70 in an ETABJ group were higher than those in other two groups (P < 0.05), suggesting clinically meaningful improvement in JIA. Meanwhile, the symptoms and side effects were reduced significantly or absent in an ETABJ group, including mental diseases, retrobulbar optic neuritis, gaining weight, infection, cutaneous vasculitis, diarrhea, uveitis and pancytopenia. Blueberries reduced the levels of IL1 alpha and beta, and increased the level of IL1RA. Thus, a combination therapy of blueberry and etanercept can reduce the severity of JIA and should be developed as a new method for JIA therapy.

  18. 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

  19. Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02

    PubMed Central

    Wen, Patrick Y.; Chang, Susan M.; Lamborn, Kathleen R.; Kuhn, John G.; Norden, Andrew D.; Cloughesy, Timothy F.; Robins, H. Ian; Lieberman, Frank S.; Gilbert, Mark R.; Mehta, Minesh P.; Drappatz, Jan; Groves, Morris D.; Santagata, Sandro; Ligon, Azra H.; Yung, W.K. Alfred; Wright, John J.; Dancey, Janet; Aldape, Kenneth D.; Prados, Michael D.; Ligon, Keith L.

    2014-01-01

    Background Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients. Methods We conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients. Results Twenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6S235/236 but possible compensatory increase in phospho-AktS473. Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho–extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months. Conclusion Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted. PMID:24470557

  20. 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

  1. Decitabine reduces transfusion dependence in older patients with acute myeloid leukemia: results from a post hoc analysis of a randomized phase III study.

    PubMed

    He, Jianming; Xiu, Liang; De Porre, Peter; Dass, Ramesh; Thomas, Xavier

    2015-04-01

    This post hoc analysis of the DACO-016 phase III study evaluates the impact of decitabine on transfusion dependence and survival in 485 elderly patients with newly diagnosed acute myeloid leukemia (AML). Red blood cell (RBC) and platelet (PLT) transfusion independence, defined as no transfusions for ≥ 8 consecutive weeks, was measured in both decitabine (n = 242) and treatment choice (TC, n = 243) arms. More RBC transfusion dependent patients at baseline became transfusion independent with decitabine than with TC (26% vs. 13%; p = 0.0026). Similar results were obtained for patients who were PLT transfusion dependent at baseline (31% vs. 13%; p = 0.0069). When excluding patients who attained complete remission (CR), survival was improved in patients who achieved RBC or PLT transfusion independence, suggesting that reaching CR is not a prerequisite for deriving benefit from treatment with decitabine. In addition, patients who achieved transfusion independence with decitabine had increased treatment continuation, even in the absence of CR.

  2. Phase I/II Trial of Imatinib and Bevacizumab in Patients With Advanced Melanoma and Other Advanced Cancers

    PubMed Central

    Hamilton, Betty K.; Rosen, Mark A.; Amaravadi, Ravi K.; Schuchter, Lynn M.; Gallagher, Maryann; Chen, Helen; Sehgal, Chandra; O’Dwyer, Peter J.

    2015-01-01

    Background. Vascular endothelial growth factor and platelet-derived growth factor signaling in the tumor microenvironment appear to cooperate in promoting tumor angiogenesis. Patients and Methods. We conducted a phase I trial combining bevacizumab (i.v. every 2 weeks) and imatinib (oral daily). Once a recommended phase II dose combination was established, a phase II trial was initiated in patients with metastatic melanoma. A Simon 2-stage design was used with 23 patients required in the first stage and 41 patients in total should the criteria to proceed be met. We required that 50% of the patients be progression-free at 16 weeks. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and power Doppler ultrasonography were performed in patients with metastatic tumors amenable to imaging with these methods at baseline and after 4 weeks. Results. A total of 17 patients were accrued to 4 dose and combination levels. Bevacizumab 10 mg/kg every 2 weeks could be safely combined with imatinib 800 mg daily. Common toxicities included fatigue, nausea, vomiting, edema, proteinuria, and anemia, but were not commonly severe. A total of 23 patients with metastatic melanoma (48% with American Joint Commission on Cancer stage M1c; median age, 63 years) were enrolled in the first stage of phase II. The 16-week progression-free survival rate was 35%, leading to termination of phase II after the first stage. In the small subset of patients who remained on study with lesions evaluable by DCE-MRI, significant decreases in tumor vascular permeability were noted, despite early disease progression using the Response Evaluation Criteria In Solid Tumors. Conclusion. Bevacizumab and imatinib can be safely combined at the maximum doses used for each agent. We did not observe significant clinical activity with this regimen in melanoma patients. Implications for Practice: Vascular endothelial growth factor (VEGF)-targeted antiangiogenic therapy has proven clinical efficacy as a

  3. Exploratory analysis of a phase III trial of pirfenidone identifies a subpopulation of patients with idiopathic pulmonary fibrosis as benefiting from treatment

    PubMed Central

    2011-01-01

    Background 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. Methods The patients in the phase III trial were stratified by baseline percentage predicted vital capacity (%VC), arterial oxygen partial pressure (PaO2), and the lowest oxygen saturation by pulse oximetry (SpO2) 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. Results Significant efficacy of pirfenidone in reducing the decline in VC could be seen in a subpopulation having %VC ≥ 70% and SpO2 < 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. Conclusions IPF patients having %VC ≥ 70% and SpO2 < 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. Trial Registration This clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13th, 2005 (Registration Number: JAPICCTI-050121). PMID:22035508

  4. A Prospective Randomised Phase III Clinical Trial Testing the Role of Prophylactic Cranial Radiotherapy in Patients Treated with Trastuzumab for Metastatic Breast Cancer - Anglo Celtic VII.

    PubMed

    Canney, P; Murray, E; Dixon-Hughes, J; Lewsley, L-A; Paul, J

    2015-08-01

    A high incidence of central nervous system (CNS) metastases has been reported in patients with HER2-positive tumours receiving trastuzumab therapy for metastatic breast cancer. This study tested whether prophylactic cranial irradiation (PCI) could reduce the incidence of CNS metastases in this setting. This was a prospective, randomised phase III trial. Patients were randomised 1:1 to no PCI or PCI delivered at around 6 weeks after study entry. Cognitive function was assessed prospectively. In total, 51 patients were randomised over a 3 year period; 25 received PCI and 26 did not. The cumulative incidence of CNS metastases at 2 years was 32.4% (standard error = 9.8%) on the no PCI arm and 21.0% (standard error = 8.6%) on the PCI arm; the associated hazard ratio was 0.57 (95% confidence interval 0.18-1.74; P = 0.32). There was no evidence of cognitive dysfunction in PCI patients.

  5. Phase I/II study of bortezomib in combination with carboplatin and bevacizumab as first line therapy in patients with advanced non-small cell lung cancer (NSCLC)

    PubMed Central

    Piperdi, Bilal; Walsh, William V; Bradley, Kendra; Zhou, Zheng; Bathini, Venu; Hanrahan-Boshes, Meredith; Hutchinson, Lloyd; Perez-Soler, Roman

    2013-01-01

    Purpose To establish the maximum tolerated dose (MTD) of weekly bortezomib in combination with fixed standard doses of carboplatin and bevacizumab and to estimate the efficacy (response rate and progression free survival) and safety of combination therapy with carboplatin, bortezomib and bevacizumab as first line therapy in patients with advanced NSCLC. Experimental Design Patients were assigned to three dose levels of weekly bortezomib with the fixed standard doses of carboplatin (AUC 6) and bevacizumab (15 mg/kg) q 3 wks using a standard phase I design. Bortezomib doses were 1.3 mg/m21.6 mg/m2 and 1.8 mg/m2 weekly on D1 and D8 of q 3wk cycle. A maximum of six cycles was administered. Patients with complete, partial response (PR) or stable disease were continued on single agent bevacizumab (15 mg/kg q 3 wks) as maintenance therapy. In phase II, either level III or MTD was administered to evaluate the efficacy and safety of the combination in first line treatment of advanced NSCLC. Results 16 patients were enrolled (3, 4 and 9 pts in dose level I, II and III respectively). There was no pre-defined dose limiting toxicity in cycle 1 in all 16 patients. The recommended phase II dose is bortezomib 1.8 mg/m2 weekly on day 1 and day 8 in combination with carboplatin AUC of 6 and bevacizumab 15 mg/kg on every 21 day cycle. Total of 9 patients were treated at the recommended phase II dose level. The most common treatment related grade 3/4 toxicities during the subsequent cycles were thrombocytopenia (58%), lymphopenia (25%), neutropenia (12%) and diarrhea (25%). The grade 1/2 neuropathy was seen in 7 out of 16 pts (44%). The response rate, PFS and OS in all patients were 37.5% (95%CI 13.8% - 61.2%), 5.0 months (m) (95%CI: 3.1-8.4), 9.9 m (95% CI: 8.2-14.1) and the 9 patients in phase II portion are 44% (95%CI 15.3% - 77.3%), 5.5 m (95%CI: 3.1-12.2) and 10.9 months (95%CI: 8.0-14.1). Conclusion The recommended phase II dose for this combination is: carboplatin AUC 6

  6. Gefitinib in Combination With Irradiation With or Without Cisplatin in Patients With Inoperable Stage III Non-Small Cell Lung Cancer: A Phase I Trial

    SciTech Connect

    Rothschild, Sacha; Bucher, Stephan E.; Bernier, Jacques; Aebersold, Daniel M.; Zouhair, Aberrahim; Ries, Gerhard; Lombrieser, Norbert; Lippuner, Thomas; Luetolf, Urs M.; Glanzmann, Christoph; Ciernik, I. Frank

    2011-05-01

    Purpose: To establish the feasibility and tolerability of gefitinib (ZD1839, Iressa) with radiation (RT) or concurrent chemoradiation (CRT) with cisplatin (CDDP) in patients with advanced non-small cell lung cancer (NSCLC). Patients and Methods: In this multicenter Phase I study, 5 patients with unresectable NSCLC received 250 mg gefitinib daily starting 1 week before RT at a dose of 63 Gy (Step 1). After a first safety analysis, 9 patients were treated daily with 250 mg gefitinib plus CRT in the form of RT and weekly CDDP 35 mg/m{sup 2} (Step 2). Gefitinib was maintained for up to 2 years until disease progression or toxicity. Results: Fourteen patients were assessed in the two steps. In Step 1 (five patients were administered only gefitinib and RT), no lung toxicities were seen, and there was no dose-limiting toxicity (DLT). Adverse events were skin and subcutaneous tissue reactions, limited to Grade 1-2. In Step 2, two of nine patients (22.2%) had DLT. One patient suffered from dyspnea and dehydration associated with neutropenic pneumonia, and another showed elevated liver enzymes. In both steps combined, 5 of 14 patients (35.7%) experienced one or more treatment interruptions. Conclusions: Gefitinib (250 mg daily) in combination with RT and CDDP in patients with Stage III NSCLC is feasible, but CDDP likely enhances toxicity. The impact of gefitinib on survival and disease control as a first-line treatment in combination with RT remains to be determined.

  7. 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.

  8. District Practices Study. Phase III Summary Report.

    ERIC Educational Resources Information Center

    Advanced Technology, Inc., Reston, VA.

    Following up on the first two phases (1976-82) of the "District Practices Study" of Title I of the Elementary and Secondary Education Act (ESEA) as presented in a resource book and seven special reports, this report is devoted to the study's third and final phase. During phase III (1982-83), researchers visited 14 sites to describe their solutions…

  9. Does Concurrent Radiochemotherapy Affect Cosmetic Results in the Adjuvant Setting After Breast-Conserving Surgery? Results of the ARCOSEIN Multicenter, Phase III Study: Patients' and Doctors' Views

    SciTech Connect

    Toledano, Alain H. . E-mail: alain.toledano@gmail.com; Bollet, Marc A.; Fourquet, Alain; Azria, David; Gligorov, Joseph; Garaud, Pascal; Serin, Daniel; Bosset, Jean-Francois; Miny-Buffet, Joelle; Favre, Anne; Le Foch, Olivier; Calais, Gilles

    2007-05-01

    Purpose: To evaluate the cosmetic results of sequential vs. concurrent adjuvant chemotherapy with radiotherapy after breast-conserving surgery for breast cancer, and to compare ratings by patients and physicians. Methods and Materials: From 1996 to 2000, 716 patients with Stage I-II breast cancers were included in a multicenter, Phase III trial (the ARCOSEIN study) comparing, after breast-conserving surgery with axillary dissection, sequential treatment with chemotherapy first followed by radiotherapy vs. chemotherapy administered concurrently with radiotherapy. Cosmetic results with regard to both the overall aspect of the breast and specific changes (color, scar) were evaluated in a total of 214 patients (107 in each arm) by means of questionnaires to both the patient and a physician whose rating was blinded to treatment allocation. Results: Patients' overall satisfaction with cosmesis was not statistically different between the two arms, with approximately 92% with at least satisfactory results (p = 0.72), although differences between the treated and untreated breasts were greater after the concurrent regimen (29% vs. 14% with more than moderate differences; p 0.0015). Physician assessment of overall cosmesis was less favorable, with lower rates of at least satisfactory results in the concurrent arm (60% vs. 85%; p = 0.001). Consequently, the concordance for overall satisfaction with cosmesis between patients and doctors was only fair ({kappa} = 0.62). Conclusion: After breast-conserving surgery, the concurrent use of chemotherapy with radiotherapy is significantly associated with greater differences between the breasts. These differences do not translate into patients' lessened satisfaction with cosmesis.

  10. Preliminary results of a phase I/II trial of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer.

    PubMed

    Bokemeyer, C; Schmoll, H J; Natt, F; Knoche, M; Beyer, J; Souchon, R

    1994-01-01

    Paclitaxel represents a novel antitumour agent with demonstrated activity in cisplatin-sensitive tumours, particularly ovarian cancer. In addition, responses to paclitaxel have been observed in patients with cisplatin-refractory ovarian cancer. The role of paclitaxel in the treatment of testicular cancer has not been explored so far. Despite the generally high cure rates in patients with metastatic testicular cancer, patients with relapsed disease not responding to platin-based salvage chemotherapy have an extremely poor prognosis. In a phase I/II trial 10 patients with relapsed, cisplatin-refractory malignant germ-cell tumours were treated with paclitaxel as 6-h infusions (8 patients) or 3-h infusions (2 patients) at doses from 135 mg/m2 to 310 mg/m2 at 3-week intervals. Three patients achieved a response to paclitaxel, but disease recurred shortly in two patients after two and four cycles of therapy, respectively. One patient has remained in marker-negative partial response for more than 5 months. The toxicity of paclitaxel was tolerable for a dose range from 135 mg/m2 to 225 mg/m2. Granulocytopenia, WHO grades 3 and 4, occurred in all patients but was of short duration (median 3 days; range: 2-7 days). Other toxicities such as mucositis (5 patients grade 1), neurotoxicity (1 patient grade 1, 2 patients grade 2), infection (1 patient grade 3) and diarrhoea (1 patient grade 2) were not dose-limiting. There were no hypersensitivity reactions, but 1 patient developed severe myalgias during therapy with paclitaxel. Six patients with documented cisplatin-refractory disease were retreated with cisplatin-based chemotherapy after paclitaxel treatment and, in 4 of these, tumour responses of 3, 4, 5 and more than 5 months duration were achieved. In order to explore the role of paclitaxel in relapsed and/or cisplatin-refractory testicular cancer a phase II study using a 3-h infusion of 225 mg/m2 paclitaxel every 3 weeks, conducted by the German Testicular Cancer Study Group

  11. Systematic review and meta-analysis of phase I/II targeted therapy combined with radiotherapy in patients with glioblastoma multiforme: quality of report, toxicity, and survival.

    PubMed

    dos Santos, Marcos A; Pignon, Jean-Pierre; Blanchard, Pierre; Lefeuvre, Delphine; Levy, Antonin; Touat, Mehdi; Louvel, Guillaume; Dhermain, Frédéric; Soria, Jean-Charles; Deutsch, Eric; Le Teuff, Gwénaël

    2015-06-01

    To perform a systematic review and meta-analysis of severe adverse events (SAE) reported in early trials combining molecularly targeted therapies (MTT) with radiotherapy (RT), and to compare them to standard therapy. A summary data meta-analysis was performed and compared to the historical standard. Inclusion criteria were phase I and/or II trials published between 2000 and 2011, with glioblastoma multiforme patients treated with RT and MTT. Pooled incidence rates (IR) of SAE were estimated as well as the pooled median progression-free survival (PFS) and overall survival (OS). Nineteen prospective trials (9 phase I, 1 phase I/II and 9 phase II) out of 29 initially selected were included (n = 755 patients). The exact number of patients who had experienced SAE was mentioned in 37 % of the trials, concerning only 17 % of the patients. Information such as the period during which adverse events were monitored, the planned treatment duration, and late toxicity were not reported in the trials. The pooled IR of overall SAE was 131.2 (95 % CI 88.8-193.7) per 1000 person-months compared to 74.7 (63.6-87.8) for standard therapy (p < 0.01). Significant differences were observed for gastrointestinal events (p = 0.05) and treatment-related deaths (p = 0.02), in favour of standard therapy. No significant difference was observed in PFS and OS. Reporting a summary of toxicity data in early clinical trials should be stringently standardized. The use of MTT with RT compared to standard therapy increased SAE while yielded comparable survival in glioblastoma multiforme patients.

  12. Capecitabine (Xeloda) improves medical resource use compared with 5-fluorouracil plus leucovorin in a phase III trial conducted in patients with advanced colorectal carcinoma.

    PubMed

    Twelves, C; Boyer, M; Findlay, M; Cassidy, J; Weitzel, C; Barker, C; Osterwalder, B; Jamieson, C; Hieke, K

    2001-03-01

    Standard therapy for advanced or metastatic colorectal cancer consists of 5-fluorouracil plus leucovorin (5-FU/LV) administered intravenously (i.v.). Capecitabine (Xeloda), an oral fluoropyrimidine carbamate which is preferentially activated by thymidine phosphorylase in tumour cells, mimics continuous 5-FU and is a recently developed alternative to i.v. 5-FU/LV. The choice of oral rather than intravenous treatment may affect medical resource use because the two regimens do not require the same intensity of medical intervention for drug administration, and have different toxicity profiles. Here we examine medical resource use in the first-line treatment of colorectal cancer patients with capecitabine compared with those receiving the Mayo Clinic regimen of 5-FU/LV. In a prospective, randomised phase III clinical trial, 602 patients with advanced or metastatic colorectal cancer recruited from 59 centres worldwide were randomised to treatment with either capecitabine or the Mayo regimen of 5-FU/LV. In addition to clinical efficacy and safety endpoints, data were collected on hospital visits required for drug administration, hospital admissions, and drugs and unscheduled consultations with physicians required for the treatment of adverse events. Capecitabine treatment in comparison to 5-FU/LV in advanced colorectal carcinoma resulted in superior response rates (26.6% versus 17.9%, P=0.013) and improved safety including less stomatitis and myelosuppression. Capecitabine patients required substantially fewer hospital visits for drug administration than 5-FU/LV patients. Medical resource use analysis showed that patients treated with capecitabine spent fewer days in hospital for the management of treatment related adverse events than did patients treated with 5-FU/LV. In addition, capecitabine reduced the requirement for expensive drugs, in particular antimicrobials fluconazole and 5-HT3-antagonists to manage adverse events. As anticipated with an oral home-based therapy

  13. DHS Phase III activities underway.

    PubMed

    1993-01-01

    Activities and improvements in the third round of the Demographic and Health Surveys (DHS) are described for the first year of the five year DHS-III project during 1992-97. Underway are data quality assessments, identification of data needs, development of a new core questionnaire and modules, and fieldwork survey implementation. Data quality studies are conducted on respondent age, age at first marriage, birth history, knowledge and use of contraception, and health of children aged under 5 years. An analysis of reinterview subsamples for Pakistan and Nigeria will test reliability of data. Emerging data needs for the decade are identified through consultations with data users in the population and health fields. A variety of organizational representatives and recognized experts provide valuable inputs on questionnaire content and module topics. This article also reveals that a shorter questionnaire length will be considered. There will be new questionnaire topics on reliance on breast feeding for contraception, induced abortion and complications, and quality of care. Reductions are made in little used data and retrospective data longer than 3-5 years preceding the survey date. Revisions are made in the Interviewer's and Supervisor's Manuals, the Service Availability Questionnaire, the Male/Husbands Questionnaire, and fifteen modules. Fieldwork is either in progress of completion in Ghana, Kenya, the Philippines, and Turkey. Bangladesh and Bolivia are scheduled for 1993. In 1994 surveys will be administered in Burundi, Central African Republic, Cote d'Ivoire, Guatemala, Haiti, Indonesia, Kazakhstan, Mali, Nigeria, Tanzania, Uganda, and Zimbabwe. PMID:12287320

  14. A phase III randomized, placebo-controlled, double-blind study of misoprostol rectal suppositories to prevent acute radiation proctitis in patients with prostate cancer

    SciTech Connect

    Hille, Andrea . E-mail: ahille@med.uni-goettingen.de; Schmidberger, Heinz; Hermann, Robert M.; Christiansen, Hans; Saile, Bernhard; Pradier, Olivier; Hess, Clemens F.

    2005-12-01

    Purpose: Acute radiation proctitis is the most relevant complication of pelvic radiation and is still mainly treated supportively. Considering the negative impact of acute proctitis symptoms on patients' daily activities and the potential relationship between the severity of acute radiation injury and late damage, misoprostol was tested in the prevention of acute radiation-induced proctitis. Methods and Materials: A total of 100 patients who underwent radiotherapy for prostate cancer were entered into this phase III randomized, placebo-controlled, double-blind study with misoprostol or placebo suppositories. Radiation-induced toxicity was evaluated weekly during radiotherapy using the Common Toxicity Criteria. Results: Between the placebo and the misoprostol groups, no significant differences in proctitis symptoms occurred: 76% of patients in each group had Grade 1 toxicity, and 26% in the placebo group and 36% in the misoprostol group had Grade 2 toxicity. No differences were found in onset or symptom duration. Comparing the peak incidence of patients' toxicity symptoms, significantly more patients experienced rectal bleeding in the misoprostol group (p = 0.03). Conclusion: Misoprostol given as a once-daily suppository did not decrease the incidence and severity of radiation-induced acute proctitis and may increase the incidence of acute bleeding.

  15. A Phase III Study of Durvalumab (MEDI4736) With or Without Tremelimumab for Previously Treated Patients With Advanced NSCLC: Rationale and Protocol Design of the ARCTIC Study.

    PubMed

    Planchard, David; Yokoi, Takashi; McCleod, Michael J; Fischer, Jürgen R; Kim, Young-Chul; Ballas, Marc; Shi, Kelvin; Soria, Jean-Charles

    2016-05-01

    Anti-programmed cell death-1 and anti-programmed cell death ligand-1 (PD-L1) monotherapies have shown promising clinical activity in advanced, refractory non-small-cell lung cancer (NSCLC), but antitumor activity appears to be greater in patients with PD-L1(+) tumors compared with patients harboring PD-L1(-) tumors. Combining the anti-PD-L1 antibody durvalumab and the anti-cytotoxic T-lymphocyte antigen 4 antibody tremelimumab offers the potential for antitumor activity in patients with advanced NSCLC, regardless of PD-L1 tumor status. ARCTIC (NCT02352948) is a global, phase III, randomized, open-label multicenter study in patients with advanced NSCLC assessing the safety and clinical activity of durvalumab versus standard of care (SoC; erlotinib, gemcitabine, or vinorelbine) in patients with PD-L1(+) tumors (≥25% of tumor cells with membrane staining using VENTANA PD-L1 [SP263] CDx Assay) (Sub-study A) and the combination of durvalumab + tremelimumab or either agent as monotherapy versus SoC in patients with PD-L1(-) tumors (Sub-study B). Eligible patients are those with locally advanced or metastatic NSCLC (Stage IIIB/IV), without epidermal growth factor receptor tyrosine kinase activating mutations or anaplastic lymphoma kinase rearrangements, who have received at least 2 prior systemic regimens, including 1 platinum-based chemotherapy regimen. Co-primary endpoints are progression-free survival and overall survival. Secondary endpoints include the proportion of patients alive at 12 months, objective response rate, duration of response, progression-free survival at 6 and 12 months, safety and tolerability, pharmacokinetics, immunogenicity, and quality of life. The exploratory endpoints will assess potential biomarkers of treatment response. Recruitment started in January 2015 and is ongoing. PMID:27265743

  16. A Phase III Study of Durvalumab (MEDI4736) With or Without Tremelimumab for Previously Treated Patients With Advanced NSCLC: Rationale and Protocol Design of the ARCTIC Study.

    PubMed

    Planchard, David; Yokoi, Takashi; McCleod, Michael J; Fischer, Jürgen R; Kim, Young-Chul; Ballas, Marc; Shi, Kelvin; Soria, Jean-Charles

    2016-05-01

    Anti-programmed cell death-1 and anti-programmed cell death ligand-1 (PD-L1) monotherapies have shown promising clinical activity in advanced, refractory non-small-cell lung cancer (NSCLC), but antitumor activity appears to be greater in patients with PD-L1(+) tumors compared with patients harboring PD-L1(-) tumors. Combining the anti-PD-L1 antibody durvalumab and the anti-cytotoxic T-lymphocyte antigen 4 antibody tremelimumab offers the potential for antitumor activity in patients with advanced NSCLC, regardless of PD-L1 tumor status. ARCTIC (NCT02352948) is a global, phase III, randomized, open-label multicenter study in patients with advanced NSCLC assessing the safety and clinical activity of durvalumab versus standard of care (SoC; erlotinib, gemcitabine, or vinorelbine) in patients with PD-L1(+) tumors (≥25% of tumor cells with membrane staining using VENTANA PD-L1 [SP263] CDx Assay) (Sub-study A) and the combination of durvalumab + tremelimumab or either agent as monotherapy versus SoC in patients with PD-L1(-) tumors (Sub-study B). Eligible patients are those with locally advanced or metastatic NSCLC (Stage IIIB/IV), without epidermal growth factor receptor tyrosine kinase activating mutations or anaplastic lymphoma kinase rearrangements, who have received at least 2 prior systemic regimens, including 1 platinum-based chemotherapy regimen. Co-primary endpoints are progression-free survival and overall survival. Secondary endpoints include the proportion of patients alive at 12 months, objective response rate, duration of response, progression-free survival at 6 and 12 months, safety and tolerability, pharmacokinetics, immunogenicity, and quality of life. The exploratory endpoints will assess potential biomarkers of treatment response. Recruitment started in January 2015 and is ongoing.

  17. A phase I/II study of biweekly capecitabine and irinotecan plus bevacizumab as second-line chemotherapy in patients with metastatic colorectal cancer

    PubMed Central

    Suenaga, Mitsukuni; Mizunuma, Nobuyuki; Matsusaka, Satoshi; Shinozaki, Eiji; Ozaka, Masato; Ogura, Mariko; Chin, Keisho; Yamaguchi, Toshiharu

    2015-01-01

    Background Triweekly capecitabine plus irinotecan (XELIRI) is not completely regarded as a valid substitute for fluorouracil, leucovorin, and irinotecan (FOLFIRI) in metastatic colorectal cancer (mCRC) because of the potential for greater toxicity. We conducted a phase I/II study to assess the efficacy and safety of biweekly XELIRI plus bevacizumab (BV) as second-line chemotherapy for mCRC. Methods Patients with mCRC who had received prior chemotherapy including oxaliplatin and BV and had a UGT1A1 genotype of wild-type or heterozygous for UGT1A1*6 or *28 were eligible for this study. Treatment comprised capecitabine 1,000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan on day 1, and BV 5 mg/kg on day 1 every 2 weeks. The phase I study consisted of two steps (irinotecan 150 and 180 mg/m2), and dose-limiting toxicity was assessed during the first treatment cycle. The primary endpoint of the phase II study was progression-free survival (PFS). Results The recommended dose of irinotecan was determined to be 180 mg/m2 in the phase I study. Between November 2010 and August 2013, 44 patients were enrolled in phase II. The patients’ characteristics were as follows (N=44): median age, 60 years (range 32–80); male/female, 21/23; and UGT1A1 wild-type/heterozygous, 29/15. The median PFS was 6.8 months (95% confidence interval, 5.3–8.2 months), and the primary endpoint was met. Median overall survival was 18.3 months. The response rate was 22.7%. There was no significant difference in PFS or overall survival according to UGT1A1 status. Grade 3 or higher adverse events were mainly neutropenia in six patients and diarrhea in five patients. There were no other severe adverse events or treatment-related deaths. Conclusion In mCRC patients with wild-type or heterozygous UGT1A1*6 or *28 genotype, biweekly XELIRI + BV is effective and feasible as second-line chemotherapy. Biweekly XELIRI + BV is considered a valid substitute for FOLFIRI

  18. Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated with darbepoetin alfa: results from STRIATA, a randomized phase III study

    PubMed Central

    Canaud, Bernard; Mingardi, Giulio; Braun, Johann; Aljama, Pedro; Kerr, Peter G.; Locatelli, Francesco; Villa, Giuseppe; Van Vlem, Bruno; McMahon, Alan W.; Kerloëguen, Cécile; Beyer, Ulrich

    2008-01-01

    Background. Extending the administration interval of erythropoiesis-stimulating agents (ESAs) represents an opportunity to improve the efficiency of anaemia management in patients with chronic kidney disease (CKD). However, effective haemoglobin (Hb) maintenance can be challenging with epoetin alfa and epoetin beta administered at extended intervals. C.E.R.A., a continuous erythropoietin receptor activator, has a unique pharmacologic profile and long half-life (∼130 h), allowing administration at extended intervals. Phase III results have demonstrated that C.E.R.A. administered once every 4 weeks effectively maintains stable Hb levels in patients with CKD on dialysis. Methods. STRIATA (Stabilizing haemoglobin TaRgets in dialysis following IV C.E.R.A. Treatment for Anaemia) was a multicentre, open-label randomized phase III study to evaluate the efficacy and safety of intravenous C.E.R.A. administered once every 2 weeks (Q2W) for Hb maintenance following direct conversion from darbepoetin alfa (DA). Adult patients on dialysis receiving stable intravenous DA once weekly (QW) or Q2W were randomized (1:1) to continue their current DA regimen (n = 156) or receive intravenous C.E.R.A. Q2W (n = 157) for 52 weeks. Doses were adjusted to maintain Hb levels within ± 1.0 g/dl of baseline and between 10.0 and 13.5 g/dl. The primary endpoint was the mean Hb change between baseline and the evaluation period (weeks 29–36). Results. Most patients (>80%) received DA QW before randomization. The mean (95% CI) difference between C.E.R.A. and DA in the primary endpoint was 0.18 g/dl (−0.05, 0.41), within a pre-defined non-inferiority limit. C.E.R.A. was clinically non-inferior to DA (P < 0.0001) in maintaining Hb levels. Both treatments were well tolerated. Conclusions. Stable Hb levels were successfully maintained in patients on haemodialysis directly converted to Q2W intravenous C.E.R.A. from DA. PMID:18586762

  19. Prospective Phase I-II Trial of Helical Tomotherapy With or Without Chemotherapy for Postoperative Cervical Cancer Patients

    SciTech Connect

    Schwarz, Julie K.; Wahab, Sasa; Grigsby, Perry W.

    2011-12-01

    Purpose: To investigate, in a prospective trial, the acute and chronic toxicity of patients with cervical cancer treated with surgery and postoperative intensity-modulated radiotherapy (RT) delivered using helical tomotherapy, with or without the administration of concurrent chemotherapy. Patients and Methods: A total of 24 evaluable patients entered the study between March 2006 and August 2009. The indications for postoperative RT were tumor size, lymphovascular space invasion, and the depth of cervical stromal invasion in 15 patients; 9 patients underwent postoperative RT because of surgically positive lymph nodes. All patients underwent pelvic RT delivered with helical tomotherapy and intracavitary high-dose-rate brachytherapy. Treatment consisted of concurrent weekly platinum in 17, sequential carboplatin/Taxol in 1, and RT alone in 6. The patients were monitored for acute and chronic toxicity using the Common Toxicity Criteria, version 3.0. Results: The median follow-up was 24 months (range, 4-49). At the last follow-up visit, 23 patients were alive and disease free. Of the 24 patients, 12 (50%) experienced acute Grade 3 gastrointestinal toxicity (anorexia in 5, diarrhea in 4, and nausea in 3). One patient developed acute Grade 4 genitourinary toxicity (vesicovaginal fistula). For patients treated with concurrent chemotherapy, the incidence of acute Grade 3 and 4 hematologic toxicity was 71% and 24%, respectively. For patients treated without concurrent chemotherapy, the incidence of acute Grade 3 and 4 hematologic toxicity was 29% and 14%, respectively. Two long-term toxicities occurred (vesicovaginal fistula at 25 months and small bowel obstruction at 30 months). The overall and progression-free survival rate at 3 years for all patients was 100% and 89%, respectively. Conclusion: The results of our study have shown that postoperative external RT for cervical cancer delivered with helical tomotherapy and high-dose-rate brachytherapy and with or without

  20. The crystal structure of methane phase III

    NASA Astrophysics Data System (ADS)

    Neumann, Marcus A.; Press, Werner; Nöldeke, Christian; Asmussen, Bernd; Prager, Michael; Ibberson, Richard M.

    2003-07-01

    Methane is the simplest organic molecule, and like many supposedly simple molecular materials it has a rich phase diagram. While crystal structures could be determined for two of the solid phases, that of the low temperature phase III remained unsolved. Using high-resolution neutron powder diffraction and a direct-space Monte Carlo simulated annealing approach, this fundamental structure has now finally been solved. It is orthorhombic with space group Cmca, and 16 molecules in the unit cell. The structure is closely related to that of phase II, yet is no subgroup of it.

  1. Complete Longitudinal Analyses of the Randomized, Placebo-controlled, Phase III Trial of Sunitinib in Patients with Gastrointestinal Stromal Tumor Following Imatinib Failure

    PubMed Central

    Demetri, George D.; Garrett, Christopher R.; Schöffski, Patrick; Shah, Manisha H.; Verweij, Jaap; Leyvraz, Serge; Hurwitz, Herbert I.; Pousa, Antonio Lopez; Le Cesne, Axel; Goldstein, David; Paz-Ares, Luis; Blay, Jean-Yves; McArthur, Grant A.; Xu, Qiang (Casey); Huang, Xin; Harmon, Charles S.; Tassell, Vanessa; Cohen, Darrel P.; Casali, Paolo G.

    2014-01-01

    Purpose To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor (GIST) patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. Experimental Design Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore crossover impact. Circulating levels of angiogenesis biomarkers were analyzed. Results In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 versus 64.9 weeks; hazard ratio [HR], 0.876; P = 0.306) as expected, given the crossover design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262–1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. Conclusions The crossover design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following crossover there was no statistical difference in OS. RPSFT analysis modeled the absence of crossover, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events. PMID:22661587

  2. FRAGMATIC: A randomised phase III clinical trial investigating the effect of fragmin® added to standard therapy in patients with lung cancer

    PubMed Central

    2009-01-01

    Background Venous thromboembolism (VTE) occurs when blood clots in the leg, pelvic or other deep vein (deep vein thrombosis) with or without transport of the thrombus into the pulmonary arterial circulation (pulmonary embolus). VTE is common in patients with cancer and is increased by surgery, chemotherapy, radiotherapy and disease progression. Low molecular weight heparin (LMWH) is routinely used to treat VTE and some evidence suggests that LMWH may also have an anticancer effect, by reduction in the incidence of metastases. The FRAGMATIC trial will assess the effect of adding dalteparin (FRAGMIN), a type of LMWH, to standard treatment for patients with lung cancer. Methods/Design The study design is a randomised multicentre phase III trial comparing standard treatment and standard treatment plus daily LMWH for 24 weeks in patients with lung cancer. Patients eligible for this study must have histopathological or cytological diagnosis of primary bronchial carcinoma (small cell or non-small cell) within 6 weeks of randomisation, be 18 or older, and must be willing and able to self-administer 5000 IU dalteparin by daily subcutaneous injection or have it administered to themselves or by a carer for 24 weeks. A total of 2200 patients will be recruited from all over the UK over a 3 year period and followed up for a minimum of 1 year after randomisation. Patients will be randomised to one of the two treatment groups in a 1:1 ratio, standard treatment or standard treatment plus dalteparin. The primary outcome measure of the trial is overall survival. The secondary outcome measures include venous thrombotic event (VTE) free survival, serious adverse events (SAEs), metastasis-free survival, toxicity, quality of life (QoL), levels of breathlessness, anxiety and depression, cost effectiveness and cost utility. Trial registration Current Controlled Trials ISRCTN80812769 PMID:19807917

  3. Effect of cumulative bortezomib dose on survival in multiple myeloma patients receiving bortezomib-melphalan-prednisone in the phase III VISTA study.

    PubMed

    Mateos, María Victoria; Richardson, Paul G; Dimopoulos, Meletios A; Palumbo, Antonio; Anderson, Kenneth C; Shi, Hongliang; Elliott, Jennifer; Dow, Edward; van de Velde, Helgi; Niculescu, Liviu; San Miguel, Jesús F

    2015-04-01

    This analysis, using data from the bortezomib-melphalan-prednisone (VMP) arm of the Phase III VISTA study, investigated whether increased cumulative bortezomib dose could improve overall survival (OS) in transplant-ineligible patients with previously untreated multiple myeloma. Median cumulative bortezomib dose received by the 340 patients was 39 mg/m(2); this was selected as the cut-off for defining the dose groups to be compared for OS. Patient characteristics were well balanced between dose groups except for age. OS was significantly longer in the higher (≥39 mg/m(2)) versus lower (<39 mg/m(2)) cumulative bortezomib dose group (median 66.3 vs. 46.2 months; hazard ratio (HR) 0.533, P < 0.0001; age-adjusted HR 0.561, P = 0.0002). To overcome confounding effects of early discontinuations/deaths, which were more common in the lower cumulative dose group (27 vs. 4% of patients discontinued due to adverse events (AEs) in the lower and higher cumulative dose groups, respectively), a landmark analysis was conducted at 180 days, eliminating patients who died or discontinued before this time from the analysis. OS from this landmark remained significantly longer in the higher dose group (median 60.4 vs. 50.3 months; HR 0.709, P = 0.0372). Thus, higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, appears associated with improved OS. Approaches to achieve higher cumulative doses could include subcutaneous bortezomib administration, dose/schedule modifications, continuing therapy in responding patients, and proactive AE management.

  4. Oral Mucositis Prevention By Low-Level Laser Therapy in Head-and-Neck Cancer Patients Undergoing Concurrent Chemoradiotherapy: A Phase III Randomized Study

    SciTech Connect

    Gouvea de Lima, Aline; Villar, Rosangela Correa; Castro, Gilberto de; Antequera, Reynaldo; Gil, Erlon; Rosalmeida, Mauro Cabral; Federico, Miriam Hatsue Honda; Snitcovsky, Igor Moises Longo

    2012-01-01

    Purpose: Oral mucositis is a major complication of concurrent chemoradiotherapy (CRT) in head-and-neck cancer patients. Low-level laser (LLL) therapy is a promising preventive therapy. We aimed to evaluate the efficacy of LLL therapy to decrease severe oral mucositis and its effect on RT interruptions. Methods and Materials: In the present randomized, double-blind, Phase III study, patients received either gallium-aluminum-arsenide LLL therapy 2.5 J/cm{sup 2} or placebo laser, before each radiation fraction. Eligible patients had to have been diagnosed with squamous cell carcinoma or undifferentiated carcinoma of the oral cavity, pharynx, larynx, or metastases to the neck with an unknown primary site. They were treated with adjuvant or definitive CRT, consisting of conventional RT 60-70 Gy (range, 1.8-2.0 Gy/d, 5 times/wk) and concurrent cisplatin. The primary endpoints were the oral mucositis severity in Weeks 2, 4, and 6 and the number of RT interruptions because of mucositis. The secondary endpoints included patient-reported pain scores. To detect a decrease in the incidence of Grade 3 or 4 oral mucositis from 80% to 50%, we planned to enroll 74 patients. Results: A total of 75 patients were included, and 37 patients received preventive LLL therapy. The mean delivered radiation dose was greater in the patients treated with LLL (69.4 vs. 67.9 Gy, p = .03). During CRT, the number of patients diagnosed with Grade 3 or 4 oral mucositis treated with LLL vs. placebo was 4 vs. 5 (Week 2, p = 1.0), 4 vs. 12 (Week 4, p = .08), and 8 vs. 9 (Week 6, p = 1.0), respectively. More of the patients treated with placebo had RT interruptions because of mucositis (6 vs. 0, p = .02). No difference was detected between the treatment arms in the incidence of severe pain. Conclusions: LLL therapy was not effective in reducing severe oral mucositis, although a marginal benefit could not be excluded. It reduced RT interruptions in these head-and-neck cancer patients, which might

  5. Silver Clear Nylon Dressing is Effective in Preventing Radiation-Induced Dermatitis in Patients With Lower Gastrointestinal Cancer: Results From a Phase III Study

    SciTech Connect

    Niazi, Tamim M.; Vuong, Te; Azoulay, Laurant; Marijnen, Corrie; Bujko, Kryzstof; Nasr, Elie; Lambert, Christine; Duclos, Marie; Faria, Sergio; David, Marc; Cummings, Bernard

    2012-11-01

    Purpose: For patients with anal canal and advanced rectal cancer, chemoradiation therapy is a curative modality or an important adjunct to surgery. Nearly all patients treated with chemoradiation experience some degree of radiation-induced dermatitis (RID). Prevention and effective treatment of RID, therefore, is of considerable clinical relevance. The present phase III randomized trial compared the efficacy of silver clear nylon dressing (SCND) with that of standard skin care for these patients. Methods and Materials: A total of 42 rectal or anal canal cancer patients were randomized to either a SCND or standard skin care group. SCND was applied from Day 1 of radiation therapy (RT) until 2 weeks after treatment completion. In the control arm, sulfadiazine cream was applied at the time of skin dermatitis. Printed digital photographs taken 2 weeks prior to, on the last day, and two weeks after the treatment completion were scored by 10 blinded readers, who used the common toxicity scoring system for skin dermatitis. Results: The radiation dose ranged from 50.4 to 59.4 Gy, and there were no differences between the 2 groups. On the last day of RT, when the most severe RID occurs, the mean dermatitis score was 2.53 (standard deviation [SD], 1.17) for the standard and 1.67 (SD, 1.2; P=.01) for the SCND arm. At 2 weeks after RT, the difference was 0.39 points in favor of SCND (P=.39). There was considerable intraclass correlation among the 10 observers. Conclusions: Silver clear nylon dressing is effective in reducing RID in patients with lower gastrointestinal cancer treated with combined chemotherapy and radiation treatment.

  6. Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention

    PubMed Central

    Bayman, N; Ardron, D; Ashcroft, L; Baldwin, D R; Booton, R; Darlison, L; Edwards, J G; Lang-Lazdunski, L; Lester, J F; Peake, M; Rintoul, R C; Snee, M; Taylor, P; Lunt, C

    2016-01-01

    Introduction Histological diagnosis of malignant mesothelioma requires an invasive procedure such as CT-guided needle biopsy, thoracoscopy, video-assisted thorascopic surgery (VATs) or thoracotomy. These invasive procedures encourage tumour cell seeding at the intervention site and patients can develop tumour nodules within the chest wall. In an effort to prevent nodules developing, it has been widespread practice across Europe to irradiate intervention sites postprocedure—a practice known as prophylactic irradiation of tracts (PIT). To date there has not been a suitably powered randomised trial to determine whether PIT is effective at reducing the risk of chest wall nodule development. Methods and analysis In this multicentre phase III randomised controlled superiority trial, 374 patients who can receive radiotherapy within 42 days of a chest wall intervention will be randomised to receive PIT or no PIT. Patients will be randomised on a 1:1 basis. Radiotherapy in the PIT arm will be 21 Gy in three fractions. Subsequent chemotherapy is given at the clinicians’ discretion. A reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy 6 months after randomisation would be clinically significant. All patients will be followed up for up to 2 years with monthly telephone contact and at least four outpatient visits in the first year. Ethics and dissemination PIT was approved by NRES Committee North West—Greater Manchester West (REC reference 12/NW/0249) and recruitment is currently on-going, the last patient is expected to be randomised by the end of 2015. The analysis of the primary end point, incidence of chest wall nodules 6 months after randomisation, is expected to be published in 2016 in a peer reviewed journal and results will also be presented at scientific meetings and summary results published online. A follow-up analysis is expected to be published in 2018. Trial registration number ISRCTN04240319; NCT01604005; Pre

  7. Efficacy and safety of maintenance erlotinib in Asian patients with advanced non-small-cell lung cancer: a subanalysis of the phase III, randomized SATURN study.

    PubMed

    Wu, Yi-Long; Kim, Joo-Hang; Park, Keunchil; Zaatar, Adel; Klingelschmitt, Gaëlle; Ng, Christina

    2012-08-01

    Maintenance therapy, commenced immediately after the completion of first-line chemotherapy, is a promising strategy for improving treatment outcomes in patients with non-small-cell lung cancer (NSCLC). The global phase III SequentiAl Tarceva in UnResectable NSCLC (SATURN) study evaluated the efficacy and safety of the epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib as maintenance treatment in NSCLC patients without progression after first-line chemotherapy. We report a retrospective subanalysis of Asian patients enrolled in SATURN. Patients with advanced NSCLC with no evidence of progression after four cycles of chemotherapy were randomized to receive erlotinib 150 mg/day or placebo, until progressive disease or limiting toxicity. The co-primary endpoints of SATURN were progression-free survival (PFS) in all patients and in those with positive EGFR immunohistochemistry (IHC) status. Secondary endpoints included overall survival (OS), disease control rate, safety, quality of life (QoL) and biomarker analyses. In total, 126 patients from East and South-East Asian centers were randomized (14% of the intent-to-treat population): 88 from Korea, 28 from China and 10 from Malaysia; one patient was excluded from this analysis due to Indian ethnicity. PFS was significantly prolonged in the erlotinib treatment arm, both overall (hazard ratio [HR]: 0.57; p=0.0067) and in patients with EGFR IHC-positive disease (HR=0.50; p=0.0057). There was a trend towards an increase in OS, which reached statistical significance in the EGFR IHC-positive subgroup (p=0.0233). The overall response rate was significantly higher with erlotinib compared with placebo (24% versus 5%; p=0.0025). Erlotinib was generally well tolerated and had no negative impact on QoL in this subpopulation. The most common treatment-related adverse events were rash, diarrhea and pruritus. Erlotinib was effective and well tolerated in Asian patients, producing benefits consistent with those

  8. Assessment of flares in lupus patients enrolled in a phase II/III study of rituximab (EXPLORER).

    PubMed

    Merrill, Jt; Buyon, Jp; Furie, Ra; Latinis, Km; Gordon, C; Hsieh, H-J; Brunetta, P

    2011-06-01

    The EXPLORER study was designed to assess the response to rituximab versus placebo in patients with moderate to severe extrarenal systemic lupus erythematosus (SLE) receiving background immunosuppression. The definition of response required reduced clinical activity without subsequent flares over 52 weeks, and the study did not meet its efficacy endpoint. The current exploratory analysis assessed flare rates in patients who achieved initial low disease activity response (British Isles Lupus Assessment Group [BILAG] C or better in all organs) during the study. Exploratory reanalysis of data from the EXPLORER trial was conducted, considering alternative definitions for flare. No difference was found between rituximab and placebo in preventing or delaying moderate to severe flares. However, when severe (BILAG A) flares alone were examined, rituximab reduced the risk of a subsequent first A flare (hazard ratio = 0.61; p = 0.052) and lowered mean ± SD annualized A flare rates (0.86 ± 1.47 vs. 1.41 ± 2.14; p = 0.038). Eighty-four (49.7%) rituximab-treated patients achieved low disease activity without subsequent A flares versus 31 (35.2%) placebo-treated patients (p = 0.027). Prednisone rescue for A flares was similar in rituximab- (24%) and placebo-treated (14%) patients (p = 0.204). This post hoc analysis evaluates the hypothesis that assessment of BILAG A flares may distinguish potential treatment effects with greater sensitivity than assessment of BILAG B flares.

  9. A phase III, randomized, non-inferiority study comparing the efficacy and safety of biosimilar filgrastim versus originator filgrastim for chemotherapy-induced neutropenia in breast cancer patients

    PubMed Central

    Hegg, Roberto; Mattar, André; de Matos, João Nunes; Pedrini, José Luiz; Aleixo, Sabina Bandeira; Rocha, Roberto Odebrecht; Cramer, Renato Peixoto; van-Eyll-Rocha, Sylvie

    2016-01-01

    OBJECTIVES: To compare the efficacy and safety of two filgrastim formulations for controlling chemotherapy-induced neutropenia and to evaluate the non-inferiority of the test drug relative to the originator. METHODS: This phase III non-inferiority study had a randomized, multicenter, and open-label design. The patients were randomized at a ratio of 1:1 with a follow-up period of 6 weeks for each patient. In both study arms, filgrastim was administered subcutaneously at a daily dose of 5 mg/kg body weight. The primary endpoint was the rate of grade 4 neutropenia in the first treatment cycle. The secondary endpoints were the duration of grade 4 neutropenia, the generation of anti-filgrastim antibodies, and the rates of adverse events, laboratory abnormalities, febrile neutropenia, and neutropenia of any grade. RESULTS: The primary efficacy analysis demonstrated the non-inferiority of the test drug compared with the originator drug; the upper limit of the 90% confidence interval (CI) for the rate of neutropenia between the two groups (12.61%) was lower than the established margin of non-inferiority. The two treatments were similar with respect to the secondary endpoints and safety. CONCLUSION: The efficacy and safety profile of the test drug were similar to those of the originator product based on the rate of grade 4 neutropenia in the first treatment cycle. This study supports Anvisa's approval of the first biosimilar drug manufactured by the Brazilian industry (Fiprima®). PMID:27759847

  10. High-Dose Intravenous Vitamin C Combined with Cytotoxic Chemotherapy in Patients with Advanced Cancer: A Phase I-II Clinical Trial

    PubMed Central

    Hoffer, L. John; Robitaille, Line; Zakarian, Robert; Melnychuk, David; Kavan, Petr; Agulnik, Jason; Cohen, Victor; Small, David; Miller, Wilson H.

    2015-01-01

    Background Biological and some clinical evidence suggest that high-dose intravenous vitamin C (IVC) could increase the effectiveness of cancer chemotherapy. IVC is widely used by integrative and complementary cancer therapists, but rigorous data are lacking as to its safety and which cancers and chemotherapy regimens would be the most promising to investigate in detail. Methods and Findings We carried out a phase I-II safety, tolerability, pharmacokinetic and efficacy trial of IVC combined with chemotherapy in patients whose treating oncologist judged that standard-of-care or off-label chemotherapy offered less than a 33% likelihood of a meaningful response. We documented adverse events and toxicity associated with IVC infusions, determined pre- and post-chemotherapy vitamin C and oxalic acid pharmacokinetic profiles, and monitored objective clinical responses, mood and quality of life. Fourteen patients were enrolled. IVC was safe and generally well tolerated, although some patients experienced transient adverse events during or after IVC infusions. The pre- and post-chemotherapy pharmacokinetic profiles suggested that tissue uptake of vitamin C increases after chemotherapy, with no increase in urinary oxalic acid excretion. Three patients with different types of cancer experienced unexpected transient stable disease, increased energy and functional improvement. Conclusions Despite IVC’s biological and clinical plausibility, career cancer investigators currently ignore it while integrative cancer therapists use it widely but without reporting the kind of clinical data that is normally gathered in cancer drug development. The present study neither proves nor disproves IVC’s value in cancer therapy, but it provides practical information, and indicates a feasible way to evaluate this plausible but unproven therapy in an academic environment that is currently uninterested in it. If carried out in sufficient numbers, simple studies like this one could identify

  11. Deterioration in quality of life (QoL) in patients with malignant ascites: results from a phase II/III study comparing paracentesis plus catumaxomab with paracentesis alone

    PubMed Central

    Wimberger, P.; Gilet, H.; Gonschior, A-K.; Heiss, M. M.; Moehler, M.; Oskay-Oezcelik, G.; Al-Batran, S-E.; Schmalfeldt, B.; Schmittel, A.; Schulze, E.; Parsons, S. L.

    2012-01-01

    Background Malignant ascites (MA) is associated with poor prognosis and limited palliative therapeutic options. Therefore, quality of life (QoL) assessment is of particular importance to demonstrate new treatment value. Following the demonstration of the superiority of catumaxomab and paracentesis over paracentesis on puncture-free survival, this analysis aimed at comparing deterioration in QoL between both the treatment options. Patients and methods In a randomised, multicentre, phase II/III study of patients with MA due to epithelial cell adhesion molecule (EpCAM) positive cancer, the QoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items (EORTC QLQ-C30) questionnaire at screening, 1, 3 and 7 months after treatment and in the case of re-puncture on the day of paracentesis. Time to first deterioration in QoL was defined as a decrease in the QoL score of at least five points and compared between the catumaxomab (n = 160) and control (n = 85) groups using the log-rank test and Cox proportional hazards models adjusted for baseline score, country and primary tumour type. Results Deterioration in QoL scores appeared more rapidly in the control than in the catumaxomab group (median 19–26 days versus 47–49 days). The difference in time to deterioration in QoL between the groups was statistically significant for all scores (P < 0.01). The hazard ratios ranged from 0.08 to 0.24 (P < 0.01). Conclusions Treatment with catumaxomab delayed deterioration in QoL in patients with MA. Compared with paracentesis alone, catumaxomab enabled patients to benefit from better QoL for a prolonged survival period. PMID:22734013

  12. Revisiting dosing regimen using PK/PD modeling: the MODEL1 phase I/II trial of docetaxel plus epirubicin in metastatic breast cancer patients.

    PubMed

    Hénin, Emilie; Meille, Christophe; Barbolosi, Dominique; You, Benoit; Guitton, Jérôme; Iliadis, Athanassios; Freyer, Gilles

    2016-04-01

    The MODEL1 trial is the first model-driven phase I/II dose-escalation study of densified docetaxel plus epirubicin administration in metastatic breast cancer patients, a regimen previously known to induce unacceptable life-threatening toxicities. The primary objective was to determine the maximum tolerated dose of this densified regimen. Study of the efficacy was a secondary objective. Her2-negative, hormone-resistant metastatic breast cancer patients were treated with escalating doses of docetaxel plus epirubicin every 2 weeks for six cycles with granulocyte colony stimulating factor support. A total of 16 patients were treated with total doses ranging from 85 to 110 mg of docetaxel plus epirubicin per cycle. Dose escalation was controlled by a non-hematological toxicity model. Dose densification was guided by a model of neutrophil kinetics, able to optimize docetaxel plus epirubicin dosing with respect to pre-defined acceptable levels of hematological toxicity while ensuring maximal efficacy. The densified treatment was safe since hematological toxicity was much lower compared to previous findings, and other adverse events were consistent with those observed with this regimen. The maximal tolerated dose was 100 mg given every 2 weeks. The response rate was 45 %; median progression-free survival was 10.4 months, whereas 54.6 months of median overall survival was achieved. The optimized docetaxel plus epirubicin dosing regimen led to fewer toxicities associated with higher efficacy as compared with standard or empirical densified dosing. This study suggests that model-driven dosage adjustment can lead to improved efficacy-toxicity balance in patients with cancer when several anticancer drugs are combined.

  13. Zabofloxacin versus moxifloxacin in patients with COPD exacerbation: a multicenter, double-blind, double-dummy, randomized, controlled, Phase III, non-inferiority trial.

    PubMed

    Rhee, Chin Kook; Chang, Jung Hyun; Choi, Eu Gene; Kim, Hyun Kuk; Kwon, Yong-Soo; Kyung, Sun Young; Lee, Ji-Hyun; Park, Myung Jae; Yoo, Kwang Ha; Oh, Yeon Mok

    2015-01-01

    A new quinolone, zabofloxacin, has now been developed; hence, a non-inferiority trial is needed to compare this new compound with another widely used quinolone to examine its efficacy and safety for the treatment of chronic obstructive pulmonary disease (COPD) exacerbations. This was a prospective, multicenter, double-blind, double-dummy, randomized, controlled, parallel-group, Phase III, non-inferiority clinical trial designed to compare oral zabofloxacin (367 mg once daily for 5 days) with moxifloxacin (400 mg once daily for 7 days) for the treatment of patients with COPD exacerbation. In all, 345 COPD patients with a moderate COPD exacerbation were enrolled in the study via the outpatient clinics at 31 university hospitals. Clinical per protocol analysis revealed that the clinical cure rate for zabofloxacin was 86.7% and that for moxifloxacin was 86.3% (the rate difference, 0.4%; 95% confidence interval, -7.7%-8.6%). Intention-to-treat analysis revealed clinical cure rates of 77.1% and 77.3% (difference, -0.2%; 95% confidence interval, -9.0%-8.8%), respectively. These results confirm that zabofloxacin is not inferior to moxifloxacin. The favorable microbiological response rate for zabofloxacin was 67.4% and that for moxifloxacin was 79.5% (P=0.22). Patients in the zabofloxacin group showed better patient-oriented outcomes, as measured by EXAcerbations of Chronic Pulmonary Disease Tool-Patient-Reported Outcome and the COPD assessment test scores, than patients in the moxifloxacin group. Adverse drug reactions related to zabofloxacin occurred in 9.7% of cases and those related to moxifloxacin occurred in 9.6% of cases (P=0.97). The dropout rate due to adverse events was 0% (0/175) in the zabofloxacin group and 1.8% (3/167) in the moxifloxacin group (P=0.12). Oral zabofloxacin (367 mg once daily for 5 days) was not inferior to oral moxifloxacin (400 mg once daily for 7 days) for the treatment of patients with COPD exacerbation. PMID:26543359

  14. Deep sequencing analysis of HIV-1 reverse transcriptase at baseline and time of failure in patients receiving rilpivirine in the phase III studies ECHO and THRIVE.

    PubMed

    Van Eygen, Veerle; Thys, Kim; Van Hove, Carl; Rimsky, Laurence T; De Meyer, Sandra; Aerssens, Jeroen; Picchio, Gaston; Vingerhoets, Johan

    2016-05-01

    Minority variants (1.0-25.0%) were evaluated by deep sequencing (DS) at baseline and virological failure (VF) in a selection of antiretroviral treatment-naïve, HIV-1-infected patients from the rilpivirine ECHO/THRIVE phase III studies. Linkage between frequently emerging resistance-associated mutations (RAMs) was determined. DS (llIumina®) and population sequencing (PS) results were available at baseline for 47 VFs and time of failure for 48 VFs; and at baseline for 49 responders matched for baseline characteristics. Minority mutations were accurately detected at frequencies down to 1.2% of the HIV-1 quasispecies. No baseline minority rilpivirine RAMs were detected in VFs; one responder carried 1.9% F227C. Baseline minority mutations associated with resistance to other non-nucleoside reverse transcriptase inhibitors (NNRTIs) were detected in 8/47 VFs (17.0%) and 7/49 responders (14.3%). Baseline minority nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) RAMs M184V and L210W were each detected in one VF (none in responders). At failure, two patients without NNRTI RAMs by PS carried minority rilpivirine RAMs K101E and/or E138K; and five additional patients carried other minority NNRTI RAMs V90I, V106I, V179I, V189I, and Y188H. Overall at failure, minority NNRTI RAMs and NRTI RAMs were found in 29/48 (60.4%) and 16/48 VFs (33.3%), respectively. Linkage analysis showed that E138K and K101E were usually not observed on the same viral genome. In conclusion, baseline minority rilpivirine RAMs and other NNRTI/NRTI RAMs were uncommon in the rilpivirine arm of the ECHO and THRIVE studies. DS at failure showed emerging NNRTI resistant minority variants in seven rilpivirine VFs who had no detectable NNRTI RAMs by PS. PMID:26412111

  15. Cisplatin, hyperthermia, and radiation (trimodal therapy) in patients with locally advanced head and neck tumors: A phase I-II study

    SciTech Connect

    Amichetti, M.; Graiff, C.; Fellin, G.; Pani, G.; Bolner, A.; Maluta, S. ); Valdagni, R. Istituto per la Ricerca Scientifica e Tecnologica, Trento )

    1993-08-01

    Hyperthermia is now being widely used to treat clinical malignancies, especially combined with radiotherapy and more rarely with chemotherapy. The combination of heat, radiation, and chemotherapy (trimodality) can lead to potent interaction. The present Phase I-II study was conducted to evaluate the feasibility and acute toxicity of a combination of cisplantin, hyperthermia, and irradiation in the treatment of superficial cervical nodal metastases from head and neck cancer. Eighteen patients with measurable neck metastases from previously untreated squamous cell head and neck tumors were entered into the trial. Therapy consisted of a conventional irradiation (total dose 70 Gy, 2 Gy five times a week) combined with a weekly administration of 20 mg/m[sup 2] iv of cisplatin and a total of two sessions of local external microwave hyperthermia (desired temperature of 42.5[degrees]C for 30 min). Feasibility of the treatment was demonstrated. Acute local toxicity was mild; no thermal blisters or ulcerations were reported and only two patients experienced local pain during hyperthermia. Cutaneous toxicity appeared greater than in previous studies with irradiation plus hyperthermia and irradiation plus cisplatin. Systematic toxicity was moderate with major toxic effects observed in three patients (World Health Organization (WHO) grade 3 anaemia). Even though it was not an aim of the study to evaluate the nodal response, they observed a complete response rate of 72.2% (95% confidence interval 51-93.4%), 16.6% of partial response and 11.1% of no change. The study confirms the feasibility of the combination of cisplantin, heat, and radiation with an acceptable toxicity profile. The trimodal therapy deserves further evaluation as a way to enhance the efficacy of irradiation in the treatment of nodal metastases from head and neck tumors. 43 refs., 3 figs., 4 tabs.

  16. Lymphadenectomy in locally advanced cervical cancer study (LiLACS): Phase III clinical trial comparing surgical with radiologic staging in patients with stages IB2-IVA cervical cancer.

    PubMed

    Frumovitz, Michael; Querleu, Denis; Gil-Moreno, Antonio; Morice, Philippe; Jhingran, Anuja; Munsell, Mark F; Macapinlac, Homer A; Leblanc, Eric; Martinez, Alejandra; Ramirez, Pedro T

    2014-01-01

    Radiation treatment planning for women with locally advanced cervical cancer (stages IB2-IVA) is often based on positron emission tomography (PET). PET, however, has poor sensitivity in detecting metastases in aortocaval nodes. We have initiated a study with the objective of determining whether pre-therapeutic laparoscopic surgical staging followed by tailored chemoradiation improves survival as compared with PET/computed tomography (CT) radiologic staging alone followed by chemoradiation. This international, multicenter phase III trial will enroll 600 women with stages IB2-IVA cervical cancer and PET/CT findings showing fluorodeoxyglucose-avid pelvic nodes and fluorodeoxyglucose-negative para-aortic nodes. Eligible patients will be randomized to undergo either pelvic radiotherapy with chemotherapy (standard-of-care arm) or surgical staging via a minimally invasive extraperitoneal approach followed by tailored radiotherapy with chemotherapy (experimental arm). The primary end point is overall survival. Secondary end points are disease-free survival, short- and long-term morbidity with pre-therapeutic surgical staging, and determination of anatomic locations of metastatic para-aortic nodes in relationship to the inferior mesenteric artery. We believe this study will show that tailored chemoradiation after pre-therapeutic surgical staging improves survival as compared with chemoradiation based on PET/CT in women with stages IB2-IVA cervical cancer.

  17. Omalizumab Improves Quality of Life and Asthma Control in Chinese Patients With Moderate to Severe Asthma: A Randomized Phase III Study

    PubMed Central

    Li, Jing; Kang, Jian; Wang, Changzheng; Yang, Jing; Wang, Linda; Kottakis, Ioannis; Humphries, Michael

    2016-01-01

    Purpose Omalizumab is the preferred add-on therapy for patients with moderate-to-severe persistent allergic asthma and has demonstrated efficacy and safety in various ethnicities. This study evaluated the efficacy and safety of omalizumab in Chinese patients with moderate-to-severe allergic asthma. Methods This randomized, double-blind, parallel-group, placebo-controlled, phase III study assessed lung function, quality of life, asthma control, and safety of omalizumab after 24-week therapy in Chinese patients (18-75 years of age). Results A total of 616 patients were randomized (1:1) to omalizumab or placebo. The primary endpoint, least squares mean treatment difference (LSM-TD) in morning peak expiratory flow (PEF) (omalizumab vs placebo), at Weeks >20-24 was 8.85 L/min (Full analysis set; P=0.062). Per-protocol analysis set showed significant improvements with LSM-TD of 11.53 L/min in mean mPEF at Weeks >20-24 (P=0.022). The FEV1 % predicted was significantly improved with omalizumab vs placebo from 8 to 24 weeks (after 24-week treatment: LSM-TD=4.12%; P=0.001). At Week 24, a higher proportion of omalizumab-treated patients achieved clinically relevant improvements in standardized AQLQ (58.2% vs 39.3%; LSM=0.51 vs 0.10; P<0.001) and ACQ (49.5% vs 35.5%; LSM=-0.51 vs -0.34; P=0.002) scores vs placebo. Total and nighttime symptom scores reduced significantly with omalizumab vs placebo (LSM-TD=-0.21, P=0.048 and -0.12, P=0.011, respectively). Although the study was not powered to study differences in exacerbation rates (P=0.097), exacerbations in winter months were less frequent in the omalizumab vs placebo group (2 vs 21). Adverse event and severe adverse event rates were comparable between omalizumab and placebo. Conclusions Omalizumab improves lung function, quality of life, and asthma control in Chinese patients with moderate-to-severe persistent allergic asthma and has a good safety profile. PMID:27126725

  18. Dolutegravir in Antiretroviral-Experienced Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week Results of the Phase III VIKING-3 Study

    PubMed Central

    Castagna, Antonella; Maggiolo, Franco; Penco, Giovanni; Wright, David; Mills, Anthony; Grossberg, Robert; Molina, Jean-Michel; Chas, Julie; Durant, Jacques; Moreno, Santiago; Doroana, Manuela; Ait-Khaled, Mounir; Huang, Jenny; Min, Sherene; Song, Ivy; Vavro, Cindy; Nichols, Garrett; Yeo, Jane M.; Aberg, J.; Akil, B.; Arribas, J. R.; Baril, J.-G.; Blanco Arévalo, J. L.; Blanco Quintana, F.; Blick, G.; Boix Martínez, V.; Bouchaud, O.; Branco, T.; Bredeek, U. F.; Castro Iglesias, M.; Clumeck, N.; Conway, B.; DeJesus, E.; Delassus, J.-L.; De Truchis, P.; Di Perri, G.; Di Pietro, M.; Duggan, J.; Duvivier, C.; Elion, R.; Eron, J.; Fish, D.; Gathe, J.; Haubrich, R.; Henderson, H.; Hicks, C.; Hocqueloux, L.; Hodder, S.; Hsiao, C.-B.; Katlama, C.; Kozal, M.; Kumar, P.; Lalla-Reddy, S.; Lazzarin, A.; Leoncini, F.; Llibre, J. M.; Mansinho, K.; Morlat, P.; Mounzer, K.; Murphy, M.; Newman, C.; Nguyen, T.; Nseir, B.; Philibert, P.; Pialoux, G.; Poizot-Martin, I.; Ramgopal, M.; Richmond, G.; Salmon Ceron, D.; Sax, P.; Scarsella, A.; Sension, M.; Shalit, P.; Sighinolfi, L.; Sloan, L.; Small, C.; Stein, D.; Tashima, K.; Tebas, P.; Torti, C.; Tribble, M.; Troisvallets, D.; Tsoukas, C.; Viciana Fernández, P.; Ward, D.; Wheeler, D.; Wilkin, T.; Yeni, G.-P.; Louise Martin-Carpenter, J.; Uhlenbrauck, Gina

    2014-01-01

    Background. The pilot phase IIb VIKING study suggested that dolutegravir (DTG), a human immunodeficiency virus (HIV) integrase inhibitor (INI), would be efficacious in INI-resistant patients at the 50 mg twice daily (BID) dose. Methods. VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INI-resistant virus received DTG 50 mg BID while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued. The primary efficacy endpoints were the mean change from baseline in plasma HIV-1 RNA at day 8 and the proportion of subjects with HIV-1 RNA <50 c/mL at week 24. Results. Mean change in HIV-1 RNA at day 8 was −1.43 log10 c/mL, and 69% of subjects achieved <50 c/mL at week 24. Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response. Response was most reduced in subjects with Q148 + ≥2 resistance-associated mutations. DTG 50 mg BID had a low (3%) discontinuation rate due to adverse events, similar to INI-naive subjects receiving DTG 50 mg once daily. Conclusions. DTG 50 mg BID–based therapy was effective in this highly treatment-experienced population with INI-resistant virus. Clinical Trials Registration. www.clinicaltrials.gov (NCT01328041) and http://www.gsk-clinicalstudywww.gsk-clinicalstudyregister.com (112574). PMID:24446523

  19. A phase 2, multicenter, open-label study of sepantronium bromide (YM155) plus docetaxel in patients with stage III (unresectable) or stage IV melanoma

    PubMed Central

    Kudchadkar, Ragini; Ernst, Scott; Chmielowski, Bartosz; Redman, Bruce G; Steinberg, Joyce; Keating, Anne; Jie, Fei; Chen, Caroline; Gonzalez, Rene; Weber, Jeffrey

    2015-01-01

    Survivin is a microtubule-associated protein believed to be involved in preserving cell viability and regulating tumor cell mitosis, and it is overexpressed in many primary tumor types, including melanoma. YM155 is a first-in-class survivin suppressant. The purpose of this Phase 2 study was to evaluate the 6-month progression-free survival (PFS) rate in patients with unresectable Stage III or IV melanoma receiving a combination of YM155 plus docetaxel. The study had two parts: Part 1 established the dose of docetaxel that was tolerable in combination with YM155, and Part 2 evaluated the tolerable docetaxel dose (75 mg/m2) in combination with YM155 (5 mg/m2 per day continuous infusion over 168 h every 3 weeks). The primary endpoint was 6-month PFS rate. Secondary endpoints were objective response rate (ORR), 1-year overall survival (OS) rate, time from first response to progression, clinical benefit rate (CBR), and safety. Sixty-four patients with metastatic melanoma were treated with docetaxel and YM155. Eight patients received an initial docetaxel dose of 100 mg/m2 and 56 patients received 75 mg/m2 of docetaxel. Six-month PFS rate per Independent Review Committee (IRC) was 34.8% (n = 64; 95% CI, 21.3–48.6%), and per Investigator was 31.3% (n = 64; 95% CI, 19.5–43.9%). The best ORR (complete response [CR] + partial response [PR]) per IRC was 12.5% (8/64). The stable disease (SD) rate was 51.6% (33/64), leading to a CBR (CR + PR + SD) of 64.1% (41/64). Estimated probability of 1-year survival was 56.3%. YM155 is a novel agent showing modest activity when combined with docetaxel for treating patients with melanoma. YM155 was generally well tolerated, but the predetermined primary efficacy endpoint (i.e., 6-month PFS rate ≥20%) was not achieved. PMID:25533314

  20. A phase III, double-blind, placebo-controlled, flexible-dose study of levomilnacipran extended-release in patients with major depressive disorder.

    PubMed

    Sambunaris, Angelo; Bose, Anjana; Gommoll, Carl P; Chen, Changzheng; Greenberg, William M; Sheehan, David V

    2014-02-01

    Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin and norepinephrine reuptake inhibitor; an extended-release (ER) formulation allows for once-daily dosing. This phase III study (NCT01034462) evaluated the efficacy, the safety, and the tolerability of 40 to 120 mg/d of levomilnacipran ER versus placebo in the treatment of patients (18-80 y) with major depressive disorder. This multicenter, randomized, double-blind, placebo-controlled, parallel-group, flexible-dose study comprised a 1-week single-blind, placebo run-in period; an 8-week double-blind treatment; and a 2-week double-blind down-taper period. The primary efficacy parameter was total score change from baseline to week 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS); the secondary efficacy was the Sheehan Disability Scale. Analysis was performed using the mixed-effects model for repeated measures on a modified intent-to-treat population. A total of 434 patients received at least 1 dose of double-blind treatment (safety population); 429 patients also had 1 or more postbaseline MADRS assessments (modified intent-to-treat population). The least squares mean differences and 95% confidence interval were statistically significant in favor of levomilnacipran ER versus placebo for the MADRS total score (-3.095 [-5.256, -0.935]; P = 0.0051) and the SDS total score (-2.632 [-4.193, -1.070]; P = 0.0010) change from baseline to week 8. Adverse events were reported in 61.8% of the placebo patients and in 81.6% of the levomilnacipran ER patients. Frequently reported adverse events (≥ 5% in levomilnacipran ER and twice the rate of placebo) were nausea, dizziness, constipation, tachycardia, urinary hesitation, hyperhidrosis, insomnia, vomiting, hypertension, and ejaculation disorder. In conclusion, there was a statistically significant difference in the score change from baseline to week 8 between levomilnacipran ER and placebo on several depression rating scales, reflecting symptomatic

  1. A Phase III, Double-Blind, Placebo-Controlled, Flexible-Dose Study of Levomilnacipran Extended-Release in Patients With Major Depressive Disorder

    PubMed Central

    Bose, Anjana; Gommoll, Carl P.; Chen, Changzheng; Greenberg, William M.; Sheehan, David V.

    2014-01-01

    Abstract Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin and norepinephrine reuptake inhibitor; an extended-release (ER) formulation allows for once-daily dosing. This phase III study (NCT01034462) evaluated the efficacy, the safety, and the tolerability of 40 to 120 mg/d of levomilnacipran ER versus placebo in the treatment of patients (18-80 y) with major depressive disorder. This multicenter, randomized, double-blind, placebo-controlled, parallel-group, flexible-dose study comprised a 1-week single-blind, placebo run-in period; an 8-week double-blind treatment; and a 2-week double-blind down-taper period. The primary efficacy parameter was total score change from baseline to week 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS); the secondary efficacy was the Sheehan Disability Scale. Analysis was performed using the mixed-effects model for repeated measures on a modified intent-to-treat population. A total of 434 patients received at least 1 dose of double-blind treatment (safety population); 429 patients also had 1 or more postbaseline MADRS assessments (modified intent-to-treat population). The least squares mean differences and 95% confidence interval were statistically significant in favor of levomilnacipran ER versus placebo for the MADRS total score (−3.095 [−5.256, −0.935]; P = 0.0051) and the SDS total score (−2.632 [−4.193, −1.070]; P = 0.0010) change from baseline to week 8. Adverse events were reported in 61.8% of the placebo patients and in 81.6% of the levomilnacipran ER patients. Frequently reported adverse events (≥5% in levomilnacipran ER and twice the rate of placebo) were nausea, dizziness, constipation, tachycardia, urinary hesitation, hyperhidrosis, insomnia, vomiting, hypertension, and ejaculation disorder. In conclusion, there was a statistically significant difference in the score change from baseline to week 8 between levomilnacipran ER and placebo on several depression rating scales

  2. 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...

  3. Voxel-based evidence of perfusion normalization in glioblastoma patients included in a phase I-II trial of radiotherapy/tipifarnib combination.

    PubMed

    Ken, Soléakhéna; Deviers, Alexandra; Filleron, Thomas; Catalaa, Isabelle; Lotterie, Jean-Albert; Khalifa, Jonathan; Lubrano, Vincent; Berry, Isabelle; Péran, Patrice; Celsis, Pierre; Moyal, Elizabeth Cohen-Jonathan; Laprie, Anne

    2015-09-01

    We previously showed that the farnesyl transferase inihibitor, Tipifarnib induced vascularization normalization, oxygenation and radiosensitization in a pre-clinical glioblastoma (GBM) model. The aim of this study was to assess by dynamic-susceptibility-contrast MRI (DSC-MRI) the effect of radiotherapy (RT) and Tipifarnib combination on tumor perfusion in GBM patients. Eighteen patients with newly diagnosed GBM, enrolled in a phase I-II clinical trial associating RT with Tipifarnib, underwent anatomical MR imaging and DSC-MRI before (M0) and two months after treatment (M2). Anatomic volumes of interest (VOIs) were delineated according to contrast-enhanced and hyper-intense signal areas on T1-Gd and T2 images, respectively. Perfusion variations between M0 and M2 were assessed with median relative cerebral blood volume (rCBV) inside these VOIs. Another voxel by voxel analysis of CBV values classified 405,117 tumor voxels into High_, Normal_ and Low_CBVTUMOR according to the distribution of CBV in the contralateral normal tissue. These three categories of CBVTUMOR voxels were color-coded over anatomical MRI. Variations of median rCBV were significantly different for two groups of patients (P < 0.013): rCBV decreased when initial rCBV was ≥ 1.0 (Group_rCBV_M0 > 1) and rCBV increased when initial rCBV was < 1.0 (Group_rCBV_M0 < 1). Mapping of color-coded voxels provided additional spatial and quantitative information about tumor perfusion: Group_rCBV_M0 > 1 presented a significant decrease of High_CBVTUMOR volume (P = 0.015) simultaneously with a significant increase of Normal_CBVTUMOR volume (P = 0.009) after treatment. Group_rCBV_M0 < 1 presented a decrease of Low_CBVTUMOR volume with an increase of Normal_ and High_CBV TUMOR volume after treatment. Pre and post-treatment CBV measurements with DSC-MRI characterized tumor perfusion evolution in GBM patients treated with RT combined to Tipifarnib; showing variations in favour of tumor perfusion

  4. 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

  5. Randomized Phase II/III Trial Assessing Gemcitabine/ Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer “Unfit” for Cisplatin-Based Chemotherapy: Phase II—Results of EORTC Study 30986

    PubMed Central

    De Santis, Maria; Bellmunt, Joaquim; Mead, Graham; Kerst, J. Martijn; Leahy, Michael; Maroto, Pablo; Skoneczna, Iwona; Marreaud, Sandrine; de Wit, Ronald; Sylvester, Richard

    2009-01-01

    Purpose There is no standard treatment for patients with advanced urothelial cancer who are ineligible (“unfit”) for cisplatin-based chemotherapy (CHT). To compare the activity and safety of two CHT combinations in this patient group, a randomized phase II/III trial was conducted by the EORTC (European Organisation for Research and Treatment of Cancer). We report here the phase II results of the study. Patients and Methods CHT-naïve patients with measurable disease and impaired renal function (30 mL/min < glomerular filtration rate [GFR] < 60 mL/min) and/or performance status (PS) 2 were randomly assigned to receive either GC (gemcitabine 1,000 mg/m2 on days 1 and 8 and carboplatin area under the serum concentration-time curve [AUC] 4.5) for 21 days or M-CAVI (methotrexate 30 mg/m2 on days 1, 15, and 22; carboplatin AUC 4.5 on day 1; and vinblastine 3 mg/m2 on days 1, 15, and 22) for 28 days. End points of response and severe acute toxicity (SAT) were evaluated with respect to treatment group, renal function, PS, and Bajorin risk groups. Results Three of 178 patients who were ineligible or did not start treatment were excluded. SAT was reported in 13.6% of patients on GC and in 23% on M-CAVI. Overall response rates were 42% (37 of 88) for GC and 30% (26 of 87) for M-CAVI. Patients with PS 2 and GFR less than 60 mL/min and patients in Bajorin risk group 2 showed a response rate of only 26% and 20% and an SAT rate of 26% and 25%, respectively. Conclusion Both combinations are active in this group of unfit patients. However, patients with PS 2 and GFR less than 60 mL/min do not benefit from combination CHT. Alternative treatment modalities should be sought in this subgroup of poor-risk patients. PMID:19786668

  6. Space Phase III - The commercial era dawns

    NASA Technical Reports Server (NTRS)

    Allnutt, R. F.

    1983-01-01

    After the 'Phase I' of space activities, the period bounded by Sputnik and Apollo, 'Phase II', has been entered, a phase in which concerns over the use and the protection of space assets which support national security predominate. However, it is only when the commercial motive becomes prominent that human activity in new regions truly prospers and enters periods of exponential growth. It is believed that there are increasing signs that such a period, called 'Space Phase III', may be coming soon. A description is presented of developments and results upon which this conclusion is based. Since 1980, there have been three developments of great importance for the future of space activities. Six highly successful flights have demonstrated that the Space Shuttle concept works. A series of Soviet missions are related to the emergence of a capability to construct and service modular space stations. Successful tests of the European Ariane 1 indicate an end to U.S. monopoly with respect to the provision of launch services to the Western World.

  7. 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.

  8. A phase III randomized trial of cyclophosphamide, mitoxantrone, and 5-fluorouracil (CNF) versus cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) in patients with metastatic breast cancer.

    PubMed

    Alonso, M C; Tabernero, J M; Ojeda, B; Llanos, M; Solà, C; Climent, M A; Seguí, M A; López, J J

    1995-04-01

    One hundred patients with metastatic breast cancer were randomly selected to receive combined chemotherapy treatment with adriamycin (50 mg/m2) or mitoxantrone (12 mg/m2) associated with 5-fluorouracil (600 mg/m2) and cyclophosphamide (600 mg/m2) administered intravenously every 21 days with a maximum of ten cycles. All patients included in this study were under 75 years of age and had ECOG performance status of less than 4. They had not been treated previously with chemotherapy for metastatic disease. Patients treated with adjuvant chemotherapy, which could not have included anthracyclines, had to have relapsed at least 12 months after the completion of therapy. There were no statistically significant differences in pretreatment characteristics or metastatic disease location between the two groups. Ninety-four patients were assessable for response. No differences were observed in response rate or in survival between the groups. The response rate (complete response (CR) and partial response (PR)) was 68% (13% CR and 55% PR for CAF; 0% CR and 68% PR for CNF). Median survival for all patients was 19 months (18 months with CAF and 19 months with CNF). All patients were assessable for toxicity. There were no differences in gastrointestinal and cardiac toxicity. More grade I-II hematologic toxicity episodes (p < 0.001) and treatment delays (p = 0.05) due to leucopenia were observed with the CNF group, and more grade III alopecia (p < 0.001) was observed with the CAF group. Patients received further therapeutic manoeuvres after finishing the study with a sequential treatment consisting of hormonal therapy and chemotherapy with mitomycin (M) -vinblastine (Vbl) (M 10 mg/m2 day 1, Vbl 5 mg/m2 days 1, 15 and 29; maximum 5 cycles). This chemotherapy treatment was received by 32 patients, with a response rate of 34% and grade III-IV hematologic toxicity of 37%. Treatment with CNF can be considered a good alternative to CAF for first-line treatment of metastatic breast cancer

  9. Phase I/II Study Evaluating Early Tolerance in Breast Cancer Patients Undergoing Accelerated Partial Breast Irradiation Treated With the MammoSite Balloon Breast Brachytherapy Catheter Using a 2-Day Dose Schedule

    SciTech Connect

    Wallace, Michelle; Martinez, Alvaro; Mitchell, Christina; Chen, Peter Y.; Ghilezan, Mihai; Benitez, Pamela; Brown, Eric; Vicini, Frank

    2010-06-01

    Purpose: Initial Phase I/II results using balloon brachytherapy to deliver accelerated partial breast irradiation (APBI) in 2 days in patients with early-stage breast cancer are presented. Materials and Methods: Between March 2004 and August 2007, 45 patients received adjuvant radiation therapy after lumpectomy with balloon brachytherapy in a Phase I/II trial delivering 2800 cGy in four fractions of 700 cGy. Toxicities were evaluated using the National Cancer Institute Common Toxicity Criteria for Adverse Events v3.0 scale and cosmesis was documented at >=6 months. Results: The median age was 66 years (range, 48-83) and median skin spacing was 12 mm (range, 8-24). The median follow-up was 11.4 months (5.4-48 months) with 21 patients (47%) followed >=1 year, 11 (24%) >=2 years, and 7 (16%) >=3 years. At <6 months (n = 45), Grade II toxicity rates were 9% radiation dermatitis, 13% breast pain, 2% edema, and 2% hyperpigmentation. Grade III breast pain was reported in 13% (n = 6). At >=6 months (n = 43), Grade II toxicity rates were: 2% radiation dermatitis, 2% induration, and 2% hypopigmentation. Grade III breast pain was reported in 2%. Infection was 13% (n = 6) at <6 months and 5% (n = 2) at >=6 months. Persistent seroma >=6 months was 30% (n = 13). Fat necrosis developed in 4 cases (2 symptomatic). Rib fractures were seen in 4% (n = 2). Cosmesis was good/excellent in 96% of cases. Conclusions: Treatment with balloon brachytherapy using a 2-day dose schedule resulted acceptable rates of Grade II/III chronic toxicity rates and similar cosmetic results observed with a standard 5-day accelerated partial breast irradiation schedule.

  10. 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

  11. Epigenetic Therapy Using Belinostat for Patients With Unresectable Hepatocellular Carcinoma: A Multicenter Phase I/II Study With Biomarker and Pharmacokinetic Analysis of Tumors From Patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group

    PubMed Central

    Yeo, Winnie; Chung, Hyun C.; Chan, Stephen L.; Wang, Ling Z.; Lim, Robert; Picus, Joel; Boyer, Michael; Mo, Frankie K.F.; Koh, Jane; Rha, Sun Y.; Hui, Edwin P.; Jeung, Hei C.; Roh, Jae K.; Yu, Simon C.H.; To, Ka F.; Tao, Qian; Ma, Brigette B.; Chan, Anthony W.H.; Tong, Joanna H.M.; Erlichman, Charles; Chan, Anthony T.C.; Goh, Boon C.

    2012-01-01

    Purpose Epigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II. Patients and Methods Major eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m2 per day (level 1), 900 mg/m2 per day (level 2), 1,200 mg/m2 per day (level 3), and 1,400 mg/m2 per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response. Results Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m2 without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4% and 45.2%, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58% and 14%, respectively (P = .036). Conclusion Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B

  12. Phase I-II Trial of Concurrent Capecitabine and Oxaliplatin With Preoperative Intensity-Modulated Radiotherapy in Patients With Locally Advanced Rectal Cancer

    SciTech Connect

    Aristu, Jose Javier Arbea, Leire; Rodriguez, Javier; Hernandez-Lizoain, Jose Luis; Sola, Jesus Javier; Moreno, Marta M.D.; Azcona, Juan Diego; Diaz-Gonzalez, Juan Antonio; Garcia-Foncillas, Jesus Miguel; Martinez-Monge, Rafael

    2008-07-01

    Purpose: To identify the maximal tolerated dose level of preoperative intensity-modulated radiotherapy combined with capecitabine and oxaliplatin and to evaluate the efficacy. Patients and Methods: Patients with rectal T3-T4 and/or N0-N+ rectal cancer received capecitabine 825 mg/m{sup 2} twice daily Monday through Friday and oxaliplatin 60 mg/m{sup 2} intravenously on Days 1, 8, and 15, concurrently with intensity-modulated radiotherapy. The radiation dose was increased in 5.0-Gy steps in cohorts of 3 patients starting from 37.5 Gy in 15 fractions (dose level [DL] 1). DL2 and DL3 were designed to reach 42.5 Gy in 17 fractions and 47.5 Gy in 19 fractions, respectively. Results: No dose-limiting toxicity was observed at DL1 or DL2. Of the 3 patients treated at DL3, 1 presented with Grade 3 diarrhea, which was considered a dose-limiting toxicity, and 3 additional patients were added. Of the 6 patients treated at DL3, no new dose-limiting toxicities were observed, and DL3 was identified as the recommended dose in this study. Eight additional patients were treated at 47.5 Gy. Grade 2 proctitis was the most frequent adverse event (40%); Grade 3 diarrhea occurred in 2 patients (10%). All patients underwent surgery, and 17 patients (85%) underwent R0 resection. Four patients (20%) presented with a histologic response of Grade 4, 11 (55%) with Grade 3+, 2 (15%) with Grade 3, and 2 patients (10%) with Grade 2. Conclusion: The maximal tolerated dose in this study was 47.5 Gy. The high rates of pathologic response of Grade 3+ and 4 must be confirmed through the accrual of new patients in the Phase II study.

  13. Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer Who Are Unfit for Cisplatin-Based Chemotherapy: EORTC Study 30986

    PubMed Central

    De Santis, Maria; Bellmunt, Joaquim; Mead, Graham; Kerst, J. Martijn; Leahy, Michael; Maroto, Pablo; Gil, Thierry; Marreaud, Sandrine; Daugaard, Gedske; Skoneczna, Iwona; Collette, Sandra; Lorent, Julie; de Wit, Ronald; Sylvester, Richard

    2012-01-01

    Purpose This is the first randomized phase II/III trial comparing two carboplatin-based chemotherapy regimens in patients with urothelial cancer who are ineligible (“unfit”) for cisplatin chemotherapy. Patients and Methods The primary objective of the phase III part of this study was to compare the overall survival (OS) of chemotherapy-naive patients with measurable disease and an impaired renal function (glomerular filtration rate < 60 but > 30 mL/min) and/or performance score of 2 who were randomly assigned to receive either gemcitabine/carboplatin (GC) or methotrexate/carboplatin/vinblastine (M-CAVI). To detect an increase of 50% in median survival with GC compared with M-CAVI (13.5 v 9 months) based on a two-sided log-rank test at error rates α = .05 and β = .20, 225 patients were required. Secondary end points were overall response rate (ORR), progression-free survival (PFS), toxicity, and quality of life. Results In all, 238 patients were randomly assigned by 29 institutions over a period of 7 years. The median follow-up was 4.5 years. Best ORRs were 41.2% (36.1% confirmed response) for patients receiving GC versus 30.3% (21.0% confirmed response) for patients receiving M-CAVI (P = .08). Median OS was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm (P = .64). There was no difference in PFS (P = .78) between the two arms. Severe acute toxicity (death, grade 4 thrombocytopenia with bleeding, grade 3 or 4 renal toxicity, neutropenic fever, or mucositis) was observed in 9.3% of patients receiving GC and 21.2% of patients receiving M-CAVI. Conclusion There were no significant differences in efficacy between the two treatment groups. The incidence of severe acute toxicities was higher for those receiving M-CAVI. PMID:22162575

  14. A Phase I/II Clinical Trial of Belinostat (PXD101) in Combination with Doxorubicin in Patients with Soft Tissue Sarcomas

    PubMed Central

    Jones, Robin L.; Rossen, Philip Blach; Lind-Hansen, Maja; Knoblauch, Poul

    2016-01-01

    Background. Belinostat is a novel histone deacetylase inhibitor. Primary Objectives. Maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of belinostat (Bel) in combination with doxorubicin (Dox) in solid tumours (phase I) and response rate (RR) in soft tissue sarcomas (phase II). Methods. Bel was administered as a 30-minute IV infusion on days 1–5 and on day 5 with Dox. The dose escalation schedule was as follows: cohort 1: Bel 600 mg/m2 and 50 mg/m2 Dox, cohort 2: Bel 600 mg/m2 and 75 mg/m2 Dox, cohort 3: Bel 800 mg/m2 and 75 mg/m2 Dox, and cohort 4: Bel 1000 mg/m2 and 75 mg/m2 Dox. Results. 41 patients were included (25 in phase I, 16 in phase II). Adverse events were fatigue (95%), nausea (76%), and alopecia (63%). There was one DLT, grade 3 rash/hand and foot syndrome. MTD was Bel 1000 mg/m2/d and Dox 75 mg/m2. Four responses were seen: 2 PR in phase I, RR of 8%; in phase II, 1 PR/1 CR, RR of 13%, and 9 patients (56%) with SD. Conclusion. The combination was well tolerated. Response rate was moderate but median time to progression was 6.0 months (95% CI, 1.6–9.7 months) which is superior to some reports of single-agent Dox. PMID:27403082

  15. A phase I/II trial of irinotecan-cisplatin combined with an anti-late-diarrhoeal programme to evaluate the safety and antitumour response of this combination therapy in patients with advanced non-small-cell lung cancer.

    PubMed

    Takeda, Y; Tsuduki, E; Izumi, S; Hojo, M; Kamimura, M; Naka, G; Kobayashi, K; Kudo, K

    2005-12-12

    We conducted a phase I/II study in patients with advanced non-small-cell lung cancer (NSCLC) to increase the therapeutic index of the cisplatin-irinotecan combination by institution of an anti-late-diarrhoeal program (ADP). A total of 77 chemotherapy-naive patients with advanced NSCLC were enrolled. The cisplatin dose was fixed at 60 mg m(-2) (Day 1). Irinotecan was escalated in 5 mg m(-2) increments, starting from 60 mg m(-2) (Days 1 and 8). ADP consisted of oral sodium bicarbonate, magnesium oxide, basic water, and ursodeoxycholic acid, and was administered orally for 4 days with each dose of irinotecan. In the phase I portion, irinotecan pharmacokinetics was also examined. After the recommended dose of irinotecan with ADP was determined, a phase II study was conducted to evaluate the response. Maximum tolerated dose was reached at an irinotecan dose of 80 mg m(-2) (Grade 4 diarrhoea and neutropenia). Pharmacokinetic studies show that the maximum concentration and the area under the curve of both irinotecan and SN38 (active metabolite of irinotecan) tend to increase in the dose-dependent manner of irinotecan. The phase II portion of the study included 48 patients, who were treated with 75 mg m(-2) of irinotecan. Grade 3/4 toxicities included neutropenia in 65%, leucopenia in 33%, and late diarrhoea in 6% of the patients. During this treatment, PS did not change in 65% of patients. At the end of the chemotherapy, PS did not decline in 90% of patients. In the phase II portion, a response occurred in 63% (95% confidential interval (CI), 47-76%) of patients. Median time to progression was 19 weeks (95% CI, 15-22 weeks), and median survival was 52 weeks (95% CI, 39-64 weeks). This regimen of irinotecan and cisplatin with ADP resulted in promising efficacy with acceptable toxicity for patients with advanced NSCLC. This regimen is a candidate for the experimental arm towards future phase III studies. PMID:16288302

  16. Utility-based optimization of phase II/III programs.

    PubMed

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

    2016-01-30

    Phase II and phase III trials play a crucial role in drug development programs. They are costly and time consuming and, because of high failure rates in late development stages, at the same time risky investments. Commonly, sample size calculation of phase III is based on the treatment effect observed in phase II. Therefore, planning of phases II and III can be linked. The performance of the phase II/III program crucially depends on the allocation of the resources to phases II and III by appropriate choice of the sample size and the rule applied to decide whether to stop the program after phase II or to proceed. We present methods for a program-wise phase II/III planning that aim at determining optimal phase II sample sizes and go/no-go decisions in a time-to-event setting. Optimization is based on a utility function that takes into account (fixed and variable) costs of the drug development program and potential gains after successful launch. The proposed methods are illustrated by application to a variety of scenarios typically met in oncology drug development.

  17. Efficacy and safety of teneligliptin, a novel dipeptidyl peptidase‐4 inhibitor, in Korean patients with type 2 diabetes mellitus: a 24‐week multicentre, randomized, double‐blind, placebo‐controlled phase III trial

    PubMed Central

    Hong, S.; Park, C.‐Y.; Han, K. A.; Chung, C. H.; Ku, B. J.; Jang, H. C.; Ahn, C. W.; Lee, M.‐K.; Moon, M. K.; Son, H. S.; Lee, C. B.; Cho, Y.‐W.

    2016-01-01

    We assessed the 24‐week efficacy and safety of teneligliptin, a novel dipeptidyl peptidase‐4 inhibitor, in Korean patients with type 2 diabetes mellitus (T2DM) that was inadequately controlled with diet and exercise. The present study was designed as a multicentre, randomized, double‐blind, placebo‐controlled, parallel‐group, phase III study. Patients (n = 142) were randomized 2 : 1 into two different treatment groups as follows: 99 received teneligliptin (20 mg) and 43 received placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) level from baseline to week 24. Teneligliptin significantly reduced the HbA1c level from baseline compared with placebo after 24 weeks. At week 24, the differences between changes in HbA1c and fasting plasma glucose (FBG) in the teneligliptin and placebo groups were −0.94% [least‐squares (LS) mean −1.22, −0.65] and −1.21 mmol/l (−1.72, −0.70), respectively (all p < 0.001). The incidence of hypoglycaemia and adverse events were not significantly different between the two groups. This phase III, randomized, placebo‐controlled study provides evidence of the safety and efficacy of 24 weeks of treatment with teneligliptin as a monotherapy in Korean patients with T2DM. PMID:26749529

  18. Bortezomib salvage followed by a phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma

    PubMed Central

    Nishihori, Taiga; Alekshun, Todd J.; Shain, Kenneth; Sullivan, Daniel M.; Baz, Rachid; Perez, Lia; Pidala, Joseph; Kharfan-Dabaja, Mohamed A.; Ochoa-Bayona, Jose L; Fernandez, Hugo F; Yarde, Danielle N.; Oliveira, Vasco; Fulp, William; Han, Gang; Kim, Jongphil; Chen, Dung-Tsa; Raychaudhuri, Jyoti; Dalton, William; Anasetti, Claudio; Alsina, Melissa

    2014-01-01

    Summary We conducted a phase 1/2 study of bortezomib administered in combination with high-dose melphalan followed by tandem autologous transplants in patients with primary resistant multiple myeloma. Thirty patients received 2 cycles of salvage bortezomib followed by stem cell mobilization with G-CSF and harvest. Melphalan 100 mg/m2/day on two consecutive days was administered, immediately followed by one dose of bortezomib (dose escalation) and stem cell infusion. The median beta 2-microglobulin was 4.35 mg/L (range: 1.8 - 11.4); albumin was 3.7 g/dL (range: 3.1 - 4.9); high-risk karyotypes were noted in 45% of patients. The maximum planned dose of bortezomib at 1.3 mg/m2 was well tolerated and a formal maximum tolerated dose was not determined. The peak of best overall response (≥PR) and complete response rates after tandem transplants were 84% and 36%, respectively. With a median follow-up of 48 months, the median progression-free survival was 15 (95% CI: 11 - 21) months and the median overall survival was 35 (95% CI: 22 - 43) months. Correlative studies demonstrated decreased expression of FANCD1 (P=0.0072) and FANCF (P=0.0458) mRNA following bortezomib treatment. Bortezomib combined with high-dose melphalan is a well tolerated conditioning with some activity in patients with resistant myeloma. PMID:22449149

  19. Citalopram versus fluoxetine: a double-blind, controlled, multicentre, phase III trial in patients with unipolar major depression treated in general practice.

    PubMed

    Patris, M; Bouchard, J M; Bougerol, T; Charbonnier, J F; Chevalier, J F; Clerc, G; Cyran, C; Van Amerongen, P; Lemming, O; Høpfner Petersen, H E

    1996-06-01

    Two selective serotonin reuptake inhibitors (SSRIs), citalopram and fluoxetine, both at a daily dose of 20 mg, were compared in patients with unipolar major depression treated in general practice. This was a multicentre, double-blind, randomized trial carried out in France. The duration of treatment was 8 weeks. Patients were assessed by means of the Montgomery-Asberg Depression Rating Scale (MADRS), the 17 items Hamilton Depression Rating Scale (HAMD) and the investigator's Clinical Global Impressions (CGI), Observed and spontaneously reported adverse events were also recorded. A total of 357 patients of both sexes, aged between 21 and 73 years, entered the double-blind phase of the trial. A clear reduction of both the MADRS and the HAMD mean total scores was observed in both treatment groups with no statistically significant differences between treatments. Apart from back pain recorded more frequently in the citalopram group, no significant difference was found between the two treatment groups with regard to adverse events, and both citalopram and fluoxetine were considered to be well tolerated. It was concluded that citalopram was as effective as fluoxetine in the treatment of unipolar major depression. Citalopram showed an earlier onset of recovery than fluoxetine. PMID:8803650

  20. 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.

  1. Effect of Granulocyte-Macrophage Colony-Stimulating Factor on Chemotherapy-Related Neutropenia in Patients with Non-Hodgkin's Lymphomas-A Phase I/II Study of Dose and Mode of Administration.

    PubMed

    Hovgaard, D J; Nissen, N I

    1991-01-01

    The effect of mammalian glycosylated recombinant granulocyte-macrophage colony-stimulating factor was investigated in 24 patients with newly diagnosed non-Hodgkin's lymphoma in a phase I/II study. All patients received standard chemotherapy with CHOP. RhGM-CSF was administered after the first cycle for 5 days, and at one of four dose levels (2, 4, 8 and 16 μg/kg). Patients were randomized to receive the drug either by continuous intravenous infusion or twice daily as subcutaneous injection. No significant difference in results was observed between subcutaneous administration of rhGM-CSF and continuous i.v. infusion and these patient groups could therefore be combined in the analysis. Administration of rhGM-CSF resulted in a significant dose-dependent increase of total WBC, mainly neutrophils, eosinophils and monocytes. The increase was observed in 18/24 patients, reaching a peak 24-72 (median 24) hours after the start of rhGM-CSF. The CHOP chemotherapy-induced leucocyte nadir occurred on day 12 (mean) compared to day 14 for the 127 historical controls. The WBC nadir values were higher (2.4 ± 1.4) than for historical controls (1.8 ± 1.1) and the leucopenic/neutropenic period was of shorter duration. Following the chemotherapy nadir a more rapid recovery of WBC was seen than in controls. GM-CSF was well tolerated, the side effects were mild and transient, and included myalgias, low grade fever, headache, chest/bone discomfort, nausea, erythema at injection site and superficial phlebitis. The encouraging results of this phase I/II study indicate the need for a prospective controlled study of GM-CSF in chemotherapy of malignant lymphoma.

  2. 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.

  3. A Phase II Study of Synchronous Three-Dimensional Conformal Boost to the Gross Tumor Volume for Patients With Unresectable Stage III Non-Small-Cell Lung Cancer: Results of Korean Radiation Oncology Group 0301 Study

    SciTech Connect

    Cho, Kwan Ho Ahn, Sung Ja; Pyo, Hong Ryull; Kim, Kyu-Sik; Kim, Young-Chul; Moon, Sung Ho; Han, Ji-Youn; Kim, Heung Tae; Koom, Woong Sub; Lee, Jin Soo

    2009-08-01

    Purpose: We evaluated the efficacy of synchronous three-dimensional (3D) conformal boost to the gross tumor volume (GTV) in concurrent chemoradiotherapy for patients with locally advanced non-small-cell lung cancer (NSCLC). Methods and Materials: Eligibility included unresectable Stage III NSCLC with no pleural effusion, no supraclavicular nodal metastases, and Eastern Cooperative Oncology Group performance score of 0-1. Forty-nine patients with pathologically proven NSCLC were enrolled. Eighteen patients had Stage IIIA and 31 had Stage IIIB. By using 3D conformal radiotherapy (RT) techniques, a dose of 1.8 Gy was delivered to the planning target volume with a synchronous boost of 0.6 Gy to the GTV, with a total dose of 60 Gy to the GTV and 45 Gy to the planning target volume in 25 fractions during 5 weeks. All patients received weekly chemotherapy consisting of paclitaxel and carboplatin during RT. Results: With a median follow-up of 36.8 months (range, 29.0-45.5 months) for surviving patients, median survival was 28.1 months. One-, 2- and 3-year overall survival rates were 77%, 56.4%, and 43.8%, respectively. Corresponding local progression-free survival rates were 71.2%, 53.7%, and 53.7%. Compliance was 90% for RT and 88% for chemotherapy. Acute esophagitis of Grade 2 or higher occurred in 29 patients. Two patients with T4 lesions died of massive bleeding and hemoptysis during treatment (Grade 5). Overall late toxicity was acceptable. Conclusions: Based on the favorable outcome with acceptable toxicity, the acceleration scheme using 3D conformal GTV boost in this trial is warranted to compare with conventional fractionation in a Phase III trial.

  4. Treatment of older patients with HER2-positive metastatic breast cancer with pertuzumab, trastuzumab, and docetaxel: subgroup analyses from a randomized, double-blind, placebo-controlled phase III trial (CLEOPATRA).

    PubMed

    Miles, David; Baselga, José; Amadori, Dino; Sunpaweravong, Patrapim; Semiglazov, Vladimir; Knott, Adam; Clark, Emma; Ross, Graham; Swain, Sandra M

    2013-11-01

    Although the incidence of cancer increases with age, older patients are under-represented in cancer treatment trials, resulting in limited data availability in this patient population. Here we present results from pre-defined subgroup analyses conducted by age group (<65 vs ≥ 65 years) from a randomized, double-blind, placebo-controlled phase III trial in patients with HER2-positive metastatic breast cancer. Patients who had not received previous chemotherapy or biological therapy for HER2-positive locally recurrent, unresectable or metastatic breast cancer were randomly assigned to treatment with placebo, trastuzumab, and docetaxel or with pertuzumab, trastuzumab, and docetaxel. Primary endpoint was independently assessed progression-free survival. We performed pre-specified subgroup analyses of progression-free survival according to age. The study is registered with ClinicalTrials.gov, NCT00567190. 808 patients were enrolled. Of those, 127 patients were 65 years of age or older (placebo arm: 67, pertuzumab arm: 60). Patients in both age groups experienced progression-free survival benefit with treatment in the pertuzumab arm (<65 years: HR: 0.65; 95 % CI 0.53-0.80; ≥65 years: HR: 0.52; 95 % CI 0.31-0.86). Diarrhoea, fatigue, asthenia, decreased appetite, vomiting, and dysgeusia were reported more frequently in patients 65 years of age or older compared with younger patients. Neutropenia and febrile neutropenia were reported less frequently in the older age group. The efficacy and safety data reported in CLEOPATRA suggest that the combined use of pertuzumab, trastuzumab, and docetaxel should not be limited by patient age.

  5. Long-term evaluation of combined prolonged-release oxycodone and naloxone in patients with moderate-to-severe chronic pain: pooled analysis of extension phases of two Phase III trials

    PubMed Central

    Blagden, M; Hafer, J; Duerr, H; Hopp, M; Bosse, B

    2014-01-01

    Background While opioids provide effective analgesia, opioid-induced constipation (OIC) can severely impact quality of life and treatment compliance. This pooled analysis evaluated the maintenance of efficacy and safety during long-term treatment with combined oxycodone/naloxone prolonged-release tablets (OXN PR) in adults with moderate-to-severe chronic pain. Methods Patients (N = 474) received open-label OXN PR during 52-week extension phases of two studies, having completed 12-week, double-blind, randomized treatment with oxycodone prolonged-release tablets (Oxy PR) or OXN PR. Analgesia and bowel function were assessed at each study visit using ‘Average pain over last 24 h scale and Bowel Function Index (BFI), respectively. Treatment Satisfaction Questionnaire for Medication was assessed at study end only. Key Results Improvement in bowel function was particularly marked in patients who switched from Oxy PR in the double-blind phase to OXN PR during the extension phase, resulting in a clinically meaningful reduction (≥12 points) in BFI score: at the start of the extension phases, mean (SD) BFI score was 44.3 (28.13), and was 29.8 (26.36) for patients who had received OXN PR in the double-blind phase. One week later, BFI scores were similar for the two groups (26.5 [24.40] and 27.5 [25.60], respectively), as was observed throughout the following months. Fewer than 10% of patients received laxatives regularly. Mean 24-h pain scores were low and stable throughout the extension phases. No unexpected adverse events were observed. Conclusions & Inferences Pooled data demonstrate OXN PR is an effective long-term therapy for patients with chronic non-cancer pain, and can address symptoms of OIC. No new safety issues were observed which were attributable to the long-term administration of OXN PR. PMID:25346155

  6. First-Line XELOX Plus Bevacizumab Followed by XELOX Plus Bevacizumab or Single-Agent Bevacizumab as Maintenance Therapy in Patients with Metastatic Colorectal Cancer: The Phase III MACRO TTD Study

    PubMed Central

    Gómez-España, Auxiliadora; Massutí, Bartomeu; Sastre, Javier; Abad, Albert; Valladares, Manuel; Rivera, Fernando; Safont, Maria J.; Martínez de Prado, Purificación; Gallén, Manuel; González, Encarnación; Marcuello, Eugenio; Benavides, Manuel; Fernández-Martos, Carlos; Losa, Ferrán; Escudero, Pilar; Arrivi, Antonio; Cervantes, Andrés; Dueñas, Rosario; López-Ladrón, Amelia; Lacasta, Adelaida; Llanos, Marta; Tabernero, Jose M.; Antón, Antonio; Aranda, Enrique

    2012-01-01

    Purpose. The aim of this phase III trial was to compare the efficacy and safety of bevacizumab alone with those of bevacizumab and capecitabine plus oxaliplatin (XELOX) as maintenance treatment following induction chemotherapy with XELOX plus bevacizumab in the first-line treatment of patients with metastatic colorectal cancer (mCRC). Patients and Methods. Patients were randomly assigned to receive six cycles of bevacizumab, capecitabine, and oxaliplatin every 3 weeks followed by XELOX plus bevacizumab or bevacizumab alone until progression. The primary endpoint was the progression-free survival (PFS) interval; secondary endpoints were the overall survival (OS) time, objective response rate (RR), time to response, duration of response, and safety. Results. The intent-to-treat population comprised 480 patients (XELOX plus bevacizumab, n = 239; bevacizumab, n = 241); there were no significant differences in baseline characteristics. The median follow-up was 29.0 months (range, 0–53.2 months). There were no statistically significant differences in the median PFS or OS times or in the RR between the two arms. The most common grade 3 or 4 toxicities in the XELOX plus bevacizumab versus bevacizumab arms were diarrhea, hand–foot syndrome, and neuropathy. Conclusion. Although the noninferiority of bevacizumab versus XELOX plus bevacizumab cannot be confirmed, we can reliably exclude a median PFS detriment >3 weeks. This study suggests that maintenance therapy with single-agent bevacizumab may be an appropriate option following induction XELOX plus bevacizumab in mCRC patients. PMID:22234633

  7. A New Approach to Designing Phase I-II Cancer Trials for Cytotoxic Chemotherapies

    PubMed Central

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

    2014-01-01

    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 (MTD) η̂ 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 2-stage design with all patients dosed at η̂. We propose a Phase I-II design that addresses the uncertainty in the estimate p = p(η̂) 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 MTD and testing if the treatment has an acceptable response rate to enter into a Phase III trial. PMID:24577750

  8. Phase I/II Trial of AEG35156 X-Linked Inhibitor of Apoptosis Protein Antisense Oligonucleotide Combined With Idarubicin and Cytarabine in Patients With Relapsed or Primary Refractory Acute Myeloid Leukemia

    PubMed Central

    Schimmer, Aaron D.; Estey, Elihu H.; Borthakur, Gautam; Carter, Bing Z.; Schiller, Gary J.; Tallman, Martin S.; Altman, Jessica K.; Karp, Judith E.; Kassis, Jeannine; Hedley, David W.; Brandwein, Joseph; Xu, Wei; Mak, Duncan H.; LaCasse, Eric; Jacob, Christine; Morris, Stephen J.; Jolivet, Jacques; Andreeff, Michael

    2009-01-01

    Purpose X-linked inhibitor of apoptosis protein (XIAP) is an inhibitor of caspases 3 and 9 which are overexpressed in acute myeloid leukemia (AML) and may contribute to chemoresistance. We report on a phase I/II trial of the XIAP antisense oligonucleotide AEG35156 in combination with reinduction chemotherapy. Patients and Methods Twenty-four patients with rapidly relapsed or refractory AML were treated with escalating doses of AEG35156 (12 to 250 mg/m2) as an intravenous solution over 2 hours and 32 patients were treated with the highest planned dose of 350 mg/m2 in combination with idarubicin and high-dose cytarabine reinduction chemotherapy. Correlative studies were conducted to determine the effects of AEG35156 on levels of XIAP mRNA. Results Knockdown of XIAP mRNA during treatment increased with the dose of the antisense. All patients who received 350 mg/m2 of AEG35156 had higher than 30% target knockdown with a median maximal knockdown of 90% (range, 48% to 100%). The overall response rate was higher among the patients receiving the highest dose of AEG35156. In this group, 15 (47%) of 32 patients achieved complete response (CR)/CR with incomplete platelet count recovery (CRp) compared with only one (4%) of 24 receiving 12 to 250 mg/m2 AEG35156. Among the patients receiving 350 mg/m2 of AEG35156 in combination with chemotherapy, 10 (91%) of 11 who were refractory to a single induction chemotherapy regimen achieved CR/CRp after reinduction with AEG35156 and chemotherapy. AEG35156 was well tolerated save for two cases of peripheral neuropathy in patients receiving multiple doses of AEG35156. Conclusion At the highest dose tested, AEG35156 knocks down its target and appears very effective when combined with chemotherapy in patients with AML refractory to a single induction regimen. PMID:19652057

  9. Intratumoural injection of the toll-like receptor-2/6 agonist ‘macrophage-activating lipopeptide-2' in patients with pancreatic carcinoma: a phase I/II trial

    PubMed Central

    Schmidt, J; Welsch, T; Jäger, D; Mühlradt, P F; Büchler, M W; Märten, A

    2007-01-01

    This phase I/II trial examined safety and efficacy of the toll-like receptor 2/6 agonist MALP-2 in combination with gemcitabine in patients with incompletely resectable pancreas carcinomas. MALP-2 is a toll-like receptor 2/6 agonist, acts as an immunological adjuvant, and has been described recently to prolong survival in a mouse model of an orthotopic, syngeneic pancreas tumour. Male and female patients with incompletely resectable pancreas carcinomas were eligible while those with R0 or R1 resections or with peritoneal carcinosis were excluded. Ten patients were injected intratumourally during surgery with 20–30 μg MALP-2 followed by postoperative chemotherapy. Samples were taken from peripheral blood and wound secretion, and assayed for cell content, cytokine and CRP levels, and NK activity. An MALP-2 dose of 20 μg was well tolerated. Clear signs of local MALP-2 effects were presented by the influx of lymphocytes and monocytes in wound secretions, and abolishment of inhibition of NK activity. The actual mean survival is 17.1±4.2 months; the median survival being 9.3 months. Two patients are still alive after 31 months. Up to 20 μg MALP-2 was well tolerated, and no systemic side effects were noted. The mean survival of 17.1 months is remarkably high. PMID:17667928

  10. Motexafin Gadolinium Combined With Prompt Whole Brain Radiotherapy Prolongs Time to Neurologic Progression in Non-Small-Cell Lung Cancer Patients With Brain Metastases: Results of a Phase III Trial

    SciTech Connect

    Mehta, Minesh P. Shapiro, William R.; Phan, See C.; Gervais, Radj; Carrie, Christian; Chabot, Pierre; Patchell, Roy A.; Glantz, Michael J.; Recht, Lawrence; Langer, Corey; Sur, Ranjan K.; Roa, Wilson H.; Mahe, Marc A.; Fortin, Andre; Nieder, Carsten; Meyers, Christina A.; Smith, Jennifer A.; Miller, Richard A.; Renschler, Markus F.

    2009-03-15

    Purpose: To determine the efficacy of motexafin gadolinium (MGd) in combination with whole brain radiotherapy (WBRT) for the treatment of brain metastases from non-small-cell lung cancer. Methods and Materials: In an international, randomized, Phase III study, patients with brain metastases from non-small-cell lung cancer were randomized to WBRT with or without MGd. The primary endpoint was the interval to neurologic progression, determined by a centralized Events Review Committee who was unaware of the treatment the patients had received. Results: Of 554 patients, 275 were randomized to WBRT and 279 to WBRT+MGd. Treatment with MGd was well tolerated, and 92% of the intended doses were administered. The most common MGd-related Grade 3+ adverse events included liver function abnormalities (5.5%), asthenia (4.0%), and hypertension (4%). MGd improved the interval to neurologic progression compared with WBRT alone (15 vs. 10 months; p = 0.12, hazard ratio [HR] = 0.78) and the interval to neurocognitive progression (p = 0.057, HR = 0.78). The WBRT patients required more salvage brain surgery or radiosurgery than did the WBRT+MGd patients (54 vs. 25 salvage procedures, p < 0.001). A statistically significant interaction between the geographic region and MGd treatment effect (which was in the prespecified analysis plan) and between treatment delay and MGd treatment effect was found. In North American patients, where treatment was more prompt, a statistically significant prolongation of the interval to neurologic progression, from 8.8 months for WBRT to 24.2 months for WBRT+MGd (p = 0.004, HR = 0.53), and the interval to neurocognitive progression (p = 0.06, HR = 0.73) were observed. Conclusion: In the intent-to-treat analysis, MGd exhibited a favorable trend in neurologic outcomes. MGd significantly prolonged the interval to neurologic progression in non-small-cell lung cancer patients with brain metastases receiving prompt WBRT. The toxicity was acceptable.

  11. Radiation-related quality of life parameters after targeted intraoperative radiotherapy versus whole breast radiotherapy in patients with breast cancer: results from the randomized phase III trial TARGIT-A

    PubMed Central

    2013-01-01

    Background Intraoperative radiotherapy (IORT) is a new treatment approach for early stage breast cancer. This study reports on the effects of IORT on radiation-related quality of life (QoL) parameters. Methods Two hundred and thirty women with stage I-III breast cancer (age, 31 to 84 years) were entered into the study. A single-center subgroup of 87 women from the two arms of the randomized phase III trial TARGIT-A (TARGeted Intra-operative radioTherapy versus whole breast radiotherapy for breast cancer) was analyzed. Furthermore, results were compared to non-randomized control groups: n = 90 receiving IORT as a tumor bed boost followed by external beam whole breast radiotherapy (EBRT) outside of TARGIT-A (IORT-boost), and n = 53 treated with EBRT followed by an external-beam boost (EBRT-boost). QoL was collected using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 (QLQ-C30) and BR23 (QLQ-BR23). The mean follow-up period in the TARGIT-A groups was 32 versus 39 months in the non-randomized control groups. Results Patients receiving IORT alone reported less general pain (21.3 points), breast (7.0 points) and arm (15.1 points) symptoms, and better role functioning (78.7 points) as patients receiving EBRT (40.9; 19.0; 32.8; and 60.5 points, respectively, P < 0.01). Patients receiving IORT alone also had fewer breast symptoms than TARGIT-A patients receiving IORT followed by EBRT for high risk features on final pathology (IORT-EBRT; 7.0 versus 29.7 points, P < 0.01). There were no significant differences between TARGIT-A patients receiving IORT-EBRT compared to non-randomized IORT-boost or EBRT-boost patients and patients receiving EBRT without a boost. Conclusions In the randomized setting, important radiation-related QoL parameters after IORT were superior to EBRT. Non-randomized comparisons showed equivalent parameters in the IORT-EBRT group and the control groups. PMID:23294485

  12. Comparison of Provider-Assessed and Patient-Reported Outcome Measures of Acute Skin Toxicity During a Phase III Trial of Mometasone Cream Versus Placebo During Breast Radiotherapy: The North Central Cancer Treatment Group (N06C4)

    SciTech Connect

    Neben-Wittich, Michelle A.; Atherton, Pamela J.; Schwartz, David J.; Sloan, Jeff A.; Griffin, Patricia C.; Deming, Richard L.; Anders, Jon C.; Loprinzi, Charles L.; Burger, Kelli N.; Martenson, James A.; Miller, Robert C.

    2011-10-01

    Purpose: Considerable interobserver variability exists among providers and between providers and patients when measuring subjective symptoms. In the recently published Phase III N06C4 trial of mometasone cream vs. placebo to prevent radiation dermatitis, the primary provider-assessed (PA) endpoint, using the Common Toxicity Criteria for Adverse Events (CTCAE), was negative. However, prospectively planned secondary analyses of patient-reported outcomes (PROs), using the Skindex-16 and Skin Toxicity Assessment Tool (STAT), were positive. This study assesses the relationship between PA outcomes and PROs. Methods and Materials: Pearson correlation coefficients were calculated to compare the three tools. Statistical correlations were defined as follows: <0.5, mild; 0.5-0.7, moderate; and >0.7, strong. Results: CTCAE dermatitis moderately correlated with STAT erythema, and CTCAE pruritus strongly correlated with STAT itching. CTCAE pruritus had a moderate correlation with Skindex-16 itching. Comparing the 2 PRO tools, Skindex-16 itching correlated moderately with STAT itching. Skindex-16 burning, hurting, irritation, and persistence all showed the strongest correlation with STAT burning; they showed moderate correlations with STAT itching and tenderness. Conclusions: The PRO Skindex-16 correlated well with the PRO portions of STAT, but neither tool correlated well with CTCAE. PROs delineated a wider spectrum of toxicity than PA measures and provided more information on rash, redness, pruritus, and annoyance measures compared with CTCAE findings of rash and pruritus. PROs may provide a more complete measure of patient experience than single-symptom, PA endpoints in clinical trials assessing radiation skin toxicity.

  13. Failure to Adhere to Protocol Specified Radiation Therapy Guidelines Was Associated With Decreased Survival in RTOG 9704 - A Phase III Trial of Adjuvant Chemotherapy and Chemoradiotherapy for Patients with Resected Adenocarcinoma of the Pancreas

    PubMed Central

    Abrams, Ross A.; Winter, Kathryn A.; Regine, William F.; Safran, Howard; Hoffman, John P.; Lustig, Robert; Konski, Andre A.; Benson, Al B.; Macdonald, John S.; Rich, Tyvin A.; Willett, Christopher G.

    2011-01-01

    Purpose In RTOG 9704, as previously published, patients with resected pancreatic adenocarcinoma received continuous infusion 5-FU and concurrent radiotherapy (5FU-RT). 5FU-RT treatment was preceded and followed by randomly assigned chemotherapy, either 5-FU or gemcitabine. This analysis explored whether failure to adhere to specified RT guidelines influenced survival and/or toxicity. Methods and Materials RT requirements were protocol specified. Adherence was scored as per protocol (PP) or less than per protocol (patient treatment outcomes. Scoring was done for all tumor locations and for the subset of pancreatic head location. Results RT was scored for 416 patients: 216 PP and 200 patients with pancreatic head tumors, both PP score and gemcitabine treatment correlated with improved MS (p=0.016, p=0.043, respectively). For all tumor locations PP score was associated with decreased risk of failure (p=0.016) and, for gemcitabine patients, a trend toward reduced grade 4/5 non-hematologic toxicity (p=0.065). Conclusions This is the first phase III, multi-center, adjuvant protocol for pancreatic adenocarcinoma to evaluate the impact of adherence to specified RT protocol guidelines on protocol outcomes. Failure to adhere to specified RT guidelines was associated with reduced survival and, for patients receiving gemcitabine, trend toward increased non-hematologic toxicity. PMID:21277694

  14. Failure to Adhere to Protocol Specified Radiation Therapy Guidelines Was Associated With Decreased Survival in RTOG 9704-A Phase III Trial of Adjuvant Chemotherapy and Chemoradiotherapy for Patients With Resected Adenocarcinoma of the Pancreas

    SciTech Connect

    Abrams, Ross A.; Winter, Kathryn A.; Regine, William F.; Safran, Howard; Hoffman, John P.; Lustig, Robert; Konski, Andre A.; Benson, Al B.; Macdonald, John S.; Rich, Tyvin A.; Willett, Christopher G.

    2012-02-01

    Purpose: In Radiation Therapy Oncology Group 9704, as previously published, patients with resected pancreatic adenocarcinoma received continuous infusion 5-FU and concurrent radiotherapy (5FU-RT). 5FU-RT treatment was preceded and followed by randomly assigned chemotherapy, either 5-FU or gemcitabine. This analysis explored whether failure to adhere to specified RT guidelines influenced survival and/or toxicity. Methods and Materials: RT requirements were protocol specified. Adherence was scored as per protocol (PP) or less than per protocol (patient treatment outcomes. Scoring was done for all tumor locations and for the subset of pancreatic head location. Results: RT was scored for 416 patients: 216 PP and 200 patients with pancreatic head tumors, both PP score and gemcitabine treatment correlated with improved MS (p = 0.016, p = 0.043, respectively). For all tumor locations, PP score was associated with decreased risk of failure (p = 0.016) and, for gemcitabine patients, a trend toward reduced Grade 4/5 nonhematologic toxicity (p = 0.065). Conclusions: This is the first Phase III, multicenter, adjuvant protocol for pancreatic adenocarcinoma to evaluate the impact of adherence to specified RT protocol guidelines on protocol outcomes. Failure to adhere to specified RT guidelines was associated with reduced survival and, for patients receiving gemcitabine, trend toward increased nonhematologic toxicity.

  15. Efficacy and safety of liraglutide, a once-daily human glucagon-like peptide-1 analogue, in Latino/Hispanic patients with type 2 diabetes: post hoc analysis of data from four phase III trials.

    PubMed

    Davidson, J A; Ørsted, D D; Campos, C

    2016-07-01

    The aim of the present analysis was to evaluate the efficacy of the glucagon-like peptide-1 receptor agonist liraglutide in Latino/Hispanic individuals with type 2 diabetes, in addition to comparing its treatment effects with those observed in non-Latino/Hispanic individuals. Analyses were performed on patient-level data from a subset of individuals self-defined as Latino/Hispanic from four phase III studies, the LEAD-3, LEAD-4, LEAD-6 and 1860-LIRA-DPP-4 trials. Endpoints included change in glycated haemoglobin (HbA1c) and body weight from baseline. In Latino/Hispanic patients (n = 505; 323 treated with liraglutide) after 26 weeks, mean HbA1c reductions were significantly greater with both liraglutide 1.2 and 1.8 mg versus comparator or placebo in the LEAD-3 and LEAD-4 studies, and with 1.8 mg liraglutide in the 1860-LIRA-DPP-4 trial. In LEAD-3 both doses led to significant differences in body weight change among Latino/Hispanic patients versus the comparator. With 1.8 mg liraglutide, difference in weight change was significant only in the 1860-LIRA-DPP-4 trial versus sitagliptin. For both endpoints Latino/Hispanic and non-Latino/Hispanic patients responded to liraglutide similarly. In summary, liraglutide is efficacious for treatment of type 2 diabetes in Latino/Hispanic patients, with a similar efficacy to that seen in non-Latino/Hispanic patients. PMID:26936426

  16. Preliminary results of a phase I/II clinical trial using in situ photoimmunotherapy combined with imiquimod for metastatic melanoma patients

    NASA Astrophysics Data System (ADS)

    Li, Xiaosong; Naylor, Mark F.; Nordquist, Robert E.; Teague, T. Kent; Howard, C. Anthony; Murray, Cynthia; Chen, Wei R.

    2010-02-01

    In Situ Photoimmunotherapy (ISPI), a newly developed modality for cancer therapy, has been shown to be able to modulate the body's own immune response. This clinical trial was designed to evaluate the safety and therapeutic effect of ISPI, using imiquimod as its immunoadjuvant for metastatic melanoma patients. ISPI consisted of three main components applied directly to the cutaneous metastases: 1) local application of topical imiquimod; 2) injection of indocyanine green; and 3) an 805 nm laser for local irradiation. All patients completed at least one cycle of treatment. All the patients completed at least one cycle of treatments; one patient received 6 cycles. The most common adverse effects were rash, pruritus, pain, fatigue and anorexia. Fever, chills, vomiting and cellulitis were relative rare. No grade 4 toxicity was observed. Complete Response (CR) was observed in 6 patients. Median overall survival of the 11 evaluated patients was 12.2 months. Six of the eleven patients were still alive at the time of this report. Treatment of ISPI using imiquimod is safe and well tolerant. Our preliminary clinical results suggest that this new method can be a promising modality for metastatic melanoma.

  17. Rationale and design of LUX-Head & Neck 1: a randomised, Phase III trial of afatinib versus methotrexate in patients with recurrent and/or metastatic head and neck squamous cell carcinoma who progressed after platinum-based therapy

    PubMed Central

    2014-01-01

    Background Patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) receiving platinum-based chemotherapy as their first-line treatment have a dismal prognosis, with a median overall survival (OS) of ~7 months. Methotrexate is sometimes used following platinum failure or in patients not fit enough for platinum therapy, but this agent has not demonstrated any OS improvement. Targeted therapies are a novel approach, with the EGFR-targeting monoclonal antibody cetuximab (plus platinum-based chemotherapy) approved in the US and Europe in the first-line R/M setting, and as monotherapy following platinum failure in the US. However, there is still a high unmet medical need for new treatments that improve outcomes in the second-line R/M setting following failure on first-line platinum-containing regimens. Afatinib, an irreversible ErbB family blocker, was recently approved for the first-line treatment of EGFR mutation-positive metastatic non-small cell lung cancer. Afatinib has also shown clinical activity similar to cetuximab in a Phase II proof-of-concept HNSCC trial. Based on these observations, the Phase III, LUX-Head & Neck 1 study is evaluating afatinib versus methotrexate in R/M HNSCC patients following progression on platinum-based chemotherapy in the R/M setting. Methods/Design Patients with progressive disease after one first-line platinum-based chemotherapy are randomised 2:1 to oral afatinib (starting dose 40 mg once daily) or IV methotrexate (starting dose 40 mg/m2 once weekly) administered as monotherapy with best supportive care until progression or intolerable adverse events. Efficacy of afatinib versus methotrexate will be assessed in terms of progression-free survival (primary endpoint). Disease progression will be evaluated according to RECIST v1.1 by investigator and independent central review. Secondary endpoints include OS, tumour response and safety. Health-related quality of life and biomarker assessments will

  18. WAIS-III and WMS-III profiles of mildly to severely brain-injured patients.

    PubMed

    Fisher, D C; Ledbetter, M F; Cohen, N J; Marmor, D; Tulsky, D S

    2000-01-01

    Wechsler Adult Intelligence Scale-III (WAIS-III) and Wechsler Memory Scale-III (WMS-III; The Psychological Corporation, 1997) scores of patients with mild traumatic brain injury (MTBI, n = 23) to moderate-severe traumatic brain injury (M-S TBI, n = 22) were compared to those of 45 matched normal control patients. WAIS-III results revealed that IQ and index scores of MTBI patients did not significantly differ from those of controls, whereas M-S TBI patients received significantly lower mean scores on all measures. All M-S TBI patients' WMS-III index scores also revealed significantly lower scores in comparison to those of control participants, with the exception of Delayed Auditory Recognition. MTBI patients showed significantly lower mean index scores compared to normal controls on measures of immediate and delayed auditory memory, immediate memory, visual delayed memory, and general memory. Eta-squared analyses revealed that WMS-III visual indexes and WAIS-III processing speed showed particularly large effect sizes. These results suggest that symptomatic MTBI patients obtain some low WMS-III test scores comparable to those of more severely injured patients.

  19. Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada Clinical Trials Group.

    PubMed

    Quirt, I C; Shelley, W E; Pater, J L; Bodurtha, A J; McCulloch, P B; McPherson, T A; Paterson, A H; Prentice, R; Silver, H K; Willan, A R

    1991-05-01

    Five hundred forty-three patients with completely resected malignant melanoma who were considered to have a significant risk of developing recurrent disease were randomized to one of four study groups. One group received levamisole 2.5 mg/kg on 2 consecutive days weekly for 3 years, a second group received bacillus Calmette-Guérin (BCG) for 3 years. A third group alternated 8-week courses of BCG and levamisole for 3 years and a fourth group underwent clinical assessment at the same frequency as the three treatment groups. The median duration of follow-up is 8.5 years. The percentage of reduction in the death rate and the recurrence rate in the treatment groups compared with the control group was calculated using the Cox proportional hazards model and adjusted for age, sex, and stage as covariants. The patients treated with levamisole were estimated to have a 29% reduction in both the death rate (P = .08) and the recurrence rate (P = .09) compared with patients receiving no further treatment. Fifty-five patients discontinued levamisole early because of gastrointestinal intolerance or arthralgia, myalgia, fever, and immune leukopenia. The patients treated with BCG alternating with levamisole experienced a 10% reduction in the death rate and a 6% reduction in the recurrence rate, and the patients treated with BCG alone experienced a 4% reduction in the death rate and a 3% increase in the recurrence rate compared with the control group. The degree of improvement experienced by the patients that were treated by levamisole is of sufficient magnitude to warrant further investigation of this dose of levamisole as adjuvant treatment in patients with melanoma.

  20. Autophagy Inhibition to Augment mTOR Inhibition: A Phase I/II Trial of RAD001 and Hydroxychloroquine in Patients With Previously Treated Renal Cell Carcinoma

    ClinicalTrials.gov

    2015-12-07

    Histological Evidence of Metastatic Clear Cell Renal Cell Carcinoma; That Has Been Previously Treated With 1-3 Prior Regimens. Phase 1 Only, Any Number of Prior Regimens; With Evidence of Progressive Disease on or Within 6 Months; of Discontinuing Sunitinib, Sorafenib or Pazopanib. Previous; Therapy With Bevacizumab, IL2, or Interferon Are Permitted.

  1. Patient-Reported Outcome Results From the Open-Label Phase III AURELIA Trial Evaluating Bevacizumab-Containing Therapy for Platinum-Resistant Ovarian Cancer

    PubMed Central

    Stockler, Martin R.; Hilpert, Felix; Friedlander, Michael; King, Madeleine T.; Wenzel, Lari; Lee, Chee Khoon; Joly, Florence; de Gregorio, Nikolaus; Arranz, José Angel; Mirza, Mansoor Raza; Sorio, Roberto; Freudensprung, Ulrich; Sneller, Vesna; Hales, Gill; Pujade-Lauraine, Eric

    2014-01-01

    Purpose To determine the effects of bevacizumab on patient-reported outcomes (PROs; secondary end point) in the AURELIA trial. Patients and Methods Patients with platinum-resistant ovarian cancer were randomly assigned to chemotherapy alone (CT) or with bevacizumab (BEV-CT). PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Ovarian Cancer Module 28 (EORTC QLQ-OV28) and Functional Assessment of Cancer Therapy–Ovarian Cancer symptom index (FOSI) at baseline and every two or three cycles (8/9 weeks) until disease progression. The primary PRO hypothesis was that more patients receiving BEV-CT than CT would achieve at least a 15% (≥ 15-point) absolute improvement on the QLQ-OV28 abdominal/GI symptom subscale (items 31-36) at week 8/9. Patients with missing week 8/9 questionnaires were included as unimproved. Questionnaires from all assessments until disease progression were analyzed using mixed-model repeated-measures (MMRM) analysis. Sensitivity analyses were used to determine the effects of differing assumptions and methods for missing data. Results Baseline questionnaires were available from 89% of 361 randomly assigned patients. More BEV-CT than CT patients achieved a ≥ 15% improvement in abdominal/GI symptoms at week 8/9 (primary PRO end point, 21.9% v 9.3%; difference, 12.7%; 95% CI, 4.4 to 20.9; P = .002). MMRM analysis covering all time points also favored BEV-CT (difference, 6.4 points; 95% CI, 1.3 to 11.6; P = .015). More BEV-CT than CT patients achieved ≥ 15% improvement in FOSI at week 8/9 (12.2% v 3.1%; difference, 9.0%; 95% CI, 2.9% to 15.2%; P = .003). Sensitivity analyses gave similar results and conclusions. Conclusion Bevacizumab increased the proportion of patients achieving a 15% improvement in patient-reported abdominal/GI symptoms during chemotherapy for platinum-resistant ovarian cancer. PMID:24687829

  2. Late Patient-Reported Toxicity After Preoperative Radiotherapy or Chemoradiotherapy in Nonresectable Rectal Cancer: Results From a Randomized Phase III Study

    SciTech Connect

    Braendengen, Morten; Tveit, Kjell Magne; Bruheim, Kjersti; Cvancarova, Milada; Berglund, Ake; Glimelius, Bengt

    2011-11-15

    Purpose: Preoperative chemoradiotherapy (CRT) is superior to radiotherapy (RT) in locally advanced rectal cancer, but the survival gain is limited. Late toxicity is, therefore, important. The aim was to compare late bowel, urinary, and sexual functions after CRT or RT. Methods and Materials: Patients (N = 207) with nonresectable rectal cancer were randomized to preoperative CRT or RT (2 Gy Multiplication-Sign 25 {+-} 5-fluorouracil/leucovorin). Extended surgery was often required. Self-reported late toxicity was scored according to the LENT SOMA criteria in a structured telephone interview and with questionnaires European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), International Index of Erectile Function (IIEF), and sexual function -vaginal changes questionnaire (SVQ). Results: Of the 105 patients alive in Norway and Sweden after 4 to 12 years of follow-up, 78 (74%) responded. More patients in the CRT group had received a stoma (73% vs. 52%, p = 0.09). Most patients without a stoma (7 of 12 in CRT group and 9 of 16 in RT group) had incontinence for liquid stools or gas. No stoma and good anal function were seen in 5 patients (11%) in the CRT group and in 11 (30%) in the RT group (p = 0.046). Of 44 patients in the CRT group, 12 (28%) had had bowel obstruction compared with 5 of 33 (15%) in the RT group (p = 0.27). One-quarter of the patients reported urinary incontinence. The majority of men had severe erectile dysfunction. Few women reported sexual activity during the previous month. However, the majority did not have concerns about their sex life. Conclusions: Fecal incontinence and erectile dysfunction are frequent after combined treatment for locally advanced rectal cancer. There was a clear tendency for the problems to be more common after CRT than after RT.

  3. Randomized, Double-Blind, Placebo-Controlled, Phase III Chemoprevention Trial of Selenium Supplementation in Patients With Resected Stage I Non–Small-Cell Lung Cancer: ECOG 5597

    PubMed Central

    Karp, Daniel D.; Lee, Sandra J.; Keller, Steven M.; Wright, Gail Shaw; Aisner, Seena; Belinsky, Steven Alan; Johnson, David H.; Johnston, Michael R.; Goodman, Gary; Clamon, Gerald; Okawara, Gordon; Marks, Randolph; Frechette, Eric; McCaskill-Stevens, Worta; Lippman, Scott M.; Ruckdeschel, John; Khuri, Fadlo R.

    2013-01-01

    Purpose Selenium has been reported to have chemopreventive benefits in lung cancer. We conducted a double-blind, placebo-controlled trial to evaluate the incidence of second primary tumors (SPTs) in patients with resected non–small-cell lung cancer (NSCLC) receiving selenium supplementation. Patients and Methods Patients with completely resected stage I NSCLC were randomly assigned to take selenized yeast 200 μg versus placebo daily for 48 months. Participation was 6 to 36 months postoperatively and required a negative mediastinal node biopsy, no excessive vitamin intake, normal liver function, negative chest x-ray, and no other evidence of recurrence. Results The first interim analysis in October 2009, with 46% of the projected end points accumulated, showed a trend in favor of the placebo group with a low likelihood that the trial would become positive; thus, the study was stopped. One thousand seven hundred seventy-two participants were enrolled, with 1,561 patients randomly assigned. Analysis was updated in June 2011 with the maturation of 54% of the planned end points. Two hundred fifty-two SPTs (from 224 patients) developed, of which 98 (from 97 patients) were lung cancer (38.9%). Lung and overall SPT incidence were 1.62 and 3.54 per 100 person-years, respectively, for selenium versus 1.30 and 3.39 per 100 person-years, respectively, for placebo (P = .294). Five-year disease-free survival was 74.4% for selenium recipients versus 79.6% for placebo recipients. Grade 1 to 2 toxicity occurred in 31% of selenium recipients and 26% of placebo recipients, and grade ≥ 3 toxicity occurred in less than 2% of selenium recipients versus 3% of placebo recipients. Compliance was excellent. No increase in diabetes mellitus or skin cancer was detected. Conclusion Selenium was safe but conferred no benefit over placebo in the prevention of SPT in patients with resected NSCLC. PMID:24002495

  4. Phase III Double-Blind, Placebo-Controlled Study of Gabapentin for the Prevention of Delayed Chemotherapy-Induced Nausea and Vomiting in Patients Receiving Highly Emetogenic Chemotherapy, NCCTG N08C3 (Alliance)

    PubMed Central

    Barton, Debra L.; Thanarajasingam, Gita; Sloan, Jeff A.; Diekmann, Brent; Fuloria, Jyotsna; Kottschade, Lisa A.; Lyss, Alan P.; Jaslowski, Anthony J.; Mazurczak, Miroslaw A.; Blair, Scott C.; Terstriep, Shelby; Loprinzi, Charles L.

    2014-01-01

    BACKGROUND Despite targeted antiemetics, data support an unmet need related to the management of delayed nausea and vomiting (NV). Promising pilot data informed this phase III trial evaluating gabapentin for delayed NV from highly emetogenic chemotherapy (HEC). METHODS Participants were randomized to receive prophylactic treatment with 20 mg of dexamethasone and a 5HT3 receptor antagonist (RA) on the day of chemotherapy, followed by gabapentin 300 mg twice a day and dexamethasone (dex) or placebo and dex after HEC. Gabapentin/placebo was started the day of chemotherapy and continued through day 5 for the first chemotherapy cycle, whereas dex was titrated down on days 2–4. The primary end point was complete response (CR), defined as no emesis and no use of rescue medications on days 2–6, using an NV diary. The percentages of those in each group with a CR were compared by Fisher’s exact test. RESULTS Four hundred thirty patients were enrolled in this study. Forty-seven percent of patients in the gabapentin arm and 41% in the placebo arm had a CR (P = .23). Mean number of emesis episodes was <0.5 daily, and mean nausea severity was <2 (mild). In both arms, patient satisfaction with NV control was greater than 8 (with 10 being perfectly satisfied). There were no significant differences in unwanted side effects. CONCLUSIONS In this study, gabapentin did not significantly improve delayed NV. Patients were satisfied with the control of their nausea and vomiting irrespective of arm. The use of a 5HT3 RA and dexamethasone provided good control of nausea and vomiting for most patients. PMID:25043153

  5. Randomized, Phase III Trial of First-Line Figitumumab in Combination With Paclitaxel and Carboplatin Versus Paclitaxel and Carboplatin Alone in Patients With Advanced Non–Small-Cell Lung Cancer

    PubMed Central

    Langer, Corey J.; Novello, Silvia; Park, Keunchil; Krzakowski, Maciej; Karp, Daniel D.; Mok, Tony; Benner, Rebecca J.; Scranton, Judith R.; Olszanski, Anthony J.; Jassem, Jacek

    2014-01-01

    Purpose Figitumumab (CP-751,871), a fully human immunoglobulin G2 monoclonal antibody, inhibits the insulin-like growth factor 1 receptor (IGF-1R). Our multicenter, randomized, phase III study compared figitumumab plus chemotherapy with chemotherapy alone as first-line treatment in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIB/IV or recurrent NSCLC disease with nonadenocarcinoma histology received open-label figitumumab (20 mg/kg) plus paclitaxel (200 mg/m2) and carboplatin (area under the concentration-time curve, 6 mg · min/mL) or paclitaxel and carboplatin alone once every 3 weeks for up to six cycles. The primary end point was overall survival (OS). Results Of 681 randomly assigned patients, 671 received treatment. The study was closed early by an independent Data Safety Monitoring Committee because of futility and an increased incidence of serious adverse events (SAEs) and treatment-related deaths with figitumumab. Median OS was 8.6 months for figitumumab plus chemotherapy and 9.8 months for chemotherapy alone (hazard ratio [HR], 1.18; 95% CI, 0.99 to 1.40; P = .06); median progression-free survival was 4.7 months (95% CI, 4.2 to 5.4) and 4.6 months (95% CI, 4.2 to 5.4), respectively (HR, 1.10; P = .27); the objective response rates were 33% and 35%, respectively. The respective rates of all-causality SAEs were 66% and 51%; P < .01). Treatment-related grade 5 adverse events were also more common with figitumumab (5% v 1%; P < .01). Conclusion Adding figitumumab to standard chemotherapy failed to increase OS in patients with advanced nonadenocarcinoma NSCLC. Further clinical development of figitumumab is not being pursued. PMID:24888810

  6. Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double-blind, multinational, placebo-controlled phase II/III trial

    PubMed Central

    Vahlquist, A; Blockhuys, S; Steijlen, P; van Rossem, K; Didona, B; Blanco, D; Traupe, H

    2014-01-01

    Summary Background Oral liarozole, a retinoic acid metabolism-blocking agent, may be an alternative to systemic retinoid therapy in patients with lamellar ichthyosis. Objective To demonstrate the efficacy and safety of once-daily oral liarozole in the treatment of moderate/severe lamellar ichthyosis. Methods This was a double-blind, multinational, parallel phase II/III trial (NCT00282724). Patients aged ≥ 14 years with moderate/severe lamellar ichthyosis [Investigator's Global Assessment (IGA) score ≥ 3] were randomized 3 : 3 : 1 to receive oral liarozole (75 or 150 mg) or placebo once daily for 12 weeks. Assessments included: IGA; a five-point scale for erythema, scaling and pruritus severity; Short Form-36 health survey; Dermatology Life Quality Index (DLQI); and safety parameters. The primary efficacy variable was response rate at week 12 (responder: ≥ 2-point decrease in IGA from baseline). Results Sixty-four patients were enrolled. At week 12, 11/27 (41%; liarozole 75 mg), 14/28 (50%; liarozole 150 mg) and one out of nine (11%; placebo) patients were responders; the difference between groups (liarozole 150 mg vs. placebo) was not significant (P = 0·056). Mean IGA and scaling scores decreased from baseline in both liarozole groups at weeks 8 and 12 vs. placebo; erythema and pruritus scores were similar between treatment groups. Improvement in DLQI score was observed in both liarozole groups. Treatment with liarozole for 12 weeks was well tolerated. Conclusions The primary efficacy variable did not reach statistical significance, possibly owing to the small sample size following premature termination. However, once-daily oral liarozole, 75 and 150 mg, improved scaling and DLQI and was well tolerated in patients with moderate/severe lamellar ichthyosis. PMID:24102348

  7. Phase III, Randomized, Open-Label Study of Daily Imatinib Mesylate 400 mg Versus 800 mg in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase Using Molecular End Points: Tyrosine Kinase Inhibitor Optimization and Selectivity Study

    PubMed Central

    Cortes, Jorge E.; Baccarani, Michele; Guilhot, François; Druker, Brian J.; Branford, Susan; Kim, Dong-Wook; Pane, Fabrizio; Pasquini, Ricardo; Goldberg, Stuart L.; Kalaycio, Matt; Moiraghi, Beatriz; Rowe, Jacob M.; Tothova, Elena; De Souza, Carmino; Rudoltz, Marc; Yu, Richard; Krahnke, Tillmann; Kantarjian, Hagop M.; Radich, Jerald P.; Hughes, Timothy P.

    2010-01-01

    Purpose To evaluate the safety and efficacy of initial treatment with imatinib mesylate 800 mg/d (400 mg twice daily) versus 400 mg/d in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Patients and Methods A total of 476 patients were randomly assigned 2:1 to imatinib 800 mg (n = 319) or 400 mg (n = 157) daily. The primary end point was the major molecular response (MMR) rate at 12 months. Results At 12 months, differences in MMR and complete cytogenetic response (CCyR) rates were not statistically significant (MMR, 46% v 40%; P = .2035; CCyR, 70% v 66%; P = .3470). However, MMR occurred faster among patients randomly assigned to imatinib 800 mg/d, who had higher rates of MMR at 3 and 6 months compared with those in the imatinib 400-mg/d arm (P = .0035 by log-rank test). CCyR also occurred faster in the 800-mg/d arm (CCyR at 6 months, 57% v 45%; P = .0146). The most common adverse events were edema, gastrointestinal problems, and rash, and all were more common in patients in the 800-mg/d arm. Grades 3 to 4 hematologic toxicity also occurred more frequently in patients receiving imatinib 800 mg/d. Conclusion MMR rates at 1 year were similar with imatinib 800 mg/d and 400 mg/d, but MMR and CCyR occurred earlier in patients treated with 800 mg/d. Continued follow-up is needed to determine the clinical significance of earlier responses on high-dose imatinib. PMID:20008622

  8. A Phase III, Double-Blind, Placebo-Controlled Prospective Randomized Clinical Trial of d-Threo-Methylphenidate HCl in Brain Tumor Patients Receiving Radiation Therapy

    SciTech Connect

    Butler, Jerome M. Case, L. Douglas; Atkins, James; Frizzell, Bart; Sanders, George; Griffin, Patricia; Lesser, Glenn; McMullen, Kevin; McQuellon, Richard; Naughton, Michelle; Rapp, Stephen; Stieber, Volker; Shaw, Edward G.

    2007-12-01

    Purpose: The quality of life (QOL) and neurocognitive function of patients with brain tumors are negatively affected by the symptoms of their disease and brain radiation therapy (RT). We assessed the effect of prophylactic d-threo-methylphenidate HCl (d-MPH), a central nervous system (CNS) stimulant on QOL and cognitive function in patients undergoing RT. Methods and Materials: Sixty-eight patients with primary or metastatic brain tumors were randomly assigned to receive d-MPH or placebo. The starting dose of d-MPH was 5 mg twice daily (b.i.d.) and was escalated by 5 mg b.i.d. to a maximum of 15 mg b.i.d. The placebo was administered as one pill b.i.d. escalating three pills b.i.d. The primary outcome was fatigue. Patients were assessed at baseline, the end of radiation therapy, and 4, 8, and 12 weeks after brain RT using the Functional Assessment of Cancer Therapy with brain and fatigue (FACIT-F) subscales, as well as the Center for Epidemiologic Studies Scale and Mini-Mental Status Exam. Results: The Mean Fatigue Subscale Score at baseline was 34.7 for the d-MPH arm and 33.3 for the placebo arm (p = 0.61). At 8 weeks after the completion of brain RT, there was no difference in fatigue between patient groups. The adjusted least squares estimate of the Mean Fatigue Subscale Score was 33.7 for the d-MPH and 35.6 for the placebo arm (p = 0.64). Secondary outcomes were not different between the two treatment arms. Conclusions: Prophylactic use of d-MPH in brain tumor patients undergoing RT did not result in an improvement in QOL.

  9. Pemetrexed combined with paclitaxel in patients with advanced or metastatic non-small-cell lung cancer: a phase I-II trial.

    PubMed

    Stathopoulos, George P; Dimitroulis, John; Toubis, Michael; Katis, Costas; Karaindros, Dimitris; Stathopoulos, John; Koutandos, John

    2007-07-01

    Pemetrexed, a novel multi-targeted agent established for the treatment of mesothelioma, has been under investigation for other malignancies, and in recent years particularly for non-small-cell lung cancer (NSCLC). In the present trial we investigated pemetrexed in combination with paclitaxel as front-line treatment in advanced or metastatic NSCLC. Our objectives were to determine the response rate, median and overall survival and toxicity. From April 2005 until May 2006, 51 patients with advanced or metastatic NSCLC were enrolled and 48 were considered evaluable. There were 39 males and nine females, median age 62 years (range 37-81 years), one patient stage IIIA N(2), 23 patients, IIIB and 24, stage IV. All patients had a cytologically- or histologically-confirmed diagnosis. Pemetrexed was administered at a standard dose of 500mg/m(2) and paclitaxel at an escalating dose starting at 135mg/m(2), then 150mg/m(2) and ending at a dose of 175mg/m(2); the level was increased every three patients. Both agents were administered on day 1, repeated every 3 weeks for six courses. A 39.6% partial response rate was observed with a median survival of 14 months. Toxicity was mild with 8.3% grade 3 and 4 neutropenia and other very mild hematologic and non-hematologic adverse reactions. The combination of pemetrexed and paclitaxel at doses of 500mg/m(2) and 175mg/m(2), respectively, has been shown to be an effective combination with very limited toxicity. PMID:17382431

  10. Effect of nivolumab on health-related quality of life in patients with treatment-naïve advanced melanoma: results from the phase III CheckMate 066 study

    PubMed Central

    Long, G. V.; Atkinson, V.; Ascierto, P. A.; Robert, C.; Hassel, J. C.; Rutkowski, P.; Savage, K. J.; Taylor, F.; Coon, C.; Gilloteau, I.; Dastani, H. B.; Waxman, I. M.; Abernethy, A. P.

    2016-01-01

    Background Nivolumab has shown significant survival benefit and a favorable safety profile compared with dacarbazine chemotherapy among treatment-naïve patients with metastatic melanoma in the CheckMate 066 phase III study. Results from the health-related quality of life (HRQoL) analyses from CheckMate 066 are presented. Patients and methods HRQoL was evaluated at baseline and every 6 weeks while on treatment using the European Organisation for Research and Treatment of Care (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire (EQ-5D). Via a multi-step statistical plan, data were analyzed descriptively, cross-sectionally, and longitudinally, adjusting for baseline covariates, in patients having baseline plus ≥1 post-baseline assessment. Results Baseline-adjusted completion rates for all HRQoL questionnaires across treatment arms were 65% and 70% for dacarbazine and nivolumab, respectively, and remained similar throughout treatment. The mean baseline HRQoL scores were similar for patients treated with nivolumab and dacarbazine. Baseline HRQoL levels with nivolumab were maintained over time. This exploratory analysis showed a between-arm difference in favor of nivolumab on the EQ-5D utility index and clinically meaningful EQ-5D improvements from baseline at several time points for patients receiving nivolumab. Patients treated with nivolumab did not show increased symptom burden as assessed by the EORTC QLQ-C30. No HRQoL change was noted with dacarbazine patients up to week 43, although the high attrition rate after week 13 did not allow any meaningful analyses. Patients receiving nivolumab deteriorated significantly later than those receiving dacarbazine on several EORTC QLQ-C30 scales and the EQ-5D utility index. Conclusions In addition to prolonged survival, these exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit, compared with dacarbazine

  11. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression†

    PubMed Central

    Obermannová, R.; Van Cutsem, E.; Yoshino, T.; Bodoky, G.; Prausová, J.; Garcia-Carbonero, R.; Ciuleanu, T.; Garcia Alfonso, P.; Portnoy, D.; Cohn, A.; Yamazaki, K.; Clingan, P.; Lonardi, S.; Kim, T. W.; Yang, L.; Nasroulah, F.; Tabernero, J.

    2016-01-01

    Background The RAISE phase III clinical trial demonstrated that ramucirumab + FOLFIRI improved overall survival (OS) [hazard ratio (HR) = 0.844, P = 0.0219] and progression-free survival (PFS) (HR = 0.793, P < 0.0005) compared with placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients previously treated with first-line bevacizumab, oxaliplatin, and a fluoropyrimidine. Since some patient or disease characteristics could be associated with differential efficacy or safety, prespecified subgroup analyses were undertaken. This report focuses on three of the most relevant ones: KRAS status (wild-type versus mutant), age (<65 versus ≥65 years), and time to progression (TTP) on first-line therapy (<6 versus ≥6 months). Patients and methods OS and PFS were evaluated by the Kaplan–Meier analysis, with HR determined by the Cox proportional hazards model. Treatment-by-subgroup interaction was tested to determine whether treatment effect was consistent between subgroup pairs. Results Patients with both wild-type and mutant KRAS benefited from ramucirumab + FOLFIRI treatment over placebo + FOLFIRI (interaction P = 0.526); although numerically, wild-type KRAS patients benefited more (wild-type KRAS: median OS = 14.4 versus 11.9 months, HR = 0.82, P = 0.049; mutant KRAS: median OS = 12.7 versus 11.3 months, HR = 0.89, P = 0.263). Patients with both longer and shorter first-line TTP benefited from ramucirumab (interaction P = 0.9434), although TTP <6 months was associated with poorer OS (TTP ≥6 months: median OS = 14.3 versus 12.5 months, HR = 0.86, P = 0.061; TTP <6 months: median OS = 10.4 versus 8.0 months, HR = 0.86, P = 0.276). The subgroups of patients ≥65 versus <65 years also derived a similar ramucirumab survival benefit (interaction P = 0.9521) (≥65 years: median OS = 13.8 versus 11.7 months, HR = 0.85, P = 0.156; <65 years: median OS = 13.1 versus 11.9 months, HR = 0.86, P = 0.098). The safety profile of ramucirumab + FOLFIRI was

  12. Genetic variants in VEGF pathway genes in neoadjuvant breast cancer patients receiving bevacizumab: Results from the randomized phase III GeparQuinto study.

    PubMed

    Hein, Alexander; Lambrechts, Diether; von Minckwitz, Gunter; Häberle, Lothar; Eidtmann, Holger; Tesch, Hans; Untch, Michael; Hilfrich, Jörn; Schem, Christian; Rezai, Mahdi; Gerber, Bernd; Dan Costa, Serban; Blohmer, Jens-Uwe; Schwedler, Kathrin; Kittel, Kornelia; Fehm, Tanja; Kunz, Georg; Beckmann, Matthias W; Ekici, Arif B; Hanusch, Claus; Huober, Jens; Liedtke, Cornelia; Mau, Christine; Moisse, Matthieu; Müller, Volkmar; Nekljudova, Valentina; Peuteman, Gilian; Rack, Brigitte; Rübner, Matthias; Van Brussel, Thomas; Wang, Liewei; Weinshilboum, Richard M; Loibl, Sibylle; Fasching, Peter A

    2015-12-15

    Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression-free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2-negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre-planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF-A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49-3.75), 1.20 (95% CI, 0.88-1.64) and 0.61 (95% CI, 0.34-1.12). Notably, some SNPs in VEGF-A exhibited a more pronounced effect in the triple-negative subgroup. Several SNPs in VEGF-A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.

  13. Randomized Phase III Trial of Ixabepilone Plus Capecitabine Versus Capecitabine in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane

    PubMed Central

    Sparano, Joseph A.; Vrdoljak, Eduard; Rixe, Oliver; Xu, Binghe; Manikhas, Alexey; Medina, Carlos; Ventilari Da Costa, Susanne Crocamo; Ro, Jungsil; Rubio, Gonzalo; Rondinon, Monica; Perez Manga, Gumersindo; Peck, Ronald; Poulart, Valerie; Conte, Pierfranco

    2010-01-01

    Purpose We sought to determine whether the combination of ixabepilone plus capecitabine improved overall survival (OS) compared with capecitabine alone in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. Patients and Methods A total of 1,221 patients with MBC previously treated with anthracycline and taxanes were randomly assigned to ixabepilone (40 mg/m2 intravenously on day 1) plus capecitabine (2,000 mg/m2 orally on days 1 through 14) or capecitabine alone (2,500 mg/m2 on the same schedule) given every 21 days. The trial was powered to detect a 20% reduction in the hazard ratio (HR) for death. Results There was no significant difference in OS between the combination and capecitabine monotherapy arm, the primary end point (median, 16.4 v 15.6 months; HR = 0.9; 95% CI, 078 to 1.03; P = .1162). The arms were well balanced with the exception of a higher prevalence of impaired performance status (Karnofsky performance status 70% to 80%) in the combination arm (32% v 25%). In a secondary Cox regression analysis adjusted for performance status and other prognostic factors, OS was improved for the combination (HR = 0.85; 95% CI, 0.75 to 0.98; P = .0231). In 79% of patients with measurable disease, the combination significantly improved progression-free survival (PFS; median, 6.2 v 4.2 months; HR = 0.79; P = .0005) and response rate (43% v 29%; P < .0001). Grade 3 to 4 neuropathy occurred in 24% treated with the combination, but was reversible. Conclusion This study confirmed a previous trial demonstrating improved PFS and response for the ixabepilone-capecitabine combination compared with capecitabine alone, although this did not result in improved survival. PMID:20530276

  14. 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.

  15. Effect of Kangfuxin Solution on Chemo/Radiotherapy-Induced Mucositis in Nasopharyngeal Carcinoma Patients: A Multicenter, Prospective Randomized Phase III Clinical Study.

    PubMed

    Luo, Yangkun; Feng, Mei; Fan, Zixuan; Zhu, Xiaodong; Jin, Feng; Li, Rongqing; Wu, Jingbo; Yang, Xia; Jiang, Qinghua; Bai, Hongfang; Huang, Yecai; Lang, Jinyi

    2016-01-01

    Objective. To evaluate the efficacy and safety of Kangfuxin Solution, a pure Chinese herbal medicine, on mucositis induced by chemoradiotherapy in nasopharyngeal carcinoma patients. Methods. A randomized, parallel-group, multicenter clinical study was performed. A total of 240 patients were randomized to receive either Kangfuxin Solution (test group) or compound borax gargle (control group) during chemoradiotherapy. Oral mucositis, upper gastrointestinal mucositis, and oral pain were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) v3.0 and the Verbal Rating Scale (VRS). Results. Of 240 patients enrolled, 215 were eligible for efficacy analysis. Compared with the control group, the incidence and severity of oral mucositis in the test group were significantly reduced (P = 0.01). The time to different grade of oral mucositis occurrence (grade 1, 2, or 3) was longer in test group (P < 0.01), and the accumulated radiation dose was also higher in test group comparing to the control group (P < 0.05). The test group showed lower incidence of oral pain and gastrointestinal mucositis than the control group (P < 0.01). No significant adverse events were observed. Conclusion. Kangfuxin Solution demonstrated its superiority to compound borax gargle on mucositis induced by chemoradiotherapy. Its safety is acceptable for clinical application. PMID:27375766

  16. Effect of Kangfuxin Solution on Chemo/Radiotherapy-Induced Mucositis in Nasopharyngeal Carcinoma Patients: A Multicenter, Prospective Randomized Phase III Clinical Study

    PubMed Central

    Luo, Yangkun; Feng, Mei; Fan, Zixuan; Zhu, Xiaodong; Jin, Feng; Li, Rongqing; Wu, Jingbo; Yang, Xia; Jiang, Qinghua; Bai, Hongfang; Huang, Yecai; Lang, Jinyi

    2016-01-01

    Objective. To evaluate the efficacy and safety of Kangfuxin Solution, a pure Chinese herbal medicine, on mucositis induced by chemoradiotherapy in nasopharyngeal carcinoma patients. Methods. A randomized, parallel-group, multicenter clinical study was performed. A total of 240 patients were randomized to receive either Kangfuxin Solution (test group) or compound borax gargle (control group) during chemoradiotherapy. Oral mucositis, upper gastrointestinal mucositis, and oral pain were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) v3.0 and the Verbal Rating Scale (VRS). Results. Of 240 patients enrolled, 215 were eligible for efficacy analysis. Compared with the control group, the incidence and severity of oral mucositis in the test group were significantly reduced (P = 0.01). The time to different grade of oral mucositis occurrence (grade 1, 2, or 3) was longer in test group (P < 0.01), and the accumulated radiation dose was also higher in test group comparing to the control group (P < 0.05). The test group showed lower incidence of oral pain and gastrointestinal mucositis than the control group (P < 0.01). No significant adverse events were observed. Conclusion. Kangfuxin Solution demonstrated its superiority to compound borax gargle on mucositis induced by chemoradiotherapy. Its safety is acceptable for clinical application. PMID:27375766

  17. Phase III Study of Radiation Therapy With or Without Cis-Platinum in Patients With Unresectable Squamous or Undifferentiated Carcinoma of the Head and Neck: An Intergroup Trial of the Eastern Cooperative Oncology Group (E2382)

    SciTech Connect

    Quon, Harry; Leong, Traci; Haselow, Robert; Leipzig, Bruce; Cooper, Jay; Forastiere, Arlene

    2011-11-01

    Purpose: The Head and Neck Intergroup conducted a Phase III randomized trial to determine whether the addition weekly cisplatin to daily radiation therapy (RT) would improve survival in patients with unresectable squamous cell head-and-neck carcinoma. Methods and Materials: Eligible patients were randomized to RT (70 Gy at 1.8-2 Gy/day) or to the identical RT with weekly cisplatin dosed at 20 mg/m{sup 2}. Failure-free survival (FFS) and overall survival (OS) curves were estimated with the Kaplan-Meier method and compared with the log rank test. Results: Between 1982 and 1987, 371 patients were accrued, and 308 patients were found eligible for analysis. Median follow-up was 62 months. The median FFS was 6.5 and 7.2 months for the RT and RT + cisplatin groups, respectively (p = 0.30). The p value for the treatment difference was p = 0.096 in multivariate modeling of FFS (compared to a p = 0.30 in univariate analysis). Expected acute toxicities were significantly increased with the addition of cisplatin except for in-field RT toxicities. Late toxicities were not significantly different except for significantly more esophageal (9% vs. 3%, p = 0.03) and laryngeal (11% vs. 4%, p = 0.05) late toxicities in the RT + cisplatin group. Conclusion: The addition of concurrent weekly cisplatin at 20 mg/m{sup 2} to daily radiation did not improve survival, although there was evidence of activity. Low-dose weekly cisplatin seems to have modest tumor radiosensitization but can increase the risk of late swallowing complications.

  18. Efficacy and safety of rilpivirine in treatment-naive, HIV-1-infected patients with hepatitis B virus/hepatitis C virus coinfection enrolled in the Phase III randomized, double-blind ECHO and THRIVE trials

    PubMed Central

    Nelson, Mark; Amaya, Gerardo; Clumeck, Nathan; Arns da Cunha, Clovis; Jayaweera, Dushyantha; Junod, Patrice; Li, Taisheng; Tebas, Pablo; Stevens, Marita; Buelens, Annemie; Vanveggel, Simon; Boven, Katia

    2012-01-01

    Objectives The efficacy and hepatic safety of the non-nucleoside reverse transcriptase inhibitors rilpivirine (TMC278) and efavirenz were compared in treatment-naive, HIV-infected adults with concurrent hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection in the pooled week 48 analysis of the Phase III, double-blind, randomized ECHO (NCT00540449) and THRIVE (NCT00543725) trials. Methods Patients received 25 mg of rilpivirine once daily or 600 mg of efavirenz once daily, plus two nucleoside/nucleotide reverse transcriptase inhibitors. At screening, patients had alanine aminotransferase/aspartate aminotransferase levels ≤5× the upper limit of normal. HBV and HCV status was determined at baseline by HBV surface antigen, HCV antibody and HCV RNA testing. Results HBV/HCV coinfection status was known for 670 patients in the rilpivirine group and 665 in the efavirenz group. At baseline, 49 rilpivirine and 63 efavirenz patients [112/1335 (8.4%)] were coinfected with either HBV [55/1357 (4.1%)] or HCV [57/1333 (4.3%)]. The safety analysis included all available data, including beyond week 48. Eight patients seroconverted during the study (rilpivirine: five; efavirenz: three). A higher proportion of patients achieved viral load <50 copies/mL (intent to treat, time to loss of virological response) in the subgroup without HBV/HCV coinfection (rilpivirine: 85.0%; efavirenz: 82.6%) than in the coinfected subgroup (rilpivirine: 73.5%; efavirenz: 79.4%) (rilpivirine, P = 0.04 and efavirenz, P = 0.49, Fisher's exact test). The incidence of hepatic adverse events (AEs) was low in both groups in the overall population (rilpivirine: 5.5% versus efavirenz: 6.6%) and was higher in HBV/HCV-coinfected patients than in those not coinfected (26.7% versus 4.1%, respectively). Conclusions Hepatic AEs were more common and response rates lower in HBV/HCV-coinfected patients treated with rilpivirine or efavirenz than in those who were not coinfected. PMID:22532465

  19. Levomilnacipran ER 40 mg and 80 mg in patients with major depressive disorder: a phase III, randomized, double-blind, fixed-dose, placebo-controlled study

    PubMed Central

    Bakish, David; Bose, Anjana; Gommoll, Carl; Chen, Changzheng; Nunez, Rene; Greenberg, William M.; Liebowitz, Michael; Khan, Arif

    2014-01-01

    Background Major depressive disorder (MDD) is a global health concern. This study examined the efficacy, safety and tolerability of an extended-release (ER) formulation of levomilnacipran, an antidepressant approved for the treatment of MDD in adults. Methods This 10-week (1-week placebo run-in period, 8-week double-blind treatment, 1-week down-taper), multicentre, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted between June 2011 and March 2012. Adult outpatients (age 18–75 yr) with MDD were randomly assigned (1:1:1) to placebo or to levomilnacipran ER 40 mg/day or 80 mg/day. For primary efficacy, we analyzed the Montgomery–Åsberg Depression Rating Scale (MADRS) change from baseline to week 8 using a mixed-effects model for repeated-measures approach on the intent-to-treat (ITT) population. For secondary efficacy, we used the Sheehan Disability Scale (SDS), and for safety, we examined adverse events and laboratory, vital sign/physical and electrocardiography findings. Results The ITT population consisted of 185 patients in the placebo group, 185 in the levomilnacipran ER 40 mg/day group and 187 in the levomilnacipran ER 80 mg/day group. Study completion rates were similar among the groups (76%–83%). On MADRS change from baseline the least squares mean difference (LSMD) and 95% confidence interval (CI) versus placebo was significant for levomilnacipran ER 40 mg/day (–3.3 [−5.5 to −1.1], p = 0.003) and 80 mg/day (−3.1, [−5.3 to −1.0], p = 0.004). On SDS change from baseline the LSMD (and 95% CI) versus placebo was also significant for levomilnacipran ER 40 mg/day (−1.8, 95% [−3.6 to 0], p = 0.046) and 80 mg/day (−2.7 [−4.5 to −0.9], p = 0.003). More patients in the levomilnacipran ER than the placebo group prematurely exited the study owing to adverse events; common adverse events (≥ 5% and ≥ double the rate of placebo) were nausea, dry mouth, increased heart rate, constipation, dizziness

  20. Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma†

    PubMed Central

    Al-Batran, S.-E.; Van Cutsem, E.; Oh, S. C.; Bodoky, G.; Shimada, Y.; Hironaka, S.; Sugimoto, N.; Lipatov, O. N.; Kim, T.-Y.; Cunningham, D.; Rougier, P.; Muro, K.; Liepa, A. M.; Chandrawansa, K.; Emig, M.; Ohtsu, A.; Wilke, H.

    2016-01-01

    Background The phase III RAINBOW trial demonstrated that the addition of ramucirumab to paclitaxel improved overall survival, progression-free survival, and tumor response rate in fluoropyrimidine–platinum previously treated patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Here, we present results from quality-of-life (QoL) and performance status (PS) analyses. Patients and methods Patients with Eastern Cooperative Oncology Group PS of 0/1 were randomized to receive ramucirumab (8 mg/kg i.v.) or placebo on days 1 and 15 of a 4-week cycle, with both arms receiving paclitaxel (80 mg/m2) on days 1, 8, and 15. Patient-reported outcomes were assessed with the QoL/health status questionnaires EORTC QLQ-C30 and EQ-5D at baseline and 6-week intervals. PS was assessed at baseline and day 1 of every cycle. Time to deterioration (TtD) in each QLQ-C30 scale was defined as randomization to first worsening of ≥10 points (on 100-point scale) and TtD in PS was defined as first worsening to ≥2. Hazard ratios (HRs) for treatment effect were estimated using stratified Cox proportional hazards models. Results Of the 665 patients randomized, 650 (98%) provided baseline QLQ-C30 and EQ-5D data, and 560 (84%) also provided data from ≥1 postbaseline time point. Baseline scores for both instruments were similar between arms. Of the 15 QLQ-C30 scales, 14 had HR < 1, indicating similar or longer TtD in QoL for ramucirumab + paclitaxel. Treatment with ramucirumab + paclitaxel was also associated with a delay in TtD in PS to ≥2 (HR = 0.798, P = 0.0941). Alternate definitions of PS deterioration yielded similar results: PS ≥ 3 (HR = 0.656, P = 0.0508), deterioration by ≥1 PS level (HR = 0.802, P = 0.0444), and deterioration by ≥2 PS levels (HR = 0.608, P = 0.0063). EQ-5D scores were comparable between treatment arms, stable during treatment, and worsened at discontinuation. Conclusion In patients with previously treated advanced gastric

  1. A three-arm phase III randomised trial assessing, in patients with extensive-disease small-cell lung cancer, accelerated chemotherapy with support of haematological growth factor or oral antibiotics

    PubMed Central

    Sculier, J P; Paesmans, M; Lecomte, J; Van Cutsem, O; Lafitte, J J; Berghmans, T; Koumakis, G; Florin, M C; Thiriaux, J; Michel, J; Giner, V; Berchier, M C; Mommen, P; Ninane, V; Klastersky, J

    2001-01-01

    The European Lung Cancer Working Party (ELCWP) designed a 3-arm phase III randomised trial to determine the role of accelerated chemotherapy in extensive-disease (ED) small-cell lung cancer (SCLC). Eligible patients were randomised between the 3 following arms: (A) Standard chemotherapy with 6 courses of EVI (epirubicin 60 mg m−2, vindesine 3 mg m−2, ifosfamide 5 g m−2; all drugs given on day 1 repeated every three weeks. (B) Accelerated chemotherapy with EVI administered every 2 weeks and GM-CSF support. (C) Accelerated chemotherapy with EVI and oral antibiotics (cotrimoxazole). Primary endpoint was survival. 233 eligible patients were randomised. Chemotherapy could be significantly accelerated in arm B with increased absolute dose-intensity. Best response rates, in the population of evaluable patients, were, respectively for arm A, B and C, 59%, 76% and 70%. The response rate was significantly higher in arm B in comparison to arm A (P = 0.04). There was, however, no survival difference with respective median duration and 2-year rate of 286 days and 5% for arm A, 264 days and 6% for arm B and 264 days and 6% for arm C. Severe thrombopenia occurred more frequently in arm B but without an increased rate of bleeding. Non-severe infections were more frequent in arm B and severe infections were less frequent in arm C. Our trial failed to demonstrate, in ED-SCLC, a survival benefit of chemotherapy acceleration by using GM-CSF support.   http://www.bjcancer.com PMID:11720426

  2. Efficacy and safety of solifenacin succinate 10 mg once Daily: A multicenter, phase III, randomized, double-blind, placebo-controlled, parallel-group trial in patients with overactive bladder

    PubMed Central

    Chu, Franklin; Smith, Neila; Uchida, Takeshi

    2009-01-01

    Background: Solifenacin succinate is an antimuscarinic drug with reported efficacy and tolerability at a recommended starting dose of 5 mg QD in patients with overactive bladder (OAB). Objective: The objective of this trial was to investigate the efficacy, safety, and tolerability of solifenacin 10 mg QD in patients with OAB. Methods: In this multicenter, Phase III, double-blind, placebo-controlled, parallel-group trial, patients aged ≥18 years with OAB were randomized at a 1:1 ratio to receive solifenacin 10 mg or placebo QD for 12 weeks. The patients were instructed to complete a micturition diary for the 3 days preceding each scheduled visit (weeks 4, 8, and 12). The primary end point was the change from baseline in the mean number of micturitions per 24 hours; secondary end points included the mean change from baseline in the number of episodes per 24 hours of urgency, incontinence, nocturnal voiding, and nocturia and the mean volume voided per micturition. Tolerability was monitored through adverse events (AEs), vital sign measurements, ECGs, laboratory assessments, and physical examination. Results: A total of 672 patients were randomized and received ≥1 dose of study drug (solifenacin, n = 340; placebo, n = 332). The mean (SE) decrease from baseline to study end in the number of micturitions per 24 hours was significantly greater in the solifenacin group compared with the placebo group (−3.0 [0.2] vs −1.5 [0.2], respectively; P < 0.001). The mean decrease in the number of episodes of incontinence was significantly greater in the solifenacin group compared with the placebo group (−2.0 [0.2] vs −1.1 [0.2]; P < 0.001), as was the mean decrease in the number of episodes of urgency (−4.1 [0.2] vs −2.1 [0.2]; P < 0.001). Of the patients with ≥1 incontinence episode per 24 hours at baseline, significantly more patients in the solifenacin group achieved complete continence at study end than did patients in the placebo group (119/225 [52.9%] vs 80

  3. 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.

  4. Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA

    PubMed Central

    Swain, S. M.; Baselga, J.; Miles, D.; Im, Y.-H.; Quah, C.; Lee, L. F.; Cortés, J.

    2014-01-01

    Background Results from the phase III trial CLEOPATRA in human epidermal growth factor receptor 2-positive first-line metastatic breast cancer demonstrated significant improvements in progression-free and overall survival with pertuzumab, trastuzumab, and docetaxel over placebo, trastuzumab, and docetaxel. We carried out exploratory analyses of the incidence and time to development of central nervous system (CNS) metastases in patients from CLEOPATRA. Patients and methods Patients received pertuzumab/placebo: 840 mg in cycle 1, then 420 mg; trastuzumab: 8 mg/kg in cycle 1, then 6 mg/kg; docetaxel: initiated at 75 mg/m2. Study drugs were administered i.v. every 3 weeks. The log-rank test was used for between-arm comparisons of time to CNS metastases as first site of disease progression and overall survival in patients with CNS metastases as first site of disease progression. The Kaplan–Meier approach was used to estimate median time to CNS metastases as first site of disease progression and median overall survival. Results The incidence of CNS metastases as first site of disease progression was similar between arms; placebo arm: 51 of 406 (12.6%), pertuzumab arm: 55 of 402 (13.7%). Median time to development of CNS metastases as first site of disease progression was 11.9 months in the placebo arm and 15.0 months in the pertuzumab arm; hazard ratio (HR) = 0.58, 95% confidence interval (CI) 0.39–0.85, P = 0.0049. Overall survival in patients who developed CNS metastases as first site of disease progression showed a trend in favor of pertuzumab, trastuzumab, and docetaxel; HR = 0.66, 95% CI 0.39–1.11. Median overall survival was 26.3 versus 34.4 months in the placebo and pertuzumab arms, respectively. Treatment comparison of the survival curves was not statistically significant for the log-rank test (P = 0.1139), but significant for the Wilcoxon test (P = 0.0449). Conclusions While the incidence of CNS metastases was similar between arms, our results suggest that

  5. HI-CHART: A Phase I/II Study on the Feasibility of High-Dose Continuous Hyperfractionated Accelerated Radiotherapy in Patients With Inoperable Non-Small-Cell Lung Cancer

    SciTech Connect

    Ruysscher, Dirk de Wanders, Rinus; Haren, Erik van; Hochstenbag, Monique; Geraedts, Wiel; Pitz, Cordula; Simons, Jean; Boersma, Liesbeth; Verschueren, Tom; Minken, Andre; Bentzen, Soren M.; Lambin, Philippe

    2008-05-01

    Purpose: To determine the feasibility of high-dose continuous hyperfractionated accelerated radiotherapy in patients with inoperable non-small-cell lung cancer (NSCLC). Patients and Methods: In a prospective, Phase I/II study, according to the risk for radiation pneumonitis, three risk groups were defined: V{sub 20} <25%, V{sub 20} 25-37%, and V{sub 20} >37%. The dose was administered in three steps from 61.2 Gy/34 fractions/23 days to 64.8 Gy/36 fractions/24 days to 68.40 Gy/38 fractions/25 days (1.8 Gy b.i.d. with 8-h interval), using a three-dimensional conformal technique. Only the mediastinal lymph node areas that were positive on the pretreatment {sup 18}F-deoxy-D-glucose positron emission tomography scan were included in the target volume. The primary endpoint was toxicity. Results: A total of 48 Stage I-IIIB patients were included. In all risk groups, 68.40 Gy/38 fractions/25 days could be administered. Maximal toxicity according to the risk groups was as follows: V{sub 20} <25% (n = 35): 1 Grade 4 (G4) lung and 1 G3 reversible esophageal toxicity; V{sub 20} 35-37% (n = 12): 1 G5 lung and 1 G3 reversible esophageal toxicity. For the whole group, local tumor recurrence occurred in 25% (95% confidence interval 14%-40%) of the patients, with 1 of 48 (2.1%; upper one-sided 95% confidence limit 9.5%) having an isolated nodal recurrence. The median actuarial overall survival was 20 months, with a 2-year survival rate of 36%. Conclusions: High-dose continuous hyperfractionated accelerated radiotherapy up to a dose of 68.40 Gy/38 fractions/25 days (a biologic equivalent of approximately 80 Gy when delivered in conventional fractionation) in patients with inoperable NSCLC and a V{sub 20} up to 37% is feasible.

  6. Study protocol for a phase III multicentre, randomised, open-label, blinded-end point trial to evaluate the efficacy and safety of immunoglobulin plus cyclosporin A in patients with severe Kawasaki disease (KAICA Trial)

    PubMed Central

    Aoyagi, Reiko; Hamada, Hiromichi; Sato, Yasunori; Suzuki, Hiroyuki; Onouchi, Yoshihiro; Ebata, Ryota; Terauchi, Moe; Terai, Masaru; Hanaoka, Hideki; Hata, Akira

    2015-01-01

    Introduction Kawasaki disease (KD) is an acute, self-limited vasculitis of unknown aetiology that predominantly affects infants and young children. We hypothesise that cyclosporin A (CsA) may be effective in treating KD by regulating the Ca2+/NFAT signalling pathway. This trial compares the current standard therapy of intravenous immunoglobulin (IVIG) and the combined IVIG+CsA therapy in paediatric patients with severe KD. Methods and analysis This trial is a phase III, multicentre, randomised, open-label, blinded-end point trial that evaluates the efficacy and safety of IVIG+CsA therapy. Patients with severe KD who satisfy the eligibility criteria are randomised (1:1) to receive either CsA (5 mg/kg/day for 5 days; Neoral) plus high-dose IVIG (2 g/kg for 24 h and aspirin 30 mg/kg/day), or high-dose IVIG alone (2 g/kg for 24 h and aspirin 30 mg/kg/day). The primary end point is the frequency of occurrence of coronary artery abnormalities during the trial period. An independent end point review committee will be in charge of the trial assessment. Ethics and dissemination The protocol was approved by the Institutional Review Board of each institution. The trial was notified and registered at the Pharmaceutical and Medical Devices Agency, in Japan. The trial is currently on-going and is scheduled to finish in April 2017. The findings will be disseminated through peer-reviewed publications and conference presentations. Trial registration number JMA-IIA00174; Pre-results. PMID:26628527

  7. Advanced Stirling Converter (ASC) Phase III Progress Update

    NASA Astrophysics Data System (ADS)

    Wood, J. Gary; Wilson, Kyle; Buffalino, Andrew; Frye, Patrick; Matejczyk, Dan; Penswick, L. B.

    2007-01-01

    Progress in the development of the Advanced Stirling Convertor (ASC) is presented here. The ASC is being developed under contact with the NASA Glenn Research Center and is supported by the Science Mission Directorate for potential use in future radioisotope power systems having significantly increased efficiency and higher specific power compared to the current thermoelectric systems. Phase II of the effort successfully demonstrated very high conversion efficiency and also demonstrated the low mass capability of the ASC design. The non-hermetic ASC-1 converters demonstrated during Phase II employ superalloy heater heads designed for greater than 14 years life at 850 °C operation. Phase III, which is reported on here, includes the fabrication of multiple next generation hermetic ASC-2 units. Phase III also includes the development of multiple lower-temperature (650 °C hot end) convertors based on the basic ASC design and designated as ASC-0 units. Multiple converters are being built for extended life testing at NASA GRC.

  8. Trimebutine-induced phase III-like activity in infants with intestinal motility disorders.

    PubMed

    Boige, N; Cargill, G; Mashako, L; Cezard, J P; Navarro, J

    1987-01-01

    Duodenal manometric recordings were performed in five male children (mean age 11.7 +/- 6.8 months) suffering from severe digestive pathology with clinical findings of dysmotility; they required total parenteral nutrition: one case of enteropathy following intestinal resection for congenital small bowel atresia, and four cases of intestinal pseudoobstruction. The basal 3-h fasting recordings showed complete disorganization of interdigestive activity characterized by an absence of migrating motor complexes and a marked basal hypomotility with motor indices lower than in control subjects. Intravenous trimebutine (3 mg/kg) produced a phase III-like activity 88 +/- 121 s after administration in four cases. The activity lasted 236 +/- 105 s and had a mean frequency of 11.75 +/- 0.86 waves/min. It was propagated aborally in the two patients having two duodenal recording sites. Trimebutine-induced phase III activity was followed by signs of peristalsis in two patients. PMID:3430262

  9. Sequential designs for phase III clinical trials incorporating treatment selection.

    PubMed

    Stallard, Nigel; Todd, Susan

    2003-03-15

    Most statistical methodology for phase III clinical trials focuses on the comparison of a single experimental treatment with a control. An increasing desire to reduce the time before regulatory approval of a new drug is sought has led to development of two-stage or sequential designs for trials that combine the definitive analysis associated with phase III with the treatment selection element of a phase II study. In this paper we consider a trial in which the most promising of a number of experimental treatments is selected at the first interim analysis. This considerably reduces the computational load associated with the construction of stopping boundaries compared to the approach proposed by Follman, Proschan and Geller (Biometrics 1994; 50: 325-336). The computational requirement does not exceed that for the sequential comparison of a single experimental treatment with a control. Existing methods are extended in two ways. First, the use of the efficient score as a test statistic makes the analysis of binary, normal or failure-time data, as well as adjustment for covariates or stratification straightforward. Second, the question of trial power is also considered, enabling the determination of sample size required to give specified power.

  10. TRIO-012: a multicenter, multinational, randomized, double-blind phase III study of IMC-1121B plus docetaxel versus placebo plus docetaxel in previously untreated patients with HER2-negative, unresectable, locally recurrent or metastatic breast cancer.

    PubMed

    Mackey, John; Gelmon, Karen; Martin, Miguel; McCarthy, Nicole; Pinter, Tamas; Rupin, Mathieu; Youssoufian, Hagop

    2009-11-01

    In this multinational, placebo-controlled, randomized phase III trial, Translational Research In Oncology (TRIO) will define the efficacy and safety of adding a novel antiangiogenic agent, IMC-1121B (ramucirumab), to standard first-line docetaxel chemotherapy for women with HER2-negative metastatic breast cancer. We will evaluate whether the addition of IMC-1121B prolongs progression-free survival and whether its use improves overall survival. Accrual is under way.

  11. 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

  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. Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty

    PubMed Central

    Golpanian, Samuel; DiFede, Darcy L.; Pujol, Marietsy V.; Lowery, Maureen H.; Levis-Dusseau, Silvina; Goldstein, Bradley J.; Schulman, Ivonne H.; Longsomboon, Bangon; Wolf, Ariel; Khan, Aisha; Heldman, Alan W.; Goldschmidt-Clermont, Pascal J.; Hare, Joshua M.

    2016-01-01

    Frailty is a syndrome associated with reduced physiological reserves that increases an individual's vulnerability for developing increased morbidity and/or mortality. While most clinical trials have focused on exercise, nutrition, pharmacologic agents, or a multifactorial approach for the prevention and attenuation of frailty, none have studied the use of cell-based therapies. We hypothesize that the application of allogeneic human mesenchymal stem cells (allo-hMSCs) as a therapeutic agent for individuals with frailty is safe and efficacious. The CRATUS trial comprises an initial non-blinded phase I study, followed by a blinded, randomized phase I/II study (with an optional follow-up phase) that will address the safety and pre-specified beneficial effects in patients with the aging frailty syndrome. In the initial phase I protocol, allo-hMSCs will be administered in escalating doses via peripheral intravenous infusion (n=15) to patients allocated to three treatment groups: Group 1 (n=5, 20 million allo-hMSCs), Group 2 (n=5, 100 million allo-hMSCs), and Group 3 (n=5, 200 million allo-hMSCs). Subsequently, in the randomized phase, allo-hMSCs or matched placebo will be administered to patients (n=30) randomly allocated in a 1:1:1 ratio to one of two doses of MSCs versus placebo: Group A (n=10, 100 million allo-hMSCs), Group B (n=10, 200 million allo-hMSCs), and Group C (n=10, placebo). Primary and secondary objectives are, respectively, to demonstrate the safety and efficacy of allo-hMSCs administered in frail older individuals. This study will determine the safety of intravenous infusion of stem cells and compare phenotypic outcomes in patients with aging frailty. PMID:26933813

  15. Caring for class III obese patients.

    PubMed

    Gardner, Lea Anne

    2013-11-01

    The Pennsylvania Patient Safety Reporting System is a confidential, statewide Internet reporting system to which all Pennsylvania hospitals, outpatient-surgery facilities, and birthing centers, as well as some abortion facilities, must file information on medical errors.Safety Monitor is a column from Pennsylvania's Patient Safety Authority, the authority that informs nurses on issues that can affect patient safety and presents strategies they can easily integrate into practice. For more information on the authority, visit www.patientsafetyauthority.org. For the original article discussed in this column or for other articles on patient safety, click on "Patient Safety Advisories" and then "Advisory Library" in the left-hand navigation menu. PMID:24149276

  16. 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.

  17. 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.

  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. 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.

  20. FAIRY: a randomized controlled patient-blind phase III study to compare the efficacy and safety of intravenous ferric carboxymaltose (Ferinject®) to placebo in patients with acute isovolemic anemia after gastrectomy - study protocol for a randomized controlled trial

    PubMed Central

    2014-01-01

    Background Isovolemic anemia (decrease in hemoglobin concentration with normal or even increased blood volume) after gastric cancer surgery may negatively influence short- and long-term outcomes. Therefore correction of isovolemic postoperative anemia is supposed to be beneficial. This prospective randomized placebo-controlled multicenter trial is designed to evaluate the efficacy of ferric carboxymaltose administration with the primary end point of successful hemoglobin level increase by 2 g/dl at 12 weeks after randomization. Methods and design Gastric cancer patients after oncologic resection and postoperative hemoglobin level ≥ 7 g/dl to <10 g/dl at postoperative days 5 to 7 will be eligible for trial inclusion. After randomization, 450 patients (225 per group) are going to be subjected either to administration of ferric carboxymaltose (treatment group) or normal (0.9%) saline (placebo group). Patients will be blinded to the intervention. Patients will undergo evaluation for hemoglobin level, hematology and quality of life assessment 3 and 12 weeks after randomization. Discussion Correction of isovolemic postoperative anemia in gastric cancer patients after oncologic resection is considered to be beneficial. Administration of ferric carboxymaltose is considered to be superior to placebo for anemia correction without the possible risks of red blood cell transfusion. Further, improved quality of life for patients with quick recovery of hemoglobin levels is expected. Trial registration NCT01725789 (international: http://www.clinicaltrials.gov) and NCCCTS-12-644 (NCC, Korea). PMID:24708660

  1. Glycerol and NEFA kinetics in long-term fasting king penguins: phase II versus phase III.

    PubMed

    Bernard, S F; Fayolle, C; Robin, J-P; Groscolas, R

    2002-09-01

    In spontaneously fasting birds such as penguins, below a body mass threshold corresponding to the phase II-phase III transition, a metabolic and hormonal shift occurs and feeding behaviour is stimulated ('refeeding signal'). The major aim of this study was to determine whether a decrease in non-esterified fatty acid (NEFA) release from adipose tissue could be a component of this signal. Lipolytic fluxes and primary triacylglycerol:fatty acid (TAG:FA) cycling were determined in vivo in breeding, fasting king penguins (Aptenodytes patagonicus) using continuous infusions of 2-[3H]glycerol and 1-[14C]palmitate under field conditions. In phase II (after approximately 8 days of fasting, large fat stores, body protein spared, N=8), the rate of appearance (R(a)) of glycerol and of NEFA were 5.7+/-0.8 and 10.5+/-0.4 micromol kg(-1) min(-1), respectively, and the percentage of primary TAG:FA cycling was 41+/-7%. In phase III (after approximately 25 days of fasting, fat stores reduced by fourfold, increased body protein catabolism, N=9), R(a) glycerol kg(-1) body mass remained unchanged, whereas R(a) glycerol kg(-1) fat mass and R(a) NEFA kg(-1) body mass were increased by 2.8-fold and 1.5-fold, respectively. Increased R(a) glycerol kg(-1) fat mass was possibly the result of a 3.5-fold increase in circulating glucagon, the increased R(a) NEFA kg(-1) body mass being attributable to decreased primary TAG:FA cycling. Thus, triggering of the refeeding signal that redirects the behavior of fasting, incubating penguins from incubation towards the search for food after entrance into phase III cannot be ascribed to a reduction in lipolytic fluxes and NEFA availability. PMID:12151380

  2. GLASS COMPOSITIONS FOR THE NEPHELINE PHASE III STUDY

    SciTech Connect

    Fox, K.; Edwards, T.

    2009-06-29

    A series of 29 test glass compositions were selected for Phase III of the nepheline study using a combination of two approaches. The first approach was based on evaluating the glass composition region allowable by all of the Defense Waste Processing Facility (DWPF) Product Composition Control System (PCCS) models with the exception of the current nepheline discriminator. This approach was taken to determine whether there are glass compositions that, while predicted to crystallize nepheline upon slow cooling, would otherwise be acceptable for processing in the DWPF. The second approach was based on quasicrystalline theory of glass structure, which helped predict compositional regions where nepheline should form. A detailed description of this methodology is forthcoming. The selection strategy outlined here will provide an opportunity to determine experimentally whether the glasses that fail the current nepheline discriminator but pass the newly proposed nepheline discriminator are indeed free of nepheline after slow cooling. If this is the case, these data will serve as a significant step toward reducing conservatism in the current nepheline discriminator. The 29 glass compositions selected for testing address both the PCCS model and quasicrystalline theory approaches in evaluating both a reduction in conservatism for the current nepheline discriminator and possible implementation of the newly proposed discriminator based on glass structural theory. These glasses will be fabricated and characterized in the laboratory, with the results and conclusions described in a technical report.

  3. Doxepin Rinse Versus Placebo in the Treatment of Acute Oral Mucositis Pain in Patients Receiving Head and Neck Radiotherapy With or Without Chemotherapy: A Phase III, Randomized, Double-Blind Trial (NCCTG-N09C6 [Alliance])

    PubMed Central

    Leenstra, James L.; Miller, Robert C.; Qin, Rui; Martenson, James A.; Dornfeld, Kenneth J.; Bearden, James D.; Puri, Dev R.; Stella, Philip J.; Mazurczak, Miroslaw A.; Klish, Marie D.; Novotny, Paul J.; Foote, Robert L.; Loprinzi, Charles L.

    2014-01-01

    Purpose Painful oral mucositis (OM) is a significant toxicity during radiotherapy for head and neck cancers. The aim of this randomized, double-blind, placebo-controlled trial was to test the efficacy of doxepin hydrochloride in the reduction of radiotherapy-induced OM pain. Patients and Methods In all, 155 patients were randomly allocated to a doxepin oral rinse or a placebo for the treatment of radiotherapy-related OM pain. Patients received a single dose of doxepin or placebo on day 1 and then crossed over to receive the opposite agent on a subsequent day. Pain questionnaires were administered at baseline and at 5, 15, 30, 60, 120, and 240 minutes. Patients were then given the option to continue doxepin. The primary end point was pain reduction as measured by the area under the curve (AUC) of the pain scale using data from day 1. Results Primary end point analysis revealed that the AUC for mouth and throat pain reduction was greater for doxepin (−9.1) than for placebo (−4.7; P < .001). Crossover analysis of patients completing both phases confirmed that patients experienced greater mouth and throat pain reduction with doxepin (intrapatient changes of 4.1 for doxepin-placebo arm and −2.8 for placebo-doxepin arm; P < .001). Doxepin was associated with more stinging or burning, unpleasant taste, and greater drowsiness than the placebo rinse. More patients receiving doxepin expressed a desire to continue treatment than did patients with placebo after completion of each of the randomized phases of the study. Conclusion A doxepin rinse diminishes OM pain. Further studies are warranted to determine its role in the management of OM. PMID:24733799

  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. PMID:25133955

  6. Phase I--II study of N4-behenoyl-1-beta-D-arabinofuranosylcytosine.

    PubMed

    Kimura, K; Yamada, K; Uzuka, Y; Maekawa, T; Takaku, F; Shimoyama, M; Ogawa, M; Amaki, I; Osamura, S; Ito, M; Sakai, Y; Oguro, M; Hattori, K; Hoshino, A; Hirota, Y; Ohta, K; Nakamura, T; Masaoka, T; Kimura, I; Ichimaru, M

    1981-01-01

    A phase I-II study of N4-behenoyl-1-beta-D-arabinofuranosyl-cytosine (BH-AC) was conducted by a cooperative study group. In phase I study, a total of 126 patients, 64 of whom had metastatic solid tumors and 62 of whom had leukemia, were administered BH-AC in a single IV dose at day 1 only or in daily IV doses for 3 to 21 days, with dose ranges of 1.5--10.0 mg/kg. Side effects included nausea and vomiting, which were significantly less in incidence and severity than those observed with ara-C. Myelosuppressive toxicity became severe with doses 3.6--5.0 mg/kg per day x 10 days. In phase II study, a total of 37 adult patients with acute leukemia were entered in the study. Responses were noted, with an overall rate of 35% complete remission. Of th 26 patients with AML, there were 13 CR. The recommended schedule of treatment for BH-AC, based on our data, is daily infusion of 4--5 mg/kg over 3 h for approximately 3 weeks. The results with BH-AC in patients with acute leukemia are superior to those which have been reported for ara-C.

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC)

    PubMed Central

    Oki, E.; Murata, A.; Yoshida, K.; Maeda, K.; Ikejiri, K.; Munemoto, Y.; Sasaki, K.; Matsuda, C.; Kotake, M.; Suenaga, T.; Matsuda, H.; Emi, Y.; Kakeji, Y.; Baba, H.; Hamada, C.; Saji, S.; Maehara, Y.

    2016-01-01

    Backgrounds Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur–uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. Patients and methods The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20–80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500–600 mg/day on days 1–5, followed by 2 days rest) or S-1 (80–120 mg/day on days 1–28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. Results In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63–0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. Conclusion One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection. PMID:27056996

  12. WMS-III performance in epilepsy patients following temporal lobectomy.

    PubMed

    Doss, Robert C; Chelune, Gordon J; Naugle, Richard I

    2004-03-01

    We examined performances on the Wechsler Memory Scale-3rd Edition (WMS-III) among patients who underwent temporal lobectomy for the control of medically intractable epilepsy. There were 51 right (RTL) and 56 left (LTL) temporal lobectomy patients. All patients were left hemisphere speech-dominant. The LTL and RTL patients were comparable in terms of general demographic, epilepsy, and intellectual/attention factors. Multivariate analyses revealed a significant crossover interaction (p <.001), with the RTL group scoring significantly lower on the visual than auditory indexes while the LTL group scored significantly lower on the auditory than visual memory indexes. Within-group pairwise analyses revealed statistically significant auditory versus visual index score comparisons (all p <.001) for both surgical groups. Discriminant analysis (p <.001) identified Verbal Paired Associates I, Faces I, and Family Pictures II to significantly discriminate RTL and LTL patients, with an overall correct classification rate of 81.3%. Our findings suggest that the WMS-III is sensitive to modality-specific memory performance associated with unilateral temporal lobectomy.

  13. Acute physiology, age, and chronic health evaluation (APACHE) III score is an alternative efficient predictor of mortality in burn patients.

    PubMed

    Tanaka, Yohei; Shimizu, Mikio; Hirabayashi, Hidemitsu

    2007-05-01

    The present study was performed to evaluate the prognostic value of the acute physiology, age, chronic health evaluation (APACHE) III score in burn patients. We hypothesised that APACHE III score efficiently predicts mortality of burn patients as it reflects the physiological changes in the acute phase and the severity of the underlying illness. Data such as age, gender, inhalation injury, total burn surface area (TBSA), burn index (BI), prognostic burn index (PBI), APACHE III score and outcome of 105 hospitalised patients were analysed retrospectively. TBSA, BI, PBI, and APACHE III score in the mortality group were significantly higher than those of surviving group. The mean scores of surviving versus mortality groups were as follows: TBSA, 19.2+/-17.8% versus 69.1+/-28.4%, p<0.0001; BI, 12.8+/-13.1% versus 66.8+/-28.6%, p<0.0001; PBI, 68.8+/-26.0% versus 124.4+/-33.6%, p<0.0001; APACHE III score, 28.4+/-22.2% versus 71.3+/-32.1%, p<0.0001. PBI and APACHE III score showed marked associations between higher scores and higher mortality. APACHE III score showed a significant correlation with PBI (p<0.0001). The present study suggested that APACHE III score could be used as an alternative efficient predictor of mortality in burn patients.

  14. Quantitative phase-amplitude microscopy. III. The effects of noise.

    PubMed

    Paganin, D; Barty, A; McMahon, P J; Nugent, K A

    2004-04-01

    We explore the effect of noise on images obtained using quantitative phase-amplitude microscopy - a new microscopy technique based on the determination of phase from the intensity evolution of propagating radiation. We compare the predictions with experimental results and also propose an approach that allows good-quality quantitative phase retrieval to be obtained even for very noisy data.

  15. 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.

  16. Rhodiola rosea, folic acid, zinc and biotin (EndEP®) is able to improve ejaculatory control in patients affected by lifelong premature ejaculation: Results from a phase I-II study

    PubMed Central

    Cai, Tommaso; Verze, Paolo; Massenio, Paolo; Tiscione, Daniele; Malossini, Gianni; Cormio, Luigi; Carrieri, Giuseppe; Mirone, Vincenzo

    2016-01-01

    The therapeutic armamentarium currently available for the treatment of premature ejaculation (PE) is not highly satisfactory. However, phytotherapeutics appear to be an interesting option for PE management. The present study aimed to evaluate the tolerability and efficacy of a phytotherapeutic combination of Rhodiola rosea, folic acid, biotin and zinc (EndEP®) in the treatment of patients affected by lifelong PE. All patients affected by lifelong PE who were attending three Urological Institutions from July to December 2014 were enrolled in this prospective, multicentre, phase I–II study. All patients were assigned to receive oral tablets of EndEP® (one tablet per day) for 90 days. Clinical and instrumental analyses were carried out at enrolment and at the end of the study. International Prostatic Symptom Score (IPSS), International Index of Erectile Function (IIEF)-15, Premature Ejaculation Diagnostic Tool (PEDT) and Short Form (SF)-36 questionnaires were used. The intravaginal ejaculation latency time (IELT) for each event was also evaluated using the stop-watch technique. The main outcome measure was the difference from baseline in PEDT questionnaire and mean IELT at the end of the follow-up period. In total, 91 patients (mean age, 32.3±5.6 years) were analysed. The baseline questionnaires mean scores were 1.1±1.6, 26.1±2.9, 15.3±3.4 and 98.2±0.5, for IPSS, IIEF-15, PEDT and SF-36, respectively. The mean IELT at baseline was 73.6±46.9s. At the follow-up examination (90 days after the start of treatment), no statistically significant differences were identified in terms of IPSS (1.4±1.5) or IIEF-15 (26.3±3.1) compared with the pre-treatment values (P=0.19 and P=0.64, respectively). A statistically significant difference was detected between the mean IELT at enrolment and after treatment (73.6±46.9 vs. 102.3±60.0; P<0.001) and SF-36 questionnaire (98.2±0.5 vs. 99.4±0.1; P<0.001). Fifty-five patients reported improvement in the control of

  17. Rhodiola rosea, folic acid, zinc and biotin (EndEP®) is able to improve ejaculatory control in patients affected by lifelong premature ejaculation: Results from a phase I-II study

    PubMed Central

    Cai, Tommaso; Verze, Paolo; Massenio, Paolo; Tiscione, Daniele; Malossini, Gianni; Cormio, Luigi; Carrieri, Giuseppe; Mirone, Vincenzo

    2016-01-01

    The therapeutic armamentarium currently available for the treatment of premature ejaculation (PE) is not highly satisfactory. However, phytotherapeutics appear to be an interesting option for PE management. The present study aimed to evaluate the tolerability and efficacy of a phytotherapeutic combination of Rhodiola rosea, folic acid, biotin and zinc (EndEP®) in the treatment of patients affected by lifelong PE. All patients affected by lifelong PE who were attending three Urological Institutions from July to December 2014 were enrolled in this prospective, multicentre, phase I–II study. All patients were assigned to receive oral tablets of EndEP® (one tablet per day) for 90 days. Clinical and instrumental analyses were carried out at enrolment and at the end of the study. International Prostatic Symptom Score (IPSS), International Index of Erectile Function (IIEF)-15, Premature Ejaculation Diagnostic Tool (PEDT) and Short Form (SF)-36 questionnaires were used. The intravaginal ejaculation latency time (IELT) for each event was also evaluated using the stop-watch technique. The main outcome measure was the difference from baseline in PEDT questionnaire and mean IELT at the end of the follow-up period. In total, 91 patients (mean age, 32.3±5.6 years) were analysed. The baseline questionnaires mean scores were 1.1±1.6, 26.1±2.9, 15.3±3.4 and 98.2±0.5, for IPSS, IIEF-15, PEDT and SF-36, respectively. The mean IELT at baseline was 73.6±46.9s. At the follow-up examination (90 days after the start of treatment), no statistically significant differences were identified in terms of IPSS (1.4±1.5) or IIEF-15 (26.3±3.1) compared with the pre-treatment values (P=0.19 and P=0.64, respectively). A statistically significant difference was detected between the mean IELT at enrolment and after treatment (73.6±46.9 vs. 102.3±60.0; P<0.001) and SF-36 questionnaire (98.2±0.5 vs. 99.4±0.1; P<0.001). Fifty-five patients reported improvement in the control of

  18. A Phase III Trial Comparing Two Dose-dense, Dose-intensified Approaches (ETC and PM(Cb)) for Neoadjuvant Treatment of Patients With High-risk Early Breast Cancer (GeparOcto)

    ClinicalTrials.gov

    2016-01-14

    Tubular Breast Cancer Stage II; Tubular Breast Cancer Stage III; Mucinous Breast Cancer Stage II; Breast Cancer Female NOS; Invasive Ductal Breast Cancer; HER2 Positive Breast Cancer; Inflammatory Breast Cancer

  19. Ten- to 15-year results of the Oxford Phase III mobile unicompartmental knee arthroplasty

    PubMed Central

    Lisowski, L. A.; Meijer, L. I.; van den Bekerom, M. P. J.; Pilot, P.; Lisowski, A. E.

    2016-01-01

    Aims The interest in unicompartmental knee arthroplasty (UKA) for medial osteoarthritis has increased rapidly but the long-term follow-up of the Oxford UKAs has yet to be analysed in non-designer centres. We have examined our ten- to 15-year clinical and radiological follow-up data for the Oxford Phase III UKAs. Patients and Methods Between January 1999 and January 2005 a total of 138 consecutive Oxford Phase III arthroplasties were performed by a single surgeon in 129 patients for medial compartment osteoarthritis (71 right and 67 left knees, mean age 72.0 years (47 to 91), mean body mass index 28.2 (20.7 to 52.2)). Both clinical data and radiographs were prospectively recorded and obtained at intervals. Of the 129 patients, 32 patients (32 knees) died, ten patients (12 knees) were not able to take part in the final clinical and radiological assessment due to physical and mental conditions, but via telephone interview it was confirmed that none of these ten patients (12 knees) had a revision of the knee arthroplasty. One patient (two knees) was lost to follow-up. Results The mean follow-up was 11.7 years (10 to 15). A total of 11 knees (8%) were revised. The survival at 15 years with revision for any reason as the endpoint was 90.6% (95% confidence interval (CI) 85.2 to 96.0) and revision related to the prosthesis was 99.3% (95% CI 97.9 to 100). The mean total Knee Society Score was 47 (0 to 80) pre-operatively and 81 (30 to 100) at latest follow-up. The mean Oxford Knee Score was 19 (12 to 40) pre-operatively and 42 (28 to 55) at final follow-up. Radiolucency beneath the tibial component occurred in 22 of 81 prostheses (27.2%) without evidence of loosening. Conclusion This study supports the use of UKA in medial compartment osteoarthritis with excellent long-term functional and radiological outcomes with an excellent 15-year survival rate. Cite this article: Bone Joint J 2016;98-B(10 Suppl B):41–7. PMID:27694515

  20. Interim analysis of postoperative chemoradiotherapy with capecitabine and oxaliplatin versus capecitabine alone for pathological stage II and III rectal cancer: a randomized multicenter phase III trial

    PubMed Central

    Feng, Yan-Ru; Zhu, Yuan; Liu, Lu-Ying; Wang, Wei-Hu; Wang, Shu-Lian; Song, Yong-Wen; Wang, Xin; Tang, Yuan; Liu, Yue-Ping; Ren, Hua; Fang, Hui; Zhang, Shi-Ping; Liu, Xin-Fan; Yu, Zi-Hao; Li, Ye-Xiong; Jin, Jing

    2016-01-01

    The aim of this study is to present an interim analysis of a phase III trial (NCT00714077) of postoperative concurrent capecitabine and radiotherapy with or without oxaliplatin for pathological stage II and III rectal cancer. Patients with pathologically confirmed stage II and III rectal cancer were randomized to either radiotherapy with concurrent capecitabine (Cap-RT group) or with capecitabine and oxaliplatin (Capox-RT group). The primary endpoint was 3-year disease-free survival rate (DFS). The 3-year DFS rate was 73.9% in the Capox-RT group and 71.6% in the Cap-RT group (HR 0.92, p = 0.647), respectively. No significant difference was observed in overall survival, cumulative incidence of local recurrence and distant metastasis between the two groups (p > 0.05). More grade 3–4 acute toxicity was observed in the Capox-RT group than in the Cap-RT group (38.1% vs. 29.2%, p = 0.041). Inclusion of oxaliplatin in the capecitabine-based postoperative regimen did not improve DFS but increased toxicities for pathological stage II and III rectal cancer in this interim analysis. PMID:27014909

  1. Effects of gelatin sponge combined with moist wound-healing nursing intervention in the treatment of phase III bedsore

    PubMed Central

    LI, YANLING; YAO, MEIYING; WANG, XIA; ZHAO, YANQING

    2016-01-01

    Pressure sore pertains to tissue damage or necrosis that occurs due to lack of adequate nutrition following long-term exposure to pressure and decreased blood circulation. The aim of the study was to examine the effects of gelatin sponge combined with moist wound-healing nursing intervention in the treatment of phase III bedsore. In total, 50 patients with phase III bedsore were included in the present study. The patients were randomly divided into the control (n=25) and observation (n=25) groups. Patients in the control group received conventional nursing, while those in the observation group received gelatin sponge combined with moist wound healing nursing. The effects of the two nursing methods were compared and analyzed. The results showed that the improvement rate of the observation group was significantly higher than that of the control group (P<0.05). The Branden score and area of pressure sore of the observation group were significantly lower than those of the control group (P<0.05). The frequency and time of dressing change and the average cost of hospitalization of the observation group were significantly lower than those of the control group (P<0.001). In conclusion, gelatin sponge combined with moist wound-healing nursing intervention may significantly improve the treatment of phase III bedsore. PMID:27313666

  2. 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. PMID:20045479

  3. An open, phase III study of lanreotide (Somatuline PR) in the treatment of acromegaly.

    PubMed

    Lin, J D; Lee, S T; Weng, H F

    1999-02-01

    Acromegaly is a disorder caused by excessive secretion of human growth hormone (GH). Somatostatin and its analogue-prolonged release formulation, lanreotide (Somatuline PR), inhibit the secretion of growth hormone. The aim of this open Phase III study was to investigate the clinical efficacy of lanreotide in the treatment of six acromegalic patients with a mean age of 44 +/- 13 yr including two patients with diabetes mellitus. All the patients previously received transsphenoidal or transcranial hypophysectomy. Lanreotide was given intramuscularly every 2 weeks at a fixed dose of 30 mg for 12 weeks. Serum GH and insulin-like growth factor-I (IGF-I) levels were evaluated before, 2, 6 and 12 weeks after treatment. After 12 weeks of treatment, mean (+/- SEM) GH levels decreased from 24.8 +/- 12.5 to 6.9 +/- 3.3 ng/ml and mean serum IGF-I levels decreased from 689 +/- 282 to 430 +/- 216 ng/ml. Abdominal ultrasonographic examinations showed no gallbladder stone or bile sand formation before or after the treatment. Three of the patients who did not receive octreotide presented with manifestations of mild gastrointestinal adverse effect such as mild abdominal pain and diarrhea. In conclusion, lanreotide is effective in the treatment of active postoperative acromegaly. PMID:10426587

  4. 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.

  5. 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

  6. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a west Japan thoracic oncology group trial (WJTOG0203).

    PubMed

    Takeda, Koji; Hida, Toyoaki; Sato, Tosiya; Ando, Masahiko; Seto, Takashi; Satouchi, Miyako; Ichinose, Yukito; Katakami, Nobuyuki; Yamamoto, Nobuyuki; Kudoh, Shinzoh; Sasaki, Jiichiro; Matsui, Kaoru; Takayama, Koichi; Kashii, Tatsuhiko; Iwamoto, Yasuo; Sawa, Toshiyuki; Okamoto, Isamu; Kurata, Takayasu; Nakagawa, Kazuhiko; Fukuoka, Masahiro

    2010-02-10

    PURPOSE Gefitinib is a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase. We conducted a phase III trial to evaluate whether gefitinib improves survival as sequential therapy after platinum-doublet chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Chemotherapy-naïve patients with advanced stage (IIIB/IV) NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function were randomly assigned to either platinum-doublet chemotherapy up to six cycles (arm A) or platinum-doublet chemotherapy for three cycles followed by gefitinib 250 mg orally once daily, until disease progression (arm B). Patients were stratified by disease stage, sex, histology, and chemotherapy regimens. The primary end point was overall survival; secondary end points included progression-free survival, tumor response, safety, and quality of life. Results Between March 2003 and May 2005, 604 patients were randomly assigned. There was a statistically significant improvement in progression-free survival in arm B (hazard ratio [HR], 0.68; 95% CI, 0.57 to 0.80; P < .001); however, overall survival results did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.03; P = .11). In an exploratory subset analysis of overall survival by histologic group, patients in arm B with adenocarcinoma did significantly better than patients in arm A with adenocarcinoma (n = 467; HR, 0.79; 95% CI, 0.65 to 0.98; P = .03). CONCLUSION This trial failed to meet the primary end point of OS in patients with NSCLC. The exploratory subset analyses demonstrate a possible survival prolongation for sequential therapy of gefitinib, especially for patients with adenocarcinoma.

  7. Toxicology study of repeat intracerebral administration of a measles virus derivative producing carcinoembryonic antigen in rhesus macaques in support of a phase I/II clinical trial for patients with recurrent gliomas.

    PubMed

    Myers, Rae; Harvey, Mary; Kaufmann, Timothy J; Greiner, Suzanne M; Krempski, James W; Raffel, Corey; Shelton, Steven E; Soeffker, Diane; Zollman, Paula; Federspiel, Mark J; Blanco, Michael; Galanis, Evanthia

    2008-07-01

    Gliomas have a dismal prognosis, with the median survival of patients with the most common histology, glioblastoma multiforme, being only 12-15 months. Development of novel therapeutic agents is urgently needed. We have previously demonstrated that oncolytic measles virus strains derived from the Edmonston vaccine lineage have significant antitumor activity against gliomas [Phuong, L.K., Allen, C., Peng, K.W., Giannini, C., Greiner, S., Teneyck, C.J., Mishra, P.K., Macura, S.I., Russell, S.J., Galanis, E.C. (2003). Cancer. Res. 63, 2462-2469]. MV-CEA is an Edmonston vaccine lineage measles virus strain engineered to express the marker peptide carcinoembryonic antigen (CEA): CEA levels can serve as a correlate of viral gene expression. In support of a phase I clinical trial of intratumoral and resection cavity administration of MV-CEA to patients with recurrent gliomas, we assessed the neurotoxicity of MV-CEA in adult immune male rhesus macaques (Macaca mulatta). The animals ' immune status and administration schedule mimicked the trial population and proposed administration schema. Macaca mulatta represents the prototype animal species for assessment of measles neurotoxicity. The animals were stereotactically administered either vehicle (n = 1) or MV-CEA at 2 x 10(5)or 2 x 10(6) TCID(50) (each, n = 2) in the right frontal lobe in two injections on days 1 and 5. Macaques were closely monitored clinically for neurotoxicity. Body weight, temperature, complete blood count, CEA, clinical chemistries, coagulation, complement levels, immunoglobulin, measles antibody titers, viremia, and shedding (buccal swabs) were tested at multiple time points. Furthermore, cisterna magna spinal taps were performed on day 9 and 1 year after the first viral dose administration, and samples were analyzed for protein, glucose, cell differential, and presence of MV-CEA. Magnetic resonance imaging (MRI) was performed between 4 and 5 months after article administration to assess for

  8. 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…

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

    PubMed Central

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

    2016-01-01

    AIM: To investigate the short-term clinical results of the Oxford phase III cementless medial unicondylar knee prosthesis (UKP) compared to the cemented medial UKP. METHODS: 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. RESULTS: 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. CONCLUSION: The cementless Oxford phase III medial UKP shows good short-term clinical results, when used in a specialist clinic by an experienced surgeon. PMID:27114932

  10. Phase III of the USO Solar Vector Magnetograph

    NASA Astrophysics Data System (ADS)

    Gosain, S.; Venkatakrishnan, P.

    The solar vector magnetograph (SVM) is a modern imaging spectropolarimeter installed at Udaipur Solar Observatory (USO). Earlier phases saw the development of the instrument using off-the-shelf components with in-house software development. Subsequently, improvements were done in the opto-mechanical design of the sub-systems and the telescope tracking system. The third phase of the instrument development saw three major improvements: (1) installation of a web-camera-based telescope guiding system, developed in-house, (2) high-cadence spectropolarimetry using liquid-crystal variable retarders and a fast CCD camera, and (3) inclusion of the Na I D1 line for chromospheric observations, in addition to the regularly used photospheric Fe I 6302 Å line.

  11. Chromium(III) oxidation by three poorly crystalline manganese(IV) oxides. 2. Solid phase analyses.

    PubMed

    Landrot, Gautier; Ginder-Vogel, Matthew; Livi, Kenneth; Fitts, Jeffrey P; Sparks, Donald L

    2012-11-01

    Layered, poorly crystalline Mn(IV)O(2) phases are abundant in the environment. These mineral phases may rapidly oxidize Cr(III) to more mobile and toxic Cr(VI) in soils. There is still, however, little knowledge of how Cr(III) oxidation by Mn(IV)O(2) proceeds at the microscopic and molecular levels. Therefore, the sorption mechanisms of Cr(III) and Cr(VI) on Random Stacked Birnessite (RSB), δ-MnO(2), and Acid Birnessite (AB) were determined by Extended X-ray Absorption Fine Structure Spectroscopy (EXAFS). These three synthetic Mn(IV)O(2), which are poorly crystalline phases and have layered structures, were reacted with 50 mM Cr(III) at pH 2.5, 3, and 3.5 before being analyzed by EXAFS. The results indicated that Cr(VI) was loosely sorbed as an outer-sphere complex on Mn(IV)O(2), while Cr(III) was tightly sorbed as an inner-sphere complex. Further research is needed to understand why Cr(III) stopped being significantly oxidized by Mn(IV)O(2) after 30 min. This study, however, demonstrated that the formation of a Cr surface precipitate is not necessarily responsible for the cessation in Cr(III) oxidation. Indeed, no Cr surface precipitate was detected at the microscopic and molecular levels on Mn(IV)O(2) surfaces reacted with Cr(III) for 1 h, although the Cr(III) oxidation ceased before 1 h of reaction at most employed experimental conditions. PMID:23050862

  12. Individualized Inservice Teacher Education (Project In-Step). Evaluation Report. Phase III.

    ERIC Educational Resources Information Center

    Thurber, John C.

    This is a report on the third phase of Project IN-STEP, which was intended to develop a viable model for individualized, multi-media in-service teacher education programs. (Phase I and II are reported in ED 033 905, and ED 042 709). The rationale for Phase III was to see if the model could be successfully transferred to an area other than teaching…

  13. 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.

  14. 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.

  15. Maintenance of Clinical and Radiographic Benefit With Intravenous Golimumab Therapy in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy: Week‐112 Efficacy and Safety Results of the Open‐Label Long‐Term Extension of a Phase III, Double‐Blind, Randomized, Placebo‐Controlled Trial

    PubMed Central

    Mendelsohn, Alan M.; Kim, Lilianne; Xu, Zhenhua; Leu, Jocelyn; Han, Chenglong; Lo, Kim Hung; Westhovens, Rene; Weinblatt, Michael E.

    2015-01-01

    Objective To evaluate the safety, efficacy, pharmacokinetics, immunogenicity, and radiographic progression through 2 years of treatment with intravenous (IV) golimumab plus methotrexate (MTX) in an open‐label extension of a phase III trial of patients with active rheumatoid arthritis (RA) despite MTX therapy. Methods In the phase III, double‐blind, randomized, placebo‐controlled GO‐FURTHER trial, 592 patients with active RA were randomized (2:1) to intravenous golimumab 2 mg/kg plus MTX (Group 1) or placebo plus MTX (Group 2) at weeks 0 and 4, then every 8 weeks thereafter; placebo patients crossed over to golimumab at week 16 (early escape) or week 24 (crossover). The final golimumab infusion was at week 100. Assessments included American College of Rheumatology 20%, 50%, 70% (ACR20, ACR50, ACR70) response criteria, 28‐joint count disease activity score using the C‐reactive protein level (DAS28‐CRP), physical function and quality of life measures, and changes in the modified Sharp/van der Heijde scores (SHS). Safety was monitored through week 112. Results In total, 486 patients (82.1%) continued treatment through week 100, and 68.1%, 43.8%, and 23.5% had an ACR20/50/70 response, respectively, at week 100. Clinical response and improvements in physical function and quality of life were generally maintained from week 24 through 2 years. Mean change from baseline to week 100 in SHS score was 0.74 in Group 1 and 2.10 in Group 2 (P = 0.005); progression from week 52 to week 100 was clinically insignificant in both groups. A total of 481 patients completed the safety followup through week 112; 79.1% had an adverse event, and 18.2% had a serious adverse event. Conclusion Clinical response to IV golimumab plus MTX was maintained through week 100. Radiographic progression following golimumab treatment was clinically insignificant between week 52 and week 100. No unexpected adverse events occurred through week 112, and the safety profile was consistent

  16. 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.

  17. Phase III (full scale) agitated mixing test plan

    SciTech Connect

    Ruff, D.T.

    1994-10-17

    Waste Receiving and Processing Facility Module 2A (WRAP 2A) is the proposed second module of the WRAP facility. This facility will provide the required treatment for contact Handled (CH) Low Level (LL) Mixed Waste (MW) to allow its permanent disposal. Solidification of a portion of this waste using a cement based grout has been selected in order to reduce the toxicity and mobility of the waste in the disposal site. Mixing of the waste with the cement paste and material handling constraints/requirements associated with the mixed material is, therefore, a key process in the overall treatment strategy. This test plan addresses Phase 3, Full Scale Testing. The objectives of these tests are to determine if there are scale-up issues associated with the mixing results obtained in Phase 1 and 2 mixing tests, verify the workability of mixtures resulting from previous formulation development efforts (Waste Immobilization Development [WID]), and provide a baseline for WRAP 2A mixing equipment design. To this end, the following objectives are of particular interest: determine geometric influence of mixing blade at full scale (i.e., size, type, and location: height/offset); determine if similar results in terms of mixing effectiveness and product quality are achievable at this scale; determine if vibration is as effective at this larger scale in fluidizing the mixture and aiding in cleaning the vessel; determine if baffles or sweeping blades are needed to aid in mixing at the larger size and for cleaning the vessel; and determine quality of the poured monolithic product and investigate exotherm and filling influences at this larger size.

  18. Association of Human Papillomavirus and p16 Status With Outcomes in the IMCL-9815 Phase III Registration Trial for Patients With Locoregionally Advanced Oropharyngeal Squamous Cell Carcinoma of the Head and Neck Treated With Radiotherapy With or Without Cetuximab

    PubMed Central

    Rosenthal, David I.; Harari, Paul M.; Giralt, Jordi; Bell, Diana; Raben, David; Liu, Joyce; Schulten, Jeltje; Ang, Kian K.

    2016-01-01

    Purpose We conducted a retrospective evaluation of the IMCL-9815 study to examine the association of human papillomavirus (HPV) and p16 protein expression status with outcomes in patients with oropharyngeal carcinoma (OPC) receiving radiotherapy (RT) plus cetuximab or RT alone. Patients and Methods In the IMCL-9815 study, patients were randomly allocated to receive RT plus weekly cetuximab or RT alone. A subpopulation of patients with p16-evaluable OPC was retrospectively evaluated on the basis of locoregional control (LRC), overall survival (OS), and progression-free survival (PFS). Evaluable samples from patients with p16-positive OPC were also tested for HPV DNA. Results Tumor p16 status was evaluable in 182 patients with OPC enrolled in the IMCL-9815 study; 41% were p16 positive. When treated with RT alone or RT plus cetuximab, p16-positive patients had a longer OS than p16-negative patients (hazard ratio, 0.40; 95% CI, 0.21 to 0.74 and hazard ratio, 0.16; 95% CI, 0.07 to 0.36, respectively). The addition of cetuximab to RT increased LRC, OS, and PFS in both patients with p16-positive OPC and those with p16-negative disease. Interaction tests for LRC, OS, and PFS did not demonstrate any significant interaction between p16 status and treatment effect (P = .087, .085, and .253, respectively). Similar trends were observed when patients with p16-positive/HPV-positive OPC (n = 49) and those with p16-positive/HPV-negative OPC (n = 14) were compared. Conclusion p16 status was strongly prognostic for patients with OPC. The data suggest that the addition of cetuximab to RT improved clinical outcomes regardless of p16 or HPV status versus RT alone. PMID:26712222

  19. Randomized Phase III Trial of Concurrent Accelerated Radiation Plus Cisplatin With or Without Cetuximab for Stage III to IV Head and Neck Carcinoma: RTOG 0522

    PubMed Central

    Ang, K. Kian; Zhang, Qiang; Rosenthal, David I.; Nguyen-Tan, Phuc Felix; Sherman, Eric J.; Weber, Randal S.; Galvin, James M.; Bonner, James A.; Harris, Jonathan; El-Naggar, Adel K.; Gillison, Maura L.; Jordan, Richard C.; Konski, Andre A.; Thorstad, Wade L.; Trotti, Andy; Beitler, Jonathan J.; Garden, Adam S.; Spanos, William J.; Yom, Sue S.; Axelrod, Rita S.

    2014-01-01

    Purpose Combining cisplatin or cetuximab with radiation improves overall survival (OS) of patients with stage III or IV head and neck carcinoma (HNC). Cetuximab plus platinum regimens also increase OS in metastatic HNC. The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival (PFS). Patients and Methods Eligible patients with stage III or IV HNC were randomly assigned to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab. Acute and late reactions were scored using Common Terminology Criteria for Adverse Events (version 3). Outcomes were correlated with patient and tumor features and markers. Results Of 891 analyzed patients, 630 were alive at analysis (median follow-up, 3.8 years). Cetuximab plus cisplatin-radiation, versus cisplatin-radiation alone, resulted in more frequent interruptions in radiation therapy (26.9% v 15.1%, respectively); similar cisplatin delivery (mean, 185.7 mg/m2 v 191.1 mg/m2, respectively); and more grade 3 to 4 radiation mucositis (43.2% v 33.3%, respectively), rash, fatigue, anorexia, and hypokalemia, but not more late toxicity. No differences were found between arms A and B in 30-day mortality (1.8% v 2.0%, respectively; P = .81), 3-year PFS (61.2% v 58.9%, respectively; P = .76), 3-year OS (72.9% v 75.8%, respectively; P = .32), locoregional failure (19.9% v 25.9%, respectively; P = .97), or distant metastasis (13.0% v 9.7%, respectively; P = .08). Patients with p16-positive oropharyngeal carcinoma (OPC), compared with patients with p16-negative OPC, had better 3-year probability of PFS (72.8% v 49.2%, respectively; P < .001) and OS (85.6% v 60.1%, respectively; P < .001), but tumor epidermal growth factor receptor (EGFR) expression did not distinguish outcome. Conclusion Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely. PFS and OS

  20. Phase III, Randomized Study of the Effects of Parenteral Iron, Oral Iron, or No Iron Supplementation on the Erythropoietic Response to Darbepoetin Alfa for Patients With Chemotherapy-Associated Anemia

    PubMed Central

    Steensma, David P.; Sloan, Jeff A.; Dakhil, Shaker R.; Dalton, Robert; Kahanic, Stephen P.; Prager, Diane J.; Stella, Philip J.; Rowland, Kendrith M.; Novotny, Paul J.; Loprinzi, Charles L.

    2011-01-01

    Purpose Functional iron deficiency may impair response to erythropoiesis-stimulating agents (ESAs) in iron-replete patients with chemotherapy-associated anemia (CAA). This study evaluated whether coadministration of parenteral iron improves ESA efficacy in patients with CAA. Patients and Methods This prospective, multicenter, randomized trial enrolled 502 patients with hemoglobin (Hb) less than 11 g/dL who were undergoing chemotherapy for nonmyeloid malignancies. All patients received darbepoetin alfa once every 3 weeks and were randomly assigned to receive either ferric gluconate 187.5 mg intravenously (IV) every 3 weeks, oral daily ferrous sulfate 325 mg, or oral placebo for 16 weeks. Results There was no difference in the erythropoietic response rate (ie, proportion of patients achieving Hb ≥12 g/dL or Hb increase ≥ 2 g/dL from baseline): 69.5% (95% CI, 61.9% to 76.5%) of IV iron-treated patients achieved an erythropoietic response compared with 66.9% (95% CI, 59.1% to 74.0%) who received oral iron and 65.0% (95% CI, 57.2% to 72.3%) who received oral placebo (P = .75). There were also no differences in the proportion of patients requiring red cell transfusions, changes in quality of life, or the dose of darbepoetin administered. Adverse events (AEs) tended to be more common in the IV iron arm: grade 3 or higher AEs occurred in 54% (95% CI, 46% to 61%) of patients receiving IV iron compared with 44% (95% CI, 36% to 52%) who received oral iron and 46% (95% CI, 38% to 54%) who received oral placebo (P = .16). Conclusion In patients with CAA, addition of IV ferric gluconate to darbepoetin failed to provide additional benefit compared with oral iron or oral placebo. PMID:21098317

  1. Tegress™ Urethral Implant Phase III Clinical Experience and Product Uniqueness

    PubMed Central

    Dmochowski, Roger R

    2005-01-01

    Advances in materials technology, coupled with a heightened understanding of wound healing and tissue-materials interactions in the lower urinary tract, have led to the development of a variety of new urethral bulking agents that are expected to be available in the near future. Experience with such bulking agents continues to grow and study results are disseminated as more clinical trials are initiated and completed. The intention of this report is to review the characteristics and initial clinical results for one of these new agents: Tegress™ Urethral Implant (C. R. Bard, Inc., Murray Hill, NJ). This material, with unique phase-change properties upon exposure to body temperature fluids, offers ease of injection and requires less volume for clinical effect than bovine collagen. Additionally, Tegress Urethral Implant performance in clinical trials has suggested improved durability and correspondingly higher continence and improvement rates versus bovine collagen. As these materials evolve, an understanding of preferential implant techniques is being gained also. Delivery method and implant site may prove to substantially alter the biologic activity of these compounds. As outlined in this review, experience with Tegress Implant resulted in changes in delivery technique that translated into improved materials and tissue interaction. PMID:16985873

  2. 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.

  3. Age Strengthening of Gray Cast Iron Phase III

    SciTech Connect

    Von L. Richards; Wayne Nicola

    2003-06-26

    The primary objective of this research is to identify the age strengthening mechanism in gray and ductile cast iron, and to quantify the parameters that control it. It is also to contribute to a new predictive model for gray and ductile iron strength and hardness. This work shows that age strengthening occurs on a sigmoidal-logarithmic scale in gray and ductile cast irons, to a statistically significant extent. This is similar to Avrami-Johnson-Mehl kinetics for phase transformations in metals. It occurs in both cupola-melted iron and induction melted iron. However, it does not happen in all compositions. We have developed some understanding of the process. Data suggests that nitrogen and nitride-forming trace elements have a significant role in the process, but that is yet not fully characterized. Also, the time dependence of the bulk hardness and strength increase, the nano-scale precipitation evidence from neutron scattering, differential scanning calorimetry results and matrix micro-hardness increase in ferrite all indicate that age strengthening occurs by a precipitation or pre-precipitate cluster formation mechanism.

  4. Paclitaxel/carboplatin with or without sorafenib in the first-line treatment of patients with stage III/IV epithelial ovarian cancer: a randomized phase II study of the Sarah Cannon Research Institute.

    PubMed

    Hainsworth, John D; Thompson, Dana S; Bismayer, John A; Gian, Victor G; Merritt, William M; Whorf, Robert C; Finney, Lindsey H; Dudley, B Stephens

    2015-05-01

    This trial compared the efficacy and toxicity of standard first-line treatment with paclitaxel/carboplatin versus paclitaxel/carboplatin plus sorafenib in patients with advanced ovarian carcinoma. Patients with stage 3 or 4 epithelial ovarian cancer with residual measurable disease or elevated CA-125 levels after maximal surgical cytoreduction were randomized (1:1) to receive treatment with paclitaxel (175 mg/m(2) , 3 h infusion, day 1) and carboplatin (AUC 6.0, IV, day 1) with or without sorafenib 400 mg orally twice daily (PO BID). Patients were reevaluated for response after completing 6 weeks of treatment (two cycles); responding or stable patients received six cycles of paclitaxel/carboplatin. Patients receiving the sorafenib-containing regimen continued sorafenib (400 PO BID) for a total of 52 weeks. Eighty-five patients were randomized and received treatment.Efficacy was similar for patients receiving paclitaxel/carboplatin/sorafenib versus paclitaxel/carboplatin: overall response rates 69% versus 74%; median progression-free survival 15.4 versus 16.3 months; 2 year survival 76% versus 81%. The addition of sorafenib added substantially to the toxicity of the regimen; rash, hand-foot syndrome, mucositis, and hypertension were significantly more common in patients treated with sorafenib. The addition of sorafenib to standard paclitaxel/carboplatin did not improve efficacy and substantially increased toxicity in the first-line treatment of advanced epithelial ovarian cancer. Based on evidence from this study and other completed trials, sorafenib is unlikely to have a role in the treatment of ovarian cancer.

  5. 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.

  6. A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282

    SciTech Connect

    Cohen, Steven J. . E-mail: S_Cohen@fccc.edu; Dobelbower, Ralph; Lipsitz, Stuart; Catalano, Paul J.; Sischy, Benjamin; Smith, Thomas J.; Haller, Daniel G.

    2005-08-01

    Purpose: The median survival time of patients with locally advanced adenocarcinoma of the pancreas is 8-10 months. Radiation therapy has been used to improve local control and palliate symptoms. This randomized study was undertaken to determine whether the addition of 5-fluorouracil (5-FU) and mitomycin-C (MMC) to radiation therapy improves outcome in this patient population. Patients and Methods: One hundred fourteen patients were randomized to receive 59.4 Gy external beam radiotherapy in 1.8 Gy fractions alone or in combination with 5-FU (1,000 mg/m{sup 2}/day for 4 days by continuous infusion Days 2-5 and 28-31) and MMC (10 mg/m{sup 2} on Day 2). Results: One hundred four patients were evaluable for efficacy. Hematologic and nonhematologic toxicities were more common in the combination arm. The response rates were 6% in the radiation therapy arm and 9% in the combination arm. There were no differences in median disease-free survival time (DFS) or overall survival time (OS) between the combination and radiation therapy alone arms: 5.1 vs. 5.0 months, respectively, for DFS (p = 0.19) and 8.4 vs. 7.1 months, respectively, for OS (p = 0.16). Conclusion: The addition of 5-FU and MMC to radiotherapy increased toxicity without improving DFS or OS in patients with locally advanced pancreatic cancer. Alternative drugs for radiosensitization may improve outcome.

  7. Phase I/II study of 131I-MIBG with vincristine and 5 days of irinotecan for advanced neuroblastoma

    PubMed Central

    DuBois, S G; Allen, S; Bent, M; Hilton, J F; Hollinger, F; Hawkins, R; Courtier, J; Mosse, Y P; Matthay, K K

    2015-01-01

    Background: 131I-metaiodobenzylguanidine (MIBG) is an active radiopharmaceutical in neuroblastoma. A previous study demonstrated that MIBG could be combined with vincristine and prolonged irinotecan, although 25% of first courses had grade 3 diarrhoea. The current phase I/II study evaluated MIBG with vincristine and 5 days of higher-dose irinotecan. Methods: Patients 1–30 years old with advanced neuroblastoma were eligible. Patients received cefixime on days −1 to +6, irinotecan (50 mg m−2 per dose IV) on days 0–4, vincristine (2 mg m−2) on day 0, MIBG (555 or 666 MBq kg−1) on day 1, and peripheral blood stem cells on day 13. UGT1A1 genotyping was performed in consenting patients. Results: Thirty-two patients (12 phase I ; 20 phase II) received 42 courses. No dose-limiting toxicities were seen during dose escalation and the recommended administered activity was 666 MBq kg−1. Myelosuppression and diarrhoea were the most common toxicities, with grade 3 diarrhoea in 6% of first courses. Patients homozygous for UGT1A1*28 had more grade 4 thrombocytopenia (80% vs 37% P=0.14). Responses (five complete and four partial) occurred in 9 out of 32 (28%) patients. Conclusions: MIBG (666 MBq kg−1) with vincristine and this irinotecan schedule is tolerable and active, with less severe diarrhoea compared with a regimen using more protracted irinotecan. PMID:25602966

  8. A Randomized Phase III Trial of IV Carboplatin and Paclitaxel x 3 Courses Followed by Observation Versus Weekly Maintenance Low Dose Paclitaxel in Patients with Early Stage Ovarian Carcinoma: a Gynecologic Oncology Group Study

    PubMed Central

    Mannel, Robert S; Brady, Mark F; Kohn, Elise C.; Hanjani, Parviz; Hiura, Masamichi; Lee, Roger; DeGeest, Koen; Cohn, David E; Monk, Bradley J.; Michael, Helen

    2011-01-01

    Purpose To compare the recurrence-free interval (RFI), and safety profile in patients with completely resected high-risk early-stage ovarian cancer patients treated with intravenous (IV) carboplatin and paclitaxel with or without maintenance low-dose paclitaxel for 24 weeks. Methods Eligibility was limited to patients with Stage I-A/B (Grade 3 or clear cell), all I-C or II epithelial ovarian cancer. All patients were to receive carboplatin AUC 6 and paclitaxel 175 mg/m2 q 3 wks × 3 courses with random assignment to either observation or maintenance paclitaxel 40 mg/m2/wk × 24 wks. Recurrence required clinical or radiological evidence of new tumor. Results There were 571 patients enrolled onto this study, of whom 29 were deemed ineligible due to inappropriate stage or pathology, leaving 542 patients. At least 3 cycles of treatment were administered to 524/542 (97%) of patients, and among those assigned to maintenance paclitaxel, 80% completed the regimen. The incidence of grade 2 or worse peripheral neuropathy (15.5% vs 6%), infection/fever (19.9% vs 8.7%), and dermatologic events (70.8% vs 52.1%) were higher on the maintenance regimen (p<0.001). The cumulative probability of recurring within 5 years for the maintenance paclitaxel regimen is 20% vs. 23% for surveillance (hazard ratio 0.807; 95% CI: 0.565–1.15). The probability of surviving 5 years was 85.4% and 86.2%, respectively. Conclusion Maintenance paclitaxel at 40 mg/m2/wk × 24 wks added to standard dose AUC6 and paclitaxel 175 mg/m2 × 3 doses provides no significant increase in RFI. PMID:21529904

  9. The impact of concurrent granulocyte macrophage-colony stimulating factor on radiation-induced mucositis in head and neck cancer patients: A double-blind placebo-controlled prospective Phase III study by Radiation Therapy Oncology Group 9901

    SciTech Connect

    Ryu, Janice K. . E-mail: janice.ryu@ucdmc.ucdavis.edu; Swann, Suzanne; LeVeque, Francis; Johnson, Darlene J.; Chen, Allan; Fortin, Andre; Kim, Harold; Ang, Kian K.

    2007-03-01

    Purpose: Based on early clinical evidence of potential mucosal protection by granulocyte-macrophage colony stimulating factor (GM-CSF), the Radiation Therapy Oncology Group conducted a double-blind, placebo-controlled, randomized study to test the efficacy and safety of GM-CSF in reducing the severity and duration of mucosal injury and pain (mucositis) associated with curative radiotherapy (RT) in head-and-neck cancer patients. Methods and Materials: Eligible patients included those with head-and-neck cancer with radiation ports encompassing >50% of oral cavity and/or oropharynx. Standard RT ports were used to cover the primary tumor and regional lymphatics at risk in standard fractionation to 60-70 Gy. Concurrent cisplatin chemotherapy was allowed. Patients were randomized to receive subcutaneous injection of GM-CSF 250 {mu}g/m{sup 2} or placebo 3 times a week. Mucosal reaction was assessed during the course of RT using the National Cancer Institute Common Toxicity Criteria and the protocol-specific scoring system. Results: Between October 2000 and September 2002, 130 patients from 36 institutions were accrued. Nine patients (7%) were excluded from the analysis, 3 as a result of drug unavailability. More than 80% of the patients participated in the quality-of-life endpoint of this study. The GM-CSF did not cause any increase in toxicity compared with placebo. There was no statistically significant difference in the average mean mucositis score in the GM-CSF and placebo arms by a t test (p = 0.4006). Conclusion: This placebo-controlled, randomized study demonstrated no significant effect of GM-CSF given concurrently compared with placebo in reducing the severity or duration of RT-induced mucositis in patients undergoing definitive RT for head-and-neck cancer.

  10. Mometasone Furoate Effect on Acute Skin Toxicity in Breast Cancer Patients Receiving Radiotherapy: A Phase III Double-Blind, Randomized Trial From the North Central Cancer Treatment Group N06C4

    SciTech Connect

    Miller, Robert C.; Schwartz, David J.; Sloan, Jeff A.; Griffin, Patricia C.; Deming, Richard L.; Anders, Jon C.; Stoffel, Thomas J.; Haselow, Robert E.; Schaefer, Paul L.; Bearden, James D.; Atherton, Pamela J.; Loprinzi, Charles L.; Martenson, James A.

    2011-04-01

    Purpose: A two-arm, double-blind, randomized trial was performed to evaluate the effect of 0.1% mometasone furoate (MMF) on acute skin-related toxicity in patients undergoing breast or chest wall radiotherapy. Methods and Materials: Patients with ductal carcinoma in situ or invasive breast carcinoma who were undergoing external beam radiotherapy to the breast or chest wall were randomly assigned to apply 0.1% MMF or placebo cream daily. The primary study endpoint was the provider-assessed maximal grade of Common Terminology Criteria for Adverse Events, version 3.0, radiation dermatitis. The secondary endpoints included provider-assessed Common Terminology Criteria for Adverse Events Grade 3 or greater radiation dermatitis and adverse event monitoring. The patient-reported outcome measures included the Skindex-16, the Skin Toxicity Assessment Tool, a Symptom Experience Diary, and a quality-of-life self-assessment. An assessment was performed at baseline, weekly during radiotherapy, and for 2 weeks after radiotherapy. Results: A total of 176 patients were enrolled between September 21, 2007, and December 7, 2007. The provider-assessed primary endpoint showed no difference in the mean maximum grade of radiation dermatitis by treatment arm (1.2 for MMF vs. 1.3 for placebo; p = .18). Common Terminology Criteria for Adverse Events toxicity was greater in the placebo group (p = .04), primarily from pruritus. For the patient-reported outcome measures, the maximum Skindex-16 score for the MMF group showed less itching (p = .008), less irritation (p = .01), less symptom persistence or recurrence (p = .02), and less annoyance with skin problems (p = .04). The group's maximal Skin Toxicity Assessment Tool score showed less burning sensation (p = .02) and less itching (p = .002). Conclusion: Patients receiving daily MMF during radiotherapy might experience reduced acute skin toxicity compared with patients receiving placebo.

  11. Randomised Phase I/II trial assessing the safety and efficacy of radiolabelled anti-carcinoembryonic antigen I131 KAb201 antibodies given intra-arterially or intravenously in patients with unresectable pancreatic adenocarcinoma

    PubMed Central

    2009-01-01

    Background Advanced pancreatic cancer has a poor prognosis, and the current standard of care (gemcitabine based chemotherapy) provides a small survival advantage. However the drawback is the accompanying systemic toxicity, which targeted treatments may overcome. This study aimed to evaluate the safety and tolerability of KAb201, an anti-carcinoembryonic antigen monoclonal antibody, labelled with I131 in pancreatic cancer (ISRCTN 16857581). Methods Patients with histological/cytological proven inoperable adenocarcinoma of the head of pancreas were randomised to receive KAb 201 via either the intra-arterial or intravenous delivery route. The dose limiting toxicities within each group were determined. Patients were assessed for safety and efficacy and followed up until death. Results Between February 2003 and July 2005, 25 patients were enrolled. Nineteen patients were randomised, 9 to the intravenous and 10 to the intra-arterial arms. In the intra-arterial arm, dose limiting toxicity was seen in 2/6 (33%) patients at 50 mCi whereas in the intravenous arm, dose limiting toxicity was noted in 1/6 patients at 50 mCi, but did not occur at 75 mCi (0/3). The overall response rate was 6% (1/18). Median overall survival was 5.2 months (95% confidence interval = 3.3 to 9 months), with no significant difference between the intravenous and intra-arterial arms (log rank test p = 0.79). One patient was still alive at the time of this analysis. Conclusion Dose limiting toxicity for KAb201 with I131 by the intra-arterial route was 50 mCi, while dose limiting toxicity was not reached in the intravenous arm. PMID:19243606

  12. Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG).

    PubMed

    Becker, Heiko; Suciu, Stefan; Rüter, Björn Hans; Platzbecker, Uwe; Giagounidis, Aristoteles; Selleslag, Dominik; Labar, Boris; Germing, Ulrich; Salih, Helmut R; Muus, Petra; Pflüger, Karl-Heinz; Hagemeijer, Anne; Schaefer, Hans-Eckart; Fiaccadori, Valeria; Baron, Frédéric; Ganser, Arnold; Aul, Carlo; de Witte, Theo; Wijermans, Pierre W; Lübbert, Michael

    2015-12-01

    In the European Organisation for Research and Treatment of Cancer (EORTC)/GMDSSG phase III trial 06011, we compared decitabine (15 mg/m(2) every 8 h for 3 days) with best supportive care (BSC) in patients ≥60 years with myelodysplastic syndromes (MDS) by French-American-British (FAB) criteria. Here, we reinvestigate trial 06011 for the activity and efficacy specifically in patients with refractory anemia with excess blasts in transformation (RAEBt). Response rates in the decitabine arm (N = 40) were as follows: complete or partial remission, 15 %; hematologic improvement, 15 %; resistant disease, 30 %. RAEBt patients in the decitabine arm had longer progression-free survival (PFS; hazard ratio (HR) 0.30, 95 % confidence interval (CI) 0.18-0.51; median, 6.2 vs 2.8 months) and overall survival (OS; HR 0.68, 95 % CI 0.42-1.11; median, 8.0 vs 6.0 months) than in the BSC arm (N = 35). Censoring at allogeneic hematopoietic stem cell transplantation, the OS difference between the treatment groups increased, particularly among patients aged 60-74 years (HR 0.48, 95 % CI 0.26-0.89). After regrouping the study cohort according to World Health Organization (WHO) criteria, patients with acute myeloid leukemia (AML) (i.e., ≥20 % blasts) in the decitabine arm (N = 27) also had longer PFS than in the BSC arm (N = 23) (HR 0.46, 95 % CI 0.26-0.83; median, 6.2 vs 2.8 months). In conclusion, 3-day decitabine displays clinical activity and efficacy in MDS and/or AML with 5-30 % blood or 20-30 % marrow blasts.

  13. Negative results in phase III trials of complex interventions: cause for concern or just good science?

    PubMed

    Crawford, Mike J; Barnicot, Kirsten; Patterson, Sue; Gold, Christian

    2016-07-01

    Not all interventions that show promise in exploratory trials will be supported in phase III studies. But the high failure rate in recent trials of complex mental health interventions is a concern. Proper consideration of trial processes and greater use of adaptive trial designs could ensure better use of available resources. PMID:27369475

  14. 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…

  15. 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 this report…

  16. 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.

  17. 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.

  18. 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…

  19. Does Zinc Sulfate Prevent Therapy-Induced Taste Alterations in Head and Neck Cancer Patients? Results of Phase III Double-Blind, Placebo-Controlled Trial from the North Central Cancer Treatment Group (N01C4)

    SciTech Connect

    Halyard, Michele Y.; Jatoi, Aminah . E-mail: Jatoi.aminah@mayo.edu; Sloan, Jeff A.; Bearden, James D.; Vora, Sujay A.; Atherton, Pamela J.; Perez, Edith A.; Soori, Gammi; Zalduendo, Anthony C.; Zhu, Angela; Stella, Philip J.; Loprinzi, Charles L.

    2007-04-01

    Purpose: Taste alterations (dysgeusia) are well described in head and neck cancer patients who undergo radiotherapy (RT). Anecdotal observations and pilot studies have suggested zinc may mitigate these symptoms. This multi-institutional, double-blind, placebo-controlled trial was conducted to provide definitive evidence of this mineral's palliative efficacy. Methods and Materials: A total of 169 evaluable patients were randomly assigned to zinc sulfate 45 mg orally three times daily vs. placebo. Treatment was to be given throughout RT and for 1 month after. All patients were scheduled to receive {>=}2,000 cGy of external beam RT to {>=}30% of the oral cavity, were able to take oral medication, and had no oral thrush at study entry. Changes in taste were assessed using the previously validated Wickham questionnaire. Results: At baseline, the groups were comparable in age, gender, and planned radiation dose (<6,000 vs. {>=}6,000 cGy). Overall, 61 zinc-treated (73%) and 71 placebo-exposed (84%) patients described taste alterations during the first 2 months (p = 0.16). The median interval to taste alterations was 2.3 vs. 1.6 weeks in the zinc-treated and placebo-exposed patients, respectively (p = 0.09). The reported taste alterations included the absence of any taste (16%), bitter taste (8%), salty taste (5%), sour taste (4%), sweet taste (5%), and the presence of a metallic taste (10%), as well as other descriptions provided by a write in response (81%). Zinc sulfate did not favorably affect the interval to taste recovery. Conclusion: Zinc sulfate, as prescribed in this trial, did not prevent taste alterations in cancer patients who were undergoing RT to the oral pharynx.

  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.

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

    PubMed Central

    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 (SBRT) in patients with painful osseous metastatic disease. Operating characteristics of the Institutional Review Board (IRB) approved design are demonstrated under various possible true scenarios via simulation studies. PMID:25962576

  2. An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants).

    PubMed

    Clarke, Joe T R; Mahuran, Don J; Sathe, Swati; Kolodny, Edwin H; Rigat, Brigitte A; Raiman, Julian A; Tropak, Michael B

    2011-01-01

    Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of ß-hexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay-Sachs variant) or the HEXB (Sandhoff variant) genes. The enzyme deficiency in many patients with juvenile or adult onset forms of the disease results from the production of an unstable protein, which becomes targeted for premature degradation by the quality control system of the smooth endoplasmic reticulum and is not transported to lysosomes. In vitro studies have shown that many mutations in either the α or β subunit of Hex A can be partially rescued, i.e. enhanced levels of both enzyme protein and activity in lysosomes, following the growth of patient cells in the presence of the drug, pyrimethamine. The objectives of the present clinical trial were to establish the tolerability and efficacy of the treatment of late-onset GM2 gangliosidosis patients with escalating doses of pyrimethamine, to a maximum of 100 mg per day, administered orally in a single daily dose, over a 16-week period . The primary objective, tolerability, was assessed by regular clinical examinations, along with a panel of hematologic and biochemical studies. Although clinical efficacy could not be assessed in this short trial, treatment efficacy was evaluated by repeated measurements of leukocyte Hex A activity, expressed relative to the activity of lysosomal ß-glucuronidase. A total of 11 patients were enrolled, 8 males and 3 females, aged 23 to 50 years. One subject failed the initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events which were not drug-related. For the remaining 8 subjects, up to a 4-fold enhancement of Hex A activity at doses of 50 mg per day or less was observed. Additionally marked individual variations in the pharmacokinetics of the drug among the patients were

  3. 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

  4. Maintenance of Clinical Efficacy and Radiographic Benefit Through Two Years of Ustekinumab Therapy in Patients With Active Psoriatic Arthritis: Results From a Randomized, Placebo‐Controlled Phase III Trial

    PubMed Central

    Puig, Lluís; Gottlieb, Alice B.; Ritchlin, Christopher; Li, Shu; Wang, Yuhua; Mendelsohn, Alan M.; Song, Michael; Zhu, Yaowei; Rahman, Proton; McInnes, Iain B.

    2015-01-01

    Objective To evaluate the efficacy and safety of ustekinumab through 2 years in adult patients with active psoriatic arthritis (PsA). Methods A total of 615 adult patients with active PsA were randomized to placebo, ustekinumab 45 mg, or ustekinumab 90 mg, at weeks 0, 4, and every 12 weeks through week 88 (last dose). At week 16, patients with <5% improvement in both tender and swollen joint counts entered blinded early escape (placebo to 45 mg, 45 mg to 90 mg, and 90 mg to 90 mg). All remaining placebo patients crossed over to ustekinumab 45 mg at week 24. Clinical efficacy measures included American College of Rheumatology criteria for 20% improvement (ACR20), Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP), and ≥75% improvement in the Psoriasis Area and Severity Index (PASI75). Radiographic progression was evaluated using the modified Sharp/van der Heijde score (SHS). Results At week 100, ACR20, DAS28‐CRP moderate/good response, and PASI75 rates ranged from 56.7–63.6%, 71.9–76.7%, and 63.9–72.5%, respectively, across the 3 treatment groups. In both ustekinumab groups, the median percent improvement in dactylitis and enthesitis was 100% at week 100. The mean changes in SHS score from week 52 to week 100 were similar to those observed from week 0 to week 52 in the ustekinumab groups. Through week 108, 70.7% and 9.7% of patients had an adverse event (AE) or serious AE, respectively. The rates and type of AEs were similar between the dose groups. Conclusion Clinical and radiographic benefits from ustekinumab treatment were maintained through week 100 in the PSUMMIT 1 study. No unexpected safety events were observed; the safety profile of ustekinumab in this population was similar to that previously observed in psoriasis patients treated with ustekinumab. PMID:26097039

  5. 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.

  6. Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia.

    PubMed

    Ghobrial, I M; Redd, R; Armand, P; Banwait, R; Boswell, E; Chuma, S; Huynh, D; Sacco, A; Roccaro, A M; Perilla-Glen, A; Noonan, K; MacNabb, M; Leblebjian, H; Warren, D; Henrick, P; Castillo, J J; Richardson, P G; Matous, J; Weller, E; Treon, S P

    2015-12-01

    We examined the combination of the mammalian target of rapamycin inhibitor everolimus with bortezomib and rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM) in a phase I/II study. All patients received six cycles of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab followed by maintenance with everolimus until progression. Forty-six patients were treated; 98% received prior rituximab and 57% received prior bortezomib. No dose-limiting toxicities were observed in the phase I. The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs. Of these 36, 2 (6%) had complete response (90% confidence interval (CI): 1-16). In all, 32/36 (89%) of patients experienced at least a minimal response (90% CI: 76-96%). The observed partial response or better response rate was 19/36 (53, 90 CI: 38-67%). For the 36 FDT patients, the median progression-free survival was 21 months (95% CI: 12-not estimable). In summary, this study demonstrates that the combination of everolimus, bortezomib and rituximab is well tolerated and achieved 89% response rate even in patients previously treated, making it a possible model of non-chemotherapeutic-based combination therapy in WM.

  7. 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.

  8. Delavirdine in Combination with Zidovudine in Treatment of Human Immunodeficiency Virus Type 1-Infected Patients: Evaluation of Efficacy and Emergence of Viral Resistance in a Randomized, Comparative Phase III Trial

    PubMed Central

    Joly, Véronique; Moroni, Mauro; Concia, Ercole; Lazzarin, Adriano; Hirschel, Bernard; Jost, Josef; Chiodo, Francesco; Bentwich, Zvi; Love, W. Campbell; Hawkins, David A.; Wilkins, Edmund G. L.; Gatell, Aritigas J.; Vetter, Norbert; Greenwald, Cynthia; Freimuth, William W.; de Cian, Wanda

    2000-01-01

    We compared the activity of delavirdine (DLV) plus zidovudine (AZT) (n = 300) with that of AZT (n = 297) against human immunodeficiency virus type 1 in a randomized, double-blind, placebo-controlled trial. DLV exerted a transient antiviral effect, and mutations for resistance to DLV were found in more than 90% of subjects at week 12. The K103N mutation, which confers nonnucleoside reverse transcriptase inhibitor cross-resistance, was found in 85% of the patients. PMID:11036040

  9. A phase I/II study of dose and administration of non-glycosylated bacterially synthesized G-M CSF in chemotherapy-induced neutropenia in patients with non-Hodgkin's lymphomas.

    PubMed

    Hovgaard, D; Nissen, N I

    1992-06-01

    Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) derived from E. coli was administered to 24 previously untreated patients with non-Hodgkin's lymphoma following the first cycle of CHOP chemotherapy. Four dose levels were examined, 1.5, 3.0, 5.5 and 11 micrograms/kg and patients were randomized to receive the drug either once or twice daily subcutaneously (s.c.). During rhGM-CSF treatment, the leucocyte counts increased up to 3-4 fold in 20/24 patients, reaching a peak 24-48 (mean 35) hours after initiation of rhGM-CSF. The leukopenic period in cycle one of the CHOP chemotherapy with rhGM-CSF, was shorter than after the course of chemotherapy without rhGM-CSF and also shorter when compared to cycle one of CHOP in the 127 historical controls (p < 0.05 and p < 0.001 respectively). Similar results were observed for neutrophil counts. No effect was seen on platelet counts at nadir but a significant, although moderate increase occurred in the recovery period on days 15 and 22 when compared to control cycles and historical controls. When dose levels were compared, there was only a trend to higher WBC counts at the higher dose groups (5.5 and 11 micrograms/kg) when compared to the two lower dose groups (1.5 and 3.0 micrograms/kg). In the overall evaluation there was no statistical significant difference in results between patients treated s.c. once daily versus twice daily. However when only the two highest dose levels (5.5 + 11 micrograms/kg) were compared, s.c. administration of rhGM-CSF twice daily led to higher leucocyte counts than once daily in the recovery period on day 15 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

  10. 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

  11. Thermodynamic analysis of III-V semiconductor alloys grown by metalorganic vapor phase epitaxy

    NASA Astrophysics Data System (ADS)

    Asai, Toshihiro; Dandy, David S.

    2000-10-01

    A thermodynamic analysis has been applied to systematically study III-V semiconductor alloy deposition, including nitrides grown by metalorganic vapor phase epitaxy. The predicted solid compositions of a number of ternary and quaternary alloys, including AlxGa1-xPyAs1-y, are compared with experimental data. For phosphorus-containing alloys, introduction of a parameter f representing incomplete PH3 pyrolysis yields good agreement with experimental data. It is shown that the input mole fraction of the group III metalorganic sources influences the incorporation of P into the solid for these alloys. Solid composition is also calculated for nitride alloys as a function of inlet gas concentration. To date, thermodynamic models have been applied solely to predict N solubility limits for nitride alloys where mixing occurs on the group V sublattice. The present model is used to predict N solid compositions in ternary and quaternary alloys, and it is demonstrated that these values are below the theoretical solubility limits for In-containing nitrides. The role of H2 in the carrier gas is investigated for III-N-V, III-III-N-V, and III-N-V-V systems.

  12. Efficacy and safety profile of combination of tramadol-diclofenac versus tramadol-paracetamol in patients with acute musculoskeletal conditions, postoperative pain, and acute flare of osteoarthritis and rheumatoid arthritis: a Phase III, 5-day open-label study

    PubMed Central

    Chandanwale, Ajay S; Sundar, Subramanian; Latchoumibady, Kaliaperumal; Biswas, Swati; Gabhane, Mukesh; Naik, Manoj; Patel, Kamlesh

    2014-01-01

    Objective We aimed to evaluate the safety and efficacy of a fixed-dose combination (FDC) of tramadol and diclofenac versus a standard approved FDC of tramadol and paracetamol, in patients with acute moderate to severe pain. Methods A total of 204 patients with moderate to severe pain due to acute musculoskeletal conditions (n=52), acute flare of osteoarthritis (n=52), acute flare of rheumatoid arthritis (n=50), or postoperative pain (n=50) were enrolled in the study at baseline. Each disease category was then randomized to receive either of two treatments for 5 days: group A received an FDC of immediate-release tramadol hydrochloride (50 mg) and sustained-release diclofenac sodium (75 mg) (one tablet, twice daily), and group B received an FDC of tramadol hydrochloride (37.5 mg) and paracetamol (325 mg) (two tablets every 4–6 hours, up to a maximum of eight tablets daily). The primary efficacy end points were reductions in pain intensity from baseline at day 3 and day 5 as assessed by a Visual Analog Scale (VAS) score. Results Group A showed a significant reduction in the VAS score for overall pain from baseline on day 3 (P=0.001) and day 5 (P<0.0001) as compared with group B. The combination of tramadol-diclofenac resulted in few mild to moderate adverse events (nausea, vomiting, epigastric pain, and gastritis), which required minimal management, without any treatment discontinuation. The number of adverse events in group A was nine (8.82%) compared with 22 (21.78%) in group B, after 5 days of treatment. Conclusion An FDC of tramadol-diclofenac showed a significantly greater reduction in pain intensity and was well tolerated compared with tramadol-paracetamol, resulting in better analgesia in patients suffering from moderate to severe pain due to acute musculoskeletal conditions, postoperative pain following orthopedic surgery, or acute flare of osteoarthritis and rheumatoid arthritis. PMID:25152629

  13. A Phase I/II Trial of Intensity Modulated Radiation (IMRT) Dose Escalation With Concurrent Fixed-dose Rate Gemcitabine (FDR-G) in Patients With Unresectable Pancreatic Cancer

    SciTech Connect

    Ben-Josef, Edgar; Schipper, Mathew; Francis, Isaac R.; Hadley, Scott; Ten-Haken, Randall; Lawrence, Theodore; Normolle, Daniel; Simeone, Diane M.; Sonnenday, Christopher; Abrams, Ross; Leslie, William; Khan, Gazala; Zalupski, Mark M.

    2012-12-01

    Purpose: Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by intensity modulated radiation with fixed-dose rate gemcitabine (FDR-G), freedom from local progression (FFLP), and overall survival (OS). Methods and Materials: Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status of 0-2, absolute neutrophil count of {>=}1500/mm{sup 3}, platelets {>=}100,000/mm{sup 3}, creatinine <2 mg/dL, bilirubin <3 mg/dL, and alanine aminotransferase/aspartate aminotransferase {<=}2.5 Multiplication-Sign upper limit of normal. FDR-G (1000 mg/m{sup 2}/100 min intravenously) was given on days -22 and -15, 1, 8, 22, and 29. Intensity modulated radiation started on day 1. Dose levels were escalated from 50-60 Gy in 25 fractions. Dose-limiting toxicity was defined as gastrointestinal toxicity grade (G) {>=}3, neutropenic fever, or deterioration in performance status to {>=}3 between day 1 and 126. Dose level was assigned using TITE-CRM (Time-to-Event Continual Reassessment Method) with the target dose-limiting toxicity (DLT) rate set to 0.25. Results: Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55 Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% confidence interval [CI]: 32-79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months. Conclusions: High-dose radiation therapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local

  14. A Phase III, Randomized, Non-Inferiority Trial to Assess the Efficacy and Safety of Dihydroartemisinin-Piperaquine in Comparison with Artesunate-Mefloquine in Patients with Uncomplicated Plasmodium falciparum Malaria in Southern Laos

    PubMed Central

    Mayxay, Mayfong; Keomany, Sommay; Khanthavong, Maniphone; Souvannasing, Phoutthalavanh; Stepniewska, Kasia; Khomthilath, Tiengthong; Keola, Siamphay; Pongvongsa, Tiengkham; Phompida, Samlane; Ubben, David; Valecha, Neena; White, Nicholas J.; Newton, Paul N.

    2010-01-01

    We conducted an open, randomized clinical trial of oral dihydroartemisinin-piperaquine (DP) versus artesunate-mefloquine (AM) in 300 patients in Laos with uncomplicated Plasmodium falciparum malaria as part of a multicentre study in Asia. Survival analysis and adjustment for re-infection showed that the 63-day cure rates (95% confidence interval [CI]) were 100% for AM and 99.5% (96.4–99.8%) for DP. The 63-day cure rates per protocol were 99% (97 of 98) for AM and 99.5% (196 of 197) for DP (P = 0.55). The difference (AM minus DP) in cure rates (95% CI) was −0.5% (−5.1 to 2.0%), which is within the 5% non-inferiority margin. The median fever and parasite clearance times were also similar for AM and DP. The proportion of patients with at least one recorded potential adverse event was significantly higher in the AM group (38 of 87, 44%) than in the DP group (57 of 182, 31%) (relative risk = 0.6, 95% CI = 0.4–0.9; P = 0.04). Dihydroartemisinin-piperaquine is not inferior to AM in the treatment of uncomplicated P. falciparum malaria in Laos and is associated with fewer adverse effects. The results of this study were similar to those of the larger multicentre study. PMID:21118925

  15. Predicted band structures of III-V semiconductors in the wurtzite phase

    SciTech Connect

    De, A.; Pryor, Craig E.

    2010-04-15

    While non-nitride III-V semiconductors typically have a zinc-blende structure, they may also form wurtzite crystals under pressure or when grown as nanowhiskers. This makes electronic structure calculation difficult since the band structures of wurtzite III-V semiconductors are poorly characterized. We have calculated the electronic band structure for nine III-V semiconductors in the wurtzite phase using transferable empirical pseudopotentials including spin-orbit coupling. We find that all the materials have direct gaps. Our results differ significantly from earlier ab initio calculations, and where experimental results are available (InP, InAs, and GaAs) our calculated band gaps are in good agreement. We tabulate energies, effective masses, and linear and cubic Dresselhaus zero-field spin-splitting coefficients for the zone-center states. The large zero-field spin-splitting coefficients we find may facilitate the development of spin-based devices.

  16. 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

  17. Solid-phase synthesis of protected peptides using new cobalt(III) ammine linkers.

    PubMed

    Arbo, B E; Isied, S S

    1993-08-01

    Cobalt(III) ammine complexes of the type cis-[CoL4(4-AMB)O-AA-Boc](CF3SO3)2, where L4 = bisethylenediamine (en)2 or tetraammine (NH3)4, and 4-AMB = 4-(aminomethyl)benzoic acid, have been synthesized and used as linkers to polystyrene resins for solid-phase synthesis of protected peptides. Boc/t-Bu-protected [Leu5]enkephalin was assembled on the two different Co(III) resins, and then cleaved from the resins by reduction of the Co(III) center in 93-96% yield. HPLC-purified protected [Leu5]enkephalin was obtained in 67-69% overall yield and characterized by amino acid analysis and 1H NMR. Stepwise synthesis on the Co(en)2-resin was also used in the assembly of Boc-Asp(OcHex)-Arg(Mts)-Gly-Asp(OcHex)-Ala-Pro-Lys(2Cl-Z)-Gl y-OH, a sequence from collagen alpha 1 Type 1. The protected peptide was cleaved from the Co(III) resin in 74% yield, and the HPLC-purified nonapeptide was characterized by amino acid analysis, 1H NMR and liquid secondary-ion mass spectrometry (LSIMS). New routes are described for the synthesis of isomerically pure Co(III) anchor complexes. The Co(III) resins were found to be compatible with both the tert-butyloxycarbonyl (Boc) and the 9-fluorenylmethoxycarbonyl (Fmoc) N alpha-protecting group strategies used in solid-phase peptide synthesis.

  18. Phase variable type III restriction-modification systems of host-adapted bacterial pathogens.

    PubMed

    Fox, Kate L; Srikhanta, Yogitha N; Jennings, Michael P

    2007-09-01

    Phase variation, the high-frequency on/off switching of gene expression, is a common feature of host-adapted bacterial pathogens. Restriction-modification (R-M) systems, which are ubiquitous among bacteria, are classically assigned the role of cellular defence against invasion of foreign DNA. These enzymes are not obvious candidates for phase variable expression, a characteristic usually associated with surface-expressed molecules subject to host immune selection. Despite this, numerous type III R-M systems in bacterial pathogens contain repetitive DNA motifs that suggest the potential for phase variation. Several roles have been proposed for phase variable R-M systems based on DNA restriction function. However, there is now evidence in several important human pathogens, including Haemophilus influenzae, Neisseria meningitidis and Neisseria gonorrhoeae, that these systems are 'phasevarions' (phase variable regulons) controlling expression of multiple genes via a novel epigenetic mechanism. PMID:17714447

  19. An orthodontic/orthopedic correction of the Class III malocclusion in young patients with a modified RPE appliance and a facemask.

    PubMed

    Park, Jae Hyun; Cruz, Claudia; Alexander, R G

    2010-01-01

    Orthopedic appliances such as palatal expanders and facemasks have been successfully used for young patients with Class III malocclusions. A modified rapid palatal expansion (RPE) appliance in conjunction with a facemask can be used for correction of transverse and sagittal discrepancies in the initial phase of treatment for these patients.

  20. Certolizumab Pegol Efficacy Across Methotrexate Regimens: A Pre‐Specified Analysis of Two Phase III Trials

    PubMed Central

    Furst, Daniel E.; Keystone, Edward C.; van der Heijde, Désirée; Luijtens, Kristel; Ionescu, Lucian; Goel, Niti; Emery, Paul

    2016-01-01

    Objective Anti–tumor necrosis factor (anti‐TNF) agents are frequently used in combination with methotrexate (MTX) to treat rheumatoid arthritis (RA). We investigated the effect of a background MTX dose, in combination with anti‐TNF certolizumab pegol (CZP), on treatment efficacy and safety in RA patients. Methods A pre‐specified subgroup analysis comparing 2 MTX dosage categories (<15 mg/week and ≥15 mg/week) was carried out using data pooled from phase III clinical trials, Rheumatoid Arthritis Prevention of Structural Damage 1 (RAPID 1) and RAPID 2, according to treatment group: CZP 200 mg, CZP 400 mg, or placebo, every 2 weeks. Inclusion criteria required MTX dosage ≥10 mg/week. Efficacy end points included week 24 American College of Rheumatology criteria for 20%, 50%, and 70% improvement (ACR20/50/70) responses analyzed by logistic regression, and changes from baseline in the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28‐ESR) and the modified Sharp/van der Heijde score (SHS) were analyzed by analysis of covariance. Incidence rates of treatment‐emergent adverse events (TEAEs) were categorized by baseline MTX dose. Post hoc sensitivity analysis investigated 3 MTX dose categories: ≤10 mg/week, >10 and ≤15 mg/week, and >15 mg/week. Results A total of 638, 635, and 325 patients received CZP 200 mg, CZP 400 mg, and placebo, respectively. At week 24, treatment responses in both CZP groups were uninfluenced by baseline MTX dose category, and were superior to the placebo group for all investigated end points: ACR20/50/70, DAS28‐ESR, and SHS. TEAE incidence rates were higher in patients receiving MTX ≥15 mg/week for most TEAE types across treatment groups. Conclusion CZP efficacy was not affected by background MTX dose category. It can be hypothesized that to minimize TEAEs, background MTX doses could be tailored to individual patient tolerance without affecting CZP efficacy. PMID:26238672

  1. Effect of licorice on the induction of phase II metabolizing enzymes and phase III transporters and its possible mechanism.

    PubMed

    Gong, Hui; Li, Huan-De; Yan, Miao; Zhang, Bi-Kui; Jiang, Pei; Fan, Xin-Rong; Deng, Yang

    2014-12-01

    Licorice has a marked detoxifying effect that can treat drug poisoning and/or relieve adverse effects. However, the exact mechanism of this action is not entirely elucidated, but is believed to be related to the modulation of drug disposition when interacting with other drugs. Additionally, Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a significant role in mediating phase II xenobiotic metabolizing enzymes (XMEs) and phase III transporters. In the present study, we showed that licorice induced the mRNA expression of phase II XMEs UDP-glucuronosyltransferases 1A1 (UGT1A1), glutamate cysteine ligase (GCL), glutathione-s-transferase (GST) and phase III transporters multidrug resistance protein 2 (MRP2), as well as a rapid increase in Nrf2 nuclear accumulation. These findings suggests that licorice may intervene in the Nrf2 signal pathway to induce UGT1A1, GCLC, GST and MRP2, which provide a novel mechanism for the use of licorice to treat drug poisoning and/or relieve adverse effects. PMID:25951662

  2. Alirocumab for hyperlipidemia: ODYSSEY Phase III clinical trial results and US FDA approval indications.

    PubMed

    Roth, Eli M

    2016-03-01

    A new class of lipid-lowering drugs, inhibitors of PCSK9 has been generating impressive clinical trial data over the last several years, and alirocumab (Praluent) has become the first to be approved by the US FDA. Alirocumab has been shown to lower low density lipoprotein cholesterol by 45-62% with a safety profile generally comparable to placebo. Alirocumab is a monoclonal antibody to PCSK9 administered subcutaneously and has been evaluated in 16 Phase III clinical trials, the majority of which have been enrolled or completed. This article will be a review of the available Phase III safety and efficacy data of the ODYSSEY studies including a brief description of each of the 16 studies. PMID:26785741

  3. Evaluation of the prognostic role of centromere 17 gain and HER2/topoisomerase II alpha gene status and protein expression in patients with breast cancer treated with anthracycline-containing adjuvant chemotherapy: pooled analysis of two Hellenic Cooperative Oncology Group (HeCOG) phase III trials

    PubMed Central

    2013-01-01

    Background The HER2 gene has been established as a valid biological marker for the treatment of breast cancer patients with trastuzumab and probably other agents, such as paclitaxel and anthracyclines. The TOP2A gene has been associated with response to anthracyclines. Limited information exists on the relationship of HER2/TOP2A gene status in the presence of centromere 17 (CEP17) gain with outcome of patients treated with anthracycline-containing adjuvant chemotherapy. Methods Formalin-fixed paraffin-embedded tumor tissue samples from 1031 patients with high-risk operable breast cancer, enrolled in two consecutive phase III trials, were assessed in a central laboratory by fluorescence in situ hybridization for HER2/TOP2A gene amplification and CEP17 gain (CEP17 probe). Amplification of HER2 and TOP2A were defined as a gene/CEP17 ratio of >2.2 and ≥2.0, respectively, or gene copy number higher than 6. Additionally, HER2, TopoIIa, ER/PgR and Ki67 protein expression was assessed by immunohistochemistry (IHC) and patients were classified according to their IHC phenotype. Treatment consisted of epirubicin-based adjuvant chemotherapy followed by hormonal therapy and radiation, as indicated. Results HER2 amplification was found in 23.7% of the patients and TOP2A amplification in 10.1%. In total, 41.8% of HER2-amplified tumors demonstrated TOP2A co-amplification. The median (range) of HER2, TOP2A and CEP17 gain was 2.55 (0.70-45.15), 2.20 (0.70-26.15) and 2.00 (0.70-26.55), respectively. Forty percent of the tumors had CEP17 gain (51% of those with HER2 amplification). Adjusting for treatment groups in the Cox model, HER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with time to relapse or time to death. Conclusion HER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with outcome in high-risk breast cancer patients treated with anthracycline-based adjuvant

  4. 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.

  5. 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.

  6. 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).

  7. Large fraction radiotherapy plus misonidazole for treatment of advanced lung cancer: report of a phase I/II trial

    SciTech Connect

    Simpson, J.R.; Perez, C.A.; Phillips, T.L.; Concannon, J.P.; Carella, R.J.

    1982-02-01

    From August 1978 through December 1979, 51 patients with advanced non-oat cell carcinoma of the lung were enrolled in a Phase I/II trial sponsored by the Radiation Therapy Oncology Group (RTOG) employing misonidazole (a 2-nitroimidazole) as a hypoxic cell sensitizer and radiation. The purpose of this study was to test drug and radiation tolerance and to assess the short term efficacy of this unconventional treatment. Tumor doses of 600 rad were given twice weekly for three weeks for a total of 3600 rad, preceded four to six hours by misonidazole in a dose of 2 gm/m/sup 2/ or 1.75 gm/m/sup 2/, administered orally. Forty-nine patients were evaluable. Serious toxicity from this treatment was rare. Grade 2 or 3 peripheral neuro-toxicity occurred in eight of 24 patients (33%) with drug doses of 2 gm/m/sup 2/ and in four of 26 patients (15%) who received 1.75 gm/m/sup 2/. Grade 3 or 4 central nervous system toxicity occurred in two patients. Two patients developed serious late radiation complications: one patient had a transverse myelitis that appeared one year following delivery of 3600 rad to the spinal cord; a second patient developed a tracheoesophageal fistula and pericarditis eight months following treatment. Objective responses were reported in 67% of patients (complete in 18%); 70% of the patients died with a median survival time of nine months. Of 32 patients eligible for 12 month follow-up, 34% survived more than one year. Patterns of relapse after initial treatment and comparison with results from other RTOG trials using conventional fractionation are discussed.

  8. Breast cancer follow-up strategies in randomized phase III adjuvant clinical trials: a systematic review

    PubMed Central

    2013-01-01

    The effectiveness of different breast cancer follow-up procedures to decrease breast cancer mortality are still an object of debate, even if intensive follow-up by imaging modalities is not recommended by international guidelines since 1997. We conducted a systematic review of surveillance procedures utilized, in the last ten years, in phase III randomized trials (RCTs) of adjuvant treatments in early stage breast cancer with disease free survival as primary endpoint of the study, in order to verify if a similar variance exists in the scientific world. Follow-up modalities were reported in 66 RCTs, and among them, minimal and intensive approaches were equally represented, each being followed by 33 (50%) trials. The minimal surveillance regimen is preferred by international and North American RCTs (P = 0.001) and by trials involving more than one country (P = 0.004), with no relationship with the number of participating centers (P = 0.173), with pharmaceutical industry sponsorship (P = 0.80) and with trials enrolling > 1000 patients (P = 0.14). At multivariate regression analysis, only geographic location of the trial was predictive for a distinct follow-up methodology (P = 0.008): Western European (P = 0.004) and East Asian studies (P = 0.010) use intensive follow-up procedures with a significantly higher frequency than international RCTs, while no differences have been detected between North American and international RCTs. Stratifying the studies according to the date of beginning of patients enrollment, before or after 1998, in more recent RCTs the minimal approach is more frequently followed by international and North American RCTs (P = 0.01), by trials involving more than one country (P = 0.01) and with more than 50 participating centers (P = 0.02). It would be highly desirable that in the near future breast cancer follow-up procedures will be homogeneous in RCTs and everyday clinical settings. PMID:24438135

  9. 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.

  10. 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.

  11. 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)

  12. An Application of Graphical Approach to Construct Multiple Testing Procedures in a Hypothetical Phase III Design

    PubMed Central

    Wang, Bushi; Ting, Naitee

    2014-01-01

    Many multiple testing procedures (MTP) have been developed in recent years. Among these new procedures, the graphical approach is flexible and easy to communicate with non-statisticians. A hypothetical Phase III clinical trial design is introduced in this manuscript to demonstrate how graphical approach can be applied in clinical product development. In this design, an active comparator is used. It is thought that this test drug under development could potentially be superior to this comparator. For comparison of efficacy, the primary endpoint is well established and widely accepted by regulatory agencies. However, an important secondary endpoint based on Phase II findings looks very promising. The target dose may have a good opportunity to deliver superiority to the comparator. Furthermore, a lower dose is included in case the target dose may demonstrate potential safety concerns. This Phase III study is designed as a non-inferiority trial with two doses, and two endpoints. This manuscript will illustrate how graphical approach is applied to this design in handling multiple testing issues. PMID:24432299

  13. Equilibrium Phase Diagrams for Stranski-Krastanov Structure Mode of III V Ternary Quantum Dots

    NASA Astrophysics Data System (ADS)

    Nakajima, Kazuo

    1999-04-01

    The strain, surface and interfacial energies of III V ternary systems were calculated for three kinds of structure modes: the Frank-van der Merwe (FM) mode, the Stranski-Krastanov (SK) mode and the Volmer-Weber (VW) mode. The free energy for each mode was estimated as functions of the thickness and composition or lattice misfit. Through comparison of the free energy of each mode, it was found that the thickness-composition phase diagrams of III V ternary systems can be determined only by considering the balance of the free energy and three kinds of structure modes appear in the phase diagrams. The SK mode appears only when the lattice misfit is large and/or the lattice layer is thick. The VW mode appears when the lattice misfit is large and the lattice layer is thin and only in the InPSb/InP and GaPSb/GaP systems which have the largest lattice misfit of III V ternary systems. The stable region of the SK mode in the GaPSb/GaP and InPSb/InP phase diagrams is largest of all because the composition dependence of the strain energy of these systems is stronger than that of the other systems. The critical number of lattice layers below which two-dimensional (2D) layers precede the three-dimensional (3D) nucleation in the SK mode at x=1.0 depends on the lattice misfit. In the InPSb/InP system, the smallest number of 2D layers precede the 3D nucleation in the SK mode.

  14. Power and Sample Size for Randomized Phase III Survival Trials under the Weibull Model

    PubMed Central

    Wu, Jianrong

    2015-01-01

    Two parametric tests are proposed for designing randomized two-arm phase III survival trials under the Weibull model. The properties of the two parametric tests are compared with the non-parametric log-rank test through simulation studies. Power and sample size formulas of the two parametric tests are derived. The impact on sample size under mis-specification of the Weibull shape parameter is also investigated. The study can be designed by planning the study duration and handling nonuniform entry and loss to follow-up under the Weibull model using either the proposed parametric tests or the well known non-parametric log-rank test. PMID:24895942

  15. Forming your phase III trial's data and safety monitoring board: a perspective on safety.

    PubMed

    Wittes, Janet

    2004-11-01

    A data safety monitoring board (DSMB) established in a phase III trial to monitor the safety of participants in a clinical trial views itself as protecting participants and ensuring the integrity of the study. The DSMB should operate under a clear charter, with expectations understood by all members of the Board, the sponsor, and the investigators. Sponsors must trust their DSMBs. The sponsor must give the DSMB the tools and the data that it needs to operate effectively in protecting the safety of the participants.

  16. 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

  17. Design of the randomized, Phase III, QUAZAR AML Maintenance trial of CC-486 (oral azacitidine) maintenance therapy in acute myeloid leukemia.

    PubMed

    Roboz, Gail J; Montesinos, Pau; Selleslag, Dominik; Wei, Andrew; Jang, Jun-Ho; Falantes, Jose; Voso, Maria T; Sayar, Hamid; Porkka, Kimmo; Marlton, Paula; Almeida, Antonio; Mohan, Sanjay; Ravandi, Farhad; Garcia-Manero, Guillermo; Skikne, Barry; Kantarjian, Hagop

    2016-02-01

    Older patients with acute myeloid leukemia (AML) have worse rates of complete remission and shorter overall survival than younger patients. The epigenetic modifier CC-486 is an oral formulation of azacitidine with promising clinical activity in patients with AML in Phase I studies. The Phase III, randomized, double-blind, placebo-controlled QUAZAR AML Maintenance trial (CC-486-AML-001) examines CC-486 maintenance therapy (300 mg/day for 14 days of 28-day treatment cycles) for patients aged ≥55 years with AML in first complete remission. The primary end point is overall survival. Secondary end points include relapse-free survival, safety, health-related quality of life and healthcare resource utilization. This trial will investigate whether CC-486 maintenance can prolong remission and improve survival for older patients with AML.

  18. [Prophylactic use of icatibant before tracheal intubation of a patient with hereditary angioedema type III. (A literature review of perioperative management of patients with hereditary angioedema type III)].

    PubMed

    Iturri Clavero, F; González Uriarte, A; Tamayo Medel, G; Gamboa Setién, P M

    2014-01-01

    Type III hereditary angioedema is a rare familial disorder that has recently been described as a separate condition. Triggers for episodes of angioedema include surgery, dental procedures, and tracheal intubation maneuvers. Since episodes affecting the upper airway are potentially life-threatening, prophylactic treatment is recommended in these situations. The use of icatibant (Firazyr(®)), for prevention of angioedema prior to tracheal intubation, is reported in a patient with type iii hereditary angioedema. A literature review on the anesthetic management of this condition was conducted.

  19. 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.

  20. 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. PMID:21851796

  1. 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.

  2. Immunologic Escape After Prolonged Progression-Free Survival With Epidermal Growth Factor Receptor Variant III Peptide Vaccination in Patients With Newly Diagnosed Glioblastoma

    PubMed Central

    Sampson, John H.; Heimberger, Amy B.; Archer, Gary E.; Aldape, Kenneth D.; Friedman, Allan H.; Friedman, Henry S.; Gilbert, Mark R.; Herndon, James E.; McLendon, Roger E.; Mitchell, Duane A.; Reardon, David A.; Sawaya, Raymond; Schmittling, Robert J.; Shi, Weiming; Vredenburgh, James J.; Bigner, Darell D.

    2010-01-01

    Purpose Immunologic targeting of tumor-specific gene mutations may allow precise eradication of neoplastic cells without toxicity. Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively activated and immunogenic mutation not expressed in normal tissues but widely expressed in glioblastoma multiforme (GBM) and other neoplasms. Patients and Methods A phase II, multicenter trial was undertaken to assess the immunogenicity of an EGFRvIII-targeted peptide vaccine and to estimate the progression-free survival (PFS) and overall survival (OS) of vaccinated patients with newly diagnosed EGFRvIII-expressing GBM with minimal residual disease. Intradermal vaccinations were given until toxicity or tumor progression was observed. Sample size was calculated to differentiate between PFS rates of 20% and 40% 6 months after vaccination. Results There were no symptomatic autoimmune reactions. The 6-month PFS rate after vaccination was 67% (95% CI, 40% to 83%) and after diagnosis was 94% (95% CI, 67% to 99%; n = 18). The median OS was 26.0 months (95% CI, 21.0 to 47.7 months). After adjustment for age and Karnofsky performance status, the OS of vaccinated patients was greater than that observed in a control group matched for eligibility criteria, prognostic factors, and temozolomide treatment (hazard ratio, 5.3; P = .0013; n = 17). The development of specific antibody (P = .025) or delayed-type hypersensitivity (P = .03) responses to EGFRvIII had a significant effect on OS. At recurrence, 82% (95% CI, 48% to 97%) of patients had lost EGFRvIII expression (P < .001). Conclusion EGFRvIII-targeted vaccination in patients with GBM warrants investigation in a phase III, randomized trial. PMID:20921459

  3. 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

  4. Evaluation of a method for arsenic(III) and antimony(III) determination by vapour phase molecular absorption spectrometry using graphite furnace volati

    NASA Astrophysics Data System (ADS)

    Galban, J.; Marcos, E.; Lamana, J.; Castillo, J. R.

    1993-01-01

    This paper presents a procedure for determining As(III) and Sb(III) by vapour phase molecular absorption spectrometry (VPMAS). The chlorides of these elements are volatilized from aqueous solutions in a L'vov platform inside the graphite furnace of an atomic absorption spectrophotometer. Molecular absorption is measured at 205 nm for arsenic chloride and 220 nm for antimony chloride. Both species are formed in the sample drying stage. A study of the temperature program led to different results in each case. In the case of arsenic, a two-step program (one mixed drying and volatilization step, and another cleaning step) is found to be best, whereas in the case of antimony, three separate steps can be used (drying, volatilization and cleaning). In both cases, optimum volatilization was obtained with low HCl concentrations, and volatilization fell off sharply as HCl concentration increased. Under optimum generation and determination conditions, the linear response range is from 0.06 to 3.75 μg for As(III), and from 0.30 to 5.0 μg for Sb(III) with relative standard deviations of 2.1% for As(III) and 2.5% for Sb(III). The effect of other anions and cations on the arsenic analytical signal was studied, and other halides were found to interfere. The method was applied to arsenic determination in an arsenic ore.

  5. 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.

  6. Defect Analysis in III-V Semiconductor Thin Films Grown by Hydride Vapor Phase Epitaxy

    NASA Astrophysics Data System (ADS)

    Schulte, Kevin Louis

    Hydride vapor phase epitaxy (HVPE) is an epitaxial growth technique renowned for its ability to grow III-V semiconductors at high growth rates using lower cost reagents compared to metal-organic vapor phase epitaxy (MOVPE), the current industry standard. Recent interest in III-V photovoltaics has led to increased attention on HVPE. While the technique came to maturity in the 70s, much is unknown about how defects incorporate in HVPE-grown materials. Further understanding of how defects incorporate in III-V materials grown by HVPE is necessary to facilitate wider adoption of the technique. This information would inform strategies for minimizing and eliminating defects in HVPE materials, allowing for the formation of high performance devices. This investigation presents a study of multiple defects in III-V semiconductors grown by HVPE in the context of specific device applications, spanning point defects comprised of individual atoms to extended defects which propagate throughout the crystal. The incorporation of the arsenic anti-site defect, AsGa, intrinsic point defect was studied in high growth rate GaAs layers with potential photovoltaic applications. Relationships between growth conditions and incorporation of AsGa in GaAs epilayers were determined. The incorporation of AsGa depended strongly on the growth conditions employed, and a model was developed to predict the concentration of anti-site defects as a function of those growth conditions. Dislocations and anti-phase domain boundaries (APDBs), two types of extended defects, were investigated in the heteroepitaxial GaAs/Ge system. It was found that the use of 6° miscut substrates and specific growth temperatures led to elimination of APDBs. Dislocation densities were reduced through the use of high growth temperatures. The third and final application investigated was the growth of InxGa1-xAs metamorphic buffer layers (MBLs) by HVPE. The relationships between the growth conditions and the alloy composition

  7. Clinical modulation of doxorubicin resistance by the calmodulin-inhibitor, trifluoperazine: a phase I/II trial.

    PubMed

    Miller, R L; Bukowski, R M; Budd, G T; Purvis, J; Weick, J K; Shepard, K; Midha, K K; Ganapathi, R

    1988-05-01

    Drug resistance to chemotherapy agents such as doxorubicin appears to be an important cause of therapeutic failure in cancer treatment. Based on preclinical information demonstrating that the phenothiazine calmodulin-inhibitor trifluoperazine can enhance retention and cytotoxicity of doxorubicin in resistant cells, a phase I/II trial of the combination was performed to determine the maximally tolerated dose (MTD) of trifluoperazine that could be administered with doxorubicin. Patients with intrinsic (no previous response) and acquired (previous response with relapse) doxorubicin resistance were eligible. Doxorubicin was administered as a 96-hour continuous infusion (60 mg/m2) on days 2 through 5. Trifluoperazine was administered in divided doses orally on days 1 through 6, with dose escalation from 20 to 100 mg/d. Thirty-six patients were evaluable. The MTD of trifluoperazine was 60 mg/d, with dose-limiting toxicity being extrapyramidal side effects. No alteration of doxorubicin toxicity was observed. Seven of the 36 patients responded (one complete response [CR], six partial responses [PR]), with seven of 21 patients having acquired resistance, and zero of 15 with intrinsic resistance demonstrating responses. Doxorubicin plasma levels were not affected by trifluoperazine, and the maximal trifluoperazine plasma levels achieved were 129.83 ng/mL. This trial demonstrates the combination of trifluoperazine and doxorubicin is well tolerated, and the schedule recommended for phase II trials is doxorubicin, 60 mg/m2 (continuous infusion) days 2 through 5, and trifluoperazine, 15 mg four times per day orally days 1 through 6. Continued investigation of this combination is indicated for patients with acquired doxorubicin resistance.

  8. Treatment Options for Class III Malocclusion in Growing Patients with Emphasis on Maxillary Protraction

    PubMed Central

    Azamian, Zeinab; Shirban, Farinaz

    2016-01-01

    It is very difficult to diagnose and treat Class III malocclusion. This type of malocclusion involves a number of cranial base and maxillary and mandibular skeletal and dental compensation components. In Class III malocclusion originating from mandibular prognathism, orthodontic treatment in growing patients is not a good choice and in most cases orthognathic surgery is recommended after the end of growth. Approximately 30–40% of Class III patients exhibit some degree of maxillary deficiency; therefore, devices can be used for maxillary protraction for orthodontic treatment in early mixed dentition. In cases in which dental components are primarily responsible for Class III malocclusion, early therapeutic intervention is recommended. An electronic search was conducted using the Medline database (Entrez PubMed), the Cochrane Collaboration Oral Health Group Database of Clinical Trials, Science Direct, and Scopus. In this review article, we described the treatment options for Class III malocclusion in growing patient with an emphasis on maxillary protraction. It seems that the most important factor for treatment of Class III malocclusion in growing patient is case selection. PMID:27144056

  9. 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.

  10. Whole Brain Radiotherapy and RRx-001: Two Partial Responses in Radioresistant Melanoma Brain Metastases from a Phase I/II Clinical Trial12

    PubMed Central

    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.

    2016-01-01

    BACKGROUND: 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. SIGNIFICANCE: 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. PMID:27084426

  11. New approach of maxillary protraction using modified C-palatal plates in Class III patients

    PubMed Central

    Bayome, Mohamed; Park, Jae Hyun; Kim, Ki Beom; Kim, Seong-Hun; Chung, Kyu-Rhim

    2015-01-01

    Maxillary protraction is the conventional treatment for growing Class III patients with maxillary deficiency, but it has undesirable dental effects. The purpose of this report is to introduce an alternative modality of maxillary protraction in patients with dentoskeletal Class III malocclusion using a modified C-palatal plate connected with elastics to a face mask. This method improved skeletal measurements, corrected overjet, and slightly improved the profile. The patients may require definitive treatment in adolescence or adulthood. The modified C-palatal plate enables nonsurgical maxillary advancement with maximal skeletal effects and minimal dental side effects. PMID:26258067

  12. 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.

  13. 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

  14. Time to Treatment in Patients With Stage III Non-Small Cell Lung Cancer

    SciTech Connect

    Wang Li; Correa, Candace R.; Hayman, James A.; Zhao Lujun; Cease, Kemp; Brenner, Dean; Arenberg, Doug; Curtis, Jeffery; Kalemkerian, Gregory P.; Kong, F.-M.

    2009-07-01

    Purpose: To determine whether time to treatment (TTT) has an effect on overall survival (OS) in patients with unresectable or medically inoperable Stage III non-small cell lung cancer (NSCLC) and whether patient or treatment factors are associated with TTT. Methods and Materials: Included in the study were 237 consecutive patients with Stage III NSCLC treated at University of Michigan Hospital (UM) or the Veterans Affairs Ann Arbor Healthcare System (VA). Patients were treated with either palliative or definitive radiotherapy and radiotherapy alone (n = 106) or either sequential (n = 69) or concurrent chemoradiation (n = 62). The primary endpoint was OS. Results: Median follow-up was 69 months, and median TTT was 57 days. On univariate analysis, the risk of death did not increase significantly with longer TTT (p = 0.093). However, subset analysis showed that there was a higher risk of death with longer TTT in patients who survived {>=} 5 years (p = 0.029). Younger age (p = 0.027), male sex (p = 0.013), lower Karnofsky Performance Score (KPS) (p = 0.002), and treatment at the VA (p = 0.001) were significantly associated with longer TTT. However, on multivariate analysis, only lower KPS remained significantly associated with longer TTT (p = 0.003). Conclusion: Time to treatment is significantly associated with OS in patients with Stage III NSCLC who lived longer than 5 years, although it is not a significant factor in Stage III patients as a whole. Lower KPS is associated with longer TTT.

  15. 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

  16. Phase I/II Clinical Evaluation of StrataGraft: A Consistent, Pathogen-Free Human Skin Substitute

    PubMed Central

    Schurr, Michael J.; Foster, Kevin N.; Centanni, John M.; Comer, Allen R.; Wicks, April; Gibson, Angela L.; Thomas-Virnig, Christina L.; Schlosser, Sandy J.; Faucher, Lee D.; Lokuta, Mary A.; Allen-Hoffmann, B. Lynn

    2009-01-01

    Background Large wounds often require temporary allograft placement to optimize the wound bed and prevent infection until permanent closure is feasible. We developed and clinically tested a second-generation living human skin substitute (StrataGraft). StrataGraft provides both a dermis and a fully-stratified, biologically-functional epidermis generated from a pathogen-free, long-lived human keratinocyte progenitor cell line, Neonatal Immortalized KeratinocyteS (NIKS). Methods Histology, electron microscopy, quantitative polymerase chain reaction, and bacterial growth in vitro were used to analyze human skin substitutes generated from primary human keratinocytes or NIKS cells. A phase I/II, National Institute of Health-funded, randomized, safety, and dose escalation trial was performed to assess autograft take in 15 patients 2 weeks after coverage with StrataGraft skin substitute or cryopreserved cadaver allograft. Results StrataGraft skin substitute exhibited a fully stratified epidermis with multilamellar lipid sheets and barrier function as well as robust human β defensin-3 mRNA levels. Analysis of the primary endpoint in the clinical study revealed no differences in autograft take between wound sites pretreated with StrataGraft skin substitute or cadaver allograft. No StrataGraft-related adverse events or serious adverse events were observed. Conclusions The major finding of this phase I/II clinical study is that performance of StrataGraft skin substitute was comparable to cadaver allograft for the temporary management of complex skin defects. StrataGraft skin substitute may also eliminate the risk for disease transmission associated with allograft tissue and offer additional protection to the wound bed through inherent antimicrobial properties. StrataGraft is a pathogen-free human skin substitute that is ideal for the management of severe skin wounds before autografting. PMID:19276766

  17. 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.

  18. 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.

  19. Flexible design of two-stage adaptive procedures for phase III clinical trials.

    PubMed

    Koyama, Tatsuki

    2007-07-01

    The recent popularity of two-stage adaptive designs has fueled a number of proposals for their use in phase III clinical trials. Many of these designs assign certain restrictive functional forms to the design elements of stage 2, such as sample size, critical value and conditional power functions. We propose a more flexible method of design without imposing any particular functional forms on these design elements. Our methodology permits specification of a design based on either conditional or unconditional characteristics, and allows accommodation of sample size limit. Furthermore, we show how to compute the P value, confidence interval and a reasonable point estimate for any design that can be placed under the proposed framework. PMID:17307399

  20. Phase III LDR rule proposes new treatment standards CWA/SDWA systems affected

    SciTech Connect

    1995-05-01

    On March 2, 1995, EPA took one more step toward fulfilling statutory/judicial mandates regarding the RCRA land disposal restrictions (LDR) program. Among the most significant aspects of this so-called Phase III LDR rule is the proposal of treatment standards for characteristic wastes managed in systems regulated by the Clean Water Act (CWA) and in Class I injection wells regulated under the Safe Drinking Water Act (SDWA). These regulations would also apply to zero-discharge systems that treat waste-water in a manner equivalent to that used by CWA dischargers (i.e., CWA-equivalent systems). According to EPA, promulgation of the proposed requirements could affect a large number of facilities that may be forced to treat their wastes for underlying hazardous constituents prior to disposal. 1 fig., 4 tabs.

  1. 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.

  2. 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.

  3. 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

  4. [Work capacity and the factors limiting it in patients with III- to IV-degree obesity].

    PubMed

    Solov'ev, M V; Savich, A B; Sedletskiĭ, Iu I; Mirchuk, K K

    1995-01-01

    There is a marked decrement in physical performance of those patients with III to IV grade obesity as compared to apparently healthy volunteers going into training. Deficient reserve capabilities of the system for utilization of oxygen and oxygen transport appear to be those factors determining and limiting physical fitness of obese individuals. Exercise testing involving recording of indices for gas exchange in real time appears to be a valuable method of diagnosis of particular features of oxygen supply in patients with III to IV grade obesity, providing a very helpful information.

  5. Unexpected relationships and inbreeding in HapMap phase III populations.

    PubMed

    Stevens, Eric L; Baugher, Joseph D; Shirley, Matthew D; Frelin, Laurence P; Pevsner, Jonathan

    2012-01-01

    Correct annotation of the genetic relationships between samples is essential for population genomic studies, which could be biased by errors or omissions. To this end, we used identity-by-state (IBS) and identity-by-descent (IBD) methods to assess genetic relatedness of individuals within HapMap phase III data. We analyzed data from 1,397 individuals across 11 ethnic populations. Our results support previous studies (Pemberton et al., 2010; Kyriazopoulou-Panagiotopoulou et al., 2011) assessing unknown relatedness present within this population. Additionally, we present evidence for 1,657 novel pairwise relationships across 9 populations. Surprisingly, significant Cotterman's coefficients of relatedness K1 (IBD1) values were detected between pairs of known parents. Furthermore, significant K2 (IBD2) values were detected in 32 previously annotated parent-child relationships. Consistent with a hypothesis of inbreeding, regions of homozygosity (ROH) were identified in the offspring of related parents, of which a subset overlapped those reported in previous studies (Gibson et al. 2010; Johnson et al. 2011). In total, we inferred 28 inbred individuals with ROH that overlapped areas of relatedness between the parents and/or IBD2 sharing at a different genomic locus between a child and a parent. Finally, 8 previously annotated parent-child relationships had unexpected K0 (IBD0) values (resulting from a chromosomal abnormality or genotype error), and 10 previously annotated second-degree relationships along with 38 other novel pairwise relationships had unexpected IBD2 (indicating two separate paths of recent ancestry). These newly described types of relatedness may impact the outcome of previous studies and should inform the design of future studies relying on the HapMap Phase III resource.

  6. 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

  7. 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. PMID:27418551

  8. Unbiased estimation in seamless phase II/III trials with unequal treatment effect variances and hypothesis-driven selection rules.

    PubMed

    Robertson, David S; Prevost, A Toby; Bowden, Jack

    2016-09-30

    Seamless phase II/III clinical trials offer an efficient way to select an experimental treatment and perform confirmatory analysis within a single trial. However, combining the data from both stages in the final analysis can induce bias into the estimates of treatment effects. Methods for bias adjustment developed thus far have made restrictive assumptions about the design and selection rules followed. In order to address these shortcomings, we apply recent methodological advances to derive the uniformly minimum variance conditionally unbiased estimator for two-stage seamless phase II/III trials. Our framework allows for the precision of the treatment arm estimates to take arbitrary values, can be utilised for all treatments that are taken forward to phase III and is applicable when the decision to select or drop treatment arms is driven by a multiplicity-adjusted hypothesis testing procedure. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID:27103068

  9. Unbiased estimation in seamless phase II/III trials with unequal treatment effect variances and hypothesis-driven selection rules.

    PubMed

    Robertson, David S; Prevost, A Toby; Bowden, Jack

    2016-09-30

    Seamless phase II/III clinical trials offer an efficient way to select an experimental treatment and perform confirmatory analysis within a single trial. However, combining the data from both stages in the final analysis can induce bias into the estimates of treatment effects. Methods for bias adjustment developed thus far have made restrictive assumptions about the design and selection rules followed. In order to address these shortcomings, we apply recent methodological advances to derive the uniformly minimum variance conditionally unbiased estimator for two-stage seamless phase II/III trials. Our framework allows for the precision of the treatment arm estimates to take arbitrary values, can be utilised for all treatments that are taken forward to phase III and is applicable when the decision to select or drop treatment arms is driven by a multiplicity-adjusted hypothesis testing procedure. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

  10. Analysis of Prognostic Factors and Patterns of Recurrence in Patients With Pathologic Stage III Endometrial Cancer

    SciTech Connect

    Patel, Samir; Portelance, Lorraine . E-mail: lorraine.portelance@muhc.mcgill.ca; Gilbert, Lucy; Tan, Leonard; Stanimir, Gerald; Duclos, Marie; Souhami, Luis

    2007-08-01

    Purpose: To retrospectively assess prognostic factors and patterns of recurrence in patients with pathologic Stage III endometrial cancer. Methods and Materials: Between 1989 and 2003, 107 patients with pathologic International Federation of Gynecology and Obstetrics Stage III endometrial adenocarcinoma confined to the pelvis were treated at our institution. Adjuvant radiotherapy (RT) was delivered to 68 patients (64%). The influence of multiple patient- and treatment-related factors on pelvic and distant control and overall survival (OS) was evaluated. Results: Median follow-up for patients at risk was 41 months. Five-year actuarial OS was significantly improved in patients treated with adjuvant RT (68%) compared with those with resection alone (50%; p = 0.029). Age, histology, grade, uterine serosal invasion, adnexal involvement, number of extrauterine sites, and treatment with adjuvant RT predicted for improved survival in univariate analysis. Multivariate analysis revealed that grade, uterine serosal invasion, and treatment with adjuvant RT were independent predictors of survival. Five-year actuarial pelvic control was improved significantly with the delivery of adjuvant RT (74% vs. 49%; p = 0.011). Depth of myometrial invasion and treatment with adjuvant RT were independent predictors of pelvic control in multivariate analysis. Conclusions: Multiple prognostic factors predicting for the outcome of pathologic Stage III endometrial cancer patients were identified in this analysis. In particular, delivery of adjuvant RT seems to be a significant independent predictor for improved survival and pelvic control, suggesting that pelvic RT should be routinely considered in the management of these patients.

  11. Cisplatin/Tegafur/Uracil/Irinotecan Triple Combination Therapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma: A Phase I/II Clinical Study

    PubMed Central

    Chen, San-Chi; Chang, Peter Mu-Hsin

    2016-01-01

    Lessons Learned Cisplatin/tegafur/uracil/irinotecan triple combination therapy shows moderate response, especially in patients without previous chemoradiotherapy within the 6 months before this combination therapy. Toxicity is tolerable, and quality of life is improved in responders. Background. The prognosis is poor in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Triple combination therapy may increase tumor response. Methods. This phase I/II prospective trial first determined the dose-limiting toxicity and recommended dose of irinotecan with cisplatin and tegafur/uracil (UFUR) in phase I. Irinotecan was supplied at doses of 40, 50, 60, and 70 mg/m2 by using a standard 3+3 design. Doses of cisplatin and UFUR were held stable. In phase II, the recommended dose of irinotecan was administered intravenously (i.v.) over 90 min on day 1, with cisplatin 50 mg/m2 i.v. over 60 min also on day 1, and oral UFUR 200 mg twice a day for 5 days every 2 weeks a cycle. Results. In the phase I portion, 14 patients were enrolled, and the dose level of irinotecan at 60 mg/m2 was defined as the recommended dose for the phase II portion of the study. Among 43 patients enrolled in the phase II portion, complete response was seen in 2 patients (4.7%) and partial response in 10 patients (23.3%), and the disease control rate was 39.5%. In a subgroup analysis of patients whose prior chemoradiotherapy was more than 6 months earlier, a response rate of 40.7% and disease control rate of 59.3% were observed. Conclusion. Cisplatin/UFUR/irinotecan triple combination therapy is tolerated and effective for selected patients. Individualized choice of treatment will influence prognosis and quality of life in R/M HNSCC patients. PMID:27091418

  12. Phase II Study of Chemoradiotherapy With 5-Fluorouracil and Cisplatin for Stage II-III Esophageal Squamous Cell Carcinoma: JCOG Trial (JCOG 9906)

    SciTech Connect

    Kato, Ken; Muro, Kei; Minashi, Keiko; Ohtsu, Atsushi; Ishikura, Satoshi; Boku, Narikazu; Takiuchi, Hiroya; Komatsu, Yoshito; Miyata, Yoshinori; Fukuda, Haruhiko

    2011-11-01

    Purpose: In this Phase II study, we evaluated the efficacy and toxicity of chemoradiotherapy (CRT) with cisplatin (CDDP) and 5-fluorouracil (5-FU) for Stage II-III esophageal squamous cell carcinoma (ESCC). Patients and Methods: Patients with clinical Stage II-III (T1N1M0 or T2-3N0-1M0) thoracic ESCC were enrolled between April 2000 and March 2002. Chemotherapy comprised two courses of protracted infusion of 5-FU (400 mg/m{sup 2}/day) on Days 1-5 and 8-12, and 2-h infusion of CDDP (40 mg/m{sup 2}) on Days 1 and 8; this regimen was repeated every 5 weeks. Concurrent radiotherapy involved 60-Gy irradiation (30 fractions) for 8 weeks with a 2-week break. Responders received two courses of 5-FU (800 mg/m{sup 2}/day) on Days 1-5 and CDDP (80 mg/m{sup 2}) on Day 1. Final analysis was conducted in March 2007. Survival and late toxicities were monitored for 5 years. Results: The characteristics of the 76 patients enrolled were as follows: median age, 61 years; male/female, 68/8; performance status 0/1, 59/17 patients; Stage IIA/IIB/III, 26/12/38 patients. Of the 74 eligible patients, 46 (62.2%) achieved complete response. Median survival time was 29 months, with 3- and 5-year survival rates of 44.7% and 36.8%, respectively. Acute toxicities included Grade 3/4 esophagitis (17%), nausea (17%), hyponatremia (16%), and infection without neutropenia (12%). Late toxicities comprised Grade 3/4 esophagitis (13%), pericardial (16%) and pleural (9%) effusion, and radiation pneumonitis (4%), causing 4 deaths. Conclusions: CRT is effective for Stage II-III ESCC with manageable acute toxicities and can provide a nonsurgical treatment option. However, further improvement is required for reduction in late toxicity.

  13. Iodixanol vs iopamidol in intravenous DSA of the abdominal aorta and lower extremity arteries: a comparative phase-III trial.

    PubMed

    Fischbach, R; Landwehr, P; Lackner, K; Nossen, J O; Heindel, W; Berg, K J; Eichhorn, G; Jacobsen, T F

    1996-01-01

    Iodixanol (Visipaque, 320 mgI/ml) was compared with iopamidol (Solutrast, 370 mgI/ml) in a double-blind, randomized, parallel group, intravenous DSA phase-III trial for evaluation of safety and efficacy. A total of 117 patients received iodixanol (n = 60) or iopamidol (n = 57). Diagnostic efficacy was evaluated using categoric and visual analogue scales. Discomfort and adverse events were recorded. A total of 39 patients collected urine up to 72 h after the examination for analysis. Diagnostic efficacy and radiographic density were similar in both groups. Discomfort was milder with iodixanol. The difference between the frequency of adverse events between both groups (iodixanol = 7, iopamidol = 2) was without statistical significance. Creatinine clearance was slightly more affected by iodixanol, whereas the increase in renal excretion of N-acetyl-beta-glucosaminidase (NAG) in the first 24-h collection period after the examination was significantly higher (p < 0.01) with iopamidol. Iodixanol was of equal diagnostic efficacy compared with iopamidol despite its reduced iodine content. Both contrast media are well suited for IV DSA.

  14. Maxillary protraction using skeletal anchorage and intermaxillary elastics in Skeletal Class III patients

    PubMed Central

    Ağlarcı, Cahide; Albayrak, Gayem Eroğlu; Fındık, Yavuz

    2015-01-01

    The aim of this case report is to describe the treatment of a patient with skeletal Class III malocclusion with maxillary retrognathia using skeletal anchorage devices and intermaxillary elastics. Miniplates were inserted between the mandibular lateral incisor and canine teeth on both sides in a male patient aged 14 years 5 months. Self-drilling mini-implants (1.6 mm diameter, 10 mm length) were installed between the maxillary second premolar and molar teeth, and Class III elastics were used between the miniplates and miniscrews. On treatment completion, an increase in the projection of the maxilla relative to the cranial base (2.7 mm) and significant improvement of the facial profile were observed. Slight maxillary counterclockwise (1°) and mandibular clockwise (3.3°) rotations were also observed. Maxillary protraction with skeletal anchorage and intermaxillary elastics was effective in correcting a case of Skeletal Class III malocclusion without dentoalveolar side effects. PMID:25798416

  15. 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

  16. 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.

  17. Late radiation toxicity after intraoperative radiotherapy (IORT) for breast cancer: results from the randomized phase III trial TARGIT A.

    PubMed

    Sperk, Elena; Welzel, Grit; Keller, Anke; Kraus-Tiefenbacher, Uta; Gerhardt, Axel; Sütterlin, Marc; Wenz, Frederik

    2012-08-01

    The randomized phase III trial TARGIT A showed non-inferiority regarding local control after intraoperative radiotherapy (IORT 20 Gy which was followed by whole breast radiotherapy (WBRT) in patients with risk factors only) in comparison to standard WBRT (50-56 Gy) after breast-conserving surgery in selected patients. This is the first analysis of long-term toxicities in the setting of TARGIT. Between 02/2002 and 12/2008, 305 patients were treated within TARGIT A (Arm A: n = 34 IORT, n = 20 IORT + WBRT for risk factors; Arm B WBRT: n = 55) or received IORT as a planned boost (control group: n = 196) at a single center. Toxicity was assessed according to the LENT SOMA scales. No significant differences were seen between Arm A and Arm B regarding fibrosis, breast edema, retraction, ulceration, lymphedema, hyperpigmentation, and pain. Arm A had significantly less telangiectases compared to Arm B (p = 0.049). In the subanalysis (Arm A IORT vs. Arm A IORT + WBRT vs. Arm B), fibrosis had a cumulative rate of 5.9 versus 37.5 versus 18.4 %, respectively (38.2 % IORT boost control group), at 3 years. No telangiectases were seen after IORT alone (0 % Arm A IORT vs. 17.5 % Arm A IORT + WBRT vs. 17.7 % Arm B). The hazard ratio of higher grade toxicity as first event was 0.46 (95 % CI, 0.26-0.83) for Arm A IORT as compared to Arm B (p = 0.010). No recurrences were seen after a median follow-up of 40 months (Arm A) and 42 months (Arm B). With its very low chronic skin toxicity rates and outstanding long-term results regarding toxicity and local control, IORT with 50 kV X-rays is a safe and effective method for treatment of selected breast cancer patients. PMID:22842984

  18. Performance characteristics of postacute traumatic brain injury patients on the WAIS-III and WMS-III.

    PubMed

    Axelrod, B N; Fichtenberg, N L; Liethen, P C; Czarnota, M A; Stucky, K

    2001-12-01

    Publication of the third editions of the Wechsler intelligence and memory batteries in 1997 created a need for research identifying Wechsler Adult Intelligence Scale-Third Edition/Wechsler Memory Scale-Third Edition (WAIS-III/WMS-III) profile patterns associated with neuropathology. The WAIS-III/WMS-III Technical Manual offers data on various diagnostic groups, including traumatic brain injury (TBI). Hawkins (1998) employed Technical Manual data to propose certain diagnostic guidelines. In order to validate the conclusions put forth by Hawkins as they apply to brain injury, we examined WAIS-III and WMS-III profiles in an independent sample of 46 TBI cases. As expected, the WAIS-III Processing Speed Index (PSI) was more sensitive to brain injury than other WAIS-III composites; and specific WAIS-III scores were stronger than certain WMS-III scores. On the other hand, the predicted relationship for WMS-III auditory and visual indexes was not found. The lack of specificity for TBI of the proposed index comparisons confirms the need to validate such hypotheses in independent samples.

  19. Early treatment of patient with Class III skeletal and dental patterns

    PubMed Central

    Bittencourt, Marcos Alan Vieira

    2015-01-01

    Abstract Class III skeletal pattern is characterized by disharmony between maxillary and mandibular basal bones anteroposteriorly, and might or might not be associated with dental changes. In general, facial esthetics is hindered significantly, which most of times is the reason why patients or patient's guardians seek treatment. This case was presented to the Brazilian Board of Orthodontics and Dentofacial Orthopedics (BBO) in partial fulfillment of the requirements for Diplomate recertification and revalidation. PMID:26691976

  20. Development and testing of commercial-scale, coal-fired combustion systems: Phase III. Final report

    SciTech Connect

    1996-03-01

    Based on studies that indicated a large potential for significantly increased coal-firing in the commercial sector, the U.S. Department of Energy`s Pittsburgh Energy Technology Center (PETC) sponsored a multi-phase development effort for advanced coal combustion systems. This Final Report presents the results of the last phase (Phase III) of a project for the development of an advanced coal-fired system for the commercial sector of the economy. The project performance goals for the system included dual-fuel capability (i.e., coal as primary fuel and natural gas as secondary fuel), combustion efficiency exceeding 99 percent, thermal efficiency greater than 80 percent, turndown of at least 3:1, dust-free and semi-automatic dry ash removal, fully automatic start-up with system purge and ignition verification, emissions performance exceeding New Source Performance Standards (NSPS) and approaching those produced by oil-fired, Commercial-sized units, and reliability, safety, operability, maintainability, and service life comparable to oil-fired units. The program also involved a site demonstration at a large facility owned by Striegel Supply Company, a portion of which was leased to MTCI. The site, mostly warehouse space, was completely unheated and the advanced coal-fired combustion system was designed and sized to heat this space. Three different coals were used in the project, one low and one high sulfur pulverized Pittsburgh No. 8 coal, and a micronized low volatile, bituminous coal. The sorbents used were Pfizer dolomitic limestone and an Anvil lime. More than 100 hours of screening test`s were performed to characterize the system. The parameters examined included coal firing rate, excess air level, ash recycle rate, coal type, dolomitic limestone feed rate, and steam injection rate. These tests indicated that some additional modifications for coal burning in the system were required.

  1. Methylation of MGMT Is Associated with Poor Prognosis in Patients with Stage III Duodenal Adenocarcinoma

    PubMed Central

    Sharmab, Anup; Xie, Fei; Liu, Yanliang; Li, Kai; Wan, Weiwei; Baylin, Stephen B.; Wolfgang, Christopher L.; Ahuja, Nita

    2016-01-01

    Background O6-methylguanine-DNA methyltransferase (MGMT) methylation status has not been extensively investigated in duodenal adenocarcinoma (DA). The aim of this study was to evaluate the MGMT methylation status and examine its possible prognostic value in patients with stage III DA. Methods Demographics, tumor characteristics and survival were available for 64 patients with stage III DA. MGMT methylation was detected by using MethyLight. A Cox proportional hazard model was built to predict survival, adjusted for clinicopathological characteristics and tumor molecular features, including the CpG island methylator phenotype (CIMP), microsatellite instability (MSI), and KRAS mutations. Results MGMT methylation was detected in 17 of 64 (26.6%) patients, and was not correlated with sex, age, tumor differentiation, CIMP, MSI, or KRAS mutations. MGMT methylation was the only one factor associated with both overall survival (OS) and disease-free survival (DFS) on both univariate and multivariate analyses. In patients treated with surgery alone, MGMT-methylated group had worse OS and DFS when compared with MGMT-unmethylated group. However, in patients treated with chemotherapy/radiotherapy, outcomes became comparable between the two groups. Conclusions Our results demonstrate MGMT methylation is a reliable and independent prognostic factor in DAs. Methylation of MGMT is associated with poor prognosis in patients with stage III DAs. PMID:27643594

  2. Abnormal collagen I to III distribution in the skin of patients with incisional hernia.

    PubMed

    Klinge, U; Si, Z Y; Zheng, H; Schumpelick, V; Bhardwaj, R S; Klosterhalfen, B

    2000-01-01

    The surgical mesh-free repair of incisional hernias has to face recurrence rates of up to 50%. Apart from technical faults this is probably due to collagen metabolic disorders, known to play an important role in the development of inguinal hernia. In particular an altered ratio of collagen types I and III with an increase in collagen type III has been claimed to reduce the mechanical strength of connective tissues. Therefore, we investigated the content of collagen types I and III in the skin of patients with incisional hernia (n = 7) and recurrent incisional hernia (n = 5) in comparison to controls with healthy skin (n = 7) and normal skin scar (n = 7) both by immunohistochemistry and Western blot analysis. Both immunohistochemistry and Western blot analysis revealed a decrease in the ratio of collagen I/III due to a concomitant increase in collagen III. The patients with incisional hernias and with recurrent incisional hernias showed a ratio of 1.0 +/- 0.1 and 0.8 +/- 0.1, respectively, whereas the controls exhibit a ratio of 2.1 +/- 0.2 in healthy skin and of 1.2 +/- 0.2 in normal skin scar, respectively. The decrease was highly significant (p < 0.01) between the patients with either primary or recurrent hernia and the controls or the normal scar, as well as between controls and normal scar, whereas there was not any significant difference between primary and recurrent hernia (p > 0.05). Our data for the first time confirmed that the presence of incisional hernia is accompanied by impaired collagen synthesis in the skin. The decreased tensile strength of collagen type III may play a key role in the development of incisional hernias. Furthermore, it might explain the high recurrence rates of hernia repair by simple closure, as a repetition of the primarily failing technique, and the improvement by the additional use of alloplastic material.

  3. 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)

  4. 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.

  5. 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…

  6. 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.

  7. 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

    ... announced in the May 6, 2013 Federal Register notice (78 FR 26319), and the document now proposes these 28... Deepwater Horizon Oil Spill; Draft Programmatic and Phase III Early Restoration Plan and Draft Early Restoration Programmatic Environmental Impact Statement AGENCY: Interior. ACTION: Notice of...

  8. 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…

  9. Fluorouracil Based Chemoradiation with Either Gemcitabine or Fluorouracil Chemotherapy Following Resection of Pancreatic Adenocarcinoma: 5-Year Analysis of the US Intergroup/RTOG 9704 Phase III Trial

    PubMed Central

    Regine, William F.; Winter, K.A.; Abrams, R.; Safran, H.; Hoffman, J.P.; Konski, A.; Benson, A.B.; Macdonald, J.S.; Rich, T.A.; Willett, C.G.

    2011-01-01

    Background The impact of the addition of gemcitabine (G) to 5-FU chemoradiation (CRT) on 5-year overall survival (OS) in resected pancreatic adenocarcinoma are presented with updated results of a phase III trial. Methods Following resection of pancreatic adenocarcinoma patients were randomized to pre and post CRT 5-FU vs. pre and post CRT G. 5-FU = continuous (CI) at 250 mg/m2/day. G = 1000 mg/m2 weekly; both given over 3 weeks pre and 12 weeks post - CRT. CRT = 50.4 Gy with CI 5-FU. Primary endpoint was survival for all patients and for pancreatic head tumor patients. Results Four hundred and fifty-one patients were eligible. Univariate analysis showed no difference in OS. Pancreatic head tumor patients (n=388) had a median survival and 5-year OS of 20.5 months and 22% with G vs. 17.1 months and 18% with 5-FU. On multivariate analysis, patients on the G arm with pancreatic head tumors experienced a trend towards improved OS (p=0.08). First site of relapse local recurrence in 28% of patients vs. distant relapse in 73%. Conclusion(s) The sequencing of 5-FU CRT with G as done in this trial is not associated with a statistically significant improvement in OS. Despite local recurrence being approximately half of that reported in previous adjuvant trials, distant disease relapse still occurs in ≥ 70% of patients. These findings serve as the basis for the recently activated EORTC/US Intergroup RTOG 0848 phase III adjuvant trial evaluating the impact of CRT after completion of a full course of G. PMID:21499862

  10. Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02

    PubMed Central

    Lee, Eudocia Q.; Kuhn, John; Lamborn, Kathleen R.; Abrey, Lauren; DeAngelis, Lisa M.; Lieberman, Frank; Robins, H. Ian; Chang, Susan M.; Yung, W. K. Alfred; Drappatz, Jan; Mehta, Minesh P.; Levin, Victor A.; Aldape, Kenneth; Dancey, Janet E.; Wright, John J.; Prados, Michael D.; Cloughesy, Timothy F.; Gilbert, Mark R.; Wen, Patrick Y.

    2012-01-01

    The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor–β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents. PMID:23099651

  11. Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02.

    PubMed

    Lee, Eudocia Q; Kuhn, John; Lamborn, Kathleen R; Abrey, Lauren; DeAngelis, Lisa M; Lieberman, Frank; Robins, H Ian; Chang, Susan M; Yung, W K Alfred; Drappatz, Jan; Mehta, Minesh P; Levin, Victor A; Aldape, Kenneth; Dancey, Janet E; Wright, John J; Prados, Michael D; Cloughesy, Timothy F; Gilbert, Mark R; Wen, Patrick Y

    2012-12-01

    The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor-β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents.

  12. Effects of interleukin-3 following chemotherapy of non-Hodgkin's lymphoma. A prospective, controlled phase I/II study.

    PubMed

    Hovgaard, D J; Nissen, N I

    1995-02-01

    The effect of rhIL-3 was investigated in 32 patients with newly diagnosed non-Hodgkin lymphoma in a phase I/II trial. All patients received 6 cycles of standard CHOP chemotherapy, and each patient was his own control where rhIL-3 was given as a daily s.c. injection for 14 days (day 2-15) in cycle 2 and 4, while cycle 1 and 3 were control cycles. Five dose levels were examined (0.5 - 1 - 5 - 7.5 - 10 micrograms/kg). Compared to the other more lineage-specific hemopoietic growth factors G- and GM-CSF, the effect of rhIL-3 on the hemopoiesis was less dramatic and more delayed, i.e. the most apparent effect was observed in the 2 weeks of treatment. Thus, the neutrophil counts from days 15 to 22 following CHOP were significantly raised and the duration of neutropenia was shorter (significantly only at 10 micrograms/kg), while the nadir values were unaffected. Platelet recovery from days 12-22 was significantly increased and nadir values occurred earlier compared to control cycles, but were only increased in some subsets. Other cell populations affected moderately in the recovery period were eosinophils and monocytes. Reticulocytes increased, but no effect on hemoglobin or RBC transfusion requirement was noted. Only moderate adverse reactions occurred such as fever, chills, flushing of the face and flu-like symptoms. There was no evidence of stimulation of tumor growth. Most significant, the rhIL-3 treatment at all but the lowest dose levels led to an improved tolerance to chemotherapy, as indicated by a decline in number of delayed cycles. A conclusion concerning the role of rhIL-3 as post-chemotherapy adjuvant should await studies using rhIL-3 in combination with more lineage-restricted hemopoietic growth factors.

  13. 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

  14. Deoxidation of (001) III-V semiconductors in metal-organic vapour phase epitaxy

    NASA Astrophysics Data System (ADS)

    Kaspari, Christian; Pristovsek, Markus; Richter, Wolfgang

    2016-08-01

    We studied the deoxidation of several (001) III-V semiconductors in metal-organic vapour phase epitaxy using in-situ reflectance anisotropy spectroscopy and in-situ spectroscopic ellipsometry. The oxide desorption started as soon as kBT reaches 1/15th of the bond strength of the crystal if there is hydrogen or group V precursor present. The oxide thickness decreases first and afterwards the surface slowly reconstructs. At a constant temperature the oxide thickness decreased according to a second order reaction. We found two processes on InAs and GaAs, but only a single one on InP. The activation energy for the removal of epi-ready oxide under group V flux was 0.64 eV, 1.1 eV, and 1.3 eV on InAs, GaAs, and InP, respectively. The end of oxide desorption is determined by the removal of the last metal rich oxides, at temperatures of 500 °C for InAs/InP and 600 °C for GaAs/GaP.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. Haematopoietic stem cell transplantation in the treatment of severe autoimmune disease: results from phase I/II studies, prospective randomized trials and future directions

    PubMed Central

    Tyndall, A; Saccardi, R

    2005-01-01

    Around 700 patients have received an autologous haematopoietic stem cell transplant (HSCT) as treatment for a severe autoimmune disease (AD). The majority of these have been within the context of phase I/II clinical trials and following international guidelines proposed 7 years ago. In general, a positive benefit/risk ratio has led to phase III prospective randomized controlled trials in multiple sclerosis (MS), systemic sclerosis (SSc) and rheumatoid arthritis (RA) in Europe. In the US, similar trials are being planned for SSc, MS and systemic lupus erythematosus (SLE). Transplant related mortality (TRM) has fallen in all disease subgroups since the inception due to more appropriate patient selection, and so far a clear advantage of the more intense myeloablative regimens in terms of remission induction and relapse rate has not emerged. Although each AD has a different profile, over a third of patients have sustained a durable remission, often with no further need for immunosuppressive drugs. In those who relapsed, many responded to agents which pre transplant had been ineffective. The study of immune reconstitution and gene expression pre and post HSCT is being undertaken to further understand the mechanism of autoimmunity. PMID:15958063

  1. Phase II Results of RTOG 0537: A Phase II/III Study Comparing Acupuncture-like Transcutaneous Electrical Nerve Stimulation Versus Pilocarpine in Treating Early Radiation-Induced Xerostomia

    PubMed Central

    Wong, Raimond K. W.; James, Jennifer L.; Sagar, Stephen; Wyatt, Gwen; Nguyen-Tân, Phuc Felix; Singh, Anurag K.; Lukaszczyk, Barbara; Cardinale, Francis; Yeh, Alexander M.; Berk, Lawrence

    2011-01-01

    Purpose This phase II component of a multi-institutional phase II/III randomized trial assessed the feasibility and preliminary efficacy of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) in reducing radiation-induced xerostomia. Methods Head and neck cancer patients who were 3–24 months from completing radiotherapy ± chemotherapy (RT±C) and experiencing xerostomia symptoms with basal whole saliva production ≥0.1 ml/min and without recurrence were eligible. Patients received twice weekly ALTENS sessions (24 over 12 weeks) using a Codetron™ unit. The primary objective assessed the feasibility of ALTENS treatment. A patient was considered compliant if 19/24 ALTENS were delivered, with a targeted 85% compliance rate. Secondary objectives measured treatment-related toxicities and ALTENS effect on overall radiation-induced xerostomia burden using the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS). Results Of 48 accrued patients, 47 were evaluable. Median age was 60 years; 84% were male, 70% completed RT±C for > 12 months and 21% had received prior pilocarpine. All ALTENS sessions were completed in 34 patients, but 9 and 1 completed 20–23 and 19 sessions respectively, representing a 94% total compliance rate. 6-month XeQOLS scores were available for 35 patients; 30 (86%) achieved a positive treatment response with a mean reduction of 35.9% (SD 36.1). Five patients developed grade 1–2 gastrointestinal toxicity and one had grade 1 pain event. Conclusions ALTENS treatment for radiation-induced xerostomia can be uniformly delivered in a cooperative multicenter setting and has possible beneficial treatment response. Given these results, the phase III component of this study was initiated. PMID:22252927

  2. WMS-III performance in patients with temporal lobe epilepsy: group differences and individual classification.

    PubMed

    Wilde, N; Strauss, E; Chelune, G J; Loring, D W; Martin, R C; Hermann, B P; Sherman, E; Hunter, M

    2001-11-01

    The utility of the WMS-III in detecting lateralized impairment was examined in a large sample of patients with temporal lobe epilepsy. Methods of analysis included evaluation of group means on the various indexes and subtest scores, the use of ROC curves, and an examination of Auditory-Visual Index discrepancy scores. In addition, performance on immediate and delayed indexes in the auditory and the visual modality was compared within each group. Of the WMS-III scores, the Auditory-Visual Delayed Index difference score appeared most sensitive to side of temporal dysfunction, although patient classification rates were not within an acceptable range to have clinical utility. The ability to predict laterality based on statistically significant index score differences was particularly weak for those with left temporal dysfunction. The use of unusually large discrepancies led to improved prediction, however, the rarity of such scores in this population limits their usefulness. Although the utility of the WMS-III in detecting laterality may be limited in preoperative cases, the WMS-III may still hold considerable promise as a measure of memory in documenting baseline performance and in detecting those that may be at risk following surgery.

  3. NOVEL CONCEPTS FOR THE COMPRESSION OF LARGE VOLUMES OF CARBON DIOXIDE-PHASE III

    SciTech Connect

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

    2014-06-30

    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.

  4. 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

  5. A simple tool for mortality prediction in burns patients: APACHE III score and FTSA.

    PubMed

    Moore, E C; Pilcher, D V; Bailey, M J; Cleland, H; McNamee, J

    2010-11-01

    Prediction of outcome for patients with major thermal injury is important to inform clinical decision making, alleviate individual suffering and improve hospital resource allocation. Age and burn size are widely accepted as the two largest contributors of mortality amongst burns patients. The APACHE (Acute Physiology and Chronic Health Evaluation) III-j score, which incorporates patient age, is also useful for mortality prediction, of intensive care populations. Validation for the burns specific cohort is unclear. A retrospective cohort study was performed on patients admitted to the Intensive Care Unit (ICU) via the Victorian Adult Burns Service (VABS), to compare observed mortality with burns specific markers of illness severity and APACHE III-j score. Our primary aim was to develop a mortality prediction tool for the burns population. Between January 1, 2002 and December 31, 2008, 228 patients were admitted to the ICU at The Alfred with acute burns. The mean age was 45.6 years and 81% (n=184) were male. Patients had severe injuries: the average percent TBSA (total body surface area) was 28% (IQR 10-40) and percent FTSA (full thickness surface area) was 18% (IQR 10-25). 86% (n=197) had airway involvement. Overall mortality in the 7-year period was 12% (n=27). Non-survivors were older, had larger and deeper burns, a higher incidence of deliberate self-harm, higher APACHE III-j scores and spent less time in hospital (but similar time in ICU), compared with survivors. Independent risk factors for death were percent FTSA (OR 1.03, 95% CI 1.01-1.05, p=0.01) and APACHE III-j score (OR 1.04, 95% CI 1.02-1.07, p<0.001). Mortality prediction based on both of these variables in combination was more specific than either individual variable alone (AUROC 0.85, 95% CI 0.79-0.92). Likelihood of death for patients with severe thermal injury can be predicted with accuracy from APACHE III-j score and percent FTSA. Prospective validation of our model on different burn populations

  6. 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

  7. 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

  8. Estimation of drug cost avoidance and pathology cost avoidance through participation in NCIC Clinical Trials Group phase III clinical trials in Canada

    PubMed Central

    Tang, P.A.; Hay, A.E.; O’Callaghan, C.J.; Mittmann, N.; Chambers, C.R.; Pater, J.L.; Leighl, N.B.

    2016-01-01

    Background Cost avoidance occurs when, because of provision of a drug therapy [drug cost avoidance (dca)] or a pathology test [pathology cost avoidance (pca)] during trial participation, health care payers need not pay for standard treatments or testing. The aim of our study was to estimate the total dca and pca for Canadian patients enrolled in relevant phase iii trials conducted by the ncic Clinical Trials Group. Methods Phase iii trials that had completed accrual and resulted in dca or pca were identified. The pca was calculated based on the number of patients screened and the test cost. The dca was estimated based on patients randomized, the protocol dosing regimen, drug cost, median dose intensity, and median duration of therapy. Costs are presented in Canadian dollars. No adjustment was made for inflation. Results From 1999 to 2011, 4 trials (1479 patients) resulted in pca and 17 trials (3195 patients) resulted in dca. The total pca was estimated at $4,194,849, which included testing for KRAS ($141,058), microsatellite instability ($18,600), and 21-gene recurrence score ($4,035,191). The total dca was estimated at $27,952,512, of which targeted therapy constituted 43% (five trials). The combined pca and dca was $32,147,361. Conclusions Over the study period, trials conducted by the ncic Clinical Trials Group resulted in total cost avoidance (pca and dca) of approximately $7,518 per patient. Although not all trials lead to cost avoidance, such savings should be taken account when the financial impact of conducting clinical research is being considered. PMID:26985151

  9. The Value of Botox-A in Acute Radiation Proctitis: Results From a Phase I/II Study Using a Three-Dimensional Scoring System

    SciTech Connect

    Vuong, Te; Waschke, Kevin; Niazi, Tamim; Richard, Carole; Parent, Josee; Liberman, Sender; Mayrand, Serge; Loungnarath, Rasmy; Stein, Barry; Devic, Slobodan

    2011-08-01

    Purpose: Acute radiation proctitis (ARP) is a common side effect of pelvic radiotherapy, and its management is challenging in daily practice. The present phase I/II study evaluates the safety and efficacy of the botulinum toxin A (BTX-A) in ARP treatment for rectal cancer patients undergoing neoadjuvant high-dose-rate endorectal brachytherapy (HDREBT). Methods and Materials: Fifteen patients, treated with neoadjuvant HDREBT, 26-Gy in 4 fractions, received the study treatment that consisted of a single injection of BTX-A into the rectal wall. The injection was performed post-HDREBT and prior to the development of ARP. The control group, 20 such patients, did not receive the BTX-A injection. Both groups had access to standard treatment with hydrocortisone rectal aerosol foam (Cortifoam) and anti-inflammatory and narcotic medication. The ARP was clinically evaluated by self-administered daily questionnaires using visual analog scores to document frequency and urgency of bowel movements, rectal burning/tenesmus, and pain symptoms before and after HDREBT. Results: At the time of this analysis, there was no observed systemic toxicity. Patient compliance with the self-administered questionnaire was 100% from week 1 to 4, 70% during week 5, and 40% during week 6. The maximum tolerated dose was established at the 100-U dose level, and noticeable mean differences were observed in bowel frequency (p = 0.016), urgency (p = 0.007), and pain (p = 0.078). Conclusions: This study confirms the feasibility and efficacy of BTX-A intervention at 100-U dose level for study patients compared to control patients. A phase III study with this dose level is planned to validate these results.

  10. Increased nitric oxide release by neutrophils of a patient with tyrosinemia type III.

    PubMed

    D'Eufemia, Patrizia; Finocchiaro, Roberto; Celli, Mauro; Raccio, Ivana; Properzi, Enrico; Zicari, Alessandra

    2009-06-01

    Tyrosinemia type III (OMIM 276710) is an autosomal recessive disorder caused by the deficiency of 4-hydroxyphenylpyruvate dioxygenase (4-HPD). Few cases have been described with mental retardation or neurological symptoms. Recently it has been demonstrated that 4-HPD participates to nitric oxide (NO) intracellular sequestration in Pseudomonas aeruginosa. 4-HPD is an ubiquitous enzyme with a prominent expression in neutrophils and neurons. In the nervous system NO has been perceived to be a potential neuromodulator although prolonged excessive generation is detrimental. We analyzed NO release by neutrophils of a patient with tyrosinemia type III in order to evaluate a possible influence of 4-HPD deficiency on this process. Our patient, previously described, is a 30-year-old women with persistent tyrosinemia (450-680 micromol/l) and deficient activity of 4-HPD. At 17 months of age she experienced an acute ataxia and drowsiness lasting for 10 days, but further clinical course showed persistent tyrosinemia with normal growth and psychomotor development. Neutrophils isolated from our patient exhibited a NO release greatly higher in respect to the controls (mean+/-SEM 23.2+/-1.8 micromol/10(6) cells vs 3.5+/-0.5 micromol/10(6) cells). Clinical findings of tyrosinemia type III include neurological symptoms and mental retardation but no consistent phenotype has emerged. Therefore the pathogenesis of neurological involvement is yet not well understood. Our results suggest that an excessive neutrophils of NO release could reflect the lack of scavenging action of 4-HPD. Considering the prominent expression of this enzyme in neurons, we hypothesize that excessive NO release could participate in neuronal damage explaining the neurological involvement described in patients with tyrosinemia type III.

  11. 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.

  12. Solid phase extraction of gold(III) on Amberlite XAD-2000 prior to its flame atomic absorption spectrometric determination.

    PubMed

    Elci, Latif; Sahan, Derya; Basaran, Aydan; Soylak, Mustafa

    2007-09-01

    A solid phase extraction method for the determination of gold(III) at trace levels by flame atomic absorption spectrometer (FAAS) was developed. The method was based on retention of gold as chloro complexes through the Amberlite XAD-2000. The effect of some analytical parameters including hydrochloric acid concentration, sample volume, sample and eluent flow rates, eluent volume, eluent concentration and interfering ions on the recovery of gold(III) was investigated. The retention of gold(III) from 1.5 mol l(-1) HCl solution and the recovery of gold with 0.07 mol l(-1) NH3 solution were quantitative (>or=95%). The relative standard deviation (RSD) was calculated as 3.2% (n = 10). The detection limit for gold was 2 microg l(-1). The accuracy was checked with the determination of gold spiked an artificial seawater and a pure copper samples.

  13. Solid phase extraction of gold(III) on Amberlite XAD-2000 prior to its flame atomic absorption spectrometric determination.

    PubMed

    Elci, Latif; Sahan, Derya; Basaran, Aydan; Soylak, Mustafa

    2007-09-01

    A solid phase extraction method for the determination of gold(III) at trace levels by flame atomic absorption spectrometer (FAAS) was developed. The method was based on retention of gold as chloro complexes through the Amberlite XAD-2000. The effect of some analytical parameters including hydrochloric acid concentration, sample volume, sample and eluent flow rates, eluent volume, eluent concentration and interfering ions on the recovery of gold(III) was investigated. The retention of gold(III) from 1.5 mol l(-1) HCl solution and the recovery of gold with 0.07 mol l(-1) NH3 solution were quantitative (>or=95%). The relative standard deviation (RSD) was calculated as 3.2% (n = 10). The detection limit for gold was 2 microg l(-1). The accuracy was checked with the determination of gold spiked an artificial seawater and a pure copper samples. PMID:17180414

  14. Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies.

    PubMed

    Beck, Bodo B; Baasner, Anne; Buescher, Anja; Habbig, Sandra; Reintjes, Nadine; Kemper, Markus J; Sikora, Przemyslaw; Mache, Christoph; Pohl, Martin; Stahl, Mirjam; Toenshoff, Burkhard; Pape, Lars; Fehrenbach, Henry; Jacob, Dorrit E; Grohe, Bernd; Wolf, Matthias T; Nürnberg, Gudrun; Yigit, Gökhan; Salido, Eduardo C; Hoppe, Bernd

    2013-02-01

    Identification of mutations in the HOGA1 gene as the cause of autosomal recessive primary hyperoxaluria (PH) type III has revitalized research in the field of PH and related stone disease. In contrast to the well-characterized entities of PH type I and type II, the pathophysiology and prevalence of type III is largely unknown. In this study, we analyzed a large cohort of subjects previously tested negative for type I/II by complete HOGA1 sequencing. Seven distinct mutations, among them four novel, were found in 15 patients. In patients of non-consanguineous European descent the previously reported c.700+5G>T splice-site mutation was predominant and represents a potential founder mutation, while in consanguineous families private homozygous mutations were identified throughout the gene. Furthermore, we identified a family where a homozygous mutation in HOGA1 (p.P190L) segregated in two siblings with an additional AGXT mutation (p.D201E). The two girls exhibiting triallelic inheritance presented a more severe phenotype than their only mildly affected p.P190L homozygous father. In silico analysis of five mutations reveals that HOGA1 deficiency is causing type III, yet reduced HOGA1 expression or aberrant subcellular protein targeting is unlikely to be the responsible pathomechanism. Our results strongly suggest HOGA1 as a major cause of PH, indicate a greater genetic heterogeneity of hyperoxaluria, and point to a favorable outcome of type III in the context of PH despite incomplete or absent biochemical remission. Multiallelic inheritance could have implications for genetic testing strategies and might represent an unrecognized mechanism for phenotype variability in PH.

  15. A phase I/II study of the pan Bcl-2 inhibitor obatoclax mesylate plus bortezomib for relapsed or refractory mantle cell lymphoma

    PubMed Central

    Goy, André; Hernandez-Ilzaliturri, Francisco J.; Kahl, Brad; Ford, Peggy; Protomastro, Ewelina; Berger, Mark

    2015-01-01

    Obatoclax, a BH3 mimetic inhibitor of anti-apoptotic Bcl-2 proteins, demonstrates synergy with bortezomib in preclinical models of mantle cell lymphoma (MCL). This phase I/II study assessed obatoclax plus bortezomib in patients with relapsed/refractory MCL. Twenty-three patients received obatoclax 30 or 45 mg plus bortezomib 1.0 or 1.3 mg/m2, administered intravenously on days 1, 4, 8 and 11 of a 21-day cycle. In phase I, the combination was feasible at all doses. Obatoclax 45 mg plus bortezomib 1.3 mg/m2 was selected for phase II study. Common adverse events were somnolence (87%), fatigue (61%) and euphoric mood (57%), all primarily grade 1/2. Grade 3/4 events included thrombocytopenia (21%), anemia (13%) and fatigue (13%). Objective responses occurred in 4/13 (31%) evaluable patients (three complete and one partial response). Six patients (46%) had stable disease lasting ≥ 8 weeks. Obatoclax plus bortezomib was feasible, but the synergy demonstrated in preclinical models was not confirmed. PMID:24679008

  16. Genomic Scans of Zygotic Disequilibrium and Epistatic SNPs in HapMap Phase III Populations

    PubMed Central

    Hu, Xin-Sheng; Hu, Yang

    2015-01-01

    Previous theory indicates that zygotic linkage disequilibrium (LD) is more informative than gametic or composite digenic LD in revealing natural population history. Further, the difference between the composite digenic and maximum zygotic LDs can be used to detect epistatic selection for fitness. Here we corroborate the theory by investigating genome-wide zygotic LDs in HapMap phase III human populations. Results show that non-Africa populations have much more significant zygotic LDs than do Africa populations. Africa populations (ASW, LWK, MKK, and YRI) possess more significant zygotic LDs for the double-homozygotes (DAABB) than any other significant zygotic LDs (DAABb, DAaBB, and DAaBb), while non-Africa populations generally have more significant DAaBb’s than any other significant zygotic LDs (DAABB, DAABb, and DAaBB). Average r-squares for any significant zygotic LDs increase generally in an order of populations YRI, MKK, CEU, CHB, LWK, JPT, CHD, TSI, GIH, ASW, and MEX. Average r-squares are greater for DAABB and DAaBb than for DAaBB and DAABb in each population. YRI and MKK can be separated from LWK and ASW in terms of the pattern of average r-squares. All population divergences in zygotic LDs can be interpreted with the model of Out of Africa for modern human origins. We have also detected 19735-95921 SNP pairs exhibiting strong signals of epistatic selection in different populations. Gene-gene interactions for some epistatic SNP pairs are evident from empirical findings, but many more epistatic SNP pairs await evidence. Common epistatic SNP pairs rarely exist among all populations, but exist in distinct regions (Africa, Europe, and East Asia), which helps to understand geographical genomic medicine. PMID:26126177

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

    PubMed

    Dobkin, Bruce H

    2009-01-01

    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.

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. Comparability of the expanded WMS-III standardization protocol to the published WMS-III among right and left temporal lobectomy patients.

    PubMed

    Doss, R C; Chelune, G J; Naugle, R I

    2000-11-01

    We examined whether differences between the expanded standardization protocol (SP) used to derive norms for the final published version (PB) of the Wechsler Memory Scale - Third Edition (WMS-III; Wechsler, 1997a) would result in differences on the Primary Indexes in a neurologic sample. Specifically, we examined the comparability of the performances of 63 patients with temporal lobectomy (TL) who were administered either the expanded SP protocol (n = 33: 22 left TL and 11 right TL) or the PB battery (n = 30: 11 left TL and 19 right TL). Patients who were administered the SP or PB were comparable in terms of age, sex, education, seizure duration, postsurgical seizure status, and Full Scale IQ. Postoperative intervals were significantly longer for the SP group, although correlational analyses demonstrated no significant relationship between postoperative follow-up interval and WMS-III performance. A series of t tests revealed no significant differences on any of the eight Primary Index scores between patients taking the two versions of the WMS-III for either left or right TL groups. Furthermore, repeated measures analyses of variance failed to show significant differences on modality-specific memory scores between the SP and PB for the left and right TL groups. The current study indicates that temporal lobectomy patients obtained comparable scores on the two versions of the WMS-III.

  3. 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.

  4. 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

  5. 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.

  6. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma

    PubMed Central

    Sampson, John H.; Aldape, Kenneth D.; Archer, Gary E.; Coan, April; Desjardins, Annick; Friedman, Allan H.; Friedman, Henry S.; Gilbert, Mark R.; Herndon, James E.; McLendon, Roger E.; Mitchell, Duane A.; Reardon, David A.; Sawaya, Raymond; Schmittling, Robert; Shi, Weiming; Vredenburgh, James J.; Bigner, Darell D.; Heimberger, Amy B.

    2011-01-01

    Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m2 per 5 days) or dose-intensified (DI) TMZ (100 mg/m2 per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3+ T-cell (P = .005) and B-cell (P = .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (TReg; P = .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P = .037) and delayed-type hypersensitivity responses (P = .036) of greater magnitude. EGFRvIII-expressing tumor cells were also eradicated in nearly all patients (91.6%; CI95: 64.0%–99.8%; P < .0001). The median progression-free survival (15.2 months; CI95: 11.0–18.5 months; hazard ratio [HR] = 0.35; P = .024) and overall survival (23.6 months; CI95: 18.5–33.1 months; HR = 0.23; P = .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIII-targeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity. PMID:21149254

  7. Two-Step Extraction of the Lower First Molar for Class III Treatment in Adult Patient

    PubMed Central

    Paulin, Ricardo Fabris; Raveli, Taísa Barnabé; Raveli, Dirceu Barnabé

    2016-01-01

    The aim of this article is to describe a case report of Class III malocclusion treatment with lower first molar extraction. The 27-year-old Caucasian male patient presented a symmetric face with a straight profile, hyperdivergent growth pattern, molar and cuspid Class III relation, and an anterior crossbite as well as a mild crowding on cuspids area, in both upper and lower arches and a tendency to posterior crossbite. The treatment was performed by the use of Haas expansion appliance followed by an initial alignment and leveling of the upper and lower arches with a fixed edgewise appliance, extraction of lower teeth aiming the correction of the incisors proclination and end the treatment with a Class I molar relationship. It resulted in a significant change in the patient's profile, dentoalveolar Class III correction, upper arch expansion, leveling and alignment of the upper and lower arches, and improvement of tipping of the upper and lowers incisors. In cases of a dentoalveolar compensation in well positioned bone bases the treatment with fixed appliances is an alternative and extraction of lower teeth is considered.

  8. Two-Step Extraction of the Lower First Molar for Class III Treatment in Adult Patient

    PubMed Central

    Paulin, Ricardo Fabris; Raveli, Taísa Barnabé; Raveli, Dirceu Barnabé

    2016-01-01

    The aim of this article is to describe a case report of Class III malocclusion treatment with lower first molar extraction. The 27-year-old Caucasian male patient presented a symmetric face with a straight profile, hyperdivergent growth pattern, molar and cuspid Class III relation, and an anterior crossbite as well as a mild crowding on cuspids area, in both upper and lower arches and a tendency to posterior crossbite. The treatment was performed by the use of Haas expansion appliance followed by an initial alignment and leveling of the upper and lower arches with a fixed edgewise appliance, extraction of lower teeth aiming the correction of the incisors proclination and end the treatment with a Class I molar relationship. It resulted in a significant change in the patient's profile, dentoalveolar Class III correction, upper arch expansion, leveling and alignment of the upper and lower arches, and improvement of tipping of the upper and lowers incisors. In cases of a dentoalveolar compensation in well positioned bone bases the treatment with fixed appliances is an alternative and extraction of lower teeth is considered. PMID:27699072

  9. 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.

  10. Phase I/II trial of whole-abdominal plus pelvic irradiation for Astler-Coller stage beta 2, C colorectal cancer

    SciTech Connect

    Patanaphan, V.; Salazar, O.M.; Slawson, R.G.; Sewchand, W.

    1988-02-01

    From 1982 to 1986, after radical surgery (S) for carcinoma of the rectum and rectosigmoid colon, 25 consecutive patients were entered into a Phase I/II study exploring adjuvant radiation (RT). The latter was given with a single fraction of whole abdomen (mid-body) irradiation (MBI), followed by conventional whole pelvis irradiation (WPI). The minimum follow-up time was 12 months, and the maximum was 44 months. There was escalation of the single MBI dose: 5 Gy in 11 patients, 6 Gy in two patients, and 8 Gy in 10 patients. The 2-year survival rate has been 100 and 45% for Stages B2 and C patients. Only 1/7 Astler-Coller Stage B2 patients failed; this failure was in the lungs. Seven of 15 patients with Stage C failed: one locally, three in the liver, and three in the lungs. Single MBI doses greater than 5 Gy have yielded a high incidence of intestinal obstruction when combined with routine WPI. Consequently, this combination requires both some modification and careful attention if used in future trials exploring new treatment approaches for colorectal cancer.

  11. Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene (HPD) in patients with tyrosinemia type III.

    PubMed

    Rüetschi, U; Cerone, R; Pérez-Cerda, C; Schiaffino, M C; Standing, S; Ugarte, M; Holme, E

    2000-06-01

    Tyrosinemia type III (OMIM 276710) is an autosomal recessive disorder caused by the deficiency of 4-hydroxyphenylpyruvate dioxygenase (HPD), the second enzyme in the tyrosine catabolic pathway. The enzyme deficiency results in an accumulation and increased excretion of tyrosine and phenolic metabolites. Only a few cases with the disorder have been described, and the clinical spectrum of the disorder is unknown. Reported patients have presented with mental retardation or neurological symptoms or have been picked up by neonatal screening. We have identified four presumed pathogenic mutations (two missense and two nonsense mutations) in the HPD gene in three unrelated families encompassing four homozygous individuals and one compound heterozygous individual with tyrosinemia type III. Furthermore, a number of polymorphic mutations have been identified in the HPD gene. No correlation of the severity of the mutation and enzyme deficiency and mental function has been found; neither do the recorded tyrosine levels correlate with the clinical phenotype.

  12. Successful management of grade III coronary perforation after percutaneous angioplasty in a high-risk patient: a case report.

    PubMed

    Coloma Araniya, Ricardo; Beas, Renato; Maticorena-Quevedo, Jesús; Anduaga-Beramendi, Alexander; Pastrana Castillo, Marco Antonio

    2016-01-01

    Coronary perforation is a rare complication in patients undergoing percutaneous coronary angioplasty. The mortality of this complication varies depending on factors related to the patient and the procedure performed, reaching 44% in patients with Ellis type III perforation. We report the case of an 81 year old male with multiple cardiovascular risk factors, who underwent percutaneous angioplasty for unstable angina management. The patient developed grade III coronary perforation in the anterior descending artery, which was successfully managed with balloon inflation to 6 atmospheres for 10 minutes twice in the affected area, with an interval of 5 minutes between each dilatation. The patient improved and was discharged. PMID:26938857

  13. Metabolism of a Lipid Nanoemulsion Resembling Low-Density Lipoprotein in Patients with Grade III Obesity

    PubMed Central

    Dantas, Simone Alves; Ficker, Elisabeth Salvatori; Vinagre, Carmen G. C.; Ianni, Barbara Maria; Maranhão, Raul Cavalcante; Mady, Charles

    2010-01-01

    INTRODUCTION: Obesity increases triglyceride levels and decreases high-density lipoprotein concentrations in plasma. Artificial emulsions resembling lipidic plasma lipoprotein structures have been used to evaluate low-density lipoprotein metabolism. In grade III obesity, low density lipoprotein metabolism is poorly understood. OBJECTIVE: To evaluate the kinetics with which a cholesterol-rich emulsion (called a low-density emulsion) binds to low-density lipoprotein receptors in a group of patients with grade III obesity by the fractional clearance rate. METHODS: A low-density emulsion was labeled with [14C]-cholesterol ester and [3H]-triglycerides and injected intravenously into ten normolipidemic non-diabetic patients with grade III obesity [body mass index higher than 40 kg/m2] and into ten non-obese healthy controls. Blood samples were collected over 24 hours to determine the plasma decay curve and to calculate the fractional clearance rate. RESULTS: There was no difference regarding plasma levels of total cholesterol or low-density lipoprotein cholesterol between the two groups. The fractional clearance rate of triglycerides was 0.086 ± 0.044 in the obese group and 0.122 ± 0.026 in the controls (p = 0.040), and the fractional clearance rate of cholesterol ester (h−1) was 0.052 ± 0.021 in the obese subjects and 0.058 ± 0.015 (p = 0.971) in the controls. CONCLUSION: Grade III obese subjects exhibited normal low-density lipoprotein removal from plasma as tested by the nanoemulsion method, but triglyceride removal was slower. PMID:20126342

  14. 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. PMID:26075487

  15. Open-label, randomized, comparative, phase III study on effects of reducing steroid use in combination with Palonosetron.

    PubMed

    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

    2015-07-01

    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.

  16. High frequency of W1327X mutation in glycogen storage disease type III patients from central Tunisia.

    PubMed

    Cherif, Wafa; Ben Rhouma, Faten; Messai, Habib; Mili, Amira; Gribaa, Moez; Kefi, Rym; Ayadi, Abdelkarim; Boughamoura, Lamia; Chemli, Jelel; Saad, Ali; Kaabachi, Naziha; Sfar, Mohamed Tahar; Ben Dridi, Marie-Françoise; Tebib, Neji; Abdelhak, Sonia

    2012-01-01

    Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by the deficiency of glycogen debranching enzyme (AGL). It is characterized by hepatomegaly, progressive myopathy, cardiomyopathy and fasting hypoglycemia. Several mutations in AGL gene have been described in different populations. The W1327X mutation was reported in one Tunisian patient resident in Italy. We looked in this report to determine the frequency of W1327X mutation among Tunisian patients. The W1327X mutation was screening in 26 GSD III patients originated from various geographic locations in Tunisia. The sequence analysis revealed that among nine patients carried the W1327X mutation. Eight of them were from six unrelated families and they were originated from Mahdia (centre of Tunisia) suggesting the existence of a founder effect in this region. Taking into account historical migratory waves, screening for this mutation should be performed in priority for molecular diagnosis confirmation of GSD III in North African populations.

  17. 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. PMID:26933681

  18. 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

  19. 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.

  20. 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

  1. Triple peptide vaccination as consolidation treatment in women affected by ovarian and breast cancer: Clinical and immunological data of a phase I/II clinical trial

    PubMed Central

    ANTONILLI, MORENA; RAHIMI, HASSAN; VISCONTI, VALERIA; NAPOLETANO, CHIARA; RUSCITO, ILARY; ZIZZARI, ILARIA GRAZIA; CAPONNETTO, SALVATORE; BARCHIESI, GIACOMO; IADAROLA, ROBERTA; PIERELLI, LUCA; RUGHETTI, AURELIA; BELLATI, FILIPPO; PANICI, PIERLUIGI BENEDETTI; NUTI, MARIANNA

    2016-01-01

    Vaccination with priming and expansion of tumour reacting T cells is an important therapeutic option to be used in combination with novel checkpoint inhibitors to increase the specificity of the T cell infiltrate and the efficacy of the treatment. In this phase I/II study, 14 high-risk disease-free ovarian (OC) and breast cancer (BC) patients after completion of standard therapies were vaccinated with MUC1, ErbB2 and carcinoembryonic antigen (CEA) HLA-A2+-restricted peptides and Montanide. Patients were subjected to 6 doses of vaccine every two weeks and a recall dose after 3 months. ECOG grade 2 toxicity was observed at the injection site. Eight out of 14 patients showed specific CD8+ T cells to at least one antigen. None of 4 patients vaccinated for compassionate use showed a CD8 activation. An OC patient who suffered from a lymph nodal recurrence, showed specific anti-ErbB2 CD8+ T cells in the bulky aortic lymph nodes suggesting homing of the activated T cells. Results confirm that peptide vaccination strategy is feasible, safe and well tolerated. In particular OC patients appear to show a higher response rate compared to BC patients. Vaccination generates a long-lasting immune response, which is strongly enhanced by recall administrations. The clinical outcome of patients enrolled in the trial appears favourable, having registered no deceased patients with a minimum follow-up of 8 years. These promising data, in line with the results of similar studies, the high compliance of patients observed and the favourable toxicity profile, support future trials of peptide vaccination in clinically disease-free patients who have completed standard treatments. PMID:26892612

  2. ASA III osteoporotic fracture in 62 patients treated with vertebroplasty under local anesthesia.

    PubMed

    Emre, Tuluhan Yunus; Gökcen, H Bahadır; Atbaşı, Zafer; Kavadar, Gülis; Enercan, Meriç; Ozturk, Cagatay

    2016-01-01

    Vertebroplasty is a minimally invasive procedure that may be performed under either local or general anesthesia. In this study, we aimed at assessing the outcomes of the vertebroplasty performed under local anesthesia in patients at high risk of general anesthesia. Vertebroplasty was performed under local anesthesia in the treatment of a total of 62 patients (68 vertebrae in total) with osteoporotic vertebral fractures between 2011 and 2013. None of the patients had a history of trauma. Patients who were classified as ASA III during the preoperative examinations were included in the study. VAS scores were evaluated before the surgery, on the first postoperative day, and in week 1 and in month 1 after the surgery. The average age was 77.5 years (age range 53-102). An average of 2 cc of cement was injected to 22 patients (35.5 %), and an average of 3 cc of cement was injected to 40 patients (64.5 %). The mean VAS scores were 7.52 (6-9) before the procedure, 3.55 (2-5) on the first day, 2.03 (0-4) in week 1 and 0.87 (0-2) in month 1 postoperatively. Asymptomatic cement embolism was detected in one patient. No other complications were observed in the study group. Vertebroplasty performed under local anesthesia is an effective and safe procedure in terms of pain control and early ambulation and is bereft of the complications associated with general anesthesia.

  3. Spinal muscular atrophy type III: Molecular genetic characterization of Turkish patients.

    PubMed

    Bora-Tatar, Gamze; Yesbek-Kaymaz, Ayse; Bekircan-Kurt, Can Ebru; Erdem-Özdamar, Sevim; Erdem-Yurter, Hayat

    2015-12-01

    Spinal Muscular Atrophy (SMA) is a neurodegenerative disease with autosomal recessive inheritance. Homozygous loss of exon 7 of the Survival of motor neuron 1 (SMN1) gene is the main cause of SMA. Although progressive muscle weakness and atrophy are common symptoms, disease severity varies from severe to mild. Type III is one of the milder and less frequent forms of SMA. In this study, we report molecular genetic characteristics of 24 Turkish type III SMA patients. Homozygous loss of SMN1 exon 7 and 8 was analysed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex ligation dependent probe amplification (MLPA). SMN2, homologue of SMN1, and Neuronal apoptosis inhibitory protein (NAIP) genes were also evaluated considering their influence on disease severity. We determined that male patients who were born in consanguineous families were predominant in our cohort and these patients mostly carry the homozygous loss of SMN1 exon 7 and 8 and four copies of SMN2 gene without NAIP deletions. PMID:26548498

  4. Outpatient bendamustine and idarubicin for upfront therapy of elderly acute myeloid leukaemia/myelodysplastic syndrome: a phase I/II study using an innovative statistical design.

    PubMed

    Lionberger, Jack M; Pagel, John M; Sandhu, Vicky K; Xie, Hu; Shadman, Mazyar; Mawad, Raya; Boehm, Alexandra; Dean, Carol; Shannon-Dorcy, Kathleen; Scott, Bart L; Deeg, Hans Joachim; Becker, Pamela S; Hendrie, Paul C; Walter, Roland B; Ostronoff, Fabiana; Appelbaum, Frederick R; Estey, Elihu H

    2014-08-01

    Combinations of agents may improve outcomes among elderly acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS) patients. We performed an adaptive phase I/II trial for newly-diagnosed AML or high-risk MDS patients aged ≥50 years using a Bayesian approach to determine whether 1 of 3 doses of bendamustine (45, 60, 75 mg/m(2) days 1-3), together with idarubicin (12 mg/m(2) days 1-2), might provide a complete response (CR) rate ≥40% with <30% grade 3-4 non-haematological toxicity. We treated 39 patients (34 AML; five MDS with >10% marrow blasts; median age 73 years). None of the three bendamustine doses in combination with idarubicin met the required CR and toxicity rates; the 75 mg/m(2) dose because of excess toxicity (two of three patients) and the 60 mg/m(2) dose because of low efficacy (CR rate 10/33), although no grade 3-4 non-haematological toxicity was seen at this dose. Median survival was 7·2 months. All patients began treatment as outpatients but hospitalization was required in 90% (35/39). Although we did not find a dose of bendamustine combined with idarubicin that would provide a CR rate of >40% with acceptable toxicity, bendamustine may have activity in AML/MDS patients, suggesting its addition to other regimens may be warranted.

  5. Carbon-ion radiotherapy for locally advanced or unfavorably located choroidal melanoma: A Phase I/II dose-escalation study

    SciTech Connect

    Tsuji, Hiroshi . E-mail: h_tsuji@nirs.go.jp; Ishikawa, Hitoshi; Yanagi, Takeshi; Hirasawa, Naoki; Kamada, Tadashi; Mizoe, Jun-Etsu; Kanai, Tatsuaki; Tsujii, Hirohiko; Ohnishi, Yoshitaka

    2007-03-01

    Purpose: To evaluate the applicability of carbon ion beams for the treatment of choroidal melanoma with regard to normal tissue morbidity and local tumor control. Methods and Materials: Between January 2001 and February 2006, 59 patients with locally advanced or unfavorably located choroidal melanoma were enrolled in a Phase I/II clinical trial of carbon-ion radiotherapy at the National Institute of Radiologic Sciences. The primary endpoint of this study was normal tissue morbidity, and secondary endpoints were local tumor control and patient survival. Of the 59 subjects enrolled, 57 were followed >6 months and analyzed. Results: Twenty-three patients (40%) developed neovascular glaucoma, and three underwent enucleation for eye pain due to elevated intraocular pressure. Incidence of neovascular glaucoma was dependent on tumor size and site. Five patients had died at analysis, three of distant metastasis and two of concurrent disease. All but one patient, who developed marginal recurrence, were controlled locally. Six patients developed distant metastasis, five in the liver and one in the lung. Three-year overall survival, disease-free survival, and local control rates were 88.2%, 84.8%, and 97.4%, respectively. No apparent dose-response relationship was observed in either tumor control or normal tissue morbidity at the dose range applied. Conclusion: Carbon-ion radiotherapy can be applied to choroidal melanoma with an acceptable morbidity and sufficient antitumor effect, even with tumors of unfavorable size or site.

  6. Orthodontic retreatment of a Class III patient with significant midline asymmetry and bilateral posterior crossbite

    PubMed Central

    Brunetto, Ademir R.

    2015-01-01

    Posterior crossbite might cause serious long-term functional problems if not early treated. Nevertheless, in older patients, treatment might include palatal expansion in order to correct such malocclusion. In view of the above, this article aims at reporting late correction of bilateral posterior crossbite associated with Angle Class III malocclusion, right subdivision, with consequent midline shift (good skeletal pattern). The case was presented to the Brazilian Board of Orthodontics and Dentofacial Orthopedics (BBO), with DI equal to or greater than 10, as a requirement for the title of certified by the BBO. PMID:25741833

  7. Association of Family History with Cancer Recurrence and Survival Among Patients with Stage III Colon Cancer

    PubMed Central

    Chan, Jennifer A.; Meyerhardt, Jeffrey A.; Niedzwiecki, Donna; Hollis, Donna; Saltz, Leonard B.; Mayer, Robert J.; Thomas, James; Schaefer, Paul; Whittom, Renaud; Hantel, Alexander; Goldberg, Richard M.; Warren, Robert S.; Bertagnolli, Monica; Fuchs, Charles S.

    2011-01-01

    Context A family history of colorectal cancer in a first-degree relative increases the risk of developing colorectal cancer. However, the influence of family history on cancer recurrence and survival among patients with established disease remains uncertain. Objective To examine the association of family history of colorectal cancer with cancer recurrence and survival of patients with colon cancer. Design, Setting, and Participants Prospective observational study of 1,087 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial (CALGB 89803) between April 1999 and May 2001. Patients provided data on family history at baseline and were followed up until March 2007 for disease recurrence and death (median follow-up 5.6 years). In a subset of patients, we assessed microsatellite instability (MSI) and expression of the mismatch repair (MMR) proteins, MLH1 and MSH2, in tumor specimens. Main Outcome Measure Disease-free survival, recurrence-free survival, and overall survival according to the presence or absence of a family history of colorectal cancer. Results Among 1,087 eligible patients, 195 (17.9%) reported a family history of colorectal cancer in a first-degree relative. Cancer recurrence or death occurred in 57/195 patients (29%; 95% confidence interval [CI], 23%-36%) with a family history of colorectal cancer and 343/892 patients (38%; 95% CI, 35%-42%) without a family history. Compared to patients without a family history, the adjusted hazard ratios (HR) among those with ≥1 affected first-degree relatives were 0.72 (95% CI, 0.54-0.96) for disease-free survival (DFS), 0.74 (95% CI, 0.55-0.99) for recurrence-free survival (RFS), and 0.75 (95% CI, 0.54-1.05) for overall survival (OS). This reduction in risk of cancer recurrence or death associated with a family history became stronger with an increasing number of affected first-degree relatives. Compared to participants without a family history of colorectal cancer, those with 1

  8. 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

  9. 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)…

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

    ClinicalTrials.gov

    2016-04-05

    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

  11. 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.…

  12. High-Dose Conformal Radiotherapy for Patients With Stage III Non-Small-Cell Lung Carcinoma

    SciTech Connect

    Nakayama, Hidetsugu; Satoh, Hiroaki; Kurishima, Koichi; Ishikawa, Hiroichi; Tokuuye, Koichi

    2010-11-01

    Purpose: To determine the effectiveness of high-dose conformal radiotherapy to the involved field for patients with Stage III non-small-cell lung cancer (NSCLC). Methods and Materials: Between May 1999 and April 2006, a total of 100 consecutive patients with inoperable Stage IIIA or IIIB NSCLC with a performance score of 0 to 2 and treatment by radical radiotherapy combined with chemotherapy were included. Up to August 2002, 33 patients underwent conventional radiotherapy of 56 Gy to 66 Gy using anteroposterior opposite ports to the primary tumor and elective lymph nodes (conventional group). After September 2002, the remaining 67 patients underwent high-dose radiotherapy of 66 Gy to 84 Gy to the involved volume with three-dimensional (3-D) conformal radiotherapy (conformal group). Results: The median survival was 13.2 months (95% confidence interval [CI], 7.5-18.5 months) in the conventional group and 17.3 months (95% CI, 10.7- 24.0 months) in the conformal group. The overall survival at 3 years were 9.1% (95% CI, -0.7-18.9%) in the conventional group and 31.0% (95% CI, 18.9-43.1%) in the conformal group; the conformal group had a significantly better overall survival (p < 0.05). The radiotherapy method (hazard ratio = 0.55, p < 0.05) and performance status (hazard ratio = 1.48, p < 0.05) were shown to be statistically significant independent prognostic factors. Conclusions: Based on the practical experience reported here, 3-D conformal radiotherapy allowed dose escalation without excessive toxicity, and may improve overall survival rates for patients with Stage III NSCLC.

  13. Continuous 7-Days-A-Week External Beam Irradiation in Locally Advanced Cervical Cancer: Final Results of the Phase I/II Study

    SciTech Connect

    Serkies, Krystyna; Dziadziuszko, Rafal; Jassem, Jacek

    2012-03-01

    Purpose: To evaluate the feasibility and efficacy of definitive continuous 7-days-a-week pelvic irradiation without breaks between external beam radiotherapy and brachytherapy in locally advanced cervical cancer. Methods and Materials: Between November 1998 and December 1999, 30 patients with International Federation of Obstetrics and Gynecology Stage IIB or IIIB cervical cancer were included in a prospective Phase I/II study of continuous 7-days-a-week pelvic irradiation, to the total Manchester point B dose of 40.0-57.6 Gy. The first 13 patients (Group A) were given a daily tumor dose of 1.6 Gy, and the remaining 17 patients (Group B) were given 1.8 Gy. One or two immediate brachytherapy applications (point A dose 10-20 Gy, each) were performed in 28 cases. Results: Two patients did not complete the irradiation because of apparent early progression of disease during the irradiation. Eleven of the 28 evaluable patients (39%; 45% and 35% in Groups A and B, respectively) completed their treatment within the prescribed overall treatment time. Acute toxicity (including severe European Organisation for Research and Treatment of Cancer/Radiation Therapy Oncology Group Grade 3 and 4 effects in 40%) was experienced by 83% of patients and resulted in unplanned treatment interruptions in 40% of all patients (31% and 47% of patients in Groups A and B, respectively). Severe intestinal side effects occurred in 31% and 41% of Patients in Groups A and B, respectively (p = 0.71). The 5-year overall survival probability was 33%. Cancer recurrence occurred in 63% of patients: 20% inside and 57% outside the pelvis. Cumulative incidence of late severe bowel and urinary bladder toxicity at 24 months was 15%. Conclusion: Continuous irradiation in locally advanced cervical cancer is associated with a high incidence of severe acute toxicity, resulting in unplanned treatment interruptions. Late severe effects and survival after continuous radiotherapy do not substantially differ from

  14. Semicontinuous Low-Dose-Rate Teletherapy for the Treatment of Recurrent Glial Brain Tumors: Final Report of a Phase I/II Study

    SciTech Connect

    Siker, Malika L.; Firat, Selim Y.; Mueller, Wade; Krouwer, Hendrikus; Schultz, Christopher J.

    2012-02-01

    Purpose: Semicontinuous low-dose-rate teletherapy (SLDR) is a novel irradiation strategy that exploits the increased radiosensitivity of glial cells in a narrow range of reduced dose rate. We present the final report of a prospective Phase I/II study testing the feasibility of SLDR for the treatment of recurrent gliomas. Methods and Materials: Patients with previously irradiated recurrent gliomas were enrolled from November 1993 to March 1998. Patients received SLDR, delivered 6 to 8 hours/day at a dose rate of 40 to 50 cGy/hour for a total dose of 30 to 35 Gy given over 12 days using a modified cobalt-60 treatment unit. Acute central nervous system toxicity after SLDR treatment was the primary endpoint. Overall survival was a secondary endpoint. Results: Twenty patients were enrolled (14 World Health Organization Grade 4 glioma, 5 Grade 2 glioma, 1 ependymoma). No patients developed {>=}Grade 3 central nervous system toxicity at 3 months without radiographic evidence of tumor progression. Overall survival after SLDR was 56% at 6 months, 28% at 12 months, and 17% at 24 months. One patient survived >48 months, and 1 patient survived >60 months after SLDR treatment. Re-resection before SLDR treatment significantly improved 1-year overall survival for all patients and patients with Grade 4 glioma. Conclusion: The delivery of SLDR is feasible in patients with recurrent gliomas and resulted in improved outcomes for patients who underwent re-resection. There were 2 long-term survivors (>48 months). This pilot study supports the notion that reduced dose rate influences the efficacy and tolerance of reirradiation in the treatment of recurrent gliomas.

  15. 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

  16. 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

  17. Effects of Single Low Dose of Dexamethasone before Noncardiac and Nonneurologic Surgery and General Anesthesia on Postoperative Cognitive Dysfunction—A Phase III Double Blind, Randomized Clinical Trial

    PubMed Central

    Pereira, Valeria Fontenelle Angelim; Pietrobon, Ricardo S.; Schmidt, Andre P.; Oses, Jean P.; Portela, Luis V.; Souza, Diogo O.; Vissoci, João Ricardo Nickenig; da Luz, Vinicius Fernando; Trintoni, Leticia Maria de Araujo de Souza; Nielsen, Karen C.; Carmona, Maria José Carvalho

    2016-01-01

    Postoperative cognitive dysfunction (POCD) is a multifactorial adverse event most frequently in elderly patients. This study evaluated the effect of dexamethasone on POCD incidence after noncardiac and nonneurologic surgery. METHODS: One hundred and forty patients (ASA I-II; age 60–87 years) took part in a prospective phase III, double blind, randomized study involving the administration or not of 8 mg of IV dexamethasone before general anesthesia under bispectral index (BIS) between 35–45 or 46–55. Neuropsychological tests were applied preoperatively and on the 3rd, 7th, 21st, 90th and 180th days after surgery and compared with normative data. S100β was evaluated before and 12 hours after induction of anesthesia. The generalized estimating equations (GEE) method was applied, followed by the posthoc Bonferroni test considering P<0.05 as significant. RESULTS: On the 3rd postoperative day, POCD was diagnosed in 25.2% and 15.3% of patients receiving dexamethasone, BIS 35–45, and BIS 46–55 groups, respectively. Meanwhile, POCD was present in 68.2% and 27.2% of patients without dexamethasone, BIS 35–45 and BIS 46–55 groups (p<0.0001). Neuropsychological tests showed that dexamethasone associated to BIS 46–55 decreased the incidence of POCD, especially memory and executive function. The administration of dexamethasone might have prevented the postoperative increase in S100β serum levels. CONCLUSION: Dexamethasone can reduce the incidence of POCD in elderly patients undergoing surgery, especially when associated with BIS 46–55. The effect of dexamethasone on S100β might be related with some degree of neuroprotection. Trial Registration: www.clinicaltrials.gov NCT01332812 PMID:27152422

  18. A Phase I Study of Dasatinib with Concurrent Chemoradiation for Stage III Non-Small Cell Lung Cancer

    PubMed Central

    Khurshid, Humera; Dipetrillo, Thomas; Ng, Thomas; Mantripragada, Kalyan; Birnbaum, Ariel; Berz, David; Radie-Keane, Kathy; Perez, Kimberly; Constantinou, Maria; Luppe, Denise; Schumacher, Andrew; Leonard, Kara; Safran, Howard

    2012-01-01

    Objectives: Src family kinases (SFKs) are expressed in non-small cell lung cancer (NSCLC) and may be involved in tumor growth and metastases. Inhibition of SFK may also enhance radiation. The purpose of this study was to evaluate if a maximum dose of 100 mg of dasatinib could be safely administered with concurrent chemoradiation and then continued as maintenance for patients with newly diagnosed stage III NSCLC. Methods: Patients with stage III locally advanced NSCLC received paclitaxel, 50 mg/m2/week, with carboplatin area under the curve (AUC) = 2, weekly for 7 weeks, and concurrent radiotherapy, 64.8 Gy. Three dose levels of dasatinib 50, 70, and 100 mg/day were planned. Results: 11 patients with locally advanced NSCLC were entered. At the 70 mg dose level 1 patient had grade 5 pneumonitis not responsive to therapy, and one patient had reversible grade 3 pneumonitis and grade 3 pericardial effusion. Due to these toxicities the Brown University Oncology Group Data Safety Monitoring Board terminated the study. Conclusion: Dasatinib could not be safely combined with concurrent chemoradiation for stage 3 lung cancer due to pneumonitis. PMID:22666662

  19. 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.

  20. Randomized Phase III study of gemcitabine plus S-1 versus gemcitabine plus cisplatin in advanced biliary tract cancer: Japan Clinical Oncology Group Study (JCOG1113, FUGA-BT).

    PubMed

    Mizusawa, Junki; Morizane, Chigusa; Okusaka, Takuji; Katayama, Hiroshi; Ishii, Hiroshi; Fukuda, Haruhiko; Furuse, Junji

    2016-04-01

    A Phase II selection design trial was conducted to identify the most promising regimen for comparison with standard therapy in chemo-naive patients with unresectable or recurrent biliary tract cancer (JCOG0805). Gemcitabine plus S-1 therapy showed better efficacy than S-1 monotherapy with acceptable safety in JCOG0805 study. Based on this result, a randomized Phase III trial was started in May 2013 to confirm the non-inferiority of gemcitabine plus S-1 therapy relative to gemcitabine plus cisplatin therapy, which is the current standard treatment for chemo-naive patients with unresectable or recurrent biliary tract cancer. A total of 350 patients will be accrued from 32 Japanese institutions within 4 years. The primary endpoint is overall survival, while the secondary endpoints are progression-free survival, adverse events, serious adverse events, clinically significant adverse events, response rate and %planned dose. This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm) and the registration number is UMIN000010667.

  1. Type III mixed cryoglobulinemia and antiphospholipid syndrome in a patient with partial DiGeorge syndrome.

    PubMed

    Chang, Alice D; Tachdjian, Raffi; Gallagher, Kerry; McCurdy, Deborah K; Lassman, Charles; Stiehm, E Richard; Yadin, Ora

    2006-01-01

    We studied a 14 year-old boy with partial DiGeorge syndrome (DGS), status post complete repair of Tetralogy of Fallot, who developed antiphospholipid syndrome (APS) and type III mixed cryoglobulinemia. He presented with recurrent fever and dyspnea upon exertion secondary to right pulmonary embolus on chest computed tomography (CT). Coagulation studies revealed homozygous methylene tetrahydrofolate reductase 677TT mutations, elevated cardiolipin IgM antibodies, and elevated beta(2)-glycoprotein I IgM antibodies. Infectious work-up revealed only positive anti-streptolysin O (ASO) and anti-DNAse B titers. Autoimmune studies showed strongly positive anti-platelet IgM, elevated rheumatoid factor (RF), and positive cryocrit. Renal biopsy for evaluation of proteinuria and hematuria showed diffuse proliferative glomerulonephritis (DPGN) with membranoproliferative features consistent with cryoglobulinemia. Immunofixation showed polyclonal bands. Our patient was treated successfully with antibiotics, prednisone, and mycophenolate mofetil (MMF). This is the first report of a patient with partial DGS presenting with APS and type III mixed cryoglobulinemia possibly due to Streptococcal infection.

  2. Type III Mixed Cryoglobulinemia and Antiphospholipid Syndrome in a Patient With Partial DiGeorge Syndrome

    PubMed Central

    Chang, Alice D.; Tachdjian, Raffi; Gallagher, Kerry; McCurdy, Deborah K.; Lassman, Charles; Stiehm, E. Richard; Yadin, Ora

    2006-01-01

    We studied a 14 year-old boy with partial DiGeorge syndrome (DGS), status post complete repair of Tetralogy of Fallot, who developed antiphospholipid syndrome (APS) and type III mixed cryoglobulinemia. He presented with recurrent fever and dyspnea upon exertion secondary to right pulmonary embolus on chest computed tomography (CT). Coagulation studies revealed homozygous methylene tetrahydrofolate reductase 677TT mutations, elevated cardiolipin IgM antibodies, and elevated β2-glycoprotein I IgM antibodies. Infectious work-up revealed only positive anti-streptolysin O (ASO) and anti-DNAse B titers. Autoimmune studies showed strongly positive anti-platelet IgM, elevated rheumatoid factor (RF), and positive cryocrit. Renal biopsy for evaluation of proteinuria and hematuria showed diffuse proliferative glomerulonephritis (DPGN) with membranoproliferative features consistent with cryoglobulinemia. Immunofixation showed polyclonal bands. Our patient was treated successfully with antibiotics, prednisone, and mycophenolate mofetil (MMF). This is the first report of a patient with partial DGS presenting with APS and type III mixed cryoglobulinemia possibly due to Streptococcal infection. PMID:17162366

  3. Unusual xanthomas in a young patient with heterozygous familial hypercholesterolemia and type III hyperlipoproteinemia

    SciTech Connect

    Feussner, G.; Dobmeyer, J.; Nissen, H.; Hansen, T.S.

    1996-10-16

    We report on a 20-year-old man with the combination of two independent familial lipoprotein disorders: heterozygous familial hypercholesterolemia (FH) and type III hyperlipoproteinemia (HLP). Familial hypercholesterolemia was diagnosed by elevated total and low density lipoprotein cholesterol levels and family history. By denaturing gradient gel electrophoresis, DNA sequencing and restriction fragment length polymorphism analysis, a G{r_arrow}A splice donor mutation in intron 3 of the proband`s low density lipoprotein receptor gene was identified as the underlying molecular defect. This mutation was described previously as a receptor-negative founder mutation in Norway (FH-Elverum) and subsequently in 6 unrelated heterozygous English patients, creating a severe phenotype of familial hypercholesterolemia. Type III HLP was confirmed by homozygosity for apolipoprotein (apo) E2 and an elevated ratio of very low density lipoprotein cholesterol to serum triglycerides (0.40; normal ratio about 0.20). The patient has unusual flat xanthomas in the interdigital webs of the hands which are normally not found in either disease. These dermatological findings might therefore be indicative of the rare combination of both disorders of lipoprotein metabolism in one individual. 29 refs., 5 figs., 1 tab.

  4. ASSESSMENT OF TEMPOROMANDIBULAR DISORDER AND OCCLUSION IN TREATED CLASS III MALOCCLUSION PATIENTS

    PubMed Central

    Valle-Corotti, Karyna; Pinzan, Arnaldo; do Valle, Caio Vinícius Martins; Nahás, Ana Carla Raphaelli; Corotti, Mauro Vinícius

    2007-01-01

    Objective: The aims of this study were to compare the prevalence of temporomandibular disorders (TMD) in individuals submitted to either orthodontic or ortho-surgical Class III malocclusion treatment and to assess the influence of occlusal aspects on TMD severity. Material and methods: The sample consisted of 50 individuals divided into two groups, according to the type of treatment (orthodontic or orthodontic with orthognathic surgery). The presence of signs and symptoms of TMD was evaluated by an anamnestic questionnaire and a clinical examination, including TMJ and muscle palpation, active mandibular range of motion, joint noises and occlusal examination. Results: Based on the anamnestic questionnaire, 48% had no TMD, 42% had mild TMD and 10% had moderate TMD. The presence and severity of TMD did not show any relationship with the type of orthodontic treatment (p>0.05). The chi-square test showed a positive association (p<0.05) between TMD and non-working side occlusal interferences. Conclusion: Based on the methodology used and the results obtained, it may be concluded that Class III orthodontic treatment was not associated with the presence of TMD signs and symptoms and the non-working side contacts can be occlusal factors of risk. There was no significant difference in TMD prevalence between the studied groups (orthodontically treated patients and patients treated with orthodontics followed by orthognathic surgery). PMID:19089112

  5. [Meaning of living with external fixation for grade III open fracture of lower limbs: patient view].

    PubMed

    Lopez, Catia Cristina Gomes; Gamba, Mônica Antar; Matheus, Maria Clara Cassuli

    2013-06-01

    The present study is aimed to understand the meaning of living with an external fixation device for grade III open fractures of the lower limbs from the perspective of the patient. The data were collected with six young adults who were undergoing outpatient orthopedic treatment in a public hospital in the city of São Paulo, through semi-structured interviews with open questions, between June and August 2010. Seeking to understand the meaning of this experience, we have maintained a phenomenological attitude during the analysis, which made it possible to reveal the phenomenon "try to live in spite of feeling trapped in a cage." Patients said that their personal desire and support from others helped them reorganize their lives, despite the several challenges they had to overcome to adapt to the fastener attached to their body and the fear of the future and doubts about the success of treatment.

  6. A Randomized Controlled Phase III Trial of Recombinant Human Granulocyte Colony-Stimulating Factor (Filgrastim) for Treatment of Severe Chronic Neutropenia

    PubMed Central

    Dale, David C.; Bonilla, Mary Ann; Davis, Mark W.; Nakanishi, Arline M.; Hammond, William P.; Kurtzberg, Joanne; Wang, Winfred; Jakubowski, Ann; Winton, Elliott; Lalezari, Parviz; Robinson, William; Glaspy, John A.; Emerson, Steve; Gabrilove, Janice; Vincent, Martha; Boxer, Laurence A.

    2014-01-01

    Patients with idiopathic, cyclic, and congenital neutropenia have recurrent severe bacterial infections. One hundred twenty-three patients with recurrent infections and severe chronic neutropenia (absolute neutrophil count < 0.5 × 109/L) due to these diseases were enrolled in this multi-center phase III trial. They were randomized to either immediately beginning recombinant human granulocyte colony-stimulating factor (filgrastim) (3.45 to 11.50 μg/kg/d, subcutaneously) or entering a 4-month observation period followed by filgrastim administration. Blood neutrophil counts, bone marrow (BM) cell histology, and incidence and duration of infection-related events were monitored. Of the 123 patients enrolled, 120 received filgrastim. On therapy, 108 patients had a median absolute neutrophil count of ≥ 1.5 × 109/L. Examination of BM aspirates showed increased proportions of maturing neutrophils. Infection-related events were significantly decreased (P < .05) with approximately 50% reduction in the incidence and duration of infection-related events and almost 70% reduction in duration of antibiotic use. Asymptomatic splenic enlargement occurred frequently: adverse events frequently reported were bone pain, headache, and rash, which were generally mild and easily manageable. These data indicate that treatment of patients with severe chronic neutropenia with filgrastim results in a stimulation of BM production and maturation of neutrophils, an increase in circulating neutrophils, and a reduction in infection-related events. PMID:8490166

  7. Methylene blue-assisted technique for harvesting lymph nodes after radical surgery for gastric cancer: a prospective randomized phase III study

    PubMed Central

    2014-01-01

    Background This randomized Phase III trial will evaluate whether the methylene blue-assisted technique is efficient for harvesting lymph nodes after radical surgery for gastric cancer. Methods/design Patients that undergo distal or total gastrectomy with radical nodal dissection will be randomly assigned to Group A: the standard group, the lymph nodes (LNs) will be harvested from the fresh specimen immediately after surgery, or Group B: the methylene blue-assisted group, where the LNs will be harvested from specimens fixed with 10% buffered formalin with methylene blue for 48 hours after surgery. The primary endpoint is the ratio of the number of the harvested LNs per time (minute). The secondary endpoint is the number of harvested LNs. A 25% reduction in the ratio of harvested lymph-node/time (minute) was determined to be necessary for this test treatment, considering the balance between the cost and benefit. Retrospective data was used to estimate the ratio of the number of the harvested LNs per time (minute) to be 40/30 minutes in Group A. A 25% risk reduction and a rate of 40/22.5 minutes is expected in Group B. Therefore, the sample size required ensuring a two-sided alpha error of 5% and statistical power of 80% is 52 patients, with 26 patients per arm. The number of patients to be accrued was set at 60 in total, due to the likelihood of enrolling ineligible patients. Trial registration UMIN000008624 PMID:24597931

  8. Trace elements and heavy metals in hair of stage III breast cancer patients.

    PubMed

    Benderli Cihan, Yasemin; Sözen, Selim; Oztürk Yıldırım, Sema

    2011-12-01

    This prospective study was designed to compare the hair levels of 36 elements in 52 patients with stage III breast cancer to those of an equal number of healthy individuals. Principal component and cluster analysis were used for source of identification and apportionment of heavy metals and trace elements in these two groups. A higher average level of iron was found in samples from patients while controls had higher levels of calcium. Both patients and controls had elevated levels of tin, magnesium, zinc, and sodium. Almost all element values in cancer patients showed higher dispersion and asymmetry than in healthy controls. Between the two groups, there were statistically significant differences in the concentrations of silver, arsenic, gold, boron, barium, beryllium, calcium, cadmium, cerium, cobalt, cesium, gadolinium, manganese, nickel, lead, antimony, scandium, selenium, and zinc (p < 0.05). Strong positive correlations were found between lead and gold (r = 0.785) in the cancer group and between palladium and cobalt (r = 0.945) in the healthy individuals. Our results show that there are distinct patterns of heavy metals and trace elements in the hair of breast cancer patients in comparison to healthy controls. These results could be of significance in the diagnosis of breast cancer. PMID:21660533

  9. Antithrombin III in patients admitted to intensive care units: a multicenter observational study

    PubMed Central

    Messori, Andrea; Vacca, Franca; Vaiani, Monica; Trippoli, Sabrina

    2002-01-01

    Introduction The administration of antithrombin III (ATIII) is useful in patients with congenital deficiency, but evidence for the other therapeutic indications of this drug is still uncertain. In Italy, the use of ATIII is very common in intensive care units (ICUs). For this reason we undertook an observational study to determine the pattern of use of ATIII in ICUs and to assess the outcome of patients given this treatment. Methods From 20 May to 20 July 2001 all consecutive patients admitted to ICUs in 20 Italian hospitals and treated with ATIII were enrolled. The following information was recorded from each patient: congenital deficiency, indication for use of ATIII, daily dose and duration of ATIII treatment, outcome of hospitalization (alive or dead). The outcome data of our observational study were compared with those reported in previously published randomized controlled trials (RCTs). Results Two hundred and sixteen patients were enrolled in the study. The clinical indications for using ATIII were sepsis (25.9%), disseminated intravascular coagulation (23.1%), and other clinical conditions (46.8%). At the end of the study, 65.3% of the patients were alive, 24.5% died and 10.2% were still in the hospital. Among the patients with sepsis (n = 56), 19 died during the observation period (33.9%; 95% confidence interval 22.1–47.5%). Discussion Our study described the pattern of use of ATIII in Italian hospitals and provided information on the outcome of the subgroup treated with sepsis. A meta-analysis of current data from RCTs, together with our findings, indicates that there is no sound basis for using this drug in ICU patients with sepsis. PMID:12398786

  10. 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.

  11. Phase III trials of new oral anticoagulants in the acute treatment and secondary prevention of VTE: comparison and critique of study methodology and results.

    PubMed

    Cohen, Alexander T; Imfeld, Stephan; Rider, Thomas

    2014-05-01

    The traditional treatment of venous thromboembolism (VTE) has been use of heparin and vitamin K antagonists (VKA), and although shown to be effective, they have numerous limitations. New oral anticoagulants (NOACs) including direct thrombin (factor IIa) inhibitors (dabigatran) and selective factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) have emerged as promising alternatives with the potential to overcome the limitations of traditional treatments. Clinical trials have been performed with a view to making significant changes to the acute, long-term and extended treatment of VTE. Data are now available on the efficacy and safety, including bleeding rates, of the NOACs in comparison with VKA in the acute treatment and secondary prevention of VTE as well as in comparison with placebo extended VTE treatment. This review compares and contrasts the design and results of the Phase III trials of NOACs in VTE and discusses the implications of the NOACs in terms of treatment strategies in VTE patients.

  12. 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.

  13. 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). PMID:26670466

  14. The Benefit of Adjuvant Chemotherapy in Elderly Patients with Stage III Colorectal Cancer is Independent of Age and Comorbidity

    PubMed Central

    Wildes, Tanya M.; Kallogjeri, Dorina; Powers, Brian; Vlahiotis, Anna; Mutch, Matthew; Spitznagel, Edward L.; Tan, Benjamin; Piccirillo, Jay F.

    2010-01-01

    Objectives To determine the combined effect of age and comorbidity on receipt of chemotherapy and its impact on survival in elderly patients with stage III colorectal cancer (CRC). Materials and methods All patients over age 65 with Stage III CRC diagnosed 1996–2006 were identified from the Barnes-Jewish Hospital Oncology Data Services registry. An age/comorbidity staging system was created using the ACE-27 comorbidity index and data from both Stage II and III CRC. The staging system was then applied to patients with Stage III CRC. Odds of receiving chemotherapy were calculated, and survival analyses determined the impact of chemotherapy on overall survival in each age/comorbidity stage. Results 435 patients with Stage III CRC were evaluated [median age 75 years (range 65–99)]. Advancing age/comorbidity stage (Alpha, Beta, Gamma) was associated with decreasing odds of receiving chemotherapy for Stage III CRC [Odds Ratio 0.83 (95% CI, 0.51–1.35) for Beta and 0.14 (95% CI, 0.08–0.24) for Gamma, compared to Alpha]. Chemotherapy was associated with lower risk of death in each of the age/comorbidity stages, compared to those who underwent surgery only. The hazard ratio for death in patients who did not receive chemotherapy, relative to those who did, within each age/comorbidity stage was 1.8 [95%CI 1.06–3.06] for Alpha, 2.24 [95%CI 1.38–3.63] for Beta and 2.10 [95% CI 1.23–3.57] for Gamma. Conclusion While stage III CRC patients with increasing age and comorbidity are less likely to receive chemotherapy, receipt of chemotherapy is associated with a lower risk of death. PMID:21113435

  15. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis.

    PubMed

    Vannucchi, Alessandro M; Kantarjian, Hagop M; Kiladjian, Jean-Jacques; Gotlib, Jason; Cervantes, Francisco; Mesa, Ruben A; Sarlis, Nicholas J; Peng, Wei; Sandor, Victor; Gopalakrishna, Prashanth; Hmissi, Abdel; Stalbovskaya, Viktoriya; Gupta, Vikas; Harrison, Claire; Verstovsek, Srdan

    2015-09-01

    Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46-0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13-0.63). Both patients with intermediate-2- or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2-risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544).

  16. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial.

    PubMed

    Douillard, Jean-Yves; Shepherd, Frances A; Hirsh, Vera; Mok, Tony; Socinski, Mark A; Gervais, Radj; Liao, Mei-Lin; Bischoff, Helge; Reck, Martin; Sellers, Mark V; Watkins, Claire L; Speake, Georgina; Armour, Alison A; Kim, Edward S

    2010-02-10

    PURPOSE In the phase III INTEREST trial, 1,466 pretreated patients with advanced non-small cell lung cancer (NSCLC) were randomly assigned to receive gefitinib or docetaxel. As a preplanned analysis, we prospectively analyzed available tumor biopsies to investigate the relationship between biomarkers and clinical outcomes. METHODS Biomarkers included epidermal growth factor receptor (EGFR) copy number by fluorescent in situ hybridization (374 assessable samples), EGFR protein expression by immunohistochemistry (n = 380), and EGFR (n = 297) and KRAS (n = 275) mutations. Results For all biomarker subgroups analyzed, survival was similar for gefitinib and docetaxel, with no statistically significant differences between treatments and no significant treatment by biomarker status interaction tests. EGFR mutation-positive patients had longer progression-free survival (PFS; hazard ratio [HR], 0.16; 95% CI, 0.05 to 0.49; P = .001) and higher objective response rate (ORR; 42.1% v 21.1%; P = .04), and patients with high EGFR copy number had higher ORR (13.0% v 7.4%; P = .04) with gefitinib versus docetaxel. CONCLUSION These biomarkers do not appear to be predictive factors for differential survival between gefitinib and docetaxel in this setting of previously treated patients; however, subsequent treatments may have influenced the survival results. For secondary end points of PFS and ORR, some advantages for gefitinib over docetaxel were seen in EGFR mutation-positive and high EGFR copy number patients. There was no statistically significant difference between gefitinib and docetaxel in biomarker-negative patients. This suggests gefitinib can provide similar overall survival to docetaxel in patients across a broad range of clinical subgroups and that EGFR biomarkers such as mutation status may additionally identify which patients are likely to gain greatest PFS and ORR benefit from gefitinib.

  17. Novel solid phase extraction procedure for gold(III) on Dowex M 4195 prior to its flame atomic absorption spectrometric determination.

    PubMed

    Tuzen, Mustafa; Saygi, Kadriye O; Soylak, Mustafa

    2008-08-15

    A method for solid phase extraction (SPE) of gold(III) using Dowex M 4195 chelating resin has been developed. The optimum experimental conditions for the quantitative sorption of gold(III), pH, effect of flow rates, eluent types, sorption capacity and the effect of diverse ions on the sorption of gold(III) have been investigated. The chelating resin can be reused for more than 100 cycles of sorption-desorption without any significant change in sorption of gold(III) ions. The recovery values for gold(III) and detection limit (LOD) of gold were greater than 95% and 1.61 microg L(-1), respectively. The preconcentration factor was 31. The relative standard deviation of the method was <5%. The adsorption capacity of the resin was 8.1 mg g(-1). The proposed method has been applied for the determination of gold(III) in some real samples including water, soil and sediment samples.

  18. A phase I/II study to evaluate radiation therapy and hyperthermia for deep-seated tumours: a report of RTOG 89-08.

    PubMed

    Myerson, R J; Scott, C B; Emami, B; Sapozink, M D; Samulski, T V

    1996-01-01

    The purpose of this paper is to evaluate the safety and efficacy of deep hyperthermia in conjunction with radiation therapy. This study employed 'second generation' electromagnetic devices which were felt to be better able to confine heating and spare normal tissue than the devices evaluated in a previous study (RTOG 84-01). Sixty six patients at six institutions were enrolled on a prospective Phase I/II study. Eligible deep seated tumours were treated with a combination of external hyperthermia and radiation therapy. Radiation consisted of 1.7-2 Gy per fraction, 4-5 fractions per week, to > 20 Gy (previously irradiated lesions) or > 50 Gy (no previous radiation). Deep hyperthermia was delivered with electromagnetic devices: BSD 2000 for 92% of cases, Thermotron for 5% of cases, other low frequency electromagnetic for 4% of cases. Hyperthermia was delivered < or = twice weekly. Overall complete and partial response rates were 34% and 16% respectively. Response was not correlated with maximum tumour temperature or disease site. There was, however, a strong association with radiation dose: 54% CR with > or = 45 Gy versus 7% with < 45 Gy (p < 0.0001). The achieved temperatures were less than ideal. Although the average maximum tumor temperature was 41.9 degrees C (range 35.7 degrees C-46.7 degrees C), the minimum tumour temperatures were low. The average minimum tumour temperature was 38.5 degrees C and was never > 41.8 degrees C. Treatment was well tolerated with no fatalities. There were four acute grade 3 or 4 toxicities (6% of patients). Patient discomfort resulted in interruption or discontinuation of sessions in 30% of the sessions. In 12 cases (18% of patients) the planned course of hyperthermia was discontinued due to acute discomfort. The devices used in this study were better tolerated than the devices used in the previous Phase I/II deep hyperthermia trial (RTOG 84-01) with less patient discomfort and no problems with severe systemic cardiovascular stress

  19. Phase I-II clinical trial of Californium-252. Treatment of stage IB carcinoma of the cervix.

    PubMed

    Maruyama, Y; VanNagell, J R; Yoneda, J; Donaldson, E; Gallion, H; Rowley, K; Kryscio, R; Beach, J L

    1987-04-15

    Intracavitary Californium-252 combined with whole-pelvis photon radiotherapy was tested as the sole form of treatment for 22 patients with Stage IB carcinoma of the cervix. Californium-252 (Cf) is a fast neutron-emitting radioisotope currently being tested in trials of neutron brachytherapy (NT). The outcomes of the treated group of patients were traced for local tumor control, survival, patterns of failure, and complications. The Cf intracavitary therapy combined with whole-pelvis photon radiotherapy resulted in 95% 2-year and 91% 5-year actuarial survival. There were 9% Grade II-III complications by the Stockholm scale and 4% local failures. These results were obtained in an early clinical trial with a group of largely poor-risk patients with tumors of mean diameter of 4.3 cm.

  20. Pre-operative chemotherapy in early stage resectable non-small-cell lung cancer: a randomized feasibility study justifying a multicentre phase III trial

    PubMed Central

    Boer, R H de; Smith, I E; Pastorino, U; O'Brien, M E R; Ramage, F; Ashley, S; Goldstraw, P

    1999-01-01

    Surgical resection offers the best chance for cure for early stage non-small-cell lung cancer (NSCLC, stage I, II, IIIA), but the 5-year survival rates are only moderate, with systemic relapse being the major cause of death. Pre-operative (neo-adjuvant) chemotherapy has shown promise in small trials restricted to stage IIIA patients. We believe similar trials are now appropriate in all stages of operable lung cancer. A feasibility study was performed in 22 patients with early stage (IB, II, IIIA) resectable NSCLC; randomized to either three cycles of chemotherapy [mitomycin-C 8 mg m−2, vinblastine 6 mg m−2 and cisplatin 50 mg m−2 (MVP)] followed by surgery (n = 11), or to surgery alone. Of 40 eligible patients, 22 agreed to participate (feasibility 55%) and all complied with the full treatment schedule. All symptomatic patients achieved either complete (50%) or partial (50%) relief of tumour-related symptoms with pre-operative chemotherapy. Fifty-five per cent achieved objective tumour response, and a further 27% minor tumour shrinkage; none had progressive disease. Partial pathological response was seen in 50%. No severe (WHO grade III–IV) toxicities occurred. No significant deterioration in quality of life was detected during chemotherapy. Pre-operative MVP chemotherapy is feasible in early stage NSCLC, and this study has now been initiated as a UK-wide Medical Research Council phase III trial. © 1999 Cancer Research Campaign PMID:10188899

  1. Bortezomib-thalidomide-based regimens improved clinical outcomes without increasing toxicity as induction treatment for untreated multiple myeloma: a meta-analysis of phase III randomized controlled trials.

    PubMed

    Huang, Hejing; Zhou, Lili; Peng, Lihui; Fu, Weijun; Zhang, Chunyang; Hou, Jian

    2014-09-01

    Novel agents thalidomide and bortezomib have significantly improved myeloma treatment. However, it remains unclear whether patients will benefit more from the combination therapy of these two agents. Our meta-analysis aims to compare the efficiency, and more importantly, the safety of bortezomib-thalidomide-based (VT-based) versus bortezomib-based or thalidomide-based (V-based/T-based) regimens as induction therapy in patients with previously untreated myeloma. Overall, five phase III RCTs including 1765 patients were identified. Compared with V-based or T-based regimens, VT-based regimens significantly improved CR (OR=2.22, 95% CI [1.44, 3.43]), ORR (OR=2.19, 95% CI [1.51, 3.19]) as well as PFS (HR=0.69, 95% CI [0.54, 0.88]), but not OS (HR=1.04, 95% CI [0.91, 1.19]). Notably, most expected side effects of bortezomib or thalidomide were comparable in both groups, including hematologic (anemia, neutropenia, thrombocytopenia), nonhematologic (peripheral neuropathy, deep venous thrombosis, infections, gastrointestinal events) side effects and discontinuation during or after induction therapy. These results suggest that combination of thalidomide and bortezomib might be a better first-line choice for patients with untreated myeloma.

  2. Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial

    PubMed Central

    Pugliese, Mariateresa; Gallo, Marco; Brignardello, Enrico; Milla, Paola; Orlandi, Fabio; Limone, Paolo Piero; Arvat, Emanuela; Boccuzzi, Giuseppe; Piovesan, Alessandro

    2016-01-01

    Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11. PMID:27766105

  3. Predicting hypothetical willingness to participate (WTP) in a future phase III HIV vaccine trial among high-risk adolescents.

    PubMed

    Giocos, Georgina; Kagee, Ashraf; Swartz, Leslie

    2008-11-01

    The present study sought to determine whether the Theory of Planned Behaviour predicted stated hypothetical willingness to participate (WTP) in future Phase III HIV vaccine trials among South African adolescents. Hierarchical logistic regression analyses showed that The Theory of Planned Behaviour (TPB) significantly predicted WTP. Of all the predictors, Subjective norms significantly predicted WTP (OR = 1.19, 95% C.I. = 1.06-1.34). A stepwise logistic regression analysis revealed that Subjective Norms (OR = 1.19, 95% C.I. = 1.07-1.34) and Attitude towards participation in an HIV vaccine trial (OR = 1.32, 95% C.I. = 1.00-1.74) were significant predictors of WTP. The addition of Knowledge of HIV vaccines and HIV vaccine trials, Perceived self-risk of HIV infection, Health-promoting behaviours and Attitudes towards HIV/AIDS yielded non-significant results. These findings provide support for the Theory of Reasoned Action (TRA) and suggest that psychosocial factors may play an important role in WTP in Phase III HIV vaccine trials among adolescents.

  4. Sediment Toxicity Identification and Evaluation (TIE) Phases I, II and III Guidance Document

    EPA Science Inventory

    This presentation summarizes the sediment toxicity identification evaluation (TIE) techniques that allow researchers to characterize and identify chemical causes of acute toxicity in sediments that can be applied using the 10-d solid-phase sediment toxicity tests.

  5. Phase I Study of Oxaliplatin in Combination With Capecitabine and Radiotherapy as Postoperative Treatment for Stage II and III Rectal Cancer

    SciTech Connect

    Jin Jing

    2008-11-01

    Purpose: A Phase I study was conducted to determine the maximal tolerated dose and the dose-limiting toxicity (DLT) of oxaliplatin (OXA) combined with capecitabine and radiotherapy as adjuvant treatment in patients with operable rectal cancer. Patients and Methods: A total of 21 patients with Stage II or III rectal adenocarcinoma after curative surgery were treated with radiotherapy to a total dose of 50 Gy in 5 weeks. OXA was administered at a dosage of 40 (n = 6), 50 (n = 3),60 (n = 3), 70 (n = 3), or 80 mg/m{sup 2} (n = 6) once a week for 2 weeks (first cycle) followed by a second cycle after a 7-day break. Capecitabine at a fixed dose of 1,300 mg/m{sup 2}/d was administered orally at the same schedule as for OXA. DLT was defined as Grade 3 or 4 hematologic and nonhematologic toxicity. Results: Grade 1-3 leukopenia, diarrhea, and nausea/vomiting were the most common toxic side effects, and most were Grade 1-2. A DLT was first observed in 1 of 3 patients at 40 mg/m{sup 2} (Grade 3 diarrhea) but was not observed in the next 3 patients at the same level or in patients who received a dose level of 50-70 mg/m{sup 2}. At 80 mg/m{sup 2}, DLT occurred in 3 of 6 patients (1 Grade 4 leukopenia and 2 Grade 3 diarrhea). Conclusions: OXA combined with a fixed dose of capecitabine at 625 mg/m{sup 2} twice daily by mouth plus radiotherapy in the adjuvant setting was tolerable and clinically feasible. The maximal tolerated dose of OXA in this setting was 80 mg/m{sup 2}, comparable to the maximal tolerated dose of OXA in the neoadjuvant setting.

  6. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial

    PubMed Central

    von Mehren, Margaret; Jones, Robin L.; Hensley, Martee L.; Schuetze, Scott M.; Staddon, Arthur; Milhem, Mohammed; Elias, Anthony; Ganjoo, Kristen; Tawbi, Hussein; Van Tine, Brian A.; Spira, Alexander; Dean, Andrew; Khokhar, Nushmia Z.; Park, Youn Choi; Knoblauch, Roland E.; Parekh, Trilok V.; Maki, Robert G.; Patel, Shreyaskumar R.

    2016-01-01

    Purpose This multicenter study, to our knowledge, is the first phase III trial to compare trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen. Patients and Methods Patients were randomly assigned in a 2:1 ratio to receive trabectedin or dacarbazine intravenously every 3 weeks. The primary end point was overall survival (OS), secondary end points were disease control—progression-free survival (PFS), time to progression, objective response rate, and duration of response—as well as safety and patient-reported symptom scoring. Results A total of 518 patients were enrolled and randomly assigned to either trabectedin (n = 345) or dacarbazine (n = 173). In the final analysis of PFS, trabectedin administration resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine (median PFS for trabectedin v dacarbazine, 4.2 v 1.5 months; hazard ratio, 0.55; P < .001); benefits were observed across all preplanned subgroup analyses. The interim analysis of OS (64% censored) demonstrated a 13% reduction in risk of death in the trabectedin arm compared with dacarbazine (median OS for trabectedin v dacarbazine, 12.4 v 12.9 months; hazard ratio, 0.87; P = .37). The safety profiles were consistent with the well-characterized toxicities of both agents, and the most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases in the trabectedin arm. Conclusion Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end point, this study supports the activity of trabectedin for patients with these malignancies. PMID:26371143

  7. Discordance between WMS-III Word Lists subtest and RAVLT scores in older patients: four case examples.

    PubMed

    Wen, Johnny H; Boone, Kyle

    2006-07-01

    To examine the adequacy of the WMS-III in the identification of memory deficits in older individuals, we administered the Word Lists subtest, along with a comparison measure, the Rey Auditory Verbal Learning Test (RAVLT), to four patients referred for assessment of dementia. Although the number of words recalled by the patients on the delayed trials of the Word Lists subtest and RAVLT were nearly identical, norms for the Word Lists subtest indicated that memory performance was within normal limits (i.e., low average or higher), while the RAVLT norms accurately characterized performance as impaired. We suspect that normative data for the WMS-III were compromised by inadvertent inclusion of older subjects with dementia or mild cognitive impairment. The findings from our cases call into question the use of the WMS-III Word Lists for older patients.

  8. Phase I-II Trial of Cetuximab, Capecitabine, Oxaliplatin, and Radiotherapy as Preoperative Treatment in Rectal Cancer

    SciTech Connect

    Roedel, Claus Arnold, Dirk; Hipp, Matthias; Liersch, Torsten; Dellas, Kathrin; Iesalnieks, Igors; Hermann, Robert Michael; Lordick, Florian; Hohenberger, Werner; Sauer, Rolf

    2008-03-15

    Purpose: To evaluate the safety and activity of preoperative radiotherapy (RT) with concurrent cetuximab, capecitabine, and oxaliplatin in rectal cancer patients. Patients and Methods: A total of 60 patients with rectal cancer (T3-T4 or N+, M1 allowed) entered the trial at five investigator sites; the data from 58 patients were assessable. Cetuximab was given as an initial dose of 400 mg/m{sup 2} 7 days before the start of RT, and then at 250 mg/m{sup 2} once weekly during RT (50.4 Gy in 28 fractions). Capecitabine and oxaliplatin were administered according to an established schedule of oxaliplatin (50 mg/m{sup 2} on Days 1, 8, 22, and 29) and capecitabine (Days 1-14 and 22-35) at three dose levels: 1,000, 1,300, and 1,650 mg/m{sup 2}/d during the Phase I part of the study. The main endpoint of the Phase II was the pathologic complete response rate. Results: Thirteen patients were included in the Phase I part of the study, and the maximal tolerated dose was not reached. Overall, 48 patients were treated at the recommended dose of capecitabine (1,650 mg/m{sup 2}) and 45 patients (94%) underwent surgery. A pathologic complete response was observed in 4 patients (9%), and moderate (n = 12), minimal (n = 10), and no tumor regression (n = 2) was noted in 24 (53%) of 45 patients. The mean radiation dose intensity, cetuximab, capecitabine, oxaliplatin was 98%, 95%, 94%, and 94%, respectively. The incidence of Grade 3-4 diarrhea was restricted to 19%. Postoperative complications of any grade occurred in 33% of patients. Conclusions: The results of our study have shown that cetuximab can be combined safely with capecitabine and oxaliplatin plus RT. The low pathologic complete response rate achieved should stimulate additional preclinical investigations to establish the best sequence of triple combinations.

  9. III-V on silicon: Observation of gallium phosphide anti-phase disorder by low-energy electron microscopy

    NASA Astrophysics Data System (ADS)

    Döscher, Henning; Borkenhagen, Benjamin; Lilienkamp, Gerhard; Daum, Winfried; Hannappel, Thomas

    2011-08-01

    The formation of anti-phase disorder is a major obstacle in the heteroepitaxy of III-V semiconductors on silicon. For an investigation of the anti-phase domain (APD) structure of GaP/Si(100) samples on mesoscopic length scales, we applied dark-field imaging in a low-energy electron microscope (LEEM) to thin GaP films grown on Si(100) substrates by metal organic vapor phase epitaxy (MOVPE). A contamination-free transfer of the samples from the MOVPE ambient to the ultra-high vacuum chamber of the microscope ensured that the atomically well-ordered, P-rich (2 × 2)/c(4 × 2) reconstruction of the surface was preserved. Mutually perpendicular oriented domains of the characteristic GaP(100) reconstruction identify the APDs in the GaP film at the surface and enabled us to achieve high contrast LEEM images. Striped patterns of APDs reflect the regular terrasse structure of the two-domain Si(100)(2 × 1) substrate far away from defects. APDs in the proximity of the defects have larger lateral extensions and are arranged in target pattern-like structures around the defects. In contrast to transmission electron microscopy, which was also applied in a specific dark-field mode for comparison, the characterization of anti-phase disorder by LEEM is non-destructive, does not require elaborate sample preparation, and addresses extended length scales.

  10. Crystal structure and investigation of phase transitions in hexa (2 amino-indolinium) dodécachlorobithallate(III) and quinolinium tetrachlorothallate(III)

    NASA Astrophysics Data System (ADS)

    Chaari, Najla; Hamdi, Besma; Chaabouni, Slaheddine; Chniba-Boudjada, Nassira; Bordet, Pierre

    2007-12-01

    Two new thallium containing salts with different aryl ammonium cations have been prepared and characterized by X-ray crystallography, infrared spectroscopy and dielectric measurements. The salt [C 8N 2H 8] 6Tl 2Cl 12 (1) crystallizes in the monoclinic system with space group Pn. The unit cell dimensions are: a = 15.120(5), b = 11.825(5), c = 17.167(5) Å, β = 104.460(5)° with Z = 2, Dcalcd = 1.818 g cm -3, R = 0.0369. The structure consists of 2 amino-indolinium cations and monomeric TlCl63- anions. The TlCl63- has a strongly octahedral geometry presenting five short and one long (Tl1-Cl13 = 2.739(5) and Tl2-Cl26 = 2.684(5) Å) Tl-Cl bonds. The presence of multiple hydrogen bonds is considered to be responsible for the octahedral distortion. However, the second compound [C 9H 8N]TlCl 4 (2) crystallizes in the Pna2 1 orthorhombic space group, with a = 9.253(1), b = 9.799(1), c = 14.558(2) Å, Z = 4, Dcalcd = 2.397 g cm -3, R = 0.0608. The structure of the quinolinium tetrachlorothallate(III) is characterized by tetracoordinate thallium, forming a regular tetrahedral TlCl 4 with Tl-Cl distances between 2.366(2) and 2.451(3) Å. The structure consists of quinolinium cations separating chains of TlCl4- tetrahedra, these chains being perpendicular to the c axis. Infrared spectra confirm the presence of the organic cations. Differential scanning calorimetry study was carried out. Electrical measurements were performed to discuss the mechanism of the phase transition.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. International Phase III Trial Assessing Neoadjuvant Cisplatin, Methotrexate, and Vinblastine Chemotherapy for Muscle-Invasive Bladder Cancer: Long-Term Results of the BA06 30894 Trial

    PubMed Central

    2011-01-01

    Purpose This article presents the long-term results of the international multicenter randomized trial that investigated the use of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) chemotherapy in patients with muscle-invasive urothelial cancer of the bladder treated by cystectomy and/or radiotherapy. Nine hundred seventy-six patients were recruited between 1989 and 1995, and median follow-up is now 8.0 years. Patients and Methods This was a randomized phase III trial of either no neoadjuvant chemotherapy or three cycles of CMV. Results The previously reported possible survival advantage of CMV is now statistically significant at the 5% level. Results show a statistically significant 16% reduction in the risk of death (hazard ratio, 0.84; 95% CI, 0.72 to 0.99; P = .037, corresponding to an increase in 10-year survival from 30% to 36%) after CMV. Conclusion We conclude that CMV chemotherapy improves outcome as first-line adjunctive treatment for invasive bladder cancer. Two large randomized trials (by the Medical Research Council/European Organisation for Research and Treatment of Cancer and Southwest Oncology Group) have confirmed a statistically significant and clinically relevant survival benefit, and neoadjuvant chemotherapy followed by definitive local therapy should be viewed as state of the art, as compared with cystectomy or radiotherapy alone, for deeply invasive bladder cancer. PMID:21502557

  16. A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results.

    PubMed

    Coronel, Jaime; Cetina, Lucely; Pacheco, Irlanda; Trejo-Becerril, Catalina; González-Fierro, Aurora; de la Cruz-Hernandez, Erick; Perez-Cardenas, Enrique; Taja-Chayeb, Lucia; Arias-Bofill, Daymi; Candelaria, Myrna; Vidal, Silvia; Dueñas-González, Alfonso

    2011-12-01

    The reversing of epigenetic aberrations using the inhibitors of DNA methylation and histone deacetylases may have therapeutic value in cervical cancer. This is a randomized phase III, placebo-controlled study of hydralazine and valproate (HV) added to cisplatin topotecan in advanced cervical cancer. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow acetylators, and valproate at 30 mg/kg, beginning a week before chemotherapy and continued until disease progression. Response, toxicity, and PFS were evaluated, and 36 patients (17 CT + HV and 19 CT + PLA) were included. The median number of cycles was 6. There were four PRs to CT + HV and one in CT + PLA. Stable disease in five (29%) and six (32%) patients, respectively, whereas eight (47%) and 12 (63%) showed progression (P = 0.27). At a median follow-up time of 7 months (1-22), the median PFS is 6 months for CT + PLA and 10 months for CT + HV (P = 0.0384, two tailed). Although preliminary, this study represents the first randomized clinical trial to demonstrate a significant advantage in progression-free survival for epigenetic therapy over one of the current standard combination chemotherapy in cervical cancer. Molecular correlates with response and survival from this trial are pending to analyze.

  17. Selective solid-phase extraction and analysis of trace-level Cr(III), Fe(III), Pb(II), and Mn(II) Ions in wastewater using diethylenetriamine-functionalized carbon nanotubes dispersed in graphene oxide colloids.

    PubMed

    Zhu, Xiangbing; Cui, Yuemei; Chang, Xijun; Wang, Hua

    2016-01-01

    Multi-walled carbon nanotubes (MCNTs) were dispersed in graphene oxide (GO) colloids to be further functionalized with diethylenetriamine (DETA), resulting in GO-MCNTs-DETA nanocomposites for the solid-phase extraction and analysis of Cr(III), Fe(III), Pb(II), and Mn(II) ions at the trace levels in wastewater. Inductively coupled plasma optical emission spectrometry (ICP-OES) indicates that this new solid-phase sorbent could facilitate the maximum static adsorption capacities of 5.4, 13.8, 6.6 and 9.5 mg g(-1) for Cr(III), Fe(III), Pb(II), and Mn(II) ions, respectively, showing the adsorption capacity up to 95% within about 30 min. Moreover, the detection limits of the GO-MCNTs-DETA-based analysis method were found to be 0.16, 0.50, 0.24 and 0.38 ng mL(-1) for Cr(III), Fe(III), Pb(II), and Mn(II) ions, respectively, with the relative standard deviation of lower than 3.0% (n=5). Importantly, common coexisting ions showed no significant interference on the separation and pre-concentration of these heavy metal ions at pH 4.0. Subsequently, the GO-MCNTs-DETA sorbent was successfully employed for the separation and analysis of trace-level Cr(III), Fe(III), Pb(II), and Mn(II) ions in wastewater samples yielding 75-folds concentration factors. PMID:26695275

  18. Concurrent Chemoradiotherapy Followed by Consolidation Chemotherapy With Bi-Weekly Docetaxel and Carboplatin for Stage III Unresectable, Non-Small-Cell Lung Cancer: Clinical Application of a Protocol Used in a Previous Phase II Study

    SciTech Connect

    Saitoh, Jun-Ichi; Saito, Yoshihiro; Kazumoto, Tomoko; Kudo, Shigehiro; Yoshida, Daisaku; Ichikawa, Akihiro; Sakai, Hiroshi; Kurimoto, Futoshi; Kato, Shingo; Shibuya, Kei

    2012-04-01

    Purpose: To assess the clinical applicability of a protocol evaluated in a previously reported phase II study of concurrent chemoradiotherapy followed by consolidation chemotherapy with bi-weekly docetaxel and carboplatin in patients with stage III, unresectable, non-small-cell lung cancer (NSCLC). Methods and Materials: Between January 2000 and March 2006, 116 previously untreated patients with histologically proven, stage III NSCLC were treated with concurrent chemoradiotherapy. Radiation therapy was administered in 2-Gy daily fractions to a total dose of 60 Gy in combination with docetaxel, 30 mg/m{sup 2}, and carboplatin at an area under the curve value of 3 every 2 weeks during and after radiation therapy. Results: The median survival time for the entire group was 25.5 months. The actuarial 2-year and 5-year overall survival rates were 53% and 31%, respectively. The 3-year cause-specific survival rate was 60% in patients with stage IIIA disease, whereas it was 35% in patients with stage IIIB disease (p = 0.007). The actuarial 2-year and 5-year local control rates were 62% and 55%, respectively. Acute hematologic toxicities of Grade {>=}3 severity were observed in 20.7% of patients, while radiation pneumonitis and esophagitis of Grade {>=}3 severity were observed in 2.6% and 1.7% of patients, respectively. Conclusions: The feasibility of the protocol used in the previous phase II study was reconfirmed in this series, and excellent treatment results were achieved.

  19. Phase I/II study of bortezomib-BEAM and autologous hematopoietic stem cell transplantation for relapsed indolent non-Hodgkin lymphoma, transformed, or mantle cell lymphoma.

    PubMed

    William, Basem M; Allen, Mary S; Loberiza, Fausto R; Bociek, Robert Gregory; Bierman, Philip J; Armitage, James O; Vose, Julie M

    2014-04-01

    A phase I/II trial was designed to evaluate the safety and efficacy of adding bortezomib to standard BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous hematopoietic stem cell transplantation (ASCT). Eligible patients had relapsed/refractory indolent or transformed non-Hodgkin lymphoma or mantle cell lymphoma (MCL) that was relapsed/refractory or in first partial (PR) or complete remission (CR). Patients received bortezomib on days -11, -8, -5, and -2 before ASCT. Phase I had 4 dose cohorts (.8, 1, 1.3, and 1.5 mg/m(2)) and 3 patients were accrued to each. Any nonhematological ASCT-related toxicity >2 on the Bearman scale occurring between day -11 and engraftment defined the maximum tolerated dose (MTD). After the MTD has been reached, another 20 patients were enrolled at this dose to determine a preliminary overall response rate (ORR). Patients who were in CR or PR at day +100 were considered responders. The study enrolled 42 patients through August 14, 2009. The median age was 58 (range, 34 to 73) years, with 33 males and 9 females. The most common diagnoses were MCL (23 patients) and follicular lymphoma (7 patients). The median number of prior therapies was 1 (range, 0 to 6). The median follow-up was 4.88 (range, 1.07 to 6.98) years. Thirteen patients were treated in phase I and 29 patients were treated in phase II. The MTD was initially determined to be 1.5 mg/m(2) but it was later decreased to 1 mg/m(2) because of excessive gastrointestinal toxicity and peripheral neuropathy. The ORR was 95% at 100 days and 87% at 1 year. For all 38 evaluable patients at 1 year, responses were CR 84%, PR 1%, and progressive disease 13%. Progression-free survival (PFS) was 83% (95% CI, 68% to 92%) at 1 year, and 32% (15% to 51%) at 5 years. Overall survival (OS) was 91% (95% CI, 79% to 96%) at 1 year and 67% (50% to 79%) at 5 years. The most common National Cancer Institute grade 3 toxicities were neutropenic fever (59%), anorexia (21%), peripheral neuropathy (19

  20. 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.

  1. Overall efficacy and safety results of sofosbuvir-based therapies in phase II and III studies.

    PubMed

    Mangia, Alessandra; Piazzolla, Valeria

    2014-12-15

    The uridine nucleotide analogue sofosbuvir is a selective hepatitis C virus NS5B polymerase inhibitor, active regardless of genotype. We analyzed data on efficacy and safety of sofosbuvir, either in combination with pegylated interferon alfa-2a and ribavirin, or in combination with ribavirin alone as part of an interferon free regimen in more than 1300 patients. Treatment with sofosbuvir for 12 weeks in combination with P/R, in naïve genotype 1 patients was mainly studied in Neutrino. The efficacy of sofosbuvir as part of an all-oral combination including ribavirin alone, was explored in 555 naïve, ineligible and previous treatment failure genotype 2/3 patients. Rates of Sustained Viral Response in genotype 1 and 2 were higher than 85%. For genotype 3 and 4, a European study, Valence, and a US study on patients of Egyptian origin showed that naïve patients are cured at high rates by the all-oral combination given for 24 weeks. The efficacy of sofosbuvir plus P/R for 12 weeks in previous treatment failure genotype 3 has also been demonstrated. Sofosbuvir-based combinations are safe and well tolerated without side effects directly related to the drug. A large body of evidence suggests that sofosbuvir marks a revolution in HCV treatment.

  2. [Hemodynamic study of intravenous milrinone in 26 patients with NYHA class III or IV cardiac failure].

    PubMed

    Boesch, C; Dubois-Rande, J L; Pochmalicki, G; Lellouche, D; Teiger, E; Saal, J P; Cachin, J C; Mallo, C; Castaigne, A; Jan, F

    1992-11-01

    The hemodynamic effects of milrinone (WIN 47203) were studied in 26 NYHA Class III or IV patients. The compound was administered intravenously using a protocol including an initial push dose of 50 micrograms/kg in 10 min, followed by a 24 hour infusion at the dose of 0.5 microgram/kg/min. Maximal response was obtained after 15 min and persisted during the infusion: cardiac index increased from 2.08 +/- 0.36 l/min/m2 to 3.09 +/- 0.68 l/min/m2, while capillary pressure fell from 25 mmHg to 16-17 mmHg. These variations were significant (p = 0.01). Heart rate was stable. Mean peripheral blood pressure fell modestly (6%). Systemic vascular resistance fell by 30% and pulmonary vascular resistance by 20%. All these results confirmed the beneficial effect of this inotropic agent administered intravenously. The increase in ventricular premature contractions noted by many justifies the careful surveillance of these patients by monitoring.

  3. Cross-sectional retrospective study of muscle function in patients with glycogen storage disease type III.

    PubMed

    Decostre, Valérie; Laforêt, Pascal; Nadaj-Pakleza, Aleksandra; De Antonio, Marie; Leveugle, Sylvain; Ollivier, Gwenn; Canal, Aurélie; Kachetel, Kahina; Petit, François; Eymard, Bruno; Behin, Anthony; Wahbi, Karim; Labrune, Philippe; Hogrel, Jean-Yves

    2016-09-01

    Glycogen storage disease type III is an inherited metabolic disorder characterized by liver and muscle impairment. This study aimed to identify promising muscle function measures for future studies on natural disease progression and therapeutic trials. The age-effect on the manual muscle testing (MMT), the hand-held dynamometry (HHD), the motor function measure (MFM) and the Purdue pegboard test was evaluated by regression analysis in a cross-sectional retrospective single site study. In patients aged between 13 and 56 years old, the Purdue pegboard test and dynamometry of key pinch and knee extension strength were age-sensitive with annual losses of 1.49, 1.10 and 0.70% of the predicted values (%pred), respectively. The MFM score and handgrip strength were also age-sensitive but only in patients older than 29 and 37 years old with annual losses of 1.42 and 1.84%pred, respectively. Muscle strength assessed by MMT and elbow extension measured by HHD demonstrated an annual loss of less than 0.50%pred and are thus unlikely to be promising outcome measures for future clinical trials. In conclusion, our results identified age-sensitive outcomes from retrospective data and may serve for future longitudinal studies in which an estimation of the minimal number of subjects is provided.

  4. Cystic versus solid vestibular schwannomas: a series of 80 grade III-IV patients.

    PubMed

    Benech, Franco; Perez, Rosa; Fontanella, Marco Maria; Morra, Bruno; Albera, Roberto; Ducati, Alessandro

    2005-07-01

    Cystic acoustic neuromas are less frequent than solid ones and present different clinical and radiological features. Cystic schwannomas are larger, show a shorter clinical history and a different risk of postoperative complications. This study was designed to compare surgical results and complications of solid and cystic vestibular schwannomas of matching size operated upon via either a retrosygmoid or a translabyrinthine approach. The study included 80 patients presenting with grade III and IV acoustic vestibular schwannomas referred to the Neurosurgical and ENT team in the Department of Neuroscience of Torino, Italy. Twenty-six were cystic and 54 were solid tumours. Clinical history, surgical results and complications were compared between the two groups. In cystic tumors, rapid clinical worsening is common, due to sudden expansion of cystic elements. Tighter adherences are found between cystic tumours and nervous elements (particularly brainstem and possibly facial nerve), once compared to solid ones. Operative morbidity appears to be higher in cystic tumours. A wait and see policy should not to be applied to patients with cystic tumours. Careful technique, possibly sharp dissection, to divide the tumour adherences from the nervous tissue must be employed, in order to avoid lesions on brainstem veins and traction on a thin facial nerve. Severe complications may be caused by the excessive efforts to dissect brainstem adherences.

  5. Development of a "First-Principles" Water Potential with Flexible Monomers. III. Liquid Phase Properties.

    PubMed

    Medders, Gregory R; Babin, Volodymyr; Paesani, Francesco

    2014-08-12

    The MB-pol full-dimensional water potential introduced in the first two papers of this series [J. Chem. Theory Comput. 2013, 9, 5395 and J. Chem. Theory Comput. 2014, 10, 1599] is employed here in classical and quantum simulations of liquid water under ambient conditions. Comparisons with the available experimental data for several structural, thermodynamic, and dynamical properties indicate that MB-pol provides a highly accurate description of the liquid phase. Combined with previous analyses of the dimer vibration-rotation tunneling spectrum, second and third virial coefficients, and cluster structures and energies, the present results demonstrate that MB-pol represents a major step toward the long-sought "universal model" capable of describing the properties of water from the gas to the condensed phases.

  6. Phase Stability of Chromium(III) Oxide Hydroxide in Alkaline Sodium Phosphate Solutions

    SciTech Connect

    S.E. Ziemniak; E.P. Opalka

    2003-07-08

    Grimaldiite ({alpha}-CrOOH) is shown to transform to a sodium-chromium(III)-hydroxyphosphate compound (SCHP) in alkaline sodium phosphate solutions at elevated temperatures via CrOOH(s) + 4Na{sup +} + 2HPO{sub 4}{sup 2-} = Na{sub 4}Cr(OH)(PO{sub 4}){sub 2}(s) + H{sub 2}O. X-ray diffraction analyses indicate that SCHP possesses an orthorhombic lattice having the same space group symmetry (Ibam, No.72) as sodium ferric hydroxyphosphate. A structurally-consistent designation for SCHP is Na{sub 3}Cr(PO{sub 4}){sub 2} {center_dot} NaOH; the molar volume of SCHP is estimated to be 1552 cm{sup 3}. The thermodynamic equilibrium for the above reaction was defined in the system Na{sub 2}O-P{sub 2}O{sub 5}-Cr{sub 2}O{sub 3}-H{sub 2}O for Na/P molar ratios between 2.0 and 2.4. On the basis of observed reaction threshold values for sodium phosphate concentration and temperature, the standard molar entropy (S{sup o}), heat capacity (C{sub p}{sup o}) and free energy of formation ({Delta}G{sub f}{sup o}) for SCHP were calculated to be 690 J/(mol-K), 622 J/(mol-K) and -3509.97 kJ/mol, respectively.

  7. 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.

  8. 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.

  9. Prognostic significance of S100A4 expression in stage II and III colorectal cancer: results from a population-based series and a randomized phase III study on adjuvant chemotherapy.

    PubMed

    Boye, Kjetil; Jacob, Havjin; Frikstad, Kari-Anne M; Nesland, Jahn M; Maelandsmo, Gunhild M; Dahl, Olav; Nesbakken, Arild; Flatmark, Kjersti

    2016-08-01

    Current clinical algorithms are unable to precisely predict which colorectal cancer patients would benefit from adjuvant chemotherapy, and there is a need for novel biomarkers to improve the selection of patients. The metastasis-promoting protein S100A4 predicts poor outcome in colorectal cancer, but whether it could be used to guide clinical decision making remains to be resolved. S100A4 expression was analyzed by immunohistochemistry in primary colorectal carcinomas from a consecutively collected, population-representative cohort and a randomized phase III study on adjuvant 5-fluorouracil/levamisole. Sensitivity to treatment with 5-fluorouracil in S100A4 knockdown cells was investigated using 2D and 3D cell culture assays. Strong nuclear expression of S100A4 was detected in 19% and 23% of the tumors in the two study cohorts, respectively. In both cohorts, nuclear immunoreactivity was associated with reduced relapse-free (P < 0.001 and P = 0.010) and overall survival (P = 0.046 and P = 0.006) in univariate analysis. In multivariate analysis, nuclear S100A4 was a predictor of poor relapse-free survival in the consecutive series (P = 0.002; HR 1.9), but not in the randomized study. Sensitivity to treatment with 5-fluorouracil was not affected by S100A4 expression in in vitro cell culture assays, and there was no indication from subgroup analyses in the randomized study that S100A4 expression was associated with increased benefit of adjuvant treatment with 5-fluorouracil/levamisole. The present study confirms that nuclear S100A4 expression is a negative prognostic biomarker in colorectal cancer, but the clinical utility in selection of patients for adjuvant fluoropyrimidine-based chemotherapy is limited. PMID:27273130

  10. Phase III Trial of Chemoradiotherapy for Anaplastic Oligodendroglioma: Long-Term Results of RTOG 9402

    PubMed Central

    Cairncross, Gregory; Wang, Meihua; Shaw, Edward; Jenkins, Robert; Brachman, David; Buckner, Jan; Fink, Karen; Souhami, Luis; Laperriere, Normand; Curran, Walter; Mehta, Minesh

    2013-01-01

    Purpose Anaplastic oligodendrogliomas, pure (AO) and mixed (anaplastic oligoastrocytoma [AOA]), are chemosensitive, especially if codeleted for 1p/19q, but whether patients live longer after chemoradiotherapy is unknown. Patients and Methods Eligible patients with AO/AOA were randomly assigned to procarbazine, lomustine, and vincristine (PCV) plus radiotherapy (RT) versus RT alone. The primary end point was overall survival (OS). Results Two hundred ninety-one eligible patients were randomly assigned: 148 to PCV plus RT and 143 to RT. For the entire cohort, there was no difference in median survival by treatment (4.6 years for PCV plus RT v 4.7 years for RT; hazard ratio [HR] = 0.79; 95% CI, 0.60 to 1.04; P = .1). Patients with codeleted tumors lived longer than those with noncodeleted tumors (PCV plus RT: 14.7 v 2.6 years, HR = 0.36, 95% CI, 0.23 to 0.57, P < .001; RT: 7.3 v 2.7 years, HR = 0.40, 95% CI, 0.27 to 0.60, P < .001), and the median survival of those with codeleted tumors treated with PCV plus RT was twice that of patients receiving RT (14.7 v 7.3 years; HR = 0.59; 95% CI, 0.37 to 0.95; P = .03). For those with noncodeleted tumors, there was no difference in median survival by treatment arm (2.6 v 2.7 years; HR = 0.85; 95% CI, 0.58 to 1.23; P = .39). In Cox models that included codeletion status, the adjusted OS for all patients was prolonged by PCV plus RT (HR = 0.67; 95% CI, 0.50 to 0.91; P = .01). Conclusion For the subset of patients with 1p/19q codeleted AO/AOA, PCV plus RT may be an especially effective treatment, although this observation was derived from an unplanned analysis. PMID:23071247

  11. 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.

  12. 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.

  13. 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.

  14. 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. PMID:25681064

  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. [Negative symptoms, depression, anxiety and alexithymia in DSM III-R schizophrenic patients].

    PubMed

    Nkam, I; Langlois-Thery, S; Dollfus, S; Petit, M

    1997-01-01

    Coined by Sifneos in 1972, alexithymia refers to a relative narrowing in emotional functioning, an inability to find appropriate words to describe their emotions, and a poverty of fantasy life. Although initially described in the context of psychosomatic illness, alexithymic characteristics may be observed in patients with a wide range of medical and psychiatric disorders: Parkinson disease, depression, anxiety, substance abuse and eating disorders. Flattening of affect and poverty of speech, major negative symptoms, referred to chronic schizophrenia: there is a lack of outward display of emotions. Accordingly, some disturbances of alexithymia's scores would be expected in schizophrenic patients. The aims of this study were: first to establish some correlations between alexithymia and some symptoms of schizophrenia, and second to estimate the intensity of alexithymia in negative versus positive and undifferentiated schizophrenic patients. Twenty-nine patients, meeting DSM III-R criteria for schizophrenia have been studied. All of them treated by neuroleptics, were in a stable clinical status for at least one month. The patients were assessed by one trained psychiatrist (IN) using six rating scales: Beth Israel Questionnaire (BIQ) for alexithymia, Positive and Negative Syndrome Scale (PANSS), Depressive Retardation Rating Scale (DRRS), Montgomery and Asberg Depression Rating Scale (MADRS), revised Physical Anhedonia Scale (PAS), and finally, Extrapyramidal Symptom Rating Scale (ESRS). In the total sample, the mean score of BIQ was 4.79 +/- 1.68 (mean +/- SD). Significant correlations were found between alexithymia and blunted affect (r = 0.376; p < 0.05), poverty of speech (r = 0.471; p < 0.01), anxiety (r = 0.370; p < 0.05), total score of DRRS (r = 0.370; p < 0.05), and motor subscore of DRRS (r = 0.429; p < 0.05). The patients with negative symptoms of schizophrenia had significantly higher total scores in alexithymia (p < 0.05), blunted affect (p < 0

  17. Phase I-II Study of Intraoperative Radiation Therapy (IORT) After Radical Prostatectomy for Prostate Cancer

    SciTech Connect

    Saracino, Biancamaria Gallucci, Michele; De Carli, Piero; Soriani, Antonella; Papalia, Rocco; Marzi, Simona; Landoni, Valeria; Petrongari, Maria Grazia; Arcangeli, Stefano; Forastiere, Ester; Sentinelli, Steno; Arcangeli, Giorgio

    2008-07-15

    Purpose: Recent studies have suggested an {alpha}/{beta} ratio in prostate cancer of 1.5-3 Gy, which is lower than that assumed for late-responsive normal tissues. Therefore the administration of a single, intraoperative dose of irradiation should represent a convenient irradiation modality in prostate cancer. Materials and Methods: Between February 2002 and June 2004, 34 patients with localized prostate cancer with only one risk factor (Gleason score {>=}7, Clinical Stage [cT] {>=}2c, or prostate-specific antigen [PSA] of 11-20 ng/mL) and without clinical evidence of lymph node metastases were treated with radical prostatectomy (RP) and intraoperative radiotherapy on the tumor bed. A dose-finding procedure based on the Fibonacci method was employed. Dose levels of 16, 18, and 20 Gy were selected, which are biologically equivalent to total doses of about 60-80 Gy administered with conventional fractionation, using an {alpha}/{beta} ratio value of 3. Results: At a median follow-up of 41 months, 24 (71%) patients were alive with an undetectable PSA value. No patients died from disease, whereas 2 patients died from other malignancies. Locoregional failures were detected in 3 (9%) patients, 2 in the prostate bed and 1 in the common iliac node chain outside the radiation field. A PSA rise without local or distant disease was observed in 7 (21%) cases. The overall 3-year biochemical progression-free survival rate was 77.3%. Conclusions: Our dose-finding study demonstrated the feasibility of intraoperative radiotherapy in prostate cancer also at the highest administered dose.

  18. Adoption of community-based cardiac rehabilitation programs and physical activity following phase III cardiac rehabilitation in Scotland: a prospective and predictive study.

    PubMed

    Sniehotta, Falko F; Gorski, Charlotta; Araujo-Soares, Vera

    2010-09-01

    Little is known about levels of physical activity and attendance at phase IV community-based Cardiac Rehabilitation (CR) programs following completion of exercise-focussed, hospital-based phase III CR. This study aims to test, compare and combine the predictive utility of the Common-Sense Self-Regulation Model (CS-SRM) and the extended Theory of Planned Behaviour (TPB) with action planning for two rehabilitation behaviours: physical activity and phase IV CR attendance. Individuals diagnosed with coronary heart disease (n = 103) completed baseline measures of illness perceptions, intentions, perceived behavioural control (PBC), action planning and past physical activity in the last week of a phase III CR program, and 95 participants completed follow-up measures of physical activity and attended phase IV CR (objectively confirmed) 2 months later. Only one predictor (PBC/cyclical timeline) significantly predicted levels and change of physical activity. While illness perceptions were not predictive of phase IV CR attendance, the extended TPB model showed good predictive power with action planning and intention as the most powerful predictors. Amongst participants who planned when and where to attend phase IV CR at the end of phase III rehabilitation, 65.9% subsequently attended a phase IV CR program compared to only 18.5% of those who had not made a plan. This study adds to our understanding of cardiac rehabilitation behaviour after completion of health service delivered programs. Comparing theoretical models and rehabilitation behaviours contributes to the development of behaviour theory.

  19. Intestinal phase of gastric secretion in patients with duodenal ulcer.

    PubMed

    Konturek, S J; Kwiecien, N; Obtułowicz, W; Sito, E; Oleksy, J

    1978-04-01

    In 10 healthy subjects and 10 duodenal ulcer patients the intestinal phase of gastric acid secretion was studied by intraduodenal infusion of a 10% liver extract meal (pH 7) at 400 ml/h for three hours. A gastroduodenal double lumen tube with two balloons was used to block the pylorus and to prevent duodenogastric reflux. Gastric acid response to a duodenal meal of liver extract reached a peak at the end of the first hour of infusion of the extract and was then followed by a relatively well-sustained plateau. When the figure was normalised as a percentage of peak response to pentagastrin it was about 45% in healthy subjects and 63% in duodenal ulcer patients. Serum gastrin concentration increased significantly during a duodenal meal of liver extract only in duodenal ulcer patients and not in healthy subjects. The combination of the duodenal meal of liver extract with pentagastrin infusion resulted in a significantly greater increase in acid output in duodenal ulcer patients than in healthy controls. Duodenal perfusion with a liver extract meal in which the pH was gradually decreased caused a pH-dependent reduction in acid output, but not in serum gastrin, both in the duodenal ulcer patients and in healthy subjects. This study shows that the intestinal phase in man results in a potent gastric acid stimulation which is pH-dependent, greatly augmented by pentagastrin, and more vigorous in duodenal ulcer patients than in healthy controls.

  20. 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

  1. A Phase II Trial of R-CHOP Followed by Radioimmunotherapy for Early Stage (Stages I/II) Diffuse Large B-Cell Non-Hodgkin Lymphoma: ECOG3402

    PubMed Central

    Witzig, Thomas E.; Hong, Fangxin; Micallef, Ivana N.; Gascoyne, Randy D.; Dogan, Ahmet; Wagner, Henry; Kahl, Brad S.; Advani, Ranjana H.; Horning, Sandra J.

    2015-01-01

    Summary Patients with early stage diffuse large B-cell lymphoma (DLBCL) receive RCHOP alone or with involved field radiotherapy (IFRT). Anti-CD20 radioimmunotherapy (RIT) delivers radiation to microscopic sites outside of known disease. This phase II study aimed to achieve a functional CR rate of ≥75% to RCHOP and 90Yttrium-ibritumomab tiuxetan RIT. Patients with stages I/II DLBCL received 4–6 cycles of RCHOP followed by RIT (0.4 mCi/kg); patients with PET positive sites of disease after RCHOP/RIT received 30Gy IFRT. Of the 62 patients enrolled; 53 were eligible. 42% (22/53) had stage I/IE; 58% (31/53) stage II/IIE. After RCHOP, 79% (42/53) were in CR/CRu. Forty–eight patients proceeded to RIT and one patient in PR after RIT received IFRT and achieved a CR. The best response after RCHOP+RIT in all 53 patients was a functional CR rate of 89% (47/53; 95% CI:77–96%). With a median follow-up of 5.9 years, 7 (13%) patients have progressed and 4 (8%) have died (2 with DLBCL). At 5 years, 78% of patients remain in remission and 94% are alive. Chemoimmunotherapy and RIT is an active regimen for early stage DLBCL patients. Eighty-nine% of patients achieved functional CR without the requirement of IFRT. This regimen is worthy of further study for early stage DLBCL in a phase III trial. PMID:25974212

  2. Intercalation-induced phases in layer compounds of the A /SUP III/ B /SUP VI/ -type

    SciTech Connect

    Kovalyuk, Z.D.; Pyrlya, M.N.; Seredyuk, A.I.; Tovstyuk, K.D.

    1986-03-01

    The authors investigate the kinetics of combined electrochemical intercalation and the physicochemical properties of the introduced phases. InSe and GaSe single crystals were used in the experiments; the crystals were grown by the Bridgman method. The authors determined the concentration dependences of the electrode potentials and electrical conductivity of the compounds InSe and GaSe intercalated with lithium and lead. The results of the measurements are presented. Lithium and lead enter into the matrix of the crystals in a nonconducting state.

  3. 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.

  4. Boron Neutron Capture Therapy in the Treatment of Locally Recurred Head-and-Neck Cancer: Final Analysis of a Phase I/II Trial

    SciTech Connect

    Kankaanranta, Leena; Seppaelae, Tiina; Koivunoro, Hanna; Saarilahti, Kauko; Atula, Timo; Collan, Juhani; Salli, Eero; Kortesniemi, Mika; Uusi-Simola, Jouni; Vaelimaeki, Petteri; Maekitie, Antti; Seppaenen, Marko; Minn, Heikki; Revitzer, Hannu; Kouri, Mauri; Kotiluoto, Petri; Seren, Tom; Auterinen, Iiro; Savolainen, Sauli; Joensuu, Heikki

    2012-01-01

    Purpose: To investigate the efficacy and safety of boron neutron capture therapy (BNCT) in the treatment of inoperable head-and-neck cancers that recur locally after conventional photon radiation therapy. Methods and Materials: In this prospective, single-center Phase I/II study, 30 patients with inoperable, locally recurred head-and-neck cancer (29 carcinomas and 1 sarcoma) were treated with BNCT. Prior treatments consisted of surgery and conventionally fractionated photon irradiation to a cumulative dose of 50 to 98 Gy administered with or without concomitant chemotherapy. Tumor responses were assessed by use of the RECIST (Response Evaluation Criteria in Solid Tumors) and adverse effects by use of the National Cancer Institute common terminology criteria version 3.0. Intravenously administered L-boronophenylalanine-fructose (400 mg/kg) was administered as the boron carrier. Each patient was scheduled to be treated twice with BNCT. Results: Twenty-six patients received BNCT twice; four were treated once. Of the 29 evaluable patients, 22 (76%) responded to BNCT, 6 (21%) had tumor growth stabilization for 5.1 and 20.3 months, and 1 (3%) progressed. The median progression-free survival time was 7.5 months (95% confidence interval, 5.4-9.6 months). Two-year progression-free survival and overall survival were 20% and 30%, respectively, and 27% of the patients survived for 2 years without locoregional recurrence. The most common acute Grade 3 adverse effects were mucositis (54% of patients), oral pain (54%), and fatigue (32%). Three patients were diagnosed with osteoradionecrosis (each Grade 3) and one patient with soft-tissue necrosis (Grade 4). Late Grade 3 xerostomia was present in 3 of the 15 evaluable patients (20%). Conclusions: Most patients who have inoperable, locally advanced head-and-neck carcinoma that has recurred at a previously irradiated site respond to boronophenylalanine-mediated BNCT, but cancer recurrence after BNCT remains frequent. Toxicity was

  5. Phase I/II trial of capecitabine, oxaliplatin, and irinotecan in combination with bevacizumab in first line treatment of metastatic colorectal cancer

    PubMed Central

    Bazarbashi, Shouki; Aljubran, Ali; Alzahrani, Ahmad; Mohieldin, Ahmed; Soudy, Hussein; Shoukri, Mohammed

    2015-01-01

    Phase III studies have demonstrated the efficacy of FOLFOXIRI regimens (5-fluorouracil/leucovorin, oxaliplatin, irinotecan) with/without bevacizumab in metastatic colorectal cancer (mCRC). Capecitabine is an orally administered fluoropyrimidine that may be used instead of 5-fluorouracil/leucovorin. We evaluated a triple-chemotherapy regimen of capecitabine, oxaliplatin, and irinotecan, plus bevacizumab in 53 patients with mCRC. A Phase I study identified the maximum tolerated dose of irinotecan as 150 mg/m2. Median follow-up in a subsequent Phase II study using this dose was 28 months (74% progressed). For all patients, a complete response was achieved in 4% and a partial response in 60%; median progression-free survival (PFS) was 16 months and median overall survival (OS) was 28 months. Median PFS was longer for patients with an early treatment response (28 vs. 9 months for others; P = 0.024), or early tumor shrinkage (25 vs. 9 months for others; P = 0.006), or for patients suitable for surgical removal of metastases with curative intent (median not reached vs. 9 months for others; P = 0.001). Median OS was longer for patients with early tumor shrinkage (median not reached vs. 22 months for others; P = 0.006) or surgery (median not reached vs. 22 months for others, P = 0.002). K-ras mutations status did not influence PFS (P = 0.88) or OS (P = 0.82). Considerable Grade 3/4 toxicity was encountered (36% for diarrhea, 21% for vomiting and 17% for fatigue). In conclusion, the 3-weekly triple-chemotherapy regimen of capecitabine, oxaliplatin, and irinotecan, plus bevacizumab, was active in the first-line treatment of mCRC, although at the expense of a high level of toxicity. PMID:26207614

  6. A phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma.

    PubMed

    Shih, Kent C; Chowdhary, Sajeel; Rosenblatt, Paul; Weir, Alva B; Shepard, Gregg C; Williams, Jeffrey T; Shastry, Mythili; Burris, Howard A; Hainsworth, John D

    2016-09-01

    Meningiomas that progress after standard therapies are challenging with limited effective chemotherapy options. This phase II trial evaluated the efficacy of everolimus plus bevacizumab in patients with recurrent, progressive meningioma after treatment with surgical resection and local radiotherapy when appropriate. Patients with recurrent meningioma (WHO grade I, II, or III) following standard treatments with surgical resection and radiotherapy received bevacizumab (10 mg/kg IV days 1 and 15) and everolimus (10 mg PO daily) each 28 day cycle. Evaluation of response occurred every 2 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, overall survival and safety. Seventeen patients with a median age of 59 years (29-84) received study treatment. WHO grades at study entry included: I, 5 (29 %); II, 7 (41 %); III, 4 (24 %); unknown, 1 (6 %). Patients received a median of 8 cycles (1-37); all patients are off study treatment. A best response of SD was observed in 15 patients (88 %), and 6 patients had SD for >12 months. Overall median PFS was 22 months (95 % CI 4.5-26.8) and was greater for patients with WHO grade II and III compared to grade I tumors (22.0 months vs 17.5 months). Four patients discontinued treatment due to toxicity (proteinuria, 2; colitis, 1, thrombocytopenia, 1). However, other grade 3 toxicity was uncommon, and no patient had grade 4 toxicity. The combination of everolimus and bevacizumab was well-tolerated, and produced stable disease in 88 % of patients; the median duration of disease stabilization of 10 months (2-29). The median PFS from this prospective trial was similar to previous retrospective reports of bevacizumab in the treatment of recurrent meningioma.

  7. Hypofractionated Versus Conventionally Fractionated Radiotherapy for Prostate Carcinoma: Final Results of Phase III Randomized Trial

    SciTech Connect

    Yeoh, Eric E.; Botten, Rochelle J.; Butters, Julie; Di Matteo, Addolorata C.; Holloway, Richard H.; Fowler, Jack

    2011-12-01

    Purpose: To evaluate the long-term efficacy and toxicity of a hypofractionated (55 Gy in 20 fractions within 4 weeks) vs. a conventionally fractionated (64 Gy in 32 fractions within 6.5 weeks) dose schedule for radiotherapy (RT) for localized carcinoma of the prostate. Methods and Materials: A total of 217 patients were randomized to either the hypofractionated (n = 108) or the conventional (n = 109) dose schedule. Most patients (n = 156) underwent RT planning and RT using a two-dimensional computed tomography method. Efficacy using the clinical, radiologic, and prostate-specific antigen data in each patient was evaluated before RT and at predetermined intervals after RT until death. Gastrointestinal and genitourinary toxicity using the modified Late Effect in Normal Tissue - Subjective Objective Management Analytic (LENT-SOMA) scales was also evaluated before and at intervals after RT to 60 months. Results: The whole group has now been followed for a median of 90 months (range, 3-138). Of the 217 patients, 85 developed biochemical relapse (nadir prostate-specific antigen level + 2 {mu}g/L), 36 in the hypofractionated and 49 in the conventional group. The biochemical relapse-free, but not overall, survival at 90 months was significantly better with the hypofractionated (53%) than with the conventional (34%) schedule. Gastrointestinal and genitourinary toxicity persisted 60 months after RT and did not differ between the two dose schedules. Multivariate analyses revealed that the conventional schedule was of independent prognostic significance, not only for biochemical failure, but also for an increased risk of worse genitourinary symptoms at 4 years. Conclusions: A therapeutic advantage of the hypofractionated compared with the conventional dose schedule for RT of prostate cancer was evident at 90 months in the present study.

  8. Calibration artefacts in radio interferometry - III. Phase-only calibration and primary beam correction

    NASA Astrophysics Data System (ADS)

    Grobler, T. L.; Stewart, A. J.; Wijnholds, S. J.; Kenyon, J. S.; Smirnov, O. M.

    2016-09-01

    This is the third installment in a series of papers in which we investigate calibration artefacts. Calibration artefacts (also known as ghosts or spurious sources) are created when we calibrate with an incomplete model. In the first two papers of this series, we developed a mathematical framework which enabled us to study the ghosting mechanism itself. An interesting concomitant of the second paper was that ghosts appear in symmetrical pairs. This could possibly account for spurious symmetrization. Spurious symmetrization refers to the appearance of a spurious source (the antighost) symmetrically opposite an unmodelled source around a modelled source. The analysis in the first two papers indicates that the antighost is usually very faint, in particular, when a large number of antennas are used. This suggests that spurious symmetrization will mainly occur at an almost undetectable flux level. In this paper, we show that phase-only calibration produces an antighost that is N-times (where N denotes the number of antennas in the array) as bright as the one produced by phase and amplitude calibration and that this already bright ghost can be further amplified by the primary beam correction.

  9. 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)

  10. Dentofacial effects of bone-anchored maxillary protraction: A controlled study of consecutively treated Class III patients

    PubMed Central

    De Clerck, Hugo; Cevidanes, Lucia; Baccetti, Tiziano

    2011-01-01

    Introduction In this cephalometric investigation, we analyzed the treatment effects of bone-anchored maxillary protraction (BAMP) with miniplates in the maxilla and mandible connected by Class III elastics in patients with Class III malocclusion. Methods The treated sample consisted of 21 Class III patients consecutively treated with the BAMP protocol before the pubertal growth spurt (mean age, 11.10 ± 1.8 years) and reevaluated after BAMP therapy, about 1 year later. The treated group was compared with a matched control group of 18 untreated Class III subjects. Significant differences between the treated and control groups were assessed with independent-sample t tests (P<0.05). Results Sagittal measurements of the maxilla showed highly significant improvements during active treatment (about 4 mm more than the untreated controls), with significant protraction effects at orbitale and pterygomaxillare. Significant improvements of overjet and molar relationship were recorded, as well as in the mandibular skeletal measures at Point B and pogonion. Vertical skeletal changes and modifications in incisor inclination were negligible, except for a significant proclination of the mandibular incisors in the treated group. Significant soft-tissue changes reflected the underlying skeletal modifications. Conclusions Compared with growth of the untreated Class III subjects, the BAMP protocol induced an average increment on skeletal and soft-tissue advancement of maxillary structures of about 4 mm, and favorable mandibular changes exceeded 2 mm. PMID:21055597

  11. Treatment Approach for Maxillary Hypoplasia in Cleft Patients: Class III Elastics with Skeletal Anchorage (Report of Two Cases)

    PubMed Central

    Jahanbin, Arezoo; Kazemian, Mozhgan; Saeedi-Pouya, Iman; Eslami, Neda; Shafaee, Hooman

    2016-01-01

    Introduction: Treatment of cleft lip and palate patients requires a multidisciplinary plan. These patients usually have a hypoplastic maxilla due to the prior surgical scars. Orthognathic surgery to advance the maxilla in these patients is not very efficient; therefore, orthopedic interventions during an appropriate age seems to be essential. Case Report: In this article, two cleft lip and palate patients have been treated with Class III elastics anchored to the maxillary posterior and mandibular anterior miniplates in order to induce maxillary advancement. Conclusion: Both cases showed a significant improvement in their profiles with minimal dentoalveolar compensations. A counterclockwise rotation of the mandible occurred.

  12. Treatment Approach for Maxillary Hypoplasia in Cleft Patients: Class III Elastics with Skeletal Anchorage (Report of Two Cases)

    PubMed Central

    Jahanbin, Arezoo; Kazemian, Mozhgan; Saeedi-Pouya, Iman; Eslami, Neda; Shafaee, Hooman

    2016-01-01

    Introduction: Treatment of cleft lip and palate patients requires a multidisciplinary plan. These patients usually have a hypoplastic maxilla due to the prior surgical scars. Orthognathic surgery to advance the maxilla in these patients is not very efficient; therefore, orthopedic interventions during an appropriate age seems to be essential. Case Report: In this article, two cleft lip and palate patients have been treated with Class III elastics anchored to the maxillary posterior and mandibular anterior miniplates in order to induce maxillary advancement. Conclusion: Both cases showed a significant improvement in their profiles with minimal dentoalveolar compensations. A counterclockwise rotation of the mandible occurred. PMID:27602343

  13. [The nutrition of acute phase in patients with metabolic syndrome].

    PubMed

    Tsutsumi, Rie; Sebe, Mayu

    2016-03-01

    In this session, we describe the acute phase in patients with metabolic syndrome from two sides; acute disease that occurs higher in patients with metabolic syndrome such as colonary heart disease and stroke, and acute aggravation of diabetes such as diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome. The electrolyte imbalance is frequently detected in critical ill patients. It is reported that the extreme abnormalities of ionized calcium concentrations are independent predictors of mortality. In addition, from clinical database MIMIC-Ⅱ,calcium supplementation improves clinical outcome in intensive care unit patients. Although metabolic syndrome; lifestyle-related disease, is a chronic disease, the possibility of falling into acute disease by having it becomes very high and improvement of electrolyte imbalance, especially hypocalcaemia is expected to effective on clinical outcome. PMID:26923986

  14. [The nutrition of acute phase in patients with metabolic syndrome].

    PubMed

    Tsutsumi, Rie; Sebe, Mayu

    2016-03-01

    In this session, we describe the acute phase in patients with metabolic syndrome from two sides; acute disease that occurs higher in patients with metabolic syndrome such as colonary heart disease and stroke, and acute aggravation of diabetes such as diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome. The electrolyte imbalance is frequently detected in critical ill patients. It is reported that the extreme abnormalities of ionized calcium concentrations are independent predictors of mortality. In addition, from clinical database MIMIC-Ⅱ,calcium supplementation improves clinical outcome in intensive care unit patients. Although metabolic syndrome; lifestyle-related disease, is a chronic disease, the possibility of falling into acute disease by having it becomes very high and improvement of electrolyte imbalance, especially hypocalcaemia is expected to effective on clinical outcome.

  15. Phase Behavior of Nematic-Nonnematic Binary Systems: III. The Effect of Hydrogen Bonding Interaction

    NASA Astrophysics Data System (ADS)

    Asaba, Kazunori; Igarashi, Atsuko; Kobinata, Shunsuke

    1998-12-01

    For the binary mixtures of nematic 4-pentyl-4‧-cyanobiphenyl (5CB) with some kinds of nonnematic solutes, which showed `unusual' increase in nematic-isotropic phase transition temperature compared with that of pure 5CB, we have measured the temperature dependence of the IR dichroic ratio for several bands of 5CB and of the solutes. The dichroic ratios and their temperature dependence distinctly showed the presence of rather firmly hydrogen-bonded complexes in these binary systems. We found some interesting results, e.g., the dichroic ratios for the OH stretching mode of phenol, which is hydrogen bonded to the CN group of 5CB, and for p-ethyl benzoic acid were larger than the dichroic ratio of the CN band. The temperature dependence of the second-order parameters derived from IR dichroic ratios was analyzed based on a Maier-Saupe-type mean field theory.

  16. Cetuximab and Radiation Therapy in Treating Patients With Stage III-IV Head and Neck Cancer

    ClinicalTrials.gov

    2016-03-11

    Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Verrucous Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Verrucous Carcinoma of the Larynx; Tongue Cancer

  17. Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Stage III Ovarian Cancer

    ClinicalTrials.gov

    2016-03-17

    Malignant Ovarian Mixed Epithelial Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage III Ovarian Cancer; Undifferentiated Ovarian Carcinoma

  18. Improvement in glycated haemoglobin evaluated by baseline body mass index: a meta-analysis of the liraglutide phase III clinical trial programme.

    PubMed

    Montanya, E; Fonseca, V; Colagiuri, S; Blonde, L; Donsmark, M; Nauck, M A

    2016-07-01

    In the liraglutide clinical trial programme, liraglutide 1.2 and 1.8 mg were found to effectively lower glycated haemoglobin (HbA1c) in patients with type 2 diabetes (T2D). It is unknown whether baseline body mass index (BMI) is a predictor of change in HbA1c observed during a clinical trial with liraglutide or placebo treatment. The present meta-analysis of patient-level data, using pooled data from seven phase III trials [LEAD-1-6 and the liraglutide versus sitagliptin trial (LIRA-DPP-4)] for liraglutide 1.2, 1.8 mg and placebo (n = 3222), identified no significant correlation between baseline BMI (<20 kg/m(2) up to 45 kg/m(2) ) and HbA1c reduction for placebo or liraglutide 1.2 mg, and a modest, clinically non-relevant, association for liraglutide 1.8 mg [-0.010 (95% confidence interval -0.020, -0.001)], whereby a 10 kg/m(2) increase in baseline BMI corresponded to 0.10%-point (1.1 mmol/mol) greater HbA1c reduction. In summary, reductions in HbA1c obtained during clinical trials with liraglutide or placebo treatment were independent of baseline BMI. PMID:26662611

  19. Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study

    PubMed Central

    Lauria, Giuseppe; Dalla Bella, Eleonora; Antonini, Giovanni; Borghero, Giuseppe; Capasso, Margherita; Caponnetto, Claudia; Chiò, Adriano; Corbo, Massimo; Eleopra, Roberto; Fazio, Raffaella; Filosto, Massimiliano; Giannini, Fabio; Granieri, Enrico; La Bella, Vincenzo; Logroscino, Giancarlo; Mandrioli, Jessica; Mazzini, Letizia; Monsurrò, Maria Rosaria; Mora, Gabriele; Pietrini, Vladimiro; Quatrale, Rocco; Rizzi, Romana; Salvi, Fabrizio; Siciliano, Gabriele; Sorarù, Gianni; Volanti, Paolo; Tramacere, Irene; Filippini, Graziella

    2015-01-01

    Objective To assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS). Methods Patients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40 000 IU or placebo fortnightly as add-on treatment to riluzole 100 mg daily for 12 months. The primary composite outcome was survival, tracheotomy or >23 h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91. Results We randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12 months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or >23 h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes. Conclusions RhEPO 40 000 IU fortnightly did not change the course of ALS. PMID:25595151

  20. Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE: a randomized, multicenter, open-label, phase III study of gemcitabine–cisplatin plus necitumumab versus gemcitabine–cisplatin alone in the first-line treatment of patients with stage IV squamous non-small-cell lung cancer

    PubMed Central

    Paz-Ares, L.; Socinski, M. A.; Shahidi, J.; Hozak, R. R.; Soldatenkova, V.; Kurek, R.; Varella-Garcia, M.; Thatcher, N.; Hirsch, F. R.

    2016-01-01

    Background SQUIRE demonstrated addition of necitumumab to gemcitabine and cisplatin significantly improved survival in patients with stage IV sq-NSCLC. Here, we report additional outcomes for the subpopulation of patients with tumor epidermal growth factor receptor (EGFR) protein expression. Patients and methods Patients with pathologically confirmed stage IV sq-NSCLC were randomized 1:1 to receive a maximum of six 3-week cycles of gemcitabine (1250 mg/m2 i.v., days 1 and 8) and cisplatin (75 mg/m2 i.v., day 1) chemotherapy with or without necitumumab (800 mg i.v., days 1 and 8). Patients in the chemotherapy plus necitumumab group with no progression continued on necitumumab alone until disease progression or intolerable toxicity. SQUIRE included mandatory tissue collection. EGFR protein expression was detected by immunohistochemistry (IHC) in a central laboratory. Exploratory analyses were pre-specified for patients with EGFR protein expressing (EGFR > 0) and non-expressing (EGFR = 0) tumors. Results A total of 982 patients [90% of intention-to-treat (ITT)] had evaluable IHC results. The large majority of these patients (95%) had tumor samples expressing EGFR protein; only 5% had tumors without detectable EGFR protein. Overall survival (OS) for EGFR > 0 patients was significantly longer in the necitumumab plus gemcitabine–cisplatin group than in the gemcitabine–cis