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Sample records for everolimus rad001 processes

  1. Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001).

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    Druce, M R; Kaltsas, G A; Fraenkel, M; Gross, D J; Grossman, A B

    2009-09-01

    Phaeochromocytoma and paraganglioma are rare neuroendocrine tumours (NETS). They may be benign or malignant but the pathological distinction is mainly made when metastases are present. Available treatments in the form of surgery, chemotherapy, and radionuclide therapy may improve symptoms and biochemical markers, but the results for the control of tumour bulk are less favourable. Furthermore, responses to treatment are frequently short-lived. This short review outlines the main molecular and histological features of malignant phaeochromocytoma and the difficulties in differentiating between benign and malignant disease. We list current therapies used for malignant pheochromocytoma; however, these generally achieve relatively low success rates. Hence, there is a need for new and more effective therapies. In vitro studies have implicated the PI3/Akt/mTOR pathway in the pathogenesis of malignant NETS, including phaeochromocytoma. Everolimus (RAD001, Novartis UK) is a compound that inhibits mTOR (mammalian Target Of Rapamycin) signalling. We have used RAD001 in four patients with progressive malignant paraganglioma/phaeochromocytoma in addition to other therapies (with institutional approval for compassionate use), and evaluated the effects of this treatment. We outline these four cases and review the theoretical background for this therapy, although the outcomes were relatively disappointing.

  2. RTOG 0913: A Phase 1 Study of Daily Everolimus (RAD001) in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

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    Chinnaiyan, Prakash, E-mail: prakash.chinnaiyan@moffitt.org [Department of Radiation Oncology, Experimental Therapeutics and Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, Florida (United States); Won, Minhee [Radiation Therapy Oncology Group, Philadelphia, Pennsylvania (United States); Wen, Patrick Y. [Center for Neuro-Oncology, Dana-Farber/Brigham and Women' s Cancer Center, Boston, Massachusetts (United States); Rojiani, Amyn M. [Department of Pathology, Medical College of Georgia, Augusta, Georgia (United States); Wendland, Merideth [Radiation Oncology, US Oncology-Willamette Valley Cancer Institute, Eugene, Oregon (United States); Dipetrillo, Thomas A. [Department of Radiation Oncology, Rhode Island Hospital, Providence, Rhode Island (United States); Corn, Benjamin W. [Department of Radiation Oncology, Tel Aviv Medical Center, Tel Aviv (Israel); Mehta, Minesh P. [Department of Radiation Oncology, University of Maryland, Baltimore, Maryland (United States)

    2013-08-01

    Purpose: To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods and Materials: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m{sup 2} per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m{sup 2} on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established daily dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. Results: Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response.

  3. The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells

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    Kuwatsuka, Y; Minami, M; Minami, Y; Sugimoto, K; Hayakawa, F; Miyata, Y; Abe, A; Goff, D J; Kiyoi, H; Naoe, T

    2011-01-01

    In Ph-positive (Ph + ) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph + acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγ null (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G 0 cells in the CD34 + CD38 − population compared with the CD34 + CD38 + and CD34 − populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34 + CD38 − population than in the other populations. Although slow-cycling G 0 cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34 + CD38 − population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34 + cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph + leukemia due to quiescence

  4. The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells

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    Kuwatsuka, Y; Minami, M; Minami, Y; Sugimoto, K; Hayakawa, F; Miyata, Y; Abe, A [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan); Goff, D J [Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA (United States); Kiyoi, H [Department of Infectious Diseases, Nagoya University Hospital, Nagoya (Japan); Naoe, T [Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan)

    2011-05-01

    In Ph-positive (Ph{sup +}) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph{sup +} acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγ{sup null} (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G{sub 0} cells in the CD34{sup +}CD38{sup −} population compared with the CD34{sup +}CD38{sup +} and CD34{sup −} populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34{sup +}CD38{sup −} population than in the other populations. Although slow-cycling G{sub 0} cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34{sup +}CD38{sup −} population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34{sup +} cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph{sup +} leukemia due to quiescence.

  5. Everolimus

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    ... that last several days; headaches; seizures; confusion; or personality changes.Everolimus may cause a blood clot in ... to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in ...

  6. Attenuation of everolimus-induced cytotoxicity by a protective autophagic pathway involving ERK activation in renal cell carcinoma cells

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    Zeng, Yizhou; Tian, Xiaofang; Wang, Quan; He, Weiyang; Fan, Jing; Gou, Xin

    2018-01-01

    Aim The mammalian target of rapamycin (mTOR) pathway is a critical target for cancer treatment and the mTOR inhibitor everolimus (RAD001) has been approved for treatment of renal cell carcinoma (RCC). However, the limited efficacy of RAD001 has led to the development of drug resistance. Autophagy is closely related to cell survival and death, which may be activated under RAD001 stimulation. The aim of the present study was to identify the underlying mechanisms of RAD001 resistance in RCC cells through cytoprotective autophagy involving activation of the extracellular signal-regulated kinase (ERK) pathway. Methods and results: RAD001 strongly induced autophagy of RCC cells in a dose- and time-dependent manner, as confirmed by Western blot analysis. Importantly, suppression of autophagy by the pharmacological inhibitor chloroquine effectively enhanced RAD001-induced apoptotic cytotoxicity, as demonstrated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western blot analysis, indicating a cytoprotective role for RAD001-induced autophagy. In addition, as was shown by the MTT assay, flow cytometry, and Western blot analysis, RAD001 robustly activated ERK, but not c-Jun N-terminal kinase and p38. Activation of ERK was inhibited by the pharmacological inhibitor selumetinib (AZD6244), which effectively promoted RAD001-induced cell death. Moreover, employing AZD6244 markedly attenuated RAD001-induced autophagy and enhanced RAD001-induced apoptosis, which play a central role in RAD001-induced cell death. Furthermore, RAD001-induced autophagy is regulated by ERK-mediated phosphorylation of Beclin-1 and B-cell lymphoma 2, as confirmed by Western blot analysis. Conclusion These results suggest that RAD001-induced autophagy involves activation of the ERK, which may impair cytotoxicity of RAD001 in RCC cells. Thus, inhibition of the activation of ERK pathway-mediated autophagy may be useful to overcome chemoresistance to RAD001. PMID:29719377

  7. The Role of Everolimus in Renal Cell Carcinoma

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    Malek Meskawi

    2015-12-01

    Full Text Available Everolimus (RAD001 is an orally administered agent that inhibits the mammalian target of rapamycin serine-threonine kinase. A phase III pivotal trial on everolimus, published in 2008, provided the first evidence for the efficacy of sequential therapy for patients with metastatic clear cell renal cell carcinoma (RCC. In this study, everolimus was used after failure of one or several previous lines of therapy, and it demonstrated a 3-month survival benefit relative to placebo. Currently, based on the level 1 evidence, everolimus represents the molecule of choice for third-line therapy after failure of previous two tyrosine kinase inhibitors (TKIs. However, second-line use after failure of one TKI is challenged by two new molecules (nivolumab and cabozantinib, which proved to have better efficacy with similar toxicity profile. In non-clear cell metastatic RCC, the current evidence recommends everolimus as a second-line therapy after failure of previous first-line sunitinib.

  8. A pilot trial of the mTOR (mammalian target of rapamycin) inhibitor RAD001 in patients with advanced B-CLL.

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    Decker, Thomas; Sandherr, Michael; Goetze, Katharina; Oelsner, Madlen; Ringshausen, Ingo; Peschel, Christian

    2009-03-01

    Although B-cell chronic lymphocytic leukemia (CLL) is treatable, it remains an incurable disease and most patients inevitably suffer relapse. Many therapeutic options exist for those requiring therapy, including monoclonal antibodies and stem cell transplantation, but remissions tend to last shorter in the course of the disease. Targeting the cell cycle has recently been realized to be an attractive therapeutic approach in solid and hematological malignancies, and the proliferative nature of B-CLL is increasingly accepted. Here, we report data on a phase II pilot trial with the oral mammalian target of rapamycin (mTOR) inhibitor RAD001 5 mg/daily in patients with advanced B-CLL who had progressive disease after at least two lines of treatment. After treatment of seven patients, this trial was stopped because of toxicity concerns, although some degree of activity was observed (one partial remission, three patients with stable disease). Interestingly, cyclin E expression decreased in responding patients. Further strategies of mTOR inhibition by RAD001 in B-CLL should focus on different treatment schedules, adequate anti-infectious prophylaxis, or combinations with cytotoxic drugs.

  9. Role of everolimus in the treatment of renal cell carcinoma

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    Saby George

    2009-08-01

    Full Text Available Saby George1, Ronald M Bukowski21University of Texas Health Sciences Center, MC-8221, Division of Hematology and Oncology, San Antonio, Texas, USA; 2CCF Lerner College of Medicine Division of Hematology and Oncology, Cleveland, Ohio, USAAbstract: The therapeutic options in metastatic renal cell carcinoma have been recently expanded by the discovery of the VHL gene, the mutation of which is associated with development of clear cell carcinoma, and overexpression of the angiogenesis pathway, resulting in a very vascular tumor. This breakthrough in science led to the development of a variety of small molecules inhibiting the VEGF-dependent angiogenic pathway, such as sunitinib and sorafenib. These agents prolong overall and progression-free survival, respectively. The result was the development of robust front-line therapies which ultimately fail and are associated with disease progression. In this setting, there existed an unmet need for developing second-line therapies for patients with refractory metastatic renal cell carcinoma (MRCC. Everolimus (RAD 001 is an oral inhibitor of the mammalian target of rapamycin (mTOR pathway. The double-blind, randomized, placebo-controlled phase III trial of everolimus (RECORD-1 conducted in MRCC patients after progression on sunitinib or sorafenib, or both, demonstrated a progression-free survival benefit favoring the study drug (4.9 months vs 1.9 months, HR 0.33, 95% CI 0.25 to 0.43, P ≤ 0 0.001. Everolimus thus established itself as a standard of care in the second-line setting for patients with MRCC who have failed treatment with VEGF receptor inhibitors.Keywords: mTOR inhibitor, mammalian target of rapamycin inhibitor, signal transduction inhibitor, renal cell carcinoma, targeted therapy

  10. Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells

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    Lui, Asona; New, Jacob; Ogony, Joshua; Thomas, Sufi; Lewis-Wambi, Joan

    2016-01-01

    mTOR inhibition of aromatase inhibitor (AI)-resistant breast cancer is currently under evaluation in the clinic. Everolimus/RAD001 (Afinitor®) has had limited efficacy as a solo agent but is projected to become part of combination therapy for AI-resistant breast cancer. This study was conducted to investigate the anti-proliferative and resistance mechanisms of everolimus in AI-resistant breast cancer cells. In this study we utilized two AI-resistant breast cancer cell lines, MCF-7:5C and MCF-7:2A, which were clonally derived from estrogen receptor positive (ER+) MCF-7 breast cancer cells following long-term estrogen deprivation. Cell viability assay, colony formation assay, cell cycle analysis and soft agar anchorage-independent growth assay were used to determine the efficacy of everolimus in inhibiting the proliferation and tumor forming potential of MCF-7, MCF-7:5C, MCF-7:2A and MCF10A cells. Confocal microscopy and transmission electron microscopy were used to evaluate LC3-II production and autophagosome formation, while ERE-luciferase reporter, Western blot, and RT-PCR analyses were used to assess ER expression and transcriptional activity. Everolimus inhibited the proliferation of MCF-7:5C and MCF-7:2A cells with relatively equal efficiency to parental MCF-7 breast cancer cells. The inhibitory effect of everolimus was due to G1 arrest as a result of downregulation of cyclin D1 and p21. Everolimus also dramatically reduced estrogen receptor (ER) expression (mRNA and protein) and transcriptional activity in addition to the ER chaperone, heat shock protein 90 protein (HSP90). Everolimus restored 4-hydroxy-tamoxifen (4OHT) sensitivity in MCF-7:5C cells and enhanced 4OHT sensitivity in MCF-7 and MCF-7:2A cells. Notably, we found that autophagy is one method of everolimus insensitivity in MCF-7 breast cancer cell lines. This study provides additional insight into the mechanism(s) of action of everolimus that can be used to enhance the utility of mTOR inhibitors as

  11. Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib

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    Chris Coppin

    2010-04-01

    Full Text Available Chris CoppinMedical Oncology, BC Cancer Agency and University of British Columbia, Vancouver, CanadaAbstract: Everolimus (RAD001, Afinitor® Novartis is the first oral inhibitor of mTOR (mammalian target of rapamycin to reach the oncology clinic. Everolimus 10 mg daily achieves complete inhibition of its target at below the maximum tolerable dose for most patients. A phase III randomized placebo-controlled trial has examined the impact of everolimus in patients with clear cell renal cancers and progressive disease on or within 6 months of the VEGFR tyrosine kinase inhibitors sunitinib and/or sorafenib. The primary endpoint of progression-free survival was increased from median 1.9 to 4.9 months (hazard ratio 0.33, P < 0.001 and 25% were still progression-free after 10 months of everolimus therapy. There was a delay in time to decline of performance status and trends to improvement in quality of life, disease-related symptoms, and overall survival despite crossover of the majority of patients assigned to placebo. In 2009, everolimus was approved in the US and Europe as the only validated option for this indication. Toxicities are usually mild to moderate and can be managed with dose reduction or interruption if necessary. Opportunistic infections and non-infectious pneumonitis are seen as a class effect. Management of common practical management issues are discussed. Clinical trials are in progress to examine additional roles for everolimus in renal cancer, alone and in combination with other agents.Keywords: everolimus, drug therapy, advanced renal cancer

  12. Overtime evaluation of the vascular HEALing process after everolimus-eluting stent implantation by optical coherence tomography. The HEAL-EES study

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    Otsuki, Shuji; Brugaletta, Salvatore, E-mail: sabrugal@clinic.ub.es; Sabaté, Manel; Shiratori, Yoshitaka; Gomez-Monterrosas, Omar; Scalone, Giancarla; Romero-Villafañe, Sebastian; Hernández-Enríquez, Marco; Freixa, Xavier; Martín-Yuste, Victoria; Masotti, Mónica

    2016-06-15

    Purpose: Second-generation drug-eluting stent (DES) have shown a better safety and efficacy as compared to first generation DES due to an improved vascular healing process. This process has not been so far evaluated in vivo in an overtime fashion by optical coherent tomography (OCT). We sought to evaluate the vascular healing process after everolimus-eluting stent (EES) implantation at 6, 9 and 12 months, by OCT. Methods: Consecutive 36 patients undergoing percutaneous coronary intervention with EES were randomized 1:1:1 to receive OCT imaging at 6 (group A), 9 (group B) or 12-month follow-up (group C). One patient from group C was excluded because of target lesion revascularization at 1-month, whereas 5 patients withdraw the informed consent. Finally, 30 patients were analyzed. Results: Neointimal thickness was not different between 3 groups (group A: 99.50 [94.06–127.79] μm, group B: 107.26 [83.48–133.59] μm, group C: 127.67 [102.51–138.49] μm; p = 0.736). Although the percentage of “uncovered struts” was significantly higher in group A as compared to the other groups (8.0% vs. 4.4% vs. 2.9%, respectively; p = 0.180), the ratio of uncovered to total struts per section < 30% was similar between 3 groups (0.3% vs. 0.3% vs. 0%, respectively; p = 1.000). Conclusion: Healing process following EES implantation seems almost completed at 6-month follow-up. These data, which need to be confirmed in a larger study, may support the decision to shorten dual antiplatelet therapy. - Highlights: • Healing process following everolimus-eluting stent implantation is complete at 6-month • There are no difference in RUTTS > 30% between 6, 9 and 12 months analyses. • This finding may support to shorten dual antiplatelet therapy in this context.

  13. Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia: Combined Subgroup Analyses of the RECORD-1 and REACT Trials.

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    Bono, Petri; Oudard, Stephane; Bodrogi, Istvan; Hutson, Thomas E; Escudier, Bernard; Machiels, Jean-Pascal; Thompson, John A; Figlin, Robert A; Ravaud, Alain; Basaran, Mert; Porta, Camillo; Bracarda, Sergio; Brechenmacher, Thomas; Lin, Chinjune; Voi, Maurizio; Grunwald, Viktor; Motzer, Robert J

    2016-10-01

    Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. Adults with vascular endothelial growth factor-refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies. Copyright

  14. A process for assessing the feasibility of a network meta-analysis: a case study of everolimus in combination with hormonal therapy versus chemotherapy for advanced breast cancer.

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    Cope, Shannon; Zhang, Jie; Saletan, Stephen; Smiechowski, Brielan; Jansen, Jeroen P; Schmid, Peter

    2014-06-05

    The aim of this study is to outline a general process for assessing the feasibility of performing a valid network meta-analysis (NMA) of randomized controlled trials (RCTs) to synthesize direct and indirect evidence for alternative treatments for a specific disease population. Several steps to assess the feasibility of an NMA are proposed based on existing recommendations. Next, a case study is used to illustrate this NMA feasibility assessment process in order to compare everolimus in combination with hormonal therapy to alternative chemotherapies in terms of progression-free survival for women with advanced breast cancer. A general process for assessing the feasibility of an NMA is outlined that incorporates explicit steps to visualize the heterogeneity in terms of treatment and outcome characteristics (Part A) as well as the study and patient characteristics (Part B). Additionally, steps are performed to illustrate differences within and across different types of direct comparisons in terms of baseline risk (Part C) and observed treatment effects (Part D) since there is a risk that the treatment effect modifiers identified may not explain the observed heterogeneity or inconsistency in the results due to unexpected, unreported or unmeasured differences. Depending on the data available, alternative approaches are suggested: list assumptions, perform a meta-regression analysis, subgroup analysis, sensitivity analyses, or summarize why an NMA is not feasible. The process outlined to assess the feasibility of an NMA provides a stepwise framework that will help to ensure that the underlying assumptions are systematically explored and that the risks (and benefits) of pooling and indirectly comparing treatment effects from RCTs for a particular research question are transparent.

  15. Everolimus in Heart Transplantation: An Update

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    Stephan W. Hirt

    2013-01-01

    Full Text Available The evidence base relating to the use of everolimus in heart transplantation has expanded considerably in recent years, providing clinically relevant information regarding its use in clinical practice. Unless there are special considerations to take into account, all de novo heart transplant patients can be regarded as potential candidates for immunosuppression with everolimus and reduced-exposure calcineurin inhibitor therapy. Caution about the use of everolimus immediately after transplantation should be exercised in certain patients with the risk of severe proteinuria, with poor wound healing, or with uncontrolled severe hyperlipidemia. Initiation of everolimus in the early phase aftertransplant is not advisable in patients with severe pretransplant end-organ dysfunction or in patients on a left ventricular assist device beforetransplant who are at high risk of infection or of wound healing complications. The most frequent reason for introducing everolimus in maintenance heart transplant patients is to support minimization or withdrawal of calcineurin inhibitor therapy, for example, due to impaired renal function or malignancy. Due to its potential to inhibit the progression of cardiac allograft vasculopathy and to reduce cytomegalovirus infection, everolimus should be initiated as soon as possible after heart transplantation. Immediate and adequate reduction of CNI exposure is mandatory from the start of everolimus therapy.

  16. Impact of everolimus: update on immunosuppressive therapy strategies and patient outcomes after renal transplantation

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    Helio Tedesco-Silva Jr

    2011-01-01

    , mainly to preserve renal function and to manage patients with malignancy. There is no definition of the ideal strategy for conversion, ie, abrupt or sequential, initial dose of everolimus, or target therapeutic trough blood concentrations. Intensive monitoring is recommended after conversion, especially for acute rejection and proteinuria. Because mTOR is ubiquitous and central to many intracellular processes, an array of adverse reactions may occur, including delayed tissue regeneration, proteinuria, dyslipidemia, diabetes, myelosuppression, infertility, ovarian cysts, and mouth ulcers. Because long-term benefits are the goal of any immunosuppressive strategy, further investigations aiming to understand, prevent, and manage everolimus-related adverse reactions are necessary to mitigate the risks and improve tolerability, allowing maximization of all the benefits of this drug.Keywords: everolimus, immunosuppression, mTOR inhibitors, calcineurin inhibitors, kidney transplantation

  17. Adjuvant Everolimus for Resected Kidney Cancer

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    In this clinical trial, patients with renal cell cancer who have undergone partial or complete nephrectomy will be randomly assigned to take everolimus tablets or matching placebo tablets daily for 54 weeks.

  18. Fatal acute pulmonary injury associated with everolimus.

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    Depuydt, Pieter; Nollet, Joke; Benoit, Dominique; Praet, Marleen; Caes, Frank

    2012-03-01

    To report a case of fatal alveolar hemorrhage associated with the use of everolimus in a patient who underwent a solid organ transplant. In a 71-year-old cardiac transplant patient, cyclosporine was replaced with everolimus because of worsening renal function. Over the following weeks, the patient developed nonproductive cough and increasing dyspnea. His condition deteriorated to acute respiratory failure with hemoptysis, requiring hospital admission. Bilateral patchy alveolar infiltrates were apparent on chest X-ray and computed tomography. Cardiac failure was ruled out and empiric antimicrobial therapy was initiated. Additional extensive workup could not document opportunistic infection. Everolimus was discontinued and high-dose corticosteroid therapy was initiated. Despite this, the patient required invasive mechanical ventilation and died because of refractory massive hemoptysis. Autopsy revealed diffuse alveolar hemorrhage. Everolimus is a mammalian target of rapamycin inhibitor approved for use as an immunosuppressant and antineoplastic agent. Its main advantage over calcineurin inhibitors (tacrolimus and cyclosporine) is a distinct safety profile. Although it has become clear that everolimus induces pulmonary toxicity more frequently than initially thought, most published cases thus far represented mild and reversible disease, and none was fatal. Here, we report a case of pulmonary toxicity developing over weeks following the introduction of everolimus, in which a fatal outcome could not be prevented by drug withdrawal and corticosteroid treatment. The association of everolimus and this syndrome was probable according to the Naranjo probability scale. This case indicates that with the increasing use of everolimus, clinicians should be aware of the rare, but life-threatening manifestation of pulmonary toxicity.

  19. Everolimus for Advanced Pancreatic Neuroendocrine Tumors.

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    Yao, James C.; Shah, Manisha H.; Ito, Tetsuhide; Bohas, Catherine Lombard; Wolin, Edward M.; Van Cutsem, Eric; Hobday, Timothy J.; Okusaka, Takuji; Capdevila, Jaume; de Vries, Elisabeth G. E.; Tomassetti, Paola; Pavel, Marianne E.; Hoosen, Sakina; Haas, Tomas; Lincy, Jeremie; Lebwohl, David; Oberg, Kjell

    2011-01-01

    Background: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. Methods: We randomly assigned 410

  20. Phosphorylation of mTOR and S6RP predicts the efficacy of everolimus in patients with metastatic renal cell carcinoma

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    Li, Siming; Kong, Yan; Si, Lu; Chi, Zhihong; Cui, Chuanliang; Sheng, Xinan; Guo, Jun

    2014-01-01

    The incidence of renal cell cancer (RCC) has been increasing for the past decade, and the 5-year survival for patients with metastatic RCC (mRCC) is rather low. Everolimus (RAD001), a new inhibitor for mammalian target of rapamycin (mTOR), is generally well tolerated, and demonstrates clinical benefit to patients with anti-VEGF-refractory mRCC. However, factors for selection of patients who may benefit from everolimus remain largely unknown. Here we aimed to explore potential molecular indicators for mRCC patients who may benefit from everolimus treatment. Paraffin-embedded tumor tissue specimens derived from 18 mRCC patients before everolimus treatment, who participated the phase 1b trial of everolimus in VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI)-refractory Chinese patients with mRCC (clinicaltrials.gov, NCT01152801), were examined for the expression levels of phosphorylated AKT, mTOR, eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4EBP1) and 40S ribosomal protein S6 (S6RP) by immunohistochemistry. Clinical benefit rate (complete response [CR], partial response [PR], plus stable disease [SD] ≥ 6 months) and progression-free survival time (PFS) were correlated with expression levels of these mTOR-associated molecules. In these 18 patients, there were 1 PR, 15 SDs (including 9 SDs ≥ 6 months), and 2 progressive diseases (PD). The clinical benefit rate (CBR) was 55.6% (10/18), and the median PFS time was 8.4 months. Patients with positive expression of phospho-mTOR showed a better CBR (71.4% versus 0%, P = 0.023) and PFS time (11.3 versus 3.7 months, P = 0.001) than those patients with negative expression. The median PFS of patients with positive phospho-S6RP expression was longer (11.3 versus 3.7 months, P = 0.002) than that of patients negative for phospho-S6RP expression. However, expression levels of phospho-4EBP1 and phospho-AKT were unassociated to efficacy of everolimus treatment with respect to CBR and PFS. Co-expression of

  1. Regression of Cardiac Rhabdomyomas in a Neonate after Everolimus Treatment

    Directory of Open Access Journals (Sweden)

    Helen Bornaun

    2016-01-01

    Full Text Available Cardiac rhabdomyoma often shows spontaneous regression and usually requires only close follow-up. However, patients with symptomatic inoperable rhabdomyomas may be candidates for everolimus treatment. Our patient had multiple inoperable cardiac rhabdomyomas causing serious left ventricle outflow-tract obstruction that showed a dramatic reduction in the size after everolimus therapy, a mammalian target of rapamycin (mTOR inhibitor. After discontinuation of therapy, an increase in the diameter of masses occurred and everolimus was restarted. After 6 months of treatment, rhabdomyomas decreased in size and therapy was stopped. In conclusion, everolimus could be a possible novel therapy for neonates with clinically significant rhabdomyomas.

  2. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma

    DEFF Research Database (Denmark)

    Motzer, Robert J; Escudier, Bernard; McDermott, David F

    2015-01-01

    BACKGROUND: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus...... of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. RESULTS: The median overall survival was 25.0 months (95% confidence...... interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate...

  3. Research and innovation in the development of everolimus for oncology.

    Science.gov (United States)

    Lebwohl, David; Thomas, George; Lane, Heidi A; O'Reilly, Terence; Escudier, Bernard; Yao, James C; Pavel, Marianne; Franz, David; Berg, William; Baladi, Jean-Francois; Stewart, Jubilee; Motzer, Robert J

    2011-03-01

    The critical role of increased activity of mammalian target of rapamycin (mTOR) in the pathophysiology of multiple diseases is well established. Inhibition of the mTOR pathway may block disease progression and improve patient outcomes. Everolimus, an mTOR inhibitor, began in clinical development as part of a regimen (Certican, Zortress) for prevention of organ transplant rejection and is now an approved oncology agent. The objective of this review is to discuss the history of key findings and innovative cancer research undertaken to successfully develop everolimus as an oncology therapy (Afinitor) now approved for patients with advanced renal cell carcinoma (RCC) and for subependymal giant cell astrocytomas (SEGAs) associated with tuberous sclerosis. In addition, data for the use of everolimus in the treatment of other cancers and rare diseases are also discussed. A PubMed search of English articles without time restrictions was conducted using the search terms 'everolimus or rapamycin' and 'cancer'. Bibliographies of retrieved articles were manually searched for additional relevant articles. Major cancer congresses were also searched. The clinical efficacy of everolimus alone and in combination with other agents has been observed in recently completed Phase II-III studies in a wide spectrum of tumors, including RCC, neuroendocrine tumors, tuberous sclerosis complex, SEGAs and angiomyolipomas, lymphoma and gastric, breast and hepatocellular cancers. These findings emphasize the importance of mTOR in diverse cancers and rare diseases and underscore the potential role for everolimus as an effective agent in multiple indications.

  4. A prospective, randomized evaluation of a novel everolimus-eluting coronary stent

    DEFF Research Database (Denmark)

    Stone, Gregg W; Teirstein, Paul S; Meredith, Ian T

    2011-01-01

    We sought to evaluate the clinical outcomes with a novel platinum chromium everolimus-eluting stent (PtCr-EES) compared with a predicate cobalt chromium everolimus-eluting stent (CoCr-EES) in patients undergoing percutaneous coronary intervention (PCI).......We sought to evaluate the clinical outcomes with a novel platinum chromium everolimus-eluting stent (PtCr-EES) compared with a predicate cobalt chromium everolimus-eluting stent (CoCr-EES) in patients undergoing percutaneous coronary intervention (PCI)....

  5. Improvement in renal function after everolimus introduction and calcineurin inhibitor reduction in maintenance thoracic transplant recipients

    DEFF Research Database (Denmark)

    Arora, Satish; Gude, Einar; Sigurdardottir, Vilborg

    2012-01-01

    The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (TTx) recipients. Nevertheless, introduction of everolimus is not recommended for patients with advanced renal failure. We evaluated...... NOCTET data to assess everolimus introduction amongst TTx recipients with advanced renal failure....

  6. Renal function three years after early conversion from a calcineurin inhibitor to everolimus

    DEFF Research Database (Denmark)

    Mjörnstedt, Lars; Schwartz Sørensen, Søren; von Zur Mühlen, Bengt

    2015-01-01

    In a 36-month, open-label, multicenter trial, 202 kidney transplant recipients were randomized at week 7 post-transplant to convert to everolimus or remain on cyclosporine: 182 were analyzed to month 36 (92 everolimus, 90 controls). Mean (SD) change in measured GFR (mGFR) from randomization to mo......, but discontinuation was more frequent with everolimus (33.7% vs. 10.0%). Conversion from cyclosporine to everolimus at 7 weeks post-transplant was associated with a significant benefit in renal function at 3 years when everolimus was continued....

  7. Everolimus Implicated in Case of Severe Gastrointestinal Hemorrhage

    Directory of Open Access Journals (Sweden)

    Paul Gonzales

    2017-01-01

    Full Text Available Breast cancer remains the leading cause of cancer and the third leading cause of cancer related deaths among our population with an estimated number of 246,660 new cases and 40,450 deaths in 2016. With treatment advancements, including targeted agents such as Everolimus, a mammalian target of rapamycin (mTOR inhibitor, survivability and quality of life continue to improve. However, with the use of these agents come adverse effects, some of which are still being characterized. Our case demonstrates recurrent episodes of gastrointestinal bleeding in a 60-year-old woman being treated with Everolimus for progressive metastatic breast cancer. On endoscopy, bleeding was secondary to erosive gastritis. Previous case reports have described bleeding due to gastric antral vascular ectasia (GAVE, which was described in two prior reported cases. In our case, bleeding also occurred on a reduced dose of Everolimus compared to what is previously reported (5 mg versus 10 mg. As a result of her gastrointestinal bleeding, she required multiple endoscopic interventions including argon plasma coagulation and multipolar heater probe to achieve hemostasis. This is the first case reported of gastrointestinal bleeding not consistent with GAVE and occurring while being on a reduced dose of Everolimus. It is important to document our case so that the Gastroenterology and Hematology communities can be educated and made aware for their patient populations on Everolimus.

  8. Recommendations of everolimus use in liver transplant.

    Science.gov (United States)

    Rubín Suárez, Angel; Bilbao Aguirre, Itxarone; Fernández-Castroagudin, Javier; Pons Miñano, José Antonio; Salcedo Plaza, Magdalena; Varo Pérez, Evaristo; Prieto Castillo, Martín

    2017-11-01

    Mammalian target of rapamycin (mTOR) inhibitors, everolimus (EVL) and sirolimus are immunosuppressive agents with a minor nephrotoxic effect, limited to the development of proteinuria in some cases. The combination of EVL and low-dose tacrolimus has proven to be as safe and effective as standard therapy with tacrolimus for the prevention of acute cellular rejection. Early initiation of EVL-based immunosuppressive regimens with reduced exposure to calcineurin inhibitors has been shown to significantly improve renal function of LT recipients during induction and maintenance phases, with comparable efficacy and safety profiles. In patients with established kidney failure, initiating EVL may enable clinicians to reduce calcineurin inhibitors exposure, thereby contributing to the improved renal function of these patients. Although there is not sufficient evidence to recommend their use to prevent the recurrence of hepatocellular carcinoma and the progression of de novo tumours, they are used in this context in routine clinical practice. Copyright © 2017 Elsevier España, S.L.U., AEEH y AEG. All rights reserved.

  9. Effects of everolimus on macrophage-derived foam cell behavior

    International Nuclear Information System (INIS)

    Hsu, Steven; Koren, Eugen; Chan, Yen; Koscec, Mirna; Sheehy, Alexander; Kolodgie, Frank; Virmani, Renu; Feder, Debra

    2014-01-01

    Purpose: The purpose of this study was to investigate the effects of everolimus on foam cell (FC) viability, mRNA levels, and inflammatory cytokine production to better understand its potential inhibitory effects on atheroma progression. Methods and materials: Human THP1 macrophage-derived FC were formed using acetylated LDL (acLDL, 100 μg/mL) for 72 hours, followed by everolimus treatment (10 -5 –10 -11 M) for 24 hours. FC viability was quantified using fluorescent calcein AM/DAPI staining. FC lysates and media supernatants were analyzed for apoptosis and necrosis using a Cell Death ELISA PLUS assay. FC lysates and media supernatants were also analyzed for inflammatory cytokine (IL1β, IL8, MCP1, TNFα) mRNA levels and protein expression using quantitative reverse transcription real-time polymerase chain reaction (QPCR) and a Procarta® immunoassay, respectively. mRNA levels of autophagy (MAP1LC3), apoptosis (survivin, clusterin), and matrix degradation (MMP1, MMP9) markers were evaluated by Quantigene® Plex assay and verified with QPCR. Additionally, hypercholesterolemic rabbits received everolimus-eluting stents (EES) for 28 or 60 days. RAM-11 immunohistochemical staining was performed to compare %RAM-11 positive area between stented sections and unstented proximal sections. Statistical significance was calculated using one-way ANOVA (p ≤ 0.05). Results: Calcein AM/DAPI staining showed that FC exposed to everolimus (10 -5 M) had significantly decreased viability compared to control. FC apoptosis was significantly increased at a high dose of everolimus (10 -5 M), with no necrotic effects at any dose tested. Everolimus did not affect endothelial (HUVEC) and smooth muscle (HCASMC) cell apoptosis or necrosis. Everolimus (10 -5 M) significantly increased MAP1LC3, caused an increased trend in clusterin (p = 0.10), and significantly decreased survivin and MMP1 mRNA levels in FC. MCP1 cytokine mRNA levels and secreted protein expression was significantly decreased

  10. Effects of everolimus on macrophage-derived foam cell behavior

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Steven, E-mail: steven.hsu@av.abbott.com [Abbott Vascular, 3200 Lakeside Drive, Santa Clara, CA 95054 (United States); Koren, Eugen; Chan, Yen; Koscec, Mirna; Sheehy, Alexander [Abbott Vascular, 3200 Lakeside Drive, Santa Clara, CA 95054 (United States); Kolodgie, Frank; Virmani, Renu [CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD 20878 (United States); Feder, Debra [Abbott Vascular, 3200 Lakeside Drive, Santa Clara, CA 95054 (United States)

    2014-07-15

    Purpose: The purpose of this study was to investigate the effects of everolimus on foam cell (FC) viability, mRNA levels, and inflammatory cytokine production to better understand its potential inhibitory effects on atheroma progression. Methods and materials: Human THP1 macrophage-derived FC were formed using acetylated LDL (acLDL, 100 μg/mL) for 72 hours, followed by everolimus treatment (10{sup -5}–10{sup -11} M) for 24 hours. FC viability was quantified using fluorescent calcein AM/DAPI staining. FC lysates and media supernatants were analyzed for apoptosis and necrosis using a Cell Death ELISA{sup PLUS} assay. FC lysates and media supernatants were also analyzed for inflammatory cytokine (IL1β, IL8, MCP1, TNFα) mRNA levels and protein expression using quantitative reverse transcription real-time polymerase chain reaction (QPCR) and a Procarta® immunoassay, respectively. mRNA levels of autophagy (MAP1LC3), apoptosis (survivin, clusterin), and matrix degradation (MMP1, MMP9) markers were evaluated by Quantigene® Plex assay and verified with QPCR. Additionally, hypercholesterolemic rabbits received everolimus-eluting stents (EES) for 28 or 60 days. RAM-11 immunohistochemical staining was performed to compare %RAM-11 positive area between stented sections and unstented proximal sections. Statistical significance was calculated using one-way ANOVA (p ≤ 0.05). Results: Calcein AM/DAPI staining showed that FC exposed to everolimus (10{sup -5} M) had significantly decreased viability compared to control. FC apoptosis was significantly increased at a high dose of everolimus (10{sup -5} M), with no necrotic effects at any dose tested. Everolimus did not affect endothelial (HUVEC) and smooth muscle (HCASMC) cell apoptosis or necrosis. Everolimus (10{sup -5} M) significantly increased MAP1LC3, caused an increased trend in clusterin (p = 0.10), and significantly decreased survivin and MMP1 mRNA levels in FC. MCP1 cytokine mRNA levels and secreted protein

  11. Everolimus Alleviates Obstructive Hydrocephalus due to Subependymal Giant Cell Astrocytomas.

    Science.gov (United States)

    Moavero, Romina; Carai, Andrea; Mastronuzzi, Angela; Marciano, Sara; Graziola, Federica; Vigevano, Federico; Curatolo, Paolo

    2017-03-01

    Subependymal giant cell astrocytomas (SEGAs) are low-grade tumors affecting up to 20% of patients with tuberous sclerosis complex (TSC). Early neurosurgical resection has been the only standard treatment until few years ago when a better understanding of the molecular pathogenesis of TSC led to the use of mammalian target of rapamycin (mTOR) inhibitors. Surgical resection of SEGAs is still considered as the first line treatment in individuals with symptomatic hydrocephalus and intratumoral hemorrhage. We describe four patients with symptomatic or asymptomatic hydrocephalus who were successfully treated with the mTOR inhibitor everolimus. We collected the clinical data of four consecutive patients presenting with symptomatic or asymptomatic hydrocephalus due to a growth of subependymal giant cell atrocytomas and who could not undergo surgery for different reasons. All patients experienced a clinically significant response to everolimus and an early shrinkage of the SEGA with improvement in ventricular dilatation. Everolimus was well tolerated by all individuals. Our clinical series demonstrate a possible expanding indication for mTOR inhibition in TSC, which can be considered in patients with asymptomatic hydrocephalus or even when the symptoms already appeared. It offers a significant therapeutic alternative to individuals that once would have undergone immediate surgery. Everolimus might also allow postponement of a neurosurgical resection, making it elective with an overall lower risk. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Comparison of an everolimus-eluting bioresorbable scaffold with an everolimus-eluting metallic stent for the treatment of coronary artery stenosis (ABSORB II)

    DEFF Research Database (Denmark)

    Serruys, Patrick W; Chevalier, Bernard; Sotomi, Yohei

    2016-01-01

    BACKGROUND: No medium-term data are available on the random comparison between everolimus-eluting bioresorbable vascular scaffolds and everolimus-eluting metallic stents. The study aims to demonstrate two mechanistic properties of the bioresorbable scaffold: increase in luminal dimensions as a re...

  13. Effect of Post-Dilatation Following Primary PCI With Everolimus-Eluting Bioresorbable Scaffold Versus Everolimus-Eluting Metallic Stent Implantation

    DEFF Research Database (Denmark)

    Yamaji, Kyohei; Brugaletta, Salvatore; Sabaté, Manel

    2017-01-01

    OBJECTIVES: This study sought to investigate the effect of post-dilatation on angiographic and intracoronary imaging parameters in the setting of primary percutaneous coronary intervention comparing the everolimus-eluting bioresorbable scaffold (BRS) with the everolimus-eluting metallic stent (EE...

  14. Everolimus: a review of its pharmacologic properties and use in solid organ transplantation

    Directory of Open Access Journals (Sweden)

    Paul Huiras

    2011-10-01

    Full Text Available The aim of this review article is to review the pharmacology, pharmacokinetics, efficacy and safety of everolimus. Primary literature was obtained via MEDLINE. Studies and abstracts evaluating everolimus in solid organ transplantation were considered for evaluation. English-language studies and abstracts only were selected for inclusion. Everolimus, a proliferation signal inhibitor that prevents growth factor-induced cell proliferation, is effective in reducing the incidence of acute rejection in solid organ transplantation. This agent is also useful in reducing cyclosporine-related nephrotoxicity. Everolimus directly inhibits vascular remodelling and intimal thickening, which are often associated with chronic rejection. Clinical trials have shown that everolimus is generally safe. The most commonly reported adverse events were haematologic effects and hyperlipidaemia. Everolimus is the second proliferation signal inhibitor to be proven effective in preventing acute rejection in solid organ transplant recipients. However, its exact role in the transplant immunosuppressive armamentarium is still unknown.

  15. Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients

    DEFF Research Database (Denmark)

    Andreassen, A K; Andersson, B; Gustafsson, F

    2014-01-01

    In a randomized, open-label trial, everolimus was compared to cyclosporine in 115 de novo heart transplant recipients. Patients were assigned within 5 days posttransplant to low-exposure everolimus (3–6 ng/mL) with reduced-exposure cyclosporine (n = 56), or standard-exposure cyclosporine (n = 59...... infection was less common with everolimus (5.4% vs. 30.5%, p heart transplantation. Since postoperative safety...

  16. Everolimus: a review of its pharmacologic properties and use in solid organ transplantation

    OpenAIRE

    Huiras, Paul; Gabardi, Steven

    2011-01-01

    The aim of this review article is to review the pharmacology, pharmacokinetics, efficacy and safety of everolimus. Primary literature was obtained via MEDLINE. Studies and abstracts evaluating everolimus in solid organ transplantation were considered for evaluation. English-language studies and abstracts only were selected for inclusion. Everolimus, a proliferation signal inhibitor that prevents growth factor-induced cell proliferation, is effective in reducing the incidence of acute rejectio...

  17. Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients

    DEFF Research Database (Denmark)

    Andreassen, A K; Andersson, B; Gustafsson, F

    2016-01-01

    In a randomized, open-label trial, de novo heart transplant recipients were randomized to everolimus (3-6 ng/mL) with reduced-exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7-11 after transplant, followed by increased everolimus exposure (target 6-10 ng/mL) with cyclosporine withdrawal...... events occurred in 37.3% and 19.6% of everolimus- and CNI-treated patients, respectively (p = 0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte-depleting induction is safe at intermediate follow...

  18. A Semi-Physiological Population Model to Quantify the Effect of Hematocrit on Everolimus Pharmacokinetics and Pharmacodynamics in Cancer Patients

    NARCIS (Netherlands)

    Erp, N.P. van; Herpen, C.M. van; Wit, D. de; Willemsen, A.; Burger, D.M.; Huitema, A.D.; Kapiteijn, E.; Heine, R. ter

    2016-01-01

    INTRODUCTION AND OBJECTIVE: Everolimus (a drug from the class of mammalian target of rapamycin [mTOR] inhibitors) is associated with frequent toxicity-related dose reductions. Everolimus accumulates in erythrocytes, but the extent to which hematocrit affects everolimus plasma pharmacokinetics and

  19. Everolimus for Primary Intestinal Lymphangiectasia With Protein-Losing Enteropathy.

    Science.gov (United States)

    Ozeki, Michio; Hori, Tomohiro; Kanda, Kaori; Kawamoto, Norio; Ibuka, Takashi; Miyazaki, Tatsuhiko; Fukao, Toshiyuki

    2016-03-01

    Primary intestinal lymphangiectasia (PIL), also known as Waldmann's disease, is an exudative enteropathy resulting from morphologic abnormalities in the intestinal lymphatics. In this article, we describe a 12-year-old boy with PIL that led to protein-losing enteropathy characterized by diarrhea, hypoalbuminemia associated with edema (serum albumin level: 1.0 g/dL), and hypogammaglobulinemia (serum IgG level: 144 mg/dL). Severe hypoalbuminemia, electrolyte abnormalities, and tetany persisted despite a low-fat diet and propranolol. Everolimus (1.6 mg/m(2)/day) was added to his treatment as an antiangiogenic agent. With everolimus treatment, the patient's diarrhea resolved and replacement therapy for hypoproteinemia was less frequent. Hematologic and scintigraphy findings also improved (serum albumin level: 2.5 g/dL). There were no adverse reactions during the 12-month follow-up. To the best of our knowledge, this is the first report of everolimus use in a patient with PIL. Copyright © 2016 by the American Academy of Pediatrics.

  20. A phase Ib study of everolimus combined with metformin for patients with advanced cancer.

    Science.gov (United States)

    Molenaar, Remco J; van de Venne, Tim; Weterman, Mariëtte J; Mathot, Ron A; Klümpen, Heinz-Josef; Richel, Dick J; Wilmink, Johanna W

    2018-02-01

    Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.

  1. Everolimus-induced pneumonitis associates with favourable outcome in patients with metastatic renal cell carcinoma

    DEFF Research Database (Denmark)

    Penttilä, P; Donskov, F; Rautiola, J

    2017-01-01

    BACKGROUND: Mammalian target of rapamycin inhibitors may induce pneumonitis. We analysed the association of pneumonitis with outcomes in everolimus treated metastatic renal cell carcinoma (mRCC) patients. PATIENTS AND METHODS: Eighty-five mRCC patients received everolimus at Helsinki University...

  2. Everolimus: a proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology.

    Science.gov (United States)

    Gabardi, Steven; Baroletti, Steven A

    2010-10-01

    Everolimus, a proliferation signal inhibitor in the mammalian target of rapamycin (mTOR) drug class, has many clinical applications, including in organ transplantation, oncology, and cardiology. It currently has United States Food and Drug Administration (FDA) approval for prophylaxis against rejection in de novo renal transplant recipients, treatment of renal cell carcinoma, and use as a drug-eluting stent. To review the pharmacology, pharmacokinetics, efficacy, and safety of everolimus, we performed a search of the MEDLINE database (January 1997-April 2010) for all English-language articles of in vitro and in vivo studies that evaluated everolimus, as well as abstracts from recent scientific meetings and the manufacturer. In transplantation, everolimus demonstrates immunosuppressive properties and has been used to prevent acute rejection in cardiac, liver, lung, and renal transplant recipients. It appears that this agent may be potent enough to allow for the minimization or removal of calcineurin inhibitors in the long-term management of renal transplant recipients. In oncology, everolimus has been proven effective for the management of treatment-resistant renal cell carcinoma. In cardiology, everolimus is available as a drug-coated stent and is used in percutaneous coronary interventions for prevention of restenosis. In transplant recipients and patients with renal cell carcinoma, everolimus appears to have an extensive adverse-event profile. The pharmacologic properties of everolimus differentiate this agent from other drugs used in these clinical areas, and its pharmacokinetic properties differentiate it from sirolimus.

  3. Optimizing everolimus exposure when combined with calcineurin inhibitors in solid organ transplantation

    NARCIS (Netherlands)

    T. van Gelder (Teun); L. Fischer (Lutz); Shihab, F. (Fuad); M. Shipkova (Maria)

    2017-01-01

    textabstractThe mammalian target of rapamycin (mTOR) inhibitor everolimus is a narrow therapeutic index drug for which optimal exposure levels are essential. The consistent pharmacokinetic profile of everolimus allows trough concentration (C0) measurement to be an appropriate and reliable index for

  4. Everolimus with reduced calcineurin inhibitor in thoracic transplant recipients with renal dysfunction: a multicenter, randomized trial

    DEFF Research Database (Denmark)

    Gullestad, Lars; Iversen, Martin; Mortensen, Svend-Aage

    2010-01-01

    The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking.......The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking....

  5. Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing

    Directory of Open Access Journals (Sweden)

    Jun Aono, MD, PhD

    2016-01-01

    Full Text Available Proliferation of smooth muscle cells (SMCs during neointima formation is prevented by drug-eluting stents. The replicative capacity of mammalian cells is enhanced by telomerase expression; however, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target are unknown. The present study investigated the mechanisms underlying the mitogenic function of telomerase, and tested the hypothesis that everolimus, which is commonly used on drug-eluting stents, suppresses SMC proliferation by targeting telomerase. Inhibition of neointima formation by everolimus was lost in mice overexpressing telomerase reverse transcriptase (TERT, indicating that repression of telomerase confers the anti-proliferative efficacy of everolimus. Everolimus reduced TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S-phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Chromatin immunoprecipitation assays demonstrated that TERT induced E2F binding to S-phase gene promoters and supported histone acetylation. These effects were sensitive to inhibition by everolimus. These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus, and further identify a novel mitogenic pathway in SMC that depends on the epigenetic activation of S-phase gene promoters by TERT.

  6. Amenorrhea as a rare drug-related adverse event associated with everolimus for pancreatic neuroendocrine tumors.

    Science.gov (United States)

    Kawaguchi, Yoshiaki; Maruno, Atsuko; Kawashima, Yohei; Ito, Hiroyuki; Ogawa, Masami; Mine, Tetsuya

    2014-11-14

    The patient was an asymptomatic 43-year-old woman. Abdominal ultrasonography and enhanced computed tomography showed a tumor lesion accompanied by multiple cystic changes in the liver and the pancreatic tail. Endoscopic ultrasound-fine needle aspiration was performed on the pancreatic tumor lesion and revealed pancreatic neuroendocrine tumor (PNET). As it was unresectable due to multiple liver metastases, the decision was made to initiate treatment with everolimus and transcatheter arterial chemoembolization. The patient ceased menstruating after the start of everolimus administration. When the administration was discontinued due to interstitial lung disease, menstruation resumed, but then again stopped with everolimus resumption. An association between everolimus and amenorrhea was highly suspected. Amenorrhea occurred as a rare adverse event of everolimus. As the younger women might be included in PNETs patients, we should put this adverse event into consideration.

  7. Glycolysis in Panc-1 human pancreatic cancer cells is inhibited by everolimus.

    Science.gov (United States)

    Liu, Ling; Gong, Liansheng; Zhang, Yangde; Li, Nianfeng

    2013-01-01

    The aim of this study was to evaluate the effects and molecular mechanisms of everolimus on Panc-1 human pancreatic cancer cells. Panc-1 human pancreatic cancer cells were treated with everolimus (10 μg/ml) at selected time points (6, 12 and 24 h). Cell proliferation and apoptosis were evaluated by MTT and flow cytometric analyses. The glycolytic activity was determined by measuring the activity of the key enzyme lactate dehydrogenase (LDH) and lactate production. The activity of mammalian target of rapamycin (mTOR) signaling was measured by western blotting. The expression of genes, including hexokinase 2 (HK2) and microRNA-143 (miR-143), was evaluated by real-time polymerase chain reaction (PCR). The administration of everolimus time-dependently inhibited proliferation and glycolysis and induced apoptosis in the Panc-1 human pancreatic cancer cells. As the time of treatment with everolimus increased, the mTOR signaling activity decreased, indicated by lower phosphorylation levels of S6 kinase; however, the phosphorylation levels of mTOR barely changed. Moreover, our data showed an everolimus-induced increase in miR-143 and decrease in HK2 in Panc-1 cells in a time-dependent manner. In conclusion, the current study indicates a novel role of everolimus in its antitumor effect as an inhibitor of glycolysis in Panc-1 human pancreatic cancer cells. Furthermore, our data highlights the significance of exploring the mechanisms of everolimus and miR-143 in malignant tumors.

  8. Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing.

    Science.gov (United States)

    Aono, Jun; Ruiz-Rodriguez, Ernesto; Qing, Hua; Findeisen, Hannes M; Jones, Karrie L; Heywood, Elizabeth B; Bruemmer, Dennis

    2016-01-01

    The present study sought to investigate the mechanisms underlying the mitogenic function of telomerase and to test the hypothesis that everolimus, commonly used on drug-eluting stents, suppresses smooth muscle cells (SMC) proliferation by targeting telomerase. Proliferation of SMC during neointima formation is prevented by drug-eluting stents. Although the replicative capacity of mammalian cells is enhanced by telomerase expression, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target remain to be investigated. We first employed constitutive expression of telomerase reverse transcriptase (TERT) in cell systems to study transcriptional mechanisms by which telomerase activates a mitogenic program. Second, overexpression of telomerase in mice provided a model to study the role of telomerase as a drug target for the antiproliferative efficacy of everolimus. Inhibition of neointima formation by everolimus is lost in mice overexpressing TERT, indicating that repression of telomerase confers the antiproliferative efficacy of everolimus. Everolimus reduces TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Using chromatin immunoprecipitation assays, we finally demonstrate that TERT induces E2F binding to S-phase gene promoters and supports histone acetylation, effects that are inhibited by everolimus and mediate its antiproliferative activity. These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus. Our studies further identify a novel mitogenic pathway in SMC

  9. Recommendations for use of everolimus after heart transplantation: results from a Latin-American Consensus Meeting.

    Science.gov (United States)

    Bocchi, E A; Ahualli, L; Amuchastegui, M; Boullon, F; Cerutti, B; Colque, R; Fernandez, D; Fiorelli, A; Olaya, P; Vulcado, N; Perrone, S V

    2006-04-01

    Despite improvements during the last decades, heart transplantation remains associated with several medical complications, which limit clinical outcomes: acute rejection with hemodynamic compromise, cytomegalovirus (CMV) infections, allograft vasculopathy, chronic renal failure, and neoplasias. Everolimus, a proliferation signal inhibitor, represents a new option for adjunctive immunosuppressive therapy. Everolimus displays better efficacy in de novo heart transplant patients than azathioprine for prophylaxis of biopsy-proven acute rejection episodes of at least ISHLT grade 3A (P Latin America produced recommendations for everolimus use in daily practice based on available data and their own experience.

  10. Improved renal function after early conversion from a calcineurin inhibitor to everolimus

    DEFF Research Database (Denmark)

    Mjörnstedt, L; Sørensen, S S; von Zur Mühlen, B

    2012-01-01

    .2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All......In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids...... controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNI-treated controls but discontinuations and BPAR were more frequent....

  11. Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer.

    Directory of Open Access Journals (Sweden)

    Tomas Pascual

    Full Text Available Metastatic breast cancer (MBC progressing after endocrine therapy frequently activates PI3K/AKT/mTOR pathway. The BOLERO-2 trial showed that everolimus-exemestane achieves increased progression free survival (PFS compared with exemestane. However, there is great inter-patient variability in toxicity and response to exemestane-everolimus treatment. The objective of this study was to perform an exploratory study analyzing the implication of single nucleotide polymorphisms (SNPs on outcomes from this treatment through a pharmacogenetic analysis.Blood was collected from 90 postmenopausal women with hormone receptor-positive, HER2-negative MBC treated with exemestane-everolimus following progression after prior treatment with a non-steroidal aromatase inhibitor. Everolimus pharmacokinetics was measured in 37 patients. Twelve SNPs in genes involved in everolimus pharmacokinetics and pharmacodynamics were genotyped and associations assessed with drug plasma levels, clinically relevant toxicities (non-infectious pneumonitis, mucositis, hyperglycemia and hematological toxicities, dose reductions or treatment suspensions due to toxicity, progression free survival (PFS and overall survival.We found that CYP3A4 rs35599367 variant (CYP3A4*22 allele carriers had higher everolimus blood concentration compared to wild type patients (P = 0.019. ABCB1 rs1045642 was associated with risk of mucositis (P = 0.031, while PIK3R1 rs10515074 and RAPTOR rs9906827 were associated with hyperglycemia and non-infectious pneumonitis (P = 0.016 and 0.024, respectively. Furthermore, RAPTOR rs9906827 was associated with PFS (P = 0.006.CYP3A4*22 allele influenced plasma concentration of everolimus and several SNPs in PI3K/AKT/mTOR pathway genes were associated with treatment toxicities and prognosis. These results require replication, but suggest that germline variation could influence everolimus outcomes in MBC.

  12. Evaluation of the Impact of the Cancer Therapy Everolimus on the Central Nervous System in Mice

    Science.gov (United States)

    Dubois, Martine; Le Joncour, Vadim; Tonon, Marie-Christine; Anouar, Youssef; Proust, François; Morin, Fabrice; Gandolfo, Pierrick; Joly, Florence; Hilber, Pascal; Castel, Hélène

    2014-01-01

    Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link between chemotherapy and cognitive dysfunctions was recently validated in animal models. New cancer targeted therapies have become widely used, and their impact on brain functions and quality of life needs to be explored. We evaluated the impact of everolimus, an anticancer agent targeting the mTOR pathway, on cognitive functions, cerebral metabolism, and hippocampal cell proliferation/vascular density in mice. Adult mice received everolimus daily for 2 weeks, and behavioral tests were performed from 1 week after the last treatment. Everolimus-treated mice displayed a marked reduction in weight gain from the last day of the treatment period. Ex vivo analysis showed altered cytochrome oxidase activity in selective cerebral regions involved in energy balance, food intake, reward, learning and memory modulation, sleep/wake cycle regulation, and arousal. Like chemotherapy, everolimus did not alter emotional reactivity, learning and memory performances, but in contrast to chemotherapy, did not affect behavioral flexibility or reactivity to novelty. In vivo hippocampal neural cell proliferation and vascular density were also unchanged after everolimus treatments. In conclusion, two weeks daily everolimus treatment at the clinical dose did not evoke alteration of cognitive performances evaluated in hippocampal- and prefrontal cortex-dependent tasks that would persist at one to four weeks after the end of the treatment completion. However, acute everolimus treatment caused selective CO modifications without altering the mTOR effector P70S6 kinase in cerebral regions involved in feeding behavior and/or the sleep/wake cycle, at least in part under control of the solitary nucleus and the parasubthalamic region of the hypothalamus. Thus, this area may represent a key target for everolimus-mediating peripheral modifications, which has been previously associated with symptoms such as

  13. Evaluation of the impact of the cancer therapy everolimus on the central nervous system in mice.

    Directory of Open Access Journals (Sweden)

    Martine Dubois

    Full Text Available Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link between chemotherapy and cognitive dysfunctions was recently validated in animal models. New cancer targeted therapies have become widely used, and their impact on brain functions and quality of life needs to be explored. We evaluated the impact of everolimus, an anticancer agent targeting the mTOR pathway, on cognitive functions, cerebral metabolism, and hippocampal cell proliferation/vascular density in mice. Adult mice received everolimus daily for 2 weeks, and behavioral tests were performed from 1 week after the last treatment. Everolimus-treated mice displayed a marked reduction in weight gain from the last day of the treatment period. Ex vivo analysis showed altered cytochrome oxidase activity in selective cerebral regions involved in energy balance, food intake, reward, learning and memory modulation, sleep/wake cycle regulation, and arousal. Like chemotherapy, everolimus did not alter emotional reactivity, learning and memory performances, but in contrast to chemotherapy, did not affect behavioral flexibility or reactivity to novelty. In vivo hippocampal neural cell proliferation and vascular density were also unchanged after everolimus treatments. In conclusion, two weeks daily everolimus treatment at the clinical dose did not evoke alteration of cognitive performances evaluated in hippocampal- and prefrontal cortex-dependent tasks that would persist at one to four weeks after the end of the treatment completion. However, acute everolimus treatment caused selective CO modifications without altering the mTOR effector P70S6 kinase in cerebral regions involved in feeding behavior and/or the sleep/wake cycle, at least in part under control of the solitary nucleus and the parasubthalamic region of the hypothalamus. Thus, this area may represent a key target for everolimus-mediating peripheral modifications, which has been previously associated

  14. Everolimus-induced Pneumonitis after Drug-eluting Stent Implantation: A Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Sakamoto, Susumu, E-mail: susumu1029@gmail.com; Kikuchi, Naoshi; Ichikawa, Atsuo; Sano, Go; Satoh, Keita; Sugino, Keishi; Isobe, Kazutoshi; Takai, Yujiro [Toho University School of Medicine, Department of Respiratory Medicine (Japan); Shibuya, Kazutoshi [Toho University School of Medicine, Department of Pathology (Japan); Homma, Sakae [Toho University School of Medicine, Department of Respiratory Medicine (Japan)

    2013-08-01

    Despite the wide use of everolimus as an antineoplastic coating agent for coronary stents to reduce the rate of restenosis, little is known about the health hazards of everolimus-eluting stents (EES). We describe a case of pneumonitis that developed 2 months after EES implantation for angina. Lung pathology demonstrated an organizing pneumonia pattern that responded to corticosteroid therapy. Although the efficacy of EES for ischemic heart disease is well established, EES carries a risk of pneumonitis.

  15. Randomised comparison of a bioresorbable everolimus-eluting scaffold with a metallic everolimus-eluting stent for ischaemic heart disease caused by de novo native coronary artery lesions

    DEFF Research Database (Denmark)

    Chevalier, Bernard; Onuma, Yoshinobu; van Boven, Ad J

    2016-01-01

    AIMS: The one-year randomised data of the ABSORB II trial showed that the everolimus-eluting bioresorbable scaffold and the everolimus-eluting metallic stent were comparable for the composite secondary clinical outcomes of patient-oriented composite endpoint (PoCE) and device-oriented composite...... Clara, CA, USA) or treatment with an everolimus-eluting metallic stent (XIENCE; Abbott Vascular). The trial enrolled 501 patients. Clinical follow-up at two years was available in 320 patients in the Absorb BVS arm and 160 patients in the XIENCE arm. At two years, the PoCE for the Absorb and XIENCE arms......-six percent and 34% of patients remained on DAPT at two years, respectively. Ninety-two percent of patients in both arms remained on aspirin. CONCLUSIONS: Two-year clinical results demonstrate sustained low rates of PoCE, MACE, DoCE and TVF with the Absorb BVS as compared to the XIENCE stent....

  16. CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma

    DEFF Research Database (Denmark)

    Escudier, Bernard; Sharma, Padmanee; McDermott, David F

    2017-01-01

    /kg every 2 wk or everolimus 10mg once daily. RESULTS AND LIMITATIONS: The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer...... Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age

  17. Comparison of an everolimus-eluting bioresorbable scaffold with an everolimus-eluting metallic stent for the treatment of coronary artery stenosis (ABSORB II): a 3 year, randomised, controlled, single-blind, multicentre clinical trial

    NARCIS (Netherlands)

    Serruys, Patrick W.; Chevalier, Bernard; Sotomi, Yohei; Cequier, Angel; Carrié, Didier; Piek, Jan J.; van Boven, Ad J.; Dominici, Marcello; Dudek, Dariusz; McClean, Dougal; Helqvist, Steffen; Haude, Michael; Reith, Sebastian; de Sousa Almeida, Manuel; Campo, Gianluca; Iñiguez, Andrés; Sabaté, Manel; Windecker, Stephan; Onuma, Yoshinobu

    2016-01-01

    No medium-term data are available on the random comparison between everolimus-eluting bioresorbable vascular scaffolds and everolimus-eluting metallic stents. The study aims to demonstrate two mechanistic properties of the bioresorbable scaffold: increase in luminal dimensions as a result of

  18. Anti-tumor effects of everolimus and metformin are complementary and glucose-dependent in breast cancer cells

    NARCIS (Netherlands)

    Ariaans, Gerke; Jalving, Mathilde; de Vries, Emma Geertruida Elisabeth; de Jong, Steven

    2017-01-01

    Background: Clinical efficacy of the mTOR inhibitor everolimus is limited in breast cancer and regularly leads to side-effects including hyperglycemia. The AMPK inhibitor and anti-diabetic drug metformin may counteract everolimus-induced hyperglycemia, as well as enhancing anti-cancer efficacy. We

  19. Effect of everolimus initiation and early calcineurin inhibitor withdrawal on myocardial FOXP3+ regulatory T cells in heart transplantation

    DEFF Research Database (Denmark)

    Mirza, Kiran; Gustafsson, Finn; Gullestad, Lars

    2016-01-01

    BACKGROUND: Through immunosuppression CD4+FoxP3+ regulatory T-cells (Tregs) play an indispensable role in allograft rejection. Post-HTx treatment with everolimus is associated with slower progression of cardiac allograft vasculopathy (CAV) - chronic rejection - than CNI based therapy. We hypothes......BACKGROUND: Through immunosuppression CD4+FoxP3+ regulatory T-cells (Tregs) play an indispensable role in allograft rejection. Post-HTx treatment with everolimus is associated with slower progression of cardiac allograft vasculopathy (CAV) - chronic rejection - than CNI based therapy. We...... hypothesized treatment with everolimus reduced the risk of CAV by modulating myocardial FoxP3 levels. METHODS: 15 patients from the Schedule trial comparing everolimus, MMF, steroid and early CNI (Everolimus, n=8) withdrawal to conventional CNI based immunosuppression (Controls, n=7) after de novo HTx were...

  20. Clinical evidence of the efficacy of everolimus and its potential in the treatment of breast cancer

    Directory of Open Access Journals (Sweden)

    Saksena R

    2013-05-01

    Full Text Available Rujuta Saksena, Serena T WongThe Cancer Institute of New Jersey, New Brunswick, NJ, USAAbstract: The PI3K/Akt/mTOR (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway regulates several key cellular functions and its dysregulation creates an environment that promotes tumorigenesis as well as resistance to therapy. The mTOR inhibitor everolimus has emerged as a promising agent in the treatment of breast cancer and was recently approved in combination with exemestane for advanced hormone receptor–positive disease after progression on a nonsteroidal aromatase inhibitor. Everolimus may also be effective in combination with cytotoxic and human epidermal growth factor receptor-2-directed therapies for the treatment of other subtypes of breast cancer. This paper highlights preclinical and clinical data that have emerged on the role of mTOR inhibition in breast cancer. Although generally well tolerated, everolimus carries a unique side effect profile of which both patients and providers should be made aware. Recommendations related to the administration of everolimus in the clinical setting are also discussed.Keywords: everolimus, breast cancer, mTOR inhibition

  1. [The drug of the month: everolimus (Afinitor) for the treatment of metastatic breast cancer].

    Science.gov (United States)

    Jerusalem, G; Rorive, A; Collignon, J

    2014-09-01

    Sequential endocrine treatments are recommended for estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER 2) negative metastatic breast cancers except in the case of symptomatic visceral disease. However, patients who suffer from disease progression while receiving a non-steroidal aromatase inhibitor (NSAI) have a very poor prognosis with standard endocrine therapy alone. Recently, based onthe results of the BOLERO 2 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus, combined with exemestane, a steroidal aromatase inhibitor, has been approved in Europe and the US for patients suffering from ER positive HER2 negative advanced breast cancer previously treated by a NSAI. The median progression-free survival (PFS) increased from 3.2 to 7.8 months in patients receiving everolimus and exemestane compared to placebo and exemestane. The magnitude of benefit was consistent in all pre-specified subgroups. Side effects were manageable and the quality of life was at least maintained. Everolimus has also beenrecently studied in HER2 positive locally advanced or metastatic disease in heavily pretreated patients (BOLERO 3 trial). This trial met its primary endpoint. The median PFS was increased in patients receiving trastuzumab, vinorelbine and everolimus compared to patients receiving trastuzumab, vinorelbine and placebo. We review pharmacological data and side effects of the drug. We also review the most important clinical trials leading to reimbursement of everolimus in metastatic breast cancer.

  2. Everolimus in clinical practice after liver transplantation: a single-center experience

    Directory of Open Access Journals (Sweden)

    O. A. Gerasimova

    2017-01-01

    Full Text Available Aim. Single-center analysis of everolimus treatment after liver transplantation. Materials and methods. 23 patients having received Certican after OLT in RSCRST were observed in period from 6 months to 5 years; comparison group consisted of 50 patients who received immunosuppressive scheme with tacrolimus. Conversion to everolimus was performed in the period from 1 month after OLT after discharge and at later time according to the indications: hepatocellular cancer, cumulative CNI nephrotoxicity, the development of malignancies, and intolerance to CNI. The concentrations of CNI and everolimus in the blood (target concentration of tacrolimus 1.5–2 ng/ml, everolimus 3–8 ng/ml were monitored. Glomerular filtration rate (GFR was determined using the CKD-EPI equation. Adverse events of everolimus were evaluated. Results. The immunosuppressive scheme with everolimus is presented; adverse events with dose-dependent hypercholesterolemia (34.7% as the main; the average level of blood cholesterol was not significantly different from that in the control group, 5.6 ± 0.9 vs 5.1 ± 1.4 mmol/l (Z = 1.3, p = 0.17. Renal function was stable throughout the observation period (35 ± 16 months. GFR (CKD-EPI before conversion was 75.8 ± 17.5 ml/min. 6 patients treated with Certican for 5 years had final GFR 96.6 ± 5.1 ml/min. GFR in the group of Certican at 12 months post conversion was 87.5 ± 16.3 ml/min vs 94.2 ± 16.8 ml/min (p = 0.08 in the control group. We revealed metastases to the liver and lungs in 5 patients from 13 patients with HCC, survival rate in this group depended on the compliance with the Milan criteria (Z = 2.4, p = 0.02. Conclusion. Everolimus allows maintaining of a stable renal function to prevent progression of renal failure; conversion should be initiated as early as possible. Combination of everolimus with reduced dose of CNI is optimal. Despite the fact that side effects are developing in most patients, adequate monitoring of

  3. Everolimus use and associated factors among post-menopausal women with hormonal receptor positive/human epidermal growth factor receptor 2 negative metastatic breast cancer.

    Science.gov (United States)

    Li, Nanxin; Hao, Yanni; Xie, Jipan; Lin, Peggy L; Zhou, Zhou; Zhong, Yichen; Signorovitch, James E; Wu, Eric Q

    2015-08-01

    Everolimus has been shown to be an effective HR+/HER2- mBC treatment in both clinical trials and real-world practice. The current study aims at understanding factors associated with everolimus use and how it is used in the real world. A retrospective chart review was conducted among postmenopausal HR+/HER2- mBC women who received everolimus, endocrine therapy (ET), or chemotherapy (CT) for mBC between 1 July 2012 and 15 April 2013 after an NSAI failure. Factors associated with everolimus use versus ET or CT were identified using multivariable logistic regressions. Reasons for prescribing everolimus and everolimus treatment patterns were described. Liver metastasis and high tumor volume were associated with a higher likelihood of everolimus use versus ET (OR = 1.67, OR = 1.62) but a lower likelihood of everolimus use versus CT (OR = 0.43, OR = 0.30). Medicare-only insurance (OR = 0.30) as well as ECOG ≥2 (OR = 3.72) and prior CT in mBC (OR = 2.76) were associated with a lower and higher likelihood of everolimus use versus CT, respectively. The top reason for prescribing everolimus was efficacy (69-85%). About 15% and 29% of everolimus users in second line and third line or above received prior CT for mBC. Exemestane was the most common concomitant therapy with everolimus (56-87%). The majority of patients initiated everolimus at the labeled dose of 10 mg daily (>80%) and maintained this dose (>80%). In the real world, everolimus was used in more severe patients than ET but less severe patients than CT based on visceral metastasis, tumor volume, and performance status. The top reason for prescribing everolimus was efficacy. A large proportion of patients received first or second line CT before everolimus initiation. The majority of patients used everolimus according to the labeled combination and dose. Future studies are needed to determine optimal sequencing of everolimus, ET, and CT for HR+/HER2- mBC.

  4. Everolimus for Advanced Pancreatic Neuroendocrine Tumours: A Subgroup Analysis Evaluating Japanese Patients in the RADIANT-3 Trial

    Science.gov (United States)

    Ito, Tetsuhide; Okusaka, Takuji; Ikeda, Masafumi; Igarashi, Hisato; Morizane, Chigusa; Nakachi, Kohei; Tajima, Takeshi; Kasuga, Akio; Fujita, Yoshie; Furuse, Junji

    2012-01-01

    Objective Everolimus, an inhibitor of the mammalian target of rapamycin, has recently demonstrated efficacy and safety in a Phase III, double-blind, randomized trial (RADIANT-3) in 410 patients with low- or intermediate-grade advanced pancreatic neuroendocrine tumours. Everolimus 10 mg/day provided a 2.4-fold improvement compared with placebo in progression-free survival, representing a 65% risk reduction for progression. The purpose of this analysis was to investigate the efficacy and safety of everolimus in the Japanese subgroup enrolled in the RADIANT-3 study. Methods Subgroup analysis of the Japanese patients was performed comparing efficacy and safety between everolimus 10 mg/day orally (n = 23) and matching placebo (n = 17). The primary endpoint was progression-free survival. Safety was evaluated on the basis of the incidence of adverse drug reactions. Results Progression-free survival was significantly prolonged with everolimus compared with placebo. The median progression-free survival was 19.45 months (95% confidence interval, 8.31–not available) with everolimus vs 2.83 months (95% confidence interval, 2.46–8.34) with placebo, resulting in an 81% risk reduction in progression (hazard ratio, 0.19; 95% confidence interval, 0.08–0.48; P< 0.001). Adverse drug reactions occurred in all 23 (100%) Japanese patients receiving everolimus and in 13 (77%) patients receiving placebo; most were grade 1/2 in severity. The most common adverse drug reactions in the everolimus group were rash (n = 20; 87%), stomatitis (n = 17; 74%), infections (n = 15; 65%), nail disorders (n = 12; 52%), epistaxis (n = 10; 44%) and pneumonitis (n = 10; 44%). Conclusions These results support the use of everolimus as a valuable treatment option for Japanese patients with advanced pancreatic neuroendocrine tumours. PMID:22859827

  5. Vitamins C and K3: A Powerful Redox System for Sensitizing Leukemia Lymphocytes to Everolimus and Barasertib.

    Science.gov (United States)

    Ivanova, Donika; Zhelev, Zhivko; Lazarova, Dessislava; Getsov, Plamen; Bakalova, Rumiana; Aoki, Ichio

    2018-03-01

    Recent studies provided convincing evidence for the anticancer activity of combined application of vitamin C and pro-vitamin K3 (menadione). The molecular pathways underlying this process are still not well established. The present study aimed to investigate the effect of the combination of vitamin C plus pro-vitamin K3 on the redox status of leukemia and normal lymphocytes, as well as their sensitizing effect for a variety of anticancer drugs. Cytotoxicity of the substances was analyzed by trypan blue staining and automated counting of live and dead cells. Apoptosis was analyzed by fluorescein isothiocyanate-annexin V test. Oxidative stress was evaluated by the intracellular levels of reactive oxygen and nitrogen species and protein-carbonyl products. Combined administration of 300 μM vitamin C plus 3 μM pro-vitamin K3 reduced the viability of leukemia lymphocytes by ~20%, but did not influence the viability of normal lymphocytes. All combinations of anticancer drug plus vitamins C and K3 were characterized by synergistic cytotoxicity towards Jurkat cells, compared to cells treated with drug alone for 24 h. In the case of barasertib and everolimus, this synergistic cytotoxicity increased within 72 hours. It was accompanied by strong induction of apoptosis, but a reduction of level of hydroperoxides and moderately increased protein-carbonyl products in leukemia cells. Leukemia lymphocytes were more sensitive to combined administration of anticancer drug (everolimus or barasertib) plus vitamins C and K3, compared to normal lymphocytes. The combination of vitamin C plus K3 seems to be a powerful redox system that could specifically influence redox homeostasis of leukemia cells and sensitize them to conventional chemotherapy. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  6. Comparison of zotarolimus-eluting and everolimus-eluting coronary stents

    DEFF Research Database (Denmark)

    Serruys, Patrick W; Silber, Sigmund; Garg, Scot

    2010-01-01

    New-generation coronary stents that release zotarolimus or everolimus have been shown to reduce the risk of restenosis. However, it is unclear whether there are differences in efficacy and safety between the two types of stents on the basis of prospectively adjudicated end points endorsed...

  7. Wound complications and surgical events in de novo heart transplant patients treated with everolimus

    DEFF Research Database (Denmark)

    Rashidi, Mitra; Esmaily, Sorosh; Fiane, Arnt E

    2016-01-01

    OBJECTIVES: The use of mammalian target of rapamycin (mTOR) inhibitors have been limited by adverse events (AE), including delayed wound healing. We retrospectively reviewed all AE and serious AE (SAE) in The Scandinavian heart transplant (HTx) everolimus (EVE) de novo trial with early calcineurin...

  8. Cost utility analysis of everolimus in the treatment of metastatic renal cell cancer in the Netherlands

    NARCIS (Netherlands)

    Mihajlović, J.; Minović, I.; Bruinsma, A.; Postma, M.J.

    2013-01-01

    Objectives: Metastatic renal cell cancer (mRCC) is becoming an important part of Dutch health care expenditure due to expensive pharmaceutical options for disease control and lack of adequate prevention methods. New targeted therapeutics, such as sunitinib, sorafenib and everolimus, have recently

  9. Incidence and Potential Mechanism(s) of Post-Procedural Rise of Cardiac Biomarker in Patients With Coronary Artery Narrowing After Implantation of an Everolimus-Eluting Bioresorbable Vascular Scaffold or Everolimus-Eluting Metallic Stent

    DEFF Research Database (Denmark)

    Ishibashi, Yuki; Muramatsu, Takashi; Nakatani, Shimpei

    2015-01-01

    OBJECTIVES: This study sought to evaluate the mechanism of post-procedural cardiac biomarker (CB) rise following device implantation. BACKGROUND: A fully bioresorbable Absorb scaffold, compared with everolimus-eluting metallic stents (EES), might be associated with a higher incidence...

  10. The SYNERGY biodegradable polymer everolimus eluting coronary stent: Porcine vascular compatibility and polymer safety study.

    Science.gov (United States)

    Wilson, Gregory J; Marks, Angela; Berg, Kimberly J; Eppihimer, Michael; Sushkova, Natalia; Hawley, Steve P; Robertson, Kimberly A; Knapp, David; Pennington, Douglas E; Chen, Yen-Lane; Foss, Aaron; Huibregtse, Barbara; Dawkins, Keith D

    2015-11-15

    SYNERGY is a novel platinum chromium alloy stent that delivers abluminal everolimus from an ultrathin poly-lactide-co-glycide (PLGA) biodegradable polymer. This study evaluated the in vivo degradation of the polymer coating, everolimus release time course, and vascular compatibility of the SYNERGY stent. SYNERGY stents were implanted in arteries of domestic swine. Devices were explanted at predetermined time points (up to 120 days) and the extent of PLGA coating or everolimus remaining on the stents was quantified. Everolimus levels in the arterial tissue were also evaluated. A pathological analysis on coronary arteries of single and overlapping stents was performed at time points between 5 and 270 days. PLGA bioabsorption began immediately after implantation, and drug release was essentially complete by 90 days; PLGA absorption was substantially complete by 120 days (>90% of polymer was absorbed) leaving a bare metal SYNERGY stent. Vascular response was similar among SYNERGY and control stents (bare metal, polymer-only, and 3× polymer-only). Mild increases in para-strut fibrin were seen for SYNERGY at an early time point with no significant differences in all other morphological and morphometric parameters through 270 days or endothelial function (eNOS immunostaining) at 90 or 180 days. Inflammation was predominantly minimal to mild for all device types. In a swine model, everolimus was released by 90 days and PLGA bioabsorption was complete shortly thereafter. The SYNERGY stent and its biodegradable polymer, even at a 3× safety margin, demonstrated vascular compatibility similar to bare metal stent controls. © 2015 Wiley Periodicals, Inc.

  11. The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients

    DEFF Research Database (Denmark)

    Gustafsson, Finn; Barth, David; Delgado, Diego H

    2009-01-01

    CsA C2 levels and blood CsA AUC(0-12) in groups of patients treated with MMF or everolimus (R(2) 0.93 and 0.96, respectively; P 2) = 0.98), there was poor correlation...... between whole-blood C2 and lymphocyte AUC(0-12) in patients treated with everolimus (R(2) = 0.24). CONCLUSION: Standard blood CsA levels accurately predict intralymphocytic exposure to CsA in patients concomitantly treated with MMF but not in patients treated with everolimus........ METHODS: Twelve-hour pharmacokinetic studies of whole-blood and intralymphocytic CsA concentrations were conducted in long-term heart-transplant recipients treated with mycophenolate mofetil (MMF) + CsA (n = 8) and everolimus + CsA (n = 9). RESULTS: There was a highly significant correlation between blood...

  12. Everolimus in advanced, progressive, well-differentiated, non-functional neuroendocrine tumors: RADIANT-4 lung subgroup analysis.

    Science.gov (United States)

    Fazio, Nicola; Buzzoni, Roberto; Delle Fave, Gianfranco; Tesselaar, Margot E; Wolin, Edward; Van Cutsem, Eric; Tomassetti, Paola; Strosberg, Jonathan; Voi, Maurizio; Bubuteishvili-Pacaud, Lida; Ridolfi, Antonia; Herbst, Fabian; Tomasek, Jiri; Singh, Simron; Pavel, Marianne; Kulke, Matthew H; Valle, Juan W; Yao, James C

    2018-01-01

    In the phase III RADIANT-4 study, everolimus improved median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated (grade 1 or grade 2), non-functional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio, 0.48; 95% confidence interval [CI], 0.35-0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT-4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, n = 63; placebo, n = 27). Median PFS (95% CI) by central review was 9.2 (6.8-10.9) months in the everolimus arm vs 3.6 (1.9-5.1) months in the placebo arm (hazard ratio, 0.50; 95% CI, 0.28-0.88). More patients who received everolimus (58%) experienced tumor shrinkage compared with placebo (13%). Most frequently reported (≥5% incidence) grade 3-4 drug-related adverse events (everolimus vs. placebo) included stomatitis (11% vs. 0%), hyperglycemia (10% vs. 0%), and any infections (8% vs. 0%). In patients with advanced, progressive, well-differentiated, non-functional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT-4 cohort. These results support the use of everolimus in patients with advanced, non-functional lung NET. The trial is registered with ClinicalTrials.gov (no. NCT01524783). © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  13. Everolimus for Previously Treated Advanced Gastric Cancer: Results of the Randomized, Double-Blind, Phase III GRANITE-1 Study

    Science.gov (United States)

    Ohtsu, Atsushi; Ajani, Jaffer A.; Bai, Yu-Xian; Bang, Yung-Jue; Chung, Hyun-Cheol; Pan, Hong-Ming; Sahmoud, Tarek; Shen, Lin; Yeh, Kun-Huei; Chin, Keisho; Muro, Kei; Kim, Yeul Hong; Ferry, David; Tebbutt, Niall C.; Al-Batran, Salah-Eddin; Smith, Heind; Costantini, Chiara; Rizvi, Syed; Lebwohl, David; Van Cutsem, Eric

    2013-01-01

    Purpose The oral mammalian target of rapamycin inhibitor everolimus demonstrated promising efficacy in a phase II study of pretreated advanced gastric cancer. This international, double-blind, phase III study compared everolimus efficacy and safety with that of best supportive care (BSC) in previously treated advanced gastric cancer. Patients and Methods Patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were randomly assigned to everolimus 10 mg/d (assignment schedule: 2:1) or matching placebo, both given with BSC. Randomization was stratified by previous chemotherapy lines (one v two) and region (Asia v rest of the world [ROW]). Treatment continued until disease progression or intolerable toxicity. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), overall response rate, and safety. Results Six hundred fifty-six patients (median age, 62.0 years; 73.6% male) were enrolled. Median OS was 5.4 months with everolimus and 4.3 months with placebo (hazard ratio, 0.90; 95% CI, 0.75 to 1.08; P = .124). Median PFS was 1.7 months and 1.4 months in the everolimus and placebo arms, respectively (hazard ratio, 0.66; 95% CI, 0.56 to 0.78). Common grade 3/4 adverse events included anemia, decreased appetite, and fatigue. The safety profile was similar in patients enrolled in Asia versus ROW. Conclusion Compared with BSC, everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy. The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers. PMID:24043745

  14. Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4.

    Science.gov (United States)

    Buzzoni, Roberto; Carnaghi, Carlo; Strosberg, Jonathan; Fazio, Nicola; Singh, Simron; Herbst, Fabian; Ridolfi, Antonia; Pavel, Marianne E; Wolin, Edward M; Valle, Juan W; Oh, Do-Youn; Yao, James C; Pommier, Rodney

    2017-01-01

    Recently, everolimus was shown to improve median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) tract compared with placebo (HR, 0.48; 95% CI, 0.35-0.67; P <0.00001) in the Phase III, RADIANT-4 study. This post hoc analysis evaluates the impact of prior therapies (somatostatin analogs [SSA], chemotherapy, and radiotherapy) on everolimus activity. ClinicalTrials.gov identifier: NCT01524783. Patients were randomized (2:1) to everolimus 10 mg/day or placebo, both with best supportive care. Subgroups of patients who received prior SSA, chemotherapy, or radiotherapy (including peptide receptor radionuclide therapy) were analyzed and reported. A total of 302 patients were enrolled, of whom, 163 (54%) had any prior SSA use (mostly for tumor control), 77 (25%) received chemotherapy, and 63 (21%) were previously exposed to radiotherapy. Patients who received everolimus had longer median PFS compared with placebo, regardless of previous SSA (with SSA: 11.1 vs 4.5 months [HR, 0.56 {95% CI, 0.37-0.85}]; without SSA: 9.5 vs 3.7 months [0.57 {0.36-0.89}]), chemotherapy (with chemotherapy: 9.2 vs 2.1 months [0.35 {0.19-0.64}]; without chemotherapy: 11.2 vs 5.4 months [0.60 {0.42-0.86}]), or radiotherapy (with radiotherapy: 9.2 vs 3.0 months [0.47 {0.24-0.94}]; without radiotherapy: 11 vs 5.1 months [0.59 {0.42-0.83}]) exposure. The most frequent drug-related adverse events included stomatitis (59%-65%), fatigue (27%-35%), and diarrhea (24%-34%) among the subgroups. These results suggest that everolimus improves PFS in patients with advanced, progressive lung or GI NET, regardless of prior therapies. Safety findings were consistent with the known safety profile of everolimus in NET.

  15. Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer

    International Nuclear Information System (INIS)

    Huijts, Charlotte M; Santegoets, Saskia J; Eertwegh, Alfons J van den; Pijpers, Laura S; Haanen, John B; Gruijl, Tanja D de; Verheul, Henk M; Vliet, Hans J van der

    2011-01-01

    For patients with metastatic renal cell cancer (mRCC) who progressed on vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs) that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide. This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part). In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels. This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus induced Treg expansion in patients with metastatic renal cell

  16. Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer

    Directory of Open Access Journals (Sweden)

    Huijts Charlotte M

    2011-11-01

    Full Text Available Abstract Background For patients with metastatic renal cell cancer (mRCC who progressed on vascular endothelial growth factor (VEGF receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide. Methods/design This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part. In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels. Discussion This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus

  17. Five-year clinical and functional multislice computed tomography angiographic results after coronary implantation of the fully resorbable polymeric everolimus-eluting scaffold in patients with de novo coronary artery disease: the ABSORB cohort A trial.

    Science.gov (United States)

    Onuma, Yoshinobu; Dudek, Dariusz; Thuesen, Leif; Webster, Mark; Nieman, Koen; Garcia-Garcia, Hector M; Ormiston, John A; Serruys, Patrick W

    2013-10-01

    This study sought to demonstrate the 5-year clinical and functional multislice computed tomography angiographic results after implantation of the fully resorbable everolimus-eluting scaffold (Absorb BVS, Abbott Vascular, Santa Clara, California). Multimodality imaging of the first-in-humans trial using a ABSORB BVS scaffold demonstrated at 2 years the bioresorption of the device while preventing restenosis. However, the long-term safety and efficacy of this therapy remain to be documented. In the ABSORB cohort A trial (ABSORB Clinical Investigation, Cohort A [ABSORB A] Everolimus-Eluting Coronary Stent System Clinical Investigation), 30 patients with a single de novo coronary artery lesion were treated with the fully resorbable everolimus-eluting Absorb scaffold at 4 centers. As an optional investigation in 3 of the 4 centers, the patients underwent multislice computed tomography (MSCT) angiography at 18 months and 5 years. Acquired MSCT data were analyzed at an independent core laboratory (Cardialysis, Rotterdam, the Netherlands) for quantitative analysis of lumen dimensions and was further processed for calculation of fractional flow reserve (FFR) at another independent core laboratory (Heart Flow, Redwood City, California). Five-year clinical follow-up is available for 29 patients. One patient withdrew consent after 6 months, but the vital status of this patient remains available. At 46 days, 1 patient experienced a single episode of chest pain and underwent a target lesion revascularization with a slight troponin increase after the procedure. At 5 years, the ischemia-driven major adverse cardiac event rate of 3.4% remained unchanged. Clopidogrel was discontinued in all but 1 patient. Scaffold thrombosis was not observed in any patient. Two noncardiac deaths were reported, 1 caused by duodenal perforation and the other from Hodgkin's disease. At 5 years, 18 patients underwent MSCT angiography. All scaffolds were patent, with a median minimal lumen area of 3

  18. Critical appraisal of the role of everolimus in advanced neuroendocrine tumors of pancreatic origin

    Directory of Open Access Journals (Sweden)

    Mulet-Margalef N

    2012-09-01

    Full Text Available Núria Mulet-Margalef, Jaume CapdevilaMedical Oncology Department, Vall d'Hebron University Hospital, Barcelona, SpainAbstract: For many years, the treatment of advanced pancreatic neuroendocrine tumors (pNETs has been limited almost entirely to somatostatin analogs and streptozocin-based chemotherapy, with modest benefit. Increasing knowledge of the biologic features of pNETs has allowed the design of molecular-based clinical trials, which have taken a step forward in the management of these tumors. In this review, we discuss the molecular rationale for the development of everolimus for patients with advanced pNETs, critically review the clinical data obtained by the main studies in this setting, and discuss essential considerations based on recent findings in pNET biology for future drug development involving the phosphatidylinositol 3' kinase-AKT-mTOR pathway.Keywords: pancreatic neuroendocrine tumors, everolimus, targeted therapies

  19. Therapeutic potential and adverse events of everolimus for treatment of hepatocellular carcinoma – systematic review and meta-analysis

    International Nuclear Information System (INIS)

    Yamanaka, Kenya; Petrulionis, Marius; Lin, Shibo; Gao, Chao; Galli, Uwe; Richter, Susanne; Winkler, Susanne; Houben, Philipp; Schultze, Daniel; Hatano, Etsuro; Schemmer, Peter

    2013-01-01

    Everolimus is an orally administrated mammalian target of rapamycin (mTOR) inhibitor. Several large-scale randomized controlled trials (RCTs) have demonstrated the survival benefits of everolimus at the dose of 10 mg/day for solid cancers. Furthermore, mTOR-inhibitor-based immunosuppression is associated with survival benefits for patients with hepatocellular carcinoma (HCC) who have received liver transplantation. However, a low rate of tumor reduction and some adverse events have been pointed out. This review summarizes the antitumor effects and adverse events of everolimus and evaluates its possible application in advanced HCC. For the meta-analysis of adverse events, we used the RCTs for solid cancers. The odds ratios of adverse events were calculated using the Peto method. Manypreclinical studies demonstrated that everolimus had antitumor effects such as antiproliferation and antiangiogenesis. However, some differences in the effects were observed among in vivo animal studies for HCC treatment. Meanwhile, clinical studies demonstrated that the response rate of single-agent everolimus was low, though survival benefits could be expected. The meta-analysis revealed the odds ratios (95% confidence interval [CI]) of stomatitis: 5.42 [4.31–6.73], hyperglycemia: 3.22 [2.37–4.39], anemia: 3.34 [2.37–4.67], pneumonitis: 6.02 [3.95–9.16], aspartate aminotransferase levels: 2.22 [1.37–3.62], and serum alanine aminotransferase levels: 2.94 [1.72–5.02], respectively. Everolimus at the dose of 10 mg/day significantly increased the risk of the adverse events. In order to enable its application to the standard conventional therapies of HCC, further studies are required to enhance the antitumor effects and manage the adverse events of everolimus

  20. Two-dose-level confirmatory study of the pharmacokinetics and tolerability of everolimus in Chinese patients with advanced solid tumors

    Directory of Open Access Journals (Sweden)

    Jappe Annette

    2011-01-01

    Full Text Available Abstract Background This phase I, randomized, multicenter, open-label study investigated the pharmacokinetics, safety, and efficacy of the oral mammalian target of rapamycin inhibitor everolimus in Chinese patients with advanced solid tumors. Methods A total of 24 patients with advanced breast cancer (n = 6, gastric cancer (n = 6, non-small cell lung cancer (n = 6, or renal cell carcinoma (n = 6 who were refractory to/unsuitable for standard therapy were randomized 1:1 to oral everolimus 5 or 10 mg/day. Primary end points were pharmacokinetic parameters and safety and tolerability. Pharmacokinetic 24-h profiles were measured on day 15; trough level was measured on days 2, 8, 15, 16, and 22. Tolerability was assessed continuously. This final analysis was performed after all patients had received 6 months of study drug or had discontinued. Results Everolimus was absorbed rapidly; median Tmax was 3 h (range, 1-4 and 2 h (range, 0.9-6 in the 5 and 10 mg/day groups, respectively. Pharmacokinetic parameters increased dose proportionally from the 5 and 10 mg/day doses. Steady-state levels were achieved by day 8 or earlier. The most common adverse events suspected to be related to everolimus therapy were increased blood glucose (16.7% and 41.7% and fatigue (16.7% and 33.3% in the everolimus 5 and 10 mg/day dose cohorts, respectively. Best tumor response was stable disease in 10 (83% and 6 (50% patients in the 5 and 10 mg/day groups, respectively. Conclusions Everolimus 5 or 10 mg/day was well tolerated in Chinese patients with advanced solid tumors. The observed safety and pharmacokinetic profile of everolimus from this study were consistent with previous studies. Trial registration Chinese Health Authorities 2008L09346

  1. Supplementary Administration of Everolimus Reduces Cardiac Systolic Function in Kidney Transplant Recipients.

    Science.gov (United States)

    Tsujimura, Kazuma; Ota, Morihito; Chinen, Kiyoshi; Nagayama, Kiyomitsu; Oroku, Masato; Nishihira, Morikuni; Shiohira, Yoshiki; Abe, Masami; Iseki, Kunitoshi; Ishida, Hideki; Tanabe, Kazunari

    2017-05-26

    BACKGROUND The effect of everolimus, one of the mammalian targets of rapamycin inhibitors, on cardiac function was evaluated in kidney transplant recipients. MATERIAL AND METHODS Seventy-six participants who underwent kidney transplant between March 2009 and May 2016 were retrospectively reviewed. To standardize everolimus administration, the following criteria were used: (1) the recipient did not have a donor-specific antigen before kidney transplantation; (2) the recipient did not have proteinuria and uncontrollable hyperlipidemia after kidney transplantation; and (3) acute rejection was not observed on protocol biopsy 3 months after kidney transplantation. According to these criteria, everolimus administration for maintenance immunosuppression after kidney transplantation was included. Cardiac function was compared between the treatment group (n=30) and non-treatment group (n=46). RESULTS The mean observation periods of the treatment and non-treatment groups were 41.3±12.6 and 43.9±19.8 months, respectively (p=0.573). The mean ejection fraction and fractional shortening of the treatment and non-treatment groups after kidney transplant were 66.5±7.9% vs. 69.6±5.5% (p=0.024) and 37.1±6.2% vs. 39.3±4.7% (p=0.045), respectively. In the treatment group, the mean ejection fraction and fractional shortening before and after kidney transplantation did not differ significantly (p=0.604 and 0.606, respectively). In the non-treatment group, the mean ejection fraction and fractional shortening before and after kidney transplantation differed significantly (p=0.004 and 0.006, respectively). CONCLUSIONS Supplementary administration of everolimus after kidney transplantation can reduce cardiac systolic function.

  2. Safety, Efficacy, and Patient Acceptability of Everolimus in the Treatment of Breast Cancer.

    Science.gov (United States)

    Lousberg, Laurence; Jerusalem, Guy

    2016-01-01

    Everolimus combined with exemestane is an important treatment option for patients suffering from estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer (ABC) who have been previously treated with a nonsteroidal aromatase inhibitor (NSAI). After presentation of phase III registration trial BOLERO-2, several phase IIIb trials have been started to evaluate this regimen in a more real-world setting. Here, we review the efficacy and safety data published or presented at selected international meetings. These studies confirmed the outcome observed in the BOLERO-2 trial. Patient acceptance rate is also discussed by focusing on the permanent everolimus discontinuation rate in these trials. Factors influencing the safety profile are also reported, including the impact of age. The optimal sequence of combined therapy approaches associating targeted and endocrine therapy (ET) has yet to be determined as new treatment options such as cyclin-dependent kinase inhibitors become available. However, everolimus-exemestane remains an important treatment option with a major impact on progression-free survival (PFS) and an acceptable safety profile.

  3. Vascular Response of the Segments Adjacent to the Proximal and Distal Edges of the ABSORB Everolimus-Eluting Bioresorbable Vascular Scaffold

    DEFF Research Database (Denmark)

    Gogas, Bill D; Serruys, Patrick W; Diletti, Roberto

    2012-01-01

    This study sought to investigate in vivo the vascular response at the proximal and distal edges of the second-generation ABSORB everolimus-eluting bioresorbable vascular scaffold (BVS).......This study sought to investigate in vivo the vascular response at the proximal and distal edges of the second-generation ABSORB everolimus-eluting bioresorbable vascular scaffold (BVS)....

  4. A randomized comparison of a durable polymer Everolimus-eluting stent with a bare metal coronary stent: The SPIRIT first trial

    NARCIS (Netherlands)

    Serruys, Patrick W.; Ong, Andrew T. L.; Piek, Jan J.; Neumann, Franz-Josef; van der Giessen, Willem J.; Wiemer, Marcus; Zeiher, Andreas; Grube, Eberhard; Haase, Jürgen; Thuesen, Leif; Hamm, Christian; Otto-Terlouw, Patricia C.

    2005-01-01

    Background: Everolimus is a sirolimus analogue with similar efficacy in animal models, and has been previously successfully tested in humans using an erodable polymer.Methods: This first-in-man single blind multi-centre randomized controlled trial assessed the safety and efficacy of everolimus

  5. A randomised comparison of an everolimus-eluting coronary stent with a paclitaxel-eluting coronary stent:the SPIRIT II trial

    NARCIS (Netherlands)

    Serruys, Patrick W.; Ruygrok, Peter; Neuzner, Jörg; Piek, Jan J.; Seth, Ashok; Schofer, Joachim J.; Richardt, Gert; Wiemer, Marcus; Carrié, Didier; Thuesen, Leif; Boone, Els; Miquel-Herbert, Karine; Daemen, Joost

    2006-01-01

    Background: Everolimus has been successfully tested in humans using both an erodable and a durable polymer in small previous studies.Methods: This single blind multi-centre non-inferiority randomised (3:1) controlled trial evaluated the safety and performance of the XIENCE V Everolimus Eluting

  6. 18F-FDG and 18F-FLT-PET Imaging for Monitoring Everolimus Effect on Tumor-Growth in Neuroendocrine Tumors

    DEFF Research Database (Denmark)

    Johnbeck, Camilla Bardram; Munk Jensen, Mette; Nielsen, Carsten Haagen

    2014-01-01

    INTRODUCTION: The mTOR inhibitor everolimus has shown promising results in some but not all neuroendocrine tumors. Therefore, early assessment of treatment response would be beneficial. In this study, we investigated the in vivo and in vitro treatment effect of everolimus in neuroendocrine tumors...

  7. Long-term outcomes of thoracic transplant recipients following conversion to everolimus with reduced calcineurin inhibitor in a multicenter, open-label, randomized trial lv

    DEFF Research Database (Denmark)

    Gullestad, Lars; Eiskjaer, Hans; Gustafsson, Finn

    2016-01-01

    The NOCTET study randomized 282 patients ≥1 year after heart or lung transplantation to continue conventional calcineurin inhibitor (CNI) therapy or to start everolimus with reduced-exposure CNI. Last follow-up, at ≥5 years postrandomization (mean: 5.6 years) was attended by 72/140 everolimus...

  8. The prognostic utility of the SYNTAX score on 1-year outcomes after revascularization with zotarolimus- and everolimus-eluting stents: a substudy of the RESOLUTE All Comers Trial

    DEFF Research Database (Denmark)

    Garg, Scot; Serruys, Patrick W; Silber, Sigmund

    2011-01-01

    This study assessed the ability of the SYNTAX score (SXscore) to stratify risk in patients treated with percutaneous coronary intervention (PCI) using zotarolimus-eluting or everolimus-eluting stents.......This study assessed the ability of the SYNTAX score (SXscore) to stratify risk in patients treated with percutaneous coronary intervention (PCI) using zotarolimus-eluting or everolimus-eluting stents....

  9. The MANDELA study: A multicenter, randomized, open-label, parallel group trial to refine the use of everolimus after heart transplantation.

    Science.gov (United States)

    Deuse, Tobias; Bara, Christoph; Barten, Markus J; Hirt, Stephan W; Doesch, Andreas O; Knosalla, Christoph; Grinninger, Carola; Stypmann, Jörg; Garbade, Jens; Wimmer, Peter; May, Christoph; Porstner, Martina; Schulz, Uwe

    2015-11-01

    In recent years a series of trials has sought to define the optimal protocol for everolimus-based immunosuppression in heart transplantation, with the goal of minimizing exposure to calcineurin inhibitors (CNIs) and harnessing the non-immunosuppressive benefits of everolimus. Randomized studies have demonstrated that immunosuppressive potency can be maintained in heart transplant patients receiving everolimus despite marked CNI reduction, although very early CNI withdrawal may be inadvisable. A potential renal advantage has been shown for everolimus, but the optimal time for conversion and the adequate reduction in CNI exposure remain to be defined. Other reasons for use of everolimus include a substantial reduction in the risk of cytomegalovirus infection, and evidence for inhibition of cardiac allograft vasculopathy, a major cause of graft loss. The ongoing MANDELA study is a 12-month multicenter, randomized, open-label, parallel-group study in which efficacy, renal function and safety are compared in approximately 200 heart transplant patients. Patients receive CNI therapy, steroids and everolimus or mycophenolic acid during months 3 to 6 post-transplant, and are then randomized at month 6 post-transplant (i) to convert to CNI-free immunosuppression with everolimus and mycophenolic acid or (ii) to continue reduced-exposure CNI, with concomitant everolimus. Patients are then followed to month 18 post-transplant The rationale and expectations for the trial and its methodology are described herein. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study.

    Directory of Open Access Journals (Sweden)

    John J Bissler

    Full Text Available We examined the long-term effects of everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.Following favorable results from the double-blind core phase of EXIST-2 (NCT00790400, patients were allowed to receive open-label everolimus (extension phase. Patients initially randomly assigned to everolimus continued on the same dose; those who were receiving placebo crossed over to everolimus 10 mg/day. Dose modifications were based on tolerability. The primary end point was angiomyolipoma response rate, defined as a ≥50% reduction from baseline in the sum volume of target renal angiomyolipomas in the absence of new target angiomyolipomas, kidney volume increase of >20% from nadir, and angiomyolipoma-related bleeding grade ≥2. The key secondary end point was safety.Of the 112 patients who received ≥1 dose of everolimus, 58% (95% CI, 48.3% to 67.3% achieved angiomyolipoma response. Almost all patients (97% experienced reduction in renal lesion volumes at some point during the study period. Median duration of everolimus exposure was 46.9 months. Sixteen (14.3% patients experienced angiomyolipoma progression at some point in the study. No angiomyolipoma-related bleeding or nephrectomies were reported. One patient on everolimus underwent embolization for worsening right flank pain. Subependymal giant cell astrocytoma lesion response was achieved in 48% of patients and skin lesion response in 68% of patients. The most common adverse events suspected to be treatment-related were stomatitis (42%, hypercholesterolemia (30.4%, acne (25.9%, aphthous stomatitis and nasopharyngitis (each 21.4%. Ten (8.9% patients withdrew because of an adverse event. Renal function remained stable, and the frequency of emergent adverse events generally decreased over time.Everolimus treatment remained safe and effective over approximately 4 years. The overall risk/benefit assessment supports the use

  11. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis.

    Science.gov (United States)

    Yardley, Denise A; Noguchi, Shinzaburo; Pritchard, Kathleen I; Burris, Howard A; Baselga, José; Gnant, Michael; Hortobagyi, Gabriel N; Campone, Mario; Pistilli, Barbara; Piccart, Martine; Melichar, Bohuslav; Petrakova, Katarina; Arena, Francis P; Erdkamp, Frans; Harb, Wael A; Feng, Wentao; Cahana, Ayelet; Taran, Tetiana; Lebwohl, David; Rugo, Hope S

    2013-10-01

    Effective treatments for hormone-receptor-positive (HR(+)) breast cancer (BC) following relapse/progression on nonsteroidal aromatase inhibitor (NSAI) therapy are needed. Initial Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival (PFS) versus placebo plus exemestane alone in this patient population. BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing everolimus (10 mg/day) plus exemestane (25 mg/day) versus placebo plus exemestane in postmenopausal women with HR(+) advanced BC with recurrence/progression during or after NSAIs. The primary endpoint was PFS by local investigator review, and was confirmed by independent central radiology review. Overall survival, response rate, and clinical benefit rate were secondary endpoints. Final study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane [investigator review: 7.8 versus 3.2 months, respectively; hazard ratio = 0.45 (95% confidence interval 0.38-0.54); log-rank P NSAIs. These results further support the use of everolimus plus exemestane in this patient population. ClinicalTrials.gov #NCT00863655.

  12. FDG-PET as a predictive biomarker for therapy with everolimus in metastatic renal cell cancer

    International Nuclear Information System (INIS)

    Chen, James L; Appelbaum, Daniel E; Kocherginsky, Masha; Cowey, Charles L; Kimryn Rathmell, Wendy; McDermott, David F; Stadler, Walter M

    2013-01-01

    The mTOR (mammalian target of rapamycin) inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and delays renal cell carcinoma (RCC) progression. Preclinical evidence suggests that baseline elevated tumor glucose metabolism as quantified by FDG-PET ([ 18 F] fluorodeoxy-glucose positron emission tomography) may predict antitumor activity. Metastatic RCC (mRCC) patients refractory to vascular endothelial growth factor (VEGF) pathway inhibition were treated with standard dose everolimus. FDG-PET scans were obtained at baseline and 2 weeks; serial computed tomography (CT) scans were obtained at baseline and every 8 weeks. Maximum standardized uptake value (SUVmax) of the most FDG avid lesion, average SUVmax of all measured lesions and their corresponding 2-week relative changes were examined for association with 8-week change in tumor size. A total of 63 patients were enrolled; 50 were evaluable for the primary endpoint of which 48 had both PET scans. Patient characteristics included the following: 36 (72%) clear cell histology and median age 59 (range: 37–80). Median pre- and 2-week treatment average SUVmax were 6.6 (1–17.9) and 4.2 (1–13.9), respectively. Response evaluation criteria in solid tumors (RECIST)-based measurements demonstrated an average change in tumor burden of 0.2% (−32.7% to 35.9%) at 8 weeks. Relative change in average SUVmax was the best predictor of change in tumor burden (all evaluable P = 0.01; clear cell subtype P = 0.02), with modest correlation. Baseline average SUVmax was correlated with overall survival and progression-free survival (PFS) (P = 0.023; 0.020), but not with change in tumor burden. Everolimus therapy decreased SUVs on follow-up PET scans in mRCC patients, but changes were only modestly correlated with changes in tumor size. Thus, clinical use of FDG-PET-based biomarkers is challenged by high variability. In this phase II trial, FDG-PET was explored as a predictive biomarker

  13. Comparison of in vivo acute stent recoil between the bioabsorbable everolimus-eluting coronary stent and the everolimus-eluting cobalt chromium coronary stent: insights from the ABSORB and SPIRIT trials

    DEFF Research Database (Denmark)

    Tanimoto, Shuzou; Serruys, Patrick W; Thuesen, Leif

    2007-01-01

    OBJECTIVES: This study sought to evaluate and compare in vivo acute stent recoil of a novel bioabsorbable stent and a metallic stent. BACKGROUND: The bioabsorbable everolimus-eluting coronary stent (BVS) is composed of a poly-L-lactic acid backbone, coated with a bioabsorbable polymer containing...... the antiproliferative drug, everolimus, and expected to be totally metabolized and absorbed in the human body. Because the BVS is made from polymer, it may have more acute recoil than metallic stents in vivo. METHODS: A total of 54 patients, who underwent elective stent implantation for single de novo native coronary...... artery lesions, were enrolled: 27 patients treated with the BVS and 27 patients treated with the everolimus-eluting cobalt chromium stent (EES). Acute absolute recoil, assessed by quantitative coronary angiography, was defined as the difference between mean diameter of the last inflated balloon...

  14. Efficacy and Safety of Everolimus for Maintenance Immunosuppression of Kidney Transplantation: A Meta-Analysis of Randomized Controlled Trials.

    Directory of Open Access Journals (Sweden)

    Jinyu Liu

    Full Text Available Conversion to everolimus is often used in kidney transplantation to overcome calcineurin inhibitor (CNI nephrotoxicity but there is conflicting evidence for this approach.To investigate the benefits and harm from randomized clinical trials (RCTs involving the conversion from CNI to everolimus after kidney transplantation.Databases were searched up to March 2016. Two reviewers independently assessed trials for eligibility and quality, and extracted data. Results are expressed as risk ratio (RR or mean difference (MD with 95% confidence intervals (CI.Eleven RCTs, with a total of 1,633 patients, met the final inclusion criteria. Patients converted to everolimus had improved renal function at 1 year posttransplant with an estimated glomerular filtration rate (eGFR of 5.36 mL/min per 1.73 m2 greater than patients remaining on CNI (p = 0.0005 and the longer-term results (> 1 year of renal function was identical to that of 1 year. There was not a substantial difference in graft loss, mortality, and the occurrence of adverse events (AEs or serious AEs. However, the risks of acute rejection and trial termination due to AEs with everolimus are respectively 1.82 and 2.63 times greater than patients staying on CNI at 1 year posttransplant (p = 0.02, p = 0.03, respectively. Further, those patients who converted to everolimus had a substantially greater risk of anemia, hyperlipidemia, hypercholesterolemia, hypokalemia, proteinuria, stomatitis, mouth ulceration, and acne.Conversion from CNI to everolimus after kidney transplantation is associated with improved renal function in the first 5 years posttransplant but increases the risk of acute rejection at 1 year posttransplant and may not be well endured.

  15. Long-Term Use of Everolimus in Patients with Tuberous Sclerosis Complex: Final Results from the EXIST-1 Study.

    Directory of Open Access Journals (Sweden)

    David N Franz

    Full Text Available Everolimus, a mammalian target of rapamycin (mTOR inhibitor, has demonstrated efficacy in treating subependymal giant cell astrocytomas (SEGAs and other manifestations of tuberous sclerosis complex (TSC. However, long-term use of mTOR inhibitors might be necessary. This analysis explored long-term efficacy and safety of everolimus from the conclusion of the EXIST-1 study (NCT00789828.EXIST-1 was an international, prospective, double-blind, placebo-controlled phase 3 trial examining everolimus in patients with new or growing TSC-related SEGA. After a double-blind core phase, all remaining patients could receive everolimus in a long-term, open-label extension. Everolimus was initiated at a dose (4.5 mg/m2/day titrated to a target blood trough of 5-15 ng/mL. SEGA response rate (primary end point was defined as the proportion of patients achieving confirmed ≥50% reduction in the sum volume of target SEGA lesions from baseline in the absence of worsening nontarget SEGA lesions, new target SEGA lesions, and new or worsening hydrocephalus. Of 111 patients (median age, 9.5 years who received ≥1 dose of everolimus (median duration, 47.1 months, 57.7% (95% confidence interval [CI], 47.9-67.0 achieved SEGA response. Of 41 patients with target renal angiomyolipomas at baseline, 30 (73.2% achieved renal angiomyolipoma response. In 105 patients with ≥1 skin lesion at baseline, skin lesion response rate was 58.1%. Incidence of adverse events (AEs was comparable with that of previous reports, and occurrence of emergent AEs generally decreased over time. The most common AEs (≥30% incidence suspected to be treatment-related were stomatitis (43.2% and mouth ulceration (32.4%.Everolimus use led to sustained reduction in tumor volume, and new responses were observed for SEGA and renal angiomyolipoma from the blinded core phase of the study. These findings support the hypothesis that everolimus can safely reverse multisystem manifestations of TSC in a

  16. Everolimus immunosuppression reduces the serum expression of fibrosis markers in liver transplant recipients.

    Science.gov (United States)

    Fernández-Yunquera, Ainhoa; Ripoll, Cristina; Bañares, Rafael; Puerto, Marta; Rincón, Diego; Yepes, Ismael; Catalina, Vega; Salcedo, Magdalena

    2014-06-24

    To evaluate the expression of serum fibrosis markers in liver transplantation (LT) recipients on everolimus monotherapy compared to patients on an anti-calcineurin regimen. This cross-sectional case-control study included LT patients on everolimus monotherapy (cases) (E) (n = 30) and matched controls on an anti-calcineurin regimen (calcineurin inhibitors, CNI), paired by etiology of liver disease and time since LT (n = 30). Clinical characteristics, blood tests and elastography were collected. Serum levels of transforming growth factor-β (TGF-β), angiopoietin-1, tumor necrosis factor (TNF), platelet derived growth factor, amino-terminal propeptide of type III procollagen (PIIINP), hyaluronic acid (HA), VCM-1 (ng/mL), interleukin (IL)-10, interferon-inducible protein 10 (IP-10), vascular endothelial growth factor and hepatocyte growth factor (HGF) (pg/mL) were determined by enzyme-linked immunosorbent assay. Expression of these markers between E and CNI was compared. Stratified analysis was done according to factors that may influence liver fibrosis. Variables are described with medians (interquartillic range) or percentages. A total of 60 patients [age: 59 (49-64), hepatitis C virus (HCV): n = 21 (35%), time from LT: 73 mo (16-105)] were included. Patients had been on everolimus for a median of 15 mo. No differences in inflammatory activity, APRI test or liver elastography were found between the groups. No significant differences were observed between the groups in serum levels of PIIINP, metalloproteinase type = 1, angiopoietin, HGF, IP-10, TNF-α, IL-10 and vascular cell adhesion molecule. Patients on E had a lower expression of TGF-β [E: 12.7 (3.7-133.6), CNI: 152.5 (14.4-333.2), P = 0.009] and HA [E: 702.89 (329.4-838.2), CNI: 1513.6 (691.9-1951.4), P = 0.001] than those on CNI. This difference was maintained in the stratified analysis when recipient age is more than 50 years (TFG-β1: P = 0.06; HA: P = 0.005), in patients without active neoplasia (TFG-β1

  17. Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4

    Directory of Open Access Journals (Sweden)

    Buzzoni R

    2017-10-01

    Full Text Available Roberto Buzzoni,1 Carlo Carnaghi,2 Jonathan Strosberg,3 Nicola Fazio,4 Simron Singh,5 Fabian Herbst,6 Antonia Ridolfi,7 Marianne E Pavel,8 Edward M Wolin,9 Juan W Valle,10 Do-Youn Oh,11 James C Yao,12 Rodney Pommier13 1IRCCS Foundation, National Institute of Tumors, Milan, Italy; 2Humanitas Clinical and Research Center, Rozzano, Italy; 3Moffitt Cancer Center, Tampa, FL, USA; 4European Institute of Oncology, Milan, Italy; 5Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 6Novartis AG, Basel, Switzerland; 7Novartis Pharma S.A.S., Rueil-Malmaison, France; 8Medizinische Klinik 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 9Montefiore Einstein Center for Cancer Care, Bronx, NY, USA; 10Institute of Cancer Sciences, University of Manchester, The Christie Hospital, Manchester, UK; 11Seoul National University Hospital, Seoul, Republic of Korea; 12University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; 13Oregon Health & Science University, Portland, OR, USA Background: Recently, everolimus was shown to improve median progression-free survival (PFS by 7.1 months in patients with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET of lung or gastrointestinal (GI tract compared with placebo (HR, 0.48; 95% CI, 0.35–0.67; P<0.00001 in the Phase III, RADIANT-4 study. This post hoc analysis evaluates the impact of prior therapies (somatostatin analogs [SSA], chemotherapy, and radiotherapy on everolimus activity. Trial registration: ClinicalTrials.gov identifier: NCT01524783. Patients and methods: Patients were randomized (2:1 to everolimus 10 mg/day or placebo, both with best supportive care. Subgroups of patients who received prior SSA, chemotherapy, or radiotherapy (including peptide receptor radionuclide therapy were analyzed and reported. Results: A total of 302 patients were enrolled, of whom, 163 (54% had any prior SSA use (mostly for tumor control, 77 (25% received

  18. A bioresorbable everolimus-eluting scaffold versus a metallic everolimus-eluting stent for ischaemic heart disease caused by de-novo native coronary artery lesions (ABSORB II): an interim 1-year analysis of clinical and procedural secondary outcomes from a randomised controlled trial

    NARCIS (Netherlands)

    Serruys, Patrick W.; Chevalier, Bernard; Dudek, Dariusz; Cequier, Angel; Carrié, Didier; Iniguez, Andres; Dominici, Marcello; van der Schaaf, René J.; Haude, Michael; Wasungu, Luc; Veldhof, Susan; Peng, Lei; Staehr, Peter; Grundeken, Maik J.; Ishibashi, Yuki; Garcia-Garcia, Hector M.; Onuma, Yoshinobu

    2015-01-01

    Despite rapid dissemination of an everolimus-eluting bioresorbable scaffold for treatment for coronary artery disease, no data from comparisons with its metallic stent counterpart are available. In a randomised controlled trial we aimed to compare an everolimus-eluting bioresorbable scaffold with an

  19. Everolimus-eluting bioresorbable stent vs. durable polymer everolimus-eluting metallic stent in patients with ST-segment elevation myocardial infarction

    DEFF Research Database (Denmark)

    Sabaté, Manel; Windecker, Stephan; Iñiguez, Andres

    2015-01-01

    AIMS: Patients with ST-segment elevation myocardial infarction (STEMI) feature thrombus-rich lesions with large necrotic core, which are usually associated with delayed arterial healing and impaired stent-related outcomes. The use of bioresorbable vascular scaffolds (Absorb) has the potential...... to overcome these limitations owing to restoration of native vessel lumen and physiology at long term. The purpose of this randomized trial was to compare the arterial healing response at short term, as a surrogate for safety and efficacy, between the Absorb and the metallic everolimus-eluting stent (EES...... was the 6-month optical frequency domain imaging healing score (HS) based on the presence of uncovered and/or malapposed stent struts and intraluminal filling defects. Main secondary endpoint included the device-oriented composite endpoint (DOCE) according to the Academic Research Consortium definition...

  20. The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma

    International Nuclear Information System (INIS)

    Pignochino, Ymera; Dell’Aglio, Carmine; Inghilleri, Simona; Zorzetto, Michele; Basiricò, Marco; Capozzi, Federica; Canta, Marta; Piloni, Davide; Cemmi, Francesca; Sangiolo, Dario; Gammaitoni, Loretta; Soster, Marco; Marchiò, Serena; Pozzi, Ernesto; Morbini, Patrizia; Luisetti, Maurizio; Aglietta, Massimo; Grignani, Giovanni; Stella, Giulia M

    2015-01-01

    Malignant Pleural Mesothelioma (MPM) is an aggressive tumor arising from mesothelial cells lining the pleural cavities characterized by resistance to standard therapies. Most of the molecular steps responsible for pleural transformation remain unclear; however, several growth factor signaling cascades are known to be altered during MPM onset and progression. Transducers of these pathways, such as PIK3CA-mTOR-AKT, MAPK, and ezrin/radixin/moesin (ERM) could therefore be exploited as possible targets for pharmacological intervention. This study aimed to identify ‘druggable’ pathways in MPM and to formulate a targeted approach based on the use of commercially available molecules, such as the multikinase inhibitor sorafenib and the mTOR inhibitor everolimus. We planned a triple approach based on: i) analysis of immunophenotypes and mutational profiles in a cohort of thoracoscopic MPM samples, ii) in vitro pharmacological assays, ii) in vivo therapeutic approaches on MPM xenografts. No mutations were found in ‘hot spot’ regions of the mTOR upstream genes (e.g. EGFR, KRAS and PIK3CA). Phosphorylated mTOR and ERM were specifically overexpressed in the analyzed MPM samples. Sorafenib and everolimus combination was effective in mTOR and ERM blockade; exerted synergistic effects on the inhibition of MPM cell proliferation; triggered ROS production and consequent AMPK-p38 mediated-apoptosis. The antitumor activity was displayed when orally administered to MPM-bearing NOD/SCID mice. ERM and mTOR pathways are activated in MPM and ‘druggable’ by a combination of sorafenib and everolimus. Combination therapy is a promising therapeutic strategy against MPM. The online version of this article (doi:10.1186/s12885-015-1363-1) contains supplementary material, which is available to authorized users

  1. An acute episode of rhabdomyolysis associated with everolimus and cabergoline intake in a postpartum kidney recipient

    Directory of Open Access Journals (Sweden)

    B. I. Yaremin

    2017-01-01

    Full Text Available Kidney transplantation is one of the most promising ways to ensure the onset and successful maintenance of pregnancy in patients with end-stage chronic renal disease. A multicomponent drug therapy in such patients creates risks for fetal development, primarily due to the teratogenicity of mTOR receptor inhibitors and mycophenolate. Moreover, the inhibitors of the proliferative signal may have potential drug interactions, which can result in additional complications.Rhabdomyolysis is one of them. The paper describes the clinical case of an acute episode of reversible rhabdomyolysis in a patient on everolimus therapy.

  2. Everolimus-associated acute kidney injury in patients with metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    A Chandra

    2017-01-01

    Full Text Available Recently, everolimus (Evl has been introduced in the management of hormone receptor-positive metastatic breast cancer, in combination with aromatase inhibitors. Evl-induced acute kidney injury has hitherto been described in other malignancies, especially renal cell cancer, but only once before in a patient with breast cancer. We describe two cases of Evl-associated nephrotoxicity in patients with breast cancer, one of whom underwent a renal biopsy showing acute tubular necrosis. Both our patients improved after withdrawal of the offending agent and have normal renal functions on follow-up.

  3. Arterial healing following primary PCI using the Absorb everolimus-eluting bioresorbable vascular scaffold (Absorb BVS) versus the durable polymer everolimus-eluting metallic stent (XIENCE) in patients with acute ST-elevation myocardial infarction

    DEFF Research Database (Denmark)

    Räber, Lorenz; Onuma, Yoshinobu; Brugaletta, Salvatore

    2015-01-01

    Aims: The Absorb bioresorbable vascular scaffold (Absorb BVS) provides similar clinical outcomes compared with a durable polymer-based everolimus-eluting metallic stent (EES) in stable coronary artery disease patients. ST-elevation myocardial infarction (STEMI) lesions have been associated with d...

  4. Cost-Effectiveness of Everolimus for Second-Line Treatment of Metastatic Renal Cell Carcinoma in Serbia

    NARCIS (Netherlands)

    Mihajlovic, Jovan; Pechlivanoglou, Petros; Sabo, Ana; Tomic, Zdenko; Postma, Maarten J.

    2013-01-01

    Background: New targeted therapeutics for metastatic renal cell carcinoma (mRCC) enable an increment in progression-free survival (PFS) ranging from 2 to 6 months. Compared with best supportive care, everolimus demonstrated an additional PFS of 3 months in patients with mRCC whose disease had

  5. Early conversion from calcineurin inhibitor- to everolimus-based therapy following kidney transplantation : Results of the randomized ELEVATE trial

    NARCIS (Netherlands)

    de Fijter, Johan W; Holdaas, Hallvard; Øyen, Ole; Sanders, Jan Stephan; Sundar, Sankaran; Bemelman, Frederike J; Sommerer, Claudia; Pascual, Julio; Avihingsanon, Yingyos; Pongskul, Cholatip; Oppenheimer, Frederic; Toselli, Lorenzo; Russ, Graeme; Wang, Zailong; Lopez, Patricia; Kochuparampil, Jossy; Cruzado, Josep M; van der Giet, Markus

    In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n=359) or remain on standard calcineurin inhibitor (CNI) therapy (n=356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and

  6. Efficacy of palbociclib plus fulvestrant after everolimus in hormone receptor-positive metastatic breast cancer.

    Science.gov (United States)

    du Rusquec, Pauline; Palpacuer, Clément; Campion, Loic; Patsouris, Anne; Augereau, Paule; Gourmelon, Carole; Robert, Marie; Dumas, Laurence; Caroline, Folliard; Campone, Mario; Frenel, Jean-Sébastien

    2018-04-01

    Palbociclib, a CDK4-6 inhibitor, combined with endocrine therapy (ET) is a new standard of treatment for Hormone Receptor-positive Metastatic Breast Cancer. We present the first real-life efficacy and tolerance data of palbociclib plus fulvestrant in this population. From November 2015 to November 2016, patients receiving in our institution palbociclib + fulvestrant according to the Temporary Authorization for Use were prospectively analyzed. 60 patients were treated accordingly; median age was 61 years; 50 patients (83.3%) had visceral metastasis, and 10 (16.7%) had bone-only disease. Patients had previously received a median of 5 (1-14) lines of treatment, including ET (median 3) and chemotherapy (median 2); 28 (46.7%) received previously fulvestrant and all everolimus. With a median follow-up of 10.3 months, median progression-free survival (mPFS) was 5.8 months (95% CI 3.9-7.3). Patients pretreated with fulvestrant had a similar PFS of 6.4 months (HR 1.00; 95% CI 0.55-1.83; P = 1.00). The most common AEs (adverse events) were neutropenia (93%), anemia (65%), and thrombocytopenia (55%). In this heavily pretreated population including everolimus, fulvestrant plus palbociclib provides an mPFS of 5.8 months with the same magnitude of benefit for fulvestrant-pretreated patients.

  7. Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas

    Science.gov (United States)

    Karajannis, Matthias A.; Legault, Geneviève; Hagiwara, Mari; Giancotti, Filippo G.; Filatov, Alexander; Derman, Anna; Hochman, Tsivia; Goldberg, Judith D.; Vega, Emilio; Wisoff, Jeffrey H.; Golfinos, John G.; Merkelson, Amanda; Roland, J. Thomas; Allen, Jeffrey C.

    2014-01-01

    Background Activation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers. Methods We conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m2/day (children <18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as ≥15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients. Results None of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules. Conclusion Everolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic (“phase 0”) study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors. PMID:24311643

  8. Two-year outcomes in thoracic transplant recipients after conversion to everolimus with reduced calcineurin inhibitor within a multicenter, open-label, randomized trial

    DEFF Research Database (Denmark)

    Gullestad, Lars; Mortensen, Svend-Aage; Eiskjær, Hans

    2010-01-01

    Use of the mammalian target of rapamycin inhibitor everolimus with an accompanying reduction in calcineurin inhibitor (CNI) exposure has shown promise in preserving renal function in maintenance thoracic transplant patients, but robust, long-term data are required....

  9. Dynamic tumor modeling of the dose–response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial

    International Nuclear Information System (INIS)

    Stein, Andrew; Wang, Wenping; Carter, Alison A; Chiparus, Ovidiu; Hollaender, Norbert; Kim, Hyewon; Motzer, Robert J; Sarr, Celine

    2012-01-01

    The phase 3 RECORD-1 trial (NCT00410124) established the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progress on sunitinib or sorafenib. In RECORD-1, patients received 10 mg everolimus daily, with dose reduction to 5 mg daily allowed for toxicity. We have developed a model of tumor growth dynamics utilizing serial measurements of the sum of the longest tumor diameters (SLD) from individual RECORD-1 patients to define the dose–response relationship of everolimus. The model predicts that after 1 year of continuous dosing, the change in SLD of target lesions will be +142.1% ± 98.3%, +22.4% ± 17.2%, and –15.7% ± 11.5% in the average patient treated with placebo, 5 mg everolimus, and 10 mg everolimus, respectively. This nonlinear, mixed-effects modeling approach can be used to describe the dynamics of each individual patient, as well as the overall population. This allows evaluation of how an actual dosing history and individual covariates impact on the observed drug effect, and offers the possibility of predicting clinical observations as a function of time. In this pharmacodynamic model of tumor response, everolimus more effectively shrinks target lesions in mRCC when dosed 10 mg daily versus 5 mg daily, although a 5-mg dose still shows an antitumor effect. These data support earlier studies that established 10 mg daily as the preferred clinical dose of everolimus, and improve our understanding of the everolimus dose–response relationship

  10. CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma.

    Science.gov (United States)

    Escudier, Bernard; Sharma, Padmanee; McDermott, David F; George, Saby; Hammers, Hans J; Srinivas, Sandhya; Tykodi, Scott S; Sosman, Jeffrey A; Procopio, Giuseppe; Plimack, Elizabeth R; Castellano, Daniel; Gurney, Howard; Donskov, Frede; Peltola, Katriina; Wagstaff, John; Gauler, Thomas C; Ueda, Takeshi; Zhao, Huanyu; Waxman, Ian M; Motzer, Robert J

    2017-12-01

    The randomized, phase 3 CheckMate 025 study of nivolumab (n=410) versus everolimus (n=411) in previously treated adults (75% male; 88% white) with advanced renal cell carcinoma (aRCC) demonstrated significantly improved overall survival (OS) and objective response rate (ORR). To investigate which baseline factors were associated with OS and ORR benefit with nivolumab versus everolimus. Subgroup OS analyses were performed using Kaplan-Meier methodology. Hazard ratios were estimated using the Cox proportional hazards model. Nivolumab 3mg/kg every 2 wk or everolimus 10mg once daily. The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age guide treatment decisions, and further supports nivolumab as the standard of care in previously treated patients with aRCC. We investigated the impact of demographic and pretreatment features on survival benefit and tumor response with nivolumab versus everolimus in advanced renal cell carcinoma (aRCC). Survival benefit and response were observed for multiple subgroups, supporting the use of nivolumab as a new standard of care across a broad range of patients with previously treated aRCC. The trial is registered on ClinicalTrials.gov as NCT01668784. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  11. Ganciclovir-Resistant Cytomegalovirus Infection in a Kidney Transplant Recipient Successfully Treated with Foscarnet and Everolimus.

    Science.gov (United States)

    Menghi, Viola; Comai, Giorgia; Baraldi, Olga; Liviano D'Arcangelo, Giovanni; Lazzarotto, Tiziana; La Manna, Gaetano

    2016-01-01

    Cytomegalovirus (CMV) infection remains a major cause of morbidity, graft failure, and death in kidney transplant recipients. We describe a case of a 53-year-old CMV-seronegative man who underwent renal transplant from a CMV-positive donor and who developed ganciclovir- (GCV-) resistant CMV infection. Foscarnet was started while immunosuppressive therapy was modified with the introduction of everolimus minimizing tacrolimus dosage. Only two weeks after the start of this treatment regimen was the patient's viral load negative. At two-year follow-up the patient has no clinical or laboratory signs of CMV infection and a good and stable renal function or graft survival. In our case, administration of an mTOR inhibitor combined with foscarnet led to rapid and persistent viral clearance without compromising short- and medium-term graft function. This combination therapy supports the need for the kidney transplant community to individualize a target therapy for each type of GCV-resistant CMV infection.

  12. Safety and Efficacy of Everolimus- Versus Sirolimus-Eluting Stents

    DEFF Research Database (Denmark)

    Jensen, Lisette Okkels; Thayssen, Per; Christiansen, Evald Høj

    2016-01-01

    BACKGROUND: Long-term safety and efficacy for everolimus-eluting stents (EES) versus those of sirolimus-eluting stents (SES) are unknown. OBJECTIVES: This study compared 5-year outcomes for EES with those for SES from the SORT OUT IV (Scandinavian Organization for Randomized Trials with Clinical...... rate was lower with EES (HR: 0.71, 95% CI: 0.55 to 0.90; p = 0.006; p interaction = 0.12). Definite stent thrombosis was lower with EES (0.4%) than with SES (2.0%; HR: 0.18, 95% CI: 0.07 to 0.46), with a lower risk of very late definite stent thrombosis in the EES group (0.2% vs. 1.4%, respectively; HR...... in Non-selected Patients With Coronary Heart Disease [SORT OUT IV]; NCT00552877)....

  13. Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation.

    Science.gov (United States)

    Lesche, Dorothea; Sigurdardottir, Vilborg; Setoud, Raschid; Englberger, Lars; Fiedler, Georg M; Largiadèr, Carlo R; Mohacsi, Paul; Sistonen, Johanna

    2015-12-01

    Everolimus (ERL) has become an alternative to calcineurin inhibitors (CNIs) due to its renal-sparing properties, especially in heart transplant (HTx) recipients with kidney dysfunction. However, ERL dosing is challenging due to its narrow therapeutic window combined with high interindividual pharmacokinetic variability. Our aim was to evaluate the effect of clinical and genetic factors on ERL dosing in a pilot cohort of 37 HTx recipients. Variants in CYP3A5, CYP3A4, CYP2C8, POR, NR1I2, and ABCB1 were genotyped, and clinical data were retrieved from patient charts. While ERL trough concentration (C0 ) was within the targeted range for most patients, over 30-fold variability in the dose-adjusted ERL C0 was observed. Regression analysis revealed a significant effect of the non-functional CYP3A5*3 variant on the dose-adjusted ERL C0 (p = 0.031). ERL dose requirement was 0.02 mg/kg/d higher in patients with CYP3A5*1/*3 genotype compared to patients with CYP3A5*3/*3 to reach the targeted C0 (p = 0.041). ERL therapy substantially improved estimated glomerular filtration rate (28.6 ± 6.6 mL/min/1.73 m(2)) in patients with baseline kidney dysfunction. Everolimus pharmacokinetics in HTx recipients is highly variable. Our preliminary data on patients on a CNI-free therapy regimen suggest that CYP3A5 genetic variation may contribute to this variability. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Efficacy of everolimus in ABO-incompatible kidney transplantation: a retrospective study

    Directory of Open Access Journals (Sweden)

    Tsujimura K

    2017-09-01

    Full Text Available Kazuma Tsujimura,1 Morihito Ota,1 Kiyoshi Chinen,1 Kiyomitsu Nagayama,2 Masato Oroku,2 Morikuni Nishihira,2 Yoshiki Shiohira,2 Kunitoshi Iseki,3 Hideki Ishida,4 Kazunari Tanabe4 1Department of Surgery, 2Department of Nephrology, 3Clinical Research Support Center, Tomishiro Central Hospital, Okinawa, Japan; 4Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan Background: There are limited reports on the use of everolimus for maintaining immunosuppression in ABO-incompatible (ABOi kidney transplantation (KT. As everolimus (EVR is effective for preventing calcineurin inhibitor (CNI nephrotoxicity without increasing the risk of chronic rejection and viral infection, we aimed to assess the efficacy of EVR in ABOi KT.Patients and methods: We retrospectively studied 22 patients who underwent KT and received EVR. Patients in the ABOi KT group (n=7 were compared with those in the ABO-compatible kidney transplantation group (ABOc KT; n=15. We recorded the frequency of CNI nephrotoxicity, chronic rejection, and viral infection in the 2 groups.Results: CNI nephrotoxicity, chronic rejection, and viral infection occurred in the ABOi KT and ANOc KT groups at rates of 28.3% (2/7 patients and 13.3% (2/15 patients (P=0.388, 28.3% (2/7 patients and 26.7% (4/15 patients (P=0.926, and 14.3% (1/7 patients and 26.7% (4/15 patients (P=0.517, respectively.Conclusion: Administration of EVR is effective in preventing CNI nephrotoxicity after KT. The rate of CNI nephrotoxicity was lower in the ABOc KT group than in the ABOi KT group. The rate of chronic rejection and viral infection was comparable between the groups. This study was conducted in a small cohort of patients. Hence, further evaluation with large sample sizes is necessary in the future to confirm the outcomes. Keywords: blood group incompatibility, immunosuppression, kidney transplantation

  15. Virtual histology assessment of cardiac allograft vasculopathy following introduction of everolimus--results of a multicenter trial

    DEFF Research Database (Denmark)

    Arora, Stina Jørgensen; Erikstad, I; Ueland, T

    2012-01-01

    of cardiac allograft vasculopathy (CAV). Parallel measurement of a range of inflammatory markers was also performed. A similar rate of quantitative CAV progression was observed in the everolimus (n = 30) and standard CNI group (n = 48) (plaque index 1.9 ± 3.8% and 1.6 ± 3.9%, respectively; p = 0.65). However...... with time since HTx >5.1 years and was accompanied by a significant increase in levels of von Willebrand (vWF) factor (p = 0.04) and vascular cell adhesion molecule (VCAM) (p = 0.03). Conversion to everolimus and reduced CNI is associated with a significant increase in calcified and necrotic intimal...

  16. A Phase 1 Study of Everolimus + Weekly Cisplatin + Intensity Modulated Radiation Therapy in Head-and-Neck Cancer

    International Nuclear Information System (INIS)

    Fury, Matthew G.; Lee, Nancy Y.; Sherman, Eric; Ho, Alan L.; Rao, Shyam; Heguy, Adriana; Shen, Ronglai; Korte, Susan; Lisa, Donna; Ganly, Ian; Patel, Snehal; Wong, Richard J.; Shaha, Ashok; Shah, Jatin; Haque, Sofia; Katabi, Nora; Pfister, David G.

    2013-01-01

    Purpose: Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. Methods and Materials: This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m 2 weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design. Results: Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. Conclusions: Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins

  17. A Phase 1 Study of Everolimus + Weekly Cisplatin + Intensity Modulated Radiation Therapy in Head-and-Neck Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Fury, Matthew G. [Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Department of Medicine, Weill Cornell Medical College, New York, New York (United States); Lee, Nancy Y. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Sherman, Eric; Ho, Alan L. [Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Department of Medicine, Weill Cornell Medical College, New York, New York (United States); Rao, Shyam [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Heguy, Adriana [Department of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Shen, Ronglai [Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Korte, Susan; Lisa, Donna [Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Ganly, Ian; Patel, Snehal; Wong, Richard J.; Shaha, Ashok; Shah, Jatin [Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Haque, Sofia [Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Katabi, Nora [Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Pfister, David G. [Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Department of Medicine, Weill Cornell Medical College, New York, New York (United States)

    2013-11-01

    Purpose: Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. Methods and Materials: This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m{sup 2} weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design. Results: Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. Conclusions: Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins.

  18. Pooled analysis of menstrual irregularities from three major clinical studies evaluating everolimus for the treatment of tuberous sclerosis complex.

    Directory of Open Access Journals (Sweden)

    Steven Sparagana

    Full Text Available To determine the impact of everolimus on female fertility, including menstrual irregularities, secondary amenorrhea, and luteinizing and follicle stimulating hormone levels in female patients.A pooled analysis from 3 prospective studies consisting of a core phase (≥6 months and a long-term follow-up open-label extension.One phase 2 single-center and two phase 3 multicenter studies.Data were obtained from female participants, restricted to those between 10 and 55 years of age, during 1 of 3 of the described clinical trials of everolimus. Patients had received ≥ 1 dose of everolimus.Incidence of fertility events.A total of 43/112 patients (38.4% experienced at least 1 menstrual irregularity. The most common events were amenorrhea (24.1% and irregular menstruation (17.0%. Seven patients (6.3% experienced grade 3/4 amenorrhea. When only the longest duration period of amenorrhea for each patient was considered, the median duration was 291 days. Fifteen patients attained menarche during the treatment period in any of the pooled studies. The mean age of menarche for this group was 12.4 years, similar to that of patients who were postmenarche at study entry (12.2 years. A total of 19/92 patients (20.7% who were postmenarche at baseline or during the study experienced an irregular menstruation event. An increased luteinizing hormone level was reported as an adverse event in 3/112 patients (3%, and follicle-stimulating hormone levels were within normal limits for these patients.No new safety concerns emerged regarding endocrine function and menstruation in female patients with tuberous sclerosis complex-associated subependymal giant cell astrocytoma or angiomyolipoma, who were receiving everolimus.ClinicalTrials.gov NCT00411619, NCT00789828, NCT00790400.

  19. The effect of everolimus on renal angiomyolipoma in pediatric patients with tuberous sclerosis being treated for subependymal giant cell astrocytoma.

    Science.gov (United States)

    Bissler, John J; Franz, David N; Frost, Michael D; Belousova, Elena; Bebin, E Martina; Sparagana, Steven; Berkowitz, Noah; Ridolfi, Antonia; Kingswood, J Christopher

    2018-01-01

    Patients with tuberous sclerosis complex (TSC) often have multiple TSC-associated hamartomas, particularly in the brain and kidney. This was a post hoc analysis of pediatric patients being treated for subependymal giant cell astrocytomas (SEGAs) during the phase 3, randomized, double-blind, placebo-controlled EXIST-1 trial. Patients were initially randomly assigned to receive everolimus 4.5 mg/m 2 /day (target blood trough 5-15 mg/dl) or placebo and could continue in an open-label extension phase. Angiomyolipoma response rates were analyzed in patients aged 20% increase in kidney volume from nadir, and angiomyolipoma-related bleeding ≥ grade 2. Tolerability was also assessed. Overall, this analysis included 33 patients. Renal angiomyolipoma response was achieved by 75.8% of patients (95% confidence interval, 57.7-88.9%), with sustained mean reductions in renal angiomyolipoma volume over nearly 4 years of treatment. In addition, most (≥80%) achieved clinically relevant reductions in angiomyolipoma volume (≥50%), beginning at week 24 and continuing for the remainder of the study. Everolimus was generally well tolerated in this subgroup, with most adverse events being grade 1 or 2 in severity. Although everolimus is currently not indicated for this use, this analysis from EXIST-1 demonstrates its long-term efficacy and safety for the treatment of renal angiomyolipoma in pediatric patients undergoing treatment for TSC-associated SEGA.

  20. [Everolimus plus exemestane in postmenopausal patients with estrogen-receptor-positive advanced breast cancer - Japanese subgroup analysis of BOLERO -2].

    Science.gov (United States)

    Ito, Yoshinori; Masuda, Norikazu; Iwata, Hiroji; Mukai, Hirofumi; Horiguchi, Jun; Tokuda, Yutaka; Kuroi, Katsumasa; Mori, Asuka; Ohno, Nobutsugu; Noguchi, Shinzaburo

    2015-01-01

    In a phase 3, double-blind, randomized, international study (the BOLERO-2), the addition of mTOR inhibitor everolimus to exemestane was evaluated in postmenopausal women with estrogen-receptor-positive (ER⁺) advanced/recurrent breast cancer that was refractory to any nonsteroidal aromatase inhibitor (NSAI). This report presents the safety and updated (18- month) efficacy results from the Japanese subset (n=106) of BOLERO-2. After a median follow-up of 18 months, the median progression-free survival time was 8.5 months with everolimus plus exemestane compared to 4.2 months with placebo plus exemestane. The most common adverse events (AEs) with everolimus plus exemestane were stomatitis, rash, dysgeusia, and non-infectious lung disease. The AEs reported with the combination therapy were mostly of grade 1 or 2 and manageable with appropriate intervention. In conclusion, this combination could be a useful addition to the armamentarium of treatments for Japanese postmenopausal women with ER⁺ advanced/recurrent breast cancer progressing on NSAIs.

  1. The Promus Premier everolimus-eluting platinum chromium stent with durable polymer evaluated in a real world all-comer population in Rotterdam cardiology hospital (the P-SEARCH registry)

    NARCIS (Netherlands)

    Lemmert, M.E.; Mieghem, N.M. van; Geuns, R.J.M. van; Diletti, R.; Bommel, R.J. van; Domburg, R.T. van; Jaegere, P.P. de; Regar, E.; Zijlstra, F.; Boersma, E.; Daemen, J.

    2017-01-01

    BACKGROUND: A new-generation everolimus eluting platinum-chromium stent (EePCS), offering improved radial strength, radiopacity and conformability compared to everolimus-eluting cobalt-chromium stents (EeCCS), was evaluated with regard to safety and efficacy in an all-comer cohort. METHODS: A total

  2. 1-year clinical outcomes of diabetic patients treated with everolimus-eluting bioresorbable vascular scaffolds: a pooled analysis of the ABSORB and the SPIRIT trials.

    Science.gov (United States)

    Muramatsu, Takashi; Onuma, Yoshinobu; van Geuns, Robert-Jan; Chevalier, Bernard; Patel, Tejas M; Seth, Ashok; Diletti, Roberto; García-García, Hector M; Dorange, Cécile C; Veldhof, Susan; Cheong, Wai-Fung; Ozaki, Yukio; Whitbourn, Robert; Bartorelli, Antonio; Stone, Gregg W; Abizaid, Alexandre; Serruys, Patrick W

    2014-05-01

    The aim of this study was to evaluate 1-year clinical outcomes of diabetic patients treated with the Absorb bioresorbable vascular scaffold (BVS). Clinical outcomes of diabetic patients after BVS implantation have been unreported. This study included 101 patients in the ABSORB Cohort B trial and the first consecutive 450 patients with 1 year of follow-up in the ABSORB EXTEND trial. A total of 136 diabetic patients were compared with 415 nondiabetic patients. In addition, 882 diabetic patients treated with everolimus-eluting metal stents (EES) in pooled data from the SPIRIT trials (SPIRIT FIRST [Clinical Trial of the Abbott Vascular XIENCE V Everolimus Eluting Coronary Stent System], SPIRIT II [A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System], SPIRIT III [Clinical Trial of the XIENCE V Everolimus Eluting Coronary Stent System (EECSS)], SPIRIT IV Clinical Trial [Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System]) were used for the comparison by applying propensity score matching. The primary endpoint was a device-oriented composite endpoint (DoCE), including cardiac death, target vessel myocardial infarction, and target lesion revascularization at 1-year follow-up. The cumulative incidence of DoCE did not differ between diabetic and nondiabetic patients treated with the BVS (3.7% vs. 5.1%, p = 0.64). Diabetic patients treated with the BVS had a similar incidence of the DoCE compared with diabetic patients treated with EES in the matched study group (3.9% for the BVS vs. 6.4% for EES, p = 0.38). There were no differences in the incidence of definite or probable scaffold/stent thrombosis (0.7% for both diabetic and nondiabetic patients with the BVS; 1.0% for diabetic patients with the BVS vs. 1.7% for diabetic patients with EES in the matched study group). In the present analyses, diabetic patients treated with the BVS showed similar rates of DoCEs compared with nondiabetic patients treated with the BVS and

  3. Everolimus and long acting octreotide as a volume reducing treatment of polycystic livers (ELATE: study protocol for a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Chrispijn Melissa

    2011-11-01

    Full Text Available Abstract Background Polycystic liver disease (PLD is defined as having more than 20 liver cysts and can present as a severe and disabling condition. Most symptoms are caused by the mass effect of the liver size and include abdominal pain and distension. The somatostatin analogues octreotide and lanreotide have proven to reduce polycystic liver volume. mTOR inhibitors such as everolimus inhibit cell proliferation and might thereby reduce growth of liver cysts. This trial aims to assess the benefit of combination therapy of everolimus and octreotide compared to octreotide monotherapy. In this study we present the structure of the trial and the characteristics of the included patients. Methods/design This is a randomized open-label clinical trial comparing the effect of 12 months of everolimus and octreotide to octreotide monotherapy in PLD patients. Primary outcome is change in liver volume determined by CT-volumetry. Secondary outcomes are changes in abdominal symptoms and quality of life. Moreover, safety and tolerability of the drugs will be assessed. Discussion This trial will compare the relative efficacy of combination therapy with octreotide and everolimus to octreotide monotherapy. Since they apply to different pathways of cystogenesis we expect that combining octreotide and everolimus will result in a cumulative reduction of polycystic liver volume. Trial registration number ClinicalTrials.gov: NCT01157858

  4. Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy

    International Nuclear Information System (INIS)

    Narayan, Vivek; Vapiwala, Neha; Mick, Rosemarie; Subramanian, Pearl; Christodouleas, John P.; Bekelman, Justin E.; Deville, Curtiland; Rajendran, Ramji; Haas, Naomi B.

    2017-01-01

    Purpose: In up to half of patients treated with salvage radiation therapy (SRT) for rising prostate-specific antigen levels, a second biochemical recurrence ultimately develops. Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin pathway can lead to tumor hypoxia and radioresistance. Everolimus is a mammalian target of rapamycin inhibitor with both antitumor and radiosensitizing effects. Methods and Materials: We performed a phase 1 study using a modified 3 + 3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of biochemical recurrence following prostatectomy. After a 2-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam computed tomography localization in 37 fractions of 1.8 Gy each (total dose, 66.6 Gy). Patients were monitored for both acute (≤90 days) and chronic (>90 days) treatment-related toxicities. Results: Eighteen patients received everolimus at dose levels of 5 mg (n=6), 7.5 mg (n=6), or 10 mg (n=6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment-related toxicities included grade 1 or 2 mucositis (55.6%), grade 1 or 2 fatigue (38.9%), grade 1 or 2 rash (61.1%), and grade 1 urinary symptoms (61.1%). A grade 3 acute toxicity occurred in 4 patients (22.2%) (n=1 for rash, anemia, lymphopenia, and neutropenia), and no patients had a chronic toxicity of grade 3 or greater. After a median follow-up time of 17.8 months (range, 1.2-46.0 months), an undetectable prostate-specific antigen nadir was achieved in 9 patients (56.3%) and a second biochemical recurrence developed in 5 patients (31.3%). Conclusions: Everolimus at a dose of ≤10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy radiation therapy.

  5. Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy.

    Science.gov (United States)

    Narayan, Vivek; Vapiwala, Neha; Mick, Rosemarie; Subramanian, Pearl; Christodouleas, John P; Bekelman, Justin E; Deville, Curtiland; Rajendran, Ramji; Haas, Naomi B

    2017-02-01

    In up to half of patients treated with salvage radiation therapy (SRT) for rising prostate-specific antigen levels, a second biochemical recurrence ultimately develops. Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin pathway can lead to tumor hypoxia and radioresistance. Everolimus is a mammalian target of rapamycin inhibitor with both antitumor and radiosensitizing effects. We performed a phase 1 study using a modified 3 + 3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of biochemical recurrence following prostatectomy. After a 2-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam computed tomography localization in 37 fractions of 1.8 Gy each (total dose, 66.6 Gy). Patients were monitored for both acute (≤90 days) and chronic (>90 days) treatment-related toxicities. Eighteen patients received everolimus at dose levels of 5 mg (n=6), 7.5 mg (n=6), or 10 mg (n=6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment-related toxicities included grade 1 or 2 mucositis (55.6%), grade 1 or 2 fatigue (38.9%), grade 1 or 2 rash (61.1%), and grade 1 urinary symptoms (61.1%). A grade 3 acute toxicity occurred in 4 patients (22.2%) (n=1 for rash, anemia, lymphopenia, and neutropenia), and no patients had a chronic toxicity of grade 3 or greater. After a median follow-up time of 17.8 months (range, 1.2-46.0 months), an undetectable prostate-specific antigen nadir was achieved in 9 patients (56.3%) and a second biochemical recurrence developed in 5 patients (31.3%). Everolimus at a dose of ≤10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy radiation therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy

    Energy Technology Data Exchange (ETDEWEB)

    Narayan, Vivek [Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Vapiwala, Neha [Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Mick, Rosemarie [Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Subramanian, Pearl [Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Christodouleas, John P.; Bekelman, Justin E.; Deville, Curtiland; Rajendran, Ramji [Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Haas, Naomi B., E-mail: naomi.haas@uphs.upenn.edu [Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (United States)

    2017-02-01

    Purpose: In up to half of patients treated with salvage radiation therapy (SRT) for rising prostate-specific antigen levels, a second biochemical recurrence ultimately develops. Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin pathway can lead to tumor hypoxia and radioresistance. Everolimus is a mammalian target of rapamycin inhibitor with both antitumor and radiosensitizing effects. Methods and Materials: We performed a phase 1 study using a modified 3 + 3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of biochemical recurrence following prostatectomy. After a 2-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam computed tomography localization in 37 fractions of 1.8 Gy each (total dose, 66.6 Gy). Patients were monitored for both acute (≤90 days) and chronic (>90 days) treatment-related toxicities. Results: Eighteen patients received everolimus at dose levels of 5 mg (n=6), 7.5 mg (n=6), or 10 mg (n=6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment-related toxicities included grade 1 or 2 mucositis (55.6%), grade 1 or 2 fatigue (38.9%), grade 1 or 2 rash (61.1%), and grade 1 urinary symptoms (61.1%). A grade 3 acute toxicity occurred in 4 patients (22.2%) (n=1 for rash, anemia, lymphopenia, and neutropenia), and no patients had a chronic toxicity of grade 3 or greater. After a median follow-up time of 17.8 months (range, 1.2-46.0 months), an undetectable prostate-specific antigen nadir was achieved in 9 patients (56.3%) and a second biochemical recurrence developed in 5 patients (31.3%). Conclusions: Everolimus at a dose of ≤10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy radiation therapy.

  7. Budget impact analysis of everolimus for the treatment of hormone receptor positive, human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer in the United States.

    Science.gov (United States)

    Xie, Jipan; Diener, Melissa; De, Gourab; Yang, Hongbo; Wu, Eric Q; Namjoshi, Madhav

    2013-01-01

    To estimate the budget impact of everolimus as the first and second treatment option after letrozole or anastrozole (L/A) failure for post-menopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC). Pharmacy and medical budget impacts (2011 USD) were estimated over the first year of everolimus use in HR+, HER2- ABC from a US payer perspective. Epidemiology data were used to estimate target population size. Pre-everolimus entry treatment options included exemestane, fulvestrant, and tamoxifen. Pre- and post-everolimus entry market shares were estimated based on market research and assumptions. Drug costs were based on wholesale acquisition cost. Patients were assumed to be on treatment until progression or death. Annual medical costs were calculated as the average of pre- and post-progression medical costs weighted by the time in each period, adjusted for survival. One-way and two-way sensitivity analyses were conducted to assess the model robustness. In a hypothetical 1,000,000 member plan, 72 and 159 patients were expected to be candidates for everolimus treatment as first and second treatment option, respectively, after L/A failure. The total budget impact for the first year post-everolimus entry was $0.044 per member per month [PMPM] (pharmacy budget: $0.058 PMPM; medical budget: -$0.014 PMPM), assuming 10% of the target population would receive everolimus. The total budget impacts for the first and second treatment options after L/A failure were $0.014 PMPM (pharmacy budget: $0.018; medical budget: -$0.004) and $0.030 PMPM (pharmacy budget: $0.040; medical budget: -$0.010), respectively. Results remained robust in sensitivity analyses. Assumptions about some model input parameters were necessary and may impact results. Increased pharmacy costs for HR+, HER2- ABC following everolimus entry are expected to be partially offset by reduced medical service costs. Pharmacy and total

  8. A comprehensive review of everolimus clinical reports: a new mammalian target of rapamycin inhibitor.

    Science.gov (United States)

    Gurk-Turner, Cheryle; Manitpisitkul, Wana; Cooper, Matthew

    2012-10-15

    As new immunosuppressive agents are introduced to the market, clinicians are faced with the daunting task of sifting through the published literature to decide the value that the agent will add to their own practice. We often must extrapolate information provided through study in other solid-organ transplantation populations than our specific area of interest as we interpret the results and outcomes. With these challenges in mind, this compilation of published work for the newest mammalian target of rapamycin inhibitor everolimus (Certican; Novartis Pharmaceuticals, Hanover, NJ) (Zortress; Novartis Pharmaceuticals, Basel, Switzerland) is intended to provide a concise but thorough presentation of available literature so that the reader who may be unfamiliar with the agent can make their own judgment. Both Ovid and PubMed search engines were queried with a particular focus on high-impact articles noted in the Web of Science or Citation Index. Work described solely in abstract or case report form was excluded, as well as meta-analyses or those that were editorial or commentary in nature. Included were publications presented using the English language that described adult human subjects who received a heart, lung, kidney, or liver allograft. The goal of this strategy was to allow for the inclusion of pertinent literature in an unbiased fashion. Tables are provided that outline trial specific information, leaving a discussion of major outcomes to the text of the review.

  9. Interstitial Lung Disease Associated with mTOR Inhibitors in Solid Organ Transplant Recipients: Results from a Large Phase III Clinical Trial Program of Everolimus and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Patricia Lopez

    2014-01-01

    Full Text Available Interstitial lung disease (ILD has been reported with the use of mammalian target of rapamycin inhibitors (mTORi. The clinical and safety databases of three Phase III trials of everolimus in de novo kidney (A2309, heart (A2310, and liver (H2304 transplant recipients (TxR were searched using a standardized MedDRA query (SMQ search for ILD followed by a case-by-case medical evaluation. A literature search was conducted in MEDLINE and EMBASE. Out of the 1,473 de novo TxR receiving everolimus in Phase III trials, everolimus-related ILD was confirmed in six cases (one kidney, four heart, and one liver TxR representing an incidence of 0.4%. Everolimus was discontinued in three of the four heart TxR, resulting in ILD improvement or resolution. Outcome was fatal in the kidney TxR (in whom everolimus therapy was continued and in the liver TxR despite everolimus discontinuation. The literature review identified 57 publications on ILD in solid organ TxR receiving everolimus or sirolimus. ILD presented months or years after mTORi initiation and symptoms were nonspecific and insidious. The event was more frequent in patients with a late switch to mTORi. In most cases, ILD was reversed after prompt mTORi discontinuation. ILD induced by mTORi is an uncommon and potentially fatal event warranting early recognition and drug discontinuation.

  10. The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington's disease

    Directory of Open Access Journals (Sweden)

    Frentzel Stefan

    2010-06-01

    Full Text Available Abstract Background Huntington's disease (HD is a progressive neurodegenerative disorder caused by a CAG repeat expansion within the huntingtin gene. Mutant huntingtin protein misfolds and accumulates within neurons where it mediates its toxic effects. Promoting mutant huntingtin clearance by activating macroautophagy is one approach for treating Huntington's disease (HD. In this study, we evaluated the mTOR kinase inhibitor and macroautophagy promoting drug everolimus in the R6/2 mouse model of HD. Results Everolimus decreased phosphorylation of the mTOR target protein S6 kinase indicating brain penetration. However, everolimus did not activate brain macroautophagy as measured by LC3B Western blot analysis. Everolimus protected against early declines in motor performance; however, we found no evidence for neuroprotection as determined by brain pathology. In muscle but not brain, everolimus significantly decreased soluble mutant huntingtin levels. Conclusions Our data suggests that beneficial behavioral effects of everolimus in R6/2 mice result primarily from effects on muscle. Even though everolimus significantly modulated its target brain S6 kinase, this did not decrease mutant huntingtin levels or provide neuroprotection.

  11. Comparison of everolimus- and paclitaxel-eluting stents in patients with acute and stable coronary syndromes: pooled results from the SPIRIT (A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) and COMPARE (A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice) Trials.

    Science.gov (United States)

    Planer, David; Smits, Pieter C; Kereiakes, Dean J; Kedhi, Elvin; Fahy, Martin; Xu, Ke; Serruys, Patrick W; Stone, Gregg W

    2011-10-01

    This study sought to compare the clinical outcomes of everolimus-eluting stents (EES) versus paclitaxel-eluting stents (PES) in patients with acute coronary syndromes (ACS) and stable coronary artery disease (CAD). Although randomized trials have shown superiority of EES to PES, the safety and efficacy of EES in ACS is unknown. We performed a patient-level pooled analysis from the prospective, randomized SPIRIT (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) II, III, IV, and COMPARE (A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice) trials in which 2,381 patients with ACS and 4,404 patients with stable CAD were randomized to EES or to PES. Kaplan-Meier estimates of death, myocardial infarction (MI), ischemia-driven target lesion revascularization, and stent thrombosis were assessed at 2 years and stratified by clinical presentation (ACS vs. stable CAD). At 2 years, patients with ACS compared with stable CAD had higher rates of death (3.2% vs. 2.4%, hazard ratio [HR]: 1.37 [95% confidence interval (CI): 1.02 to 1.85], p = 0.04) and MI (4.9% vs. 3.4%, HR: 1.45 [95% CI: 1.14 to 1.85], p = 0.02). In patients with ACS, EES versus PES reduced the rate of death or MI (6.6% vs. 9.3%, HR: 0.70 [95% CI: 0.52 to 0.94], p = 0.02), stent thrombosis (0.7% vs. 2.9%, HR: 0.25 [95% CI: 0.12 to 0.52], p = 0.0002), and ischemia-driven target lesion revascularization (4.7% vs. 6.2%, HR: 0.69 [95% CI: 0.48 to 0.99], p = 0.04). In patients with stable CAD, EES reduced the rate of death or MI (4.5% vs. 7.1%, HR: 0.62 [95% CI: 0.48 to 0.80], p = 0.0002), stent thrombosis (0.7% vs. 1.8%, HR: 0.34 [95% CI: 0.19 to 0.62], p = 0.0002), and ischemia-driven target lesion revascularization (3.9% vs. 6.9%, HR: 0.55 [95% CI: 0.42 to 0.73], p SPIRIT II]; NCT00180310; SPIRIT III: A Clinical Evaluation of the Investigational Device XIENCE V Everolimus Eluting Coronary Stent System [EECSS] in the

  12. Effects of cobalt-chromium everolimus eluting stents or bare metal stent on fatal and non-fatal cardiovascular events: patient level meta-analysis.

    Science.gov (United States)

    Valgimigli, Marco; Sabaté, Manel; Kaiser, Christoph; Brugaletta, Salvatore; de la Torre Hernandez, Jose Maria; Galatius, Soeren; Cequier, Angel; Eberli, Franz; de Belder, Adam; Serruys, Patrick W; Ferrante, Giuseppe

    2014-11-04

    To examine the safety and effectiveness of cobalt-chromium everolimus eluting stents compared with bare metal stents. Individual patient data meta-analysis of randomised controlled trials. Cox proportional regression models stratified by trial, containing random effects, were used to assess the impact of stent type on outcomes. Hazard ratios with 95% confidence interval for outcomes were reported. Medline, Embase, the Cochrane Central Register of Controlled Trials. Randomised controlled trials that compared cobalt-chromium everolimus eluting stents with bare metal stents were selected. The principal investigators whose trials met the inclusion criteria provided data for individual patients. The primary outcome was cardiac mortality. Secondary endpoints were myocardial infarction, definite stent thrombosis, definite or probable stent thrombosis, target vessel revascularisation, and all cause death. The search yielded five randomised controlled trials, comprising 4896 participants. Compared with patients receiving bare metal stents, participants receiving cobalt-chromium everolimus eluting stents had a significant reduction of cardiac mortality (hazard ratio 0.67, 95% confidence interval 0.49 to 0.91; P=0.01), myocardial infarction (0.71, 0.55 to 0.92; P=0.01), definite stent thrombosis (0.41, 0.22 to 0.76; P=0.005), definite or probable stent thrombosis (0.48, 0.31 to 0.73; Pstents the use of cobalt-chromium everolimus eluting stents improves global cardiovascular outcomes including cardiac survival, myocardial infarction, and overall stent thrombosis. © Valgimigli et al 2014.

  13. Everolimus and sirolimus in combination with cyclosporine have different effects on renal metabolism in the rat.

    Directory of Open Access Journals (Sweden)

    Rahul Bohra

    Full Text Available Enhancement of calcineurin inhibitor nephrotoxicity by sirolimus (SRL is limiting the clinical use of this drug combination. We compared the dose-dependent effects of the structurally related everolimus (EVL and sirolimus (SRL alone, and in combination with cyclosporine (CsA, on the rat kidney. Lewis rats were treated by oral gavage for 28 days using a checkerboard dosing format (0, 3.0, 6.0 and 10.0 CsA and 0, 0.5, 1.5 and 3.0 mg/kg/day SRL or EVL, n = 4/dose combination. After 28 days, oxidative stress, energy charge, kidney histologies, glomerular filtration rates, and concentrations of the immunosuppressants were measured along with (1H-magnetic resonance spectroscopy (MRS and gas chromatography- mass spectrometry profiles of cellular metabolites in urine. The combination of CsA with SRL led to higher urinary glucose concentrations and decreased levels of urinary Krebs cycle metabolites when compared to controls, suggesting that CsA+SRL negatively impacted proximal tubule metabolism. Unsupervised principal component analysis of MRS spectra distinguished unique urine metabolite patterns of rats treated with CsA+SRL from those treated with CsA+EVL and the controls. SRL, but not EVL blood concentrations were inversely correlated with urine Krebs cycle metabolite concentrations. Interestingly, the higher the EVL concentration, the closer urine metabolite patterns resembled those of controls, while in contrast, the combination of the highest doses of CsA+SRL showed the most significant differences in metabolite patterns. Surprisingly in this rat model, EVL and SRL in combination with CsA had different effects on kidney biochemistry, suggesting that further exploration of EVL in combination with low dose calcineurin inhibitors may be of potential benefit.

  14. Efficacy and safety of everolimus in combination with trastuzumab and paclitaxel in Asian patients with HER2+ advanced breast cancer in BOLERO-1.

    Science.gov (United States)

    Toi, Masakazu; Shao, Zhimin; Hurvitz, Sara; Tseng, Ling-Ming; Zhang, Qingyuan; Shen, Kunwei; Liu, Donggeng; Feng, Jifeng; Xu, Binghe; Wang, Xiaojia; Lee, Keun Seok; Ng, Ting Ying; Ridolfi, Antonia; Noel-Baron, Florence; Ringeisen, Francois; Jiang, Zefei

    2017-04-11

    The current exploratory analysis was performed to evaluate the efficacy and safety of everolimus for treatment of human epidermal growth factor receptor 2-positive (HER2+) advanced breast cancer in the Asian subset of patients in the BOLERO-1 trial. Postmenopausal women with HER2+ advanced breast cancer, who had not received systemic therapy for advanced disease, were randomized 2:1 to receive everolimus or placebo, plus trastuzumab and paclitaxel. The two primary end points were investigator-assessed progression-free survival (PFS) in the full population and in the hormone receptor-negative (HR-) subpopulation. Secondary end points included assessment of the objective response rate, the clinical benefit rate, and safety. In the Asian subset, median PFS was similar in the everolimus (n = 198) and placebo (n = 105) arms in the full analysis set (hazard ratio = 0.82 (95% CI 0.61-1.11)). In the HR- subpopulation, everolimus prolonged median PFS by 10.97 months vs placebo (25.46 vs 14.49 months; hazard ratio = 0.48 (95% CI 0.29-0.79)). In the everolimus arm of the Asian subset, the most common adverse events of any grade were stomatitis (62.2%), diarrhea (48.0%), rash (43.4%) and neutropenia (42.3%). Neutropenia (grade 3: 27.6%; grade 4: 4.6%) and decreased neutrophil count (grade 3: 11.2%; grade 4: 3.6%) were the most frequent grade 3/4 adverse events. Serious adverse events included pneumonia (5.1%), pneumonitis (3.1%), and interstitial lung disease (3.1%). There were three deaths (1.5%) during treatment in the everolimus arm vs none in the placebo arm. The efficacy and safety of everolimus plus trastuzumab and paclitaxel as first-line treatment for HER2+ advanced breast cancer in the Asian subset was consistent with that reported previously in the overall population. ClinicalTrials.gov, NCT00876395 . Registered on 2 April 2009.

  15. A randomized study to compare bioactive titanium stents and everolimus-eluting stents in diabetic patients (TITANIC XV): 1-year results.

    Science.gov (United States)

    López-Mínguez, José R; Nogales-Asensio, Juan M; Doncel-Vecino, Luis J; Merchán-Herrera, Antonio; Pomar-Domingo, Francisco; Martínez-Romero, Pedro; Fernández-Díaz, José A; Valdesuso-Aguilar, Raúl; Moreu-Burgos, José; Díaz-Fernández, José

    2014-07-01

    Up to 25% of patients who undergo a percutaneous coronary intervention show some limitation in the use of drug-eluting stents. The aim of this study was to evaluate if titanium-nitride-oxide-coated stents could be a good alternative to everolimus-eluting stents in diabetic patients. A total of 173 diabetic patients with lesions at moderate risk of restenosis (exclusion criteria: diameter 28 mm in vessels < 3mm, chronic occlusion) were randomized to a titanium group (83 patients) or an everolimus group (90 patients). Baseline characteristics were well balanced; 28.3% of patients were insulin dependent. At 1 year, the incidence of major adverse cardiac events (death, nonfatal myocardial infarction, stroke, or repeat target vessel revascularization) was significantly higher in the titanium group than in the everolimus group (total, 14.5% vs 4.4%; P = .02; noninsulin-dependent subgroup, 9.7% vs 3.2%; P = .14; insulin-dependent subgroup, 28.6% vs 7.1%; P = .04). The incidence of death, nonfatal myocardial infarction, stroke, or any revascularization was 16.9% in the titanium group and 7.8% in the everolimus group (P = .06). Target lesion and vessel revascularizations occurred in 8.4% compared with 3.3% (P = .15) and in 13.3% compared with 3.3% (P = .01) in the titanium and everolimus groups, respectively. Angiographic follow-up at 9 months showed significantly less late lumen loss in the everolimus group (in-segment, 0.52 [standard deviation, 0.58) mm vs -0.05 [0.32] mm; in-stent, 0.76 [0.54] mm vs 0.13 [0.31] mm; P < .0001). The everolimus-eluting stent is superior to the titanium stent for clinical and angiographic end points in diabetic patients with lesions at moderate risk of restenosis. Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

  16. Early Introduction of Everolimus Immunosuppressive Regimen in Liver Transplantation with Extra-Anatomic Aortoiliac-Hepatic Arterial Graft Anastomosis

    Directory of Open Access Journals (Sweden)

    Emanuele Felli

    2014-01-01

    Full Text Available Liver transplantation is the treatment of choice for patients with acute and chronic end-stage liver disease, when no other medical treatment is possible. Despite high rates of 1- to 5-year survival, long-term adverse effects of immunosuppressant agents remain of major concern. Current research and clinical efforts are made to develop immunosuppressant agents that minimize adverse effects along with a low rate of graft rejection. Tailoring immunosuppressive therapy to individual patients by the use of proliferation signal inhibitors seems to be the best way to minimize toxicity and increase efficacy. Recently everolimus has been introduced in clinical practice; among its adverse effects an increased incidence of arterial graft thrombosis in renal transplants, vascular anastomosis leakage, impaired wound healing, and thrombotic microangiopathy have been reported. We present the case of a 54-year-old patient submitted to liver transplantation for end-stage liver disease treated by an extra-anatomic aortoiliac-hepatic arterial graft anastomosis and early postoperative introduction of everolimus for acute renal failure. Postoperative period was characterized by two abdominal collections and reactivation of cytomegalovirus infection that were treated by percutaneous drainage and antiviral therapy, respectively; the patient is well after 8-month followup with patency of the arterial conduit and no leakage.

  17. Cabozantinib Versus Everolimus in Patients with Advanced Renal Cell Carcinoma: Results of a Randomised Phase III Trial (METEOR

    Directory of Open Access Journals (Sweden)

    Toni Choueiri

    2015-11-01

    Full Text Available The METEOR trial of cabozantinib versus everolimus in advanced renal cell carcinoma (RCC was reported by Prof Choueiri at the European Cancer Congress 2015. This presentation follows the publication in the New England Journal of Medicine of the METEOR trial back-to-back with the CheckMate 025 trial of nivolumab versus everolimus in the same patient setting. Excitingly, these trials demonstrated, for the first time, significant benefits over the standard of care for heavily pre-treated patients with advanced RCC. Cabozantinib, an oral multi-targeted tyrosine kinase inhibitor (TKI aims to address the challenge of resistance to targeted therapy with TKIs. While the METEOR trial has not yet reached its final analysis of overall survival (OS, the clear progression-free survival (PFS benefit, acceptable safety profile, and similar tolerability to other TKIs shown by cabozantinib indicate that this represents a promising new treatment option for second-line or subsequent therapy for patients with advanced RCC.

  18. Biodegradable-Polymer Biolimus-Eluting Stents versus Durable-Polymer Everolimus-Eluting Stents at One-Year Follow-Up: A Registry-Based Cohort Study.

    Science.gov (United States)

    Parsa, Ehsan; Saroukhani, Sepideh; Majlessi, Fereshteh; Poorhosseini, Hamidreza; Lofti-Tokaldany, Masoumeh; Jalali, Arash; Salarifar, Mojtaba; Nematipour, Ebrahim; Alidoosti, Mohammad; Aghajani, Hassan; Amirzadegan, Alireza; Kassaian, Seyed Ebrahim

    2016-04-01

    We compared outcomes of percutaneous coronary intervention patients who received biodegradable-polymer biolimus-eluting stents with those who received durable-polymer everolimus-eluting stents. At Tehran Heart Center, we performed a retrospective analysis of the data from January 2007 through December 2011 on 3,270 consecutive patients with coronary artery disease who underwent percutaneous coronary intervention with the biodegradable-polymer biolimus-eluting stent or the durable-polymer everolimus-eluting stent. We excluded patients with histories of coronary artery bypass grafting or percutaneous coronary intervention, acute ST-segment-elevation myocardial infarction, or the implantation of 2 different stent types. Patients were monitored for 12 months. The primary endpoint was a major adverse cardiac event, defined as a composite of death, nonfatal myocardial infarction, and target-vessel and target-lesion revascularization. Durable-polymer everolimus-eluting stents were implanted in 2,648 (81%) and biodegradable-polymer biolimus-eluting stents in 622 (19%) of the study population. There was no significant difference between the 2 groups (2.7% vs 2.7%; P=0.984) in the incidence of major adverse cardiac events. The cumulative adjusted probability of major adverse cardiac events in the biodegradable-polymer biolimus-eluting stent group did not differ from that of such events in the durable-polymer everolimus-eluting stent group (hazard ratio=0.768; 95% confidence interval, 0.421-1.44; P=0.388). We conclude that in our patients the biodegradable-polymer biolimus-eluting stent was as effective and safe, during the 12-month follow-up period, as was the durable-polymer everolimus-eluting stent.

  19. Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.

    Science.gov (United States)

    Perrin, Allison; Sherman, Steven; Pal, Sumanta; Chua, Andrew; Gorritz, Magdaliz; Liu, Zhimei; Wang, Xufang; Culver, Kenneth; Casciano, Roman; Garrison, Louis P

    2015-03-01

    Everolimus and axitinib are approved in the US to treat patients with advanced renal cell carcinoma (RCC) after failure on sunitinib or sorafenib, and one prior systemic therapy (e.g., sunitinib), respectively. Two indirect comparisons performed to evaluate progression-free survival in patients treated with everolimus vs axitinib suggested similar efficacy between the two treatments. Therefore, this analysis compares the lifetime costs of these two therapies among sunitinib-refractory advanced RCC patients from a US payer perspective. A Markov model was developed to simulate a cohort of sunitinib-refractory advanced RCC patients and estimate the cost of treating patients with everolimus vs axitinib. The following health states were included: stable disease without adverse events (AEs), stable disease with AEs, disease progression (PD), and death. The model included the following resources: active treatments, post-progression treatments, adverse events, physician and nurse visits, scans and tests, and palliative care. Resource utilization inputs were derived from a US claims database analysis. Additionally, a 3% annual discount rate was applied to costs, and the robustness of the model results was tested by conducting sensitivity analyses, including those on dosing scheme and post-progression treatment costs. Base case results demonstrated that patients treated with everolimus cost an average of $12,985 (11%) less over their lifetimes than patients treated with axitinib. The primary difference in costs was related to active treatment, which was largely driven by axitinib's higher dose intensity. RESULTS remained consistent across sensitivity analyses for AE and PD treatment costs, as well as dose intensity and discount rates. The results suggest that everolimus likely leads to lower lifetime costs than axitinib for sunitinib-refractory advanced RCC patients in the US.

  20. Five-year clinical and functional multislice computed tomography angiographic results after coronary implantation of the fully resorbable polymeric everolimus-eluting scaffold in patients with de novo coronary artery disease

    DEFF Research Database (Denmark)

    Onuma, Yoshinobu; Dudek, Dariusz; Thuesen, Leif

    2013-01-01

    This study sought to demonstrate the 5-year clinical and functional multislice computed tomography angiographic results after implantation of the fully resorbable everolimus-eluting scaffold (Absorb BVS, Abbott Vascular, Santa Clara, California).......This study sought to demonstrate the 5-year clinical and functional multislice computed tomography angiographic results after implantation of the fully resorbable everolimus-eluting scaffold (Absorb BVS, Abbott Vascular, Santa Clara, California)....

  1. The Impact of Post-Procedural Asymmetry, Expansion, and Eccentricity of Bioresorbable Everolimus-Eluting Scaffold and Metallic Everolimus-Eluting Stent on Clinical Outcomes in the ABSORB II Trial.

    Science.gov (United States)

    Suwannasom, Pannipa; Sotomi, Yohei; Ishibashi, Yuki; Cavalcante, Rafael; Albuquerque, Felipe N; Macaya, Carlos; Ormiston, John A; Hill, Jonathan; Lang, Irene M; Egred, Mohaned; Fajadet, Jean; Lesiak, Maciej; Tijssen, Jan G; Wykrzykowska, Joanna J; de Winter, Robbert J; Chevalier, Bernard; Serruys, Patrick W; Onuma, Yoshinobu

    2016-06-27

    The study sought to investigate the relationship between post-procedural asymmetry, expansion, and eccentricity indices of metallic everolimus-eluting stent (EES) and bioresorbable vascular scaffold (BVS) and their respective impact on clinical events at 1-year follow-up. Mechanical properties of a fully BVS are inherently different from those of permanent metallic stent. The ABSORB II (A bioresorbable everolimus-eluting scaffold versus a metallic everolimus-eluting stent for ischaemic heart disease caused by de-novo native coronary artery lesions) trial compared the BVS and metallic EES in the treatment of a de novo coronary artery stenosis. Protocol-mandated intravascular ultrasound imaging was performed pre- and post-procedure in 470 patients (162 metallic EES and 308 BVS). Asymmetry index (AI) was calculated per lesion as: (1 - minimum scaffold/stent diameter/maximum scaffold/stent diameter). Expansion index and optimal scaffold/stent expansion followed the definition of the MUSIC (Multicenter Ultrasound Stenting in Coronaries) study. Eccentricity index (EI) was calculated as the ratio of minimum and maximum scaffold/stent diameter per cross section. The incidence of device-oriented composite endpoint (DoCE) was collected. Post-procedure, the metallic EES group was more symmetric and concentric than the BVS group. Only 8.0% of the BVS arm and 20.0% of the metallic EES arm achieved optimal scaffold/stent expansion (p 0.30 is an independent predictor of DoCE (hazard ratio: 3.43; 95% confidence interval: 1.08 to 10.92; p = 0.037). BVS implantation is more frequently associated with post-procedural asymmetric and eccentric morphology compared to metallic EES. Post-procedural devices asymmetry were independently associated with DoCE following percutaneous coronary intervention. However, this approach should be viewed as hypothesis generating due to low event rates. (ABSORB II Randomized Controlled Trial [ABSORB II]; NCT01425281). Copyright © 2016 American

  2. Safety and efficacy of everolimus-eluting stents for bare-metal in-stent restenosis

    Energy Technology Data Exchange (ETDEWEB)

    Ota, Hideaki [Division of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC 20010 (United States); Mahmoudi, Michael [University of Surrey, Guildford Road, Surrey, GU2-7XH (United Kingdom); Torguson, Rebecca; Satler, Lowell F.; Suddath, William O.; Pichard, Augusto D. [Division of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC 20010 (United States); Waksman, Ron, E-mail: ron.waksman@medstar.net [Division of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC 20010 (United States)

    2015-04-15

    Objective: The aim of this study was to compare the safety and efficacy of the everolimus-eluting stents (EES) with the paclitaxel-eluting stent (PES) and sirolimus-eluting stent (SES) for the treatment of bare-metal in-stent restenosis. Background: The optimal treatment for bare-metal in-stent restenosis remains controversial. Methods: The study cohort comprised 322 consecutive patients (543 lesions) who presented with bare-metal in-stent restenosis to our institution and underwent coronary artery stent implantation with EES (114 patients; 181 lesions), PES (65 patients; 116 lesions) and SES (143 patients; 246 lesions). The analyzed clinical parameters were the 1-year rates of death, Q-wave myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), definite stent thrombosis (ST) and major adverse cardiac events (MACE) defined as the composite of death, MI, or TLR at 1-year. Results: The three groups were well matched for the conventional risk factors except for age and chronic kidney disease. The 1-year analyzed clinical parameters were similar in the three groups: death (EES = 3.5%, PES = 4.6%, SES = 4.2%; p = 0.94), MI (EES = 3.5%, PES = 6.3%, SES = 2.1%; p = 0.31), TLR (EES = 9.8%, PES = 9.5%, SES = 5.7%; p = 0.42), TVR (EES = 14.3%, PES = 11.1%, SES = 11.3%; p = 0.74), definite ST (EES = 0.9%, PES = 3.1%, SES = 3.5%; p = 0.38) and MACE (EES = 14.0%, PES = 15.4%, SES = 10.5%; p = 0.54). Male gender (hazard ratio = 0.47; 95% confidence interval = 0.25–0.88) and number of treated lesions (hazard ratio = 1.47; 95% confidence interval = 1.06–2.05) were found to be independent predictors of MACE. Conclusion: The results of the present study indicate that EES may provide similar safety and efficacy as first generation DES for the treatment of patients presenting with bare-metal in-stent restenosis.

  3. Real-world effectiveness of everolimus-based therapy versus fulvestrant monotherapy in HR(+)/HER2(-) metastatic breast cancer.

    Science.gov (United States)

    Hao, Yanni; Lin, Peggy L; Xie, Jipan; Li, Nanxin; Koo, Valerie; Ohashi, Erika; Wu, Eric Q; Rogerio, Jaqueline

    2015-08-01

    Assessing real-world effectiveness of everolimus-based therapy (EVE) versus fulvestrant monotherapy (FUL) among postmenopausal women with hormone receptor-positive (HR(+))/HER2(-) metastatic breast cancer (mBC) after progression on nonsteroidal aromatase inhibitor (NSAI). Medical charts of community-based patients who received EVE or FUL for mBC after NSAI were examined. Progression-free survival (PFS), time on treatment and time to chemotherapy were compared using Kaplan-Meier curves and Cox proportional hazards models adjusting for line of therapy and patient characteristics. 192 patients received EVE and 156 FUL. After adjusting for patient characteristics, EVE was associated with significantly longer PFS than FUL (hazard ratio: 0.71; p = 0.045). EVE was associated with better PFS than FUL among NSAI-refractory postmenopausal HR(+)/HER2(-) mBC patients.

  4. Bioavailability of everolimus administered as a single 5 mg tablet versus five 1 mg tablets: a randomized, open-label, two-way crossover study of healthy volunteers.

    Science.gov (United States)

    Thudium, Karen; Gallo, Jorge; Bouillaud, Emmanuel; Sachs, Carolin; Eddy, Simantini; Cheung, Wing

    2015-01-01

    The mammalian target of rapamycin (mTOR) inhibitor everolimus has a well-established pharmacokinetics profile. We conducted a randomized, single-center, open-label, two-sequence, two-period crossover study of healthy volunteers to assess the relative bioavailability of everolimus administered as one 5 mg tablet or five 1 mg tablets. Subjects were randomized 1:1 to receive everolimus dosed as one 5 mg tablet or as five 1 mg tablets on day 1, followed by a washout period on days 8-14 and then the opposite formulation on day 15. Blood sampling for pharmacokinetic evaluation was performed at prespecified time points, with 17 samples taken for each treatment period. Primary variables for evaluation of relative bioavailability were area under the concentration-time curve from time zero to infinity (AUCinf) and maximum blood concentration (Cmax). Safety was assessed by reporting the incidence of adverse events (AEs). Twenty-two participants received everolimus as one 5 mg tablet followed by five 1 mg tablets (n=11) or the opposite sequence (n=11). The Cmax of five 1 mg tablets was 48% higher than that of one 5 mg tablet (geometric mean ratio, 1.48; 90% confidence interval [CI], 1.35-1.62). AUCinf was similar (geometric mean ratio, 1.08; 90% CI, 1.02-1.16), as were the extent of absorption and the distribution and elimination kinetics. AEs, all grade 1 or 2, were observed in 54.5% of subjects. Although the extent of absorption was similar, the Cmax of five 1 mg tablets was higher than that of one 5 mg tablet, suggesting these formulations lead to different peak blood concentrations and are not interchangeable at the dose tested.

  5. Addition of Everolimus Post VEGFR Inhibition Treatment Failure in Advanced Sarcoma Patients Who Previously Benefited from VEGFR Inhibition: A Case Series

    OpenAIRE

    ElNaggar, Adam C.; Hays, John L.; Chen, James L.

    2016-01-01

    Background Patients with metastatic sarcoma who progress on vascular endothelial growth factor receptor inhibitors (VEGFRi) have limited treatment options. Upregulation of the mTOR pathway has been demonstrated to be a means of resistance to targeted VEGFRi in metastatic sarcoma. Patients and methods Retrospective cohort study to evaluate the clinical benefit at four months of combining mTOR inhibition (mTORi) via everolimus with VEGFRi in patients who have derived benefit from single-agent V...

  6. Economic evaluation of everolimus versus sorafenib for the treatment of metastatic renal cell carcinoma after failure of first-line sunitinib.

    Science.gov (United States)

    Casciano, Roman; Chulikavit, Maruit; Di Lorenzo, Giuseppe; Liu, Zhimei; Baladi, Jean-Francois; Wang, Xufang; Robertson, Justin; Garrison, Lou

    2011-01-01

    A recent indirect comparison study showed that sunitinib-refractory metastatic renal cell carcinoma (mRCC) patients treated with everolimus are expected to have improved overall survival outcomes compared to patients treated with sorafenib. This analysis examines the likely cost-effectiveness of everolimus versus sorafenib in this setting from a US payer perspective. A Markov model was developed to simulate a cohort of sunitinib-refractory mRCC patients and to estimate the cost per incremental life-years gained (LYG) and quality-adjusted life-years (QALYs) gained. Markov states included are stable disease without adverse events, stable disease with adverse events, disease progression, and death. Transition probabilities were estimated using a subset of the RECORD-1 patient population receiving everolimus after sunitinib, and a comparable population receiving sorafenib in a single-arm phase II study. Costs of antitumor therapies were based on wholesale acquisition cost. Health state costs accounted for physician visits, tests, adverse events, postprogression therapy, and end-of-life care. The model extrapolated beyond the trial time horizon for up to 6 years based on published trial data. Deterministic and probabilistic sensitivity analyses were conducted. The estimated gain over sorafenib treatment was 1.273 LYs (0.916 QALYs) at an incremental cost of $81,643. The deterministic analysis resulted in an incremental cost-effectiveness ratio (ICER) of $64,155/LYG ($89,160/QALY). The probabilistic sensitivity analysis demonstrated that results were highly consistent across simulations. As the ICER fell within the cost per QALY range for many other widely used oncology medicines, everolimus is projected to be a cost-effective treatment relative to sorafenib for sunitinib-refractory mRCC. Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  7. The role of mTOR inhibitors in the prevention of organ rejection in adult liver transplant patients: a focus on everolimus

    Directory of Open Access Journals (Sweden)

    Casanovas T

    2014-06-01

    Full Text Available Teresa Casanovas Liver Transplant Unit, Bellvitge University Hospital, Barcelona, Spain Abstract: Liver transplantation remains the therapy of choice for patients with end-stage liver disease and in selected cases of hepatocellular carcinoma. While short-term allograft survival has improved significantly in recent years, there has been little improvement in long-term survival after liver transplantation. A growing body of evidence on factors influencing the long-term outcomes and the safety profiles of existing immunosuppressive agents after liver transplant points to a need to continue searching for alternative strategies. The calcineurin inhibitors (CNIs (cyclosporine and tacrolimus currently represent the backbone of most immunosuppressor regimens. They have had a revolutionary effect on the overall success of transplantation, as is reflected in greatly reduced rates of acute rejection. However, the CNIs have significant toxicities that produce renal dysfunction, cardiovascular disease, and other unwanted effects, such as malignancies. The recognition of these risk factors has sparked interest in regimens that limit exposure to CNIs. Nowadays, the use of immunosuppressive drugs with different mechanisms of action, which allow for a reduction or avoidance of CNIs, is common. Everolimus, which belongs to the mammalian target-of-rapamycin inhibitor family and is best known for its use in kidney and heart transplantation, has recently been approved for liver transplantation. This overview discusses the emerging evidence on the role of everolimus in the prevention of rejection after liver transplantation, in de novo transplants, conversion regimens, or as a rescue therapy. In addition, some of the most relevant and current clinical problems related to everolimus in this field are discussed. Keywords: everolimus, mTOR inhibitors, tacrolimus, liver transplant, cyclosporine, renal impairment

  8. FTY720 and everolimus in de novo renal transplant patients at risk for delayed graft function: results of an exploratory one-yr multicenter study.

    Science.gov (United States)

    Tedesco-Silva, H; Lorber, M I; Foster, C E; Sollinger, H W; Mendez, R; Carvalho, D B; Shapiro, R; Rajagopalan, P R; Mayer, H; Slade, J; Kahan, B D

    2009-01-01

    This exploratory, multicenter, open-label study evaluated the efficacy and safety of FTY720, as a part of an immunosuppressive regimen, in combination with everolimus and steroids in de novo renal transplant recipients at increased risk of delayed graft function (DGF). Patients received FTY720 (5 mg) and everolimus (4 mg) 2-12 h pre-transplantation, followed by 2.5 mg/d FTY720 and concentration-controlled everolimus (4-8 ng/mL) post-transplant for 12 months. Induction therapy was prohibited. After enrollment of 56 of the planned 200 patients between 2000 and 2002, the recruitment was terminated. The primary endpoint, rate of graft loss, or death at three months was 15.4% and the biopsy-confirmed acute rejection was 42.3%. Death or graft loss at 12 months in the DGF and non-DGF arms was 36.0% and 25.9%, respectively. The mean estimated creatinine clearance at three months was 63 and 55 mL/min in the non-DGF and DGF groups, respectively, while at 12 months it was 56 mL/min in both the groups. Although there was no comparator arm, the results from this exploratory study (compared with data from other phases II and III trials) indicated no apparent benefits of FTY720-based regimens for prevention of acute rejection and preservation of renal function in renal transplant recipients at high risk of DGF.

  9. RECORD-4 multicenter phase 2 trial of second-line everolimus in patients with metastatic renal cell carcinoma: Asian versus non-Asian population subanalysis.

    Science.gov (United States)

    Yang, Lin; Alyasova, Anna; Ye, Dingwei; Ridolfi, Antonia; Dezzani, Luca; Motzer, Robert J

    2018-02-17

    RECORD-4 assessed everolimus in patients with metastatic renal cell carcinoma (mRCC) who progressed after 1 prior anti-vascular endothelial growth factor (VEGF) or cytokine and reinforced the clinical benefit of second-line everolimus. Because of the high percentage of patients from China enrolled in RECORD-4 (41%) and some reported differences in responses to certain targeted agents between Chinese and Western patients, this subanalysis evaluated outcomes in Asian versus non-Asian patients. RECORD-4 enrolled patients with clear cell mRCC into 3 cohorts based on prior first-line therapy: sunitinib, other anti-VEGF (sorafenib, bevacizumab, pazopanib, other), or cytokines. Patients received everolimus 10 mg/d until progression of disease (RECIST, v1.0) or intolerance. Primary end point was progression-free survival per investigator review. Data cutoff was Sept 1, 2014. Among Asian (n = 55) versus non-Asian (n = 79) patients, 98% versus 84% had good/intermediate MSKCC prognosis; 73% versus 65% were men, and 85% versus 73% were < 65 years of age. All (100%) Asian patients were of Chinese ethnicity. Median duration of exposure was 5.5 mo for Asian and 6.0 mo for non-Asian patients. Among Asian versus non-Asian patients, median progression-free survival (months) was 7.4 versus 7.8 overall, 7.4 versus 4.0 with prior sunitinib, and 5.7 versus 9.2 with prior other anti-VEGFs. Clinical benefit rate was similar between populations: 74.5% (95% CI 61.0-85.3) for Asian patients and 74.7% (95% CI 63.6-83.8) for non-Asian patients. Most patients achieved stable disease as best overall response (Asian, 63.6%; non-Asian, 69.6%). Overall rate of grade 3/4 adverse events appeared similar for Asian (58%) and non-Asian patients (54%). This RECORD-4 subanalysis demonstrated comparable efficacy and adverse event profiles of second-line everolimus in Asian and non-Asian patients. Efficacy and safety outcomes by prior therapy should be interpreted with caution because of small

  10. The use of everolimus in the treatment of neurocognitive problems in tuberous sclerosis (TRON): study protocol for a randomised controlled trial.

    Science.gov (United States)

    Randell, Elizabeth; McNamara, Rachel; Davies, D Mark; Owen-Jones, Eleri; Kirby, Nigel; Angel, Lianna; Drew, Cheney; Cannings-John, Rebecca; Smalley, Michelle; Saxena, Anurag; McDermott, Emer; Stockwell, Laura; de Vries, Petrus J; Hood, Kerry; Sampson, Julian R

    2016-08-11

    Tuberous sclerosis complex (TSC) is a genetic disorder affecting about 1 in 6000 people and is characterised by the development of tumours in many organs, including the skin and kidneys, and by a range of neurological and neuropsychiatric manifestations. TSC-associated neuropsychiatric disorders (TAND) occur in the majority of those with TSC, and they have a significant impact on patients and their families, given the everyday impact of TAND on education, employment, family and social life. The potential benefits of better treatment for TAND therefore include reduction in health care demands and wider benefits for patients and their carers. We have planned a single-centre, two-arm, individually randomised, phase II, double-blind, placebo-controlled trial of everolimus versus placebo in the treatment of neurocognitive problems in patients with tuberous sclerosis. Everolimus is a licensed medicine in this patient group, but for a different target of effect. The present trial is a proof-of-principle study developed to provide effect size estimates which may be used to inform the design of subsequent trials. Forty-eight patients aged 16-60 years with tuberous sclerosis who have an IQ >60 and a significant deficit (at least -2 SD) in one or more primary outcome measures will be randomly allocated in a ratio of 2:1 to receive everolimus or placebo, respectively. Participants will be assessed for eligibility and then be started on study medication 4 weeks later. They will then be randomised and receive placebo or everolimus for 24 weeks. Neurocognitive and safety assessments will be carried out at baseline and weeks 4, 12, 24 and 36. This study is designed to determine the effect sizes of treatment with everolimus or placebo for 6 months on specific neurocognitive functions-recall memory (verbal and non-verbal) and executive function-in people affected by TSC who have significant deficits in these functions. These data will provide new evidence to determine whether

  11. Comparative vascular responses three months after paclitaxel and everolimus-eluting stent implantation in streptozotocin-induced diabetic porcine coronary arteries

    Directory of Open Access Journals (Sweden)

    Sheehy Alexander

    2012-06-01

    Full Text Available Abstract Background Diabetes remains a significant risk factor for restenosis/thrombosis following stenting. Although vascular healing responses following drug-eluting stent (DES treatment have been characterized previously in healthy animals, comparative assessments of different DES in a large animal model with isolated features of diabetes remains limited. We aimed to comparatively assess the vascular response to paclitaxel-eluting (PES and everolimus-eluting (EES stents in a porcine coronary model of streptozotocin (STZ-induced type I diabetes. Method Twelve Yucatan swine were induced hyperglycemic with a single STZ dose intravenously to ablate pancreatic β-cells. After two months, each animal received one XIENCE V® (EES and one Taxus Liberte (PES stent, respectively, in each coronary artery. After three months, vascular healing was assessed by angiography and histomorphometry. Comparative in vitro effects of everolimus and paclitaxel (10-5 M–10-12 M after 24 hours on carotid endothelial (EC and smooth muscle (SMC cell viability under hyperglycemic (42 mM conditions were assayed by ELISA. Caspase-3 fluorescent assay was used to quantify caspase-3 activity of EC treated with everolimus or paclitaxel (10-5 M, 10-7 M for 24 hours. Results After 3 months, EES reduced neointimal area (1.60 ± 0.41 mm, p vs. 0.08 ± 0.05, greater medial necrosis grade (0.52 ± 0.26 vs. 0.0 ± 0.0, and persistently elevated fibrin scores (1.60 ± 0.60 vs. 0.63 ± 0.41 with PES compared to EES (p In vitro, paclitaxel significantly increased (p -7 M, while everolimus did not affect EC/SMC apoptosis/necrosis within the dose range tested. In ECs, paclitaxel (10-5 M significantly increased caspase-3 activity (p  Conclusion After 3 months, both DES exhibited signs of delayed healing in a STZ-induced diabetic swine model. PES exhibited greater neointimal area, increased inflammation, greater medial necrosis, and

  12. The Additional Costs per Month of Progression-Free Survival and Overall Survival: An Economic Model Comparing Everolimus with Cabozantinib, Nivolumab, and Axitinib for Second-Line Treatment of Metastatic Renal Cell Carcinoma.

    Science.gov (United States)

    Swallow, Elyse; Messali, Andrew; Ghate, Sameer; McDonald, Evangeline; Duchesneau, Emilie; Perez, Jose Ricardo

    2018-04-01

    When considering optimal second-line treatments for metastatic renal cell carcinoma (mRCC), clinicians and payers seek to understand the relative clinical benefits and costs of treatment. To use an economic model to compare the additional cost per month of overall survival (OS) and of progression-free survival (PFS) for cabozantinib, nivolumab, and axitinib with everolimus for the second-line treatment of mRCC from a third-party U.S. payer perspective. The model evaluated mean OS and PFS and costs associated with drug acquisition/administration; adverse event (AE) treatment; monitoring; and postprogression (third-line treatment, monitoring, and end-of-life costs) over 1- and 2-year horizons. Efficacy, safety, and treatment duration inputs were estimated from regimens' pivotal clinical trials; for everolimus, results were weighted across trials. Mean 1- and 2-year OS and mean 1-year PFS were estimated using regimens' reported OS and PFS Kaplan-Meier curves. Dosing and administration inputs were consistent with approved prescribing information and the clinical trials used to estimate efficacy and safety inputs. Cost inputs came from published literature and public data. Additional cost per additional month of OS or PFS was calculated using the ratio of the cost difference per treated patient and the corresponding difference in mean OS or PFS between everolimus and each comparator. One-way sensitivity analyses were conducted by varying efficacy and cost inputs. Compared with everolimus, cabozantinib, nivolumab, and axitinib were associated with 1.6, 0.3, and 0.5 additional months of PFS, respectively, over 1 year. Cabozantinib and nivolumab were associated with additional months of OS compared with everolimus (1 year: 0.7 and 0.8 months; 2 years: 1.6 and 2.3 months; respectively); axitinib was associated with fewer months (1 year: -0.2 months; 2 years: -0.7 months). The additional costs of treatment with cabozantinib, nivolumab, or axitinib versus everolimus over 1

  13. Simultaneous Determination of Cyclosporine A, Tacrolimus, Sirolimus, and Everolimus in Whole-Blood Samples by LC-MS/MS

    Directory of Open Access Journals (Sweden)

    Mustafa Karapirli

    2012-01-01

    Full Text Available Objectives. Cyclosporine A (CyA, tacrolimus (TRL, sirolimus (SIR, and everolimus (RAD are immunosuppressive drugs frequently used in organ transplantation. Our aim was to confirm a robust sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS method for determination of CyA, TRL, SIR, and RAD in whole-blood samples. Materials and Methods. We used an integrated online solid-phase extraction-LC-MS/MS system and atmospheric pressure ionization tandem mass spectrometry (API-MS/MS in the multiple reaction monitoring (MRM detection mode. CyA, TRL, SIR, and RAD were simultaneously analyzed in whole blood treated with precipitation reagent taken from transplant patients. Results. System performance parameters were suitable for using this method as a high-throughput technique in clinical practice. The high concentration of one analyte in the sample did not affect the concentration of other analytes. Total analytical time was 2.5 min, and retention times of all analytes were shorter than 2 minutes. Conclusion. This LC-MS/MS method can be preferable for therapeutic drug monitoring of these immunosuppressive drugs (CyA, TRL, SRL, and RAD in whole blood. Sample preparation was too short and simple in this method, and it permits robust, rapid, sensitive, selective, and simultaneous determination of these drugs.

  14. Effect of conversion from calcineurin inhibitors to everolimus on hepatitis C viremia in adult kidney transplant recipients.

    Science.gov (United States)

    Pacheco, Larissa Sgaria; Garcia, Valter Duro; Prá, Ronivan Luis Dal; Cardoso, Bruna Doleys; Rodrigues, Mariana Ferras; Zanetti, Helen Kris; Meinerz, Gisele; Neumann, Jorge; Gnatta, Diego; Keitel, Elizete

    2018-05-14

    Currently, there is no specific immunosuppressive protocol for hepatitis C (HCV)-positive renal transplants recipients. Thus, the aim of this study was to evaluate the conversion effect to everolimus (EVR) on HCV in adult kidney recipients. This is an exploratory single-center, prospective, randomized, open label controlled trial with renal allograft recipients with HCV-positive serology. Participants were randomized for conversion to EVR or maintenance of calcineurin inhibitors. Thirty patients were randomized and 28 were followed-up for 12 months (conversion group, Group 1 =15 and control group, Group 2 =13). RT-PCR HCV levels reported in log values were comparable in both groups and among patients in the same group. The statistical analysis showed no interaction effect between time and group (p value G*M= 0.852), overtime intra-groups (p-value M=0.889) and between group (p-value G=0.286). Group 1 showed a higher incidence of dyslipidemia (p=0.03) and proteinuria events (p=0.01), while no difference was observed in the incidence of anemia (p=0.17), new onset of post-transplant diabetes mellitus (p=1.00) or urinary tract infection (p=0.60). The mean eGFR was similar in both groups. Our study did not show viral load decrease after conversion to EVR with maintenance of antiproliferative therapy.

  15. Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: A Clinical Trial.

    Science.gov (United States)

    Royce, Melanie; Bachelot, Thomas; Villanueva, Cristian; Özgüroglu, Mustafa; Azevedo, Sergio J; Cruz, Felipe Melo; Debled, Marc; Hegg, Roberto; Toyama, Tatsuya; Falkson, Carla; Jeong, Joon; Srimuninnimit, Vichien; Gradishar, William J; Arce, Christina; Ridolfi, Antonia; Lin, Chinjune; Cardoso, Fatima

    2018-03-22

    Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer. To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor-positive, human epidermal growth receptor 2-negative advanced breast cancer. In the multicenter, open-label, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17, 2016). Patients received first-line treatment with everolimus, 10 mg/d, plus letrozole, 2.5 mg/d. Second-line treatment with everolimus, 10 mg/d, plus exemestane, 25 mg/d, was offered at the investigator's discretion upon initial disease progression. The primary end point was investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment. A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range, 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95% CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7% (95% CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95% CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4

  16. Clinical Application of Everolimus in Field of Organ Transplantation%依维莫司在器官移植领域的临床应用

    Institute of Scientific and Technical Information of China (English)

    刘丽; 王华光

    2015-01-01

    Objective To summary the clinical application of everolimus in the field of organ transplantation by describing the action mechanism, pharmacokinetics, influence factors, clinical evaluation, adverse reaction, and so on. Methods By consulting the literatures about the mechanism, pharmacokinetics and clinical researches of everolimus in recent years, the important informations were extracted, analyzed and summarized for conducting this review. Results and Conclusion Everolimus can maintain better renal function in the as-pect of organ transplantation;various factors, such as food, drugs, can affect its pharmacokinetic properties. With the existing research clin-ical treatment regimen as the guidance, individualized medication regime and monitoring its blood concentration can increase the curative effect and reduce the adverse reactions.%目的:从作用机制、药代动力学性质及影响因素、临床评价、不良反应等方面简述依维莫司在器官移植领域的临床应用。方法查阅近几年文献,提取重要信息,通过分析、归纳进行综述。结果与结论依维莫司用于器官移植能维持较好的肾功能。食物、药物等多种因素均能影响其药代动力学性质。以已有的研究性临床治疗方案为指导,采用依维莫司个体化给药方案,监测其血药浓度,可提高疗效、降低不良反应。

  17. Incidence and risk of treatment-related mortality with mTOR inhibitors everolimus and temsirolimus in cancer patients: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Wei-Xiang Qi

    Full Text Available BACKGROUND: Two novel mammalian targets of rapamycin (mTOR inhibitors everolimus and temsirolimus are now approved by regulatory agencies and have been widely investigated among various types of solid tumors, but the risk of fatal adverse events (FAEs with these drugs is not well defined. METHODS: We searched PubMed, EMBASE, and Cochrane library databases for relevant trials. Eligible studies included prospective phase II and III trials evaluating everolimus and temsirolimus in patients with all malignancies and data on FAEs were available. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs by using either random effects or fixed effect models according to the heterogeneity of the included studies. RESULTS: A total of 3322 patients with various advanced solid tumors from 12 trials were included. The overall incidence of mTOR inhibitors associated FAEs was 1.8% (95%CI: 1.3-2.5%, and the incidences of everolimus related FAEs were comparable to that of temsirolimus (1.7% versus 1.8%. Compared with the controls, the use of mTOR inhibitors was associated with an increased risk of FAEs, with a RR of 3.24 (95%CI: 1.21-8.67, p = 0.019. On subgroup analysis, a non-statistically significant increase in the risk of FAEs was found according to different mTOR inhibitors, tumor types or controlled therapy. No evidence of publication bias was observed. CONCLUSION: With the present evidence, the use of mTOR inhibitors seems to increase the risk of FAEs in patients with advanced solid tumors. More high quality trials are still needed to investigate this association.

  18. Risk and timing of clinical events according to diabetic status of patients treated with everolimus-eluting bioresorbable vascular scaffolds versus everolimus-eluting stent: 2-year results from a propensity score matched comparison of ABSORB EXTEND and SPIRIT trials.

    Science.gov (United States)

    Campos, Carlos M; Caixeta, Adriano; Franken, Marcelo; Bartorelli, Antonio L; Whitbourn, Robert J; Wu, Chiung-Jen; Li Paul Kao, Hsien; Rosli, Mohd Ali; Carrie, Didier; De Bruyne, Bernard; Stone, Gregg W; Serruys, Patrick W; Abizaid, Alexandre

    2018-02-15

    to compare the occurrence of clinical events in diabetics treated with the Absorb bioresorbable vascular scaffold (Absorb BVS; Abbott Vascular, Santa Clara, CA) versus everolimus-eluting metal stents (EES; XIENCE V; Abbott Vascular, Santa Clara, CA) BACKGROUND: There are limited data dedicated to clinical outcomes of diabetic patients treated with bioresorbable scaffolds (BRS) at 2-year horizon. The present study included 812 patients in the ABSORB EXTEND study in which a total of 215 diabetic patients were treated with Absorb BVS. In addition, 882 diabetic patients treated with EES in pooled data from the SPIRIT clinical program (SPIRIT II, SPIRIT III and SPIRIT IV trials) were used for comparison by applying propensity score matching using 29 different variables. The primary endpoint was ischemia driven major adverse cardiac events (ID-MACE), including cardiac death, myocardial infarction (MI), and ischemia driven target lesion revascularization (ID-TLR). After 2 years, the ID-MACE rate was 6.5% in the Absorb BVS vs. 8.9% in the Xience group (P = 0.40). There was no difference for MACE components or definite/probable device thrombosis (HR: 1.43 [0.24,8.58]; P = 0.69). The occurrence of MACE was not different for both diabetic status (insulin- and non-insulin-requiring diabetes) in all time points up to the 2-year follow-up for the Absorb and Xience groups. In this largest ever patient-level pooled comparison on the treatment of diabetic patients with BRS out to two years, individuals with diabetes treated with the Absorb BVS had a similar rate of MACE as compared with diabetics treated with the Xience EES. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  19. Rationale and Design of a Randomized Clinical Comparison of Everolimus-Eluting (Xience V/Promus) and Sirolimus-Eluting (Cypher Select+) Coronary Stents in Unselected Patients with Coronary Heart Disease

    DEFF Research Database (Denmark)

    Jensen, Lisette Okkels; Thayssen, Per; Tilsted, Hans Henrik

    2010-01-01

    with Clinical Outcome (SORT OUT) IV trial was designed as a prospective, multi-center, open-label, all-comer, two-arm, randomized, non-inferiority study comparing the everolimus-eluting stent with the sirolimus-eluting stent in the treatment of atherosclerotic coronary artery lesions. Based on a non...

  20. Tissue coverage of a hydrophilic polymer-coated zotarolimus-eluting stent vs. a fluoropolymer-coated everolimus-eluting stent at 13-month follow-up: an optical coherence tomography substudy from the RESOLUTE All Comers trial

    DEFF Research Database (Denmark)

    Gutiérrez-Chico, Juan Luis; van Geuns, Robert Jan; Regar, Evelyn

    2011-01-01

    To compare the tissue coverage of a hydrophilic polymer-coated zotarolimus-eluting stent (ZES) vs. a fluoropolymer-coated everolimus-eluting stent (EES) at 13 months, using optical coherence tomography (OCT) in an 'all-comers' population of patients, in order to clarify the mechanism of eventual...

  1. Long-Term Follow-Up of Patients after Percutaneous Coronary Intervention with Everolimus-Eluting Bioresorbable Vascular Scaffold.

    Science.gov (United States)

    Meneguz-Moreno, Rafael Alexandre; Costa, José de Ribamar; Moscoso, Freddy Antônio Britto; Staico, Rodolfo; Tanajura, Luiz Fernando Leite; Centemero, Marinella Patrizia; Chaves, Auréa Jacob; Abizaid, Andrea Claudia Leão de Sousa; Sousa, Amanda Guerra de Moraes Rego E; Abizaid, Alexandre Antonio Cunha

    2017-02-01

    Bioresorbable vascular scaffolds (BVS) were developed to improve the long-term results of percutaneous coronary intervention, restoring vasomotion. To report very late follow-up of everolimus-eluting Absorb BVS (Abbott Vascular, Santa Clara, USA) in our center. Observational retrospective study, in a single Brazilian center, from August 2011 to October 2013, including 49 patients submitted to Absorb BVS implantation. Safety and efficacy outcomes were analyzed in the in-hospital and very late follow-up phases (> 2 years). All 49 patients underwent a minimum follow-up of 2.5 years and a maximum of 4.6 years. Mean age was 56.8 ± 7.6 years, 71.4% of the patients were men, and 26.5% were diabetic. Regarding clinical presentation, the majority (94%) had stable angina or silent ischemia. Device success was achieved in 100% of cases with 96% overall procedure success rate. Major adverse cardiovascular events rate was 4% at 30 days, 8.2% at 1 year, and 12.2% at 2 years, and there were no more events until 4.6 years. There were 2 cases of thrombosis (1 subacute and 1 late). In this preliminary analysis, Absorb BVS showed to be a safe and effective device in the very late follow-up. Establishing the efficacy and safety profiles of these devices in more complex scenarios is necessary. Os suportes vasculares bioabsorvíveis (SVB) foram desenvolvidos com o intuito de melhorar os resultados da intervenção coronária percutânea a longo prazo, restabelecendo-se a vasomotricidade. Reportar o seguimento muito tardio do implante do SVB eluidor de everolimus Absorb® (Abbot Vascular, Santa Clara, EUA) em nosso centro. Estudo observacional, retrospectivo, em um único centro brasileiro, que incluiu 49 pacientes submetidos ao implante do SVB Absorb® entre agosto/2011 e outubro/2013. Foram analisados os desfechos de segurança e eficácia na fase hospitalar e bastante tardia (> 2 anos). Todos os 49 pacientes completaram um seguimento mínimo de 2,5 anos, sendo o máximo de 4,6 anos

  2. ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer.

    Science.gov (United States)

    Lev, Avital; Lulla, Amriti R; Ross, Brian C; Ralff, Marie D; Makhov, Petr B; Dicker, David T; El-Deiry, Wafik S

    2018-05-01

    Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is a mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most prostate cancers eventually become androgen-independent and resistant to ADT with patients progressing to metastatic castration-resistant prostate cancer (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance to AR-targeted therapy and the progression of mCRPC, and they represent an important therapeutic target. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant, and its expression correlates with ADT resistance. ONC201/TIC10 is the founding member of the imipridone class of small molecules and has shown anticancer activity in a broad range of tumor types. ONC201 is currently being tested in phase I/II clinical trials for advanced solid tumors, including mCRPC, and hematologic malignancies. There has been promising activity observed in patients in early clinical testing. This study demonstrates preclinical single-agent efficacy of ONC201 using in vitro and in vivo models of prostate cancer. ONC201 has potent antiproliferative and proapoptotic effects in both castration-resistant and -sensitive prostate cancer cells. Furthermore, the data demonstrate that ONC201 downregulates the expression of key drivers of prostate cancer such as AR-V7 and downstream target genes including the clinically used biomarker PSA (KLK3). Finally, the data also provide a preclinical rationale for combination of ONC201 with approved therapeutics for prostate cancer such as enzalutamide, everolimus (mTOR inhibitor), or docetaxel. Implications: The preclinical efficacy of ONC201 as a single agent or in combination, in hormone-sensitive or castration-resistant prostate cancer, suggests the potential for immediate clinical translation. Mol Cancer Res; 16(5); 754-66. ©2018 AACR . ©2018 American Association for Cancer

  3. 18F-FDG and 18F-FLT-PET imaging for monitoring everolimus effect on tumor-growth in neuroendocrine tumors: studies in human tumor xenografts in mice.

    Directory of Open Access Journals (Sweden)

    Camilla Bardram Johnbeck

    Full Text Available The mTOR inhibitor everolimus has shown promising results in some but not all neuroendocrine tumors. Therefore, early assessment of treatment response would be beneficial. In this study, we investigated the in vivo and in vitro treatment effect of everolimus in neuroendocrine tumors and evaluated the performance of 18F-FDG and the proliferation tracer 18F-FLT for treatment response assessment by PET imaging.The effect of everolimus on the human carcinoid cell line H727 was examined in vitro with the MTT assay and in vivo on H727 xenograft tumors. The mice were scanned at baseline with 18F-FDG or 18F-FLT and then treated with either placebo or everolimus (5 mg/kg daily for 10 days. PET/CT scans were repeated at day 1,3 and 10.Everolimus showed significant inhibition of H727 cell proliferation in vitro at concentrations above 1 nM. In vivo tumor volumes measured relative to baseline were significantly lower in the everolimus group compared to the control group at day 3 (126±6% vs. 152±6%; p = 0.016, day 7 (164±7% vs. 226±13%; p<0.001 and at day 10 (194±10% vs. 281±18%; p<0.001. Uptake of 18F-FDG and 18F-FLT showed little differences between control and treatment groups, but individual mean uptake of 18F-FDG at day 3 correlated with tumor growth day 10 (r2 = 0.45; P = 0.034, 18F-FLT mean uptake at day 1 correlated with tumor growth day 7 (r2 = 0.63; P = 0.019 and at day 3 18F-FLT correlated with tumor growth day 7 (r2 = 0.87; P<0.001 and day 10 (r2 = 0.58; P = 0.027.Everolimus was effective in vitro and in vivo in human xenografts lung carcinoid NETs and especially early 18F-FLT uptake predicted subsequent tumor growth. We suggest that 18F-FLT PET can be used for tailoring therapy for neuroendocrine tumor patients through early identification of responders and non-responders.

  4. Comparative effectiveness of everolimus-based therapy versus endocrine monotherapy among postmenopausal women with HR+/HER2- metastatic breast cancer: a retrospective chart review in community oncology practices in the US.

    Science.gov (United States)

    Xie, Jipan; Hao, Yanni; Li, Nanxin; Lin, Peggy L; Ohashi, Erika; Koo, Valerie; Signorovitch, James E; Wu, Eric Q; Yardley, Denise A

    2015-06-01

    Everolimus-based therapy and endocrine monotherapy are used among postmenopausal women with hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (mBC) whose disease progressed or recurred on a non-steroidal aromatase inhibitor (NSAI). However, limited evidence exists regarding the real-world comparative effectiveness of these agents. This retrospective chart review examined postmenopausal HR+/HER2- mBC patients in community-based oncology practices who received everolimus-based therapy or endocrine monotherapy (index therapy) as any line of therapy for mBC between 1 July 2012 and 15 April 2013 after NSAI failure. Time on treatment (TOT), progression-free survival (PFS), and time to chemotherapy (TTC) from index therapy initiation were compared using Kaplan-Meier analyses and Cox proportional hazards models adjusting for baseline characteristics. A total of 243 and 270 patients received everolimus-based therapy or endocrine monotherapy in a quota-based sample. Patients treated with everolimus-based therapy had a higher proportion of visceral metastases, high tumor burden, and use of prior chemotherapies for mBC. After adjusting for baseline characteristics, everolimus-based therapy was associated with significantly longer TOT (HR = 0.67, 95% CI: 0.51-0.87) and PFS (HR = 0.75, 95% CI: 0.57-0.98) than endocrine monotherapy. No significant difference was found between everolimus-based therapy and endocrine monotherapy in TTC (HR = 0.81, 95% CI: 0.52-1.27). Results stratified by line of therapy were generally consistent with the overall results. Limitations include recall and information bias with potentially absent or erroneous chart data, unobserved factors due to non-randomization, inability to measure outcome assessments paired with measuring outcomes prior to exposures, and potential patient selection bias associated with chart review. Among a nationwide sample of postmenopausal HR+/HER2- m

  5. Differentiated analysis of an everolimus-eluting stent and a paclitaxel-eluting stent among higher risk subgroups for restenosis: results from the SPIRIT II trial.

    Science.gov (United States)

    Khattab, Ahmed A; Richardt, Gert; Verin, Vitali; Kelbaek, Henning; Macaya, Carlos; Berland, Jacques; Miquel-Hebert, Karine; Dorange, Cécile; Serruys, Patrick W

    2008-03-01

    Restenosis is higher among certain subpopulations when subjected to percutaneous coronary interventions even when using drug-eluting stents. The randomised SPIRIT II trial demonstrated the superiority of the XIENCE V Everolimus Eluting Coronary Stent System over the TAXUS Paclitaxel-Eluting Stent System in terms of in-stent late loss at six months among 300 patients treated for de novo native coronary artery lesions. In this post-hoc analysis of SPIRIT II we focused on six-month angiographic outcomes of diabetic patients (n=69), left anterior descending arteries (n=149), long lesions >20 mm (n=43), small vessels B2 and C lesions (n=233). In-stent late loss was consistently less among all subgroups when treated by everolimus-eluting stents compared to paclitaxel-eluting stents: diabetics 0.15+/-0.26 mm versus 0.39+/-0.34 mm, p=0.006; LAD 0.12+/-0.23 mm versus 0.44+/-0.37 mm, pB2/C lesions 0.12+/-0.31 mm versus 0.36+/-0.36 mm, pSPIRIT II trial population.

  6. A pilot study of JI-101, an inhibitor of VEGFR-2, PDGFR-β, and EphB4 receptors, in combination with everolimus and as a single agent in an ovarian cancer expansion cohort.

    Science.gov (United States)

    Werner, Theresa L; Wade, Mark L; Agarwal, Neeraj; Boucher, Kenneth; Patel, Jesal; Luebke, Aaron; Sharma, Sunil

    2015-12-01

    JI-101 is an oral multi-kinase inhibitor that targets vascular endothelial growth factor receptor type 2 (VEGFR-2), platelet derived growth factor receptor β (PDGFR-β), and ephrin type-B receptor 4 (EphB4). None of the currently approved angiogenesis inhibitors have been reported to inhibit EphB4, and therefore, JI-101 has a novel mechanism of action. We conducted a pilot trial to assess the pharmacokinetics (PK), tolerability, and efficacy of JI-101 in combination with everolimus in advanced cancers, and pharmacodynamics (PD), tolerability, and efficacy of JI-101 in ovarian cancer. This was the first clinical study assessing anti-tumor activity of JI-101 in a combinatorial regimen. In the PK cohort, four patients received single agent 10 mg everolimus on day 1, 10 mg everolimus and 200 mg JI-101 combination on day 8, and single agent 200 mg JI-101 on day 15. In the PD cohort, eleven patients received single agent JI-101 at 200 mg twice daily for 28 day treatment cycles. JI-101 was well tolerated as a single agent and in combination with everolimus. No serious adverse events were observed. Common adverse events were hypertension, nausea, and abdominal pain. JI-101 increased exposure of everolimus by approximately 22%, suggestive of drug-drug interaction. The majority of patients had stable disease at their first set of restaging scans (two months), although no patients demonstrated a response to the drug per RECIST criteria. The novel mechanism of action of JI-101 is promising in ovarian cancer treatment and further prospective studies of this agent may be pursued in a less refractory patient population or in combination with cytotoxic chemotherapy.

  7. Comparison of medical costs and healthcare resource utilization of post-menopausal women with HR+/HER2- metastatic breast cancer receiving everolimus-based therapy or chemotherapy: a retrospective claims database analysis.

    Science.gov (United States)

    Li, Nanxin; Hao, Yanni; Koo, Valerie; Fang, Anna; Peeples, Miranda; Kageleiry, Andrew; Wu, Eric Q; Guérin, Annie

    2016-01-01

    To analyze medical costs and healthcare resource utilization (HRU) associated with everolimus-based therapy or chemotherapy among post-menopausal women with hormone-receptor-positive, human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC). Patients with HR+/HER2- mBC who discontinued a non-steroidal aromatase inhibitor and began a new line of treatment with everolimus-based therapy or chemotherapy (index therapy/index date) between July 20, 2012 and April 30, 2014 were identified from two large claims databases. All-cause, BC-related, and adverse event (AE)-related medical costs (in 2014 USD) and all-cause HRU per patient per month (PPPM) were analyzed for both treatment groups across patients' first four lines of therapies for mBC. Adjusted differences in costs and HRU between the everolimus and chemotherapy treatment group were estimated pooling all lines and using multivariable generalized linear models, accounting for difference in patient characteristics. A total of 3298 patients were included: 902 everolimus-treated patients and 2636 chemotherapy-treated patients. Compared to chemotherapy, everolimus was associated with significantly lower all-cause (adjusted mean difference = $3455, p well as significantly lower HRU (emergency room incidence rate ratio [IRR] = 0.83; inpatient IRR = 0.74; inpatient days IRR = 0.65; outpatient IRR = 0.71; BC-related outpatient IRR = 0.57; all p chemotherapy.

  8. The SPIRIT V study: a clinical evaluation of the XIENCE V everolimus-eluting coronary stent system in the treatment of patients with de novo coronary artery lesions.

    Science.gov (United States)

    Grube, Eberhard; Chevalier, Bernard; Smits, Peter; Džavík, Vladimir; Patel, Tejas M; Mullasari, Ajit S; Wöhrle, Jochen; Stuteville, Marrianne; Dorange, Cécile; Kaul, Upendra

    2011-02-01

    The SPIRIT V (A Clinical Evaluation of the XIENCE V Everolimus-Eluting Coronary Stent System in the Treatment of Patients With De Novo Coronary Artery Lesions) study is a post-market surveillance experience of the XIENCE V (Abbott Vascular, Santa Clara, California) everolimus-eluting stent (EES) in patients with higher-risk coronary anatomy. Previous pre-approval studies have shown the safety and efficacy of EES in highly selected groups of patients. The SPIRIT V trial is a prospective, open label, single arm, multicenter study. Two thousand seven hundred patients with multiple de novo coronary artery lesions suitable for treatment with a planned maximum of 4 EES were enrolled at 93 centers in Europe, Asia Pacific, Canada, and South Africa. Lesions had a reference vessel diameter between 2.25 and 4.0 mm and a length of ≤ 28 mm by visual estimation. An independent clinical events committee adjudicated all end point-related events. The primary end point was the composite rate of all death, myocardial infarction (MI), and target vessel revascularization at 30 days. Secondary end points included stent thrombosis and acute success (clinical device and procedure success). At 30 days, the primary composite end point of all death, MI, and target vessel revascularization was 2.7%. At 1 year, rates of cardiac death, overall MI, and target lesion revascularization were 1.1%, 3.5%, and 1.8%, respectively. The cumulative rate of definite and probable stent thrombosis was low at 0.66% at 1 year. Use of EES in patients with multiple, complex de novo lesions yielded 1-year major adverse cardiac events, stent thrombosis, and target lesion revascularization rates that are comparable to those of the more controlled SPIRIT II and SPIRIT III trials-which included patients with restricted inclusion/exclusion criteria-and other all-comer population, physician-initiated studies like the X-SEARCH (Xience Stent Evaluated At Rotterdam Cardiology Hospital) and COMPARE (A Randomized

  9. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial.

    Science.gov (United States)

    Grignani, Giovanni; Palmerini, Emanuela; Ferraresi, Virginia; D'Ambrosio, Lorenzo; Bertulli, Rossella; Asaftei, Sebastian Dorin; Tamburini, Angela; Pignochino, Ymera; Sangiolo, Dario; Marchesi, Emanuela; Capozzi, Federica; Biagini, Roberto; Gambarotti, Marco; Fagioli, Franca; Casali, Paolo Giovanni; Picci, Piero; Ferrari, Stefano; Aglietta, Massimo

    2015-01-01

    Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. Although the combination of sorafenib and everolimus showed activity as a further-line treatment

  10. Comparison of Outcomes in Patients With Versus Without Diabetes Mellitus After Revascularization With Everolimus- and Sirolimus-Eluting Stents (from the SORT OUT IV Trial)

    DEFF Research Database (Denmark)

    Jensen, Lisette Okkels; Thayssen, Per; Junker, Anders

    2012-01-01

    Diabetes is associated with increased risk of major adverse cardiac events (MACEs) after percutaneous coronary intervention. The purpose of this substudy of the SORT OUT IV trial was to compare clinical outcomes in patients with and without diabetes mellitus treated with everolimus-eluting stents...... (EESs) or sirolimus-eluting stents (SESs). In total 2,774 patients (390 with diabetes, 14.1%) were randomized to stent implantation with EESs (n = 1,390, diabetes in 14.0%) or SESs (n = 1,384, diabetes in 14.2%). Randomization was stratified by presence/absence of diabetes. The primary end point...... was MACEs, a composite of cardiac death, myocardial infarction, definite stent thrombosis, or target vessel revascularization within 18 months. MACEs were higher in diabetic than in nondiabetic patients (13.1% vs 6.4%, hazard ratio [HR] 2.08, 95% confidence interval [CI] 1.51 to 2.86). In diabetic patients...

  11. An everolimus-eluting stent versus a paclitaxel-eluting stent in small vessel coronary artery disease: a pooled analysis from the SPIRIT II and SPIRIT III trials.

    Science.gov (United States)

    Bartorelli, Antonio L; Serruys, Patrick W; Miquel-Hébert, Karine; Yu, Shui; Pierson, Wes; Stone, Gregg W

    2010-07-01

    To evaluate the safety and efficacy of the XIENCE V everolimus-eluting stent compared to the TAXUS paclitaxel-eluting stent in small vessels. The XIENCE V everolimus-eluting stent (EES) has been shown to improve angiographic and clinical outcomes after percutaneous myocardial revascularization, but its performance in small coronary arteries has not been investigated. In this pooled analysis, we studied a cohort of 541 patients with small coronary vessels (reference diameter SPIRIT II and SPIRIT III studies. TAXUS Express (73% of lesions) and TAXUS Liberté (27% of lesions) paclitaxel-eluting stents (PES) were used as controls in SPIRIT II. In SPIRIT III, Taxus Express(2) PES was the control. Mean angiographic in-stent and in-segment late loss was significantly less in the EES group compared with the PES group, (0.15 +/- 0.37 mm vs. 0.30 +/- 0.44 mm; P = 0.011 for in-stent; 0.10 +/- 0.38 mm vs. 0.21 +/- 0.34 mm; P = 0.034 for in-segment). EES also resulted in a significant reduction in composite major adverse cardiac events at 1 year (19/366 [5.2%] vs. 17/159 [10.7%]; P = 0.037), due to fewer non-Q-wave myocardial infarctions and target lesion revascularizations. At 1 year, the rate of non-Q-wave myocardial infarction was significantly lower in the EES group compared with that of the PES group (6/366 [1.6%] vs. 8/159 [5.0%]; P = 0.037). In patients with small vessel coronary arteries, the XIENCE V EES was superior to the TAXUS PES. (c) 2010 Wiley-Liss, Inc.

  12. Serial optical coherence tomography assessment of malapposed struts after everolimus-eluting stent implantation. A subanalysis from the HEAL-EES study

    Energy Technology Data Exchange (ETDEWEB)

    Ishida, Kohki [Cardiology Department, Cardiovascular Institute, Hospital Clínic, Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona (Spain); Otsuki, Shuji [Division of Cardiology, Teikyo University Hospital, Tokyo (Japan); Giacchi, Giuseppe; Ortega-Paz, Luis [Cardiology Department, Cardiovascular Institute, Hospital Clínic, Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona (Spain); Shiratori, Yoshitaka [Division of Cardiology, Teikyo University Hospital, Tokyo (Japan); Freixa, Xavier; Martín-Yuste, Victoria; Masotti, Mónica; Sabaté, Manel [Cardiology Department, Cardiovascular Institute, Hospital Clínic, Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona (Spain); Brugaletta, Salvatore, E-mail: sabrugal@clinic.ub.es [Cardiology Department, Cardiovascular Institute, Hospital Clínic, Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona (Spain)

    2017-01-15

    Background: Incomplete stent apposition (ISA) is related to stent thrombosis, which is a serious adverse event. We aim to assess the time-course of ISA after 2nd generation everolimus-eluting stent (EES) implantation. Methods: In HEAL-EES study, we enrolled 36 patients who underwent percutaneous coronary intervention (PCI) with EES. OCT imaging was performed at baseline and follow-up. Patients were randomized 1:1:1 into 3 groups according to the time in which follow-up was performed: group A (6-month), group B (9-month), and group C (12-month). In this subanalysis, patients who had ISA segments at baseline and/or follow-up OCT were analyzed. Result: At baseline, among 41 lesions in 36 patients, 20 lesions in 18 patients had ISA segments and were analyzed. At baseline, there were 3.0% ISA struts in group A (n = 8), 2.8% in group B (n = 4), and 4.5% in group C (n = 8). At follow-up, ISA struts were present in 0.09%, 0.16% and 0.64%; respectively in groups A, B, and C. At follow-up, there was a significant decrease in the frequency of ISA: group A 3.0% vs. 0.09% (p < 0.001), group B 2.8% vs. 0.16% (p < 0.001), and group C 4.5% vs. 0.64% (p < 0.001). In group A, there was one late acquired ISA at follow-up. Conclusions: In patients undergoing 2nd generation EES implantation, area of acute ISA assessed by OCT, was almost resolved at 6-month follow-up. - Highlights: • Time-course of incomplete stent apposition of everolimus-eluting stent was assessed. • Serial optical coherence tomography images at baseline and follow-up were evaluated. • Acute incomplete stent apposition was almost resolved as early as at 6 months.

  13. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial.

    Science.gov (United States)

    Rugo, Hope S; Seneviratne, Lasika; Beck, J Thaddeus; Glaspy, John A; Peguero, Julio A; Pluard, Timothy J; Dhillon, Navneet; Hwang, Leon Christopher; Nangia, Chaitali; Mayer, Ingrid A; Meiller, Timothy F; Chambers, Mark S; Sweetman, Robert W; Sabo, J Randy; Litton, Jennifer K

    2017-05-01

    Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer. This US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093. Between May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29-8·24), versus 159 (33%) of 482 patients (95% CI 28·8-37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently

  14. Intimal hyperplasia and vascular remodeling after everolimus-eluting and sirolimus-eluting stent implantation in diabetic patients the randomized diabetes and drug-eluting stent (DiabeDES) IV intravascular ultrasound trial

    DEFF Research Database (Denmark)

    Antonsen, Lisbeth; Maeng, Michael; Thayssen, Per

    2013-01-01

    OBJECTIVE: To evaluate the effects of the everolimus-eluting Xience™/Promus™ stent (EES) and the sirolimus-eluting Cypher™ stent (SES) on intimal hyperplasia (IH) in diabetic patients. BACKGROUND: Patients with diabetes mellitus have increased risk of in-stent restenosis after coronary stent...... implantation due to intimal hyperplasia (IH). METHODS: In a sub study of the Randomized Comparison of Everolimus-Eluting and Sirolimus-Eluting Stents in Patients Treated with Percutaneous Coronary Intervention (SORT OUT IV trial), serial intravascular ultrasound (IVUS) 10-month follow-up data were available...... in 88 patients, including 48 EES and 40 SES treated patients. IVUS endpoints included IH volume, in-stent % volume obstruction and changes in external elastic membrane (EEM) volume. RESULTS: Compared with the SES group, IH volume was increased in the EES group [median (interquartile range): 2.8 mm(3) (0...

  15. Activation of phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin pathway and response to everolimus in endocrine receptor-positive metastatic breast cancer – A retrospective pilot analysis and viewpoint

    Directory of Open Access Journals (Sweden)

    Jyoti Bajpai

    2017-01-01

    Full Text Available Introduction: Biomarkers predictive of response to mechanistic target of rapamycin (mTOR inhibitor, everolimus, in endocrine receptor (ER-positive metastatic breast cancer (MBC are a work in progress. We evaluated the feasibility of directly measuring mTOR activity and phosphatase and tensin homolog (PTEN expression and correlating their expression with response and survival. Materials and Methods: MBC patients who received everolimus with endocrine therapy (ET after progression on an aromatase inhibitor and had adequate tissue preservation for estimation of mTOR activity and PTEN expression were selected for analysis from a prospectively maintained database. Progression-free survival (PFS and overall survival (OS were estimated by Kaplan–Meier method, and correlation between mTOR activity and PTEN expression with survival was done by log-rank test. Results: Thirteen ER-positive MBC patients were available for analysis. PTEN expression was lost in 11/13 (84.6% patients and retained in 2/13 patients (15.4%. mTOR activity was absent in four patients (30.7%, weak in six patients (46.1%, and moderate in 3 patients (23.2%. Median PFS for the entire population was 2.5 months while median OS was not reached. Patients with an absent mTOR activity showed a longer PFS (5 vs. 1.5 vs. 2 months than those with weak and moderate activity, respectively (P = 0.043. There was no correlation between loss of PTEN expression and PFS. Conclusions: Measurement of direct mTOR activity in patients with MBC receiving everolimus/ET combination appears feasible. Absent mTOR activity may predict for longer PFS with everolimus-ET combination and requires further study.

  16. Patient-reported outcomes in a phase iii study of everolimus versus placebo in patients with metastatic carcinoma of the kidney that has progressed on vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy.

    Science.gov (United States)

    Beaumont, Jennifer L; Butt, Zeeshan; Baladi, Jeanfrancois; Motzer, Robert J; Haas, Tomas; Hollaender, Norbert; Kay, Andrea; Cella, David

    2011-01-01

    A phase III, randomized, double-blind, placebo-controlled trial was conducted in patients with metastatic renal cell carcinoma. The focus of this paper is to evaluate the patient-reported outcomes. Patients were randomly assigned (2:1) to receive oral everolimus 10 mg once daily or placebo. The Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS) and European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 were administered before randomization and on day 1 of each cycle. The FKSI-DRS and the EORTC QLQ-C30 Physical Functioning and Global Quality of Life scores were the primary endpoints examined. Longitudinal models were used to compare treatment arms. Sensitivity analyses were conducted to explore the impact of missing data assumptions. Longitudinal trends for FKSI-DRS scores did not differ by treatment arm. Taking nonignorable missing data into account, there were significant differences between treatment arms in the trend over time for physical functioning and global quality of life, with the everolimus arm exhibiting greater decreases. All three of these measures of health-related quality of life were significantly related to progression-free survival. There was no evidence of a difference between everolimus and placebo in longitudinal patterns of disease-related symptoms, and little difference between the arms in physical functioning or global quality of life trends. This supports the conclusion that delay in tumor progression demonstrated by everolimus is associated with minimal impact on symptoms, physical functioning, or quality of life, as reported by patients.

  17. Safety and efficacy of everolimus in Chinese patients with metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy: an open-label phase 1b study

    International Nuclear Information System (INIS)

    Guo, Jun; Straub, Patrick; Pirotta, Nicoletta; Gogov, Sven; Huang, Yiran; Zhang, Xu; Zhou, Fangjian; Sun, Yinghao; Qin, Shukui; Ye, Zhangqun; Wang, Hui; Jappe, Annette

    2013-01-01

    In China, there are currently no approved therapies for the treatment of metastatic renal cell carcinoma (mRCC) following progression with vascular endothelial growth factor (VEGF)-targeted agents. In the phase 3 RECORD-1 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus afforded clinical benefit with good tolerability in Western patients with mRCC whose disease had progressed despite VEGF receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. This phase 1b study was designed to further evaluate the safety and efficacy of everolimus in VEGFr-TKI-refractory Chinese patients with mRCC. An open-label, multicenter phase 1b study enrolled Chinese patients with mRCC who were intolerant to, or progressed on, previous VEGFr-TKI therapy (N = 64). Patients received everolimus 10 mg daily until objective tumor progression (according to RECIST, version 1.0), unacceptable toxicity, death, or study discontinuation for any other reason. The final data analysis cut-off date was November 30, 2011. A total of 64 patients were included in the study. Median age was 52 years (range, 19–75 years) and 69% of patients were male. Median duration of everolimus therapy was 4.1 months (range, 0.0-16.1 months). Expected known class-effect toxicities related to mTOR inhibitor therapy were observed, including anemia (64%), hypertriglyceridemia (55%), mouth ulceration (53%), hyperglycemia (52%), hypercholesterolemia (50%), and pulmonary events (31%). Common grade 3/4 adverse events were anemia (20%), hyperglycemia (13%), increased gamma-glutamyltransferase (11%), hyponatremia (8%), dyspnea (8%), hypertriglyceridemia (6%), and lymphopenia (6%). Median PFS was 6.9 months (95% CI, 3.7-12.5 months) and the overall tumor response rate was 5% (95% CI, 1-13%). The majority of patients (61%) had stable disease as their best overall tumor response. Safety and efficacy results were comparable to those of the RECORD-1 trial. Everolimus is generally well tolerated and provides clinical

  18. Evaluation of chemical stability of polymers of XIENCE everolimus-eluting coronary stents in vivo by pyrolysis-gas chromatography/mass spectrometry.

    Science.gov (United States)

    Kamberi, Marika; Pinson, David; Pacetti, Stephen; Perkins, Laura E L; Hossainy, Syed; Mori, Hiroyoshi; Rapoza, Richard J; Kolodgie, Frank; Virmani, Renu

    2017-09-07

    The polymers poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) and poly(n-butyl methacrylate) (PBMA) are employed in manufacturing the XIENCE family of coronary stents. PBMA serves as a primer and adheres to both the stent and the drug coating. PVDF-HFP is employed in the drug matrix layer to hold the drug everolimus on the stent and control its release. Chemical stability of the polymers of XIENCE stents in the in-vivo environment was evaluated by pyrolysis-gas chromatography with mass spectrometry (Py-GC/MS) detection. For this evaluation, XIENCE stents explanted from porcine coronary arteries and from human coronary artery specimens at autopsy after 2-4 and 5-7 years of implantation, respectively, were compared to freshly manufactured XIENCE stents (controls). The comparison of pyrograms of explanted stent samples and controls showed identical fragmentation fingerprints of polymers, indicating that PVDF-HFP and PBMA maintained their chemical integrity after multiple years of XIENCE coronary stent implantation. The findings of the present study demonstrate the chemical stability of PVDF-HFP and PBMA polymers of the XIENCE family of coronary stents in the in-vivo environment, and constitute a further proof of the suitability of PVDF-HFP as a drug carrier for the drug eluting stent applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2017. © 2017 Wiley Periodicals, Inc.

  19. Everolimus plus exemestane as first-line therapy in HR⁺, HER2⁻ advanced breast cancer in BOLERO-2.

    Science.gov (United States)

    Beck, J Thaddeus; Hortobagyi, Gabriel N; Campone, Mario; Lebrun, Fabienne; Deleu, Ines; Rugo, Hope S; Pistilli, Barbara; Masuda, Norikazu; Hart, Lowell; Melichar, Bohuslav; Dakhil, Shaker; Geberth, Matthias; Nunzi, Martina; Heng, Daniel Y C; Brechenmacher, Thomas; El-Hashimy, Mona; Douma, Shyanne; Ringeisen, Francois; Piccart, Martine

    2014-02-01

    The present exploratory analysis examined the efficacy, safety, and quality-of-life effects of everolimus (EVE) + exemestane (EXE) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting. In BOLERO-2, patients with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor (NSAI) were randomly assigned (2:1) to receive EVE (10 mg/day) + EXE (25 mg/day) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local assessment. Overall, 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37). Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE (hazard ratio = 0.39; 95 % CI 0.25-0.62), while maintaining quality of life. This was confirmed by central assessment (15.2 vs 4.2 months; hazard ratio = 0.32; 95 % CI 0.18-0.57). The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting. Furthermore, the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR(+), HER2(-) advanced breast cancer in postmenopausal patients.

  20. ELEVATE: an innovative study design to assess the efficacy, safety, and evolution of cardiovascular parameters in de novo kidney transplant recipients after early conversion from a calcineurin inhibitor to everolimus

    Directory of Open Access Journals (Sweden)

    van der Giet M

    2014-03-01

    Full Text Available Markus van der Giet,1 Josep M Cruzado,2 Johan W de Fijter,3 Hallvard Holdaas,4 Zailong Wang,5 Antonio Speziale,6 Guido Junge61Department of Nephrology, Campus Benjamin Franklin, Charite'-Universitätsmedizin, Berlin, Germany; 2Department of Nephrology, University Hospital of Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain; 3Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; 4Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 5Biometrics and Statistical Science, Novartis Pharmaceuticals, East Hanover, NJ, USA; 6Research and Development, Novartis Pharma AG, Basel, SwitzerlandAbstract: Progressive decline in allograft function and cardiovascular mortality after kidney transplantation remain major clinical challenges that can potentially be addressed by the mammalian target of rapamycin (mTOR inhibitors, everolimus and sirolimus. mTOR inhibitors maintain immunosuppressive efficacy after minimization of calcineurin inhibitor (CNI therapy and can achieve significant long-term improvements in renal function. Recently, data have accumulated that suggest mTOR inhibitors may offer cardioprotective effects. In animal models, inhibition of mTOR leads to regression of cardiac hypertrophy, and the limited data consistently point to a remodeling benefit following heart transplantation. Experimentally, mTOR inhibitors restrict atherogenesis, confirmed clinically by intravascular ultrasound data demonstrating lower rates of transplant vasculopathy in heart transplant recipients on everolimus. Lastly, mTOR inhibitors appear to ameliorate arterial stiffness, a known risk factor for post-transplant cardiovascular events, but data remain sparse. The ELEVATE study will examine the renal effect of early conversion from CNI therapy to everolimus after kidney transplantation. Key secondary endpoints include the change in left ventricular mass index, the first time

  1. The REMEDEE-OCT Study: An Evaluation of the Bioengineered COMBO Dual-Therapy CD34 Antibody-Covered Sirolimus-Eluting Coronary Stent Compared With a Cobalt-Chromium Everolimus-Eluting Stent in Patients With Acute Coronary Syndromes: Insights From Optical Coherence Tomography Imaging Analysis

    NARCIS (Netherlands)

    Jaguszewski, Milosz; Aloysius, Romila; Wang, Wei; Bezerra, Hiram G.; Hill, Jonathan; de Winter, Robbert J.; Karjalainen, Pasi P.; Verheye, Stefan; Wijns, William; Lüscher, Thomas F.; Joner, Michael; Costa, Marco; Landmesser, Ulf

    2017-01-01

    The aim of the present study was to evaluate vascular healing of the bioengineered COMBO Dual Therapy Stent compared with a cobalt-chromium (CoCr) everolimus-eluting stent (EES) as assessed by optical coherence tomography in patients with acute coronary syndromes. CD34+ cells promote endothelial

  2. Bioresorbable Everolimus-Eluting Vascular Scaffold for Patients With Peripheral Artery Disease (ESPRIT I): 2-Year Clinical and Imaging Results.

    Science.gov (United States)

    Lammer, Johannes; Bosiers, Marc; Deloose, Koen; Schmidt, Andrej; Zeller, Thomas; Wolf, Florian; Lansink, Wouter; Sauguet, Antoine; Vermassen, Frank; Lauwers, Geert; Scheinert, Dierk; Popma, Jeffrey J; McGreevy, Robert; Rapoza, Richard; Schwartz, Lewis B; Jaff, Michael R

    2016-06-13

    This is the first-in-human study of a drug-eluting bioresorbable vascular scaffold (BVS) for treatment of peripheral artery disease (PAD) involving the external iliac artery (EIA) and superficial femoral artery (SFA). Drug-eluting BVS has shown promise in coronary arteries. The ESPRIT BVS system is a device-drug combination consisting of an everolimus-eluting poly-l-lactide scaffold. Safety and performance were evaluated in 35 subjects with symptomatic claudication. Lesions were located in the SFA (88.6%) and EIA (11.4%). Mean lesion length was 35.7 ± 16.0 mm. The study device was successfully deployed in 100% of cases, without recoil. Procedure-related minor complications were observed in 3 patients (groin hematoma, dissection). Within 2 years there was 1 unrelated death, but no patients in this cohort had an amputation. At 1 and 2 years, the binary restenosis rates were 12.1% and 16.1%, respectively, and target lesion revascularization was performed in 3 of 34 patients (8.8%) and 4 of 32 patients (11.8%), respectively. The ankle brachial index 0.75 ± 0.14 improved from pre-procedure to 0.96 ± 0.16 at 2 years' follow-up. At 2 years, 71.0% of the patients were Rutherford-Becker 0, and 93.5% achieved a maximum walking distance of 1,500 feet. The safety of the ESPRIT BVS was demonstrated with no procedure or device-related deaths or amputations within 2 years. The low occurrence of revascularizations was consistent with duplex-ultrasonography showing sustained patency at 2-years. (A Clinical Evaluation of the Abbott Vascular ESPRIT BVS [Bioresorbable Vascular Scaffold] System [ESPRIT I]; NCT01468974). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  3. Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen.

    Directory of Open Access Journals (Sweden)

    Gianluigi Zaza

    Full Text Available The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined.We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group, and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group.A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05. Flagellar motor switch protein (fliNY and type IV pilus assembly protein pilM (pilM were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity.Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this objective.

  4. Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen.

    Science.gov (United States)

    Zaza, Gianluigi; Dalla Gassa, Alessandra; Felis, Giovanna; Granata, Simona; Torriani, Sandra; Lupo, Antonio

    2017-01-01

    The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined. We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group), and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group). A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity) at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05). Flagellar motor switch protein (fliNY) and type IV pilus assembly protein pilM (pilM) were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA) was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity. Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this objective.

  5. Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen

    Science.gov (United States)

    Dalla Gassa, Alessandra; Felis, Giovanna; Granata, Simona; Torriani, Sandra; Lupo, Antonio

    2017-01-01

    Background The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined. Methods We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group), and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group). Results A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity) at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05). Flagellar motor switch protein (fliNY) and type IV pilus assembly protein pilM (pilM) were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA) was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity. Conclusions Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this

  6. Paclitaxel-eluting stents versus everolimus-eluting coronary stents in a diabetic population: two-year follow-up of the TUXEDO-India trial.

    Science.gov (United States)

    Kaul, Upendra; Bhagwat, Ajit; Pinto, Brian; Goel, Praveen K; Jagtap, Prashant; Sathe, Shireesh; Wander, Gurpreet S; Arambam, Priyadarshini; Bangalore, Sripal

    2017-11-20

    The aim of this study was to report whether the superiority of the everolimus-eluting stent (EES) vs. the paclitaxel-eluting stent (PES) at one-year follow-up in the Taxus Element versus Xience Prime in a Diabetic Population (TUXEDO)-India trial was sustained at longer-term follow-up. One thousand eight hundred and thirty (1,830) patients with diabetes mellitus and coronary artery disease were randomised to EES vs. PES. Follow-up data up to two years were available in 1,701 (92.9%) patients. The primary endpoint was target vessel failure (TVF), defined as the composite of cardiac death, target vessel myocardial infarction (TV-MI), or ischaemia-driven target vessel revascularisation (TVR). Treatment with EES had a lower two-year rate of TVF (4.3% vs. 6.6%, p=0.03). Of the secondary endpoints, EES significantly reduced any MI (1.6% vs. 3.5%, p=0.01), TV-MI (0.7% vs. 3.1%, p=0.0001), ST (0.4% vs. 2.2%, p=0.001), cardiac death or target vessel MI (2.9% vs. 4.8%, p=0.04) and TLR (1.9% vs. 3.7%, p=0.02), compared with PES. Between one year and two years, no significant differences in the clinical outcomes were observed (pinteraction >0.05). In this adequately powered trial, the benefits of EES vs. PES in a diabetic population seen at one year were maintained at two years.

  7. Percutaneous coronary intervention with second-generation paclitaxel-eluting stents versus everolimus-eluting stents in United States contemporary practice (REWARDS TLX Trial).

    Science.gov (United States)

    Waksman, Ron; Ghali, Magdi; Goodroe, Randy; Ryan, Thomas; Turco, Mark; Ring, Michael; McGarry, Thomas; Dobies, David; Shammas, Nicolas; Steinberg, Daniel H; Swymelar, Stacy; Kaneshige, Kimberly; Torguson, Rebecca

    2012-10-15

    Registry Experience at the Washington Hospital Center, DES - Taxus Liberte Versus Xience V (REWARDS TLX) is a physician-initiated, retrospective, real-world, multicenter, observational study for all patients >18 years of age subjected to percutaneous coronary intervention with everolimus-eluting stents (EESs) or paclitaxel-eluting stents (PESs). Outcomes of patients receiving a TAXUS Liberté or XIENCE V drug-eluting stent were compared. Baseline clinical, procedural, and follow-up data at 12 months were collected from 10 clinical centers by an electronic data capture system. The study's primary end point was major adverse cardiac events: a composite of all-cause death, Q-wave myocardial infarction, target vessel revascularization, and stent thrombosis. The trial is registered with http://www.clinicaltrials.gov (NCT01134159). Data were entered for 1,195 patients (PES, n = 595; EES, n = 600). Baseline clinical characteristics were similar except for higher dyslipidemia, systemic hypertension, and family history of coronary artery disease in the EES group. In-hospital outcome was similar between groups, with an overall in-hospital stent thrombosis rate of 0.2%. The primary end point at 12 months was similar (EES 7.8% vs 10.8%, p = 0.082). Overall stent thrombosis rate was lower in the EES group (0.3% vs 1.2%, respectively, p = 0.107); however, target lesion revascularization was similar (PES, hazard ratio 1.46, 95% confidence interval 0.98 to 2.19, p = 0.064). There was no difference in overall mortality between groups. In conclusion, second-generation EESs and PESs demonstrated similar efficacy and safety profiles for broadened patient and lesion subsets compared to a selected population from the pivotal trials. However, for composite efficacy and safety end points, EESs outperformed second-generation PESs. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2.

    Science.gov (United States)

    Noguchi, Shinzaburo; Masuda, Norikazu; Iwata, Hiroji; Mukai, Hirofumi; Horiguchi, Jun; Puttawibul, Puttisak; Srimuninnimit, Vichien; Tokuda, Yutaka; Kuroi, Katsumasa; Iwase, Hirotaka; Inaji, Hideo; Ohsumi, Shozo; Noh, Woo-Chul; Nakayama, Takahiro; Ohno, Shinji; Rai, Yoshiaki; Park, Byeong-Woo; Panneerselvam, Ashok; El-Hashimy, Mona; Taran, Tetiana; Sahmoud, Tarek; Ito, Yoshinori

    2014-11-01

    The addition of mTOR inhibitor everolimus (EVE) to exemestane (EXE) was evaluated in an international, phase 3 study (BOLERO-2) in patients with hormone-receptor-positive (HR(+)) breast cancer refractory to letrozole or anastrozole. The safety and efficacy of anticancer treatments may be influenced by ethnicity (Sekine et al. in Br J Cancer 99:1757-62, 2008). Safety and efficacy results from Asian versus non-Asian patients in BOLERO-2 are reported. Patients were randomized (2:1) to 10 mg/day EVE + EXE or placebo (PBO) + EXE. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, clinical benefit rate, and safety. Of 143 Asian patients, 98 received EVE + EXE and 45 received PBO + EXE. Treatment with EVE + EXE significantly improved median PFS versus PBO + EXE among Asian patients by 38 % (HR = 0.62; 95 % CI, 0.41-0.94). Median PFS was also improved among non-Asian patients by 59 % (HR = 0.41; 95 % CI, 0.33-0.50). Median PFS duration among EVE-treated Asian patients was 8.48 versus 4.14 months for PBO + EXE, and 7.33 versus 2.83 months, respectively, in non-Asian patients. The most common grade 3/4 adverse events (stomatitis, anemia, elevated liver enzymes, hyperglycemia, and dyspnea) occurred at similar frequencies in Asian and non-Asian patients. Grade 1/2 interstitial lung disease occurred more frequently in Asian patients. Quality of life was similar between treatment arms in Asian patients. Adding EVE to EXE provided substantial clinical benefit in both Asian and non-Asian patients with similar safety profiles. This combination represents an improvement in the management of postmenopausal women with HR(+)/HER2(-) advanced breast cancer progressing on nonsteroidal aromatase inhibitors, regardless of ethnicity.

  9. Safety and efficacy of everolimus-eluting stents compared with first-generation drug-eluting stents in patients undergoing primary percutaneous coronary intervention

    Energy Technology Data Exchange (ETDEWEB)

    Escárcega, Ricardo O.; Baker, Nevin C.; Magalhaes, Marco A.; Lipinski, Michael J.; Minha, Sa’ar; Torguson, Rebecca; Satler, Lowell F.; Pichard, Augusto D.; Suddath, William O.; Waksman, Ron, E-mail: ron.waksman@medstar.net

    2014-09-15

    Objective: To assess the safety and efficacy everolimus-eluting stents (EES) compared with first-generation drug-eluting stents (DES) in patients with acute myocardial infarction (MI) undergoing primary percutaneous coronary intervention (PCI). Background: EES have been associated with improved clinical outcomes compared to paclitaxel-eluting stents (PES) and with similar outcomes compared to sirolimus-eluting stents (SES). Methods: A total of 520 patients who presented with ST-elevation myocardial infarction (STEMI) from 2003 to 2013, who underwent primary PCI with DES, were retrospectively analyzed. Of these, 247 received SES, 136 PES, and 137 EES. Patients were followed up to 2 years for major adverse cardiac events (MACE). Univariate and multivariate models detected correlates to outcome. Results: EES implantation, compared with PES and SES, resulted in comparable rates of MACE (8.8% vs. 16.2%, p = 0.06 and 8.8% vs. 12.6%, respectively, p = 0.26), stent thrombosis, MI, and target lesion revascularization. Patients who received EES had lower rates of all-cause mortality (3.7% vs. 12.6% vs. 9.4%, p = 0.03) at 1-year follow up. However, in the univariate and multivariate analyses, stent type was not independently associated with the primary outcome or with all-cause mortality. Diabetes mellitus and number of stents implanted were independently associated with the primary outcome. Conclusion: While EES seem to be associated with better outcome when compared to PES, the main correlates of STEMI patients are the presence of diabetes and number of stents implanted, and not the type of stent used for intervention.

  10. Everolimus plus exemestane versus bevacizumab-based chemotherapy for second-line treatment of hormone receptor-positive metastatic breast cancer in Greece: An economic evaluation study.

    Science.gov (United States)

    Kourlaba, Georgia; Rapti, Vasiliki; Alexopoulos, Athanasios; Relakis, John; Koumakis, Georgios; Chatzikou, Magdalini; Maniadakis, Nikos; Georgoulias, Vassilis

    2015-08-05

    The objective of our study was to conduct a cost-effectiveness (CE) study of combined everolimus (EVE) and exemestane (EXE) versus the common clinical practice in Greece for the treatment of postmenopausal women with HR+/HER2- advanced breast cancer (BC) progressing on nonsteroidal aromatase inhibitors (NSAI). The combinations of bevacizumab (BEV) plus paclitaxel (PACL) and BEV plus capecitabine (CAPE) were selected as comparators. A Markov model, consisting of three health states, was used to describe disease progression and evaluate the CE of the comparators from a third-party payer perspective over a lifetime horizon. Efficacy and safety data as well as utility values considered in the model were extracted from the relevant randomized Phase III clinical trials and other published studies. Direct medical costs referring to the year 2014 were incorporated in the model. A probabilistic sensitivity analysis was conducted to account for uncertainty and variation in the parameters of the model. Primary outcomes were patient survival (life-years), quality-adjusted life years (QALYs), total direct costs and incremental cost-effectiveness ratios (ICER). The discounted quality-adjusted survival of patients treated with EVE plus EXE was greater by 0.035 and 0.004 QALYs, compared to BEV plus PACL and BEV plus CAPE, respectively. EVE plus EXE was the least costly treatment in terms of drug acquisition, administration, and concomitant medications. The total lifetime cost per patient was estimated at €55,022, €67,980, and €62,822 for EVE plus EXE, BEV plus PACL, and BEV plus CAPE, respectively. The probabilistic analysis confirmed the deterministic results. Our results suggest that EVE plus EXE may be a dominant alternative relative to BEV plus PACL and BEV plus CAPE for the treatment of HR+/HER2- advanced BC patients failing initial therapy with NSAIs.

  11. Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor-positive breast cancer in BOLERO-2.

    Science.gov (United States)

    Pritchard, Kathleen I; Burris, Howard A; Ito, Yoshinori; Rugo, Hope S; Dakhil, Shaker; Hortobagyi, Gabriel N; Campone, Mario; Csöszi, Tibor; Baselga, José; Puttawibul, Puttisak; Piccart, Martine; Heng, Daniel; Noguchi, Shinzaburo; Srimuninnimit, Vichien; Bourgeois, Hugues; Gonzalez Martin, Antonio; Osborne, Karen; Panneerselvam, Ashok; Taran, Tetiana; Sahmoud, Tarek; Gnant, Michael

    2013-12-01

    Postmenopausal women with hormone receptor-positive (HR(+)) breast cancer in whom disease progresses or there is recurrence while taking a nonsteroidal aromatase inhibitor (NSAI) are usually treated with exemestane (EXE), but no single standard of care exists in this setting. The BOLERO-2 trial demonstrated that adding everolimus (EVE) to EXE improved progression-free survival (PFS) while maintaining quality of life when compared with EXE alone. Because many women with HR(+) advanced breast cancer are elderly, the tolerability profile of EVE plus EXE in this population is of interest. BOLERO-2, a phase III randomized trial, compared EVE (10 mg/d) and placebo (PBO), both plus EXE (25 mg/d), in 724 postmenopausal women with HR(+) advanced breast cancer recurring/progressing after treatment with NSAIs. Safety and efficacy data in elderly patients are reported at 18-month median follow-up. Baseline disease characteristics and treatment histories among the elderly subsets (≥ 65 years, n = 275; ≥ 70 years, n = 164) were generally comparable with younger patients. The addition of EVE to EXE improved PFS regardless of age (hazard ratio, 0.59 [≥ 65 years] and 0.45 [≥ 70 years]). Adverse events (AEs) of special interest (all grades) that occurred more frequently with EVE than with PBO included stomatitis, infections, rash, pneumonitis, and hyperglycemia. Elderly EVE-treated patients had similar incidences of these AEs as did younger patients but had more on-treatment deaths. Adding EVE to EXE offers substantially improved PFS over EXE and was generally well tolerated in elderly patients with HR(+) advanced breast cancer. Careful monitoring and appropriate dose reductions or interruptions for AE management are recommended during treatment with EVE in this patient population. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Absorb bioresorbable vascular scaffold versus everolimus-eluting metallic stent in ST-segment elevation myocardial infarction: 1-year results of a propensity score matching comparison: the BVS-EXAMINATION Study (bioresorbable vascular scaffold-a clinical evaluation of everolimus eluting coronary stents in the treatment of patients with ST-segment elevation myocardial infarction).

    Science.gov (United States)

    Brugaletta, Salvatore; Gori, Tommaso; Low, Adrian F; Tousek, Petr; Pinar, Eduardo; Gomez-Lara, Josep; Scalone, Giancarla; Schulz, Eberhard; Chan, Mark Y; Kocka, Viktor; Hurtado, Jose; Gomez-Hospital, Juan Antoni; Münzel, Thomas; Lee, Chi-Hang; Cequier, Angel; Valdés, Mariano; Widimsky, Petr; Serruys, Patrick W; Sabaté, Manel

    2015-01-01

    The purpose of this study was to compare the 1-year outcome between bioresorbable vascular scaffold (BVS) and everolimus-eluting metallic stent (EES) in ST-segment elevation myocardial infarction (STEMI) patients. The Absorb BVS (Abbott Vascular, Santa Clara, California) is a polymeric scaffold approved for treatment of stable coronary lesions. Limited and not randomized data are available on its use in ST-segment elevation myocardial infarction (STEMI) patients. This study included 290 consecutive STEMI patients treated by BVS, compared with either 290 STEMI patients treated with EES or 290 STEMI patients treated with bare-metal stents (BMS) from the EXAMINATION (A Clinical Evaluation of Everolimus Eluting Coronary Stents in the Treatment of Patients With ST-segment Elevation Myocardial Infarction) trial, by applying propensity score matching. The primary endpoint was a device-oriented endpoint (DOCE), including cardiac death, target vessel myocardial infarction, and target lesion revascularization, at 1-year follow-up. Device thrombosis, according to the Academic Research Consortium criteria, was also evaluated. The cumulative incidence of DOCE did not differ between the BVS and EES or BMS groups either at 30 days (3.1% vs. 2.4%, hazard ratio [HR]: 1.31 [95% confidence interval (CI): 0.48 to 3.52], p = 0.593; vs. 2.8%, HR: 1.15 [95% CI: 0.44 to 2.30], p = 0.776, respectively) or at 1 year (4.1% vs. 4.1%, HR: 0.99 [95% CI: 0.23 to 4.32], p = 0.994; vs. 5.9%, HR: 0.50 [95% CI: 0.13 to 1.88], p = 0.306, respectively). Definite/probable BVS thrombosis rate was numerically higher either at 30 days (2.1% vs. 0.3%, p = 0.059; vs. 1.0%, p = 0.324, respectively) or at 1 year (2.4% vs. 1.4%, p = 0.948; vs. 1.7%, p = 0.825, respectively), as compared with EES or BMS. At 1-year follow-up, STEMI patients treated with BVS showed similar rates of DOCE compared with STEMI patients treated with EES or BMS, although rate of scaffolds thrombosis, mostly clustered in the early phase

  13. Biodegradable Polymer Biolimus-Eluting Stents Versus Durable Polymer Everolimus-Eluting Stents in Patients With Coronary Artery Disease: Final 5-Year Report From the COMPARE II Trial (Abluminal Biodegradable Polymer Biolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent).

    Science.gov (United States)

    Vlachojannis, Georgios J; Smits, Pieter C; Hofma, Sjoerd H; Togni, Mario; Vázquez, Nicolás; Valdés, Mariano; Voudris, Vassilis; Slagboom, Ton; Goy, Jean-Jaques; den Heijer, Peter; van der Ent, Martin

    2017-06-26

    This analysis investigates the 5-year outcomes of the biodegradable polymer biolimus-eluting stent (BP-BES) and durable polymer everolimus-eluting stent (DP-EES) in an all-comers population undergoing percutaneous coronary intervention. Recent 1- and 3-year results from randomized trials have indicated similar safety and efficacy outcomes of BP-BES and DP-EES. Whether benefits of the biodegradable polymer device arise over longer follow-up is unknown. Moreover, in-depth, prospective, long-term follow-up data on metallic drug-eluting stents with durable or biodegradable polymers are scarce. The COMPARE II trial (Abluminal Biodegradable Polymer Biolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent) was a prospective, randomized, multicenter, all-comers trial in which 2,707 patients were randomly allocated (2:1) to BP-BES or DP-EES. The pre-specified endpoint at 5 years was major adverse cardiac events, a composite of cardiac death, nonfatal myocardial infarction, or target vessel revascularization. Five-year follow-up was available in 2,657 patients (98%). At 5 years, major adverse cardiac events occurred in 310 patients (17.3%) in the BP-BES group and 142 patients (15.6%) in the DP-EES group (p = 0.26). The rate of the combined safety endpoint all-cause death or myocardial infarction was 15.0% in the BP-BES group versus 14.8% in the DP-EES group (p = 0.90), whereas the efficacy measure target vessel revascularization was 10.6% versus 9.0% (p = 0.18), respectively. Interestingly, definite stent thrombosis rates did not differ between groups (1.5% for BP-BES vs. 0.9% for DP-EES; p = 0.17). The 5-year analysis comparing biodegradable polymer-coated BES and the durable polymer-coated EES confirms the initial early- and mid-term results regarding similar safety and efficacy outcomes in this all-comers percutaneous coronary intervention population. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights

  14. Outcome of everolimus eluting bioabsorbable vascular scaffold (BVS) compared to non BVS drug eluting stent in the management of ST-segment elevation myocardial infarction (STEMI) — A comparative study

    Energy Technology Data Exchange (ETDEWEB)

    Chakraborty, Rabin; Patra, Soumya, E-mail: dr_soumyapatra@rediffmail.com; Banerjee, Suvro; Pande, Arindam; Khan, Aftab; Mandol, Prakash Chandra; Ghosh, Debashish; De, Swapan Kumar; Das, Sankha Subhro; Nag, Raja

    2016-04-15

    Background: The safety and efficacy of everolimus eluting bioabsorbable vascular scaffold (BVS) in the management of “ST” segment elevation myocardial infarction (STEMI) are yet to be established. Aims: To evaluate immediate and short term safety and efficacy of the everolimus-eluting ABSORB BVS compared with non BVS drug eluting stent (DES) in patients with STEMI. Methods: From December 2013 to December 2014, 220 patients with STEMI were included in this study. Among them, 35 patients treated with BVS were compared with a control group composed of 180 patients who underwent non BVS DES implantation in the same time period. The incidence of major adverse cardiac events (MACE: stent thrombosis: death, non-fatal myocardial infarction, or target vessel/lesion revascularization) before discharge and up to six months was evaluated. Results: 1 vessel disease was more frequent whereas, 2 and 3 vessel disease was less frequent in BVS group. Procedural characteristics were also similar between groups, except for the use of post dilation (p = 0.04). Procedural success, in-hospital, and up to six-month MACE rates were similar between both groups. Definite or probable stent thrombosis did not occur (according to the ARC criteria) in BVS patients, though two patients during the index admission and another two patients in the first month after DES implantation had stent thrombosis. Conclusion: The use of the ABSORB BVS for STEMI is feasible and associated with good procedural safety, and angiographic success rate.

  15. Outcome of everolimus eluting bioabsorbable vascular scaffold (BVS) compared to non BVS drug eluting stent in the management of ST-segment elevation myocardial infarction (STEMI) — A comparative study

    International Nuclear Information System (INIS)

    Chakraborty, Rabin; Patra, Soumya; Banerjee, Suvro; Pande, Arindam; Khan, Aftab; Mandol, Prakash Chandra; Ghosh, Debashish; De, Swapan Kumar; Das, Sankha Subhro; Nag, Raja

    2016-01-01

    Background: The safety and efficacy of everolimus eluting bioabsorbable vascular scaffold (BVS) in the management of “ST” segment elevation myocardial infarction (STEMI) are yet to be established. Aims: To evaluate immediate and short term safety and efficacy of the everolimus-eluting ABSORB BVS compared with non BVS drug eluting stent (DES) in patients with STEMI. Methods: From December 2013 to December 2014, 220 patients with STEMI were included in this study. Among them, 35 patients treated with BVS were compared with a control group composed of 180 patients who underwent non BVS DES implantation in the same time period. The incidence of major adverse cardiac events (MACE: stent thrombosis: death, non-fatal myocardial infarction, or target vessel/lesion revascularization) before discharge and up to six months was evaluated. Results: 1 vessel disease was more frequent whereas, 2 and 3 vessel disease was less frequent in BVS group. Procedural characteristics were also similar between groups, except for the use of post dilation (p = 0.04). Procedural success, in-hospital, and up to six-month MACE rates were similar between both groups. Definite or probable stent thrombosis did not occur (according to the ARC criteria) in BVS patients, though two patients during the index admission and another two patients in the first month after DES implantation had stent thrombosis. Conclusion: The use of the ABSORB BVS for STEMI is feasible and associated with good procedural safety, and angiographic success rate.

  16. Zotarolimus-eluting Resolute Integrity versus everolimus-eluting Xience Xpedition stents in the management of very long (>30 mm) de novo coronary artery stenosis

    Energy Technology Data Exchange (ETDEWEB)

    Patra, Soumya, E-mail: dr_soumyapatra@rediffmail.com; Chakraborty, Rabindra Nath; Pande, Arindam; Banerjee, Suvro; Jena, Manabhanjan; Mandal, Prakash Chandra; De, Swapan Kumar; Khan, Aftab; Das, Sankha Suvro; Ghosh, Debashish; Nag, Raja

    2017-04-15

    Background: Procedural and clinical outcomes in patients with very long (>30 mm) coronary lesions who underwent stent-based percutaneous coronary interventions are still unfavorable. Therefore, we compared the relative efficacy and safety of resolute zotarolimus-eluting stents (R-ZES) and Xpedition everolimus-eluting stents (X-EES) for patients with de novo very long coronary lesions. Methods: This comparative single-centre, retrospective study compared long R-ZES and X-EES in consecutive patients admitted with very long (≥30 mm) native ACC/AHA type C coronary lesions in 2014. All patients were followed up clinically at 1, 3, 6 and 12 months. In this study, only symptom-driven angiogram was advised. The study end point was to evaluate immediate procedural success and one-year rate of target lesion failure (TLF), which is a composite of cardiac death, target lesion myocardial infarction, or target lesion revascularization (TLR). Results: Total number of patients enrolled in this study was 185 (R-ZES = 107; X-EES = 78). The baseline characteristics and post procedural success rate were similar between R-ZES and X-EES groups, including the post stenting lesion lengths (36.6 ± 1.92 mm vs 40.71 ± 6.175 mm, P = 0.09). At 12-month follow-up, there were no significant between-group differences in the rate of adverse clinical events (death, myocardial infarction, stent thrombosis, target lesion revascularization, and composite outcomes). Procedural success was achieved in 94% in R-ZES group and 93% in X-EES group (P = 0.24). The incidence of TLF was 5% in R-ZES and 4% in X-EES groups (HR-1.25; 95% CI-0.86-5.6; P = 0.19). Conclusion: Patients with de novo long coronary artery disease, R-ZES implantation showed similar clinical outcome as compared with X-EES implantation. - Highlights: • This is the first study comparing between R-ZES (Resolute Integrity) and X-EES (Xience Xpedition) used in PCI for long coronary artery disease. Here, single stent length of more than 30

  17. Quality-of-Life After Everolimus-Eluting Stents or Bypass Surgery for Left-Main Disease: Results From the EXCEL Trial.

    Science.gov (United States)

    Baron, Suzanne J; Chinnakondepalli, Khaja; Magnuson, Elizabeth A; Kandzari, David E; Puskas, John D; Ben-Yehuda, Ori; van Es, Gerrit-Anne; Taggart, David P; Morice, Marie-Claude; Lembo, Nicholas J; Brown, W Morris; Banning, Adrian; Simonton, Charles A; Kappetein, A Pieter; Sabik, Joseph F; Serruys, Patrick W; Stone, Gregg W; Cohen, David J

    2017-12-26

    The EXCEL (Evaluation of Xience Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial compared outcomes in patients with unprotected left main coronary artery disease (LMCAD) treated with coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) using everolimus-eluting stents. Whereas rates of death, stroke, and myocardial infarction were similar at 36 months, event timing and repeat revascularization rates differed by treatment group. To understand the effects of revascularization strategy from the patient's perspective, a prospective quality of life (QoL) substudy was performed alongside the EXCEL trial. Between September 2010 and March 2014, 1,905 patients with LMCAD were randomized to undergo CABG or PCI, of whom 1,788 participated in the QoL substudy. QoL was assessed at baseline and 1, 12, and 36 months using the Seattle Angina Questionnaire, the 12-Item Short Form Health Survey, the Rose Dyspnea Scale, the Patient Health Questionnaire-8, and the EQ-5D. Differences between PCI and CABG were assessed using longitudinal random-effect growth curve models. Over 36 months, both PCI and CABG were associated with significant improvements in QoL compared with baseline. At 1 month, PCI was associated with better QoL than CABG. By 12 months though, these differences were largely attenuated, and by 36 months, there were no significant QoL differences between PCI and CABG. Among selected patients with LMCAD, both PCI and CABG result in similar QoL improvement through 36 months, although a greater early benefit is seen with PCI. Taken together with the 3-year clinical results of EXCEL, these findings suggest that PCI and CABG provide similar intermediate-term outcomes for patients with LMCAD. (Evaluation of Xience Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization [EXCEL]; NCT01205776). Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier

  18. Biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents for primary percutaneous coronary revascularisation of acute myocardial infarction.

    Science.gov (United States)

    Pilgrim, Thomas; Piccolo, Raffaele; Heg, Dik; Roffi, Marco; Tüller, David; Vuilliomenet, André; Muller, Olivier; Cook, Stéphane; Weilenmann, Daniel; Kaiser, Christoph; Jamshidi, Peiman; Khattab, Ahmed A; Taniwaki, Masanori; Rigamonti, Fabio; Nietlispach, Fabian; Blöchlinger, Stefan; Wenaweser, Peter; Jüni, Peter; Windecker, Stephan

    2016-12-10

    Our aim was to compare the safety and efficacy of a novel, ultrathin strut, biodegradable polymer sirolimus-eluting stent (BP-SES) with a thin strut, durable polymer everolimus-eluting stent (DP-EES) in a pre-specified subgroup of patients with acute ST-segment elevation myocardial infarction (STEMI) enrolled in the BIOSCIENCE trial. The BIOSCIENCE trial is an investigator-initiated, single-blind, multicentre, randomised non-inferiority trial (NCT01443104). Randomisation was stratified according to the presence or absence of STEMI. The primary endpoint, target lesion failure (TLF), is a composite of cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularisation within 12 months. Between February 2012 and May 2013, 407 STEMI patients were randomly assigned to treatment with BP-SES or DP-EES. At one year, TLF occurred in seven (3.4%) patients treated with BP-SES and 17 (8.8%) patients treated with DP-EES (RR 0.38, 95% CI: 0.16-0.91, p=0.024). Rates of cardiac death were 1.5% in the BP-SES group and 4.7% in the DP-EES group (RR 0.31, 95% CI: 0.08-1.14, p=0.062); rates of target vessel myocardial infarction were 0.5% and 2.6% (RR 0.18, 95% CI: 0.02-1.57, p=0.082), respectively, and rates of clinically indicated target lesion revascularisation were 1.5% in the BP-SES group versus 2.1% in the DP-EES group (RR 0.69, 95% CI: 0.16-3.10, p=0.631). There was no difference in the risk of definite stent thrombosis. In this pre-specified subgroup analysis, BP-SES was associated with a lower rate of target lesion failure at one year compared to DP-EES in STEMI patients. These findings require confirmation in a dedicated STEMI trial.

  19. Health-related quality of life and disease symptoms in postmenopausal women with HR(+), HER2(-) advanced breast cancer treated with everolimus plus exemestane versus exemestane monotherapy.

    Science.gov (United States)

    Campone, Mario; Beck, J Thaddeus; Gnant, Michael; Neven, Patrick; Pritchard, Kathleen I; Bachelot, Thomas; Provencher, Louise; Rugo, Hope S; Piccart, Martine; Hortobagyi, Gabriel N; Nunzi, Martina; Heng, Daniel Y C; Baselga, José; Komorowski, Anna; Noguchi, Shinzaburo; Horiguchi, Jun; Bennett, Lee; Ziemiecki, Ryan; Zhang, Jie; Cahana, Ayelet; Taran, Tetiana; Sahmoud, Tarek; Burris, Howard A

    2013-11-01

    Everolimus (EVE)+exemestane (EXE; n = 485) more than doubled median progression-free survival versus placebo (PBO) + EXE (n = 239), with a manageable safety profile and no deterioration in health-related quality-of-life (HRQOL) in patients with hormone-receptor-positive (HR(+)) advanced breast cancer (ABC) who recurred or progressed on/after nonsteroidal aromatase inhibitor (NSAI) therapy. To further evaluate EVE + EXE impact on disease burden, we conducted additional post-hoc analyses of patient-reported HRQOL. HRQOL was assessed using EORTC QLQ-C30 and QLQ-BR23 questionnaires at baseline and every 6 weeks thereafter until treatment discontinuation because of disease progression, toxicity, or consent withdrawal. Endpoints included the QLQ-C30 Global Health Status (QL2) scale, the QLQ-BR23 breast symptom (BRBS), and arm symptom (BRAS) scales. Between-group differences in change from baseline were assessed using linear mixed models with selected covariates. Sensitivity analysis using pattern-mixture models determined the effect of study discontinuation on/before week 24. Treatment arms were compared using differences of least squares mean (LSM) changes from baseline and 95% confidence intervals (CIs) at each timepoint and overall. Clinicaltrials.gov: NCT00863655. Progression-free survival, survival, response rate, safety, and HRQOL. Linear mixed models (primary model) demonstrated no statistically significant overall difference between EVE + EXE and PBO + EXE for QL2 (LSM difference = -1.91; 95% CI = -4.61, 0.78), BRBS (LSM difference = -0.18; 95% CI = -1.98, 1.62), or BRAS (LSM difference = -0.42; 95% CI = -2.94, 2.10). Based on pattern-mixture models, patients who dropped out early had worse QL2 decline on both treatments. In the expanded pattern-mixture model, EVE + EXE-treated patients who did not drop out early had stable BRBS and BRAS relative to PBO + EXE. HRQOL data were not collected after disease progression. These analyses confirm

  20. Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study.

    Science.gov (United States)

    Campone, Mario; Bachelot, Thomas; Gnant, Michael; Deleu, Ines; Rugo, Hope S; Pistilli, Barbara; Noguchi, Shinzaburo; Shtivelband, Mikhail; Pritchard, Kathleen I; Provencher, Louise; Burris, Howard A; Hart, Lowell; Melichar, Bohuslav; Hortobagyi, Gabriel N; Arena, Francis; Baselga, José; Panneerselvam, Ashok; Héniquez, Aurelia; El-Hashimyt, Mona; Taran, Tetiana; Sahmoud, Tarek; Piccart, Martine

    2013-08-01

    Everolimus (EVE; an inhibitor of mammalian target of rapamycin [mTOR]) enhances treatment options for postmenopausal women with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer (ABC) who progress on a non-steroidal aromatase inhibitor (NSAI). This is especially true for patients with visceral disease, which is associated with poor prognosis. The BOLERO-2 (Breast cancer trial of OraLEveROlimus-2) trial showed that combination treatment with EVE and exemestane (EXE) versus placebo (PBO)+EXE prolonged progression-free survival (PFS) by both investigator (7.8 versus 3.2 months, respectively) and independent (11.0 versus 4.1 months, respectively) central assessment in postmenopausal women with HR(+), HER2(-) ABC recurring/progressing during/after NSAI therapy. The BOLERO-2 trial included a substantial proportion of patients with visceral metastases (56%). Prespecified exploratory subgroup analysis conducted to evaluate the efficacy and safety of EVE+EXE versus PBO+EXE in a prospectively defined subgroup of patients with visceral metastases. At a median follow-up of 18 months, EVE+EXE significantly prolonged median PFS compared with PBO+EXE both in patients with visceral metastases (N=406; 6.8 versus 2.8 months) and in those without visceral metastases (N=318; 9.9 versus 4.2 months). Improvements in PFS with EVE+EXE versus PBO+EXE were also observed in patients with visceral metastases regardless of Eastern Cooperative Oncology Group performance status (ECOG PS). Patients with visceral metastases and ECOG PS 0 had a median PFS of 6.8 months with EVE+EXE versus 2.8 months with PBO+EXE. Among patients with visceral metastases and ECOG PS ≥1, EVE+EXE treatment more than tripled median PFS compared with PBO+EXE (6.8 versus 1.5 months). Adding EVE to EXE markedly extended PFS by ≥4 months among patients with HR(+) HER2(-) ABC regardless of the presence of visceral metastases. Copyright © 2013 The

  1. UV-visible spectroscopy as an alternative to liquid chromatography for determination of everolimus in surfactant-containing dissolution media: a useful approach based on solid-phase extraction.

    Science.gov (United States)

    Kamberi, Marika; Tran, Thu-Ngoc

    2012-11-01

    High-throughput 96-well solid phase extraction (SPE) plate with C-18 reversed phase sorbent followed by UV-visible (UV-Vis) microplate reader was applied to the analysis of hydrophobic drugs in surfactant-containing dissolution media, which are often used to evaluate the in-vitro drug release of drug eluting stents (DES). Everolimus and dissolution medium containing Triton X-405 were selected as representatives, and the appropriate SPE conditions (adsorption, washing and elution) were investigated to obtain a practical and reliable sample clean-up. It was shown that the developed SPE procedure was capable of removing interfering components (Triton X-405 and its impurities), allowing for an accurate automated spectrophotometric analysis to be performed. The proposed UV-Vis spectrophotometric method yielded equivalent results compared to a classical LC analysis method. Linear regression analysis indicated that both methods have the ability to obtain test results that are directly proportional to the concentration of analyte in the sample within the selected range of 1.0-10 μg/ml for everolimus, with a coefficient of correlation (r(2)) value of >0.998 and standard deviation of the residuals (Syx) of UV-Vis spectrophotometric method and from 98 to 102 for the HPLC method, respectively. The 95% CI of the mean recovery for the UV-Vis spectrophotometric method was 99-102% and for the HPLC method was 99-101%. No statistical difference was found between the mean recoveries of the methods (p=0.42). Hence the methods are free from interference due to Triton and other chemicals present in the dissolution medium. The variation in the amount of everolimus estimated by UV-Vis spectrophotometric and HPLC methods was ≤3.5%, and the drug release profiles obtained by both methods were found to be equivalent by evaluation with two-one-sided t-test (two-tailed, p=0.62; mean of differences, 0.17; 95% CI, 0.62-0.96) and similarity factor f2 (f2 value, 87). The excellent conformity of

  2. Economic Outcomes of Bioresorbable Vascular Scaffolds Versus Everolimus-Eluting Stents in Patients Undergoing Percutaneous Coronary Intervention: 1-Year Results From the ABSORB III Trial.

    Science.gov (United States)

    Baron, Suzanne J; Lei, Yang; Chinnakondepalli, Khaja; Vilain, Katherine; Magnuson, Elizabeth A; Kereiakes, Dean J; Ellis, Stephen G; Stone, Gregg W; Cohen, David J

    2017-04-24

    The purpose of this study was to evaluate the economic impact of the Absorb bioresorbable vascular scaffold compared with the Xience everolimus-eluting stent in patients undergoing percutaneous coronary intervention. The ABSORB III trial (Everolimus-Eluting Bioresorbable Scaffolds for Coronary Artery Disease) demonstrated that the Absorb scaffold was noninferior to the Xience stent with respect to target lesion failure at 1 year. Whether health care costs differ between the Absorb scaffold and the Xience stent is unknown. We performed a prospective health economic study alongside the ABSORB III trial, in which patients undergoing percutaneous coronary intervention for stable or unstable angina were randomized to receive the Absorb scaffold (n = 1,322) or Xience stent (n = 686). Resource use data were collected through 1 year of follow-up. Costs were assessed using resource-based accounting (for procedures), MedPAR data (for other index hospitalization costs), and Medicare reimbursements (for follow-up costs and physician fees). Initial procedural costs were higher with the Absorb scaffold than the Xience stent ($6,316 ± 1,892 vs. $6,103 ± 1,895; p = 0.02), driven mainly by greater balloon catheter use and the higher cost of the scaffold in the Absorb group. Nonetheless, index hospitalization costs ($15,035 ± 2,992 for Absorb vs. $14,903 ± 3,449 for Xience; p = 0.37) and total 1-year costs ($17,848 ± 6,110 for Absorb vs. $17,498 ± 7,411 for Xience; p = 0.29) were similar between the 2 groups. Although initial procedural costs were higher with the Absorb scaffold, there were no differences in total 1-year health care costs between the 2 cohorts. Longer term follow-up is needed to determine whether meaningful cost savings emerge after scaffold resorption. (A Clinical Evaluation of Absorb™ BVS, the Everolimus-Eluting Bioresorbable Vascular Scaffold in the Treatment of Subjects With de Novo Native Coronary Artery Lesions; NCT01751906). Copyright © 2017

  3. Long-term forecasting and comparison of mortality in the Evaluation of the Xience Everolimus Eluting Stent vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial: prospective validation of the SYNTAX Score II.

    Science.gov (United States)

    Campos, Carlos M; van Klaveren, David; Farooq, Vasim; Simonton, Charles A; Kappetein, Arie-Pieter; Sabik, Joseph F; Steyerberg, Ewout W; Stone, Gregg W; Serruys, Patrick W

    2015-05-21

    To prospectively validate the SYNTAX Score II and forecast the outcomes of the randomized Evaluation of the Xience Everolimus-Eluting Stent Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) Trial. Evaluation of the Xience Everolimus Eluting Stent vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization is a prospective, randomized multicenter trial designed to establish the efficacy and safety of percutaneous coronary intervention (PCI) with the everolimus-eluting stent compared with coronary artery bypass graft (CABG) surgery in subjects with unprotected left-main coronary artery (ULMCA) disease and low-intermediate anatomical SYNTAX scores (EXCEL, the SYNTAX Score II was prospectively applied to predict 4-year mortality in the CABG and PCI arms. The 95% prediction intervals (PIs) for mortality were computed using simulation with bootstrap resampling (10 000 times). For the entire study cohort, the 4-year predicted mortalities were 8.5 and 10.5% in the PCI and CABG arms, respectively [odds ratios (OR) 0.79; 95% PI 0.43-1.50). In subjects with low (≤22) anatomical SYNTAX scores, the predicted OR was 0.69 (95% PI 0.34-1.45); in intermediate anatomical SYNTAX scores (23-32), the predicted OR was 0.93 (95% PI 0.53-1.62). Based on 4-year mortality predictions in EXCEL, clinical characteristics shifted long-term mortality predictions either in favour of PCI (older age, male gender and COPD) or CABG (younger age, lower creatinine clearance, female gender, reduced left ventricular ejection fraction). The SYNTAX Score II indicates at least an equipoise for long-term mortality between CABG and PCI in subjects with ULMCA disease up to an intermediate anatomical complexity. Both anatomical and clinical characteristics had a clear impact on long-term mortality predictions and decision making between CABG and PCI. Published on behalf of the European Society of Cardiology. All rights reserved. © The

  4. Long-Term Results of Everolimus-Eluting Stents Versus Drug-Eluting Balloons in Patients With Bare-Metal In-Stent Restenosis: 3-Year Follow-Up of the RIBS V Clinical Trial.

    Science.gov (United States)

    Alfonso, Fernando; Pérez-Vizcayno, María José; García Del Blanco, Bruno; Otaegui, Imanol; Masotti, Mónica; Zueco, Javier; Veláquez, Maite; Sanchís, Juan; García-Touchard, Arturo; Lázaro-García, Rosa; Moreu, José; Bethencourt, Armando; Cuesta, Javier; Rivero, Fernando; Cárdenas, Alberto; Gonzalo, Nieves; Jiménez-Quevedo, Pilar; Fernández, Cristina

    2016-06-27

    The aim of this study was to compare the long-term efficacy of everolimus-eluting stents (EES) and drug-eluting balloons (DEB) in patients with bare-metal stent in-stent restenosis (ISR). The relative long-term clinical efficacy of current therapeutic modalities in patients with ISR remains unknown. The 3-year clinical follow-up (pre-specified endpoint) of patients included in the RIBS V (Restenosis Intra-Stent of Bare-Metal Stents: Drug-Eluting Balloon vs Everolimus-Eluting Stent Implantation) randomized clinical trial was analyzed. All patients were followed yearly using a pre-defined structured questionnaire. A total of 189 patients with bare-metal stent ISR were allocated to either EES (n = 94) or DEB (n = 95). Clinical follow-up at 1, 2, and 3 years was obtained in all patients (100%). Compared with patients treated with DEB, those treated with EES obtained better angiographic results, including larger minimal luminal diameter at follow-up (primary study endpoint; 2.36 ± 0.6 mm vs. 2.01 ± 0.6 mm; p 1 year) target vessel (3 [3.2%] vs. 3 [3.2%]; p = 0.95) and target lesion (1 [1%] vs. 2 [2.1%]; p = 0.54) revascularization was low and similar in the 2 arms. Rates of definite or probable stent thrombosis (1% vs. 0%) were also similar in the 2 arms. The 3-year clinical follow-up of the RIBS V clinical trial confirms the sustained safety and efficacy of EES and DEB in patients treated for bare-metal stent ISR. In this setting, EES reduce the need for target lesion revascularization at very long-term follow-up. (RIBS V [Restenosis Intra-Stent of Bare Metal Stents: Paclitaxel-Eluting Balloon vs Everolimus-Eluting Stent] [RIBS V]; NCT01239953). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  5. A sirolimus-eluting bioabsorbable polymer-coated stent (MiStent) versus an everolimus-eluting durable polymer stent (Xience) after percutaneous coronary intervention (DESSOLVE III): a randomised, single-blind, multicentre, non-inferiority, phase 3 trial.

    Science.gov (United States)

    de Winter, Robbert J; Katagiri, Yuki; Asano, Taku; Milewski, Krzysztof P; Lurz, Philipp; Buszman, Pawel; Jessurun, Gillian A J; Koch, Karel T; Troquay, Roland P T; Hamer, Bas J B; Ophuis, Ton Oude; Wöhrle, Jochen; Wyderka, Rafał; Cayla, Guillaume; Hofma, Sjoerd H; Levesque, Sébastien; Żurakowski, Aleksander; Fischer, Dieter; Kośmider, Maciej; Goube, Pascal; Arkenbout, E Karin; Noutsias, Michel; Ferrari, Markus W; Onuma, Yoshinobu; Wijns, William; Serruys, Patrick W

    2018-02-03

    MiStent is a drug-eluting stent with a fully absorbable polymer coating containing and embedding a microcrystalline form of sirolimus into the vessel wall. It was developed to overcome the limitation of current durable polymer drug-eluting stents eluting amorphous sirolimus. The clinical effect of MiStent sirolimus-eluting stent compared with a durable polymer drug-eluting stents has not been investigated in a large randomised trial in an all-comer population. We did a randomised, single-blind, multicentre, phase 3 study (DESSOLVE III) at 20 hospitals in Germany, France, Netherlands, and Poland. Eligible participants were any patients aged at least 18 years who underwent percutaneous coronary intervention in a lesion and had a reference vessel diameter of 2·50-3·75 mm. We randomly assigned patients (1:1) to implantation of either a sirolimus-eluting bioresorbable polymer stent (MiStent) or an everolimus-eluting durable polymer stent (Xience). Randomisation was done by local investigators via web-based software with random blocks according to centre. The primary endpoint was a non-inferiority comparison of a device-oriented composite endpoint (DOCE)-cardiac death, target-vessel myocardial infarction, or clinically indicated target lesion revascularisation-between the groups at 12 months after the procedure assessed by intention-to-treat. A margin of 4·0% was defined for non-inferiority of the MiStent group compared with the Xience group. All participants were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02385279. Between March 20, and Dec 3, 2015, we randomly assigned 1398 patients with 2030 lesions; 703 patients with 1037 lesions were assigned to MiStent, of whom 697 received the index procedure, and 695 patients with 993 lesions were asssigned to Xience, of whom 690 received the index procedure. At 12 months, the primary endpoint had occurred in 40 patients (5·8%) in the sirolimus-eluting stent group and in 45

  6. Efficacy and Safety of the Absorb Everolimus-Eluting Bioresorbable Scaffold for Treatment of Patients With Diabetes Mellitus: Results of the Absorb Diabetic Substudy.

    Science.gov (United States)

    Kereiakes, Dean J; Ellis, Stephen G; Kimura, Takeshi; Abizaid, Alexandre; Zhao, Weiying; Veldhof, Susan; Vu, Minh-Thien; Zhang, Zhen; Onuma, Yoshinobu; Chevalier, Bernard; Serruys, Patrick W; Stone, Gregg W

    2017-01-09

    The study sought to evaluate the efficacy and safety of the Absorb everolimus-eluting bioresorbable vascular scaffold (BVS) (Abbott Vascular, Abbott Park, Illinois) in patients with diabetes mellitus. Randomized, controlled trials have demonstrated comparable clinical outcomes following percutaneous coronary intervention with either Absorb BVS or metallic Xience everolimus-eluting stent. However, these trials lack power required to provide reliable treatment effect estimates in this high-risk population. In a pre-specified, powered analysis, patients with diabetes who received ≥1 Absorb were pooled from the ABSORB II, III, and JAPAN randomized trials and from the single arm ABSORB EXTEND registry. The study composite primary endpoint was target lesion failure (TLF) at 1 year following Absorb BVS compared with a performance goal of 12.7%. Among 754 diabetic patients included in analysis (27.3% insulin treated), the 1-year TLF rate was 8.3% (upper 1-sided 95% confidence limit: 10.1%; p = 0.0001 vs. performance goal). Scaffold thrombosis (definite or probable) was observed in 2.3% of patients. Multivariable regression identified older age, insulin treatment, and smaller pre-procedure reference vessel diameter as significant independent predictors of 1-year TLF. The Absorb diabetic substudy suggests efficacy and safety of the Absorb BVS for treatment of patients with diabetes mellitus. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  7. Drug Monographs: Atezolizumab and Everolimus.

    Science.gov (United States)

    Green, Matthew A; Waddell, J Aubrey; Solimando, Dominic A

    2016-11-01

    The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr., President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, email: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. The authors are not employees of, under contract to, recipients of funding to review products from, or in any other way affiliated with either Genentech, Inc. or Novartis Pharmaceuticals Corporation. The information presented in this review is based on published data and clinical expertise and includes information not included in the product labeling. Incorporation of such published data provides a more robust assessment of the drugs and assists pharmacists in evaluation of orders for off-label use of these agents.

  8. A randomized multicenter comparison of hybrid sirolimus-eluting stents with bioresorbable polymer versus everolimus-eluting stents with durable polymer in total coronary occlusion: rationale and design of the Primary Stenting of Occluded Native Coronary Arteries IV study

    Directory of Open Access Journals (Sweden)

    Teeuwen Koen

    2012-12-01

    Full Text Available Abstract Background Percutaneous recanalization of total coronary occlusion (TCO was historically hampered by high rates of restenosis and reocclusions. The PRISON II trial demonstrated a significant restenosis reduction in patients treated with sirolimus-eluting stents compared with bare metal stents for TCO. Similar reductions in restenosis were observed with the second-generation zotarolimus-eluting stent and everolimus-eluting stent. Despite favorable anti-restenotic efficacy, safety concerns evolved after identifying an increased rate of very late stent thrombosis (VLST with drug-eluting stents (DES for the treatment of TCO. Late malapposition caused by hypersensitivity reactions and chronic inflammation was suggested as a probable cause of these VLST. New DES with bioresorbable polymer coatings were developed to address these safety concerns. No randomized trials have evaluated the efficacy and safety of the new-generation DES with bioresorbable polymers in patients treated for TCO. Methods/Design The prospective, randomized, single-blinded, multicenter, non-inferiority PRISON IV trial was designed to evaluate the safety, efficacy, and angiographic outcome of hybrid sirolimus-eluting stents with bioresorbable polymers (Orsiro; Biotronik, Berlin, Germany compared with everolimus-eluting stents with durable polymers (Xience Prime/Xpedition; Abbott Vascular, Santa Clara, CA, USA in patients with successfully recanalized TCOs. In total, 330 patients have been randomly allocated to each treatment arm. Patients are eligible with estimated duration of TCO ≥4 weeks with evidence of ischemia in the supply area of the TCO. The primary endpoint is in-segment late luminal loss at 9-month follow-up angiography. Secondary angiographic endpoints include in-stent late luminal loss, minimal luminal diameter, percentage of diameter stenosis, in-stent and in-segment binary restenosis and reocclusions at 9-month follow-up. Additionally, optical coherence

  9. Optical coherence tomography findings after chronic total occlusion interventions: Insights from the “AngiographiC evaluation of the everolimus-eluting stent in chronic Total occlusions” (ACE-CTO) study (NCT01012869)

    Energy Technology Data Exchange (ETDEWEB)

    Sherbet, Daniel P.; Christopoulos, Georgios; Karatasakis, Aris; Danek, Barbara Anna; Kotsia, Anna; Navara, Rachita; Michael, Tesfaldet T.; Roesle, Michele; Rangan, Bavana V.; Haagen, Donald [VA North Texas Healthcare System and University of Texas Southwestern Medical Center, Dallas, TX (United States); Garcia, Santiago [Minneapolis VA Healthcare System and University of Minnesota, Minneapolis, MN (United States); Maniu, Calin [Bon Secours Health System, Suffolk, VA (United States); Pershad, Ashish [Banner Good Samaritan Medical Center, Phoenix, AZ (United States); Abdullah, Shuaib M.; Hastings, Jeffrey L.; Kumbhani, Dharam J.; Luna, Michael; Addo, Tayo; Banerjee, Subhash [VA North Texas Healthcare System and University of Texas Southwestern Medical Center, Dallas, TX (United States); Brilakis, Emmanouil S., E-mail: esbrilakis@gmail.com [VA North Texas Healthcare System and University of Texas Southwestern Medical Center, Dallas, TX (United States)

    2016-10-15

    Background: There is limited information on optical coherence tomography (OCT) findings after percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs). OCT allows high resolution imaging that can enhance understanding of the vascular response after stenting of chronically occluded vessels. Methods: The Angiographic Evaluation of the Everolimus-Eluting Stent in Chronic Total Occlusions (ACE-CTO) study collected angiographic and clinical outcomes from 100 patients undergoing CTO PCI with the everolimus-eluting stent (EES). OCT was performed 8-months post stenting in 62 patients. Every third frame was analyzed throughout the course of the stented arterial segment. Lumen contours were semi-automatically traced and stent struts were manually delineated, with automatic measurement of the strut to lumen distance. Struts on the luminal side of the lumen contour were classified as malapposed if the distance to the lumen contour exceeded 0.108 mm. Results: A total of 44,450 struts in 6047 frames were analyzed, of which 4113 9.3%, 95% confidence intervals [CI] 9.0% to 9.5%) were malapposed and 1230 (2.8%, 95% CI 2.6% to 2.9%) were uncovered. Fifty-five of 62 patients (88.7%, 95% CI 78.5% to 98.4%) had at least one malapposed stent strut and 50 patients (80.7%, 95% CI 69.2% to 88.6%) had at least one uncovered stent strut. Mean strut-intimal thickness of the apposed and malapposed struts was 0.126 ± 0.140 mm and − 0.491 ± 0.440 mm, respectively. Conclusion: High rates of stent strut malapposition and incomplete stent strut coverage were observed after CTO PCI using EES, highlighting unique challenges associated with stent implantation in CTOs. - Highlights: • Percutaneous coronary intervention with drug-eluting stents for chronic total occlusion is associated with a 40% rate of binary in-stent restenosis at 8 months • Of patients who receive a drug eluting stent for a chronic total occlusion 88.7% will have stent strut malapposition and 80.7% will

  10. Percutaneous Coronary Intervention of Left Main Disease: Pre- and Post-EXCEL (Evaluation of XIENCE Everolimus Eluting Stent Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) and NOBLE (Nordic-Baltic-British Left Main Revascularization Study) Era.

    Science.gov (United States)

    Park, Duk-Woo; Park, Seung-Jung

    2017-06-01

    For nearly half a century, coronary artery bypass grafting has been the standard treatment for patients with obstructive left main coronary artery (LMCA) disease. However, there has been considerable evolution in the field of percutaneous coronary intervention, and especially, percutaneous coronary intervention for LMCA disease has been rapidly expanded with adoption of drug-eluting stents. Some, but not all randomized trials, have shown that percutaneous coronary intervention with drug-eluting stents might be a suitable alternative for selected patients with LMCA disease instead of bypass surgery. However, none of previous trials involving early-generation drug-eluting stents was sufficiently powered and comparative trials using contemporary drug-eluting stents were limited. Recently, primary results of 2 new trials of EXCEL (Evaluation of XIENCE Everolimus Eluting Stent Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) and NOBLE (Nordic-Baltic-British Left Main Revascularization Study) were reported. However, these trials showed conflicting results, which might pose uncertainty on the optimal revascularization strategy for LMCA disease. In this article, with the incorporation of a key review on evolution of LMCA treatment, we summarize the similarity or disparity of the EXCEL and NOBLE trials, focus on how they relate to previous trials in the field, and finally speculate on how the treatment strategy may be changed or recommended for LMCA treatment. © 2017 American Heart Association, Inc.

  11. Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer.

    Science.gov (United States)

    Ribas, Ricardo; Pancholi, Sunil; Rani, Aradhana; Schuster, Eugene; Guest, Stephanie K; Nikitorowicz-Buniak, Joanna; Simigdala, Nikiana; Thornhill, Allan; Avogadri-Connors, Francesca; Cutler, Richard E; Lalani, Alshad S; Dowsett, Mitch; Johnston, Stephen R; Martin, Lesley-Ann

    2018-06-08

    Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER + ) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. A panel of ER + BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1 wt or ESR1 Y537S , modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER

  12. 3-Year Clinical Follow-Up of the RIBS IV Clinical Trial: A Prospective Randomized Study of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis in Coronary Arteries Previously Treated With Drug-Eluting Stents.

    Science.gov (United States)

    Alfonso, Fernando; Pérez-Vizcayno, María José; Cuesta, Javier; García Del Blanco, Bruno; García-Touchard, Arturo; López-Mínguez, José Ramón; Masotti, Mónica; Zueco, Javier; Cequier, Angel; Velázquez, Maite; Moreno, Raúl; Mainar, Vicente; Domínguez, Antonio; Moris, Cesar; Molina, Eduardo; Rivero, Fernando; Jiménez-Quevedo, Pilar; Gonzalo, Nieves; Fernández-Pérez, Cristina

    2018-05-28

    This study sought to compare the long-term safety and efficacy of drug-eluting balloons (DEB) and everolimus-eluting stents (EES) in patients with in-stent restenosis (ISR) of drug-eluting stents (DES). Treatment of patients with DES-ISR remains a challenge. The RIBS IV (Restenosis Intra-Stent of Drug-Eluting Stents: Drug-Eluting Balloons vs Everolimus-Eluting Stents) trial is a prospective multicenter randomized clinical trial comparing DEB and EES in patients with DES-ISR. The pre-specified comparison of the 3-year clinical outcomes obtained with these interventions is the main objective of the present study. A total of 309 patients with DES-ISR were randomized to DEB (n = 154) or EES (n = 155). At angiographic follow-up, the in-segment minimal lumen diameter was larger in the EES arm (2.03 ± 0.7 mm vs. 1.80 ± 0.6 mm; p 1 year) target lesion revascularization (2.6% vs. 4%) and target vessel revascularization (4% vs. 6.6%) was similar in the 2 arms. Rates of cardiac death (3.9% vs. 3.2%), myocardial infarction (2.6% vs. 4.5%), and stent thrombosis (1.3% vs. 2.6%) at 3 years were also similar in both arms. The 3-year clinical follow-up of this randomized clinical trial demonstrates that in patients with DES-ISR, EES reduce the need for repeat interventions compared with DEB. (Restenosis Intra-Stent of Drug-Eluting Stents: Drug-Eluting Balloons vs Everolimus-Eluting Stents [RIBS IV]; NCT01239940). Published by Elsevier Inc.

  13. Comparison of the Absorbable Polymer Sirolimus-Eluting Stent (MiStent) to the Durable Polymer Everolimus-Eluting Stent (Xience) (from the DESSOLVE I/II and ISAR-TEST-4 Studies).

    Science.gov (United States)

    Lansky, Alexandra J; Kastrati, Adnan; Edelman, Elazer R; Parise, Helen; Ng, Vivian G; Ormiston, John; Wijns, William; Byrne, Robert A

    2016-02-15

    We compared the outcomes of a novel, thin-strut, cobalt-chromium, absorbable, polymer sirolimus-eluting stent (APSES; MiStent) to the durable polymer cobalt-chromium everolimus-eluting stent (EES; Xience). A propensity-matched analysis was performed comparing data from the DES With Sirolimus and a Bioabsorbable Polymer for the Treatment of Patients With De Novo Lesions in the Native Coronary Arteries (DESSOLVE) I and II studies, evaluating the APSES to the EES arm of the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents-4 study. Target lesion failure (TLF) and its components were evaluated at 12 months and annually to 3 years; 805 patients (APSES = 153; EES = 652) were included with propensity matching in 204 patients (APSES = 102; EES = 102). APSES compared with EES had lower TLF at 1 year (3.0% vs 8.0%, p = 0.12) driven by a difference in target lesion revascularization (TLR; 1% vs 6%, p = 0.05), with no difference in target vessel myocardial infarction (p = 0.56) or stent thrombosis (p = 0.31). At 3 years, TLF (5.0% vs 12.5%, p = 0.07) and TLR (2.0% vs 8.4%, p = 0.04) remained lower with APSES. By landmark analysis, there was no significant difference in TLF between 1 and 3 years (p = 0.36). In conclusion, in a propensity-matched analysis, the APSES demonstrated reduced clinically indicated TLR rates at 1 and 3 years compared with the durable polymer EES, with minimal accrual of events between 1 and 3 years. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Morphological and functional evaluation of the bioresorption of the bioresorbable everolimus-eluting vascular scaffold using IVUS, echogenicity and vasomotion testing at two year follow-up: a patient level insight into the ABSORB A clinical trial.

    Science.gov (United States)

    Sarno, Giovanna; Bruining, Nico; Onuma, Yoshinobu; Garg, Scot; Brugaletta, Salvatore; De Winter, Sebastiaan; Regar, Evelyn; Thuesen, Leif; Dudek, Dariusz; Veldhof, Susan; Dorange, Cecile; Garcia-Garcia, Hector M; Ormiston, John A; Serruys, Patrick W

    2012-01-01

    The aim of this study was to describe vaso-reactivity (by Acetylcholine and Methergine tests) at 2 year follow-up in parallel with the individual changes in the echogenicity characteristics of the polymer struts of the everolimus eluting bioresorbable vascular scaffold (BVS), from post-treatment to 2 year follow-up, in patients enrolled in the ABSORB Cohort A study. Intravascular ultrasound assessment was performed with a phased array catheter (EagleEye, Volcano Corporation, Cordova, CA, USA) with automated pullback at 0.5 mm per second. The % ratio at 6 months and 2 years [(Scaffold Area post PCI- Lumen Area)/Scaffold Area post PCI] was calculated as a measure of scaffold shrinkage. The % change of hyperechogenicity was defined as: ([post-procedural hyperechogenicity] - [2 year follow up hyperechogenicity])/[post-procedural hyperechogenicity]) × 100. The vasomotion test with intracoronary acetylcholine (10(-6) M) or intravenous methergine (0.4 mg) was performed at 2 years. Overall nine patients received all these analyses and were enrolled in the present analysis. A 50-96% reduction in hyperechogenicity was observed between baseline and 2 years, which corresponded to a change in vasoreactivity between 2 and 22%. A vasoconstriction of the scaffolded segment was observed in the 5 patients, who underwent the methergine test, with a mean decrease in lumen diameter after methergine of 9 ± 7% (P = 0.06), while vasodilatation occurred in the 4 patients who underwent the acetylcholine test with a mean increase in lumen diameter after acetylcholine of 8 ± 5% (P = 0.125). Bioresorption of the BVS is accompanied by re-establishment of both endothelial and non-endothelial dependent vasomotion.

  15. Stent coverage and neointimal proliferation in bare metal stents postdilated with a Paclitaxel-eluting balloon versus everolimus-eluting stents: prospective randomized study using optical coherence tomography at 6-month follow-up.

    Science.gov (United States)

    Poerner, Tudor C; Otto, Sylvia; Gassdorf, Johannes; Nitsche, Kristina; Janiak, Florian; Scheller, Bruno; Goebel, Björn; Jung, Christian; Figulla, Hans R

    2014-12-01

    In this randomized trial, strut coverage and neointimal proliferation of a therapy of bare metal stents (BMSs) postdilated with the paclitaxel drug-eluting balloon (DEB) was compared with everolimus drug-eluting stents (DESs) at 6-month follow-up using optical coherence tomography. We hypothesized sufficient stent coverage at follow-up. A total of 105 lesions in 90 patients were treated with either XIENCE V DES (n=51) or BMS postdilated with the SeQuent Please DEB (n=54). At follow-up, comparable results on the primary optical coherence tomography end point (percentage uncovered struts 5.64±9.65% in BMS+DEB versus 4.93±9.29% in DES; P=0.366) were found. Thus, BMS+DEB achieved the prespecified noninferiority margin of 5% uncovered struts versus DES (difference between treatment means, 0.71%; one-sided upper 95% confidence interval, 4.14%; noninferiority P=0.04). Optical coherence tomography analysis showed significantly more global neointimal proliferation in the BMS+DEB group (15.7±7.8 versus 11.0±5.2 mm(3) proliferation volume/cm stent length; P=0.002). No significant focal in-stent stenosis analyzed with angiography (percentage diameter stenosis at follow-up, 22.8±11.9 versus 16.9±10.4; P=0.014) and optical coherence tomography (peak local area stenosis, 39.5±13.8% versus 36.8±15.6%; P=0.409) was found. Good stent strut coverage of >94% was found in both therapy groups. Despite greater suppression of global neointimal growth in DES, both DES and BMS+DEB effectively prevented clinically relevant focal restenosis at 6-month follow-up. http://www.clinicaltrials.gov. Unique identifier: NCT01056744. © 2014 American Heart Association, Inc.

  16. A randomized comparison of novel bioresorbable polymer sirolimus-eluting stent and durable polymer everolimus-eluting stent in patients with acute coronary syndromes: The CENTURY II high risk ACS substudy

    International Nuclear Information System (INIS)

    Jiménez, Victor A.; Iñiguez, Andrés; Baz, José A.; Valdés, Mariano; Ortiz, Alberto; Vuilliomenet, André; Mainar, Vicente; Dudek, Dariusz; Banai, Shmuel; Tüller, David; Bonnet, Jean-Louis; De Miguel, Antonio; Bastos, Guillermo; Wijns, William; Saito, Shigeru

    2016-01-01

    Background: To investigate clinical outcomes of percutaneous coronary intervention using a sirolimus-eluting stent with bioresorbable polymer, Ultimaster (BP-SES) compared with a permanent polymer everolimus-eluting stent, Xience (PP-EES) in patients with high risk (ST-segment elevation and non-ST-segment elevation myocardial infarction) acute coronary syndromes (ACS) enrolled in the CENTURY II trial. Methods: CENTURY II is a prospective, multicenter, randomized, single blind, controlled trial comparing BP-SES and PP-EES, with primary endpoint of target lesion failure (TLF) at 9 month post-stent implantation. Out of 1123 patients enrolled in CENTURY II trial, 264 high risk ACS patients were included in this subgroup analysis, and the clinical outcomes including target lesion failure (TLF), target vessel failure (TVF), cardiac death, myocardial infarction, and stent thrombosis were evaluated at 24 months. Results: The baseline clinical, angiographic and procedural characteristics were similar between two groups. At 24 months, TLF occurred in 6.3% of patients receiving a BP-SES and 6.5% of patients receiving a PP-EES (P = 0.95); TVF was 6.3% in patients receiving a BP-SES and 9.4% in patients receiving a PP-EES (P = 0.36). There were no significant differences in cardiac death, myocardial infarction and stent thrombosis rate. Conclusions: BP-SES achieved similar safety and efficacy outcomes as PP-EES in this ACS subgroup of CENTURY II study, at 24-month follow-up. This finding is hypothesis-generating and needs to be confirmed in larger trials with longer follow-up. - Highlights: • This study reported the 24-month clinical outcomes of new-generation BP-SES compared with PP-EES in ACS subgroup from CENTURY II study. • This is a pre-specified subgroup analysis of a large randomized, prospective, multicenter clinical trial. • The BP-SES showed good and comparable clinical performance as PP-EES at 24 months. • This substudy has a relatively small sample size and

  17. Evaluation of XIENCE V everolimus-eluting and Taxus Express2 paclitaxel-eluting coronary stents in patients with jailed side branches from the SPIRIT IV trial at 2 years.

    Science.gov (United States)

    Forrest, John K; Lansky, Alexandra J; Meller, Stephanie M; Hou, Liming; Sood, Poornima; Applegate, Robert J; Wang, John C; Skelding, Kimberly A; Shah, Aakar; Kereiakes, Dean J; Sudhir, Krishnankutty; Cristea, Ecaterina; Yaqub, Manejeh; Stone, Gregg W

    2013-06-01

    The aim of this study was to determine whether patients from the Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With de Novo Native Coronary Artery Lesions (SPIRIT) IV trial who underwent percutaneous coronary intervention, who had target lesions with jailed side branches, had improved clinical outcomes when treated with the XIENCE V versus Taxus Express(2) drug-eluting stent. In the SPIRIT III randomized trial, patients with target lesions with jailed side branches after XIENCE V compared with Taxus Express(2) implantation had lower 2-year rates of major adverse cardiac events. The SPIRIT IV trial represents a larger more diverse patient population compared with SPIRIT III. In the large-scale, prospective, multicenter, randomized SPIRIT IV trial, 3,687 patients who underwent coronary stenting with up to 3 de novo native coronary artery lesions were randomized 2:1 to receive XIENCE V versus Taxus Express(2) stents. Two-year clinical outcomes of patients with or without jailed side branches after stenting were compared. A jailed side branch was defined as any side branch >1.0 mm in diameter within the target segment being stented, excluding bifurcations deemed to require treatment. Of the 3,687 patients in SPIRIT IV, a total of 1,426 had side branches that were jailed during angioplasty of the target lesion. Patients with jailed side branches after XIENCE V compared with Taxus Express(2) implantation had significantly lower 2-year rates of target lesion failure (6.5% vs 11.9%, p = 0.001), major adverse cardiac events (6.6% vs 12.2%, p = 0.0008), ischemia-driven target vessel revascularization (4.1% vs 7.9%, p = 0.004), and stent thrombosis (0.6% vs 2.8%, p = 0.001). In conclusion, patients with jailed side branches after stenting with XIENCE V compared to Taxus Express(2) devices had superior clinical outcomes at 2 years in the large-scale randomized SPIRIT IV trial. Copyright © 2013 Elsevier Inc. All

  18. A randomized comparison of novel bioresorbable polymer sirolimus-eluting stent and durable polymer everolimus-eluting stent in patients with acute coronary syndromes: The CENTURY II high risk ACS substudy

    Energy Technology Data Exchange (ETDEWEB)

    Jiménez, Victor A., E-mail: victor.alfonso.jimenez.diaz@sergas.es [Interventional Cardiology Unit, Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital of Vigo, Vigo (Spain); Iñiguez, Andrés; Baz, José A. [Interventional Cardiology Unit, Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital of Vigo, Vigo (Spain); Valdés, Mariano [Hospital Universitario V. Arrixaca, Murcia (Spain); Ortiz, Alberto [Interventional Cardiology Unit, Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital of Vigo, Vigo (Spain); Vuilliomenet, André [Kantonsspital Aarau, Aarau (Switzerland); Mainar, Vicente [Department of Cardiology, University General Hospital of Alicante, Alicante (Spain); Dudek, Dariusz [Department of Interventional Cardiology, Jagiellonian University Medical College, Krakow (Poland); Banai, Shmuel [Tel Aviv Sourasky Medical Centre, Tel Aviv (Israel); Tüller, David [Department of Cardiology, Stadtspital Triemli, Zürich (Switzerland); Bonnet, Jean-Louis [Department of Cardiology, Hospital La Timone, Marseille (France); De Miguel, Antonio; Bastos, Guillermo [Interventional Cardiology Unit, Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital of Vigo, Vigo (Spain); Wijns, William [Cardiovascular Center Aalst, OLV Hospital, Aalst (Belgium); Saito, Shigeru [Department of Cardiology and Catheterization Laboratory, Shonan Kamakura General Hospital, Kamakura (Japan)

    2016-09-15

    Background: To investigate clinical outcomes of percutaneous coronary intervention using a sirolimus-eluting stent with bioresorbable polymer, Ultimaster (BP-SES) compared with a permanent polymer everolimus-eluting stent, Xience (PP-EES) in patients with high risk (ST-segment elevation and non-ST-segment elevation myocardial infarction) acute coronary syndromes (ACS) enrolled in the CENTURY II trial. Methods: CENTURY II is a prospective, multicenter, randomized, single blind, controlled trial comparing BP-SES and PP-EES, with primary endpoint of target lesion failure (TLF) at 9 month post-stent implantation. Out of 1123 patients enrolled in CENTURY II trial, 264 high risk ACS patients were included in this subgroup analysis, and the clinical outcomes including target lesion failure (TLF), target vessel failure (TVF), cardiac death, myocardial infarction, and stent thrombosis were evaluated at 24 months. Results: The baseline clinical, angiographic and procedural characteristics were similar between two groups. At 24 months, TLF occurred in 6.3% of patients receiving a BP-SES and 6.5% of patients receiving a PP-EES (P = 0.95); TVF was 6.3% in patients receiving a BP-SES and 9.4% in patients receiving a PP-EES (P = 0.36). There were no significant differences in cardiac death, myocardial infarction and stent thrombosis rate. Conclusions: BP-SES achieved similar safety and efficacy outcomes as PP-EES in this ACS subgroup of CENTURY II study, at 24-month follow-up. This finding is hypothesis-generating and needs to be confirmed in larger trials with longer follow-up. - Highlights: • This study reported the 24-month clinical outcomes of new-generation BP-SES compared with PP-EES in ACS subgroup from CENTURY II study. • This is a pre-specified subgroup analysis of a large randomized, prospective, multicenter clinical trial. • The BP-SES showed good and comparable clinical performance as PP-EES at 24 months. • This substudy has a relatively small sample size and

  19. Comparing Stent Thrombosis associated with Zotarolimus Eluting Stents versus Everolimus Eluting Stents at 1 year follow up: a systematic review and meta-analysis of 6 randomized controlled trials.

    Science.gov (United States)

    Bundhun, Pravesh Kumar; Yanamala, Chandra Mouli; Huang, Wei-Qiang

    2017-03-16

    Two thousand fifteen has been a winning year for Drug Eluting Stents (DES). Increase in the number of patients with cardiovascular diseases treated by Percutaneous Coronary Intervention (PCI) has resulted to a high demand for second generation DES. This current analysis aimed to compare the different types of Stent Thrombosis (ST) associated with Zotarolimus Eluting Stents (ZES) versus Everolimus Eluting Stents (EES) at 1 year follow up. Electronic databases were searched for studies comparing ZES with EES. Different types of ST reported at 1 year follow up were considered as the primary endpoints in this analysis. Odds Ratios (OR) with 95% Confidence Intervals (CIs) were used as the statistical parameters and the pooled analyses were carried out by the RevMan 5 · 3 software. A total number of 10,512 patients were included in this analysis. No significant difference in any definite ST, acute definite ST, subacute definite ST, and late definite ST were observed between ZES and EES, at 1 year follow up with OR: 1.70, 95% CI: 0.92 - 3.16; P = 0.09, OR: 3.44, 95% CI: 0.82 - 14.43; P = 0.09, OR: 1.13, 95% CI: 0.43 - 2.95; P = 0.80 and OR: 2.39, 95% CI: 0.83 - 6.85; P = 0.11 respectively. Moreover, any definite or probable ST and definite/probable/possible ST were also not significantly different with OR: 1.39, 95% CI: 0.89 - 2.17; P = 0.15 and OR: 1.19, 95% CI: 0.84 - 1.70; P = 0.33 respectively. In addition, any probable ST, acute probable ST, late probable ST and possible ST were also not significantly different at 1 year follow up with OR: 1.11, 95% CI: 0.60 - 2.05; P = 0.75, OR: 0.53, 95% CI: 0.12 - 2.40; P = 0.41, OR: 1.67, 95% CI: 0.35 - 7.86; P = 0.52 and OR: 1.08, 95% CI: 0.64 - 1.82; P = 0.78 respectively. At 1 year follow up, ZES were not associated with significantly lower or higher definite and probable ST compared to EES. In addition, no significant difference was observed in acute, subacute and late

  20. Quantitative analysis of the side-branch orifice after bifurcation stenting using en-face processing of OCT images: a comparison between Xience V and Resolute Integrity stents.

    Science.gov (United States)

    Minami, Yoshiyasu; Wang, Zhao; Aguirre, Aaron D; Lee, Stephen; Uemura, Shiro; Soeda, Tsunenari; Vergallo, Rocco; Raffel, Owen C; Barlis, Peter; Itoh, Tomonori; Lee, Hang; Fujimoto, James; Jang, Ik-Kyung

    2016-01-01

    Methods for intravascular assessment of the side-branch (SB) orifice after stenting are not readily available. The aim of this study was to assess the utility of an en-face projection processing for optical coherence tomography (OCT) images for SB evaluation. Measurements of the SB orifice obtained using en-face OCT images were validated using a phantom model. Linear regression modeling was applied to estimated area measurements made on the en-face images. The SB orifice was then analyzed in 88 patients with bifurcation lesions treated with either Xience V (everolimus-eluting stent) or Resolute Integrity [zotarolimus-eluting stent (ZES)]. The SB orifice area (A) and the area obstructed by struts (B) were calculated, and the %open area was evaluated as (A-B)/A*100. Linear regression modeling demonstrated that the observed departures of the intercept and slope were not significantly different from 0 (-0.12 ± 0.22, P=0.59) and 1 (1.01 ± 0.06, R(2)=0.88, P=0.87), respectively. In cases without SB dilatation, the %open area was significantly larger in the everolimus-eluting stent group (n=25) than in the ZES group [n=32; 89.2% (83.7-91.3) vs. 84.3% (78.9-87.8), P=0.04]. A significant difference in %open area between cases with and those without SB dilatation was demonstrated in the ZES group [91.4% (86.1-94.0) vs. 84.3% (78.9-87.8), P=0.04]. The accuracy of SB orifice measurement on an en-face OCT image was validated using a phantom model. This novel approach enables quantitative evaluation of the differences in SB orifice area free from struts among different stent types and different treatment strategies in vivo.

  1. Evaluation of the short- and long-term safety and therapy outcomes of the everolimus-eluting bioresorbable vascular scaffold system in patients with coronary artery stenosis: Rationale and design of the German–Austrian ABSORB RegIstRy (GABI-R)

    Energy Technology Data Exchange (ETDEWEB)

    Nef, Holger, E-mail: holger.nef@innere.med.uni-giessen.de [University of Giessen, Medizinische Klinik I, Department of Cardiology, Giessen (Germany); Wiebe, Jens [University of Giessen, Medizinische Klinik I, Department of Cardiology, Giessen (Germany); Achenbach, Stefan [University of Erlangen, Medizinische Klinik II, Department of Cardiology, Erlangen (Germany); Münzel, Thomas [Department of Medicine II, University Medical Center, Johannes Gutenberg University Mainz, Mainz (Germany); Naber, Christoph [Klinik für Kardiologie und Angiologie, Elisabeth-Krankenhaus, Essen (Germany); Richardt, Gert [Herzzentrum, Segeberger Kliniken GmbH, Bad Segeberg (Germany); Mehilli, Julinda [Department of Cardiology, Klinikum Großhadern, Ludwig- Maximilian Universität, Munich (Germany); Wöhrle, Jochen [Department of Internal Medicine II, University of Ulm, Ulm (Germany); Neumann, Till; Biermann, Janine [University of Essen, Department of Cardiology, Essen (Germany); Zahn, Ralf [Abteilung für Kardiologie, Herzzentrum Ludwigshafen, Ludwigshafen (Germany); Kastner, Johannes [Department of Cardiology, University of Vienna Medical School, Vienna (Austria); Schmermund, Axel [CCB, Cardioangiologisches Centrum Bethanien, Frankfurt (Germany); Pfannebecker, Thomas [Abbott Vascular Deutschland GmbH, Wetzlar (Germany); Schneider, Steffen; Limbourg, Tobias [Institut für Herzinfarktforschung, Ludwigshafen (Germany); Hamm, Christian W. [University of Giessen, Medizinische Klinik I, Department of Cardiology, Giessen (Germany); Kerckhoff Heart and Thorax Center, Department of Cardiology, Bad Nauheim (Germany)

    2016-01-15

    Background: Third-generation drug-eluting metal stents are the gold standard for treatment of coronary artery disease. The permanent metallic caging of the vessel, however, can result in limited vasomotion, chronic inflammation, and late expansive remodeling, conditions that can lead to late and very late stent thrombosis. The development of bioresorbable scaffolds (BRSs) promises advantages over metal stents due to complete biodegradation within 2–4 years. Theoretically, since vessel scaffolding is temporary and no permanent implant remains in the vessel, BRSs, as opposed to metal stents, once degraded would no longer be potential triggers for stent-related adverse events or side effects. Methods/design: The short- and long-term outcome after implantation of an everolimus-eluting, poly-L-lactic acid-based bioresorbable scaffold system (ABSORB, Abbott Vascular, Santa Clara, CA, USA) in the world-wide greatest all-comers cohort will be evaluated in the prospective, non-interventional, multicenter German–Austrian ABSORB RegIstRy (GABI-R). GABI-R will include over 5000 patients from about 100 study sites in Austria and Germany. Safety endpoints such as cardiac death, myocardial infarction, and clinically driven percutaneous or surgical target lesion and vessel revascularization will be evaluated during hospitalization and in the follow-up period (minimum of 5 years). Conclusion: Although two randomized controlled trials and several registries have documented safety and efficacy as well as non-inferiority of this everolimus-eluting ABSORB device compared with drug-eluting metal stents, the current knowledge regarding clinical application, treatment success, and long-term safety of using this BRS in daily routine is limited. Thus, the goal of GABI-R is to address this lack of information. - Highlights: • The GABI-R addresses a lack of data about bioresorbable scaffolds in daily practice. • 5000 patients with minimal in- and exclusion criteria at 100 sites will

  2. Evaluation of the short- and long-term safety and therapy outcomes of the everolimus-eluting bioresorbable vascular scaffold system in patients with coronary artery stenosis: Rationale and design of the German–Austrian ABSORB RegIstRy (GABI-R)

    International Nuclear Information System (INIS)

    Nef, Holger; Wiebe, Jens; Achenbach, Stefan; Münzel, Thomas; Naber, Christoph; Richardt, Gert; Mehilli, Julinda; Wöhrle, Jochen; Neumann, Till; Biermann, Janine; Zahn, Ralf; Kastner, Johannes; Schmermund, Axel; Pfannebecker, Thomas; Schneider, Steffen; Limbourg, Tobias; Hamm, Christian W.

    2016-01-01

    Background: Third-generation drug-eluting metal stents are the gold standard for treatment of coronary artery disease. The permanent metallic caging of the vessel, however, can result in limited vasomotion, chronic inflammation, and late expansive remodeling, conditions that can lead to late and very late stent thrombosis. The development of bioresorbable scaffolds (BRSs) promises advantages over metal stents due to complete biodegradation within 2–4 years. Theoretically, since vessel scaffolding is temporary and no permanent implant remains in the vessel, BRSs, as opposed to metal stents, once degraded would no longer be potential triggers for stent-related adverse events or side effects. Methods/design: The short- and long-term outcome after implantation of an everolimus-eluting, poly-L-lactic acid-based bioresorbable scaffold system (ABSORB, Abbott Vascular, Santa Clara, CA, USA) in the world-wide greatest all-comers cohort will be evaluated in the prospective, non-interventional, multicenter German–Austrian ABSORB RegIstRy (GABI-R). GABI-R will include over 5000 patients from about 100 study sites in Austria and Germany. Safety endpoints such as cardiac death, myocardial infarction, and clinically driven percutaneous or surgical target lesion and vessel revascularization will be evaluated during hospitalization and in the follow-up period (minimum of 5 years). Conclusion: Although two randomized controlled trials and several registries have documented safety and efficacy as well as non-inferiority of this everolimus-eluting ABSORB device compared with drug-eluting metal stents, the current knowledge regarding clinical application, treatment success, and long-term safety of using this BRS in daily routine is limited. Thus, the goal of GABI-R is to address this lack of information. - Highlights: • The GABI-R addresses a lack of data about bioresorbable scaffolds in daily practice. • 5000 patients with minimal in- and exclusion criteria at 100 sites will

  3. Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real-world population of hormone receptor-positive (ER+/PgR+), HER2-negative advanced breast cancer (ABC) patients: a multicenter Italian experience.

    Science.gov (United States)

    Ciccarese, Mariangela; Fabi, Alessandra; Moscetti, Luca; Cazzaniga, Maria Elena; Petrucelli, Luciana; Forcignanò, Rosachiara; Lupo, Laura Isabella; De Matteis, Elisabetta; Chiuri, Vincenzo Emanuele; Cairo, Giuseppe; Febbraro, Antonio; Giordano, Guido; Giampaglia, Marianna; Bilancia, Domenico; La Verde, Nicla; Maiello, Evaristo; Morritti, Maria; Giotta, Francesco; Lorusso, Vito; Latorre, Agnese; Scavelli, Claudio; Romito, Sante; Cusmai, Antonio; Palmiotti, Gennaro; Surico, Giammarco

    2017-06-01

    This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability. 163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C). RR was 29.8% (A), 27.8% (B) (p = 0.953), and not evaluable (C). PFS was 9 months (95% CI 7-11) (A), 10 months (95% CI 9-11) (B), and 5 months (95% CI 2-8) (C), p = 0.956. OS was 38 months (95% CI 24-38) (A), median not reached (B), and 13 months (95% CI 10-25) (C), p = 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3-4), asthenia 46.0% (6.1% grade 3-4), hypercholesterolemia 46.0% (0.6% grade 3-4), and hyperglycemia 35.6% (5.5% grade 3-4). The main reason for discontinuation/interruption was grade 2-3 stomatitis. No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy.

  4. Serial 5-Year Evaluation of Side Branches Jailed by Bioresorbable Vascular Scaffolds Using 3-Dimensional Optical Coherence Tomography: Insights From the ABSORB Cohort B Trial (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions).

    Science.gov (United States)

    Onuma, Yoshinobu; Grundeken, Maik J; Nakatani, Shimpei; Asano, Taku; Sotomi, Yohei; Foin, Nicolas; Ng, Jaryl; Okamura, Takayuki; Wykrzykowska, Joanna J; de Winter, Robbert J; van Geuns, Robert-Jan; Koolen, Jacques; Christiansen, Evald; Whitbourn, Robert; McClean, Dougal; Smits, Pieter; Windecker, Stephan; Ormiston, John A; Serruys, Patrick W

    2017-09-01

    The long-term fate of Absorb bioresorbable vascular scaffold (Abbott Vascular, Santa Clara, CA) struts jailing side branch ostia has not been clarified. We therefore evaluate serially (post-procedure and at 6 months, 1, 2, 3, and 5 years) the appearance and fate of jailed Absorb bioresorbable vascular scaffold struts. We performed 3-dimensional optical coherence tomographic analysis of the ABSORB Cohort B trial (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) up to 5 years using a novel, validated cut-plane analysis method. We included 29 patients with a total of 85 side branch ostia. From the 12 ostia which could be assessed in true serial fashion, 7 showed a pattern of initial decrease in the ostial area free from struts, followed by an increase in strut-free ostial area toward the end of the 5 years of follow-up. In a repeated-measures analysis with time as fixed variable and ostial area free from struts as dependent variable, we showed a numeric decrease in the estimated ostial area free from struts from 0.75 mm 2 (baseline) to 0.68 mm 2 (first follow-up visit at 6 months or 1 year) and 0.63 mm 2 (second follow-up visit at 2 or 3 years). However, from the second visit to the 5-year follow-up visit, there was a statistically significant increase from 0.63 to 0.89 mm 2 ( P =0.001). Struts overlying an ostium divided the ostium into compartments, and the number of these compartments decreased over time. This study showed that in most cases, the side branch ostial area free from struts initially decreased. However, with full scaffold bioresorption, the ostial area free from scaffold increased between 2 to 3 years and 5 years in the vast majority of patients. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856856. © 2017 American Heart Association, Inc.

  5. Meta-analysis of Absorb Bioresorbable Vascular Scaffold Versus Cobalt Chromium-everolimus Eluting Stent for Treating the Patients With Coronary Artery Disease%生物可吸收支架与钴铬合金依维莫司洗脱支架治疗冠心病的Meta分析

    Institute of Scientific and Technical Information of China (English)

    庞思; 潘道蓉; 朱灏; 吴文; 蔡金赞; 冒晨昱; 张瑶俊

    2016-01-01

    Objective: To systemically review the safety and efficacy of Absorb bioresorbable vascular scaffold (Absorb BVS) versus cobalt chromium-everolimus eluting stent (CoCr-EES) for treating the patients with coronary artery disease (CAD) by percutaneous coronary intervention (PCI). Methods: We searched relevant literatures in PubMed, Embase, Cochrane Library, CNKI and Wanfang database from 2008-01 to 2015-10, meanwhile, collected published data and randomized controlled trials from meeting abstracts and websites to compare Absorb BVS and CoCr-EES for treating CAD patients. The quality of literatures were assessed and extracted by modiifed Jadad score, Meta-analysis was conducted by STATA 12.0 soft ware. Results: There were 4 eligible trials with 3,389 patients were enrolled. Absorb BVS group, n=2,164 and CoCr-EES group, n=1,225. During the mean of 1.1 years follow-up period, the following incidences were similar between 2 groups:target lesion failure (OR=1.29, 95%CI 0.95-1.74, P=0.10), all cause death (OR=1.31, 95%CI 0.60-2.87, P=0.50), cardiac death (OR=1.38, 95%CI 0.45-4.24, P=0.57), myocardial infarction (OR=1.30, 95%CI 0.93-1.80, P=0.12), deifnite or probable stent thrombosis (OR=2.08, 95%CI 0.95-4.54, P=0.07), re-vascularization (OR=1.03, 95%CI 0.80-1.33, P=0.81), target lesion re-vascularization (OR=1.06, 95%CI 0.67-1.66, P=0.81) and the patient-oriented composite endpoint (OR=0.95, 95%CI 0.66-1.35, P=0.76). Conclusion: Absorb BVS and CoCr-EES had the similar safety and efifcacy for treating the low and moderate risk CAD patients who had angina, ischemia while without symptoms. The longer period of follow-up study and larger randomized, controlled clinical trials were needed for Absorb BVS application in clinical practice.%目的:系统评价Absorb 生物可吸收支架(BVS)对比钴铬合金依维莫司洗脱支架(cobalt chromium-everolimus eluting stent,CoCr-EES)在冠心病介入治疗中的安全性和有效性。  方法:计算机检索Pub

  6. Fuel processing. Wastes processing

    International Nuclear Information System (INIS)

    Bourgeois, M.

    2000-01-01

    The gaseous, liquid and solid radioactive effluents generated by the fuel reprocessing, can't be release in the environment. They have to be treated in order to respect the limits of the pollution regulations. These processing are detailed and discussed in this technical paper. A second part is devoted to the SPIN research program relative to the separation of the long life radionuclides in order to reduce the radioactive wastes storage volume. (A.L.B.)

  7. Process Accounting

    OpenAIRE

    Gilbertson, Keith

    2002-01-01

    Standard utilities can help you collect and interpret your Linux system's process accounting data. Describes the uses of process accounting, standard process accounting commands, and example code that makes use of process accounting utilities.

  8. Three-year patient-related and stent-related outcomes of second-generation everolimus-eluting Xience V stents versus zotarolimus-eluting resolute stents in real-world practice (from the Multicenter Prospective EXCELLENT and RESOLUTE-Korea Registries).

    Science.gov (United States)

    Lee, Joo Myung; Park, Kyung Woo; Han, Jung-Kyu; Yang, Han-Mo; Kang, Hyun-Jae; Koo, Bon-Kwon; Bae, Jang-Whan; Woo, Sung-Il; Park, Jin Sik; Jin, Dong-Kyu; Jeon, Dong Woon; Oh, Seok Kyu; Park, Jong-Seon; Kim, Doo-Il; Hyon, Min Su; Jeon, Hui-Kyung; Lim, Do-Sun; Kim, Myeong-Gon; Rha, Seung-Woon; Her, Sung-Ho; Hwang, Jin-Yong; Kim, Sanghyun; Choi, Young Jin; Kang, Jin Ho; Moon, Keon-Woong; Jang, Yangsoo; Kim, Hyo-Soo

    2014-11-01

    Long-term outcomes are imperative to confirm safety of drug-eluting stents. There have been 2 randomized controlled trials comparing everolimus-eluting stents (EESs) and Resolute zotarolimus-eluting stents (ZES-Rs). To date, long-term clinical outcomes of these stents were limited to only 1 report, which has recently reported 4-year comparisons of these stents. Therefore, more evidence is needed regarding long-term clinical outcomes of the second-generation stents. This study compared the long-term clinical outcomes of EES with ZES-R in "all-comer" cohorts up to 3-year follow-up. The EXCELLENT and RESOLUTE-Korea registries prospectively enrolled 3,056 patients treated with EES and 1,998 with ZES-R, respectively, without exclusions. Stent-related composite outcomes (target lesion failure) and patient-related composite events up to 3-year follow-up were compared in crude and propensity score-matched analyses. Of 5,054 patients, 3,830 patients (75.8%) had off-label indication (2,217 treated with EES and 1,613 treated with ZES-R). The stent-related outcome (189 [6.2%] vs 127 [6.4%], p = 0.812) and the patient-related outcome (420 [13.7%] vs 250 [12.5%], p = 0.581) did not differ between EES and ZES-R, respectively, at 3 years, which was corroborated by similar results from the propensity score-matched cohort (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.70 to 1.20, p = 0.523 and 0.85, 95% CI 0.70 to 1.02, p = 0.081, for stent- and patient-related outcomes, respectively). The rate of definite or probable stent thrombosis up to 3 years (22 [0.7%] vs 10 [0.5%], p = 0.370) was also similar. The rate of very late definite or probable stent thrombosis was very low and comparable between the 2 stents (3 [0.1%] vs 1 [0.1%], p = 0.657). In multivariate analysis, chronic renal failure (adjusted HR 3.615, 95% CI 2.440 to 5.354, p stents showed comparable safety and efficacy at 3-year follow-up in this robust real-world registry with unrestricted use of EES and

  9. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma

    DEFF Research Database (Denmark)

    Choueiri, Toni K; Escudier, Bernard; Powles, Thomas

    2015-01-01

    BACKGROUND: Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to an...

  10. Meat Processing.

    Science.gov (United States)

    Legacy, Jim; And Others

    This publication provides an introduction to meat processing for adult students in vocational and technical education programs. Organized in four chapters, the booklet provides a brief overview of the meat processing industry and the techniques of meat processing and butchering. The first chapter introduces the meat processing industry and…

  11. Immunosuppressant therapeutic drug monitoring by LC-MS/MS: workflow optimization through automated processing of whole blood samples.

    Science.gov (United States)

    Marinova, Mariela; Artusi, Carlo; Brugnolo, Laura; Antonelli, Giorgia; Zaninotto, Martina; Plebani, Mario

    2013-11-01

    Although, due to its high specificity and sensitivity, LC-MS/MS is an efficient technique for the routine determination of immunosuppressants in whole blood, it involves time-consuming manual sample preparation. The aim of the present study was therefore to develop an automated sample-preparation protocol for the quantification of sirolimus, everolimus and tacrolimus by LC-MS/MS using a liquid handling platform. Six-level commercially available blood calibrators were used for assay development, while four quality control materials and three blood samples from patients under immunosuppressant treatment were employed for the evaluation of imprecision. Barcode reading, sample re-suspension, transfer of whole blood samples into 96-well plates, addition of internal standard solution, mixing, and protein precipitation were performed with a liquid handling platform. After plate filtration, the deproteinised supernatants were submitted for SPE on-line. The only manual steps in the entire process were de-capping of the tubes, and transfer of the well plates to the HPLC autosampler. Calibration curves were linear throughout the selected ranges. The imprecision and accuracy data for all analytes were highly satisfactory. The agreement between the results obtained with manual and those obtained with automated sample preparation was optimal (n=390, r=0.96). In daily routine (100 patient samples) the typical overall total turnaround time was less than 6h. Our findings indicate that the proposed analytical system is suitable for routine analysis, since it is straightforward and precise. Furthermore, it incurs less manual workload and less risk of error in the quantification of whole blood immunosuppressant concentrations than conventional methods. © 2013.

  12. Process development

    Energy Technology Data Exchange (ETDEWEB)

    Schuegerl, K

    1984-01-01

    The item 'process development' comprises the production of acetonic/butonal with C. acetobylicum and the yeasting of potato waste. The target is to increase productivity by taking the following measures - optimation of media, on-line process analysis, analysis of reaction, mathematic modelling and identification of parameters, process simulation, development of a state estimator with the help of the on-line process analysis and the model, optimization and adaptive control.

  13. Poisson processes

    NARCIS (Netherlands)

    Boxma, O.J.; Yechiali, U.; Ruggeri, F.; Kenett, R.S.; Faltin, F.W.

    2007-01-01

    The Poisson process is a stochastic counting process that arises naturally in a large variety of daily life situations. We present a few definitions of the Poisson process and discuss several properties as well as relations to some well-known probability distributions. We further briefly discuss the

  14. Data processing

    CERN Document Server

    Fry, T F

    2013-01-01

    Data Processing discusses the principles, practices, and associated tools in data processing. The book is comprised of 17 chapters that are organized into three parts. The first part covers the characteristics, systems, and methods of data processing. Part 2 deals with the data processing practice; this part discusses the data input, output, and storage. The last part discusses topics related to systems and software in data processing, which include checks and controls, computer language and programs, and program elements and structures. The text will be useful to practitioners of computer-rel

  15. Stochastic processes

    CERN Document Server

    Parzen, Emanuel

    1962-01-01

    Well-written and accessible, this classic introduction to stochastic processes and related mathematics is appropriate for advanced undergraduate students of mathematics with a knowledge of calculus and continuous probability theory. The treatment offers examples of the wide variety of empirical phenomena for which stochastic processes provide mathematical models, and it develops the methods of probability model-building.Chapter 1 presents precise definitions of the notions of a random variable and a stochastic process and introduces the Wiener and Poisson processes. Subsequent chapters examine

  16. Magnetics Processing

    Data.gov (United States)

    Federal Laboratory Consortium — The Magnetics Processing Lab equipped to perform testing of magnetometers, integrate them into aircraft systems, and perform data analysis, including noise reduction...

  17. Data processing

    International Nuclear Information System (INIS)

    Cousot, P.

    1988-01-01

    The 1988 progress report of the Data Processing laboratory (Polytechnic School, France), is presented. The laboratory research fields are: the semantics, the tests and the semantic analysis of the codes, the formal calculus, the software applications, the algorithms, the neuron networks and VLSI (Very Large Scale Integration). The investigations concerning the polynomial rings are performed by means of the standard basis approach. Among the research topics, the Pascal codes, the parallel processing, the combinatorial, statistical and asymptotic properties of the fundamental data processing tools, the signal processing and the pattern recognition. The published papers, the congress communications and the thesis are also included [fr

  18. Suppurative processes

    International Nuclear Information System (INIS)

    Vinner, M.G.

    1983-01-01

    Suppurative process in the case of bronchiectatic disease, abscess and gang rene of lungs, has been described. Characteristic signs of roentgenologic pictu re of the above-mentioned diseases are considered. It is shown,that in most cas es roentgenologic studies give a possibility to make a high-quality diagnosis of suppurative processes

  19. Design Processes

    DEFF Research Database (Denmark)

    Ovesen, Nis

    2009-01-01

    Inspiration for most research and optimisations on design processes still seem to focus within the narrow field of the traditional design practise. The focus in this study turns to associated businesses of the design professions in order to learn from their development processes. Through interviews...... and emerging production methods....

  20. Process development

    International Nuclear Information System (INIS)

    Zapata G, G.

    1989-01-01

    Process development: The paper describes the organization and laboratory facilities of the group working on radioactive ore processing studies. Contains a review of the carried research and the plans for the next future. A list of the published reports is also presented

  1. Sustainable processing

    DEFF Research Database (Denmark)

    Kristensen, Niels Heine

    2004-01-01

    Kristensen_NH and_Beck A: Sustainable processing. In Otto Schmid, Alexander Beck and Ursula Kretzschmar (Editors) (2004): Underlying Principles in Organic and "Low-Input Food" Processing - Literature Survey. Research Institute of Organic Agriculture FiBL, CH-5070 Frick, Switzerland. ISBN 3-906081-58-3...

  2. Food processing

    NARCIS (Netherlands)

    Teodorowicz, Malgorzata; Neerven, Van Joost; Savelkoul, Huub

    2017-01-01

    The majority of foods that are consumed in our developed society have been processed. Processing promotes a non-enzymatic reaction between proteins and sugars, the Maillard reaction (MR). Maillard reaction products (MRPs) contribute to the taste, smell and color of many food products, and thus

  3. Membrane processes

    Science.gov (United States)

    Staszak, Katarzyna

    2017-11-01

    The membrane processes have played important role in the industrial separation process. These technologies can be found in all industrial areas such as food, beverages, metallurgy, pulp and paper, textile, pharmaceutical, automotive, biotechnology and chemical industry, as well as in water treatment for domestic and industrial application. Although these processes are known since twentieth century, there are still many studies that focus on the testing of new membranes' materials and determining of conditions for optimal selectivity, i. e. the optimum transmembrane pressure (TMP) or permeate flux to minimize fouling. Moreover the researchers proposed some calculation methods to predict the membrane processes properties. In this article, the laboratory scale experiments of membrane separation techniques, as well their validation by calculation methods are presented. Because membrane is the "heart" of the process, experimental and computational methods for its characterization are also described.

  4. Process mining

    DEFF Research Database (Denmark)

    van der Aalst, W.M.P.; Rubin, V.; Verbeek, H.M.W.

    2010-01-01

    Process mining includes the automated discovery of processes from event logs. Based on observed events (e.g., activities being executed or messages being exchanged) a process model is constructed. One of the essential problems in process mining is that one cannot assume to have seen all possible...... behavior. At best, one has seen a representative subset. Therefore, classical synthesis techniques are not suitable as they aim at finding a model that is able to exactly reproduce the log. Existing process mining techniques try to avoid such “overfitting” by generalizing the model to allow for more...... support for it). None of the existing techniques enables the user to control the balance between “overfitting” and “underfitting”. To address this, we propose a two-step approach. First, using a configurable approach, a transition system is constructed. Then, using the “theory of regions”, the model...

  5. Partial processing

    International Nuclear Information System (INIS)

    1978-11-01

    This discussion paper considers the possibility of applying to the recycle of plutonium in thermal reactors a particular method of partial processing based on the PUREX process but named CIVEX to emphasise the differences. The CIVEX process is based primarily on the retention of short-lived fission products. The paper suggests: (1) the recycle of fission products with uranium and plutonium in thermal reactor fuel would be technically feasible; (2) it would, however, take ten years or more to develop the CIVEX process to the point where it could be launched on a commercial scale; (3) since the majority of spent fuel to be reprocessed this century will have been in storage for ten years or more, the recycling of short-lived fission products with the U-Pu would not provide an effective means of making refabrication fuel ''inaccessible'' because the radioactivity associated with the fission products would have decayed. There would therefore be no advantage in partial processing

  6. Process monitoring

    International Nuclear Information System (INIS)

    Anon.

    1981-01-01

    Many of the measurements and observations made in a nuclear processing facility to monitor processes and product quality can also be used to monitor the location and movements of nuclear materials. In this session information is presented on how to use process monitoring data to enhance nuclear material control and accounting (MC and A). It will be seen that SNM losses can generally be detected with greater sensitivity and timeliness and point of loss localized more closely than by conventional MC and A systems if process monitoring data are applied. The purpose of this session is to enable the participants to: (1) identify process unit operations that could improve control units for monitoring SNM losses; (2) choose key measurement points and formulate a loss indicator for each control unit; and (3) describe how the sensitivities and timeliness of loss detection could be determined for each loss indicator

  7. Process automation

    International Nuclear Information System (INIS)

    Moser, D.R.

    1986-01-01

    Process automation technology has been pursued in the chemical processing industries and to a very limited extent in nuclear fuel reprocessing. Its effective use has been restricted in the past by the lack of diverse and reliable process instrumentation and the unavailability of sophisticated software designed for process control. The Integrated Equipment Test (IET) facility was developed by the Consolidated Fuel Reprocessing Program (CFRP) in part to demonstrate new concepts for control of advanced nuclear fuel reprocessing plants. A demonstration of fuel reprocessing equipment automation using advanced instrumentation and a modern, microprocessor-based control system is nearing completion in the facility. This facility provides for the synergistic testing of all chemical process features of a prototypical fuel reprocessing plant that can be attained with unirradiated uranium-bearing feed materials. The unique equipment and mission of the IET facility make it an ideal test bed for automation studies. This effort will provide for the demonstration of the plant automation concept and for the development of techniques for similar applications in a full-scale plant. A set of preliminary recommendations for implementing process automation has been compiled. Some of these concepts are not generally recognized or accepted. The automation work now under way in the IET facility should be useful to others in helping avoid costly mistakes because of the underutilization or misapplication of process automation. 6 figs

  8. Perceptual Processing Affects Conceptual Processing

    Science.gov (United States)

    van Dantzig, Saskia; Pecher, Diane; Zeelenberg, Rene; Barsalou, Lawrence W.

    2008-01-01

    According to the Perceptual Symbols Theory of cognition (Barsalou, 1999), modality-specific simulations underlie the representation of concepts. A strong prediction of this view is that perceptual processing affects conceptual processing. In this study, participants performed a perceptual detection task and a conceptual property-verification task…

  9. Sewer Processes

    DEFF Research Database (Denmark)

    Hvitved-Jacobsen, Thorkild; Vollertsen, Jes; Nielsen, Asbjørn Haaning

    Since the first edition was published over a decade ago, advancements have been made in the design, operation, and maintenance of sewer systems, and new problems have emerged. For example, sewer processes are now integrated in computer models, and simultaneously, odor and corrosion problems caused...... by hydrogen sulfide and other volatile organic compounds, as well as other potential health issues, have caused environmental concerns to rise. Reflecting the most current developments, Sewer Processes: Microbial and Chemical Process Engineering of Sewer Networks, Second Edition, offers the reader updated...... and valuable information on the sewer as a chemical and biological reactor. It focuses on how to predict critical impacts and control adverse effects. It also provides an integrated description of sewer processes in modeling terms. This second edition is full of illustrative examples and figures, includes...

  10. Electrochemical Processes

    DEFF Research Database (Denmark)

    Bech-Nielsen, Gregers

    1997-01-01

    The notes describe in detail primary and secondary galvanic cells, fuel cells, electrochemical synthesis and electroplating processes, corrosion: measurments, inhibitors, cathodic and anodic protection, details of metal dissolution reactions, Pourbaix diagrams and purification of waste water from...

  11. Dissolution processes

    International Nuclear Information System (INIS)

    Silver, G.L.

    1976-01-01

    This review contains more than 100 observations and 224 references on the dissolution phenomenon. The dissolution processes are grouped into three categories: methods of aqueous attack, fusion methods, and miscellaneous observations on phenomena related to dissolution problems

  12. Renewal processes

    CERN Document Server

    Mitov, Kosto V

    2014-01-01

    This monograph serves as an introductory text to classical renewal theory and some of its applications for graduate students and researchers in mathematics and probability theory. Renewal processes play an important part in modeling many phenomena in insurance, finance, queuing systems, inventory control and other areas. In this book, an overview of univariate renewal theory is given and renewal processes in the non-lattice and lattice case are discussed. A pre-requisite is a basic knowledge of probability theory.

  13. Lung cancer, intracellular signaling pathways, and preclinical models

    International Nuclear Information System (INIS)

    Mordant, P.

    2012-01-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Activation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) can induce cellular immortalization, proliferation, and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy. This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced anti-tumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF mutations, using immunoblotting to evaluate the inhibitors, and MTT and clonogenic assays for effects on cell viability and proliferation. Subcutaneous xenografts were used to assess the activity of the combination in vivo. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the anti-tumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing anti-tumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein. We then focus on animal models. Preclinical models of NSCLC require better clinical relevance to study disease mechanisms and innovative

  14. Fuel processing

    International Nuclear Information System (INIS)

    Allardice, R.H.

    1990-01-01

    The technical and economic viability of the fast breeder reactor as an electricity generating system depends not only upon the reactor performance but also on a capability to recycle plutonium efficiently, reliably and economically through the reactor and fuel cycle facilities. Thus the fuel cycle is an integral and essential part of the system. Fuel cycle research and development has focused on demonstrating that the challenging technical requirements of processing plutonium fuel could be met and that the sometimes conflicting requirements of the fuel developer, fuel fabricator and fuel reprocessor could be reconciled. Pilot plant operation and development and design studies have established both the technical and economic feasibility of the fuel cycle but scope for further improvement exists through process intensification and flowsheet optimization. These objectives and the increasing processing demands made by the continuing improvement to fuel design and irradiation performance provide an incentive for continuing fuel cycle development work. (author)

  15. Organizing Process

    DEFF Research Database (Denmark)

    Hull Kristensen, Peer; Bojesen, Anders

    This paper invites to discuss the processes of individualization and organizing being carried out under what we might see as an emerging regime of change. The underlying argumentation is that in certain processes of change, competence becomes questionable at all times. The hazy characteristics...... of this regime of change are pursued through a discussion of competencies as opposed to qualifications illustrated by distinct cases from the Danish public sector in the search for repetitive mechanisms. The cases are put into a general perspective by drawing upon experiences from similar change processes...... in MNCs. The paper concludes by asking whether we can escape from a regime of competence in a world defined by a rhetoric of change and create a more promising world in which doubt and search serve as a strategy for gaining knowledge and professionalism that improve on our capability for mutualism....

  16. Welding process

    International Nuclear Information System (INIS)

    Abdul Nassir Ibrahim; Azali Muhammad; Ab. Razak Hamzah; Abd. Aziz Mohamed; Mohamad Pauzi Ismail

    2008-01-01

    For the final chapter of this book, there is basic introduction on welding process. The good radiography must know somehow on welding process so that they can know what kind of welding that must rejected or not. All of the exposure technique that mention in earlier chapter almost applicable in this field because welding process is critical problem if there is no inspection will be done. So, for this chapter, all the discontinuity that usually appeared will be discussed and there is another discontinuity maybe not to important and do not give big impact if found it, do not described here. On top of that, the decision to accept or reject based on code, standard and specification that agreed by both to make sure that decision that agreed is corrected and more meaningful.

  17. Markov Processes in Image Processing

    Science.gov (United States)

    Petrov, E. P.; Kharina, N. L.

    2018-05-01

    Digital images are used as an information carrier in different sciences and technologies. The aspiration to increase the number of bits in the image pixels for the purpose of obtaining more information is observed. In the paper, some methods of compression and contour detection on the basis of two-dimensional Markov chain are offered. Increasing the number of bits on the image pixels will allow one to allocate fine object details more precisely, but it significantly complicates image processing. The methods of image processing do not concede by the efficiency to well-known analogues, but surpass them in processing speed. An image is separated into binary images, and processing is carried out in parallel with each without an increase in speed, when increasing the number of bits on the image pixels. One more advantage of methods is the low consumption of energy resources. Only logical procedures are used and there are no computing operations. The methods can be useful in processing images of any class and assignment in processing systems with a limited time and energy resources.

  18. Film processing

    International Nuclear Information System (INIS)

    Abdul Nassir Ibrahim; Azali Muhammad; Ab. Razak Hamzah; Abd. Aziz Mohamed; Mohamad Pauzi Ismail

    2008-01-01

    The processing was made not only to show what are in the film but also to produce radiograph with high quality where the information gathered really presented level of the quality of the object inspected. Besides that, good procedure will make the film with good quality can keep the film in long time for reference. Here, more detailed on how the dark room functioned and its design. So, the good procedure while processed the film will be discussed detailed in this chapter from entering the dark room to exit from there.

  19. Extraction process

    International Nuclear Information System (INIS)

    Rendall, J.S.; Cahalan, M.J.

    1979-01-01

    A process is described for extracting at least two desired constituents from a mineral, using a liquid reagent which produces the constituents, or compounds thereof, in separable form and independently extracting those constituents, or compounds. The process is especially valuable for the extraction of phosphoric acid and metal values from acidulated phosphate rock, the slurry being contacted with selective extractants for phosphoric acid and metal (e.g. uranium) values. In an example, uranium values are oxidized to uranyl form and extracted using an ion exchange resin. (U.K.)

  20. Process simulation

    International Nuclear Information System (INIS)

    Cao, E.G.; Suarez, P.S.; Pantaleon, J.C.

    1984-01-01

    The search for an optimal design of a heavy water plant is done by means of a simulation model for the mass and enthalpy balances of the SH 2 -H 2 O exchange process. A symplified model for the simulation diagram where the entire plant is represented by a sole tray tower with recicles, and heat and mass feeds/extractions was used. The tower is simulated by the method developed by Tomich with the convergence part given by the algorithm of Broyden. The concluding part of the work is centered in setting the design parameters (flowrates, heat exchange rates, number of plates) wich give the desired process operating conditions. (author) [es

  1. Processing Proteases

    DEFF Research Database (Denmark)

    Ødum, Anders Sebastian Rosenkrans

    -terminal of the scissile bond, leaving C-terminal fusions to have non-native C-termini after processing. A solution yielding native C-termini would allow novel expression and purification systems for therapeutic proteins and peptides.The peptidyl-Lys metallopeptidase (LysN) of the fungus Armillaria mellea (Am) is one...... of few known proteases to have substrate specificity for the C-terminal side of the scissile bond. LysN exhibits specificity for lysine, and has primarily been used to complement trypsin in to proteomic studies. A working hypothesis during this study was the potential of LysN as a processing protease...

  2. Processing Branches

    DEFF Research Database (Denmark)

    Schindler, Christoph; Tamke, Martin; Tabatabai, Ali

    2014-01-01

    Angled and forked wood – a desired material until 19th century, was swept away by industrialization and its standardization of processes and materials. Contemporary information technology has the potential for the capturing and recognition of individual geometries through laser scanning...

  3. BENTONITE PROCESSING

    Directory of Open Access Journals (Sweden)

    Anamarija Kutlić

    2012-07-01

    Full Text Available Bentonite has vide variety of uses. Special use of bentonite, where its absorbing properties are employed to provide water-tight sealing is for an underground repository in granites In this paper, bentonite processing and beneficiation are described.

  4. Purex process

    International Nuclear Information System (INIS)

    Starks, J.B.

    1977-01-01

    The following aspects of the Purex Process are discussed: head end dissolution, first solvent extraction cycle, second plutonium solvent extraction cycle, second uranium solvent extraction cycle, solvent recovery systems, primary recovery column for high activity waste, low activity waste, laboratory waste evaporation, vessel vent system, airflow and filtration, acid recovery unit, fume recovery, and discharges to seepage basin

  5. Innovation process

    DEFF Research Database (Denmark)

    Kolodovski, A.

    2006-01-01

    Purpose of this report: This report was prepared for RISO team involved in design of the innovation system Report provides innovation methodology to establish common understanding of the process concepts and related terminology The report does not includeRISO- or Denmark-specific cultural, econom...

  6. Processing Determinism

    Science.gov (United States)

    O'Grady, William

    2015-01-01

    I propose that the course of development in first and second language acquisition is shaped by two types of processing pressures--internal efficiency-related factors relevant to easing the burden on working memory and external input-related factors such as frequency of occurrence. In an attempt to document the role of internal factors, I consider…

  7. Shale processing

    Energy Technology Data Exchange (ETDEWEB)

    Hampton, W H

    1928-05-29

    The process of treating bituminiferous solid materials such as shale or the like to obtain valuable products therefrom, which comprises digesting a mixture of such material in comminuted condition with a suitable digestion liquid, such as an oil, recovering products vaporized in the digestion, and separating residual solid matter from the digestion liquid by centrifuging.

  8. Radiation processing

    International Nuclear Information System (INIS)

    Noriah Mod Ali

    2005-01-01

    This chapter covers the basic principle and application of radiation technology. The topic titled specific application discussed briefly the following subtopics: 1) Polymer modification - crosslinking, polymerisation, degradation, grafting; 2) Medical sterilisation; 3) Food irradiation; 4) Environmental protection - waste processing, pollutants treatment

  9. Leaching process

    International Nuclear Information System (INIS)

    Heinen, H.J.; McClelland, G.E.; Lindstrom, R.E.

    1982-01-01

    A gold and uranium ore is heap leached in accordance with the process comprising initial agglomeration of fines in the feed by means of a binding agent and cyanide solution. The lixiviant comprises a compatible mixture of sodium cyanide and sodium bicarbonate

  10. Leaching process

    Energy Technology Data Exchange (ETDEWEB)

    Heinen, H J; McClelland, G E; Lindstrom, R E

    1982-10-18

    A gold and uranium ore is heap leached in accordance with the process comprising initial agglomeration of fines in the feed by means of a binding agent and cyanide solution. The lixiviant comprises a compatible mixture of sodium cyanide and sodium bicarbonate.

  11. Signal Processing

    International Nuclear Information System (INIS)

    Anon.

    1992-01-01

    Signal processing techniques, extensively used nowadays to maximize the performance of audio and video equipment, have been a key part in the design of hardware and software for high energy physics detectors since pioneering applications in the UA1 experiment at CERN in 1979

  12. Process validation for radiation processing

    International Nuclear Information System (INIS)

    Miller, A.

    1999-01-01

    Process validation concerns the establishment of the irradiation conditions that will lead to the desired changes of the irradiated product. Process validation therefore establishes the link between absorbed dose and the characteristics of the product, such as degree of crosslinking in a polyethylene tube, prolongation of shelf life of a food product, or degree of sterility of the medical device. Detailed international standards are written for the documentation of radiation sterilization, such as EN 552 and ISO 11137, and the steps of process validation that are described in these standards are discussed in this paper. They include material testing for the documentation of the correct functioning of the product, microbiological testing for selection of the minimum required dose and dose mapping for documentation of attainment of the required dose in all parts of the product. The process validation must be maintained by reviews and repeated measurements as necessary. This paper presents recommendations and guidance for the execution of these components of process validation. (author)

  13. Stochastic processes

    CERN Document Server

    Borodin, Andrei N

    2017-01-01

    This book provides a rigorous yet accessible introduction to the theory of stochastic processes. A significant part of the book is devoted to the classic theory of stochastic processes. In turn, it also presents proofs of well-known results, sometimes together with new approaches. Moreover, the book explores topics not previously covered elsewhere, such as distributions of functionals of diffusions stopped at different random times, the Brownian local time, diffusions with jumps, and an invariance principle for random walks and local times. Supported by carefully selected material, the book showcases a wealth of examples that demonstrate how to solve concrete problems by applying theoretical results. It addresses a broad range of applications, focusing on concrete computational techniques rather than on abstract theory. The content presented here is largely self-contained, making it suitable for researchers and graduate students alike.

  14. Offshoring Process

    DEFF Research Database (Denmark)

    Slepniov, Dmitrij; Sørensen, Brian Vejrum; Katayama, Hiroshi

    2011-01-01

    The purpose of this chapter is to contribute to the knowledge on how production offshoring and international operations management vary across cultural contexts. The chapter attempts to shed light on how companies approach the process of offshoring in different cultural contexts. In order...... of globalisation. Yet there are clear differences in how offshoring is conducted in Denmark and Japan. The main differences are outlined in a framework and explained employing cultural variables. The findings lead to a number of propositions suggesting that the process of offshoring is not simply a uniform...... technical-rational calculation of the most efficient organisation of activities across national borders, but it is rather specific to the parent companies’ national contexts....

  15. Photobiomodulation Process

    Directory of Open Access Journals (Sweden)

    Yang-Yi Xu

    2012-01-01

    Full Text Available Photobiomodulation (PBM is a modulation of laser irradiation or monochromatic light (LI on biosystems. There is little research on PBM dynamics although its phenomena and mechanism have been widely studied. The PBM was discussed from dynamic viewpoint in this paper. It was found that the primary process of cellular PBM might be the key process of cellular PBM so that the transition rate of cellular molecules can be extended to discuss the dose relationship of PBM. There may be a dose zone in which low intensity LI (LIL at different doses has biological effects similar to each other, so that biological information model of PBM might hold. LIL may self-adaptively modulate a chronic stress until it becomes successful.

  16. Multiphoton processes

    International Nuclear Information System (INIS)

    Manus, C.; Mainfray, G.

    1980-01-01

    The main features of multiphoton processes are described on a somewhat elementary basis. The emphasis is put on multiphoton ionization of atoms where the influence of resonance effects is given through typical examples. The important role played by the coherence of light is shown to produce a very dramatic influence on multiphoton absorption. Different observations concerning molecules, electrons, as well as solid surfaces illustrate the generality of these very non linear interaction between light and matter

  17. Process heat. Triggering the processes

    Energy Technology Data Exchange (ETDEWEB)

    Augsten, Eva

    2012-07-01

    If solar process heat is to find a market, then the decision makers in industrial companies need to be aware that it actually exists. This was one of the main goals of the So-Pro project, which officially drew to a close in April 2012. (orig.)

  18. Speech Processing.

    Science.gov (United States)

    1983-05-01

    The VDE system developed had the capability of recognizing up to 248 separate words in syntactic structures. 4 The two systems described are isolated...AND SPEAKER RECOGNITION by M.J.Hunt 5 ASSESSMENT OF SPEECH SYSTEMS ’ ..- * . by R.K.Moore 6 A SURVEY OF CURRENT EQUIPMENT AND RESEARCH’ by J.S.Bridle...TECHNOLOGY IN NAVY TRAINING SYSTEMS by R.Breaux, M.Blind and R.Lynchard 10 9 I-I GENERAL REVIEW OF MILITARY APPLICATIONS OF VOICE PROCESSING DR. BRUNO

  19. Markov processes

    CERN Document Server

    Kirkwood, James R

    2015-01-01

    Review of ProbabilityShort HistoryReview of Basic Probability DefinitionsSome Common Probability DistributionsProperties of a Probability DistributionProperties of the Expected ValueExpected Value of a Random Variable with Common DistributionsGenerating FunctionsMoment Generating FunctionsExercisesDiscrete-Time, Finite-State Markov ChainsIntroductionNotationTransition MatricesDirected Graphs: Examples of Markov ChainsRandom Walk with Reflecting BoundariesGambler’s RuinEhrenfest ModelCentral Problem of Markov ChainsCondition to Ensure a Unique Equilibrium StateFinding the Equilibrium StateTransient and Recurrent StatesIndicator FunctionsPerron-Frobenius TheoremAbsorbing Markov ChainsMean First Passage TimeMean Recurrence Time and the Equilibrium StateFundamental Matrix for Regular Markov ChainsDividing a Markov Chain into Equivalence ClassesPeriodic Markov ChainsReducible Markov ChainsSummaryExercisesDiscrete-Time, Infinite-State Markov ChainsRenewal ProcessesDelayed Renewal ProcessesEquilibrium State f...

  20. Coking processes

    Energy Technology Data Exchange (ETDEWEB)

    Hiller, H K

    1917-11-20

    A gas suitable for use in containers or motor-vehicles, etc., and consisting mainly of methane, is obtained by distilling at a temperature not exceeding 500/sup 0/C bastard cannel coal, lignite, wood, peat, shale, etc., in an horizontal or vertical retort, through which the material is continuously fed in a thin layer or column by means of a screw conveyor or the like. Cracking or dissociation of the gaseous products is prevented by introducing into the retort part of the gas which is the result of the process and which is compressed to a pressure of at least 15 atmospheres and allowed to expand into the retort to cool and carry away the gaseous products produced. These are then passed through condensers for extracting liquid hydrocarbons, and other hydrocarbons are extracted by passage through washing-oils. The gas is then compressed by a water-cooled pump to a pressure of 15 atmospheres, whereby a spirit similar to petrol is formed, and a stable gas left which is mainly methane, part of the gas being used to carry out the process described above.

  1. Etherification process

    Science.gov (United States)

    Smith, L.A. Jr.; Hearn, D.; Jones, E.M. Jr.

    1990-08-21

    A liquid phase process is described for oligomerization of C[sub 4] and C[sub 5] isoolefins or the etherification thereof with C[sub 1] to C[sub 6] alcohols wherein the reactants are contacted in a reactor with a fixed bed acid cation exchange resin catalyst at an LHSV of 5 to 20, pressure of 0 to 400 psig and temperature of 120 to 300 F wherein the improvement is the operation of the reactor at a pressure to maintain the reaction mixture at its boiling point whereby at least a portion but less than all of the reaction mixture is vaporized. By operating at the boiling point and allowing a portion of the reaction mixture to vaporize, the exothermic heat of reaction is dissipated by the formation of more boil up and the temperature in the reactor is controlled. 2 figs.

  2. Oligomerization process

    Science.gov (United States)

    Smith, L.A. Jr.; Hearn, D.; Jones, E.M. Jr.

    1991-03-26

    A liquid phase process is described for oligomerization of C[sub 4] and C[sub 5] isoolefins or the etherification thereof with C[sub 1] to C[sub 6] alcohols wherein the reactants are contacted in a reactor with a fixed bed acid cation exchange resin catalyst at an LHSV of 5 to 20, pressure of 0 to 400 psig and temperature of 120 to 300 F wherein the improvement is the operation of the reactor at a pressure to maintain the reaction mixture at its boiling point whereby at least a portion but less than all of the reaction mixture is vaporized. By operating at the boiling point and allowing a portion of the reaction mixture to vaporize, the exothermic heat of reaction is dissipated by the formation of more boil up and the temperature in the reactor is controlled. 2 figures.

  3. Lithospheric processes

    Energy Technology Data Exchange (ETDEWEB)

    Baldridge, W. [and others

    2000-12-01

    The authors used geophysical, geochemical, and numerical modeling to study selected problems related to Earth's lithosphere. We interpreted seismic waves to better characterize the thickness and properties of the crust and lithosphere. In the southwestern US and Tien Shari, crust of high elevation is dynamically supported above buoyant mantle. In California, mineral fabric in the mantle correlate with regional strain history. Although plumes of buoyant mantle may explain surface deformation and magmatism, our geochemical work does not support this mechanism for Iberia. Generation and ascent of magmas remains puzzling. Our work in Hawaii constrains the residence of magma beneath Hualalai to be a few hundred to about 1000 years. In the crust, heat drives fluid and mass transport. Numerical modeling yielded robust and accurate predictions of these processes. This work is important fundamental science, and applies to mitigation of volcanic and earthquake hazards, Test Ban Treaties, nuclear waste storage, environmental remediation, and hydrothermal energy.

  4. Lithospheric processes

    International Nuclear Information System (INIS)

    Baldridge, W.S.

    2000-01-01

    The authors used geophysical, geochemical, and numerical modeling to study selected problems related to Earth's lithosphere. We interpreted seismic waves to better characterize the thickness and properties of the crust and lithosphere. In the southwestern US and Tien Shari, crust of high elevation is dynamically supported above buoyant mantle. In California, mineral fabric in the mantle correlate with regional strain history. Although plumes of buoyant mantle may explain surface deformation and magmatism, our geochemical work does not support this mechanism for Iberia. Generation and ascent of magmas remains puzzling. Our work in Hawaii constrains the residence of magma beneath Hualalai to be a few hundred to about 1000 years. In the crust, heat drives fluid and mass transport. Numerical modeling yielded robust and accurate predictions of these processes. This work is important fundamental science, and applies to mitigation of volcanic and earthquake hazards, Test Ban Treaties, nuclear waste storage, environmental remediation, and hydrothermal energy

  5. Carbonizing process

    Energy Technology Data Exchange (ETDEWEB)

    1923-11-22

    In the downward distillation of coal, shale, lignite, or the like, the heat is generated by the combustion of liquid or gaseous fuel above the charge the zone of carbonization thus initiated travelling downwards through the charge. The combustible gases employed are preferably those resulting from the process but gases such as natural gas may be employed. The charge is in a moistened and pervious state the lower parts being maintained at a temperature not above 212/sup 0/F until influenced by contact with the carbonization zone and steam may be admitted to increase the yield of ammonia. The combustible gases may be supplied with insufficient air so as to impart to them a reducing effect.

  6. WELDING PROCESS

    Science.gov (United States)

    Zambrow, J.; Hausner, H.

    1957-09-24

    A method of joining metal parts for the preparation of relatively long, thin fuel element cores of uranium or alloys thereof for nuclear reactors is described. The process includes the steps of cleaning the surfaces to be jointed, placing the sunfaces together, and providing between and in contact with them, a layer of a compound in finely divided form that is decomposable to metal by heat. The fuel element members are then heated at the contact zone and maintained under pressure during the heating to decompose the compound to metal and sinter the members and reduced metal together producing a weld. The preferred class of decomposable compounds are the metal hydrides such as uranium hydride, which release hydrogen thus providing a reducing atmosphere in the vicinity of the welding operation.

  7. Processing Disability.

    Science.gov (United States)

    Harris, Jasmine

    2015-01-01

    This Article argues that the practice of holding so many adjudicative proceedings related to disability in private settings (e.g., guardianship, special education due process, civil commitment, and social security) relative to our strong normative presumption of public access to adjudication may cultivate and perpetuate stigma in contravention of the goals of inclusion and enhanced agency set forth in antidiscrimination laws. Descriptively, the law has a complicated history with disability--initially rendering disability invisible; later, underwriting particular narratives of disability synonymous with incapacity; and, in recent history, promoting the full socio-economic visibility of people with disabilities. The Americans with Disabilities Act (ADA), the marquee civil rights legislation for people with disabilities (about to enter its twenty-fifth year), expresses a national approach to disability that recognizes the role of society in its construction, maintenance, and potential remedy. However, the ADA’s mission is incomplete. It has not generated the types of interactions between people with disabilities and nondisabled people empirically shown to deconstruct deeply entrenched social stigma. Prescriptively, procedural design can act as an "ntistigma agent"to resist and mitigate disability stigma. This Article focuses on one element of institutional design--public access to adjudication--as a potential tool to construct and disseminate counter-narratives of disability. The unique substantive focus in disability adjudication on questions of agency provides a potential public space for the negotiation of nuanced definitions of disability and capacity more reflective of the human condition.

  8. [In process.

    Science.gov (United States)

    Kaasch, Michael; Kaasch, Joachim

    -increasing competitiveness which came to a head as an embroiled dispute resulting from differences in scientific and scientific policy views. In the process a battle was fought over research resources so that, what was at first an apparently personal quarrel, affected the course of research promotion at an institutional level in the area of life sciences in the GDR. Despite several attempts at mediation, old age finally forced the adversaries to put aside their differences.

  9. Data Processing

    Science.gov (United States)

    Grangeat, P.

    A new area of biology has been opened up by nanoscale exploration of the living world. This has been made possible by technological progress, which has provided the tools needed to make devices that can measure things on such length and time scales. In a sense, this is a new window upon the living world, so rich and so diverse. Many of the investigative methods described in this book seek to obtain complementary physical, chemical, and biological data to understand the way it works and the way it is organised. At these length and time scales, only dedicated instrumentation could apprehend the relevant phenomena. There is no way for our senses to observe these things directly. One important field of application is molecular medicine, which aims to explain the mechanisms of life and disease by the presence and quantification of specific molecular entities. This involves combining information about genes, proteins, cells, and organs. This in turn requires the association of instruments for molecular diagnosis, either in vitro, e.g., the microarray or the lab-on-a-chip, or in vivo, e.g., probes for molecular biopsy, and tools for molecular imaging, used to localise molecular information in living organisms in a non-invasive way. These considerations concern both preclinical research for drug design and human medical applications. With the development of DNA and RNA chips [1], genomics has revolutionised investigative methods for cells and cell processes [2,3]. By sequencing the human genome, new ways have been found for understanding the fundamental mechanisms of life [4]. A revolution is currently under way with the analysis of the proteome [5-8], i.e., the complete set of proteins that can be found in some given biological medium, such as the blood plasma. The goal is to characterise certain diseases by recognisable signatures in the proteomic profile, as determined from a blood sample or a biopsy, for example [9-13]. What is at stake is the early detection of

  10. Hydrothermal Processes

    Science.gov (United States)

    German, C. R.; von Damm, K. L.

    2003-12-01

    What is Hydrothermal Circulation?Hydrothermal circulation occurs when seawater percolates downward through fractured ocean crust along the volcanic mid-ocean ridge (MOR) system. The seawater is first heated and then undergoes chemical modification through reaction with the host rock as it continues downward, reaching maximum temperatures that can exceed 400 °C. At these temperatures the fluids become extremely buoyant and rise rapidly back to the seafloor where they are expelled into the overlying water column. Seafloor hydrothermal circulation plays a significant role in the cycling of energy and mass between the solid earth and the oceans; the first identification of submarine hydrothermal venting and their accompanying chemosynthetically based communities in the late 1970s remains one of the most exciting discoveries in modern science. The existence of some form of hydrothermal circulation had been predicted almost as soon as the significance of ridges themselves was first recognized, with the emergence of plate tectonic theory. Magma wells up from the Earth's interior along "spreading centers" or "MORs" to produce fresh ocean crust at a rate of ˜20 km3 yr-1, forming new seafloor at a rate of ˜3.3 km2 yr-1 (Parsons, 1981; White et al., 1992). The young oceanic lithosphere formed in this way cools as it moves away from the ridge crest. Although much of this cooling occurs by upward conduction of heat through the lithosphere, early heat-flow studies quickly established that a significant proportion of the total heat flux must also occur via some additional convective process (Figure 1), i.e., through circulation of cold seawater within the upper ocean crust (Anderson and Silbeck, 1981). (2K)Figure 1. Oceanic heat flow versus age of ocean crust. Data from the Pacific, Atlantic, and Indian oceans, averaged over 2 Ma intervals (circles) depart from the theoretical cooling curve (solid line) indicating convective cooling of young ocean crust by circulating seawater

  11. Multidimensional process discovery

    NARCIS (Netherlands)

    Ribeiro, J.T.S.

    2013-01-01

    Typically represented in event logs, business process data describe the execution of process events over time. Business process intelligence (BPI) techniques such as process mining can be applied to get strategic insight into business processes. Process discovery, conformance checking and

  12. PC image processing

    International Nuclear Information System (INIS)

    Hwa, Mok Jin Il; Am, Ha Jeng Ung

    1995-04-01

    This book starts summary of digital image processing and personal computer, and classification of personal computer image processing system, digital image processing, development of personal computer and image processing, image processing system, basic method of image processing such as color image processing and video processing, software and interface, computer graphics, video image and video processing application cases on image processing like satellite image processing, color transformation of image processing in high speed and portrait work system.

  13. The influence of immunosuppressive drugs on neural stem/progenitor cell fate in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Skardelly, Marco, E-mail: Marco.Skardelly@med.uni-tuebingen.de [Department of Neurosurgery, University Hospital, Leipzig (Germany); Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig (Germany); Glien, Anja; Groba, Claudia; Schlichting, Nadine [Department of Neurosurgery, University Hospital, Leipzig (Germany); Kamprad, Manja [Institute of Clinical Immunology, Medical Faculty, University of Leipzig, Leipzig (Germany); Meixensberger, Juergen [Department of Neurosurgery, University Hospital, Leipzig (Germany); Milosevic, Javorina [Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig (Germany)

    2013-12-10

    In allogenic and xenogenic transplantation, adequate immunosuppression plays a major role in graft survival, especially over the long term. The effect of immunosuppressive drugs on neural stem/progenitor cell fate has not been sufficiently explored. The focus of this study is to systematically investigate the effects of the following four different immunotherapeutic strategies on human neural progenitor cell survival/death, proliferation, metabolic activity, differentiation and migration in vitro: (1) cyclosporine A (CsA), a calcineurin inhibitor; (2) everolimus (RAD001), an mTOR-inhibitor; (3) mycophenolic acid (MPA, mycophenolate), an inhibitor of inosine monophosphate dehydrogenase and (4) prednisolone, a steroid. At the minimum effective concentration (MEC), we found a prominent decrease in hNPCs' proliferative capacity (BrdU incorporation), especially for CsA and MPA, and an alteration of the NAD(P)H-dependent metabolic activity. Cell death rate, neurogenesis, gliogenesis and cell migration remained mostly unaffected under these conditions for all four immunosuppressants, except for apoptotic cell death, which was significantly increased by MPA treatment. - Highlights: • Four immunosuppresants (ISs) were tested in human neural progenitor cells in vitro. • Cyclosporine A and mycophenolic acid showed a prominent anti-proliferative activity • Mycophenolic acid exhibited a significant pro-apoptotic effect. • NAD(P)H-dependent metabolic activity was occasionally induced by ISs. • Neuronal differentiation and migration potential remained unaffected by ISs treatment.

  14. AN ADVANCED OXIDATION PROCESS : FENTON PROCESS

    Directory of Open Access Journals (Sweden)

    Engin GÜRTEKİN

    2008-03-01

    Full Text Available Biological wastewater treatment is not effective treatment method if raw wastewater contains toxic and refractory organics. Advanced oxidation processes are applied before or after biological treatment for the detoxification and reclamation of this kind of wastewaters. The advanced oxidation processes are based on the formation of powerful hydroxyl radicals. Among advanced oxidation processes Fenton process is one of the most promising methods. Because application of Fenton process is simple and cost effective and also reaction occurs in a short time period. Fenton process is applied for many different proposes. In this study, Fenton process was evaluated as an advanced oxidation process in wastewater treatment.

  15. A national, multicenter, non-interventional, observational study on treatment patterns in patients with metastatic renal cell carcinoma in Turkey – NOTES study

    Directory of Open Access Journals (Sweden)

    Yalcin Ş

    2018-03-01

    histologically confirmed mRCC were enrolled in the study from 11 centers between June 2012 and March 2014 (70 males and 30 females. Efficacy was assessed on the basis of progression-free survival and overall survival; safety of everolimus was assessed on the basis of adverse event occurrence. Results: The study results showed that the median progression-free survival with everolimus treatment was 8.1 months (95% CI: 5.1–11.1 and the median overall survival was 17.6 months (95% CI: 10.1–25.1, thus indicating a better overall response based on survival durations than those from the randomized Phase III REnal Cell cancer treatment with Oral RAD001 given Daily study results (4.9 and 14.8 months, respectively. Conclusion: The study showed that everolimus treatment is a safe and effective treatment option in the treatment of mRCC after VEGF-TKI, with an acceptable safety and tolerability profile in real-life settings. Keywords: metastatic renal cell carcinoma, mTOR inhibitors, everolimus, observational study, real-life setting, treatment patterns

  16. Management of processes of electrochemical dimensional processing

    Science.gov (United States)

    Akhmetov, I. D.; Zakirova, A. R.; Sadykov, Z. B.

    2017-09-01

    In different industries a lot high-precision parts are produced from hard-processed scarce materials. Forming such details can only be acting during non-contact processing, or a minimum of effort, and doable by the use, for example, of electro-chemical processing. At the present stage of development of metal working processes are important management issues electrochemical machining and its automation. This article provides some indicators and factors of electrochemical machining process.

  17. Extensible packet processing architecture

    Science.gov (United States)

    Robertson, Perry J.; Hamlet, Jason R.; Pierson, Lyndon G.; Olsberg, Ronald R.; Chun, Guy D.

    2013-08-20

    A technique for distributed packet processing includes sequentially passing packets associated with packet flows between a plurality of processing engines along a flow through data bus linking the plurality of processing engines in series. At least one packet within a given packet flow is marked by a given processing engine to signify by the given processing engine to the other processing engines that the given processing engine has claimed the given packet flow for processing. A processing function is applied to each of the packet flows within the processing engines and the processed packets are output on a time-shared, arbitered data bus coupled to the plurality of processing engines.

  18. BPMN process views construction

    NARCIS (Netherlands)

    Yongchareon, S.; Liu, Chengfei; Zhao, X.; Kowalkiewicz, M.; Kitagawa, H.; Ishikawa, Y.

    2010-01-01

    Process view technology is catching more attentions in modern business process management, as it enables the customisation of business process representation. This capability helps improve the privacy protection, authority control, flexible display, etc., in business process modelling. One of

  19. Silicon integrated circuit process

    International Nuclear Information System (INIS)

    Lee, Jong Duck

    1985-12-01

    This book introduces the process of silicon integrated circuit. It is composed of seven parts, which are oxidation process, diffusion process, ion implantation process such as ion implantation equipment, damage, annealing and influence on manufacture of integrated circuit and device, chemical vapor deposition process like silicon Epitaxy LPCVD and PECVD, photolithography process, including a sensitizer, spin, harden bake, reflection of light and problems related process, infrared light bake, wet-etch, dry etch, special etch and problems of etching, metal process like metal process like metal-silicon connection, aluminum process, credibility of aluminum and test process.

  20. Silicon integrated circuit process

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Duck

    1985-12-15

    This book introduces the process of silicon integrated circuit. It is composed of seven parts, which are oxidation process, diffusion process, ion implantation process such as ion implantation equipment, damage, annealing and influence on manufacture of integrated circuit and device, chemical vapor deposition process like silicon Epitaxy LPCVD and PECVD, photolithography process, including a sensitizer, spin, harden bake, reflection of light and problems related process, infrared light bake, wet-etch, dry etch, special etch and problems of etching, metal process like metal process like metal-silicon connection, aluminum process, credibility of aluminum and test process.

  1. The Newest Laser Processing

    International Nuclear Information System (INIS)

    Lee, Baek Yeon

    2007-01-01

    This book mentions laser processing with laser principle, laser history, laser beam property, laser kinds, foundation of laser processing such as laser oscillation, characteristic of laser processing, laser for processing and its characteristic, processing of laser hole including conception of processing of laser hole and each material, and hole processing of metal material, cut of laser, reality of cut, laser welding, laser surface hardening, application case of special processing and safety measurement of laser.

  2. Minimal and careful processing

    OpenAIRE

    Nielsen, Thorkild

    2004-01-01

    In several standards, guidelines and publications, organic food processing is strongly associated with "minimal processing" and "careful processing". The term "minimal processing" is nowadays often used in the general food processing industry and described in literature. The term "careful processing" is used more specifically within organic food processing but is not yet clearly defined. The concept of carefulness seems to fit very well with the processing of organic foods, especially if it i...

  3. Thinning spatial point processes into Poisson processes

    DEFF Research Database (Denmark)

    Møller, Jesper; Schoenberg, Frederic Paik

    2010-01-01

    are identified, and where we simulate backwards and forwards in order to obtain the thinned process. In the case of a Cox process, a simple independent thinning technique is proposed. In both cases, the thinning results in a Poisson process if and only if the true Papangelou conditional intensity is used, and......In this paper we describe methods for randomly thinning certain classes of spatial point processes. In the case of a Markov point process, the proposed method involves a dependent thinning of a spatial birth-and-death process, where clans of ancestors associated with the original points......, thus, can be used as a graphical exploratory tool for inspecting the goodness-of-fit of a spatial point process model. Several examples, including clustered and inhibitive point processes, are considered....

  4. Thinning spatial point processes into Poisson processes

    DEFF Research Database (Denmark)

    Møller, Jesper; Schoenberg, Frederic Paik

    , and where one simulates backwards and forwards in order to obtain the thinned process. In the case of a Cox process, a simple independent thinning technique is proposed. In both cases, the thinning results in a Poisson process if and only if the true Papangelou conditional intensity is used, and thus can......This paper describes methods for randomly thinning certain classes of spatial point processes. In the case of a Markov point process, the proposed method involves a dependent thinning of a spatial birth-and-death process, where clans of ancestors associated with the original points are identified...... be used as a diagnostic for assessing the goodness-of-fit of a spatial point process model. Several examples, including clustered and inhibitive point processes, are considered....

  5. A process insight repository supporting process optimization

    OpenAIRE

    Vetlugin, Andrey

    2012-01-01

    Existing solutions for analysis and optimization of manufacturing processes, such as online analysis processing or statistical calculations, have shortcomings that limit continuous process improvements. In particular, they lack means of storing and integrating the results of analysis. This makes the valuable information that can be used for process optimizations used only once and then disposed. The goal of the Advanced Manufacturing Analytics (AdMA) research project is to design an integrate...

  6. Process mining: making knowledge discovery process centric

    NARCIS (Netherlands)

    Aalst, van der W.M.P.

    2011-01-01

    Recently, the Task Force on Process Mining released the Process Mining Manifesto. The manifesto is supported by 53 organizations and 77 process mining experts contributed to it. The active contributions from end-users, tool vendors, consultants, analysts, and researchers illustrate the growing

  7. Business process model repositories : efficient process retrieval

    NARCIS (Netherlands)

    Yan, Z.

    2012-01-01

    As organizations increasingly work in process-oriented manner, the number of business process models that they develop and have to maintain increases. As a consequence, it has become common for organizations to have collections of hundreds or even thousands of business process models. When a

  8. Uranium enrichment. Enrichment processes

    International Nuclear Information System (INIS)

    Alexandre, M.; Quaegebeur, J.P.

    2009-01-01

    Despite the remarkable progresses made in the diversity and the efficiency of the different uranium enrichment processes, only two industrial processes remain today which satisfy all of enriched uranium needs: the gaseous diffusion and the centrifugation. This article describes both processes and some others still at the demonstration or at the laboratory stage of development: 1 - general considerations; 2 - gaseous diffusion: physical principles, implementation, utilisation in the world; 3 - centrifugation: principles, elementary separation factor, flows inside a centrifuge, modeling of separation efficiencies, mechanical design, types of industrial centrifuges, realisation of cascades, main characteristics of the centrifugation process; 4 - aerodynamic processes: vortex process, nozzle process; 5 - chemical exchange separation processes: Japanese ASAHI process, French CHEMEX process; 6 - laser-based processes: SILVA process, SILMO process; 7 - electromagnetic and ionic processes: mass spectrometer and calutron, ion cyclotron resonance, rotating plasmas; 8 - thermal diffusion; 9 - conclusion. (J.S.)

  9. The permanental process

    DEFF Research Database (Denmark)

    McCullagh, Peter; Møller, Jesper

    2006-01-01

    We extend the boson process first to a large class of Cox processes and second to an even larger class of infinitely divisible point processes. Density and moment results are studied in detail. These results are obtained in closed form as weighted permanents, so the extension i called a permanental...... process. Temporal extensions and a particularly tractable case of the permanental process are also studied. Extensions of the fermion process along similar lines, leading to so-called determinantal processes, are discussed....

  10. The permanent process

    DEFF Research Database (Denmark)

    Møller, Jesper; McCullagh, Peter

    We extend the boson process first to a large class of Cox processes and second an even larger class of infinitely divisible point processes. Density and moment results are studied in detail. These results are obtained in closed form as weighted permanents, so the extension is called a permanent...... process. Temporal extensions and a particularly tractable case of the permanent process are also studied. Extensions of the ferminon process along similar lines, leading to so-called determinant processes, are discussed at the end. While the permanent process is attractive, the determinant process...

  11. Explosive processes in nucleosynthesis

    International Nuclear Information System (INIS)

    Boyd, R.N.

    2002-01-01

    There are many explosive processes in nucleosynthesis: big bang nucleosynthesis, the rp-process, the γ-process, the ν-process, and the r-process. However, I will discuss just the rp-process and the r-process in detail, primarily because both seem to have been very active research areas of late, and because they have great potential for studies with radioactive nuclear beams. I will also discuss briefly the γ-process because of its inevitability in conjunction with the rp-process. (orig.)

  12. Process Intensification: A Perspective on Process Synthesis

    DEFF Research Database (Denmark)

    Lutze, Philip; Gani, Rafiqul; Woodley, John

    2010-01-01

    In recent years, process intensification (PI) has attracted considerable academic interest as a potential means for process improvement, to meet the increasing demands for sustainable production. A variety of intensified operations developed in academia and industry creates a large number...... of options to potentially improve the process but to identify the set of feasible solutions for PI in which the optimal can be found takes considerable resources. Hence, a process synthesis tool to achieve PI would potentially assist in the generation and evaluation of PI options. Currently, several process...... design tools with a clear focus on specific PI tasks exist. Therefore, in this paper, the concept of a general systematic framework for synthesis and design of PI options in hierarchical steps through analyzing an existing process, generating PI options in a superstructure and evaluating intensified...

  13. Mining processes in dentistry

    NARCIS (Netherlands)

    Mans, R.S.; Reijers, H.A.; van Genuchten, M.; Wismeijer, D.

    2012-01-01

    Business processes in dentistry are quickly evolving towards "digital dentistry". This means that many steps in the dental process will increasingly deal with computerized information or computerized half products. A complicating factor in the improvement of process performance in dentistry,

  14. Realtime Color Stereovision Processing

    National Research Council Canada - National Science Library

    Formwalt, Bryon

    2000-01-01

    .... This research takes a step forward in real time machine vision processing. It investigates techniques for implementing a real time stereovision processing system using two miniature color cameras...

  15. Business Process Customization using Process Merging Techniques

    NARCIS (Netherlands)

    Bulanov, Pavel; Lazovik, Alexander; Aiello, Marco

    2012-01-01

    One of the important application of service composition techniques lies in the field of business process management. Essentially a business process can be considered as a composition of services, which is usually prepared by domain experts, and many tasks still have to be performed manually. These

  16. From Process Understanding to Process Control

    NARCIS (Netherlands)

    Streefland, M.

    2010-01-01

    A licensed pharmaceutical process is required to be executed within the validated ranges throughout the lifetime of product manufacturing. Changes to the process usually require the manufacturer to demonstrate that the safety and efficacy of the product remains unchanged. Recent changes in the

  17. Idaho Chemical Processing Plant Process Efficiency improvements

    International Nuclear Information System (INIS)

    Griebenow, B.

    1996-03-01

    In response to decreasing funding levels available to support activities at the Idaho Chemical Processing Plant (ICPP) and a desire to be cost competitive, the Department of Energy Idaho Operations Office (DOE-ID) and Lockheed Idaho Technologies Company have increased their emphasis on cost-saving measures. The ICPP Effectiveness Improvement Initiative involves many activities to improve cost effectiveness and competitiveness. This report documents the methodology and results of one of those cost cutting measures, the Process Efficiency Improvement Activity. The Process Efficiency Improvement Activity performed a systematic review of major work processes at the ICPP to increase productivity and to identify nonvalue-added requirements. A two-phase approach was selected for the activity to allow for near-term implementation of relatively easy process modifications in the first phase while obtaining long-term continuous improvement in the second phase and beyond. Phase I of the initiative included a concentrated review of processes that had a high potential for cost savings with the intent of realizing savings in Fiscal Year 1996 (FY-96.) Phase II consists of implementing long-term strategies too complex for Phase I implementation and evaluation of processes not targeted for Phase I review. The Phase II effort is targeted for realizing cost savings in FY-97 and beyond

  18. Making process improvement 'stick'.

    Science.gov (United States)

    Studer, Quint

    2014-06-01

    To sustain gains from a process improvement initiative, healthcare organizations should: Explain to staff why a process improvement initiative is needed. Encourage leaders within the organization to champion the process improvement, and tie their evaluations to its outcomes. Ensure that both leaders and employees have the skills to help sustain the sought-after process improvements.

  19. Fractional Poisson process (II)

    International Nuclear Information System (INIS)

    Wang Xiaotian; Wen Zhixiong; Zhang Shiying

    2006-01-01

    In this paper, we propose a stochastic process W H (t)(H-bar (12,1)) which we call fractional Poisson process. The process W H (t) is self-similar in wide sense, displays long range dependence, and has more fatter tail than Gaussian process. In addition, it converges to fractional Brownian motion in distribution

  20. Genetic process mining

    NARCIS (Netherlands)

    Aalst, van der W.M.P.; Alves De Medeiros, A.K.; Weijters, A.J.M.M.; Ciardo, G.; Darondeau, P.

    2005-01-01

    The topic of process mining has attracted the attention of both researchers and tool vendors in the Business Process Management (BPM) space. The goal of process mining is to discover process models from event logs, i.e., events logged by some information system are used to extract information about

  1. Business process quality management

    NARCIS (Netherlands)

    Reijers, H.A.; Mendling, J.; Recker, J.; Brocke, vom J.; Rosemann, M.

    2010-01-01

    Abstract Process modeling is a central element in any approach to Business Process Management (BPM). However, what hinders both practitioners and aca demics is the lack of support for assessing the quality of process models — let alone realizing high quality process models. Existing frameworks are

  2. Shell coal gasification process

    Energy Technology Data Exchange (ETDEWEB)

    Hennekes, B. [Shell Global Solutions (US) Inc. (United States). Technology Marketing

    2002-07-01

    The presentation, on which 17 slides/overheads are included in the papers, explained the principles of the Shell coal gasification process and the methods incorporated for control of sulfur dioxide, nitrogen oxides, particulates and mercury. The economics of the process were discussed. The differences between gasification and burning, and the differences between the Shell process and other processes were discussed.

  3. Exploring processes and deviations

    NARCIS (Netherlands)

    Leemans, S.J.J.; Fahland, D.; Aalst, van der W.M.P.; Fournier, F.; Mendling, J.

    2015-01-01

    In process mining, one of the main challenges is to discover a process model, while balancing several quality criteria. This often requires repeatedly setting parameters, discovering a map and evaluating it, which we refer to as process exploration. Commercial process mining tools like Disco,

  4. Distributed genetic process mining

    NARCIS (Netherlands)

    Bratosin, C.C.; Sidorova, N.; Aalst, van der W.M.P.

    2010-01-01

    Process mining aims at discovering process models from data logs in order to offer insight into the real use of information systems. Most of the existing process mining algorithms fail to discover complex constructs or have problems dealing with noise and infrequent behavior. The genetic process

  5. Dosimetry and process control for radiation processing

    International Nuclear Information System (INIS)

    Mod Ali, N.

    2002-01-01

    Complete text of publication follows. Accurate radiation dosimetry can provide quality assurance in radiation processing. Considerable relevant experiences in dosimetry by the SSDL-MINT has necessitate the development of methods making measurement at gamma plant traceable to the national standard. It involves the establishment of proper calibration procedure and selection of appropriate transfer system/technique to assure adequate traceability to a primary radiation standard. The effort forms the basis for irradiation process control, the legal approval of the process by the public health authorities (medical product sterilization and food preservation) and the safety and acceptance of the product

  6. Thin film processes

    CERN Document Server

    Vossen, John L

    1978-01-01

    Remarkable advances have been made in recent years in the science and technology of thin film processes for deposition and etching. It is the purpose of this book to bring together tutorial reviews of selected filmdeposition and etching processes from a process viewpoint. Emphasis is placed on the practical use of the processes to provide working guidelines for their implementation, a guide to the literature, and an overview of each process.

  7. A Campbell random process

    International Nuclear Information System (INIS)

    Reuss, J.D.; Misguich, J.H.

    1993-02-01

    The Campbell process is a stationary random process which can have various correlation functions, according to the choice of an elementary response function. The statistical properties of this process are presented. A numerical algorithm and a subroutine for generating such a process is built up and tested, for the physically interesting case of a Campbell process with Gaussian correlations. The (non-Gaussian) probability distribution appears to be similar to the Gamma distribution

  8. Business process transformation the process tangram framework

    CERN Document Server

    Sharma, Chitra

    2015-01-01

    This book presents a framework through transformation and explains  how business goals can be translated into realistic plans that are tangible and yield real results in terms of the top line and the bottom line. Process Transformation is like a tangram puzzle, which has multiple solutions yet is essentially composed of seven 'tans' that hold it together. Based on practical experience and intensive research into existing material, 'Process Tangram' is a simple yet powerful framework that proposes Process Transformation as a program. The seven 'tans' are: the transformation program itself, triggers, goals, tools and techniques, culture, communication and success factors. With its segregation into tans and division into core elements, this framework makes it possible to use 'pick and choose' to quickly and easily map an organization's specific requirements. Change management and process modeling are covered in detail. In addition, the book approaches managed services as a model of service delivery, which it ex...

  9. Dry process potentials

    International Nuclear Information System (INIS)

    Faugeras, P.

    1997-01-01

    Various dry processes have been studied and more or less developed in order particularly to reduce the waste quantities but none of them had replaced the PUREX process, for reasons departing to policy errors, un-appropriate demonstration examples or too late development, although realistic and efficient dry processes such as a fluoride selective volatility based processes have been demonstrated in France (CLOVIS, ATILA) and would be ten times cheaper than the PUREX process. Dry processes could regain interest in case of a nuclear revival (following global warming fears) or thermal wastes over-production. In the near future, dry processes could be introduced in complement to the PUREX process, especially at the end of the process cycle, for a more efficient recycling and safer storage (inactivation)

  10. Honing process optimization algorithms

    Science.gov (United States)

    Kadyrov, Ramil R.; Charikov, Pavel N.; Pryanichnikova, Valeria V.

    2018-03-01

    This article considers the relevance of honing processes for creating high-quality mechanical engineering products. The features of the honing process are revealed and such important concepts as the task for optimization of honing operations, the optimal structure of the honing working cycles, stepped and stepless honing cycles, simulation of processing and its purpose are emphasized. It is noted that the reliability of the mathematical model determines the quality parameters of the honing process control. An algorithm for continuous control of the honing process is proposed. The process model reliably describes the machining of a workpiece in a sufficiently wide area and can be used to operate the CNC machine CC743.

  11. Defense waste processing facility precipitate hydrolysis process

    International Nuclear Information System (INIS)

    Doherty, J.P.; Eibling, R.E.; Marek, J.C.

    1986-03-01

    Sodium tetraphenylborate and sodium titanate are used to assist in the concentration of soluble radionuclide in the Savannah River Plant's high-level waste. In the Defense Waste Processing Facility, concentrated tetraphenylborate/sodium titanate slurry containing cesium-137, strontium-90 and traces of plutonium from the waste tank farm is hydrolyzed in the Salt Processing Cell forming organic and aqueous phases. The two phases are then separated and the organic phase is decontaminated for incineration outside the DWPF building. The aqueous phase, containing the radionuclides and less than 10% of the original organic, is blended with the insoluble radionuclides in the high-level waste sludge and is fed to the glass melter for vitrification into borosilicate glass. During the Savannah River Laboratory's development of this process, copper (II) was found to act as a catalyst during the hydrolysis reactions, which improved the organic removal and simplified the design of the reactor

  12. The Diazo Copying Process.

    Science.gov (United States)

    Osterby, Bruce

    1989-01-01

    Described is an activity which demonstrates an organic-based reprographic method that is used extensively for the duplication of microfilm and engineering drawings. Discussed are the chemistry of the process and how to demonstrate the process for students. (CW)

  13. Waste processing air cleaning

    International Nuclear Information System (INIS)

    Kriskovich, J.R.

    1998-01-01

    Waste processing and preparing waste to support waste processing relies heavily on ventilation. Ventilation is used at the Hanford Site on the waste storage tanks to provide confinement, cooling, and removal of flammable gases

  14. Radiochemical Processing Laboratory (RPL)

    Data.gov (United States)

    Federal Laboratory Consortium — The Radiochemical Processing Laboratory (RPL)�is a scientific facility funded by DOE to create and implement innovative processes for environmental clean-up and...

  15. Laser material processing

    CERN Document Server

    Steen, William

    2010-01-01

    This text moves from the basics of laser physics to detailed treatments of all major materials processing techniques for which lasers are now essential. New chapters cover laser physics, drilling, micro- and nanomanufacturing and biomedical laser processing.

  16. Business Process Inventory

    Data.gov (United States)

    Office of Personnel Management — Inventory of maps and descriptions of the business processes of the U.S. Office of Personnel Management (OPM), with an emphasis on the processes of the Office of the...

  17. Process evaluation distributed system

    Science.gov (United States)

    Moffatt, Christopher L. (Inventor)

    2006-01-01

    The distributed system includes a database server, an administration module, a process evaluation module, and a data display module. The administration module is in communication with the database server for providing observation criteria information to the database server. The process evaluation module is in communication with the database server for obtaining the observation criteria information from the database server and collecting process data based on the observation criteria information. The process evaluation module utilizes a personal digital assistant (PDA). A data display module in communication with the database server, including a website for viewing collected process data in a desired metrics form, the data display module also for providing desired editing and modification of the collected process data. The connectivity established by the database server to the administration module, the process evaluation module, and the data display module, minimizes the requirement for manual input of the collected process data.

  18. Group Decision Process Support

    DEFF Research Database (Denmark)

    Gøtze, John; Hijikata, Masao

    1997-01-01

    Introducing the notion of Group Decision Process Support Systems (GDPSS) to traditional decision-support theorists.......Introducing the notion of Group Decision Process Support Systems (GDPSS) to traditional decision-support theorists....

  19. Cognitive processes in CBT

    NARCIS (Netherlands)

    Becker, E.S.; Vrijsen, J.N.; Hofmann, S.G.; Asmundson, G.J.G.

    2017-01-01

    Automatic cognitive processing helps us navigate the world. However, if the emotional and cognitive interplay becomes skewed, those cognitive processes can become maladaptive and result in psychopathology. Although biases are present in most mental disorders, different disorders are characterized by

  20. Improving Healthcare Logistics Processes

    DEFF Research Database (Denmark)

    Feibert, Diana Cordes

    logistics processes in hospitals and aims to provide theoretically and empirically based evidence for improving these processes to both expand the knowledge base of healthcare logistics and provide a decision tool for hospital logistics managers to improve their processes. Case studies were conducted...... processes. Furthermore, a method for benchmarking healthcare logistics processes was developed. Finally, a theoretically and empirically founded framework was developed to support managers in making an informed decision on how to improve healthcare logistics processes. This study contributes to the limited...... literature concerned with the improvement of logistics processes in hospitals. Furthermore, the developed framework provides guidance for logistics managers in hospitals on how to improve their processes given the circumstances in which they operate....

  1. Flavor changing lepton processes

    International Nuclear Information System (INIS)

    Kuno, Yoshitaka

    2002-01-01

    The flavor changing lepton processes, or in another words the lepton flavor changing processes, are described with emphasis on the updated theoretical motivations and the on-going experimental progress on a new high-intense muon source. (author)

  2. Process innovation laboratory

    DEFF Research Database (Denmark)

    Møller, Charles

    2007-01-01

    to create a new methodology for developing and exploring process models and applications. The paper outlines the process innovation laboratory as a new approach to BPI. The process innovation laboratory is a comprehensive framework and a collaborative workspace for experimenting with process models....... The process innovation laboratory facilitates innovation by using an integrated action learning approach to process modelling in a controlled environment. The study is based on design science and the paper also discusses the implications to EIS research and practice......Most organizations today are required not only to operate effective business processes but also to allow for changing business conditions at an increasing rate. Today nearly every business relies on their enterprise information systems (EIS) for process integration and future generations of EIS...

  3. The Integrated Renovation Process

    DEFF Research Database (Denmark)

    Galiotto, Nicolas; Heiselberg, Per; Knudstrup, Mary-Ann

    The Integrated Renovation Process (IRP) is a user customized methodology based on judiciously selected constructivist and interactive multi-criteria decision making methods (Galiotto, Heiselberg, & Knudstrup, 2014 (expected)). When applied for home renovation, the Integrated Renovation Process...

  4. Wetland Groundwater Processes

    National Research Council Canada - National Science Library

    Williams, Greg

    1993-01-01

    This technical note summarizes hydrologic and hydraulic (H AND H) processes and the related terminology that will likely be encountered during an evaluation of the effect of ground-water processes on wetland function...

  5. Flue Gas Desulphurization Processes

    International Nuclear Information System (INIS)

    Aly, A.I.M.; Halhouli, K.A.; Abu-Ashur, B.M.

    1999-01-01

    Flue gas desulphurization process are discussed. These processes can be grouped into non-regenerable systems and regenerable systems. The non-regenerable systems produce a product which is either disposed of as waste or sold as a by-product e.g. lime/limestone process. While in the regenerable systems, e.g. Wellman-Lord process, the SO 2 is regenerated from the sorbent(sodium sulphite), which is returned to absorb more SO 2 . Also a newer technology for flue gas desulphurization is discussed. The Ispra process uses bromine as oxidant, producing HBr, from which bromine is regenerated by electrolysis. The only by-products of this process are sulphuric acid and hydrogen, which are both valuable products, and no waste products are produced. Suggested modifications on the process are made based on experimental investigations to improve the efficiency of the process and to reduce its costs

  6. Chemical radwaste solidification processes

    International Nuclear Information System (INIS)

    Malloy, C.W.

    1979-01-01

    Some of these processes and their problems are briefly reviewed: early cement systems; urea-formaldehyde; Dow solidification process; low-viscosity chemical agents (POLYPAC); and water-extensible polyester. 9 refs

  7. The plasma hearth process: Process residuals characterization

    International Nuclear Information System (INIS)

    Leatherman, G.L.; Geimer, R.; Batdorf, J.; Hassel, G.; Wolfe, P.; Carney, K.P.

    1994-01-01

    The Plasma Hearth Process (PHP) is a high-temperature waste treatment process being developed by Science Applications International Corporation (SAIC) for the Department of Energy (DOE) that destroys hazardous organics while stabilizing radionuclides and hazardous metals in a vitreous slag waste form. The PHP has potential application for the treatment of a wide range of mixed waste types in both the low-level and transuranic (TRU) mixed waste categories. DOE, through the Office of Technology Development's Mixed Waste Integrated Program (MWIP) is conducting a three phase development project to ready the PHP for implementation in the DOE complex

  8. Process and device for processing radioactive wastes

    International Nuclear Information System (INIS)

    1974-01-01

    A method is described for processing liquid radioactive wastes. It includes the heating of the liquid wastes so that the contained liquids are evaporated and a practically anhydrous mass of solid particles inferior in volume to that of the wastes introduced is formed, then the transformation of the solid particles into a monolithic structure. This transformation includes the compressing of the particles and sintering or fusion. The solidifying agent is a mixture of polyethylene and paraffin wax or a styrene copolymer and a polyester resin. The device used for processing the radioactive liquid wastes is also described [fr

  9. Grind hardening process

    CERN Document Server

    Salonitis, Konstantinos

    2015-01-01

    This book presents the grind-hardening process and the main studies published since it was introduced in 1990s.  The modelling of the various aspects of the process, such as the process forces, temperature profile developed, hardness profiles, residual stresses etc. are described in detail. The book is of interest to the research community working with mathematical modeling and optimization of manufacturing processes.

  10. Software Process Improvement Defined

    DEFF Research Database (Denmark)

    Aaen, Ivan

    2002-01-01

    This paper argues in favor of the development of explanatory theory on software process improvement. The last one or two decades commitment to prescriptive approaches in software process improvement theory may contribute to the emergence of a gulf dividing theorists and practitioners....... It is proposed that this divide be met by the development of theory evaluating prescriptive approaches and informing practice with a focus on the software process policymaking and process control aspects of improvement efforts...

  11. Modeling multiphase materials processes

    CERN Document Server

    Iguchi, Manabu

    2010-01-01

    ""Modeling Multiphase Materials Processes: Gas-Liquid Systems"" describes the methodology and application of physical and mathematical modeling to multi-phase flow phenomena in materials processing. The book focuses on systems involving gas-liquid interaction, the most prevalent in current metallurgical processes. The performance characteristics of these processes are largely dependent on transport phenomena. This volume covers the inherent characteristics that complicate the modeling of transport phenomena in such systems, including complex multiphase structure, intense turbulence, opacity of

  12. Dosimetry for radiation processing

    DEFF Research Database (Denmark)

    Miller, Arne

    1986-01-01

    During the past few years significant advances have taken place in the different areas of dosimetry for radiation processing, mainly stimulated by the increased interest in radiation for food preservation, plastic processing and sterilization of medical products. Reference services both...... and sterilization dosimetry, optichromic dosimeters in the shape of small tubes for food processing, and ESR spectroscopy of alanine for reference dosimetry. In this paper the special features of radiation processing dosimetry are discussed, several commonly used dosimeters are reviewed, and factors leading...

  13. Generating process model collections

    NARCIS (Netherlands)

    Yan, Z.; Dijkman, R.M.; Grefen, P.W.P.J.

    2017-01-01

    Business process management plays an important role in the management of organizations. More and more organizations describe their operations as business processes. It is common for organizations to have collections of thousands of business processes, but for reasons of confidentiality these

  14. Multiphoton processes: conference proceedings

    International Nuclear Information System (INIS)

    Lambropoulos, P.; Smith, S.J.

    1984-01-01

    The chapters of this volume represent the invited papers delivered at the conference. They are arranged according to thermatic proximity beginning with atoms and continuing with molecules and surfaces. Section headings include multiphoton processes in atoms, field fluctuations and collisions in multiphoton process, and multiphoton processes in molecules and surfaces. Abstracts of individual items from the conference were prepared separately for the data base

  15. Semisolid Metal Processing Consortium

    Energy Technology Data Exchange (ETDEWEB)

    Apelian,Diran

    2002-01-10

    Mathematical modeling and simulations of semisolid filling processes remains a critical issue in understanding and optimizing the process. Semisolid slurries are non-Newtonian materials that exhibit complex rheological behavior. There the way these slurries flow in cavities is very different from the way liquid in classical casting fills cavities. Actually filling in semisolid processing is often counter intuitive

  16. How yogurt is processed

    Science.gov (United States)

    This month’s Processing column on the theme of “How Is It Processed?” focuses on yogurt. Yogurt is known for its health-promoting properties. This column will provide a brief overview of the history of yogurt and the current market. It will also unveil both traditional and modern yogurt processing t...

  17. Clinical Process Intelligence

    DEFF Research Database (Denmark)

    Vilstrup Pedersen, Klaus

    2006-01-01

    .e. local guidelines. From a knowledge management point of view, this externalization of generalized processes, gives the opportunity to learn from, evaluate and optimize the processes. "Clinical Process Intelligence" (CPI), will denote the goal of getting generalized insight into patient centered health...

  18. Process research and development

    Science.gov (United States)

    Bickler, D. B.

    1986-01-01

    The following major processes involved in the production of crystalline-silicon solar cells were discussed: surface preparation, junction formation, metallization, and assembly. The status of each of these processes, and the sequence in which these processes are applied, were described as they were in 1975, as they were in 1985, and what they might be in the future.

  19. The Constitutional Amendment Process

    Science.gov (United States)

    Chism, Kahlil

    2005-01-01

    This article discusses the constitutional amendment process. Although the process is not described in great detail, Article V of the United States Constitution allows for and provides instruction on amending the Constitution. While the amendment process currently consists of six steps, the Constitution is nevertheless quite difficult to change.…

  20. Teaching Process Design through Integrated Process Synthesis

    Science.gov (United States)

    Metzger, Matthew J.; Glasser, Benjamin J.; Patel, Bilal; Hildebrandt, Diane; Glasser, David

    2012-01-01

    The design course is an integral part of chemical engineering education. A novel approach to the design course was recently introduced at the University of the Witwatersrand, Johannesburg, South Africa. The course aimed to introduce students to systematic tools and techniques for setting and evaluating performance targets for processes, as well as…

  1. Statistical Process Control for KSC Processing

    Science.gov (United States)

    Ford, Roger G.; Delgado, Hector; Tilley, Randy

    1996-01-01

    The 1996 Summer Faculty Fellowship Program and Kennedy Space Center (KSC) served as the basis for a research effort into statistical process control for KSC processing. The effort entailed several tasks and goals. The first was to develop a customized statistical process control (SPC) course for the Safety and Mission Assurance Trends Analysis Group. The actual teaching of this course took place over several weeks. In addition, an Internet version of the same course complete with animation and video excerpts from the course when it was taught at KSC was developed. The application of SPC to shuttle processing took up the rest of the summer research project. This effort entailed the evaluation of SPC use at KSC, both present and potential, due to the change in roles for NASA and the Single Flight Operations Contractor (SFOC). Individual consulting on SPC use was accomplished as well as an evaluation of SPC software for KSC use in the future. A final accomplishment of the orientation of the author to NASA changes, terminology, data format, and new NASA task definitions will allow future consultation when the needs arise.

  2. Process-based costing.

    Science.gov (United States)

    Lee, Robert H; Bott, Marjorie J; Forbes, Sarah; Redford, Linda; Swagerty, Daniel L; Taunton, Roma Lee

    2003-01-01

    Understanding how quality improvement affects costs is important. Unfortunately, low-cost, reliable ways of measuring direct costs are scarce. This article builds on the principles of process improvement to develop a costing strategy that meets both criteria. Process-based costing has 4 steps: developing a flowchart, estimating resource use, valuing resources, and calculating direct costs. To illustrate the technique, this article uses it to cost the care planning process in 3 long-term care facilities. We conclude that process-based costing is easy to implement; generates reliable, valid data; and allows nursing managers to assess the costs of new or modified processes.

  3. Colloid process engineering

    CERN Document Server

    Peukert, Wolfgang; Rehage, Heinz; Schuchmann, Heike

    2015-01-01

    This book deals with colloidal systems in technical processes and the influence of colloidal systems by technical processes. It explores how new measurement capabilities can offer the potential for a dynamic development of scientific and engineering, and examines the origin of colloidal systems and its use for new products. The future challenges to colloidal process engineering are the development of appropriate equipment and processes for the production and obtainment of multi-phase structures and energetic interactions in market-relevant quantities. The book explores the relevant processes and for controlled production and how they can be used across all scales.

  4. Nonaqueous processing methods

    International Nuclear Information System (INIS)

    Coops, M.S.; Bowersox, D.F.

    1984-09-01

    A high-temperature process utilizing molten salt extraction from molten metal alloys has been developed for purification of spent power reactor fuels. Experiments with laboratory-scale processing operations show that purification and throughput parameters comparable to the Barnwell Purex process can be achieved by pyrochemical processing in equipment one-tenth the size, with all wastes being discharged as stable metal alloys at greatly reduced volume and disposal cost. This basic technology can be developed for large-scale processing of spent reactor fuels. 13 references, 4 figures

  5. Data processing made simple

    CERN Document Server

    Wooldridge, Susan

    2013-01-01

    Data Processing: Made Simple, Second Edition presents discussions of a number of trends and developments in the world of commercial data processing. The book covers the rapid growth of micro- and mini-computers for both home and office use; word processing and the 'automated office'; the advent of distributed data processing; and the continued growth of database-oriented systems. The text also discusses modern digital computers; fundamental computer concepts; information and data processing requirements of commercial organizations; and the historical perspective of the computer industry. The

  6. Thin film processes II

    CERN Document Server

    Kern, Werner

    1991-01-01

    This sequel to the 1978 classic, Thin Film Processes, gives a clear, practical exposition of important thin film deposition and etching processes that have not yet been adequately reviewed. It discusses selected processes in tutorial overviews with implementation guide lines and an introduction to the literature. Though edited to stand alone, when taken together, Thin Film Processes II and its predecessor present a thorough grounding in modern thin film techniques.Key Features* Provides an all-new sequel to the 1978 classic, Thin Film Processes* Introduces new topics, and sever

  7. FFTF gas processing systems

    International Nuclear Information System (INIS)

    Halverson, T.G.

    1977-01-01

    The design and operation of the two radioactive gas processing systems at the Fast Flux Test Facility (FFTF) exemplifies the concept that will be used in the first generation of Liquid Metal Fast Breeder Reactors (LMFBR's). The two systems, the Radioactive Argon Processing System (RAPS) and the Cell Atmosphere Processing System (CAPS), process the argon and nitrogen used in the FFTF for cover gas on liquid metal systems and as inert atmospheres in steel lined cells housing sodium equipment. The RAPS specifically processes the argon cover gas from the reactor coolant system, providing for decontamination and eventual reuse. The CAPS processes radioactive gasses from inerted cells and other liquid metal cover gas systems, providing for decontamination and ultimate discharge to the atmosphere. The cryogenic processing of waste gas by both systems is described

  8. Recomendaciones para el uso de everolimus en trasplante renal de novo: falsas creencias, mitos y realidades

    Directory of Open Access Journals (Sweden)

    Julio Pascual

    2017-05-01

    Estas recomendaciones tratan de aportar la evidencia científica que apoya esta práctica, discuten las falsas creencias, mitos y realidades de la combinación y concretan pautas que permiten utilizarla con seguridad y evitar complicaciones.

  9. Everolimus and Lenalidomide in Treating Patients With Relapsed or Refractory Non-Hodgkin or Hodgkin Lymphoma

    Science.gov (United States)

    2018-02-07

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Splenic Marginal Zone Lymphoma; Waldenstrom Macroglobulinemia

  10. XIENCE V everolimus-eluting coronary stent system: a novel second generation drug-eluting stent

    NARCIS (Netherlands)

    Beijk, Marcel A. M.; Piek, Jon J.

    2007-01-01

    Drug-eluting stents (DES) have been shown to be safe and significantly reduce clinical events and angiographic restenosis in the percutaneous treatment of coronary artery disease. Currently, three DES have been approved in Europe and Northern America: the sirolimus-eluting stent (SES), the

  11. Poisson branching point processes

    International Nuclear Information System (INIS)

    Matsuo, K.; Teich, M.C.; Saleh, B.E.A.

    1984-01-01

    We investigate the statistical properties of a special branching point process. The initial process is assumed to be a homogeneous Poisson point process (HPP). The initiating events at each branching stage are carried forward to the following stage. In addition, each initiating event independently contributes a nonstationary Poisson point process (whose rate is a specified function) located at that point. The additional contributions from all points of a given stage constitute a doubly stochastic Poisson point process (DSPP) whose rate is a filtered version of the initiating point process at that stage. The process studied is a generalization of a Poisson branching process in which random time delays are permitted in the generation of events. Particular attention is given to the limit in which the number of branching stages is infinite while the average number of added events per event of the previous stage is infinitesimal. In the special case when the branching is instantaneous this limit of continuous branching corresponds to the well-known Yule--Furry process with an initial Poisson population. The Poisson branching point process provides a useful description for many problems in various scientific disciplines, such as the behavior of electron multipliers, neutron chain reactions, and cosmic ray showers

  12. A secondary fuel removal process: plasma processing

    Energy Technology Data Exchange (ETDEWEB)

    Min, J Y; Kim, Y S [Hanyang Univ., Seoul (Korea, Republic of); Bae, K K; Yang, M S [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

    1997-07-01

    Plasma etching process of UO{sub 2} by using fluorine containing gas plasma is studied as a secondary fuel removal process for DUPIC (Direct Use of PWR spent fuel Into Candu) process which is taken into consideration for potential future fuel cycle in Korea. CF{sub 4}/O{sub 2} gas mixture is chosen for reactant gas and the etching rates of UO{sub 2} by the gas plasma are investigated as functions of CF{sub 4}/O{sub 2} ratio, plasma power, substrate temperature, and plasma gas pressure. It is found that the optimum CF{sub 4}/O{sub 2} ratio is around 4:1 at all temperatures up to 400 deg C and the etching rate increases with increasing r.f. power and substrate temperature. Under 150W r.f. power the etching rate reaches 1100 monolayers/min at 400 deg C, which is equivalent to about 0.5mm/min. (author).

  13. The SILVA atomic process

    International Nuclear Information System (INIS)

    Cazalet, J.

    1997-01-01

    The SILVA laser isotope separation process is based on the laser selective photo-ionization of uranium atomic vapour; the process is presently under development by CEA and COGEMA in France, with the aim to reduce by a factor three the cost of uranium enrichment. The two main components of a SILVA process plant are the lasers (copper vapour lasers and dye lasers) and the separator for the vaporization (with a high energy electron beam), ionization and separation operations. Researches on the SILVA process started in 1985 and the technical and economical feasibility is to be demonstrated in 1997. The progresses of similar rival processes and other processes are discussed and the remaining research stages and themes of the SILVA program are presented

  14. Technology or Process First?

    DEFF Research Database (Denmark)

    Siurdyban, Artur Henryk; Svejvig, Per; Møller, Charles

    Enterprise Systems Management (ESM) and Business Pro- cess Management (BPM), although highly correlated, have evolved as alternative and mutually exclusive approaches to corporate infrastruc- ture. As a result, companies struggle to nd the right balance between technology and process factors...... in infrastructure implementation projects. The purpose of this paper is articulate a need and a direction to medi- ate between the process-driven and the technology-driven approaches. Using a cross-case analysis, we gain insight into two examples of sys- tems and process implementation. We highlight the dierences...... between them using strategic alignment, Enterprise Systems and Business Process Management theories. We argue that the insights from these cases can lead to a better alignment between process and technology. Implications for practice include the direction towards a closer integration of process...

  15. Badge Office Process Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Haurykiewicz, John Paul [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Dinehart, Timothy Grant [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Parker, Robert Young [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-05-12

    The purpose of this process analysis was to analyze the Badge Offices’ current processes from a systems perspective and consider ways of pursuing objectives set forth by SEC-PS, namely increased customer flow (throughput) and reduced customer wait times. Information for the analysis was gathered for the project primarily through Badge Office Subject Matter Experts (SMEs), and in-person observation of prevailing processes. Using the information gathered, a process simulation model was constructed to represent current operations and allow assessment of potential process changes relative to factors mentioned previously. The overall purpose of the analysis was to provide SEC-PS management with information and recommendations to serve as a basis for additional focused study and areas for potential process improvements in the future.

  16. Business process transformation

    CERN Document Server

    Grover, Varun

    2015-01-01

    Featuring contributions from prominent thinkers and researchers, this volume in the ""Advances in Management Information Systems"" series provides a rich set of conceptual, empirical, and introspective studies that epitomize fundamental knowledge in the area of Business Process Transformation. Processes are interpreted broadly to include operational and managerial processes within and between organizations, as well as those involved in knowledge generation. Transformation includes radical and incremental change, its conduct, management, and outcome. The editors and contributing authors pay clo

  17. Rational Unified Process

    OpenAIRE

    Kopal, Nils

    2016-01-01

    In this German seminar paper, which was written in the year 2011 at the University of Duisburg for a Bachelor Colloquium in Applied computer science, we show a brief overview of the Rational Unified Process (RUP). Thus, interested students or generally interested people in software development gain a first impression of RUP. The paper includes a survey and overview of the underlying process structure, the phases of the process, its workflows, and describes the always by the RUP developers pos...

  18. Deference and Due Process

    OpenAIRE

    Vermeule, Cornelius Adrian

    2015-01-01

    In the textbooks, procedural due process is a strictly judicial enterprise; although substantive entitlements are created by legislative and executive action, it is for courts to decide independently what process the Constitution requires. The notion that procedural due process might be committed primarily to the discretion of the agencies themselves is almost entirely absent from the academic literature. The facts on the ground are very different. Thanks to converging strands of caselaw ...

  19. Process Improvement Essentials

    CERN Document Server

    Persse, James R

    2006-01-01

    Process Improvement Essentials combines the foundation needed to understand process improvement theory with the best practices to help individuals implement process improvement initiatives in their organization. The three leading programs: ISO 9001:2000, CMMI, and Six Sigma--amidst the buzz and hype--tend to get lumped together under a common label. This book delivers a combined guide to all three programs, compares their applicability, and then sets the foundation for further exploration.

  20. Basic digital signal processing

    CERN Document Server

    Lockhart, Gordon B

    1985-01-01

    Basic Digital Signal Processing describes the principles of digital signal processing and experiments with BASIC programs involving the fast Fourier theorem (FFT). The book reviews the fundamentals of the BASIC program, continuous and discrete time signals including analog signals, Fourier analysis, discrete Fourier transform, signal energy, power. The text also explains digital signal processing involving digital filters, linear time-variant systems, discrete time unit impulse, discrete-time convolution, and the alternative structure for second order infinite impulse response (IIR) sections.

  1. Multiphoton processes: conference proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Lambropoulos, P.; Smith, S.J. (eds.)

    1984-01-01

    The chapters of this volume represent the invited papers delivered at the conference. They are arranged according to thermatic proximity beginning with atoms and continuing with molecules and surfaces. Section headings include multiphoton processes in atoms, field fluctuations and collisions in multiphoton process, and multiphoton processes in molecules and surfaces. Abstracts of individual items from the conference were prepared separately for the data base. (GHT)

  2. TEP process flow diagram

    Energy Technology Data Exchange (ETDEWEB)

    Wilms, R Scott [Los Alamos National Laboratory; Carlson, Bryan [Los Alamos National Laboratory; Coons, James [Los Alamos National Laboratory; Kubic, William [Los Alamos National Laboratory

    2008-01-01

    This presentation describes the development of the proposed Process Flow Diagram (PFD) for the Tokamak Exhaust Processing System (TEP) of ITER. A brief review of design efforts leading up to the PFD is followed by a description of the hydrogen-like, air-like, and waterlike processes. Two new design values are described; the mostcommon and most-demanding design values. The proposed PFD is shown to meet specifications under the most-common and mostdemanding design values.

  3. Standard Model processes

    CERN Document Server

    Mangano, M.L.; Aguilar-Saavedra, Juan Antonio; Alekhin, S.; Badger, S.; Bauer, C.W.; Becher, T.; Bertone, V.; Bonvini, M.; Boselli, S.; Bothmann, E.; Boughezal, R.; Cacciari, M.; Carloni Calame, C.M.; Caola, F.; Campbell, J.M.; Carrazza, S.; Chiesa, M.; Cieri, L.; Cimaglia, F.; Febres Cordero, F.; Ferrarese, P.; D'Enterria, D.; Ferrera, G.; Garcia i Tormo, X.; Garzelli, M.V.; Germann, E.; Hirschi, V.; Han, T.; Ita, H.; Jäger, B.; Kallweit, S.; Karlberg, A.; Kuttimalai, S.; Krauss, F.; Larkoski, A.J.; Lindert, J.; Luisoni, G.; Maierhöfer, P.; Mattelaer, O.; Martinez, H.; Moch, S.; Montagna, G.; Moretti, M.; Nason, P.; Nicrosini, O.; Oleari, C.; Pagani, D.; Papaefstathiou, A.; Petriello, F.; Piccinini, F.; Pierini, M.; Pierog, T.; Pozzorini, S.; Re, E.; Robens, T.; Rojo, J.; Ruiz, R.; Sakurai, K.; Salam, G.P.; Salfelder, L.; Schönherr, M.; Schulze, M.; Schumann, S.; Selvaggi, M.; Shivaji, A.; Siodmok, A.; Skands, P.; Torrielli, P.; Tramontano, F.; Tsinikos, I.; Tweedie, B.; Vicini, A.; Westhoff, S.; Zaro, M.; Zeppenfeld, D.; CERN. Geneva. ATS Department

    2017-06-22

    This report summarises the properties of Standard Model processes at the 100 TeV pp collider. We document the production rates and typical distributions for a number of benchmark Standard Model processes, and discuss new dynamical phenomena arising at the highest energies available at this collider. We discuss the intrinsic physics interest in the measurement of these Standard Model processes, as well as their role as backgrounds for New Physics searches.

  4. Scientific information processing procedures

    Directory of Open Access Journals (Sweden)

    García, Maylin

    2013-07-01

    Full Text Available The paper systematizes several theoretical view-points on scientific information processing skill. It decomposes the processing skills into sub-skills. Several methods such analysis, synthesis, induction, deduction, document analysis were used to build up a theoretical framework. Interviews and survey to professional being trained and a case study was carried out to evaluate the results. All professional in the sample improved their performance in scientific information processing.

  5. Integrated Renovation Process

    DEFF Research Database (Denmark)

    Galiotto, Nicolas; Heiselberg, Per; Knudstrup, Mary-Ann

    2016-01-01

    renovation to be overcome. The homeowners were better integrated and their preferences and immaterial values were better taken into account. To keep the decision-making process economically viable and timely, the process as known today still needs to be improved, and new tools need to be developed....... This paper presents a new scheme: the integrated renovation process. One successful case study is introduced, and recommendations for future developments needed in the field are provided....

  6. Transuranium processing plant

    International Nuclear Information System (INIS)

    King, L.J.

    1983-01-01

    The Transuranium Processing Plant (TRU) is a remotely operated, hot-cell, chemical processing facility of advanced design. The heart of TRU is a battery of nine heavily shielded process cells housed in a two-story building. Each cell, with its 54-inch-thick walls of a special high-density concrete, has enough shielding to stop the neutrons and gamma radiation from 1 gram of 252/sub Cf/ and associated fission products. Four cells contain chemical processing equipment, three contain equipment for the preparation and inspection of HFIR targets, and two cells are used for analytical chemistry operations. In addition, there are eight laboratories used for process development, for part of the process-control analyses, and for product finishing operations. Although the Transuranium Processing Plant was built for the purpose of recovering transuranium elements from targets irradiated in the High Flux Isotope Reactor (HFIR), it is also a highly versatile facility which has extensive provisions for changing and modifying equipment. Thus, it was a relatively simple matter to install a Solvent Extraction Test Facility (SETF) in one of the TRU chemical processing cells for use in the evaluation and demonstration of solvent extraction flowsheets for the recovery of fissile and fertile materials from irradiated reactor fuels. The equipment in the SETF has been designed for process development and demonstrations and the particular type of mixer-settler contactors was chosen because it is easy to observe and sample

  7. Linearity in Process Languages

    DEFF Research Database (Denmark)

    Nygaard, Mikkel; Winskel, Glynn

    2002-01-01

    The meaning and mathematical consequences of linearity (managing without a presumed ability to copy) are studied for a path-based model of processes which is also a model of affine-linear logic. This connection yields an affine-linear language for processes, automatically respecting open......-map bisimulation, in which a range of process operations can be expressed. An operational semantics is provided for the tensor fragment of the language. Different ways to make assemblies of processes lead to different choices of exponential, some of which respect bisimulation....

  8. Refractometry in process engineering

    Energy Technology Data Exchange (ETDEWEB)

    Roepscher, H

    1980-02-01

    Following a brief historical introduction into general refractometry, the limiting angle refractometer is dealt with in the first section and the differential refractometer in the second section, as well as process engineering information on this measuring method being given. An attempt is made with an extensive close-to-practice description to introduce the planner and technician to this physical measuring method in process engineering in order that they be able to use it themselves if necessary. When properly applied, it can be a valuable help to process control in compliance with process automization.

  9. Process modeling style

    CERN Document Server

    Long, John

    2014-01-01

    Process Modeling Style focuses on other aspects of process modeling beyond notation that are very important to practitioners. Many people who model processes focus on the specific notation used to create their drawings. While that is important, there are many other aspects to modeling, such as naming, creating identifiers, descriptions, interfaces, patterns, and creating useful process documentation. Experience author John Long focuses on those non-notational aspects of modeling, which practitioners will find invaluable. Gives solid advice for creating roles, work produ

  10. The Critical Design Process

    DEFF Research Database (Denmark)

    Brunsgaard, Camilla; Knudstrup, Mary-Ann; Heiselberg, Per

    2014-01-01

    within Danish tradition of architecture and construction. The objective of the research presented in this paper, is to compare the different design processes behind the making of passive houses in a Danish context. We evaluated the process with regard to the integrated and traditional design process....... Data analysis showed that the majority of the consortiums worked in an integrated manner; though there was room for improvment. Additionally, the paper discusses the challanges of implementing the integrated design process in practice and suggests ways of overcomming some of the barriers . In doing so...

  11. Multimodal Processes Rescheduling

    DEFF Research Database (Denmark)

    Bocewicz, Grzegorz; Banaszak, Zbigniew A.; Nielsen, Peter

    2013-01-01

    Cyclic scheduling problems concerning multimodal processes are usually observed in FMSs producing multi-type parts where the Automated Guided Vehicles System (AGVS) plays a role of a material handling system. Schedulability analysis of concurrently flowing cyclic processes (SCCP) exe-cuted in the......Cyclic scheduling problems concerning multimodal processes are usually observed in FMSs producing multi-type parts where the Automated Guided Vehicles System (AGVS) plays a role of a material handling system. Schedulability analysis of concurrently flowing cyclic processes (SCCP) exe...

  12. Fuels Processing Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — NETL’s Fuels Processing Laboratory in Morgantown, WV, provides researchers with the equipment they need to thoroughly explore the catalytic issues associated with...

  13. Quantum information processing

    National Research Council Canada - National Science Library

    Leuchs, Gerd; Beth, Thomas

    2003-01-01

    ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5 SimulationofHamiltonians... References... 1 1 1 3 5 8 10 2 Quantum Information Processing and Error Correction with Jump Codes (G. Alber, M. Mussinger...

  14. Exhaust gas processing facility

    International Nuclear Information System (INIS)

    Terada, Shin-ichi.

    1995-01-01

    The facility of the present invention comprises a radioactive liquid storage vessel, an exhaust gas dehumidifying device for dehumidifying gases exhausted from the vessel and an exhaust gas processing device for reducing radioactive materials in the exhaust gases. A purified gas line is disposed to the radioactive liquid storage vessel for purging exhaust gases generated from the radioactive liquid, then dehumidified and condensed liquid is recovered, and exhaust gases are discharged through an exhaust gas pipe disposed downstream of the exhaust gas processing device. With such procedures, the scale of the exhaust gas processing facility can be reduced and exhaust gases can be processed efficiently. (T.M.)

  15. Chemical process hazards analysis

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-02-01

    The Office of Worker Health and Safety (EH-5) under the Assistant Secretary for the Environment, Safety and Health of the US Department (DOE) has published two handbooks for use by DOE contractors managing facilities and processes covered by the Occupational Safety and Health Administration (OSHA) Rule for Process Safety Management of Highly Hazardous Chemicals (29 CFR 1910.119), herein referred to as the PSM Rule. The PSM Rule contains an integrated set of chemical process safety management elements designed to prevent chemical releases that can lead to catastrophic fires, explosions, or toxic exposures. The purpose of the two handbooks, ``Process Safety Management for Highly Hazardous Chemicals`` and ``Chemical Process Hazards Analysis,`` is to facilitate implementation of the provisions of the PSM Rule within the DOE. The purpose of this handbook ``Chemical Process Hazards Analysis,`` is to facilitate, within the DOE, the performance of chemical process hazards analyses (PrHAs) as required under the PSM Rule. It provides basic information for the performance of PrHAs, and should not be considered a complete resource on PrHA methods. Likewise, to determine if a facility is covered by the PSM rule, the reader should refer to the handbook, ``Process Safety Management for Highly Hazardous Chemicals`` (DOE- HDBK-1101-96). Promulgation of the PSM Rule has heightened the awareness of chemical safety management issues within the DOE. This handbook is intended for use by DOE facilities and processes covered by the PSM rule to facilitate contractor implementation of the PrHA element of the PSM Rule. However, contractors whose facilities and processes not covered by the PSM Rule may also use this handbook as a basis for conducting process hazards analyses as part of their good management practices. This handbook explains the minimum requirements for PrHAs outlined in the PSM Rule. Nowhere have requirements been added beyond what is specifically required by the rule.

  16. Processer og procesledelse

    DEFF Research Database (Denmark)

    Madsen, Benedicte

    Bogen udfolder, nuancerer og konkretiserer procesledelse ift. mentale, relationelle og organisatoriske processer. Eksempler på kapitel-overskrifter: Procesbegrebet, Rammesætning, Kontraktredskabet, Mødeledelse, Samtaler, Reflekterende positioner og processer, Konflikthåndtering og teamudvikling......, Invitation til det dialogiske rum - om at arbejde over og under stregen, og Mentale omstruktureringer....

  17. The Player Engagement Process

    DEFF Research Database (Denmark)

    Schoenau-Fog, Henrik

    2011-01-01

    , categories and triggers involved in this process. By applying grounded theory to the analysis of the responses, a process-oriented player engagement framework was developed and four main components consisting of objectives, activities, accomplishments and affects as well as the corresponding categories...

  18. Mineral Processing Technology Roadmap

    Energy Technology Data Exchange (ETDEWEB)

    none,

    2000-09-01

    This document represents the roadmap for Processing Technology Research in the US Mining Industry. It was developed based on the results of a Processing Technology Roadmap Workshop sponsored by the National Mining Association in conjunction with the US Department of Energy, Office of Energy Efficiency and Renewable Energy, Office of Industrial Technologies. The Workshop was held January 24 - 25, 2000.

  19. Process control program development

    International Nuclear Information System (INIS)

    Dameron, H.J.

    1985-01-01

    This paper details the development and implementation of a ''Process Control Program'' at Duke Power's three nuclear stations - Oconee, McGuire, and Catawba. Each station is required by Technical Specification to have a ''Process Control Program'' (PCP) to control all dewatering and/or solidification activities for radioactive wastes

  20. Valuing the Accreditation Process

    Science.gov (United States)

    Bahr, Maria

    2018-01-01

    The value of the National Association for Developmental Education (NADE) accreditation process is far-reaching. Not only do students and programs benefit from the process, but also the entire institution. Through data collection of student performance, analysis, and resulting action plans, faculty and administrators can work cohesively towards…

  1. CMOS/SOS processing

    Science.gov (United States)

    Ramondetta, P.

    1980-01-01

    Report describes processes used in making complementary - metal - oxide - semiconductor/silicon-on-sapphire (CMOS/SOS) integrated circuits. Report lists processing steps ranging from initial preparation of sapphire wafers to final mapping of "good" and "bad" circuits on a wafer.

  2. Management oriented process

    International Nuclear Information System (INIS)

    2004-01-01

    ANAV decided to implement process-oriented management by adopting the U. S. NEI (Nuclear Electric Industry) model. The article describes the initial phases of the project, its current status and future prospects. The project has been considered as an improvement in the areas of organization and human factors. Recently, IAEA standard drafts are including processes as an accepted management model. (Author)

  3. Hybrid quantum information processing

    Energy Technology Data Exchange (ETDEWEB)

    Furusawa, Akira [Department of Applied Physics, School of Engineering, The University of Tokyo (Japan)

    2014-12-04

    I will briefly explain the definition and advantage of hybrid quantum information processing, which is hybridization of qubit and continuous-variable technologies. The final goal would be realization of universal gate sets both for qubit and continuous-variable quantum information processing with the hybrid technologies. For that purpose, qubit teleportation with a continuousvariable teleporter is one of the most important ingredients.

  4. Industrial separation processes : fundamentals

    NARCIS (Netherlands)

    Haan, de A.B.; Bosch, Hans

    2013-01-01

    Separation processes on an industrial scale comprise well over half of the capital and operating costs. They are basic knowledge in every chemical engineering and process engineering study. This book provides comprehensive and fundamental knowledge of university teaching in this discipline,

  5. METAL PLATING PROCESS

    Science.gov (United States)

    Walker, D.E.; Noland, R.A.

    1958-08-12

    A process ts described for obtaining a closely bonded coating of steel or iron on uranium. The process consists of providing, between the steel and uramium. a layer of silver. amd then pressure rolling tbe assembly at about 600 deg C until a reduction of from l0 to 50% has been obtained.

  6. The Analytical Hierarchy Process

    DEFF Research Database (Denmark)

    Barfod, Michael Bruhn

    2007-01-01

    The technical note gathers the theory behind the Analytical Hierarchy Process (AHP) and present its advantages and disadvantages in practical use.......The technical note gathers the theory behind the Analytical Hierarchy Process (AHP) and present its advantages and disadvantages in practical use....

  7. Semantic Business Process Modeling

    OpenAIRE

    Markovic, Ivan

    2010-01-01

    This book presents a process-oriented business modeling framework based on semantic technologies. The framework consists of modeling languages, methods, and tools that allow for semantic modeling of business motivation, business policies and rules, and business processes. Quality of the proposed modeling framework is evaluated based on the modeling content of SAP Solution Composer and several real-world business scenarios.

  8. Process energy analysis

    International Nuclear Information System (INIS)

    Kaiser, V.

    1993-01-01

    In Chapter 2 process energy cost analysis for chemical processing is treated in a general way, independent of the specific form of energy and power production. Especially, energy data collection and data treatment, energy accounting (metering, balance setting), specific energy input, and utility energy costs and prices are discussed. (R.P.) 14 refs., 4 figs., 16 tabs

  9. Continuous affine processes

    DEFF Research Database (Denmark)

    Buchardt, Kristian

    2016-01-01

    Affine processes possess the property that expectations of exponential affine transformations are given by a set of Riccati differential equations, which is the main feature of this popular class of processes. In this paper we generalise these results for expectations of more general transformati...

  10. Food-Processing Wastes.

    Science.gov (United States)

    Frenkel, Val S; Cummings, Gregg A; Maillacheruvu, K Y; Tang, Walter Z

    2017-10-01

    Literature published in 2016 and early 2017 related to food processing wastes treatment for industrial applications are reviewed. This review is a subsection of the Treatment Systems section of the annual Water Environment Federation literature review and covers the following food processing industries and applications: general, meat and poultry, fruits and vegetables, dairy and beverage, and miscellaneous treatment of food wastes.

  11. Food processing and allergenicity.

    Science.gov (United States)

    Verhoeckx, Kitty C M; Vissers, Yvonne M; Baumert, Joseph L; Faludi, Roland; Feys, Marcel; Flanagan, Simon; Herouet-Guicheney, Corinne; Holzhauser, Thomas; Shimojo, Ryo; van der Bolt, Nieke; Wichers, Harry; Kimber, Ian

    2015-06-01

    Food processing can have many beneficial effects. However, processing may also alter the allergenic properties of food proteins. A wide variety of processing methods is available and their use depends largely on the food to be processed. In this review the impact of processing (heat and non-heat treatment) on the allergenic potential of proteins, and on the antigenic (IgG-binding) and allergenic (IgE-binding) properties of proteins has been considered. A variety of allergenic foods (peanuts, tree nuts, cows' milk, hens' eggs, soy, wheat and mustard) have been reviewed. The overall conclusion drawn is that processing does not completely abolish the allergenic potential of allergens. Currently, only fermentation and hydrolysis may have potential to reduce allergenicity to such an extent that symptoms will not be elicited, while other methods might be promising but need more data. Literature on the effect of processing on allergenic potential and the ability to induce sensitisation is scarce. This is an important issue since processing may impact on the ability of proteins to cause the acquisition of allergic sensitisation, and the subject should be a focus of future research. Also, there remains a need to develop robust and integrated methods for the risk assessment of food allergenicity. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Business process intelligence

    NARCIS (Netherlands)

    Castellanos, M.; Alves De Medeiros, A.K.; Mendling, J.; Weber, B.; Weijters, A.J.M.M.; Cardoso, J.; Aalst, van der W.M.P.

    2009-01-01

    Business Process Intelligence (BPI,) is an emerging area that is getting increasingly popularfor enterprises. The need to improve business process efficiency, to react quickly to changes and to meet regulatory compliance is among the main drivers for BPI. BPI refers to the application of Business

  13. Correctness of concurrent processes

    NARCIS (Netherlands)

    E.R. Olderog (Ernst-Rüdiger)

    1989-01-01

    textabstractA new notion of correctness for concurrent processes is introduced and investigated. It is a relationship P sat S between process terms P built up from operators of CCS [Mi 80], CSP [Ho 85] and COSY [LTS 79] and logical formulas S specifying sets of finite communication sequences as in

  14. Uranium processing and properties

    CERN Document Server

    2013-01-01

    Covers a broad spectrum of topics and applications that deal with uranium processing and the properties of uranium Offers extensive coverage of both new and established practices for dealing with uranium supplies in nuclear engineering Promotes the documentation of the state-of-the-art processing techniques utilized for uranium and other specialty metals

  15. Relational Processing Following Stroke

    Science.gov (United States)

    Andrews, Glenda; Halford, Graeme S.; Shum, David; Maujean, Annick; Chappell, Mark; Birney, Damian

    2013-01-01

    The research examined relational processing following stroke. Stroke patients (14 with frontal, 30 with non-frontal lesions) and 41 matched controls completed four relational processing tasks: sentence comprehension, Latin square matrix completion, modified Dimensional Change Card Sorting, and n-back. Each task included items at two or three…

  16. Contaminated nickel scrap processing

    International Nuclear Information System (INIS)

    Compere, A.L.; Griffith, W.L.; Hayden, H.W.; Johnson, J.S. Jr.; Wilson, D.F.

    1994-12-01

    The DOE will soon choose between treating contaminated nickel scrap as a legacy waste and developing high-volume nickel decontamination processes. In addition to reducing the volume of legacy wastes, a decontamination process could make 200,000 tons of this strategic metal available for domestic use. Contaminants in DOE nickel scrap include 234 Th, 234 Pa, 137 Cs, 239 Pu (trace), 60 Co, U, 99 Tc, and 237 Np (trace). This report reviews several industrial-scale processes -- electrorefining, electrowinning, vapormetallurgy, and leaching -- used for the purification of nickel. Conventional nickel electrolysis processes are particularly attractive because they use side-stream purification of process solutions to improve the purity of nickel metal. Additionally, nickel purification by electrolysis is effective in a variety of electrolyte systems, including sulfate, chloride, and nitrate. Conventional electrorefining processes typically use a mixed electrolyte which includes sulfate, chloride, and borate. The use of an electrorefining or electrowinning system for scrap nickel recovery could be combined effectively with a variety of processes, including cementation, solvent extraction, ion exchange, complex-formation, and surface sorption, developed for uranium and transuranic purification. Selected processes were reviewed and evaluated for use in nickel side-stream purification. 80 refs

  17. Production process of VE

    International Nuclear Information System (INIS)

    1987-07-01

    This book tells of synopsis of production process of VE(value engineering), object selection method and establishment of target, collection of object information, design of function, write improvement suggestion, evaluation of improvement suggestion, all sorts of worksheets of production process of VE, explanation of IE, explanation of PERT.

  18. Perspectives on Innovation Processes

    NARCIS (Netherlands)

    Garud, R.; Tuertscher, P.R.; Van de Ven, A.H.

    2013-01-01

    Innovation is often thought of as an outcome. In this chapter, we review the literatures on innovation processes pertaining to the invention, development, and implementation of ideas. In particular, we explore how these processes unfold within firms, across multi-party networks, and within

  19. Hyperspectral image processing methods

    Science.gov (United States)

    Hyperspectral image processing refers to the use of computer algorithms to extract, store and manipulate both spatial and spectral information contained in hyperspectral images across the visible and near-infrared portion of the electromagnetic spectrum. A typical hyperspectral image processing work...

  20. Methods of information processing

    Energy Technology Data Exchange (ETDEWEB)

    Kosarev, Yu G; Gusev, V D

    1978-01-01

    Works are presented on automation systems for editing and publishing operations by methods of processing symbol information and information contained in training selection (ranking of objectives by promise, classification algorithm of tones and noise). The book will be of interest to specialists in the automation of processing textural information, programming, and pattern recognition.

  1. Process for preparing radiopharmaceuticals

    International Nuclear Information System (INIS)

    Barak, M.; Winchell, H.S.

    1977-01-01

    A process for the preparation of technetium-99m labeled pharmaceuticals is disclosed. The process comprises initially isolating technetium-99m pertechnetate by adsorption upon an adsorbent packing in a chromatographic column. The technetium-99m is then eluted from the packing with a biological compound to form a radiopharmaceutical

  2. Contaminated nickel scrap processing

    Energy Technology Data Exchange (ETDEWEB)

    Compere, A.L.; Griffith, W.L.; Hayden, H.W.; Johnson, J.S. Jr.; Wilson, D.F.

    1994-12-01

    The DOE will soon choose between treating contaminated nickel scrap as a legacy waste and developing high-volume nickel decontamination processes. In addition to reducing the volume of legacy wastes, a decontamination process could make 200,000 tons of this strategic metal available for domestic use. Contaminants in DOE nickel scrap include {sup 234}Th, {sup 234}Pa, {sup 137}Cs, {sup 239}Pu (trace), {sup 60}Co, U, {sup 99}Tc, and {sup 237}Np (trace). This report reviews several industrial-scale processes -- electrorefining, electrowinning, vapormetallurgy, and leaching -- used for the purification of nickel. Conventional nickel electrolysis processes are particularly attractive because they use side-stream purification of process solutions to improve the purity of nickel metal. Additionally, nickel purification by electrolysis is effective in a variety of electrolyte systems, including sulfate, chloride, and nitrate. Conventional electrorefining processes typically use a mixed electrolyte which includes sulfate, chloride, and borate. The use of an electrorefining or electrowinning system for scrap nickel recovery could be combined effectively with a variety of processes, including cementation, solvent extraction, ion exchange, complex-formation, and surface sorption, developed for uranium and transuranic purification. Selected processes were reviewed and evaluated for use in nickel side-stream purification. 80 refs.

  3. Microcontroller base process emulator

    OpenAIRE

    Jovrea Titus Claudiu

    2009-01-01

    This paper describes the design of a microcontroller base emulator for a conventional industrial process. The emulator is made with microcontroller and is used for testing and evaluating the performances of the industrial regulators. The parameters of the emulated process are fully customizable online and downloadable thru a serial communication from a personal computer.

  4. Cementation process study

    International Nuclear Information System (INIS)

    Park, H.H.; Han, K.W.; Ahn, S.J.; Choi, K.S.; Lee, M.W.; Ryu, Y.K.

    1985-01-01

    In the cementation process study, in 1984, design of the waste treatment simulator was finished for the first step. We can experience not only the operation of solidification system but the design and construction of comming large scale plant through the design of cementation process. (Author)

  5. Monitoring of operating processes

    International Nuclear Information System (INIS)

    Barry, R.F.

    1981-01-01

    Apparatus is described for monitoring the processes of a nuclear reactor to detect off-normal operation of any process and for testing the monitoring apparatus. The processes are evaluated by response to their paramters, such as temperature, pressure, etc. The apparatus includes a pair of monitoring paths or signal processing units. Each unit includes facilities for receiving on a time-sharing basis, a status binary word made up of digits each indicating the status of a process, whether normal or off-normal, and test-signal binary words simulating the status binary words. The status words and test words are processed in succession during successive cycles. During each cycle, the two units receive the same status word and the same test word. The test words simulate the status words both when they indicate normal operation and when they indicate off-normal operation. Each signal-processing unit includes a pair of memories. Each memory receives a status word or a test word, as the case may be, and converts the received word into a converted status word or a converted test word. The memories of each monitoring unit operate into a non-coincidence which signals non-coincidence of the converted word out of one memory of a signal-processing unit not identical to the converted word of the other memory of the same unit

  6. Teaching the Writing Process

    Science.gov (United States)

    Keen, John

    2017-01-01

    This article outlines some cognitive process models of writing composition. Possible reasons why students' writing capabilities do not match their abilities in some other school subjects are explored. Research findings on the efficacy of process approaches to teaching writing are presented and potential shortcomings are discussed. Product-based…

  7. Heavy oils processing materials requirements crude processing

    Energy Technology Data Exchange (ETDEWEB)

    Sloley, Andrew W. [CH2M Hill, Englewood, CO (United States)

    2012-07-01

    Over time, recommended best practices for crude unit materials selection have evolved to accommodate new operating requirements, feed qualities, and product qualities. The shift to heavier oil processing is one of the major changes in crude feed quality occurring over the last 20 years. The three major types of crude unit corrosion include sulfidation attack, naphthenic acid attack, and corrosion resulting from hydrolyzable chlorides. Heavy oils processing makes all three areas worse. Heavy oils have higher sulfur content; higher naphthenic acid content; and are more difficult to desalt, leading to higher chloride corrosion rates. Materials selection involves two major criteria, meeting required safety standards, and optimizing economics of the overall plant. Proper materials selection is only one component of a plant integrity approach. Materials selection cannot eliminate all corrosion. Proper materials selection requires appropriate support from other elements of an integrity protection program. The elements of integrity preservation include: materials selection (type and corrosion allowance); management limits on operating conditions allowed; feed quality control; chemical additives for corrosion reduction; and preventive maintenance and inspection (PMI). The following discussion must be taken in the context of the application of required supporting work in all the other areas. Within that context, specific materials recommendations are made to minimize corrosion due to the most common causes in the crude unit. (author)

  8. Nuclear process heat

    International Nuclear Information System (INIS)

    Barnert, H.; Hohn, H.; Schad, M.; Schwarz, D.; Singh, J.

    1993-01-01

    In a system for the application of high temperature heat from the HTR one must distinguish between the current generation and the use of process heat. In this respect it is important that the current can be generated by dual purpose power plants. The process heat is used as sensible heat, vaporisation heat and as chemical energy at the chemical conversion for the conversion of raw materials, the refinement of fossil primary energy carriers and finally circuit processes for the fission of water. These processes supply the market for heat, fuels, motor fuels and basic materials. Fifteen examples of HTR heat processes from various projects and programmes are presented in form of energy balances, however in a rather short way. (orig./DG) [de

  9. Nonhomogeneous fractional Poisson processes

    Energy Technology Data Exchange (ETDEWEB)

    Wang Xiaotian [School of Management, Tianjin University, Tianjin 300072 (China)]. E-mail: swa001@126.com; Zhang Shiying [School of Management, Tianjin University, Tianjin 300072 (China); Fan Shen [Computer and Information School, Zhejiang Wanli University, Ningbo 315100 (China)

    2007-01-15

    In this paper, we propose a class of non-Gaussian stationary increment processes, named nonhomogeneous fractional Poisson processes W{sub H}{sup (j)}(t), which permit the study of the effects of long-range dependance in a large number of fields including quantum physics and finance. The processes W{sub H}{sup (j)}(t) are self-similar in a wide sense, exhibit more fatter tail than Gaussian processes, and converge to the Gaussian processes in distribution in some cases. In addition, we also show that the intensity function {lambda}(t) strongly influences the existence of the highest finite moment of W{sub H}{sup (j)}(t) and the behaviour of the tail probability of W{sub H}{sup (j)}(t)

  10. Nonhomogeneous fractional Poisson processes

    International Nuclear Information System (INIS)

    Wang Xiaotian; Zhang Shiying; Fan Shen

    2007-01-01

    In this paper, we propose a class of non-Gaussian stationary increment processes, named nonhomogeneous fractional Poisson processes W H (j) (t), which permit the study of the effects of long-range dependance in a large number of fields including quantum physics and finance. The processes W H (j) (t) are self-similar in a wide sense, exhibit more fatter tail than Gaussian processes, and converge to the Gaussian processes in distribution in some cases. In addition, we also show that the intensity function λ(t) strongly influences the existence of the highest finite moment of W H (j) (t) and the behaviour of the tail probability of W H (j) (t)

  11. Identification of wastewater processes

    DEFF Research Database (Denmark)

    Carstensen, Niels Jacob

    The introduction of on-line sensors for monitoring of nutrient salts concentrations on wastewater treatment plants with nutrient removal, opens a wide new area of modelling wastewater processes. The subject of this thesis is the formulation of operational dynamic models based on time series...... of ammonia, nitrate, and phosphate concentrations, which are measured in the aeration tanks of the biological nutrient removal system. The alternatign operation modes of the BIO-DENITRO and BIO-DENIPHO processes are of particular interest. Time series models of the hydraulic and biological processes are very......-known theory of the processes with the significant effects found in data. These models are called grey box models, and they contain rate expressions for the processes of influent load of nutrients, transport of nutrients between the aeration tanks, hydrolysis and growth of biomass, nitrification...

  12. Quantum independent increment processes

    CERN Document Server

    Franz, Uwe

    2006-01-01

    This is the second of two volumes containing the revised and completed notes of lectures given at the school "Quantum Independent Increment Processes: Structure and Applications to Physics". This school was held at the Alfried-Krupp-Wissenschaftskolleg in Greifswald in March, 2003, and supported by the Volkswagen Foundation. The school gave an introduction to current research on quantum independent increment processes aimed at graduate students and non-specialists working in classical and quantum probability, operator algebras, and mathematical physics. The present second volume contains the following lectures: "Random Walks on Finite Quantum Groups" by Uwe Franz and Rolf Gohm, "Quantum Markov Processes and Applications in Physics" by Burkhard Kümmerer, Classical and Free Infinite Divisibility and Lévy Processes" by Ole E. Barndorff-Nielsen, Steen Thorbjornsen, and "Lévy Processes on Quantum Groups and Dual Groups" by Uwe Franz.

  13. Integrated biofuels process synthesis

    DEFF Research Database (Denmark)

    Torres-Ortega, Carlo Edgar; Rong, Ben-Guang

    2017-01-01

    Second and third generation bioethanol and biodiesel are more environmentally friendly fuels than gasoline and petrodiesel, andmore sustainable than first generation biofuels. However, their production processes are more complex and more expensive. In this chapter, we describe a two-stage synthesis......% used for bioethanol process), and steam and electricity from combustion (54%used as electricity) in the bioethanol and biodiesel processes. In the second stage, we saved about 5% in equipment costs and 12% in utility costs for bioethanol separation. This dual synthesis methodology, consisting of a top......-level screening task followed by a down-level intensification task, proved to be an efficient methodology for integrated biofuel process synthesis. The case study illustrates and provides important insights into the optimal synthesis and intensification of biofuel production processes with the proposed synthesis...

  14. Managing Software Process Evolution

    DEFF Research Database (Denmark)

    This book focuses on the design, development, management, governance and application of evolving software processes that are aligned with changing business objectives, such as expansion to new domains or shifting to global production. In the context of an evolving business world, it examines...... the complete software process lifecycle, from the initial definition of a product to its systematic improvement. In doing so, it addresses difficult problems, such as how to implement processes in highly regulated domains or where to find a suitable notation system for documenting processes, and provides...... essential insights and tips to help readers manage process evolutions. And last but not least, it provides a wealth of examples and cases on how to deal with software evolution in practice. Reflecting these topics, the book is divided into three parts. Part 1 focuses on software business transformation...

  15. Beryllium chemistry and processing

    CERN Document Server

    Walsh, Kenneth A

    2009-01-01

    This book introduces beryllium; its history, its chemical, mechanical, and physical properties including nuclear properties. The 29 chapters include the mineralogy of beryllium and the preferred global sources of ore bodies. The identification and specifics of the industrial metallurgical processes used to form oxide from the ore and then metal from the oxide are thoroughly described. The special features of beryllium chemistry are introduced, including analytical chemical practices. Beryllium compounds of industrial interest are identified and discussed. Alloying, casting, powder processing, forming, metal removal, joining and other manufacturing processes are covered. The effect of composition and process on the mechanical and physical properties of beryllium alloys assists the reader in material selection. The physical metallurgy chapter brings conformity between chemical and physical metallurgical processing of beryllium, metal, alloys, and compounds. The environmental degradation of beryllium and its all...

  16. Business process support

    Energy Technology Data Exchange (ETDEWEB)

    Carle, Adriana; Fiducia, Daniel [Transportadora de Gas del Sur S.A. (TGS), Buenos Aires (Argentina)

    2005-07-01

    This paper is about the own development of business support software. The developed applications are used to support two business processes: one of them is the process of gas transportation and the other is the natural gas processing. This software has interphases with the ERP SAP, software SCADA and on line gas transportation simulation software. The main functionalities of the applications are: entrance on line real time of clients transport nominations, transport programming, allocation of the clients transport nominations, transport control, measurements, balanced pipeline, allocation of gas volume to the gas processing plants, calculate of product tons processed in each plant and tons of product distributed to clients. All the developed software generates information to the internal staff, regulatory authorities and clients. (author)

  17. Branching processes in biology

    CERN Document Server

    Kimmel, Marek

    2015-01-01

    This book provides a theoretical background of branching processes and discusses their biological applications. Branching processes are a well-developed and powerful set of tools in the field of applied probability. The range of applications considered includes molecular biology, cellular biology, human evolution and medicine. The branching processes discussed include Galton-Watson, Markov, Bellman-Harris, Multitype, and General Processes. As an aid to understanding specific examples, two introductory chapters, and two glossaries are included that provide background material in mathematics and in biology. The book will be of interest to scientists who work in quantitative modeling of biological systems, particularly probabilists, mathematical biologists, biostatisticians, cell biologists, molecular biologists, and bioinformaticians. The authors are a mathematician and cell biologist who have collaborated for more than a decade in the field of branching processes in biology for this new edition. This second ex...

  18. EDITORIAL: Industrial Process Tomography

    Science.gov (United States)

    Anton Johansen, Geir; Wang, Mi

    2008-09-01

    There has been tremendous development within measurement science and technology over the past couple of decades. New sensor technologies and compact versatile signal recovery electronics are continuously expanding the limits of what can be measured and the accuracy with which this can be done. Miniaturization of sensors and the use of nanotechnology push these limits further. Also, thanks to powerful and cost-effective computer systems, sophisticated measurement and reconstruction algorithms previously only accessible in advanced laboratories are now available for in situ online measurement systems. The process industries increasingly require more process-related information, motivated by key issues such as improved process control, process utilization and process yields, ultimately driven by cost-effectiveness, quality assurance, environmental and safety demands. Industrial process tomography methods have taken advantage of the general progress in measurement science, and aim at providing more information, both quantitatively and qualitatively, on multiphase systems and their dynamics. The typical approach for such systems has been to carry out one local or bulk measurement and assume that this is representative of the whole system. In some cases, this is sufficient. However, there are many complex systems where the component distribution varies continuously and often unpredictably in space and time. The foundation of industrial tomography is to conduct several measurements around the periphery of a multiphase process, and use these measurements to unravel the cross-sectional distribution of the process components in time and space. This information is used in the design and optimization of industrial processes and process equipment, and also to improve the accuracy of multiphase system measurements in general. In this issue we are proud to present a selection of the 145 papers presented at the 5th World Congress on Industrial Process Tomography in Bergen

  19. States in Process Calculi

    Directory of Open Access Journals (Sweden)

    Christoph Wagner

    2014-08-01

    Full Text Available Formal reasoning about distributed algorithms (like Consensus typically requires to analyze global states in a traditional state-based style. This is in contrast to the traditional action-based reasoning of process calculi. Nevertheless, we use domain-specific variants of the latter, as they are convenient modeling languages in which the local code of processes can be programmed explicitly, with the local state information usually managed via parameter lists of process constants. However, domain-specific process calculi are often equipped with (unlabeled reduction semantics, building upon a rich and convenient notion of structural congruence. Unfortunately, the price for this convenience is that the analysis is cumbersome: the set of reachable states is modulo structural congruence, and the processes' state information is very hard to identify. We extract from congruence classes of reachable states individual state-informative representatives that we supply with a proper formal semantics. As a result, we can now freely switch between the process calculus terms and their representatives, and we can use the stateful representatives to perform assertional reasoning on process calculus models.

  20. Welding processes handbook

    CERN Document Server

    Weman, Klas

    2003-01-01

    Deals with the main commercially significant and commonly used welding processes. This title takes the student or novice welder through the individual steps involved in each process in an easily understood way. It covers many of the requirements referred to in European Standards including EN719, EN 729, EN 729 and EN 287.$bWelding processes handbook is a concise, explanatory guide to the main commercially significant and commonly-used welding processes. It takes the novice welder or student through the individual steps involved in each process in a clear and easily understood way. It is intended to provide an up-to-date reference to the major applications of welding as they are used in industry. The contents have been arranged so that it can be used as a textbook for European welding courses in accordance with guidelines from the European Welding Federation. Welding processes and equipment necessary for each process are described so that they can be applied to all instruction levels required by the EWF and th...

  1. Organic waste incineration processes

    Energy Technology Data Exchange (ETDEWEB)

    Lemort, F.; Charvillat, J.P.; Nabot, J.P. [CEA Valrho, Bagnols sur Ceze Cedex (France); Chateauvieux, H.; Thiebaut, C. [CEA Valduc, 21 - Is-sur-Tille (France)

    2001-07-01

    Nuclear activities produce organic waste compatible with thermal processes designed to obtain a significant weight and volume reduction as well as to stabilize the inorganic residue in a form suitable for various interim storage or disposal routes. Several processes may be implemented (e.g. excess air, plasma, fluidized bed or rotating furnace) depending on the nature of the waste and the desired objectives. The authors focus on the IRIS rotating-kiln process, which was used for the first time with radioactive materials during the first half of 1999. IRIS is capable of processing highly chlorinated and {alpha}-contaminated waste at a rate of several kilograms per hour, while limiting corrosion due to chlorine as well as mechanical entrainment of radioactive particles in the off-gas stream. Although operated industrially, the process is under continual development to improve its performance and adapt it to a wider range of industrial applications. The main focus of attention today is on adapting the pyrolytic processes to waste with highly variable compositions and to enhance the efficiency of the off-gas purification systems. These subjects are of considerable interest for a large number of heat treatment processes (including all off-gas treatment systems) for which extremely durable, high-performance and low-flow electrostatic precipitators are now being developed. (author)

  2. Organic waste incineration processes

    International Nuclear Information System (INIS)

    Lemort, F.; Charvillat, J.P.; Nabot, J.P.; Chateauvieux, H.; Thiebaut, C.

    2001-01-01

    Nuclear activities produce organic waste compatible with thermal processes designed to obtain a significant weight and volume reduction as well as to stabilize the inorganic residue in a form suitable for various interim storage or disposal routes. Several processes may be implemented (e.g. excess air, plasma, fluidized bed or rotating furnace) depending on the nature of the waste and the desired objectives. The authors focus on the IRIS rotating-kiln process, which was used for the first time with radioactive materials during the first half of 1999. IRIS is capable of processing highly chlorinated and α-contaminated waste at a rate of several kilograms per hour, while limiting corrosion due to chlorine as well as mechanical entrainment of radioactive particles in the off-gas stream. Although operated industrially, the process is under continual development to improve its performance and adapt it to a wider range of industrial applications. The main focus of attention today is on adapting the pyrolytic processes to waste with highly variable compositions and to enhance the efficiency of the off-gas purification systems. These subjects are of considerable interest for a large number of heat treatment processes (including all off-gas treatment systems) for which extremely durable, high-performance and low-flow electrostatic precipitators are now being developed. (author)

  3. IT Project Prioritization Process

    DEFF Research Database (Denmark)

    Shollo, Arisa; Constantiou, Ioanna

    2013-01-01

    In most of the large companies IT project prioritization process is designed based on principles of evidencebased management. We investigate a case of IT project prioritization in a financial institution, and in particular, how managers practice evidence-based management during this process. We use...... a rich dataset built from a longitudinal study of the prioritization process for the IT projects. Our findings indicate that managers reach a decision not only by using evidence but from the interplay between the evidence and the judgment devices that managers employ. The interplay between evidence...

  4. Revealing the programming process

    DEFF Research Database (Denmark)

    Bennedsen, Jens; Caspersen, Michael Edelgaard

    2005-01-01

    One of the most important goals of an introductory programming course is that the students learn a systematic approach to the development of computer programs. Revealing the programming process is an important part of this; however, textbooks do not address the issue -- probably because...... the textbook medium is static and therefore ill-suited to expose the process of programming. We have found that process recordings in the form of captured narrated programming sessions are a simple, cheap, and efficient way of providing the revelation.We identify seven different elements of the programming...

  5. Process of performance assessment

    International Nuclear Information System (INIS)

    King, C.M.; Halford, D.K.

    1987-01-01

    Performance assessment is the process used to evaluate the environmental consequences of disposal of radioactive waste in the biosphere. An introductory review of the subject is presented. Emphasis is placed on the process of performance assessment from the standpoint of defining the process. Performance assessment, from evolving experience at DOE sites, has short-term and long-term subprograms, the components of which are discussed. The role of mathematical modeling in performance assessment is addressed including the pros and cons of current approaches. Finally, the system/site/technology issues as the focal point of this symposium are reviewed

  6. Semi-Markov processes

    CERN Document Server

    Grabski

    2014-01-01

    Semi-Markov Processes: Applications in System Reliability and Maintenance is a modern view of discrete state space and continuous time semi-Markov processes and their applications in reliability and maintenance. The book explains how to construct semi-Markov models and discusses the different reliability parameters and characteristics that can be obtained from those models. The book is a useful resource for mathematicians, engineering practitioners, and PhD and MSc students who want to understand the basic concepts and results of semi-Markov process theory. Clearly defines the properties and

  7. Irreversible processes kinetic theory

    CERN Document Server

    Brush, Stephen G

    2013-01-01

    Kinetic Theory, Volume 2: Irreversible Processes deals with the kinetic theory of gases and the irreversible processes they undergo. It includes the two papers by James Clerk Maxwell and Ludwig Boltzmann in which the basic equations for transport processes in gases are formulated, together with the first derivation of Boltzmann's ""H-theorem"" and a discussion of this theorem, along with the problem of irreversibility.Comprised of 10 chapters, this volume begins with an introduction to the fundamental nature of heat and of gases, along with Boltzmann's work on the kinetic theory of gases and s

  8. Catalytic biomass pyrolysis process

    Science.gov (United States)

    Dayton, David C.; Gupta, Raghubir P.; Turk, Brian S.; Kataria, Atish; Shen, Jian-Ping

    2018-04-17

    Described herein are processes for converting a biomass starting material (such as lignocellulosic materials) into a low oxygen containing, stable liquid intermediate that can be refined to make liquid hydrocarbon fuels. More specifically, the process can be a catalytic biomass pyrolysis process wherein an oxygen removing catalyst is employed in the reactor while the biomass is subjected to pyrolysis conditions. The stream exiting the pyrolysis reactor comprises bio-oil having a low oxygen content, and such stream may be subjected to further steps, such as separation and/or condensation to isolate the bio-oil.

  9. DWPF process control

    International Nuclear Information System (INIS)

    Heckendoin, F.M. II

    1983-01-01

    The Defense Waste Processing Facility (DWPF) for waste vitrification at the Savannah River Plant (SRP) is in the final design stage. Instrumentation to provide the parameter sensing required to assure the quality of the two-foot-diameter, ten-foot-high waste canister is in the final stage of development. All step of the process and instrumentation are now operating as nearly full-scale prototypes at SRP. Quality will be maintained by assuring that only the intended material enters the canisters, and by sensing the resultant condition of the filled canisters. Primary emphasis will be on instrumentation of the process

  10. Advanced uranium enrichment processes

    International Nuclear Information System (INIS)

    Clerc, M.; Plurien, P.

    1986-01-01

    Three advanced Uranium enrichment processes are dealt with in the report: AVLIS (Atomic Vapour LASER Isotope Separation), MLIS (Molecular LASER Isotope Separation) and PSP (Plasma Separation Process). The description of the physical and technical features of the processes constitutes a major part of the report. If further presents comparisons with existing industrially used enrichment technologies, gives information on actual development programmes and budgets and ends with a chapter on perspectives and conclusions. An extensive bibliography of the relevant open literature is added to the different subjects discussed. The report was drawn up by the nuclear research Centre (CEA) Saclay on behalf of the Commission of the European Communities

  11. Plasma processing for VLSI

    CERN Document Server

    Einspruch, Norman G

    1984-01-01

    VLSI Electronics: Microstructure Science, Volume 8: Plasma Processing for VLSI (Very Large Scale Integration) discusses the utilization of plasmas for general semiconductor processing. It also includes expositions on advanced deposition of materials for metallization, lithographic methods that use plasmas as exposure sources and for multiple resist patterning, and device structures made possible by anisotropic etching.This volume is divided into four sections. It begins with the history of plasma processing, a discussion of some of the early developments and trends for VLSI. The second section

  12. Radioactive waste processing method

    International Nuclear Information System (INIS)

    Sakuramoto, Naohiko.

    1992-01-01

    When granular materials comprising radioactive wastes containing phosphorus are processed at first in a fluidized bed type furnace, if the granular materials are phosphorus-containing activated carbon, granular materials comprising alkali compound such as calcium hydroxide and barium hydroxide are used as fluidizing media. Even granular materials of slow burning speed can be burnt stably in a fluidizing state by high temperature heat of the fluidizing media, thereby enabling to take a long burning processing time. Accordingly, radioactive activated carbon wastes can be processed by burning treatment. (T.M.)

  13. Nano integrated circuit process

    International Nuclear Information System (INIS)

    Yoon, Yung Sup

    2004-02-01

    This book contains nine chapters, which are introduction of manufacture of semiconductor chip, oxidation such as Dry-oxidation, wet oxidation, oxidation model and oxide film, diffusion like diffusion process, diffusion equation, diffusion coefficient and diffusion system, ion implantation, including ion distribution, channeling, multiimplantation and masking and its system, sputtering such as CVD and PVD, lithography, wet etch and dry etch, interconnection and flattening like metal-silicon connection, silicide, multiple layer metal process and flattening, an integrated circuit process, including MOSFET and CMOS.

  14. Transnational Learning Processes

    DEFF Research Database (Denmark)

    Nedergaard, Peter

    This paper analyses and compares the transnational learning processes in the employment field in the European Union and among the Nordic countries. Based theoretically on a social constructivist model of learning and methodologically on a questionnaire distributed to the relevant participants......, a number of hypotheses concerning transnational learning processes are tested. The paper closes with a number of suggestions regarding an optimal institutional setting for facilitating transnational learning processes.Key words: Transnational learning, Open Method of Coordination, Learning, Employment......, European Employment Strategy, European Union, Nordic countries....

  15. Nano integrated circuit process

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Yung Sup

    2004-02-15

    This book contains nine chapters, which are introduction of manufacture of semiconductor chip, oxidation such as Dry-oxidation, wet oxidation, oxidation model and oxide film, diffusion like diffusion process, diffusion equation, diffusion coefficient and diffusion system, ion implantation, including ion distribution, channeling, multiimplantation and masking and its system, sputtering such as CVD and PVD, lithography, wet etch and dry etch, interconnection and flattening like metal-silicon connection, silicide, multiple layer metal process and flattening, an integrated circuit process, including MOSFET and CMOS.

  16. Getting Started with Processing

    CERN Document Server

    Reas, Casey

    2010-01-01

    Learn computer programming the easy way with Processing, a simple language that lets you use code to create drawings, animation, and interactive graphics. Programming courses usually start with theory, but this book lets you jump right into creative and fun projects. It's ideal for anyone who wants to learn basic programming, and serves as a simple introduction to graphics for people with some programming skills. Written by the founders of Processing, this book takes you through the learning process one step at a time to help you grasp core programming concepts. You'll learn how to sketch wi

  17. Quantum Information Processing

    CERN Document Server

    Leuchs, Gerd

    2005-01-01

    Quantum processing and communication is emerging as a challenging technique at the beginning of the new millennium. This is an up-to-date insight into the current research of quantum superposition, entanglement, and the quantum measurement process - the key ingredients of quantum information processing. The authors further address quantum protocols and algorithms. Complementary to similar programmes in other countries and at the European level, the German Research Foundation (DFG) started a focused research program on quantum information in 1999. The contributions - written by leading experts - bring together the latest results in quantum information as well as addressing all the relevant questions

  18. Robot welding process control

    Science.gov (United States)

    Romine, Peter L.

    1991-01-01

    This final report documents the development and installation of software and hardware for Robotic Welding Process Control. Primary emphasis is on serial communications between the CYRO 750 robotic welder, Heurikon minicomputer running Hunter & Ready VRTX, and an IBM PC/AT, for offline programming and control and closed-loop welding control. The requirements for completion of the implementation of the Rocketdyne weld tracking control are discussed. The procedure for downloading programs from the Intergraph, over the network, is discussed. Conclusions are made on the results of this task, and recommendations are made for efficient implementation of communications, weld process control development, and advanced process control procedures using the Heurikon.

  19. Lasers in chemical processing

    International Nuclear Information System (INIS)

    Davis, J.I.

    1982-01-01

    The high cost of laser energy is the crucial issue in any potential laser-processing application. It is expensive relative to other forms of energy and to most bulk chemicals. We show those factors that have previously frustrated attempts to find commercially viable laser-induced processes for the production of materials. Having identified the general criteria to be satisfied by an economically successful laser process and shown how these imply the laser-system requirements, we present a status report on the uranium laser isotope separation (LIS) program at the Lawrence Livermore National Laboratory

  20. Dosimetry for radiation processing

    International Nuclear Information System (INIS)

    Miller, Arne

    1986-01-01

    During the past few years significant advances have taken place in the different areas of dosimetry for radiation processing, mainly stimulated by the increased interest in radiation for food preservation, plastic processing and sterilization of medical products. Reference services both by international organizations (IAEA) and national laboratories have helped to improve the reliability of dose measurements. In this paper the special features of radiation processing dosimetry are discussed, several commonly used dosimeters are reviewed, and factors leading to traceable and reliable dosimetry are discussed. (author)

  1. The SILVA atomic process

    International Nuclear Information System (INIS)

    Cazalet, J.

    1996-01-01

    The SILVA isotopic laser separation process of atomic uranium vapor requires the use of specific high power visible light laser devices and systems for uranium evaporation and management (separation modules). The CEA, in collaboration with industrialists, has developed these components and built some demonstration plants. The scientific and technological challenges raised by this process are now surmounted. The principle of the SILVA process is the selective photo-ionization of uranium isotopes using laser photon beams tuned to the exact excitation frequency of the isotope electron layers. This paper describes the principle of the SILVA process (lasers and separator), the technical feasibility and actual progress of the program and its future steps, its economical stakes, and the results obtained so far. (J.S.). 2 figs., 2 photos

  2. Cognitive Processing Hardware Elements

    National Research Council Canada - National Science Library

    Widrow, Bernard; Eliashberg, Victor; Kamenetsky, Max

    2005-01-01

    The purpose of this research is to identify and develop cognitive information processing systems and algorithms that can be implemented with novel architectures and devices with the goal of achieving...

  3. Ferrous Metal Processing Plants

    Data.gov (United States)

    Department of Homeland Security — This map layer includes ferrous metal processing plants in the United States. The data represent commodities covered by the Minerals Information Team (MIT) of the...

  4. Nonferrous Metal Processing Plants

    Data.gov (United States)

    Department of Homeland Security — This map layer includes nonferrous metal processing plants in the United States. The data represent commodities covered by the Minerals Information Team (MIT) of the...

  5. Canada's hydrocarbon processing evolution

    International Nuclear Information System (INIS)

    Wise, T.H.; Horton, R.

    2000-01-01

    The development of petroleum refining, petrochemicals and natural gas industries in Canada are discussed together with future issues and prospects. Figures give data on (a) refined products trade 1998; (b) refining capacity; (c) product demand 1980-1999; (d) refinery crude runs and capacity; (e) refining and marketing, historical returns 1993-1999; (f) processing power index for Canada and USA; (g) ethylene capacity; (eye) Montreal petrochemical capacities; (j) Sarnia petrochemical capacities in 2000; (k) Alberta petrochemicals capacities 2001; (l) ethylene net equivalent trade; (m) ethylene costs 1999 for W. Canada and other countries. It was concluded that the hydrocarbon processing business continues to expand in Canada and natural gas processing is likely to increase. Petrochemicals may expand in W. Canada, possibly using feed stock from the Far North. Offshore developments may stimulate new processing on the E. Coast

  6. Essentials of stochastic processes

    CERN Document Server

    Durrett, Richard

    2016-01-01

    Building upon the previous editions, this textbook is a first course in stochastic processes taken by undergraduate and graduate students (MS and PhD students from math, statistics, economics, computer science, engineering, and finance departments) who have had a course in probability theory. It covers Markov chains in discrete and continuous time, Poisson processes, renewal processes, martingales, and option pricing. One can only learn a subject by seeing it in action, so there are a large number of examples and more than 300 carefully chosen exercises to deepen the reader’s understanding. Drawing from teaching experience and student feedback, there are many new examples and problems with solutions that use TI-83 to eliminate the tedious details of solving linear equations by hand, and the collection of exercises is much improved, with many more biological examples. Originally included in previous editions, material too advanced for this first course in stochastic processes has been eliminated while treatm...

  7. Product and Process Modelling

    DEFF Research Database (Denmark)

    Cameron, Ian T.; Gani, Rafiqul

    . These approaches are put into the context of life cycle modelling, where multiscale and multiform modelling is increasingly prevalent in the 21st century. The book commences with a discussion of modern product and process modelling theory and practice followed by a series of case studies drawn from a variety......This book covers the area of product and process modelling via a case study approach. It addresses a wide range of modelling applications with emphasis on modelling methodology and the subsequent in-depth analysis of mathematical models to gain insight via structural aspects of the models...... to biotechnology applications, food, polymer and human health application areas. The book highlights to important nature of modern product and process modelling in the decision making processes across the life cycle. As such it provides an important resource for students, researchers and industrial practitioners....

  8. HYDICE postflight data processing

    Science.gov (United States)

    Aldrich, William S.; Kappus, Mary E.; Resmini, Ronald G.; Mitchell, Peter A.

    1996-06-01

    The hyperspectral digital imagery collection experiment (HYDICE) sensor records instrument counts for scene data, in-flight spectral and radiometric calibration sequences, and dark current levels onto an AMPEX DCRsi data tape. Following flight, the HYDICE ground data processing subsystem (GDPS) transforms selected scene data from digital numbers (DN) to calibrated radiance levels at the sensor aperture. This processing includes: dark current correction, spectral and radiometric calibration, conversion to radiance, and replacement of bad detector elements. A description of the algorithms for post-flight data processing is presented. A brief analysis of the original radiometric calibration procedure is given, along with a description of the development of the modified procedure currently used. Example data collected during the 1995 flight season, but uncorrected and processed, are shown to demonstrate the removal of apparent sensor artifacts (e.g., non-uniformities in detector response over the array) as a result of this transformation.

  9. Reconfigurable network processing platforms

    NARCIS (Netherlands)

    Kachris, C.

    2007-01-01

    This dissertation presents our investigation on how to efficiently exploit reconfigurable hardware to design flexible, high performance, and power efficient network devices capable to adapt to varying processing requirements of network applications and traffic. The proposed reconfigurable network

  10. Towards processable Afrikaans

    CSIR Research Space (South Africa)

    Pretorius, L

    2009-06-01

    Full Text Available In this paper researchers discuss a number of structural problems that are faced with when designing a machine-oriented controlled natural language for Afrikaans taking the underlying principles of Attempto Controlled English (ACE) and Processable...

  11. Gas processing device

    International Nuclear Information System (INIS)

    Kobayashi, Yoshihiro; Seki, Eiji.

    1991-01-01

    State of electric discharge is detected based on a gas pressure in a sealed container and a discharging current flowing between both of electrodes. When electric arc discharges occur, introduction of gases to be processed is stopped and a voltage applied to both of the electrodes is interrupted. Then, when the gas pressure in the sealed container is lowered to a predetermined value, a power source voltage is applied again to both of the electrodes to recover glow discharges, and the introduction of the gas to be processed is started. With such steps, even if electric arc discharges occur, they are eliminated automatically and, accordingly, normal glow discharges can be recovered, to prevent failures of the device due to electric arc discharges. The glow discharges are recovered automatically without stopping the operation of the gas processing device, and gas injection and solidification processing can be conducted continuously and stably. (T.M.)

  12. Cooperative processing data bases

    Science.gov (United States)

    Hasta, Juzar

    1991-01-01

    Cooperative processing for the 1990's using client-server technology is addressed. The main theme is concepts of downsizing from mainframes and minicomputers to workstations on a local area network (LAN). This document is presented in view graph form.

  13. Radiation processing in Japan

    International Nuclear Information System (INIS)

    Makuuchi, Keizo

    2001-01-01

    Economic scale of radiation application in the field of industry, agriculture and medicine in Japan in 1997 was investigated to compare its economic impacts with that of nuclear energy industry. Total production value of radiation application accounted for 54% of nuclear industry including nuclear energy industry and radiation applications in three fields above. Industrial radiation applications were further divided into five groups, namely nondestructive test, RI instruments, radiation facilities, radiation processing and ion beam processing. More than 70% of the total production value was brought about by ion beam processing for use with IC and semiconductors. Future economic prospect of radiation processing of polymers, for example cross-linking, EB curing, graft polymerization and degradation, is reviewed. Particular attention was paid to radiation vulcanization of natural rubber latex and also to degradation of natural polymers. (S. Ohno)

  14. Logistics Innovation Process Revisited

    DEFF Research Database (Denmark)

    Gammelgaard, Britta; Su, Shong-Iee Ivan; Yang, Su-Lan

    2011-01-01

    Purpose – The purpose of this paper is to learn more about logistics innovation processes and their implications for the focal organization as well as the supply chain, especially suppliers. Design/methodology/approach – The empirical basis of the study is a longitudinal action research project...... that was triggered by the practical needs of new ways of handling material flows of a hospital. This approach made it possible to revisit theory on logistics innovation process. Findings – Apart from the tangible benefits reported to the case hospital, five findings can be extracted from this study: the logistics...... innovation process model may include not just customers but also suppliers; logistics innovation in buyer-supplier relations may serve as an alternative to outsourcing; logistics innovation processes are dynamic and may improve supplier partnerships; logistics innovations in the supply chain are as dependent...

  15. Negative ion detachment processes

    International Nuclear Information System (INIS)

    Champion, R.L.; Doverspike, L.D.

    1990-10-01

    This paper discusses the following topics: H - and D - collisions with atomic hydrogen; collisional decomposition of SF 6 - ; two-electron loss processes in negative ion collisions; associative electron detachment; and negative ion desorption from surfaces

  16. Acoustic MIMO signal processing

    CERN Document Server

    Huang, Yiteng; Chen, Jingdong

    2006-01-01

    A timely and important book addressing a variety of acoustic signal processing problems under multiple-input multiple-output (MIMO) scenarios. It uniquely investigates these problems within a unified framework offering a novel and penetrating analysis.

  17. Introduction to stochastic processes

    CERN Document Server

    Cinlar, Erhan

    2013-01-01

    Clear presentation employs methods that recognize computer-related aspects of theory. Topics include expectations and independence, Bernoulli processes and sums of independent random variables, Markov chains, renewal theory, more. 1975 edition.

  18. Dosimetry for radiation processing

    International Nuclear Information System (INIS)

    McLaughlin, W.L.; Boyd, A.W.; Chadwick, K.H.; McDonald, J.C.; Miller, A.

    1989-01-01

    Radiation processing is a relatively young industry with broad applications and considerable commercial success. Dosimetry provides an independent and effective way of developing and controlling many industrial processes. In the sterilization of medical devices and in food irradiation, where the radiation treatment impacts directly on public health, the measurements of dose provide the official means of regulating and approving its use. In this respect, dosimetry provides the operator with a means of characterizing the facility, of proving that products are treated within acceptable dose limits and of controlling the routine operation. This book presents an up-to-date review of the theory, data and measurement techniques for radiation processing dosimetry in a practical and useful way. It is hoped that this book will lead to improved measurement procedures, more accurate and precise dosimetry and a greater appreciation of the necessity of dosimetry for radiation processing. (author)

  19. SIMULATION OF LOGISTICS PROCESSES

    Directory of Open Access Journals (Sweden)

    Yu. Taranenko

    2016-08-01

    Full Text Available The article deals with the theoretical basis of the simulation. The study shows the simulation of logistic processes in industrial countries is an integral part of many economic projects aimed at the creation or improvement of logistics systems. The paper was used model Beer Game for management of logistics processes in the enterprise. The simulation model implements in AnyLogic package. AnyLogic product allows us to consider the logistics processes as an integrated system, which allows reaching better solutions. Logistics process management involves pooling the sales market, production and distribution to ensure the temporal level of customer service at the lowest cost overall. This made it possible to conduct experiments and to determine the optimal size of the warehouse at the lowest cost.

  20. Digital image processing

    National Research Council Canada - National Science Library

    Gonzalez, Rafael C; Woods, Richard E

    2008-01-01

    Completely self-contained-and heavily illustrated-this introduction to basic concepts and methodologies for digital image processing is written at a level that truly is suitable for seniors and first...

  1. Ultrahigh bandwidth signal processing

    DEFF Research Database (Denmark)

    Oxenløwe, Leif Katsuo

    2016-01-01

    Optical time lenses have proven to be very versatile for advanced optical signal processing. Based on a controlled interplay between dispersion and phase-modulation by e.g. four-wave mixing, the processing is phase-preserving, an hence useful for all types of data signals including coherent multi......-level modulation founats. This has enabled processing of phase-modulated spectrally efficient data signals, such as orthogonal frequency division multiplexed (OFDM) signa In that case, a spectral telescope system was used, using two time lenses with different focal lengths (chirp rates), yielding a spectral...... regeneratio These operations require a broad bandwidth nonlinear platform, and novel photonic integrated nonlinear platform like aluminum gallium arsenide nano-waveguides used for 1.28 Tbaud optical signal processing will be described....

  2. Rubber compounding and processing

    CSIR Research Space (South Africa)

    John, MJ

    2014-06-01

    Full Text Available This chapter presents an overview on the compounding and processing techniques of natural rubber compounds. The introductory portion deals with different types of rubbers and principles of rubber compounding. The primary and secondary fillers used...

  3. Radiation processing in Japan

    Energy Technology Data Exchange (ETDEWEB)

    Makuuchi, Keizo [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment

    2001-03-01

    Economic scale of radiation application in the field of industry, agriculture and medicine in Japan in 1997 was investigated to compare its economic impacts with that of nuclear energy industry. Total production value of radiation application accounted for 54% of nuclear industry including nuclear energy industry and radiation applications in three fields above. Industrial radiation applications were further divided into five groups, namely nondestructive test, RI instruments, radiation facilities, radiation processing and ion beam processing. More than 70% of the total production value was brought about by ion beam processing for use with IC and semiconductors. Future economic prospect of radiation processing of polymers, for example cross-linking, EB curing, graft polymerization and degradation, is reviewed. Particular attention was paid to radiation vulcanization of natural rubber latex and also to degradation of natural polymers. (S. Ohno)

  4. Desalination processes and technologies

    International Nuclear Information System (INIS)

    Furukawa, D.H.

    1996-01-01

    Reasons of the development of desalination processes, the modern desalination technologies, such as multi-stage flash evaporation, multi-effect distillation, reverse osmosis, and the prospects of using nuclear power for desalination purposes are discussed. 9 refs

  5. Enrichment: centrifuge process

    International Nuclear Information System (INIS)

    Soubbaramayer.

    1989-01-01

    This short course is divided into three sections devoted respectively to the physics of the process, some practical problems raised by the design of a centrifuge and the present situation of centrifugation in the World. 31 figs., 18 refs

  6. Constitutional reform as process

    OpenAIRE

    Schultze, Rainer-Olaf (Prof.)

    2000-01-01

    Constitutional reform as process. - In: The politics of constitutional reform in North America / Rainer-Olaf Schultze ... (eds.). - Opladen : Leske + Budrich, 2000. - S. 11-31. - (Politikwissenschaftliche paperbacks ; 30)

  7. Paper 2: Process characterisation

    African Journals Online (AJOL)

    drinie

    A variety of names represent the prefermentation process, due to emphasis placed on ... monitoring and control instrumentation employed successfully at existing side-stream ..... MÜNCH E (1998) DSP-Prefermenter Technology Book. Science ...

  8. Project management process.

    Science.gov (United States)

    2007-03-01

    This course provides INDOT staff with foundational knowledge and skills in project management principles and methodologies. INDOTs project management processes provide the tools for interdisciplinary teams to efficiently and effectively deliver pr...

  9. Processed Products Database System

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Collection of annual data on processed seafood products. The Division provides authoritative advice, coordination and guidance on matters related to the collection,...

  10. Model Process Control Language

    Data.gov (United States)

    National Aeronautics and Space Administration — The MPC (Model Process Control) language enables the capture, communication and preservation of a simulation instance, with sufficient detail that it can be...

  11. Digital image processing

    National Research Council Canada - National Science Library

    Gonzalez, Rafael C; Woods, Richard E

    2008-01-01

    ...-year graduate students in almost any technical discipline. The leading textbook in its field for more than twenty years, it continues its cutting-edge focus on contemporary developments in all mainstream areas of image processing-e.g...

  12. CAPSULE REPORT: EVAPORATION PROCESS

    Science.gov (United States)

    Evaporation has been an established technology in the metal finishing industry for many years. In this process, wastewaters containing reusable materials, such as copper, nickel, or chromium compounds are heated, producing a water vapor that is continuously removed and condensed....

  13. Aerospace Materials Process Modelling

    Science.gov (United States)

    1988-08-01

    Cooling Transformation diagram ( CCT diagram ) When a IT diagram is used in the heat process modelling, we suppose that a sudden cooling (instantaneous...processes. CE, chooses instead to study thermo-mechanical properties referring to a CCT diagram . This is thinked to be more reliable to give a true...k , mm-_____sml l ml A I 1 III 12.4 This determination is however based on the following approximations: i) A CCT diagram is valid only for the

  14. Radiopharmaceutical drug review process

    International Nuclear Information System (INIS)

    Frankel, R.

    1985-01-01

    To ensure proper radioactive drug use (such as quality, diagnostic improvement, and minimal radioactive exposure), the Food and Drug Administration evaluates new drugs with respect to safety, effectiveness, and accuracy and adequacy of the labeling. The IND or NDA process is used for this purpose. A brief description of the process, including the Chemical Classification System and the therapeutic potential classification, is presented as it applies to radiopharmaceuticals. Also, the status of the IND or NDA review of radiopharmaceuticals is given

  15. Qualification of conditioning process

    International Nuclear Information System (INIS)

    Wolf, J.

    1989-01-01

    A conditioning process is qualified by the PTB if the execution of pre-treatment and conditioning occurs so that a safe and orderly final storage of the products and waste containers produced can be assumed. All the relevant operating conditions for the plant are laid down by the producer/conditioner of the waste in a handbook. The elements of product inspection by process qualification are shown in tabular form. (DG) [de

  16. Hydrogen recovery process

    Science.gov (United States)

    Baker, Richard W.; Lokhandwala, Kaaeid A.; He, Zhenjie; Pinnau, Ingo

    2000-01-01

    A treatment process for a hydrogen-containing off-gas stream from a refinery, petrochemical plant or the like. The process includes three separation steps: condensation, membrane separation and hydrocarbon fraction separation. The membrane separation step is characterized in that it is carried out under conditions at which the membrane exhibits a selectivity in favor of methane over hydrogen of at least about 2.5.

  17. Process through practice

    DEFF Research Database (Denmark)

    Burry, Jane; Burry, Mark; Tamke, Martin

    2012-01-01

    This paper describes the development of a design and prototype production system for novel structural use of networked small components of wood deploying elastic and plastic bending. The design process engaged with a significant number of different overlapping and interrelated design criteria...... simulation and feedback. The outcome was amplified through carrying out the research over a series of workshops with distinct foci and participation. Two full scale demonstrators have so far been constructed and exhibited as outputs of the process....

  18. Process for compound transformation

    KAUST Repository

    Basset, Jean-Marie

    2016-12-29

    Embodiments of the present disclosure provide for methods of using a catalytic system to chemically transform a compound (e.g., a hydrocarbon). In an embodiment, the method does not employ grafting the catalyst prior to catalysis. In particular, embodiments of the present disclosure provide for a process of hydrocarbon (e.g., C1 to C20 hydrocarbon) metathesis (e.g., alkane, olefin, or alkyne metathesis) transformation, where the process can be conducted without employing grafting prior to catalysis.

  19. Processes of Strategic Renewal,

    OpenAIRE

    Harald Aadne, John; Mahnke, Volker

    2010-01-01

    We discuss strategic renewal from a competence perspective. We argue that the management of speed and timing in this process is viewed distinctively when perceived through a cognitive lens. Managers need more firmly grounded process-understanding. The key idea of this paper is to dynamically conceptualize key activities of strategic renewal, and possible sources of break-down as they relate to the managment of speed and timing. Based on a case from the media industry, we identi...

  20. Hydrogen production processes

    International Nuclear Information System (INIS)

    2003-01-01

    The goals of this first Gedepeon workshop on hydrogen production processes are: to stimulate the information exchange about research programs and research advances in the domain of hydrogen production processes, to indicate the domains of interest of these processes and the potentialities linked with the coupling of a nuclear reactor, to establish the actions of common interest for the CEA, the CNRS, and eventually EDF, that can be funded in the framework of the Gedepeon research group. This document gathers the slides of the 17 presentations given at this workshop and dealing with: the H 2 question and the international research programs (Lucchese P.); the CEA's research program (Lucchese P., Anzieu P.); processes based on the iodine/sulfur cycle: efficiency of a facility - flow-sheets, efficiencies, hard points (Borgard J.M.), R and D about the I/S cycle: Bunsen reaction (Colette S.), R and D about the I/S cycle: the HI/I 2 /H 2 O system (Doizi D.), demonstration loop/chemical engineering (Duhamet J.), materials and corrosion (Terlain A.); other processes under study: the Westinghouse cycle (Eysseric C.), other processes under study at the CEA (UT3, plasma,...) (Lemort F.), database about thermochemical cycles (Abanades S.), Zn/ZnO cycle (Broust F.), H 2 production by cracking, high temperature reforming with carbon trapping (Flamant G.), membrane technology (De Lamare J.); high-temperature electrolysis: SOFC used as electrolyzers (Grastien R.); generic aspects linked with hydrogen production: technical-economical evaluation of processes (Werkoff F.), thermodynamic tools (Neveu P.), the reactor-process coupling (Aujollet P.). (J.S.)