Therapeutic options to manage bleeding in a dentist’s office

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Rostetter, Claudio; Finkenstädt, Tim; Rücker, Martin; Lübbers, Heinz-Theo

2018-06-18

This manuscript provides an overview of therapeutic options for the problem of bleeding in a dentist’s office. Bleeding after tooth extraction is a very common finding in dental medicine and persistent blood in the mouth is obviously uncomfortable and sometimes terrifying for the patient. Most bleedings can be stopped simply with compression, in some cases a homeostatic therapy is necessary. For local compression, a swab with tranexamic acid is useful. If local compression is not sufficient, sutures are often an option. A very effective therapy would also be Tabotamp®, a local hemostypticum which is placed onto the bleeding and should increase the thrombocytic aggregation. In the worst case Floseal®, a human Thrombin, can be placed locally. It stops the bleeding very fast and sufficiently.

Therapeutic Options for the Management of the Cardiorenal Syndrome

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Katerina Koniari

2011-01-01

Full Text Available Patients with heart failure often present with impaired renal function, which is a predictor of poor outcome. The cardiorenal syndrome is the worsening of renal function, which is accelerated by worsening of heart failure or acute decompensated heart failure. Although it is a frequent clinical entity due to the improved survival of heart failure patients, still its pathophysiology is not well understood, and thus its therapeutic approach remains controversial and sometimes ineffective. Established therapeutic strategies, such as diuretics and inotropes, are often associated with resistance and limited clinical success. That leads to an increasing concern about novel options, such as the use of vasopressin antagonists, adenosine A1 receptor antagonists, and renal-protective dopamine. Initial clinical trials have shown quite encouraging results in some heart failure subpopulations but have failed to demonstrate a clear beneficial role of these agents. On the other hand, ultrafiltration appears to be a more promising therapeutic procedure that will improve volume regulation, while preserving renal and cardiac function. Further clinical studies are required in order to determine their net effect on renal function and potential cardiovascular outcomes. Until then, management of the cardiorenal syndrome remains quite empirical.

Rectal cancer and Fournier's gangrene - current knowledge and therapeutic options.

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Bruketa, Tomislav; Majerovic, Matea; Augustin, Goran

2015-08-14

Fournier's gangrene (FG) is a rapid progressive bacterial infection that involves the subcutaneous fascia and part of the deep fascia but spares the muscle in the scrotal, perianal and perineal region. The incidence has increased dramatically, while the reported incidence of rectal cancer-induced FG is unknown but is extremely low. Pathophysiology and clinical presentation of rectal cancer-induced FG per se does not differ from the other causes. Only rectal cancer-specific symptoms before presentation can lead to the diagnosis. The diagnosis of rectal cancer-induced FG should be excluded in every patient with blood on digital rectal examination, when urogenital and dermatological causes are excluded and when fever or sepsis of unknown origin is present with perianal symptomatology. Therapeutic options are more complex than for other forms of FG. First, the causative rectal tumor should be removed. The survival of patients with rectal cancer resection is reported as 100%, while with colostomy it is 80%. The preferred method of rectal resection has not been defined. Second, oncological treatment should be administered but the timing should be adjusted to the resolution of the FG and sometimes for the healing of plastic reconstructive procedures that are commonly needed for the reconstruction of large perineal, scrotal and lower abdominal wall defects.

First- and Second-Line Targeted Systemic Therapy in Hepatocellular Carcinoma—An Update on Patient Selection and Response Evaluation

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Johann von Felden

2016-11-01

Full Text Available Advanced hepatocellular carcinoma (HCC with vascular invasion and/or extrahepatic spread and preserved liver function, according to stage C of the Barcelona Clinic Liver Cancer (BCLC classification, has a dismal prognosis. The multi-targeted tyrosine-kinase receptor inhibitor (TKI sorafenib is the only proven active substance in systemic HCC therapy for first-line treatment. In this review, we summarize current aspects in patient selection and management of side effects, and provide an update on response evaluation during first-line sorafenib therapy. Since second-line treatment options have been improved with the successful completion of the RESORCE trial, demonstrating a survival benefit for second-line treatment with the TKI regorafenib, response monitoring during first-line therapy will be critical to deliver optimal systemic therapy in HCC. To this regard, specific side effects, in particular worsening of arterial hypertension and diarrhea, might suggest treatment response during first-line sorafenib therapy; however, clear predictive clinical markers, as well as laboratory test or serum markers, are not established. Assessment of radiologic response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST is helpful to identify patients who do not benefit from sorafenib treatment.

Options for the second commitment period of the Kyoto Protocol

Energy Technology Data Exchange (ETDEWEB)

Hoehne, Niklas; Phylipsen, Dian; Ullrich, Simone; Blok, Kornelis

2005-02-15

This study assesses available options for the second commitment period of the Kyoto Protocol. The study includes the following sections: An introduction, an overview of proposals and establishing a network, analysis of interests of countries, selected country case studies, an overview of the issues to be considered, options for adaptation to climate change, a new approach ''Common but Differentiated Convergence'', an update of the Triptych approach, a comprehensive compromise proposal, the comparison of emission allowances under various approaches and a negotiation strategy for the EU and Germany. (orig.)

Options for the second commitment period of the Kyoto Protocol

Energy Technology Data Exchange (ETDEWEB)

Hoehne, Niklas; Phylipsen, Dian; Ullrich, Simone; Blok, Kornelis

2005-02-15

This study assesses available options for the second commitment period of the Kyoto Protocol. The study includes the following sections: An introduction, an overview of proposals and establishing a network, analysis of interests of countries, selected country case studies, an overview of the issues to be considered, options for adaptation to climate change, a new approach ''Common but Differentiated Convergence'', an update of the Triptych approach, a comprehensive compromise proposal, the comparison of emission allowances under various approaches and a negotiation strategy for the EU and Germany. (orig.)

Therapeutic Success of the Ketogenic Diet as a Treatment Option for Epilepsy: a Meta-analysis

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Li, Hai-feng; Zou, Yan; Ding, Gangqiang

2013-01-01

Objective To systematically evaluate therapeutic success of the ketogenic diet (KD) as a treatment option for epilepsy. Methods Using MEDLINE and Google Scholar search, we searched for studies investigating the therapeutic success of ketogenic diet for epilepsy. We estimated therapeutic success rate for ketogenic diet as a treatment option for epilepsy and its 95% CIs using generic inverse variance method. Findings A total of 38 studies met the inclusion criteria. In retrospective studies, the weighted success rate of the patients who take the KD as a treatment option for epilepsy was 58.4% (95% confidence interval (95%CI)=48.7% – 69.9%) at 3 months (n=336); 42.8% (95%CI =36.3% – 50.3%) at 6 months (n=492), and 30.1% (95%CI =24.3% – 37.2%) at 12 months (n=387); in prospective studies, weighted success rate was 53.9% (95%CI 45.5% – 63.8%) at 3 months (n=474); 53.2% (95%CI =44.0% – 64.2%) at 6 months (n=321), and 55.0% (95%CI =45.9% – 65.9%) at 12 months (n=347). Conclusion This meta-analysis provides formal statistical support for the efficacy of the ketogenic diet in the treatment of epileptic patients. PMID:24910737

Hemibody irradiation. An effective second-line therapy in drug-resistance multiple myeloma

International Nuclear Information System (INIS)

Singer, C.R.; Tobias, J.S.; Giles, F.; Rudd, G.N.; Blackman, G.M.; Richards, J.D.

1989-01-01

The authors report the results of treatment of 41 patients with melphalan-resistant multiple myeloma using single half-body irradiation (HBI) or double half-body irradiation (DHBI). Patients were grouped using prognostic classification reported by the Medical Research Council. Patients in group I and II showed the best response to therapy with reduction in serum of urinary paraprotein and improvement in symptoms, most notably a marked reduction in bone pain. In these groups five patients have survived over 2 years after therapy. The therapeutic response appeared better in those patients who received DHBI as opposed to those whom treated with single HBI. Patients in group III did not achieve prolonged survival but effective relief of bone pain was a consistent finding in these patients also. Thus HBI represents an alternative to combination chemotherapy as second-line treatment of patients with melphalan-resistant multiple myeloma. A comparative study of HBI versus combination chemotherapy is now indicated to establish which therapeutic approach is most effective

Efficacy and safety of pharmacological interventions in second- or later-line treatment of patients with advanced soft tissue sarcoma: a systematic review

International Nuclear Information System (INIS)

Sharma, Sheetal; Takyar, Shweta; Manson, Stephanie C; Powell, Sarah; Penel, Nicolas

2013-01-01

Current guidelines recommend anthracycline-based chemotherapy primarily with doxorubicin either as monotherapy or in combination with ifosfamide as the first-line treatment for most advanced STS subtypes. Therapeutic options after failure of doxorubicin and/or ifosfamide are limited. This study aimed to comprehensively review available data on the activity and safety of interventions in second- or later-line treatment of advanced STS. Electronic literature databases (Embase ® , MEDLINE ® , MEDLINE ® In-Process, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews) were searched from 1980 to 01 March 2012 to identify randomised controlled trials (RCTs) and non-randomised studies (both prospective and retrospective) evaluating pharmacological interventions in patients with advanced STS pre-treated with anthracycline- and/or ifosfamide-based therapy. The review identified six RCTs (one phase III and five phase II trials) and 94 non-randomised studies. Based on the primary trial endpoints, RCTs demonstrated favourable efficacy for pazopanib over placebo (PFS: 4.6 months vs. 1.6 months), gemcitabine plus dacarbazine over dacarbazine monotherapy (3-month PFS rate: 54.2% vs. 35.2%), and trabectedin 3-weekly schedule over weekly schedule (TTP: 3.7 months vs. 2.3 months. The non-randomised studies demonstrated heterogeneity in efficacy and safety results. Across the RCTs, pazopanib over placebo, gemcitabine-dacarbazine over dacarbazine, and trabectedin 3-weekly over weekly regimen clearly demonstrated a PFS advantage in the second- and later-line treatment of advanced STS. With only one phase III trial in this setting, there is a clear need for additional comparative trials to better understand the risk: benefit ratios of available agents and combinations

Skewed Epigenetics: An Alternative Therapeutic Option for Diabetes Complications

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Gabriele Togliatto

2015-01-01

Full Text Available Vascular complications are major causes of morbidity and mortality in type 2 diabetes patients. Mitochondrial reactive oxygen species (ROS generation and a lack of efficient antioxidant machinery, a result of hyperglycaemia, mainly contribute to this problem. Although advances in therapy have significantly reduced both morbidity and mortality in diabetic individuals, diabetes-associated vascular complications are still one of the most challenging health problems worldwide. New healing options are urgently needed as current therapeutics are failing to improve long-term outcomes. Particular effort has recently been devoted to understanding the functional relationship between chromatin structure regulation and the persistent change in gene expression which is driven by hyperglycaemia and which accounts for long-lasting diabetic complications. A detailed investigation into epigenetic chromatin modifications in type 2 diabetes is underway. This will be particularly useful in the design of mechanism-based therapeutics which interfere with long-lasting activating epigenetics and improve patient outcomes. We herein provide an overview of the most relevant mechanisms that account for hyperglycaemia-induced changes in chromatin structure; the most relevant mechanism is called “metabolic memory.”

Therapeutic options in pediatric non alcoholic fatty liver disease: current status and future directions

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Vajro Pietro

2012-10-01

Full Text Available Abstract The epidemics of overweight and obesity has resulted in a significant increase of non alcoholic fatty liver disease (NAFLD, a potentially progressive condition. Currently, obesity related hepatopathy represents therefore the main cause of pediatric chronic liver disease. The first choice treatment at all ages is weight loss and/or lifestyle changes, however compliance is very poor and a pharmacological approach has become necessary. In the present article we present a systematic literature review focusing on established pediatric NALFD drugs (ursodeoxycholic acid, insulin sensitizers, and antioxidants and on innovative therapeutic options as well. Regarding the former ones, a pediatric pilot study highlighted that ursodeoxycholic acid is not efficient on transaminases levels and bright liver. Similarly, a recent large scale, multicenter randomized clinical trial (TONIC study showed that also insulin sensitizers and antioxidant vitamin E have scarce effects on serum transaminase levels. Among a large series of novel therapeutic approaches acting on recently proposed different pathomechanisms, probiotics seem hitherto the most interesting and reasonable option for their safety and tolerability. Toll-like receptors modifiers, Pentoxifylline, and Farnesoid X receptors agonists have been still poorly investigated, and will need further studies before becoming possible promising innovative therapeutic strategies.

Rectal cancer and Fournier’s gangrene - current knowledge and therapeutic options

Science.gov (United States)

Bruketa, Tomislav; Majerovic, Matea; Augustin, Goran

2015-01-01

Fournier’s gangrene (FG) is a rapid progressive bacterial infection that involves the subcutaneous fascia and part of the deep fascia but spares the muscle in the scrotal, perianal and perineal region. The incidence has increased dramatically, while the reported incidence of rectal cancer-induced FG is unknown but is extremely low. Pathophysiology and clinical presentation of rectal cancer-induced FG per se does not differ from the other causes. Only rectal cancer-specific symptoms before presentation can lead to the diagnosis. The diagnosis of rectal cancer-induced FG should be excluded in every patient with blood on digital rectal examination, when urogenital and dermatological causes are excluded and when fever or sepsis of unknown origin is present with perianal symptomatology. Therapeutic options are more complex than for other forms of FG. First, the causative rectal tumor should be removed. The survival of patients with rectal cancer resection is reported as 100%, while with colostomy it is 80%. The preferred method of rectal resection has not been defined. Second, oncological treatment should be administered but the timing should be adjusted to the resolution of the FG and sometimes for the healing of plastic reconstructive procedures that are commonly needed for the reconstruction of large perineal, scrotal and lower abdominal wall defects. PMID:26290629

Effectiveness of carboplatin and paclitaxel as first- and second-line treatment in 61 patients with metastatic melanoma.

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Annette Pflugfelder

Full Text Available BACKGROUND: Patients with metastatic melanoma have a very unfavorable prognosis with few therapeutic options. Based on previous promising experiences within a clinical trial involving carboplatin and paclitaxel a series of advanced metastatic melanoma patients were treated with this combination. METHODS: Data of all patients with cutaneous metastatic melanoma treated with carboplatin and paclitaxel (CP at our institution between October 2005 and December 2007 were retrospectively evaluated. For all patients a once-every-3-weeks dose-intensified regimen was used. Overall and progression free survival were calculated using the method of Kaplan and Meier. Tumour response was evaluated according to RECIST criteria. RESULTS: 61 patients with cutaneous metastatic melanoma were treated with CP. 20 patients (85% M1c received CP as first-line treatment, 41 patients (90.2% M1c had received at least one prior systemic therapy for metastatic disease. Main toxicities were myelosuppression, fatigue and peripheral neuropathy. Partial responses were noted in 4.9% of patients, stable disease in 23% of patients. No complete response was observed. Median progression free survival was 10 weeks. Median overall survival was 31 weeks. Response, progression-free and overall survival were equivalent in first- and second-line patients. 60 patients of 61 died after a median follow up of 7 months. Median overall survival differed for patients with controlled disease (PR+SD (49 weeks compared to patients with progressive disease (18 weeks. CONCLUSIONS: Among patients with metastatic melanoma a subgroup achieved disease control under CP therapy which may be associated with a survival benefit. This potential advantage has to be weighed against considerable toxicity. Since response rates and survival were not improved in previously untreated patients compared to pretreated patients, CP should thus not be applied as first-line treatment.

Herbal Medicine Offered as an Initiative Therapeutic Option for the Management of Hepatocellular Carcinoma.

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Chen, Shao-Ru; Qiu, Hong-Cong; Hu, Yang; Wang, Ying; Wang, Yi-Tao

2016-06-01

Hepatocellular carcinoma (HCC) is a common malignant cancer and is the third leading cause of death worldwide. Effective treatment of this disease is limited by the complicated molecular mechanism underlying HCC pathogenesis. Thus, therapeutic options for HCC management are urgently needed. Targeting the Wnt/β-catenin, Hedgehog, Notch, and Hippo-YAP signaling pathways in cancer stem cell development has been extensively investigated as an alternative treatment. Herbal medicine has emerged as an initiative therapeutic option for HCC management because of its multi-level, multi-target, and coordinated intervention effects. In this article, we summarized the recent progress and clinical benefits of targeting the above mentioned signaling pathways and using natural products such as herbal medicine formulas to treat HCC. Proving the clinical success of herbal medicine is expected to deepen the knowledge on herbal medicine efficiency and hasten the adoption of new therapies. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Metastatic melanoma: results of 'classical' second-line treatment with cytotoxic chemotherapies.

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Perrin, Christophe; Pracht, Marc; Talour, Karen; Adamski, Henri; Cumin, Isabelle; Porneuf, Marc; Talarmin, Marie; Mesbah, Habiba; Audrain, Odile; Moignet, Aline; Lefeuvre-Plesse, Claudia; Lesimple, Thierry

2014-10-01

Metastatic melanoma is one of the most aggressive tumours, with a median survival that does not exceed 12 months. None of the cytotoxic first-line therapies have shown survival benefit in randomised clinical trials. To describe clinical benefit of second-line cytotoxic chemotherapy in the second line of treatment for metastatic melanoma. In a retrospective study, we analyse the outcome of patients with metastatic melanoma who had received two lines or more of cytotoxic treatments in four French dermato-oncology departments between 1999 and 2009. We describe the outcomes for 109 patients. Most of these patients received dacarbazine for the first line of chemotherapy and fotemustine for the second line of chemotherapy (67.0 and 64.2%, respectively). A clinical benefit was observed in 24.1% of the patients and overall survival was 4.1 months after the second-line treatment. At least 23.8% of patients suffered from grade 3 or 4 toxicities. The presence of more than two sites of metastasis and an M1c staging according to the AJCC classification represented negative predictive factors of clinical benefit. This study shows the modest benefit of a second line of cytotoxic chemotherapy in a nonselected population. If eligible, these patients should be proposed for ongoing clinical trials or for targeted therapies.

Preliminary study of the effects of an educational workshop on therapeutic use of music and aesthetic experience with music in first-line nurses.

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Lai, Hui-Ling

2011-11-01

The purpose of this study was to assess the effects of an educational workshop on knowledge of and attitude toward therapeutic use of music and aesthetic experiences with music among first-line nurses. A one-group pre-test/post-test design was used. Forty-six first-line nurses, aged 21-56 years, were recruited from seven different hospitals. Questionnaires were used to assess the nurses' knowledge of and attitude toward therapeutic use of music and aesthetic experience with music before and after the workshop, and 3 months after the workshop. The workshop comprised three sessions; the nurses participated in 8h of instruction the first week and 4h, the second week covering analytical music appreciation, music staves comprehension, theory and practice of music therapy, and evidence-based music intervention. Educational workshop significantly improved knowledge of and attitudes toward therapeutic use of music and music aesthetic experiences (pmusic aesthetic experiences between nurse with and without music backgrounds differed significantly (p=0.01). The workshop enhanced the knowledge of and attitude toward therapeutic use of music and aesthetic experiences with music among first-line nurses. Copyright © 2010 Elsevier Ltd. All rights reserved.

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Indian Academy of Sciences (India)

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Merkel Cell Carcinoma: Chemotherapy and Emerging New Therapeutic Options

International Nuclear Information System (INIS)

Desch, L.; Kunstfeld, R.

2013-01-01

Merkel cell carcinoma (MCC) is a rare neuroendocrine skin tumor that typically occurs in elderly, immunosuppressed patients. Infection with Merkel cell virus (MCV) and immunosuppression play an important role in the development of MCC. Different staging systems make it difficult to compare the existing clinical data. Furthermore, there predominantly exist single case reports and case series, but no randomized controlled trials. However, it is necessary to develop further therapy options because MCC tends to grow rapidly and metastasizes early. In the metastatic disease, therapeutic attempts were made with various chemotherapeutic combination regimens. Because of the high toxicity of these combinations, especially those established in SCLC, and regarding the unsatisfying results, the challenge is to balance the pros and cons of chemotherapy individually and carefully. Up to now, emerging new therapy options as molecular-targeted agents, for example, pipebuzone, imatinib, or somatostatin analogues as well as immunologic als, for example, imiquimod and interferons, also showed less success concerning the disease-free response rates. According to the literature, neither chemotherapy nor molecular-targeted agents or immunotherapeutic strategies have shown promising effects in the therapy of the metastatic disease of MCC so far. There is a great demand for randomized controlled studies and a need for an MCC registry and multicenter clinical trials due to the tumors curiosity.

Role of regorafenib as second-line therapy and landscape of investigational treatment options in advanced hepatocellular carcinoma

Directory of Open Access Journals (Sweden)

Trojan J

2016-09-01

Full Text Available Jörg Trojan, Oliver Waidmann Medizinische Klinik 1, Universitätsklinikum Frankfurt, Germany Abstract: Sorafenib is still the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC. In recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development due to either toxicity or lack of benefit. Recently, data of the RESORCE trial, a placebo-controlled Phase III study that evaluated the efficacy and safety of regorafenib in patients with HCC and documented disease progression after systemic first-line treatment with sorafenib, were presented at the ESMO World Congress on Gastrointestinal Cancer, 2016. Regorafenib treatment resulted in a 2.8-month survival benefit compared to placebo (10.6 months vs 7.8 months. Side effects were consistent with the known profile of regorafenib. The approval of regorafenib for this indication is expected in 2017. Further candidate agents in Phase III evaluation for second-line treatment of patients with HCC are the MET inhibitors tivantinib and cabozantinib, the vascular endothelial growth factor receptor-2 antibody ramucirumab, and the programmed death receptor-1 (PD-1 blocking antibody pembrolizumab. Furthermore, results from two first-line trials with either the tyrosine kinase inhibitor lenvatinib or the PD-1 antibody nivolumabin in comparison to sorafenib are awaited in the near future and might further change the treatment sequence of advanced HCC. Keywords: hepatocellular carcinoma, receptor tyrosine kinase inhibitor, sorafenib, regorafenib, lenvatinib, tivantinib, cabozantinib, ramucirumab, immunotherapy, anti-CTLA-4, anti-PD-1, oncolytic virus

Exploration of BEOL line-space patterning options at 12 nm half-pitch and below

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Decoster, S.; Lazzarino, F.; Petersen Barbosa Lima, L.; Li, W.; Versluijs, J.; Halder, S.; Mallik, A.; Murdoch, G.

2018-03-01

While the semiconductor industry is almost ready for high-volume manufacturing of the 7 nm technology node, research centers are defining and troubleshooting the patterning options for the 5 nm technology node (N5) and below. The target dimension for imec's N5 BEOL applications is 20-24 nm Metal Pitch (MP), which requires Self-Aligned multiple (Double/Quadruple/Octuple) Patterning approaches (SAxP) in combination with EUV or immersion lithography at 193 nm. There are numerous technical challenges to enable gratings at the hard mask level such as good uniformity across wafer, low line edge/width roughness (LER/LWR), large process window, and all of this at low cost. An even greater challenge is to transfer these gratings into the dielectric material at such critical dimensions, where increased line edge roughness, line wiggling and even pattern collapse can be expected for materials with small mechanical stability such as highly porous low-k dielectrics. In this work we first compare three different patterning options for 12 nm half-pitch gratings at the hard mask level: EUV-based SADP and 193i-based SAQP and SAOP. This comparison will be based on process window, line edge/width roughness and cost. Next, the transfer of 12 nm line/space gratings in the dielectric material is discussed and presented. The LER of the dielectric lines is investigated as a function of the dielectric material, the trench depth, and the stress in the sacrificial hard mask. Finally, we elaborate on the different options to enable scaling down from 24 nm MP to 16 nm MP, and demonstrate 8 nm line/space gratings with 193i-based SAOP.

Cost effectiveness of regorafenib as second-line therapy for patients with advanced hepatocellular carcinoma.

Science.gov (United States)

Parikh, Neehar D; Singal, Amit G; Hutton, David W

2017-10-01

Regorafenib, a multikinase inhibitor, has demonstrated prolonged survival by 2.8 months as a second-line agent in patients with hepatocellular carcinoma (HCC) who progress on sorafenib therapy. The objective of the current study was to examine the cost effectiveness of regorafenib for the treatment of HCC. The authors constructed a Markov simulation model of patients with unresectable HCC and Child-Pugh A cirrhosis who received treatment with regorafenib versus best supportive care. Model inputs for regorafenib effectiveness and rates of adverse events in patients with HCC were based on published clinical trial data and literature review. Quality-adjusted life years (QALYs) were calculated along with the incremental cost-effectiveness ratio (ICER) of regorafenib therapy. One-way sensitivity analyses also were conducted simultaneously on all model parameters and on various Monte-Carlo simulation parameters, and the regorafenib cost threshold at which cost effectiveness would be achieved was determined. Regorafenib provided an increase of 0.18 QALYs at a cost of $47,112. The ICER for regorafenib, compared with best supportive care, was $224,362. In 1-way sensitivity analyses, there were no scenarios in which regorafenib was cost effective. In cost threshold analysis, regorafenib would have to be priced at or below $67 per pill to be cost effective at an ICER of $100,000. Regorafenib is not cost effective as a second-line agent in the treatment of HCC, with a marginal increase in QALYs at a high cost. Lowering the cost of regorafenib or improving the selection of patients who can achieve maximal survival benefit would improve its value as a second-line treatment option for patients with HCC. Cancer 2017;123:3725-3731. © 2017 American Cancer Society. © 2017 American Cancer Society.

Second-line systemic therapy for metastatic colorectal cancer.

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Mocellin, Simone; Baretta, Zora; Roqué I Figuls, Marta; Solà, Ivan; Martin-Richard, Marta; Hallum, Sara; Bonfill Cosp, Xavier

2017-01-27

The therapeutic management of people with metastatic colorectal cancer (CRC) who did not respond to first-line treatment represents a formidable challenge. To determine the efficacy and toxicity of second-line systemic therapy in people with metastatic CRC. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 4), Ovid MEDLINE (1950 to May 2016), Ovid MEDLINE In-process & Other Non-Indexed Citations (1946 to May 2016) and Ovid Embase (1974 to May 2016). There were no language or date of publication restrictions. Randomized controlled trials (RCTs) assessing the efficacy (survival, tumour response) and toxicity (incidence of severe adverse effects (SAEs)) of second-line systemic therapy (single or combined treatment with any anticancer drug, at any dose and number of cycles) in people with metastatic CRC that progressed, recurred or did not respond to first-line systemic therapy. Authors performed a descriptive analysis of each included RCT in terms of primary (survival) and secondary (tumour response, toxicity) endpoints. In the light of the variety of drug regimens tested in the included trials, we could carry out meta-analysis considering classes of (rather than single) anticancer regimens; to this aim, we applied the random-effects model to pool the data. We used hazard ratios (HRs) and risk ratios (RRs) to describe the strength of the association for survival (overall (OS) and progression-free survival (PFS)) and dichotomous (overall response rate (ORR) and SAE rate) data, respectively, with 95% confidence intervals (CI). Thirty-four RCTs (enrolling 13,787 participants) fulfilled the eligibility criteria. Available evidence enabled us to address multiple clinical issues regarding the survival effects of second-line systemic therapy of people with metastatic CRC.1. Chemotherapy (irinotecan) was more effective than best supportive care (HR for OS: 0.58, 95% CI 0.43 to 0.80; 1 RCT; moderate-quality evidence); 2

[Usher syndrome: clinical features, diagnostic options, and therapeutic prospects].

Science.gov (United States)

Seeliger, M W; Fischer, M D; Pfister, M

2009-06-01

Usher syndrome denotes a clinically and genetically heterogeneous combination of retinitis pigmentosa and sensorineural deafness. The division into subtypes I, II, and III is based on the degree of hearing loss: Type I is characterized by deafness from birth together with ataxia and retarded motor development, type II by a stationary deafness of a moderate degree, and type III by a progressive deafness with adult onset. In Germany, Usher syndrome currently bears particular relevance because in January 2009 a new compulsory screening of auditory function in newborn infants was introduced. Consequently, it can be expected that a higher number of patients with Usher syndrome will be identified in early childhood and referred to ophthalmologists. The focus of this work is to introduce the typical clinical picture of Usher syndrome, summarize diagnostic options, and give an overview of therapeutic strategies.

Treatment Failure in HIV-Infected Children on Second-line Protease Inhibitor-Based Antiretroviral Therapy.

Science.gov (United States)

Suaysod, Rapeepan; Ngo-Giang-Huong, Nicole; Salvadori, Nicolas; Cressey, Tim R; Kanjanavanit, Suparat; Techakunakorn, Pornchai; Krikajornkitti, Sawitree; Srirojana, Sakulrat; Laomanit, Laddawan; Chalermpantmetagul, Suwalai; Lallemant, Marc; Le Cœur, Sophie; McIntosh, Kenneth; Traisathit, Patrinee; Jourdain, Gonzague

2015-07-01

Human immunodeficiency virus (HIV)-infected children failing second-line antiretroviral therapy (ART) have no access to third-line antiretroviral drugs in many resource-limited settings. It is important to identify risk factors for second-line regimen failure. HIV-infected children initiating protease inhibitor (PI)-containing second-line ART within the Program for HIV Prevention and Treatment observational cohort study in Thailand between 2002 and 2010 were included. Treatment failure was defined as confirmed HIV type 1 RNA load >400 copies/mL after at least 6 months on second-line regimen or death. Adherence was assessed by drug plasma levels and patient self-report. Cox proportional hazards regression analyses were used to identify risk factors for failure. A total of 111 children started a PI-based second-line regimen, including 59 girls (53%). Median first-line ART duration was 1.9 years (interquartile range [IQR], 1.4-3.3 years), and median age at second-line initiation was 10.7 years (IQR, 6.3-13.4 years). Fifty-four children (49%) experienced virologic failure, and 2 (2%) died. The risk of treatment failure 24 months after second-line initiation was 41%. In multivariate analyses, failure was independently associated with exposure to first-line ART for >2 years (adjusted hazard ratio [aHR], 1.8; P = .03), age >13 years (aHR, 2.9; P < .001), body mass index-for-age z score < -2 standard deviations at second-line initiation (aHR, 2.8; P = .03), and undetectable drug levels within 6 months following second-line initiation (aHR, 4.5; P < .001). Children with longer exposure to first-line ART, entry to adolescence, underweight, and/or undetectable drug levels were at higher risk of failing second-line ART and thus should be closely monitored. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Reemergence of Splenectomy for ITP Second-line Treatment?

Science.gov (United States)

Chater, Charbel; Terriou, Louis; Duhamel, Alain; Launay, David; Chambon, Jean P; Pruvot, François R; Rogosnitzky, Moshe; Zerbib, Philippe

2016-11-01

Corticosteroids are still the standard first-line treatment for immune thrombocytopenic purpura (ITP). As second-line therapy, splenectomy and Rituximab are both recommended. The aim of our study was to compare the efficacy of Rituximab to splenectomy in persistent or chronic ITP patients. Between January 1999 and March 2015, we retrospectively selected all consecutive patients who underwent an ITP second-line treatment: Rituximab or splenectomy. The distinction between open (OS) and laparoscopic splenectomy (LS) was analyzed. Primary outcome was composite: hospitalization for bleeding and/or thrombocytopenia and death from hemorrhage or infection. Secondary outcomes were based on response (R) and complete response (CR) rates as defined by the American Society of Hematology. Ninety-six patients were included: 30 patients received Rituximab, 37 underwent OS, and 29 underwent LS. The follow-up was 30, 60, and 120 months in Rituximab, LS, and OS groups, respectively. At 30 month, the primary outcome-free survival rate was higher in splenectomy groups (84% for OS, 86% for LS) than Rituximab group (47%) (P = 0.0002). Similarly, at 30 month, R and CR rates were higher for OS (86.5% and 75.7%, respectively) and LS groups (93.1% and 89.7%) than Rituximab (46.7% and 30%) (P = 0.0001). Moreover, R rates remained elevated at 60 month for OS and LS groups (83.7% and 89.6% respectively) and 78.4% at 120 month for OS group. We observed that splenectomy for ITP second-line treatment was more effective than Rituximab regarding maintenance of R, CR, and overall response rates. OS and LS had similar efficacy.

Perceived adherence barriers among patients failing second-line ...

African Journals Online (AJOL)

Perceived adherence barriers among patients failing second-line antiretroviral therapy in Khayelitsha, South Africa. W Barnett, G Patten, B Kerschberger, K Conradie, DB Garone, G van Cutsem, CJ Colvin ...

Therapeutic Recreation in the Community: An Inclusive Approach. Second Edition

Science.gov (United States)

Carter, Marcia Jean; LeConey, Stephen P.

2004-01-01

The second edition of Therapeutic Recreation in the Community: An Inclusive Approach reflects the changing and evolving nature of recreation and health care services. A number of social, economic, and political directives and technological advancements have fostered recreation in the community for all individuals. Due in part to a rising awareness…

Initial Results of Image-Guided Percutaneous Ablation as Second-Line Treatment for Symptomatic Vascular Anomalies

International Nuclear Information System (INIS)

Thompson, Scott M.; Callstrom, Matthew R.; McKusick, Michael A.; Woodrum, David A.

2015-01-01

PurposeThe purpose of this study was to determine the feasibility, safety, and early effectiveness of percutaneous image-guided ablation as second-line treatment for symptomatic soft-tissue vascular anomalies (VA).Materials and MethodsAn IRB-approved retrospective review was undertaken of all patients who underwent percutaneous image-guided ablation as second-line therapy for treatment of symptomatic soft-tissue VA during the period from 1/1/2008 to 5/20/2014. US/CT- or MRI-guided and monitored cryoablation or MRI-guided and monitored laser ablation was performed. Clinical follow-up began at one-month post-ablation.ResultsEight patients with nine torso or lower extremity VA were treated with US/CT (N = 4) or MRI-guided (N = 2) cryoablation or MRI-guided laser ablation (N = 5) for moderate to severe pain (N = 7) or diffuse bleeding secondary to hemangioma–thrombocytopenia syndrome (N = 1). The median maximal diameter was 9.0 cm (6.5–11.1 cm) and 2.5 cm (2.3–5.3 cm) for VA undergoing cryoablation and laser ablation, respectively. Seven VA were ablated in one session, one VA initially treated with MRI-guided cryoablation for severe pain was re-treated with MRI-guided laser ablation due to persistent moderate pain, and one VA was treated in a planned two-stage session due to large VA size. At an average follow-up of 19.8 months (range 2–62 months), 7 of 7 patients with painful VA reported symptomatic pain relief. There was no recurrence of bleeding at five-year post-ablation in the patient with hemangioma–thrombocytopenia syndrome. There were two minor complications and no major complications.ConclusionImage-guided percutaneous ablation is a feasible, safe, and effective second-line treatment option for symptomatic VA

Initial Results of Image-Guided Percutaneous Ablation as Second-Line Treatment for Symptomatic Vascular Anomalies

Energy Technology Data Exchange (ETDEWEB)

Thompson, Scott M., E-mail: Thompson.scott@mayo.edu [Mayo Clinic, Mayo Graduate School, Mayo Medical School and the Mayo Clinic Medical Scientist Training Program, College of Medicine (United States); Callstrom, Matthew R., E-mail: callstrom.matthew@mayo.edu; McKusick, Michael A., E-mail: mckusick.michael@mayo.edu; Woodrum, David A., E-mail: woodrum.david@mayo.edu [Mayo Clinic, Department of Radiology, College of Medicine (United States)

2015-10-15

PurposeThe purpose of this study was to determine the feasibility, safety, and early effectiveness of percutaneous image-guided ablation as second-line treatment for symptomatic soft-tissue vascular anomalies (VA).Materials and MethodsAn IRB-approved retrospective review was undertaken of all patients who underwent percutaneous image-guided ablation as second-line therapy for treatment of symptomatic soft-tissue VA during the period from 1/1/2008 to 5/20/2014. US/CT- or MRI-guided and monitored cryoablation or MRI-guided and monitored laser ablation was performed. Clinical follow-up began at one-month post-ablation.ResultsEight patients with nine torso or lower extremity VA were treated with US/CT (N = 4) or MRI-guided (N = 2) cryoablation or MRI-guided laser ablation (N = 5) for moderate to severe pain (N = 7) or diffuse bleeding secondary to hemangioma–thrombocytopenia syndrome (N = 1). The median maximal diameter was 9.0 cm (6.5–11.1 cm) and 2.5 cm (2.3–5.3 cm) for VA undergoing cryoablation and laser ablation, respectively. Seven VA were ablated in one session, one VA initially treated with MRI-guided cryoablation for severe pain was re-treated with MRI-guided laser ablation due to persistent moderate pain, and one VA was treated in a planned two-stage session due to large VA size. At an average follow-up of 19.8 months (range 2–62 months), 7 of 7 patients with painful VA reported symptomatic pain relief. There was no recurrence of bleeding at five-year post-ablation in the patient with hemangioma–thrombocytopenia syndrome. There were two minor complications and no major complications.ConclusionImage-guided percutaneous ablation is a feasible, safe, and effective second-line treatment option for symptomatic VA.

Achalasia: Treatment Options Revisited

Directory of Open Access Journals (Sweden)

Willemijntje A Hoogerwerf

2000-01-01

Full Text Available The aim of all current forms of treatment of achalasia is to enable the patient to eat without disabling symptoms such as dysphagia, regurgitation, coughing or choking. Historically, this has been accomplished by mechanical disruption of the lower esophageal sphincter fibres, either by means of pneumatic dilation (PD or by open surgical myotomy. The addition of laparoscopic myotomy and botulinum toxin (BTX injection to the therapeutic armamentarium has triggered a recent series of reviews to determine the optimal therapeutic approach. Both PD and BTX have excellent short term (less than three months efficacy in the majority of patients. New data have been published that suggest that PD and BTX (with repeat injections can potentially obtain long term efficacy. PD is still considered the first-line treatment by most physicians; its main disadvantage is risk of perforation. BTX injection is evolving as an excellent, safe option for patients who are considered high risk for more invasive procedures. Laparoscopic myotomy with combined antireflux surgery is an increasingly attractive option in younger patients with achalasia, but long term follow-up studies are required to establish its efficacy and the potential for reflux-related sequelae.

Delays in switching patients onto second-line antiretroviral treatment ...

African Journals Online (AJOL)

Background: South Africa has one of the largest antiretroviral treatment (ART) programmes globally. In addition to increasing access to ART, it is important that the health system also focuses on the appropriate management of patients who fail first-line ART. Delays in switching patients onto second-line ART can adversely ...

Determinants of durability of first-line antiretroviral therapy regimen and time from first-line failure to second-line antiretroviral therapy initiation

DEFF Research Database (Denmark)

Desmonde, Sophie; Eboua, François T; Malateste, Karen

2015-01-01

BACKGROUND: We described reasons for switching to second-line antiretroviral treatment (ART) and time to switch in HIV-infected children failing first-line ART in West Africa. METHODS: We included all children aged 15 years or less, starting ART (at least three drugs) in the paediatric Ie...... post-ART initiation, 188 (7%) had switched to second-line. The most frequent reasons were drug stock outs (20%), toxicity (18%), treatment failure (16%) and poor adherence (8%). Over the 24-month follow-up period, 322 (12%) children failed first-line ART after a median time of 7 months...... rare and switches after an immunological failure were insufficient. These gaps reveal that it is crucial to advocate for both sustainable access to first-line and alternative regimens to provide adequate roll-out of paediatric ART programmes....

Cabazitaxel as second-line or third-line therapy in patients with metastatic castration-resistant prostate cancer

DEFF Research Database (Denmark)

Kongsted, Per; Svane, Inge M; Lindberg, Henriette

2016-01-01

To compare treatment outcomes in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel (CA) as second-line or third-line therapy in the everyday clinical setting. Charts from 94 patients treated with CA as second-line (n=28) or third-line therapy (n=66) were...... evaluated. Common Terminology Criteria for Adverse Events were used to register grade 3-4 nonhematological toxicity during treatment with CA. Baseline metastatic castration-resistant prostate cancer-related prognostic factors, duration of therapy, and maximum prostate-specific antigen (PSA) percentage...... change were registered during treatment with CA and previous/subsequent novel androgen receptor targeting therapies. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. A median of 6 versus 5 treatment cycles was administered in patients treated...

Life on the line: the therapeutic potentials of computer-mediated conversation.

Science.gov (United States)

Miller, J K; Gergen, K J

1998-04-01

In what ways are computer networking practices comparable to face-to-face therapy? With the exponential increase in computer-mediated communication and the increasing numbers of people joining topically based computer networks, the potential for grass-roots therapeutic (or antitherapeutic) interchange is greatly augmented. Here we report the results of research into exchanges on an electronic bulletin board devoted to the topic of suicide. Over an 11-month period participants offered each other valuable resources in terms of validation of experience, sympathy, acceptance, and encouragement. They also asked provocative questions and furnished broad-ranging advice. Hostile entries were rare. However, there were few communiques that parallel the change-inducing practices more frequent within many therapeutic settings. In effect, on-line dialogues seemed more sustaining than transforming. Further limits and potentials of on-line communication are explored.

Perceived adherence barriers among patients failing second-line ...

African Journals Online (AJOL)

1 School of Public Health and Family Medicine, University of Cape Town, South Africa ... To examine factors affecting adherence to second-line ART from the perspective of clinic staff and .... because she did not realise her VL would go up.

Qualitative study of patients’ decision-making when accepting second-line treatment after failure of first-line chemotherapy

Science.gov (United States)

Roch, Benoît; Roth, Caroline; Mérel, Jean-Pierre

2018-01-01

Objective Treatment failures in advanced lung cancer are frequent events affecting patients during or after first-line chemotherapy. International guidelines recommend second-line chemotherapy. However, around one half of patients who experience disease progression enter a systemic second-line therapy. In the herein qualitative study, we investigated patients' thoughts and attitudes determining the decision to undergo a second-line chemotherapy. Methods Thirty-three purposively selected patients who recently accepted second-line or palliative chemotherapy were invited to participate in this survey consisting of semi-structured in-depth interviews. Grounded theory was applied to investigate participants’ perceptions of the context that have surrounded their decision to undergo palliative chemotherapy. Results For most patients, tumor burden and reduced quality of life in relation with lung cancer itself were major drivers of the decision-making process. There was a balance between two different attitudes: making a decision to undergo a new line of chemotherapy or starting a psychological process in order to accept end of life. Choosing between these two attitudes allowed the patient to keep the matter of palliative care at a distance. Even in case of low chance of success, many patients who worried about their life partner's future would accept a new chemotherapy line. Some patients experienced ambivalent thoughts regarding social network, particularly about their family as daily function impairment required an increased need for relative's support. The initial "Worrying about others" thoughts left place to in an increasing self-need of care as those provided by relatives; this phenomenon might increase patients' self- perception of being a burden for others. Confidence previously established with formal caregiver support was another major decision driver: some patients with sustained confidence in their medical staff may have privileged this formal support rather

IFN-αα induced psoriatic arthritis and HCV-related liver cirrhosis. Therapeutic options and patient’s opinion

Directory of Open Access Journals (Sweden)

M. Piga

2011-09-01

Full Text Available Hepatitis C virus (HCV infection in the setting of Psoriatic Arthritis is an additional variable to be considered in the therapeutic approach to the disease because of the complications of an immunosuppressive treatment in the course of a chronic infection and the possible hepatotoxicity of many drugs conventionally used to treat psoriatic arthritis. The case reported explores the therapeutic options in a patient with IFN-α induced psoriatic arthritis, characterised by severe arthritis and psoriasis but also the concomitant presence of HCV chronic hepatitis, in light of the patient’s concerns

[Epigenetic regulations and cerebral plasticity: towards new therapeutic options in neurodegenerative diseases?

Science.gov (United States)

Merienne, Karine; Boutillier, Anne-Laurence

2016-01-01

Although revealed in the 1950's, epigenetics is still a fast-growing field. Its delineations continuously evolve and become clarified. In particular, "neuroepigenetics", a notion that encompasses epigenetic regulations associated with neuronal processes, appears very promising. Indeed, the challenge to be undertaken in this sub-field is double. On the one hand, it should bring molecular comprehension of specific neuronal processes, some of them falling within the long term regulations, such as learning and memory. On the other hand, it could bring therapeutic options for brain diseases, e.g. neurodegenerative diseases such as Alzheimer's or Huntington's diseases. © Société de Biologie, 2017.

Studies on nonsense mediated decay reveal novel therapeutic options for genetic diseases.

Science.gov (United States)

Bashyam, Murali D

2009-01-01

Scientific breakthroughs have often led to commercially viable patents mainly in the field of engineering. Commercialization in the field of medicine has been restricted mostly to machinery and engineering on the one hand and therapeutic drugs for common chronic ailments such as cough, cold, headache, etc, on the other. Sequencing of the human genome has attracted the attention of pharmaceutical companies and now biotechnology has become a goldmine for commercialization of products and processes. Recent advances in our understanding of basic biological processes have resulted in the opening of new avenues for treatment of human genetic diseases, especially single gene disorders. A significant proportion of human genetic disorders have been shown to be caused due to degradation of transcripts for specific genes through a process called nonsense mediated decay (NMD). The modulation of NMD provides a viable therapeutic option for treatment of several genetic disorders and therefore has been a good prospect for patenting and commercialization. In this review the molecular basis for NMD and attempts to treat genetic diseases which result from NMD are discussed.

Gemcitabine plus nedaplatin as salvage therapy is a favorable option for patients with progressive metastatic urothelial carcinoma after two lines of chemotherapy.

Science.gov (United States)

Matsumoto, Kazumasa; Mochizuki, Kohei; Hirayama, Takahiro; Ikeda, Masaomi; Nishi, Morihiro; Tabata, Ken-ichi; Okazaki, Miyoko; Fujita, Tetsuo; Taoka, Yoshinori; Iwamura, Masatsugu

2015-01-01

This study was conducted to evaluate the effectiveness of a combination of gemcitabine and nedaplatin therapy among patients with metastatic urothelial carcinoma previously treated with two lines of chemotherapy. Between February 2009 and August 2013, 30 patients were treated with gemcitabine and paclitaxel as a second-line chemotherapy. All had received a first-line chemotherapy consisting of methotrexate, vinblastine, doxorubicin and cisplatin. Ten patients who had measurable histologically proven advanced or metastatic urothelial carcinoma of the urinary bladder and upper urinary tract received gemcitabine 1,000 mg/m2 on days 1, 8 and 15 and nedaplatin 70 mg/m2 on day 2 as a third-line chemotherapy. Tumors were assessed by imaging every two cycles. The median number of treatment cycles was 3.5. One patient had partial response and three had stable disease. The disease-control rate was 40%, the median overall survival was 8.8 months and the median progression-free survival was 5.0 months. The median overall survival times for the first-line and second-line therapies were 29.1 and 13.9 months, respectively. Among disease-controlled patients (n=4), median overall survival was 14.2 months. Myelosuppression was the most common toxicity. There were no therapy-related deaths. Gemcitabine and nedaplatin chemotherapy is a favorable third-line chemotherapeutic option for patients with metastatic urothelial carcinoma. Given the safety and benefit profile seen in this study, further prospective trials are warranted given the implications of our results with regard to strategic chemotherapy for patients with advanced or metastatic urothelial carcinoma.

Effect of therapy switch on time to second-line antiretroviral treatment failure in HIV-infected patients.

Science.gov (United States)

Häggblom, Amanda; Santacatterina, Michele; Neogi, Ujjwal; Gisslen, Magnus; Hejdeman, Bo; Flamholc, Leo; Sönnerborg, Anders

2017-01-01

Switch from first line antiretroviral therapy (ART) to second-line ART is common in clinical practice. However, there is limited knowledge of to which extent different reason for therapy switch are associated with differences in long-term consequences and sustainability of the second line ART. Data from 869 patients with 14601 clinical visits between 1999-2014 were derived from the national cohort database. Reason for therapy switch and viral load (VL) levels at first-line ART failure were compared with regard to outcome of second line ART. Using the Laplace regression model we analyzed the median, 10th, 20th, 30th and 40th percentile of time to viral failure (VF). Most patients (n = 495; 57.0%) switched from first-line to second-line ART without VF. Patients switching due to detectable VL with (n = 124; 14.2%) or without drug resistance mutations (DRM) (n = 250; 28.8%) experienced VF to their second line regimen sooner (median time, years: 3.43 (95% CI 2.90-3.96) and 3.20 (95% 2.65-3.75), respectively) compared with those who switched without VF (4.53 years). Furthermore level of VL at first-line ART failure had a significant impact on failure of second-line ART starting after 2.5 years of second-line ART. In the context of life-long therapy, a median time on second line ART of 4.53 years for these patients is short. To prolong time on second-line ART, further studies are needed on the reasons for therapy changes. Additionally patients with a high VL at first-line VF should be more frequently monitored the period after the therapy switch.

Effect of therapy switch on time to second-line antiretroviral treatment failure in HIV-infected patients.

Directory of Open Access Journals (Sweden)

Amanda Häggblom

Full Text Available Switch from first line antiretroviral therapy (ART to second-line ART is common in clinical practice. However, there is limited knowledge of to which extent different reason for therapy switch are associated with differences in long-term consequences and sustainability of the second line ART.Data from 869 patients with 14601 clinical visits between 1999-2014 were derived from the national cohort database. Reason for therapy switch and viral load (VL levels at first-line ART failure were compared with regard to outcome of second line ART. Using the Laplace regression model we analyzed the median, 10th, 20th, 30th and 40th percentile of time to viral failure (VF.Most patients (n = 495; 57.0% switched from first-line to second-line ART without VF. Patients switching due to detectable VL with (n = 124; 14.2% or without drug resistance mutations (DRM (n = 250; 28.8% experienced VF to their second line regimen sooner (median time, years: 3.43 (95% CI 2.90-3.96 and 3.20 (95% 2.65-3.75, respectively compared with those who switched without VF (4.53 years. Furthermore level of VL at first-line ART failure had a significant impact on failure of second-line ART starting after 2.5 years of second-line ART.In the context of life-long therapy, a median time on second line ART of 4.53 years for these patients is short. To prolong time on second-line ART, further studies are needed on the reasons for therapy changes. Additionally patients with a high VL at first-line VF should be more frequently monitored the period after the therapy switch.

Second line drug susceptibility testing to inform the treatment of rifampin-resistant tuberculosis: a quantitative perspective

Directory of Open Access Journals (Sweden)

Emily A. Kendall

2017-03-01

Full Text Available Treatment failure and resistance amplification are common among patients with rifampin-resistant tuberculosis (TB. Drug susceptibility testing (DST for second-line drugs is recommended for these patients, but logistical difficulties have impeded widespread implementation of second-line DST in many settings. To provide a quantitative perspective on the decision to scale up second-line DST, we synthesize literature on the prevalence of second-line drug resistance, the expected clinical and epidemiologic benefits of using second-line DST to ensure that patients with rifampin-resistant TB receive effective regimens, and the costs of implementing (or not implementing second-line DST for all individuals diagnosed with rifampin-resistant TB. We conclude that, in most settings, second-line DST could substantially improve treatment outcomes for patients with rifampin-resistant TB, reduce transmission of drug-resistant TB, prevent amplification of drug resistance, and be affordable or even cost-saving. Given the large investment made in each patient treated for rifampin-resistant TB, these payoffs would come at relatively small incremental cost. These anticipated benefits likely justify addressing the real challenges faced in implementing second-line DST in most high-burden settings.

Second-Line Hormonal Therapy for Men With Chemotherapy-Naïve, Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion.

Science.gov (United States)

Virgo, Katherine S; Basch, Ethan; Loblaw, D Andrew; Oliver, Thomas K; Rumble, R Bryan; Carducci, Michael A; Nordquist, Luke; Taplin, Mary-Ellen; Winquist, Eric; Singer, Eric A

2017-06-10

Purpose ASCO provisional clinical opinions (PCOs) offer direction to the ASCO membership after publication or presentation of potential practice-changing data. This PCO addresses second-line hormonal therapy for chemotherapy-naïve men with castration-resistant prostate cancer (CRPC) who range from being asymptomatic with only biochemical evidence of CRPC to having documented metastases but minimal symptoms. Clinical Context The treatment goal for CRPC is palliation. Despite resistance to initial androgen deprivation therapy, most men respond to second-line hormonal therapies. However, guidelines have neither addressed second-line hormonal therapy for nonmetastatic CRPC nor provided specific guidance with regard to the chemotherapy-naïve population. Recent Data Six phase III randomized controlled trials and expert consensus opinion inform this PCO. Provisional Clinical Opinion For men with CRPC, a castrate state should be maintained indefinitely. Second-line hormonal therapy (eg, antiandrogens, CYP17 inhibitors) may be considered in patients with nonmetastatic CRPC at high risk for metastatic disease (rapid prostate-specific antigen doubling time or velocity) but otherwise is not suggested. In patients with radiographic evidence of metastases and minimal symptoms, enzalutamide or abiraterone plus prednisone should be offered after discussion with patients about potential harms, benefits, costs, and patient preferences. Radium-223 and sipuleucel-T also are options. No evidence provides guidance about the optimal order of hormonal therapies for CRPC beyond second-line treatment. Prostate-specific antigen testing every 4 to 6 months is reasonable for men without metastases. Routine radiographic restaging generally is not suggested but can be considered for patients at risk for metastases or who exhibit symptoms or other evidence of progression. Additional information is available at www.asco.org/genitourinary-cancer-guidelines and www.asco.org/guidelineswiki .

Survival predictors for second-line chemotherapy in Caucasian patients with metastatic gastric cancer

OpenAIRE

Bohanes, Pierre; Courvoisier, Delphine; Perneger, Thomas; Morel, Philippe; Huber, Olivier; Roth, Arnaud

2011-01-01

There are very limited data suggesting a benefit for second-line chemotherapy in advanced gastric cancer. Therefore, the number of patients who receive further treatment after failure of first-line chemotherapy varies considerably, ranging from 14% to 75%. In the absence of a demonstrated survival benefit of second-line chemotherapy, appropriate selection of patients based on survival predictors is essential. However, no clinico-pathologic parameters are currently widely adopted in clinical p...

Acupuncture as a therapeutic treatment option for threatened miscarriage

Directory of Open Access Journals (Sweden)

Betts Debra

2012-03-01

Full Text Available Abstract Background Threatened miscarriage involves vaginal bleeding in a pregnancy that remains viable. This is a common early pregnancy complication with increased risk factors for early pregnancy loss, preterm premature rupture of membranes (PPROM, preterm delivery, low birth weight babies and maternal antepartum haemorrhage. Currently there are no recommended medical treatment options, rather women receive advice that centres on a 'wait and see' approach. For women with a history of unexplained recurrent miscarriage providing supportive care in a subsequent pregnancy improves live birthing outcomes, but the provision of supportive care to women experiencing threatened miscarriage has to date not been examined. Discussion While it is known that 50-70% of miscarriages occur due to chromosomal abnormalities, the potential for therapeutic intervention amongst the remaining percentage of women remains unknown. Complementary and alternative medicine (CAM therapies have the potential to provide supportive care for women presenting with threatened miscarriage. Within fertility research, acupuncture demonstrates beneficial hormonal responses with decreased miscarriage rates, raising the possibility acupuncture may promote specific beneficial effects in early pregnancy. With the lack of current medical options for women presenting with threatened miscarriage it is timely to examine the possible treatment benefits of providing CAM therapies such as acupuncture. Summary Despite vaginal bleeding being a common complication of early pregnancy there is often reluctance from practitioners to discuss with women and medical personal how and why CAM may be beneficial. In this debate article, the physiological processes of early pregnancy together with the concept of providing supportive care and acupuncture are examined. The aim is to raise awareness and promote discussion as to the beneficial role CAM may have for women presenting with threatened miscarriage.

Current Therapeutic Options for Esophageal Motor Disorders as Defined by the Chicago Classification.

Science.gov (United States)

Zerbib, Frank; Roman, Sabine

2015-07-01

With the development of high-resolution manometry and specific metrics to characterize esophageal motility, the Chicago Classification has become the gold standard for the diagnosis of esophageal motor disorders. Major and significant disorders, that is, never observed in healthy subjects, are achalasia, esophagogastric junction outflow obstruction, distal esophageal spasm, absent peristalsis, and hypercontractile (Jackhammer) esophagus. Achalasia subtyping is relevant to predict the response to endoscopic and surgical therapies as several studies suggest that, pneumatic dilation is less effective than Heller myotomy, in type III achalasia. Peroral endoscopic myotomy, initially developed in expert centers, is a promising technique for the treatment of achalasia. The medical therapeutic options for distal esophageal spasm and hypercontractile esophagus are smooth muscle relaxants and pain modulators. Intraesophageal injection of botulinum toxin might be an interesting option for treatment of these disorders but further studies are required to determine the optimal injection protocol and the best candidates based on manometric patterns. The treatment of hypotensive motility disorders is disappointing and relies mainly on dietary and lifestyle changes as no effective esophageal prokinetic is currently available.

Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

Science.gov (United States)

Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Naïra; Rau, Frédérique; Jollet, Arnaud; Edom-Vovard, Frédérique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois; Mouly, Vincent; Klein, Arnaud F.

2017-01-01

ABSTRACT Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations. PMID:28188264

Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

Directory of Open Access Journals (Sweden)

Ludovic Arandel

2017-04-01

Full Text Available Myotonic dystrophy type 1 (DM1 and type 2 (DM2 are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations.

Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds.

Science.gov (United States)

Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Naïra; Rau, Frédérique; Jollet, Arnaud; Edom-Vovard, Frédérique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois; Mouly, Vincent; Klein, Arnaud F; Furling, Denis

2017-04-01

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations. © 2017. Published by The Company of Biologists Ltd.

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer patients: prospective evaluation of activity, safety, and quality of life.

Science.gov (United States)

Palumbo, Raffaella; Sottotetti, Federico; Trifirò, Giuseppe; Piazza, Elena; Ferzi, Antonella; Gambaro, Anna; Spinapolice, Elena Giulia; Pozzi, Emma; Tagliaferri, Barbara; Teragni, Cristina; Bernardo, Antonio

2015-01-01

A prospective, multicenter trial was undertaken to assess the activity, safety, and quality of life of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer (MBC). Fifty-two women with HER2-negative MBC who were candidates for second-line chemotherapy for the metastatic disease were enrolled and treated at three centers in Northern Italy. All patients had previously received taxane-based chemotherapy in the adjuvant or first-line metastatic setting. Single-agent nab-paclitaxel was given at the dose of 260 mg/m(2) as a 30-minute intravenous infusion on day 1 each treatment cycle, which lasted 3 weeks, in the outpatient setting. No steroid or antihistamine premedication was provided. Treatment was stopped for documented disease progression, unacceptable toxicity, or patient refusal. All of the enrolled patients were evaluable for the study endpoints. The objective response rate was 48% (95% CI, 31.5%-61.3%) and included complete responses from 13.5%. Disease stabilization was obtained in 19 patients and lasted >6 months in 15 of them; the overall clinical benefit rate was 77%. The median time to response was 70 days (range 52-86 days). The median progression-free survival time was 8.9 months (95% CI, 8.0-11.6 months, range 5-21+ months). The median overall survival point has not yet been reached. Toxicities were expected and manageable with good patient compliance and preserved quality of life in patients given long-term treatment. Our results showed that single-agent nab-paclitaxel 260 mg/m(2) every 3 weeks is an effective and well tolerated regimen as second-line chemotherapy in HER2-negative, taxane-pretreated MBC patients, and that it produced interesting values of objective response rate and progression-free survival without the concern of significant toxicity. Specifically, the present study shows that such a regimen is a valid therapeutic option for that 'difficult to

Title of the paper goes here second line

Indian Academy of Sciences (India)

Title of the paper goes here second line. AUTHOR11, AUTHOR21 and AUTHOR32,*. 1 Department of P, University X. 2 Department of Q, University Z. Abstract. Abstract text goes here. Abstract text goes here. Abstract text goes here. Abstract text goes here. Abstract text goes here. Abstract text goes here. Abstract text goes ...

Hereditary angioedema as a metabolic liver disorder: novel therapeutic options and prospects for cure

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Rohan Ameratuga

2016-11-01

Full Text Available Hereditary angioedema (HAE is a rare autosomal dominant disorder caused by mutations of the SERPING1 or the Factor 12 genes. It is potentially fatal, particularly if not identified at an early stage. Apart from androgens, which are contraindicated in children and in pregnant women, a range of effective, albeit very expensive treatments have recently become available for HAE patients. The cost of these new treatments is beyond the reach of most developing countries. At this time, there is no cure for the disorder. In spite of mutations of the SERPING1 gene, autoimmunity and infections are not prominent features of the condition. Here we present the argument that HAE should be viewed primarily as a metabolic liver disorder. This conceptual paradigm shift will stimulate basic research and may facilitate new therapeutic approaches to HAE outlined in this paper. We suggest several novel potential treatment options for HAE from the perspectives of clinical immunology, molecular biology and liver transplantation. Many of these offer the prospect of curing the disorder. The effectiveness of these options are rapidly improving in many cases and their risks are decreasing. Given the very high costs of treating HAE, some of these curative options may become feasible in the next decade.

Aflibercept as a second-line therapy in metastatic colorectal cancer: A limited Indian experience

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Govind Babu

2016-01-01

Full Text Available Introduction: Aflibercept in combination with FOLFIRI has been shown to improve overall survival in the pivotal VELOUR study. Aflibercept has not yet been marketed in India. Sanofi has made available this drug for Indian patients under a program called Named Patient Access Program (NPP. We present a limited clinical experience with the use of aflibercept at our center. Materials and Methods: We analyzed the data of the patients who received aflibercept under NPP. Aflibercept was given in combination with FOLFIRI as second-line for patients who progressed on oxaliplatin based therapy. Aflibercept was given at 4 mg/kg intravenous (IV every 15 days. Chemotoxicities were assessed as per CTCAE. Response evaluation was done every four cycles. Results: Five patients were enrolled. The median age was 34 years. The median number of aflibercept cycles administered was 12. Common grade 2/3 toxicities were mucositis, diarrhea, neutropenia thrombocytopenia, and hypertension seen in three (60%, three (60%, two (40%, two (40%, and one patient respectively. After four cycles, the response was assessed as: One complete remission (CR, three partial remissions (PR, and one progressive disease (PD. Three patients completed 12 cycles of chemotherapy and aflibercept. At the end of 12 cycles, one patient still in CR and two patients were in PR. Four patients were alive till date. Conclusion: As we had very less number of patients, it was very difficult to compare it with VELOUR data. It is one of option as second-line in metastatic colorectal cancer (mCRC who progressed on oxaliplatin chemotherapy. Mucositis, diarrhea, and hematological toxicity were the most common toxicity in our patient.

Inhibition of mTOR's Catalytic Site by PKI-587 Is a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease.

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Freitag, Helma; Christen, Friederike; Lewens, Florentine; Grass, Irina; Briest, Franziska; Iwaszkiewicz, Sara; Siegmund, Britta; Grabowski, Patricia

2017-01-01

The characteristic clinical heterogeneity and mostly slow-growing behavior of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) cause problems in finding appropriate treatments. Thus, the current therapy options are not satisfactory. PKI-587 is a highly potent, novel dual inhibitor of PI3K and mTORC1/C2. We assessed the effects of PKI-587 in different GEP-NEN tumor models, including the poorly differentiated cell line LCC-18, and compared them with those of the established mTORC1 inhibitor everolimus. We treated BON, QGP-1, KRJ-I, and LCC-18 cell lines with increasing concentrations of the inhibitor PKI-587, and compared the results with those of everolimus and DMSO. We assessed the impact of the treatments on viability (WST-1 assay), on apoptotic processes (caspase 3/7 assay, JC-1), and on cell cycle regulation (flow cytometry). We determined alterations in signaling mediators by phosphor-specific Western blot analysis and conducted multiplexed gene expression analysis (nCounter® technology). In all cell lines, PKI-587 dose-dependently inhibited proliferation, whereas everolimus was less effective. Treatment with PKI-587 led to cell cycle arrest and induction of apoptosis and successfully suppressed activity of the direct mTORC1 target 4E-BP1, a crucial factor for tumor genesis only partially inhibited by everolimus. Gene expression analyses revealed relevant changes of RAS, MAPK, STAT, and PI3K pathway genes after treatment. Treatment-dependent and cell line-characteristic effects on AKT/Rb/E2F signaling regarding cell cycle control and apoptosis are extensively discussed in this paper. PI3K/mTOR dual targeting is a promising new therapeutic approach in neuroendocrine tumor disease that should be evaluated in further clinical trials. © 2016 The Author(s) Published by S. Karger AG, Basel.

Predicting for activity of second-line trastuzumab-based therapy in her2-positive advanced breast cancer

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Rottenfusser Andrea

2009-10-01

Full Text Available Abstract Background In Her2-positive advanced breast cancer, the upfront use of trastuzumab is well established. Upon progression on first-line therapy, patients may be switched to lapatinib. Others however remain candidates for continued antibody treatment (treatment beyond progression. Here, we aimed to identify factors predicting for activity of second-line trastuzumab-based therapy. Methods Ninety-seven patients treated with > 1 line of trastuzumab-containing therapy were available for this analysis. Her2-status was determined by immunohistochemistry and re-analyzed by FISH if a score of 2+ was gained. Time to progression (TTP on second-line therapy was defined as primary study endpoint. TTP and overall survival (OS were estimated using the Kaplan-Meier product limit method. Multivariate analyses (Cox proportional hazards model, multinomial logistic regression were applied in order to identify factors associated with TTP, response, OS, and incidence of brain metastases. p values Results Median TTP on second-line trastuzumab-based therapy was 7 months (95% CI 5.74-8.26, and 8 months (95% CI 6.25-9.74 on first-line, respectively (n.s.. In the multivariate models, none of the clinical or histopthological features could reliably predict for activity of second-line trastuzumab-based treatment. OS was 43 months suggesting improved survival in patients treated with trastuzumab in multiple-lines. A significant deterioration of cardiac function was observed in three patients; 40.2% developed brain metastases while on second-line trastuzumab or thereafter. Conclusion Trastuzumab beyond progression showed considerable activity. None of the variables investigated correlated with activity of second-line therapy. In order to predict for activity of second-line trastuzumab, it appears necessary to evaluate factors known to confer trastuzumab-resistance.

Second-line salvage treatment of AIDS-associated Pneumocystis jirovecii pneumonia: a case series and systematic review

DEFF Research Database (Denmark)

Benfield, T.; Atzori, C.; Miller, R.F.

2008-01-01

BACKGROUND: Limited clinical data exist to guide the choice of second-line salvage treatment for AIDS-associated Pneumocystis jirovecii pneumonia (PCP). METHODS: We did a systematic search of MEDLINE for all randomized and observational studies of PCP treatment published up to August 2007...... and included individual treatment data of AIDS-associated PCP from a tricenter study. We calculated pooled estimates of reported outcome of second-line treatment using averaged odds ratios (ORs). RESULTS: Twenty-nine studies with sufficient detail of second-line treatment and outcome, including data from 82...... individual cases from the tricenter study, yielded a total of 468 PCP second-line treatment episodes. Response rates to second-line treatment were comparable for trimethoprim-sulfamethoxazole (TMP-SMX; 68%) and clindamycin-primaquine (73%) (OR for response = 2.1 [95% confidence interval (CI): 1.1 to 3...

Symptom burden & quality of life among patients receiving second-line treatment of metastatic colorectal cancer

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Walker Mark S

2012-06-01

Full Text Available Abstract Background Bevacizumab (B and cetuximab (C are both approved for use in the treatment of metastatic colorectal cancer (mCRC in the second-line. We examined patient reported symptom burden during second-line treatment of mCRC. Methods Adult mCRC patients treated in the second-line setting with a regimen that included B, C, or chemotherapy only (O and who had completed ≥ 1 Patient Care Monitor (PCM surveys as part of routine clinical care were drawn from the ACORN Data Warehouse. Primary endpoints were rash, dry skin, itching, nail changes, nausea, vomiting, fatigue, burning in hands/feet, and diarrhea. Linear mixed models examined change in PCM scores across B, C and O (B = reference. Results 182 patients were enrolled (B: n = 106, C: n = 38, O: n = 38. Patients were 51% female, 67% Caucasian, with mean age of 62.0 (SD = 12.6. Groups did not differ on demographic or clinical characteristics. The most common second-line regimens were FOLFIRI ± B or C (23.1% and FOLFOX ± B or C (22.5%. Results showed baseline scores to be strongly predictive of second-line symptoms across all PCM items (all p’s  Conclusions Patients receiving second-line treatment for mCRC with B report less symptom burden, especially dermatologic, compared to patients treated with C.

Constraining second language word order optionality : scrambling in advanced English-German and Japanese-German interlanguage

NARCIS (Netherlands)

Hopp, Holger

2005-01-01

This study documents knowledge of UG-mediated aspects of optionality in word order in the second language (L2) German of advanced English and Japanese speakers (n = 39). A bimodal grammaticality judgement task, which controlled for context and intonation, was administered to probe judgements on a

Graves' disease. Manifestations and therapeutic options

International Nuclear Information System (INIS)

McFarland, K.F.; Saleeby, G.

1988-01-01

Graves' disease is the most common cause of hyperthyroidism. Clinical features include thyroid enlargement, eye signs, tachycardia, heat intolerance, emotional lability, weight loss, and hyperkinesis. Three modes of therapy are available. The preferences of the patient and physician are usually prime considerations in devising the therapeutic plan. Radioactive iodine is the most frequently used and safest method of treatment for adults. Antithyroid drugs are preferred for children and pregnant women. Surgery is usually reserved for patients in whom the other forms of treatment are not acceptable. Considerable patient education during the decision-making process enhances the success of the therapeutic plan

[Are therapeutics decisions homogeneous in multidisciplinary onco-urology staff meeting? Comparison of therapeutic options taken in four departments from Paris].

Science.gov (United States)

Audenet, F; Lejay, V; Mejean, A; De La Taille, A; Abbou, C-C; Lebret, T; Botto, H; Bitker, M-O; Roupret, M

2012-06-01

One of the priorities of the "Plan against the Cancer" in France is to ensure the discussion of all cancer cases in a multidisciplinary meeting staff (RCP). The multidisciplinary collaboration is proposed to guarantee a discussion between specialists in every cases, particularly in complex cases. The aim of this study was to compare the therapeutic decision taken in four RCP in Paris Île-de-France academic centres for three identical cases. Three cases of urological oncology (prostate cancer [PCa], renal cell carcinoma [RCC] and bladder tumour) were selected by a single urologist, not involved in further discussion. These cases were blindly presented in four academic urology department from Paris: Pitié-Salpêtrière Hospital, Mondor Hospital, the Georges-Pompidou European Hospital and Foch Hospital. The four centres met the criteria of quality of RCP in terms of multidisciplinarity, frequency and standardization. The therapeutic suggestions were similar in the RCC cases, there were differences in the surgical approaches and preoperative work-up in the PCa case and, lastly, the proposals were different for the bladder cancer case. The decisions relies on clinical data and preoperative work-up but also on the experience and habits of the centre of excellence. For complex cases that does not fit with current guidelines, the panel discussion can lead to different therapeutic options from a centre to another and is largely influenced by the local organisation of the RCP. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Comparison of Second-Line Quadruple Therapies with or without Bismuth for Helicobacter pylori Infection

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Guang-Hong Jheng

2015-01-01

Full Text Available The bismuth-based quadruple regimen has been applied in Helicobacter pylori rescue therapy worldwide. The non-bismuth-based quadruple therapy or “concomitant therapy” is an alternative option in first-line eradication but has not been used in second-line therapy. Discovering a valid regimen for rescue therapy in bismuth-unavailable countries is important. We conducted a randomized controlled trial to compare the efficacies of the standard quadruple therapy and a modified concomitant regimen. One hundred and twenty-four patients were randomly assigned into two groups: RBTM (rabeprozole 20 mg bid., bismuth subcitrate 120 mg qid, tetracycline 500 mg qid, and metronidazole 250 mg qid and RATM (rabeprozole 20 mg bid., amoxicillin 1 g bid., tetracycline 500 mg qid, and metronidazole 250 mg qid for 10 days. The eradication rate of the RBTM and RATM regimen was 92.1% and 90.2%, respectively, in intention-to-treat analysis. Patients in both groups had good compliance (~96%. The overall incidence of adverse events was higher in the RATM group (42.6% versus 22.2%, P=0.02, but only seven patients (11.5% experienced grades 2-3 events. In conclusion, both regimens had good efficacy, compliance, and acceptable side effects. The 10-day RATM treatment could be an alternative rescue therapy in bismuth-unavailable countries.

Clinical Benefit of Second-Line Palliative Chemotherapy in Advanced Soft-Tissue Sarcoma

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Anna Minchom

2010-01-01

Full Text Available Background. This paper aimed to assess the utility of second-line chemotherapy in patients with advanced soft-tissue sarcoma. Materials and Methods. A retrospective search of a prospectively maintained database identified patients treated between 1991 and 2005. Patients with gastrointestinal stromal tumours, small round cell tumours, and Ewing's sarcoma were excluded. Response was assessed using WHO and RECIST. Patients who achieved stable disease for 6 months or more were classified as having disease control. Results. Three hundred and seventy-nine patients received second-line chemotherapy. Eighty-six (22.7% achieved disease control. Median duration of response was 11 months (95% CI: 9–13. On multivariate analysis, pathological subtype, absence of lung metastases, and the use of combination chemotherapy were independent predictors of disease control. Twenty-eight (16.1% patients who failed to respond to first-line therapy achieved disease control. Eight (2.1% patients had sufficient downstaging to enable complete surgical resection. Progression-free survival was 23% at 6 months. Median overall survival was 8 months (95% CI: 7–10 months. On multivariate analysis, synovial histology and absence of lung metastases were associated with improved survival. Conclusion. Second-line chemotherapy can provide clinical benefit in over 20% of soft-tissue sarcoma patients.

Biflorin induces cytotoxicity by DNA interaction in genetically different human melanoma cell lines.

Science.gov (United States)

Ralph, Ana Carolina Lima; Calcagno, Danielle Queiroz; da Silva Souza, Luciana Gregório; de Lemos, Telma Leda Gomes; Montenegro, Raquel Carvalho; de Arruda Cardoso Smith, Marília; de Vasconcellos, Marne Carvalho

2016-08-01

Cancer is a public health problem and the second leading cause of death worldwide. The incidence of cutaneous melanoma has been notably increasing, resulting in high aggressiveness and poor survival rates. Taking into account the antitumor activity of biflorin, a substance isolated from Capraria biflora L. roots that is cytotoxic in vitro and in vivo, this study aimed to demonstrate the action of biflorin against three established human melanoma cell lines that recapitulate the molecular landscape of the disease in terms of genetic alterations and mutations, such as the TP53, NRAS and BRAF genes. The results presented here indicate that biflorin reduces the viability of melanoma cell lines by DNA interactions. Biflorin causes single and double DNA strand breaks, consequently inhibiting cell cycle progression, replication and DNA repair and promoting apoptosis. Our data suggest that biflorin could be considered as a future therapeutic option for managing melanoma. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ozone-augmented percutaneous discectomy: a novel treatment option for refractory discogenic sciatica.

Science.gov (United States)

Crockett, M T; Moynagh, M; Long, N; Kilcoyne, A; Dicker, P; Synnott, K; Eustace, S J

2014-12-01

To assess the short and medium-term efficacy and safety of a novel, minimally invasive therapeutic option combining automated percutaneous lumbar discectomy, intradiscal ozone injection, and caudal epidural: ozone-augmented percutaneous discectomy (OPLD). One hundred and forty-seven patients with a clinical and radiological diagnosis of discogenic sciatica who were refractory to initial therapy were included. Fifty patients underwent OPLD whilst 97 underwent a further caudal epidural. Outcomes were evaluated using McNab's score, improvement in visual analogue score (VAS) pain score, and requirement for further intervention. Follow-up occurred at 1 and 6 months, and comparison was made between groups. OPLD achieved successful outcomes in almost three-quarters of patients in the short and medium term. OPLD achieved superior outcomes at 1 and 6 months compared to caudal epidural. There was a reduced requirement for further intervention in the OPLD group. No significant complications occurred in either group. OPLD is a safe and effective treatment for patients with refractory discogenic sciatica in the short and medium term. OPLD has the potential to offer an alternative second-line minimally invasive treatment option that could reduce the requirement for surgery in this patient cohort. Copyright © 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8)

DEFF Research Database (Denmark)

Soria, Jean-Charles; Felip, Enriqueta; Cobo, Manuel

2015-01-01

BACKGROUND: There is a major unmet need for effective treatments in patients with squamous cell carcinoma of the lung. LUX-Lung 8 compared afatinib (an irreversible ErbB family blocker) with erlotinib (a reversible EGFR tyrosine kinase inhibitor), as second-line treatment for patients with advanced...... squamous cell carcinoma of the lung. METHODS: We did this open-label, phase 3 randomised controlled trial at 183 cancer centres in 23 countries worldwide. We enrolled adults with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after at least four cycles of platinum...... be an additional option for the treatment of patients with squamous cell carcinoma of the lung. FUNDING: Boehringer Ingelheim....

Capecitabine and oxaliplatin as second-line treatment in patients with carcinoma of unknown primary site

DEFF Research Database (Denmark)

Møller, Anne Kirstine Hundahl; Pedersen, Karen Damgaard; Abildgaard, Julie Rafn

2010-01-01

tumours may be overrepresented. These patients could be candidates for GI tract-directed therapy. We here report the results obtained with oxaliplatin and capecitabine as second-line therapy in 25 recurrent/refractory CUP patients following first-line treatment with paclitaxel, cisplatin and gemcitabine.......Treatment of patients with carcinoma of unknown primary site (CUP) remains a challenge, and no effective second-line treatment has been identified. In CUP patients who are non-responsive or relapse early after first-line platinum/taxane-based regimens, it is likely that gastrointestinal (GI) tract...

A budget-impact and cost-effectiveness model for second-line treatment of major depression.

Science.gov (United States)

Malone, Daniel C

2007-07-01

Depressed patients who initially fail to achieve remission when placed on a selective serotonin reuptake inhibitor (SSRI) may require a second treatment. The purpose of this study was to evaluate the effectiveness, cost, cost-effectiveness, and budget impact of second-line pharmacologic treatment for major depressive disorder (MDD). A cost-effectiveness analysis was conducted to evaluate second-line therapies (citalopram, escitalopram, fluoxetine, paroxetine, paroxetine controlled release [CR], sertraline, and venlafaxine extended release [XR]) for the treatment of depression. Effectiveness data were obtained from published clinical studies. The primary outcome was remission defined as a score of 7 or less on the Hamilton Rating Scale for Depression (HAM-D) or a score of 10 or less on the montgomery-Asberg Depression Rating Scale (MADRS) depression rating scales. The wholesale acquisition cost (WAC) for medications and medical treatment costs for depression were included. The perspective was derived from a managed care organization (MCO) with 500,000 members, a 1.9% annual incidence of depression, and treatment duration of 6 months. Assumptions included: second-line treatment is not as effective as first-line treatment, WAC price reflects MCO costs, and side effects were identical. Sensitivity analyses were conducted to determine variables that influenced the results. Second-line remission rates were 20.4% for venlafaxine XR, 16.9% for sertraline, 16.4% for escitalopram, 15.1% for generic SSRIs (weighted average), and 13.6% for paroxetine CR. Pharmacy costs ranged from $163 for generic SSRIs to $319 for venlafaxine SR. Total cost per patient achieving remission was $14,275 for venlafaxine SR, followed by $16,100 for escitalopram. The incremental cost-effectiveness ratio (ICER) for venlafaxine SR compared with generic SSRIs was $2,073 per patient achieving remission, followed by escitalopram with an ICER of $3,566. The model was most sensitive to other therapies

Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

OpenAIRE

Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Na?ra; Rau, Fr?d?rique; Jollet, Arnaud; Edom-Vovard, Fr?d?rique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois

2017-01-01

International audience; Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded rep...

METHODICAL APPROACHES TO THE CHOICE OF THE NEW GENERATION OF HIGH-VOLTAGE POWER TRANSMISSION LINE 220 kV OPTIONS

Directory of Open Access Journals (Sweden)

POSTOLATI V.M.

2010-08-01

Full Text Available The Transmission Power Lines of new generation are described in the article (single- compact, double-circuit compact, double-circuit Controlled Self-compensating High Voltage Transmission Power Lines (CSHVL. Basic principles of creation, design elements and comparative characteristics of the transmission lines of the new generation are described, the advantages of its are showed. Methodical approaches to the choosing of a new generation of transmission lines and facilities management FACTS are formulated. Methodical approaches to the choice of options for transmission lines 220 kV and facilities management are shown.

New therapeutic options for allergic rhinitis: back to the future with intranasal corticosteroid aerosols.

Science.gov (United States)

Carr, Warner W

2013-01-01

Under current guidelines, intranasal corticosteroids (INSs) are considered the most effective first-line therapy to improve allergic rhinitis (AR) symptoms and burden of disease. In the late 1980s-1990s, chlorofluorocarbon (CFC)-propelled corticosteroid aerosol nasal sprays formed the standard of care for the treatment of AR. Because of environmental concerns, CFC aerosols were gradually phased out, and aqueous INS formulations of nasal sprays became the standard of care. Although many aqueous INS sprays are available, specific product-related factors can reduce patient adherence to an INS and subsequently reduce treatment efficacy. The purpose of this paper was to review the evolution of AR therapeutics and drug devices and how it may have an effect on patient adherence/compliance and patient satisfaction with current available therapies and show the unmet need to improve INS delivery systems. Although aqueous INSs are effective and well tolerated, use in some patients may be compromised because of patient sensory perception and device preference. A historical review of the evolution of intranasal delivery of INSs was undertaken to provide further insight into improving treatment options for patients with AR. Although the various approved INSs appear to be equivalent in terms of reducing AR disease burden, the method in which an INS is delivered to a patient has significant bearing on the overall success of each specific drug product. Hydrofluoroalkane-propelled INS drug products offer a back-to-the-future delivery approach that may be further tailored to the individual patient's needs. Past experiences and the development of new devices are paving the way toward further therapy choices, ultimately affording health care providers access to the most effective treatments for patients with AR.

Therapeutic options in chronic heart failure. Findings on chest X-ray; Nicht medikamentoese Therapieoptionen der chronischen Herzinsuffizienz. Befunde in der Projektionsradiografie des Thorax

Energy Technology Data Exchange (ETDEWEB)

Granitz, M.R.; Meissnitzer, T.; Meissnitzer, M.W.; Hergan, K.; Altenberger, J.; Granitz, C. [Uniklinikum Salzburg - Landeskrankenhaus (Austria)

2016-05-15

The contribution covers drugless therapeutic options for chronic heart failure: the implantable cardioverter/defibrillator (ICD), the cardiac resynchronization therapy (CRT), the interventional catheter treatment of functional mitral insufficiency, and mechanical heart supporting systems and heart transplantation.

Comparable Efficacy of Abatacept Used as First-line or Second-line Biological Agent for Severe Juvenile Idiopathic Arthritis-related Uveitis.

Science.gov (United States)

Birolo, Carolina; Zannin, Maria Elisabetta; Arsenyeva, Svetlana; Cimaz, Rolando; Miserocchi, Elisabetta; Dubko, Margarita; Deslandre, Chantal Job; Falcini, Fernanda; Alessio, Maria; La Torre, Francesco; Denisova, Ekaterina; Martini, Giorgia; Nikishina, Irina; Zulian, Francesco

2016-11-01

Abatacept (ABA) has recently been proposed as second-line treatment in patients with juvenile idiopathic arthritis (JIA)-associated uveitis refractory to anti-tumor necrosis factor-α (anti-TNF) agents, but little is known about its efficacy as a first-line approach. The aim of the present study was to compare the safety and efficacy of ABA as a first-line biological agent (ABA-1) with that of ABA as a second-line treatment after 1 or more anti-TNF agents (ABA-2), in patients with severe JIA-related uveitis. In this multicenter study, we collected data on patients with severe JIA-related uveitis treated with ABA as a first-line or second-line biological agent. Changes in frequency of uveitis flares/year and ocular complications before and after ABA treatment, clinical remission, and side effects were recorded. Thirty-five patients with a mean age of 10.8 years were treated with ABA for a mean period of 19.6 months. In 4 patients, ABA administration was discontinued, owing to inefficacy on arthritis in 3 cases and allergic reaction in 1. Thirty-one patients, 14 in the ABA-1 group and 17 in the ABA-2 group, completed the 12-month followup period; of these, 17 (54.8%) had clinical remission. The mean frequency of uveitis flares decreased from 4.1 to 1.2 in the ABA-1 group (p = 0.002) and from 3.7 to 1.2 in the ABA-2 group (p = 0.004). Preexisting ocular complications improved or remained stable in all but 5 patients, all in the ABA-2 group. No significant difference was found between the efficacy of the 2 treatment modalities. ABA confirmed its good safety profile. ABA, used as first-line biological treatment or after 1 or more anti-TNF agents, induces a comparable improvement in severe refractory JIA-related uveitis.

Systematic review, meta-analysis, and meta-regression: Successful second-line treatment for Helicobacter pylori.

Science.gov (United States)

Muñoz, Neus; Sánchez-Delgado, Jordi; Baylina, Mireia; Puig, Ignasi; López-Góngora, Sheila; Suarez, David; Calvet, Xavier

2018-06-01

Multiple Helicobacter pylori second-line schedules have been described as potentially useful. It remains unclear, however, which are the best combinations, and which features of second-line treatments are related to better cure rates. The aim of this study was to determine that second-line treatments achieved excellent (>90%) cure rates by performing a systematic review and when possible a meta-analysis. A meta-regression was planned to determine the characteristics of treatments achieving excellent cure rates. A systematic review for studies evaluating second-line Helicobacter pylori treatment was carried out in multiple databases. A formal meta-analysis was performed when an adequate number of comparative studies was found, using RevMan5.3. A meta-regression for evaluating factors predicting cure rates >90% was performed using Stata Statistical Software. The systematic review identified 115 eligible studies, including 203 evaluable treatment arms. The results were extremely heterogeneous, with 61 treatment arms (30%) achieving optimal (>90%) cure rates. The meta-analysis favored quadruple therapies over triple (83.2% vs 76.1%, OR: 0.59:0.38-0.93; P = .02) and 14-day quadruple treatments over 7-day treatments (91.2% vs 81.5%, OR; 95% CI: 0.42:0.24-0.73; P = .002), although the differences were significant only in the per-protocol analysis. The meta-regression did not find any particular characteristics of the studies to be associated with excellent cure rates. Second-line Helicobacter pylori treatments achieving>90% cure rates are extremely heterogeneous. Quadruple therapy and 14-day treatments seem better than triple therapies and 7-day ones. No single characteristic of the treatments was related to excellent cure rates. Future approaches suitable for infectious diseases-thus considering antibiotic resistances-are needed to design rescue treatments that consistently achieve excellent cure rates. © 2018 John Wiley & Sons Ltd.

Graves' disease. Manifestations and therapeutic options

Energy Technology Data Exchange (ETDEWEB)

McFarland, K.F.; Saleeby, G.

1988-03-01

Graves' disease is the most common cause of hyperthyroidism. Clinical features include thyroid enlargement, eye signs, tachycardia, heat intolerance, emotional lability, weight loss, and hyperkinesis. Three modes of therapy are available. The preferences of the patient and physician are usually prime considerations in devising the therapeutic plan. Radioactive iodine is the most frequently used and safest method of treatment for adults. Antithyroid drugs are preferred for children and pregnant women. Surgery is usually reserved for patients in whom the other forms of treatment are not acceptable. Considerable patient education during the decision-making process enhances the success of the therapeutic plan.

Lumbar sympathectomy under CT guidance: therapeutic option in critical limb ischaemia

International Nuclear Information System (INIS)

Pieri, Stefano; Agresti, Paolo; Di Cesare, Fabio; Ricci, Guiseppe

2005-01-01

Purpose: Lumbar sympathectomy is a complementary therapeutic option for patients with severe peripheral vascular occlusive disease presenting rest pain or gangrene and not eligible for surgical revascularisation. Traditional surgical sympathectomy was widely used in the past. However, due to its invasive character, it has increasingly been replaced by percutaneous techniques and, in some recent cases, by laparoscopic procedures. Percutaneous lumbar sympathectomy is a safe, cost-effective and widely available treatment option. We report our experience on 19 patients subjected to percutaneous sympathectomy under CT guidance. Materials and methods: Between 1998 and 2000, 19 patients underwent percutaneous sympathectomy under CT guidance. All patients had severe vascular disease of the lower extremities (Fontaine stage IV), with rest pain and gangrene. They were not eligible for surgical revascularization. Phenol was injected at the level of L2 and L4 using two 22 G needles (15 cm long). Signs of interrupted sympathetic activity usually occur 2'-15' after the procedure with warmth and flushing and dryness of the lower extremities. Results: Percutaneous sympathectomy under CT guidance is a simple, safe and well-tolerated procedure with a low rate of complications. Of the 19 patients, 9 (47.3%) showed clinical improvement, whereas 5 experienced a worsening of ischaemia in the month immediately following the procedure. Discussion: Results suggest that percutaneous lumbar sympathectomy causes a sympathetic blockade in patients with advanced vascular disease of the limb. CT guidance ensures a high level of precision in drug dosing, thus lowering the risk of complications. Although the results are demoralizing. the impossibility of achieving surgical revascularisation in advanced peripheral arteriosclerosis enhances the role of Ct-guided percutaneous sympathectomy in relieving rest pain and healing ulcers in order to postpone the amputation [it

Splenectomy vs. rituximab as a second-line therapy in immune thrombocytopenic purpura: a single center experience.

Science.gov (United States)

Al Askar, Ahmed S; Shaheen, Naila A; Al Zahrani, Mohsen; Al Otaibi, Mohammed G; Al Qahtani, Bader S; Ahmed, Faris; Al Zughaibi, Mohand; Kamran, Ismat; Mendoza, May Anne; Khan, Altaf

2018-01-01

Immune thrombocytopenic purpura (ITP) is a common hematological disease treated primarily by corticosteroids. The aim of the present study was to compare response rate between patients, underwent splenectomy vs. rituximab as second-line therapy. Adult patients diagnosed with ITP who did not respond to corticosteroids or relapsed during the period 1990-2014 were included in a quasi-experimental study. Categorical variables were compared using Fisher exact test. Response to treatment was compared using logistic regression. Data were analyzed using SAS V9.2. One-hundred and forty-three patients with ITP were identified through medical records. Of 62 patients treated, 30 (48.38%) required second-line therapy. 19 (63%) patients received rituximab, and 11 (37%) underwent splenectomy. Platelets at diagnosis were not different between study groups (p = 0.062). Splenectomy group patients were younger (p = 0.011). Response to second-line therapy showed no significant difference between two groups (OR 2.03, 95% CI (0.21-22.09), p = 0.549). Results did not show a statistically significant difference in platelet counts over time between treatment groups (p = 0.101). When used exclusively as a second-line therapy for steroid-refractory ITP, the response rate was not statistically different between rituximab and splenectomy. However, further large studies are needed to assess the response rates for these treatment modalities as a second-line therapy.

Cost minimisation analysis of fingolimod vs natalizumab as a second line of treatment for relapsing-remitting multiple sclerosis.

Science.gov (United States)

Crespo, C; Izquierdo, G; García-Ruiz, A; Granell, M; Brosa, M

2014-05-01

At present, there is a lack of economic assessments of second-line treatments for relapsing-recurring multiple sclerosis. The aim of this study was to compare the efficiency between fingolimod and natalizumab in Spain. A cost minimisation analysis model was developed for a 2-year horizon. The same relapse rate was applied to both treatment arms and the cost of resources was calculated using Spain's stipulated rates for 2012 in euros. The analysis was conducted from the perspective of Spain's national health system and an annual discount rate of 3% was applied to future costs. A sensitivity analysis was performed to validate the robustness of the model. Indirect comparison of fingolimod with natalizumab revealed no significant differences (hazard ratio between 0.82 and 1.07). The total direct cost, considering a 2-year analytical horizon, a 7.5% discount stipulated by Royal Decree, and a mean annual relapse rate of 0.22, was € 40914.72 for fingolimod and € 45890.53 for natalizumab. Of the total direct costs that were analysed, the maximum cost savings derived from prescribing fingolimod prescription was € 4363.63, corresponding to lower administration and treatment maintenance costs. Based on the sensitivity analysis performed, fingolimod use was associated with average savings of 11% (range 3.1%-18.7%). Fingolimod is more efficient than natalizumab as a second-line treatment option for relapsing-remitting multiple sclerosis and it generates savings for the Spanish national health system. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH): cascade of events, clinical aspects, and pharmacotherapy options.

Science.gov (United States)

Teschke, Rolf

2018-06-01

Clinicians caring for patients with alcoholic hepatitis (AH) are often confronted with the question of the best pharmacotherapy to be used. Areas covered: This article covers metabolic aspects of alcohol as the basis of understanding pharmacotherapy and to facilitate choosing the drug therapeutic options for patients with severe AH. Expert opinion: Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH) as terms are often used interchangeably in scientific literature but a stringent differentiation is recommended for proper clarity. As opposed to ASH, the clinical course of AH is often severe and requires an effective drug treatment strategy, in addition to absolute alcohol abstinence and nutritional support. Drug options include corticosteroids as a first choice and pentoxifylline, an inhibitor of phosphodiesterase, as a second line therapy, especially in patients with contraindications for a corticosteroid therapy such as infections or sepsis. At seven days under corticosteroids, treatment should be terminated in non-responders, and patients must then be evaluated for liver transplantation. Pentoxifylline is not effective as a rescue therapy for these patients. Other treatments such as infliximab, propylthiouracil, N-acetylcysteine, silymarin, colchicine, insulin and glucagon, oxandrolone, testosterone, and polyunsaturated lecithin are not effective in severe AH. For liver transplantation, few patients will be eligible.

Virologic failure of protease inhibitor-based second-line antiretroviral therapy without resistance in a large HIV treatment program in South Africa.

Directory of Open Access Journals (Sweden)

Julie H Levison

Full Text Available We investigated the prevalence of wild-type virus (no major drug resistance and drug resistance mutations at second-line antiretroviral treatment (ART failure in a large HIV treatment program in South Africa.HIV-infected patients ≥ 15 years of age who had failed protease inhibitor (PI-based second-line ART (2 consecutive HIV RNA tests >1000 copies/ml on lopinavir/ritonavir, didanosine, and zidovudine were identified retrospectively. Patients with virologic failure were continued on second-line ART. Genotypic testing for drug resistance was performed on frozen plasma samples obtained closest to and after the date of laboratory confirmed second-line ART failure. Of 322 HIV-infected patients on second-line ART, 43 were adults with confirmed virologic failure, and 33 had available plasma for viral sequencing. HIV-1 RNA subtype C predominated (n = 32, 97%. Mean duration on ART (SD prior to initiation of second-line ART was 23 (17 months, and time from second-line ART initiation to failure was 10 (9 months. Plasma samples were obtained 7(9 months from confirmed failure. At second-line failure, 22 patients (67% had wild-type virus. There was no major resistance to PIs found. Eleven of 33 patients had a second plasma sample taken 8 (5.5 months after the first. Median HIV-1 RNA and the genotypic resistance profile were unchanged.Most patients who failed second-line ART had wild-type virus. We did not observe evolution of resistance despite continuation of PI-based ART after failure. Interventions that successfully improve adherence could allow patients to continue to benefit from second-line ART therapy even after initial failure.

The current treatment options for epilepsy

International Nuclear Information System (INIS)

Sykora, P.; Svecova, L.

2014-01-01

Epilepsy is the most prevalent chronic brain disease manifesting with epileptic seizures. Epilepsy itself is not one nosological entity, it rather includes several diseases with various etiology, clinics, course and therapy. Antiepileptic therapy aims seizure freedom without affecting psychical and physical functions. The therapy is in first line pharmacological. The choice of antiepileptic drug depends not only on the seizure phenomenology, but also on the respective type of epilepsy syndrome. Most patients achieve seizure freedom or at least significant seizure frequency reduction. In 20-30% of the patients is the pharmacotherapy ineffective. In these cases of refractory epilepsy therapeutical options include epilepsy surgery, vagal stimulation or ketogenic diet. Despite recent advances in the diagnostics and therapy, epilepsy remains a serious medical and social issue. (author)

"To look at death another way": Black teenage males' perspectives on second-lines and regular funerals in New Orleans.

Science.gov (United States)

Bordere, Tashel C

The purpose of this study was to describe how Black adolescent males understand "second-line" (musical processions) and "regular"/traditional funeral rituals in New Orleans following the violent deaths of significant persons in their lives. In-depth interviews were conducted with 10 Black males between the ages of 12 and 15 using descriptive phenomenology methodology. Findings revealed that these participants understood death as a cause for celebration, remembrance, and unity related to their experiences with the second-line ritual. Three elements of the life world of Black teenage males were descriptive of second lines, including: a) observed locations of second lines; b) dancing to good music; and c) observed messages conveyed through t-shirts. Participants provided gender-based descriptions of perceived spoken and unspoken rights in grieving at the two distinct rituals. Related to their second-line experience, the teens reflect on ways in which they wish to have their deaths ritualized.

Second Line of Defense Spares Program Assessment

Energy Technology Data Exchange (ETDEWEB)

Henderson, Dale L.; Muller, George; Mercier, Theresa M.; Brigantic, Robert T.; Perkins, Casey J.; Cooley, Scott K.

2012-11-20

The Office of the Second Line of Defense (SLD) is part of the Department of Energy‘s (DOE) National Nuclear Security Administration (NNSA). The SLD Program accomplishes its critical global security mission by forming cooperative relationships with partner countries to install passive radiation detection systems that augment traditional inspection and law enforcement measures by alerting border officials to the presence of special nuclear or other radiological materials in cross-border traffic. An important tenet of the program is to work collaboratively with these countries to establish the necessary processes, procedures, infrastructure and conditions that will enable them to fully assume the financial and technical responsibilities for operating the equipment. As the number of operational deployments grows, the SLD Program faces an increasingly complex logistics process to promote the timely and efficient supply of spare parts.

The need for second-line antiretroviral therapy in adults in sub-Saharan Africa up to 2030: a mathematical modelling study.

Science.gov (United States)

Estill, Janne; Ford, Nathan; Salazar-Vizcaya, Luisa; Haas, Andreas D; Blaser, Nello; Habiyambere, Vincent; Keiser, Olivia

2016-03-01

The number of patients in need of second-line antiretroviral drugs is increasing in sub-Saharan Africa. We aimed to project the need of second-line antiretroviral therapy in adults in sub-Saharan Africa up to 2030. We developed a simulation model for HIV and applied it to each sub-Saharan African country. We used the WHO country intelligence database to estimate the number of adult patients receiving antiretroviral therapy from 2005 to 2014. We fitted the number of adult patients receiving antiretroviral therapy to observed estimates, and predicted first-line and second-line needs between 2015 and 2030. We present results for sub-Saharan Africa, and eight selected countries. We present 18 scenarios, combining the availability of viral load monitoring, speed of antiretroviral scale-up, and rates of retention and switching to second-line. HIV transmission was not included. Depending on the scenario, 8·7-25·6 million people are expected to receive antiretroviral therapy in 2020, of whom 0·5-3·0 million will be receiving second-line antiretroviral therapy. The proportion of patients on treatment receiving second-line therapy was highest (15·6%) in the scenario with perfect retention and immediate switching, no further scale-up, and universal routine viral load monitoring. In 2030, the estimated range of patients receiving antiretroviral therapy will remain constant, but the number of patients receiving second-line antiretroviral therapy will increase to 0·8-4·6 million (6·6-19·6%). The need for second-line antiretroviral therapy was two to three times higher if routine viral load monitoring was implemented throughout the region, compared with a scenario of no further viral load monitoring scale-up. For each monitoring strategy, the future proportion of patients receiving second-line antiretroviral therapy differed only minimally between countries. Donors and countries in sub-Saharan Africa should prepare for a substantial increase in the need for second-line

Pharmacokinetics of Second-Line Antituberculosis Drugs after Multiple Administrations in Healthy Volunteers.

Science.gov (United States)

Park, Sang-In; Oh, Jaeseong; Jang, Kyungho; Yoon, Jangsoo; Moon, Seol Ju; Park, Jong Sun; Lee, Jae Ho; Song, Junghan; Jang, In-Jin; Yu, Kyung-Sang; Chung, Jae-Yong

2015-08-01

Therapeutic drug monitoring (TDM) of second-line antituberculosis drugs would allow for optimal individualized dosage adjustments and improve drug safety and therapeutic outcomes. To evaluate the pharmacokinetic (PK) characteristics of clinically relevant, multidrug treatment regimens and to improve the feasibility of TDM, we conducted an open-label, multiple-dosing study with 16 healthy subjects who were divided into two groups. Cycloserine (250 mg), p-aminosalicylic acid (PAS) (5.28 g), and prothionamide (250 mg) twice daily and pyrazinamide (1,500 mg) once daily were administered to both groups. Additionally, levofloxacin (750 mg) and streptomycin (1 g) once daily were administered to group 1 and moxifloxacin (400 mg) and kanamycin (1 g) once daily were administered to group 2. Blood samples for PK analysis were collected up to 24 h following the 5 days of drug administration. The PK parameters, including the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve during a dosing interval at steady state (AUCτ), were evaluated. The correlations between the PK parameters and the concentrations at each time point were analyzed. The mean Cmax and AUCτ, respectively, for each drug were as follows: cycloserine, 24.9 mg/liter and 242.3 mg · h/liter; PAS, 65.9 mg/liter and 326.5 mg · h/liter; prothionamide, 5.3 mg/liter and 22.1 mg · h/liter; levofloxacin, 6.6 mg/liter and 64.4 mg · h/liter; moxifloxacin, 4.7 mg/liter and 54.2 mg · h/liter; streptomycin, 42.0 mg/liter and 196.7 mg · h/liter; kanamycin, 34.5 mg/liter and 153.5 mg · h/liter. The results indicated that sampling at 1, 2.5, and 6 h postdosing is needed for TDM when all seven drugs are administered concomitantly. This study indicates that PK characteristics must be considered when prescribing optimal treatments for patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT02128308.). Copyright © 2015, American Society for

Epirubicin plus paclitaxel regimen as second-line treatment of patients with small-cell lung cancer.

Science.gov (United States)

Pasello, Giulia; Carli, Paolo; Canova, Fabio; Bonanno, Laura; Polo, Valentina; Zago, Giulia; Urso, Loredana; Conte, Pierfranco; Favaretto, Adolfo

2015-04-01

Most patients with small cell lung cancer (SCLC) experience relapse within one year after first-line treatment. The aim of this study was to describe activity and safety of second-line with epirubicin at 70 mg/m(2) followed by paclitaxel at 135 mg/m(2) on day 1 every three weeks for a maximum of six cycles. This is a retrospective review of all patients with SCLC evaluated for second-line treatment between 2003 and 2013 at our Institution. Sixty-eight patients received the study regimen of epirubicin with paclitaxel. We observed partial response in 19 (30%), stable disease in 22 (34%) and total early failure rate in 23 (36%) patients. Median progression free and overall survival were 21.8 and 26.5 weeks, respectively. Haematological toxicities were as follows: grade 3-4 leukopenia and neutropenia in 18 (31%) and 30 (22%) of patients, respectively; grade 3 anaemia and grade 4 thrombocytopenia were reported in 2 (3%) and 5 (9%) of patients, respectively. Epirubicin with paclitaxel is an active and tolerable second-line regimen in patients with SCLC. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Comparison of different options for harvest of a therapeutic protein product from high cell density yeast fermentation broth.

Science.gov (United States)

Wang, Alice; Lewus, Rachael; Rathore, Anurag S

2006-05-05

Recovery of therapeutic protein from high cell density yeast fermentations at commercial scale is a challenging task. In this study, we investigate and compare three different harvest approaches, namely centrifugation followed by depth filtration, centrifugation followed by filter-aid enhanced depth filtration, and microfiltration. This is achieved by presenting a case study involving recovery of a therapeutic protein from Pichia pastoris fermentation broth. The focus of this study is on performance of the depth filtration and the microfiltration steps. The experimental data has been fitted to the conventional models for cake filtration to evaluate specific cake resistance and cake compressibility. In the case of microfiltration, the experimental data agrees well with flux predicted by shear induced diffusion model. It is shown that, under optimal conditions, all three options can deliver the desired product recovery ( >80%), harvest time ( making a final decision on a harvesting approach.

Therapeutic antibodies as a treatment option for dengue fever.

Science.gov (United States)

Chan, Kuan Rong; Ong, Eugenia Z; Ooi, Eng Eong

2013-11-01

Dengue fever is the most prevalent mosquito-borne viral disease globally with about 100 million cases of acute dengue annually. Severe dengue infection can result in a life-threatening illness. In the absence of either a licensed vaccine or antiviral drug against dengue, therapeutic antibodies that neutralize dengue virus (DENV) may serve as an effective medical countermeasure against severe dengue. However, therapeutic antibodies would need to effectively neutralize all four DENV serotypes. It must not induce antibody-dependent enhancement of DENV infection in monocytes/macrophages through Fc gamma receptor (FcγR)-mediated phagocytosis, which is hypothesized to increase the risk of severe dengue. Here, we review the strategies and technologies that can be adopted to develop antibodies for therapeutic applications. We also discuss the mechanism of antibody neutralization in the cells targeted by DENV that express Fc gamma receptor. These studies have provided significant insight toward the use of therapeutic antibodies as a potentially promising bulwark against dengue.

Nintedanib plus docetaxel as second-line therapy in patients with non-small-cell lung cancer

DEFF Research Database (Denmark)

Popat, Sanjay; Mellemgaard, Anders; Fahrbach, Kyle

2015-01-01

BACKGROUND: Nintedanib plus docetaxel has proven an overall survival benefit over docetaxel monotherapy in second-line treatment of non-small-cell lung cancer of adenocarcinoma histology in the LUME-Lung 1 pivotal trial. No published trials have previously compared nintedanib plus docetaxel...... with advanced non-small-cell lung cancer of adenocarcinoma histology, results suggest that nintedanib plus docetaxel offers clinical benefit compared with docetaxel alone, when used as second-line treatment, and suggests that this combination may also add clinical benefit compared with erlotinib in this patient...

Second Line of Defense Spares Program

Energy Technology Data Exchange (ETDEWEB)

Henderson, Dale L.; Holmes, Aimee E.; Muller, George; Mercier, Theresa M.; Brigantic, Robert T.; Perkins, Casey J.; Cooley, Scott K.; Thorsen, Darlene E.

2012-11-20

During Fiscal Year 2012, a team from the Pacific Northwest National Laboratory (PNNL) conducted an assessment and analysis of the Second Line of Defense (SLD) Sustainability spare parts program. Spare parts management touches many aspects of the SLD Sustainability Program including contracting and integration of Local Maintenance Providers (LMP), equipment vendors, analyses and metrics on program performance, system state of health, and maintenance practices. Standardized spares management will provide better data for decisions during site transition phase and will facilitate transition to host country sustainability ownership. The effort was coordinated with related SLD Sustainability Program initiatives, including a configuration items baselining initiative, a metrics initiative, and a maintenance initiative. The spares study has also led to pilot programs for sourcing alternatives that include regional intermediate inventories and partnering agreements that leverage existing supply chains. Many partners from the SLD Sustainability program contributed to and were consulted in the course of the study. This document provides a description of the findings, recommendations, and implemented solutions that have resulted from the study.

An Asian poverty line? Issues and options

OpenAIRE

Klasen, Stephan

2016-01-01

Given Asia's record of rapid economic growth and the conceptual and empirical problems of the current international income poverty line ('dollar-a-day'), this paper discusses whether there is merit to develop an Asia-specific poverty line that addresses some of the shortcomings of the dollar-a-day line and additionally considers Asia's particular economic situation. We consider various ways of creating an Asia-specific poverty line, including an Asia-specific international income poverty line...

automated (centrifugal) therapeutic plasma exchange option for ...

African Journals Online (AJOL)

Therapeutic plasma exchange (TPE) is performed frequently and effectively in developed countries, whereas the reverse is the case in developing countries. Guillain‑Barre syndrome (GBS), synonymous with acute inflammatory demyelinating polyneuropathy, is an important indication for TPE, but this is rarely administered ...

SGLT2 inhibitors: a promising new therapeutic option for treatment of type 2 diabetes mellitus.

Science.gov (United States)

Misra, Monika

2013-03-01

Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose reabsorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications. Sodium glucose cotransporter 2 (SGLT2) has a key role in reabsorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes. To discuss the therapeutic potential of SGLT2 inhibitors currently in clinical development. A number of preclinical and clinical studies of SGLT2 inhibitors have demonstrated a good safety profile and beneficial effects in lowering plasma glucose levels, diminishing glucotoxicity, improving glycemic control and reducing weight in diabetes. Of all the SGLT2 inhibitors, dapagliflozin is a relatively advanced compound with regards to clinical development. SGLT2 inhibitors are emerging as a promising therapeutic option for the treatment of diabetes. Their unique mechanism of action offers them the potential to be used in combination with other oral anti-diabetic drugs as well as with insulin. © 2012 The Author. JPP © 2012 Royal Pharmaceutical Society.

Current Nondopaminergic Therapeutic Options for Motor Symptoms of Parkinson's Disease

Institute of Scientific and Technical Information of China (English)

Juan-Juan Du; Sheng-Di Chen

2017-01-01

Objective:The aim of this study was to summarize recent studies on nondopaminergic options for the treatment of motor symptoms in Parkinson's disease (PD).Data Sources:Papers in English published in PubMed,Cochrane,and Ovid Nursing databases between January 1988 and November 2016 were searched using the following keywords:PD,nondopaminergic therapy,adenosine,glutamatergic,adrenergic,serotoninergic,histaminic,and iron chelator.We also reviewed the ongoing clinical trials in the website of clinicaltrials.gov.Study Selection:Articles related to the nondopaminergic treatment of motor symptoms in PD were selected for this review.Results:PD is conventionally treated with dopamine replacement strategies,which are effective in the early stages of PD.Long-term use oflevodopa could result in motor complications.Recent studies revealed that nondopaminergic systems such as adenosine,glutamatergic,adrenergic,serotoninergic,histaminic,and iron chelator pathways could include potential therapeutic targets for motor symptoms,including motor fluctuations,levodopa-induced dyskinesia,and gait disorders.Some nondopaminergic drugs,such as istradefylline and amantadine,are currently used clinically,while most such drugs are in preclinical testing stages.Transitioning of these agents into clinically beneficial strategies requires reliable evaluation since several agents have failed to show consistent results despite positive findings at the preclinical level.Conclusions:Targeting nondopaminergic transmission could improve some motor symptoms in PD,especially the discomfort ofdyskinesia.Although nondopaminergic treatments show great potential in PD treatment as an adjunct therapy to levodopa,further investigation is required to ensure their success.

Therapeutic Vaccination for HPV Induced Cervical Cancers

Directory of Open Access Journals (Sweden)

Joeli A. Brinkman

2007-01-01

Full Text Available Cervical Cancer is the second leading cause of cancer–related deaths in women worldwide and is associated with Human Papillomavirus (HPV infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence.

Changing Profiles of Diagnostic and Treatment Options in Subclavian Artery Aneurysms

NARCIS (Netherlands)

Vierhout, B. P.; Zeebregts, C. J.; van den Dungen, J. J. A. M.; Reijnen, M. M. P. J.

Background: Subclavian artery aneurysms (SAAs) are rare and may cause life- and limb-threatening complications. Therapeutic options greatly differ as do access alternatives. The aim of the study was to assess its clinical presentation, diagnostics and therapeutic options as reported in the

Emerging therapeutic options for sporadic inclusion body myositis

Directory of Open Access Journals (Sweden)

Alfano LN

2015-09-01

Full Text Available Lindsay N Alfano, Linda P Lowes Nationwide Children’s Hospital, Center for Gene Therapy, Columbus, OH, USA Abstract: Sporadic inclusion body myositis is the most common inflammatory muscle disorder preferentially affecting males over the age of 40 years. Progressive muscle weakness of the finger flexors and quadriceps muscles results in loss of independence with activities of daily living and eventual wheelchair dependence. Initial signs of disease are often overlooked and can lead to mis- or delayed diagnosis. The underlying cause of disease is unknown, and disease progression appears refractory to available treatment options. This review discusses the clinical presentation of inclusion body myositis and the current efforts in diagnosis, and focuses on the current state of research for both nonpharmacological and pharmacological treatment options for this patient group. Keywords: myositis, inclusion body myositis, inflammatory myopathy, treatment, function, outcomes

Addressing Therapeutic Options for Ebola Virus Infection in Current and Future Outbreaks.

Science.gov (United States)

Haque, Azizul; Hober, Didier; Blondiaux, Joel

2015-10-01

Ebola virus can cause severe hemorrhagic disease with high fatality rates. Currently, no specific therapeutic agent or vaccine has been approved for treatment and prevention of Ebola virus infection of humans. Although the number of Ebola cases has fallen in the last few weeks, multiple outbreaks of Ebola virus infection and the likelihood of future exposure highlight the need for development and rapid evaluation of pre- and postexposure treatments. Here, we briefly review the existing and future options for anti-Ebola therapy, based on the data coming from rare clinical reports, studies on animals, and results from in vitro models. We also project the mechanistic hypotheses of several potential drugs against Ebola virus, including small-molecule-based drugs, which are under development and being tested in animal models or in vitro using various cell types. Our paper discusses strategies toward identifying and testing anti-Ebola virus properties of known and medically approved drugs, especially those that can limit the pathological inflammatory response in Ebola patients and thereby provide protection from mortality. We underline the importance of developing combinational therapy for better treatment outcomes for Ebola patients. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Nuclear data for production of therapeutic radionuclides. Summary report of second research coordination meeting

International Nuclear Information System (INIS)

Sublet, J.-Ch.; Capote Noy, R.

2004-11-01

A summary is given of the Second Research Coordination Meeting on Nuclear Data for Production of Therapeutic Radionuclides. The new library of evaluated cross section will cover the reactor and/or accelerator production of therapeutic radionuclides to appropriate specific activities and purity along with the relevant decay data. There are a significant number of radioisotopes in use or being proposed for therapeutic applications. As a consequence of the work undertaken during the course of this CRP, the resulting completeness and accuracy of the nuclear data for the production of these nuclides to appropriate specific activities and purity along with the re-definition of their decay data should be adequate for safe and efficient medical applications. The radioisotopes to be considered in the CRP were divided into two categories: Established Radioisotopes (therapeutic radioisotopes that have established clinical uses) and Emerging Radioisotopes (less-commonly used but potentially interesting radioisotopes for which medical applications have been demonstrated). Experimental data compilations and selection and preliminary evaluations for each of the reactions were extensively discussed during the meeting. The recommendations for both established and emerging radionuclides, and validation/testing of the cross section library are summarized. Technical discussions and the resulting work plan of the Coordinated Research Programme are summarized for every reaction path to be evaluated, along with actions and deadlines. Participants' contributions to the RCM are also attached. (author)

Efficacy and Safety of Capecitabine, Irinotecan, Gemcitabine, and Bevacizumab as Second-Line Treatment in Advanced Biliary Tract Cancer

DEFF Research Database (Denmark)

Larsen, Finn Ole; Markussen, Alice; Diness, Laura V

2018-01-01

, there are no phase III trials supporting second-line treatment, and the phase II trials with chemotherapy do not show any clear benefit. In this study, we investigated the effect of adding bevacizumab to chemotherapy in second-line treatment. METHODS: From November 2013 to January 2016, 50 patients with advanced...

Disease-related mortality exceeds treatment-related mortality in patients with chronic myeloid leukemia on second-line or later therapy.

Science.gov (United States)

Pearson, Edward; McGarry, Lisa; Gala, Smeet; Nieset, Christopher; Nanavaty, Merena; Mwamburi, Mkaya; Levy, Yair

2016-04-01

Treatment of newly-diagnosed patients with chronic-phase chronic myeloid leukemia (CP-CML) with tyrosine kinase inhibitors (TKIs) results in near-normal life expectancy. However, CP-CML patients resistant to initial TKIs face a poorer prognosis and significantly higher CML-related mortality. We conducted a systematic literature review to evaluate the specific causes of deaths (diseases progression versus drug-related) in CP-CML patients receiving second- or third-line therapy. We identified eight studies based on our criteria that reported causes of death. Overall, 5% of second-line and 10% of third-line patients died during the study follow-up period. For second-line, (7 studies, n=1926), mortality was attributed to disease progression for 41% of deaths, 2% to treatment-related causes, 3% were treatment-unrelated, and 50% were unspecified adverse events (AEs), not likely related to study drug. In third-line, (2 studies, n=144), 71% deaths were attributed to disease progression, 7% treatment-related AEs, 14% treatment-unrelated and 7% unspecified AEs. Annual death rates for second- and third-line therapy were significantly higher than for general population in similar age group. Our findings suggest death attributed to disease progression is approximately 10 times that due to treatment-related AEs in patients with CP-CML receiving second- or third-line therapy. Therefore, the potential benefits of effective treatment for these patients with the currently available TKIs outweigh the risks of treatment-induced AEs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sequential treatment of icotinib after first-line pemetrexed in advanced lung adenocarcinoma with unknown EGFR gene status.

Science.gov (United States)

Zheng, Yulong; Fang, Weijia; Deng, Jing; Zhao, Peng; Xu, Nong; Zhou, Jianying

2014-07-01

In non-small cell lung cancer (NSCLC), the well-developed epidermal growth factor receptor (EGFR) is an important therapeutic target. EGFR activating gene mutations have been proved strongly predictive of response to EGFR-tyrosine kinase inhibitors (TKI) in NSCLC. However, both in daily clinical practice and clinical trials, patients with unknown EGFR gene status (UN-EGFR-GS) are very common. In this study, we assessed efficacy and tolerability of sequential treatment of first-line pemetrexed followed by icotinib in Chinese advanced lung adenocarcinoma with UN-EGFR-GS. We analyzed 38 patients with advanced lung adenocarcinoma with UN-EGFR-GS treated with first-line pemetrexed-based chemotherapy followed by icotinib as maintenance or second-line therapy. The response rates to pemetrexed and icotinib were 21.1% and 42.1%, respectively. The median overall survival was 27.0 months (95% CI, 19.7-34.2 months). The 12-month overall survival probability was 68.4%. The most common toxicities observed in icotinib phase were rashes, diarrheas, and elevated aminotransferase. Subgroup analysis indicated that the overall survival is correlated with response to icotinib. The sequence of first-line pemetrexed-based chemotherapy followed by icotinib treatment is a promising option for advanced lung adenocarcinoma with UN-EGFR-GS in China.

The use of radiotherapy as a therapeutic option in the juvenile nasopharyngeal angiofibroma: An update of results in 11 patients

International Nuclear Information System (INIS)

Alert Silva, Jose; Perez Penna, Lourdes; Caballero Aguirrechu, Iraida; Reno Cespedes, Jesus; Garcia Socarras, Debora; Perez Trejo, Migdalia

2009-01-01

The juvenile nasopharyngeal angiofibroma is a rare benign tumor composed of fibrous connective tissue and abundant vascular spaces lined with endothelium, almost exclusively male and adolescence. The recommended treatment of choice is surgical excision of the tumor after embolization, however, in patients with bulky tumors, in which no surgical treatment is possible or it is refused, or where excision was incomplete, or the case of recurrence, radiation therapy (RT) is a therapeutic option. Results are presented in a series of 11 patients suffering from juvenile nasopharyngeal angiofibroma, all male, between 9 and 16 years of age, treated at INOR from 1990 to 2005. Nine patients were used as initial therapy irradiated and 2 relapse treated. The radiation treatment was applied in the irradiation of the entire tumor volume with a margin of safety, dose between 40 and 60 Gy, 1.8 Gy per session, associated with RT, was used postirradiation interferon from 3 to 6 months in 10 poly chemotherapy patients and in 1 patient. They keep 10 of the 11 patients with sustained complete remission (90.9%) without recurrence. In one patient only partial remission was achieved, using then surgical treatment. Early complications were all patients, and late in some. In the management of juvenile nasopharyngeal angiofibroma, RT is a treatment that maintains its usefulness, with their specific indications. (Author)

Characterization of a PEGylated protein therapeutic by ion exchange chromatography with on-line detection by native ESI MS and MS/MS.

Science.gov (United States)

Muneeruddin, K; Bobst, C E; Frenkel, R; Houde, D; Turyan, I; Sosic, Z; Kaltashov, I A

2017-01-16

Detailed profiling of both enzymatic (e.g., glycosylation) and non-enzymatic (e.g., oxidation and deamidation) post-translational modifications (PTMs) is frequently required for the quality assessment of protein-based drugs. Challenging as it is, this task is further complicated for the so-called second-generation biopharmaceuticals, which also contain "designer PTMs" introduced to either enhance their pharmacokinetic profiles (e.g., PEGylated proteins) or endow them with therapeutic activity (e.g., protein-drug conjugates). Such modifications of protein covalent structure can dramatically increase structural heterogeneity, making the very notion of "molecular mass" meaningless, as ions representing different glycoforms of a PEGylated protein may have nearly identical distributions of ionic current as a function of m/z, making their contributions to the mass spectrum impossible to distinguish. In this work we demonstrate that a combination of ion exchange chromatography (IXC) with on-line detection by electrospray ionization mass spectrometry (ESI MS) and methods of ion manipulation in the gas phase (limited charge reduction and collision-induced dissociation) allows meaningful structural information to be obtained on a structurally heterogeneous sample of PEGylated interferon β-1a. IXC profiling of the protein sample gives rise to a convoluted chromatogram with several partially resolved peaks which can represent both deamidation and different glycosylation patterns within the protein, as well as varying extent of PEGylation. Thus, profiling the protein with on-line IXC/ESI/MS/MS allows it to be characterized by providing information on three different types of PTMs (designer, enzymatic and non-enzymatic) within a single protein therapeutic.

Proceedings of the twenty-second LAMPF users groupd meeting

International Nuclear Information System (INIS)

Marinuzzi, R.

1989-04-01

The Twenty-Second Annual LAMPF Users Group Meeting was held October 17--18, 1988, at the Clinton P. Anderson Meson Physics Facility. The program included a number of invited talks on various aspects of nuclear and particle physics as well as status reports on LAMPF and discussions of upgrade options. The LAMPF working groups met and discussed plans for the secondary beam lines, experimental programs, and computing facilities

Nevada Transportation Options Study

International Nuclear Information System (INIS)

P. GEHNER; E.M. WEAVER; L. FOSSUM

2006-01-01

This study performs a cost and schedule analysis of three Nevada Transportation options that support waste receipt at the repository. Based on the U.S. Department of Energy preference for rail transportation in Nevada (given in the Final Environmental Impact Statement), it has been assumed that a branch rail line would be constructed to support waste receipt at the repository. However, due to potential funding constraints, it is uncertain when rail will be available. The three Nevada Transportation options have been developed to meet a varying degree of requirements for transportation and to provide cost variations used in meeting the funding constraints given in the Technical Direction Letter guidelines for this study. The options include combinations of legal-weight truck, heavy-haul truck, and rail. Option 1 uses a branch rail line that would support initial waste receipt at the repository in 2010. Rail transportation would be the primary mode, supplemented by legal weight trucks. This option provides the highest level of confidence in cost and schedule, lowest public visibility, greatest public acceptability, lowest public dose, and is the recommended option for support of waste receipt. The completion of rail by 2010 will require spending approximately $800 million prior to 2010. Option 2 uses a phased rail approach to address a constrained funding scenario. To meet funding constraints, Option 2 uses a phased approach to delay high cost activities (final design and construction) until after initial waste receipt in 2010. By doing this, approximately 95 percent of the cost associated with completion of a branch rail line is deferred until after 2010. To support waste receipt until a branch rail line is constructed in Nevada, additional legal-weight truck shipments and heavy-haul truck shipments (on a limited basis for naval spent nuclear fuel) would be used to meet the same initial waste receipt rates as in Option 1. Use of heavy-haul shipments in the absence

Pharmacoeconomic analysis of the use of first- and second-line drugs in the treatment of multiple sclerosis

Directory of Open Access Journals (Sweden)

V. R. Mkrtchyan

2015-01-01

Full Text Available Objective: to make a pharmacoeconomic comparison of the administration of first- and second-line drugs in the treatment of multiple sclerosis through cost, cost-effectiveness, and budget impact analyses using the 2015 state prices.Material and methods. A pharmacoeconomic analysis was carried out on the basis of the data available in the literature on trials of the effects of the drugs on the rates of exacerbations and disability. On calculating, the authors took into account the current standards for the out- and inpatient management of patients with this nosological entity in accordance with the compulsory health insurance (CHI program; prices for state drug purchases in March 2015; prices for medical services in compliance with the CHI standards in Moscow in 2015; the average sizes of minimum wage, salary, and disability grants with consideration for a discount rate of 3%. The cost-effectiveness and budget impact analyses were performed for intramuscular interferon (INF-β1a (avonex, 30 μg, subcutaneous INF-β1a (rebif, 44 μg, subcutaneous INF-β1b (ronbetal, 8,000,000 IU, subcutaneous INF-β1b (betaferon, 9,600,000 IU, subcutaneous glatiramer acetate (copaxone, 20 mg, intravenous natalizumab (tyzabri, 300 mg, and oral fingolimod (gilenya, 0.5 mg.Results and discussion. The second-line drug tyzabri outperforms the first-line agents for cost-effectiveness. The first-line drugs betaferon and copaxone is slightly exceeded in this indicator by tyzabri; the other both first- and second-line agents compared are all the more inferior in this indicator. The budget impact analysis has shown that the cost of the second-line drugs was higher than that of the first-line ones.

Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

Directory of Open Access Journals (Sweden)

Athanassios Argiris

2017-05-01

Full Text Available The major development of the past decade in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy (CT, followed by maintenance cetuximab (the “EXTREME” regimen. This regimen is supported by a phase 3 randomized trial and subsequent observational studies, and it confers well-documented survival benefits, with median survival ranging between approximately 10 and 14 months, overall response rates between 36 and 44%, and disease control rates of over 80%. Furthermore, as indicated by patient-reported outcome measures, the addition of cetuximab to platinum-based CT leads to a significant reduction in pain and problems with social eating and speech. Conversely, until very recently, there has been a lack of evidence-based second-line treatment options, and the therapies that have been available have shown low response rates and poor survival outcomes. Presently, a promising new treatment option in R/M SCCHN has emerged: immune checkpoint inhibitors (ICIs, which have demonstrated favorable results in second-line clinical trials. Nivolumab and pembrolizumab are the first two ICIs that were approved by the US Food and Drug Administration. We note that the trials that showed benefit with ICIs included not only patients who previously received ≥1 platinum-based regimens for R/M SCCHN but also patients who experienced recurrence within 6 months after combined modality therapy with a platinum agent for locally advanced disease. In this review, we outline the available clinical and observational evidence for the EXTREME regimen and the initial results from clinical trials for ICIs in patients with R/M SCCHN. We propose that these treatment options can be integrated into a new continuum of care paradigm, with first-line EXTREME regimen followed by second-line ICIs. A number of ongoing clinical trials

First and second line mechanisms of cadmium detoxification in the lichen photobiont Trebouxia impressa (Chlorophyta)

International Nuclear Information System (INIS)

Sanita di Toppi, L.; Pawlik-Skowronska, B.; Vurro, E.; Vattuone, Z.; Kalinowska, R.; Restivo, F.M.; Musetti, R.; Skowronski, T.

2008-01-01

'First line' defence mechanisms, such as phytochelatin biosynthesis, and 'second line' mechanisms, such as stress protein induction, were investigated in cadmium-exposed cells of Trebouxia impressa Ahmadjian, a green microalgal species that is a common photobiont of the lichen Physcia adscendens (Fr.) H. Olivier. When T. impressa cells were exposed to 0, 9 and 18 μM Cd for 6, 18 and 48 h, glutathione and phytochelatins efficiently protected the cells against Cd damage. By contrast, the highest Cd concentration (36 μM) at the longest exposure-time (48 h) caused marked drops in glutathione and phytochelatin content, several types of ultrastructural damage, and decreases in cell density and total chlorophyll concentration. In this case, induction of stress proteins was observed, but only long after the induction of phytochelatins. Thus, stress proteins could represent a 'second line' mechanism to counteract Cd stress, activated when there is a decline in the 'first line' mechanism of Cd detoxification given by phytochelatins. - Trebouxia impressa photobionts protect themselves against cadmium stress by means of phytochelatins and stress proteins

First and second line mechanisms of cadmium detoxification in the lichen photobiont Trebouxia impressa (Chlorophyta)

Energy Technology Data Exchange (ETDEWEB)

Sanita di Toppi, L. [Dipartimento di Biologia Evolutiva e Funzionale, viale G.P. Usberti 11/A, Universita di Parma, 43100 Parma (Italy)], E-mail: luigi.sanitaditoppi@unipr.it; Pawlik-Skowronska, B. [Centre for Ecological Research, Polish Academy of Sciences, Experimental Station, Niecala 18/3, 20080 Lublin (Poland); Vurro, E. [Dipartimento di Biologia Evolutiva e Funzionale, viale G.P. Usberti 11/A, Universita di Parma, 43100 Parma (Italy); Vattuone, Z. [Dipartimento di Biologia Evolutiva e Funzionale, viale G.P. Usberti 11/A, Universita di Parma, 43100 Parma (Italy); Centre for Ecological Research, Polish Academy of Sciences, Experimental Station, Niecala 18/3, 20080 Lublin (Poland); Kalinowska, R. [Centre for Ecological Research, Polish Academy of Sciences, Experimental Station, Niecala 18/3, 20080 Lublin (Poland); Restivo, F.M. [Dipartimento di Genetica, Biologia dei Microrganismi, Antropologia, Evoluzione, viale G.P. Usberti 11/A, Universita di Parma, 43100 Parma (Italy); Musetti, R. [Dipartimento di Biologia Applicata alla Difesa delle Piante, via delle Scienze 208, Universita di Udine, 33100 Udine (Italy); Skowronski, T. [Centre for Ecological Research, Polish Academy of Sciences, Experimental Station, Niecala 18/3, 20080 Lublin (Poland)

2008-01-15

'First line' defence mechanisms, such as phytochelatin biosynthesis, and 'second line' mechanisms, such as stress protein induction, were investigated in cadmium-exposed cells of Trebouxia impressa Ahmadjian, a green microalgal species that is a common photobiont of the lichen Physcia adscendens (Fr.) H. Olivier. When T. impressa cells were exposed to 0, 9 and 18 {mu}M Cd for 6, 18 and 48 h, glutathione and phytochelatins efficiently protected the cells against Cd damage. By contrast, the highest Cd concentration (36 {mu}M) at the longest exposure-time (48 h) caused marked drops in glutathione and phytochelatin content, several types of ultrastructural damage, and decreases in cell density and total chlorophyll concentration. In this case, induction of stress proteins was observed, but only long after the induction of phytochelatins. Thus, stress proteins could represent a 'second line' mechanism to counteract Cd stress, activated when there is a decline in the 'first line' mechanism of Cd detoxification given by phytochelatins. - Trebouxia impressa photobionts protect themselves against cadmium stress by means of phytochelatins and stress proteins.

HIV multi-drug resistance at first-line antiretroviral failure and subsequent virological response in Asia

OpenAIRE

Jiamsakul, Awachana; Sungkanuparph, Somnuek; Law, Matthew; Kantor, Rami; Praparattanapan, Jutarat; Li, Patrick CK; Phanuphak, Praphan; Merati, Tuti; Ratanasuwan, Winai; Lee, Christopher KC; Ditangco, Rossana; Mustafa, Mahiran; Singtoroj, Thida; Kiertiburanakul, Sasisopin

2014-01-01

Introduction: First-line antiretroviral therapy (ART) failure often results from the development of resistance-associated mutations (RAMs). Three patterns, including thymidine analogue mutations (TAMs), 69 Insertion (69Ins) and the Q151M complex, are associated with resistance to multiple-nucleoside reverse transcriptase inhibitors (NRTIs) and may compromise treatment options for second-line ART. Methods: We investigated patterns and factors associated with multi-NRTI RAMs at first-line failu...

Room/corner tests of wall linings with 100/300 kW burner

Science.gov (United States)

M. A. Dietenberger; O. Grexa; R. H. White; M. S. Sweet; M. Janssens

1995-01-01

Six room/comer tests of common wall linings were conducted with gypsum-lined ceiling exposed to propane burning at 100 kW for 10 min followed by 300 kW for 10 min. This test protocol is an option provided by ISO 9705. The flashover event occurred at 1,000 kW rate of heat release within several seconds of observing flames out the doorway. The time to flashover of the...

High-dose chemotherapy and auto-SCT for relapsed and refractory Hodgkin's lymphoma patients refractory to first-line salvage chemotherapy but responsive to second-line salvage chemotherapy.

Science.gov (United States)

Rauf, Muhammad Shahzad; Maghfoor, Irfan; Elhassan, Tusneem Ahmed M; Akhtar, Saad

2015-01-01

Relapsed or primary refractory Hodgkin's lymphoma (HL) patients refractory to first-line salvage chemotherapy (first salvage) and unable to undergo high-dose chemotherapy (HDC) and autologous stem cell transplant (auto-SCT) have very poor outcome. Some patients are offered second-line salvage chemotherapy (second salvage), if they are responsive and may receive HDC auto-SCT. We identified 31 patients (18 males, 13 females) from 1996-2012 who received second salvage prior to auto-SCT. Median age at auto-SCT is 22 years. Patients were grouped as (1) relapsed-refractory (Rel:Ref): patients with prior complete response (CR) and on relapse found refractory to first salvage and received second salvage and (2) refractory-refractory (Ref:Ref): patients refractory to both primary treatment and first salvage and received second salvage. Median follow-up is 63 months (18-170). Disease status after second salvage prior to HDC was CR 16 %, partial response (PR) 71 % and stable disease 13 %. After HDC auto-SCT, CR:PR: progressive disease was observed in 18 (58 %): four (12 %): nine (29 %) patients, respectively. Five-year overall survival (OS) for whole group is 57 % (Rel:Ref vs. Ref:Ref, 73 % vs. 48 %, p = 0.48). Progression-free survival (PFS) for whole group is 52 % (Rel:Ref vs. Ref:Ref, 73 % vs. 40 % respectively, p = 0.11). Second-line salvage is a valid approach with no long-term side effects for those HL patients who do not respond to first-line salvage chemotherapy and they can be candidate of HDC and stem cell transplant with a high ORR, the PFS and OS in relapse-refractory and refractory-refractory group of patients.

Second-line treatment of recurrent HNSCC: tumor debulking in combination with high-dose-rate brachytherapy and a simultaneous cetuximab-paclitaxel protocol

International Nuclear Information System (INIS)

Ritter, M.; Teudt, I. U.; Meyer, J. E.; Schröder, U.; Kovács, G.; Wollenberg, B.

2016-01-01

After the failure of first-line treatment, the clinical prognosis in head and neck cancer (HNSCC) deteriorates. Effective therapeutic strategies are limited due to the toxicity of previous treatments and the diminished tolerance of surrounding normal tissue. This study demonstrates a promising second-line regimen, with function preserving surgical tumor debulking, followed by a combination of postoperative interstitial brachytherapy and a simultaneous protocol of cetuximab and taxol. From January 2006 to May 2013, 197 patients with HNSCC were treated with brachytherapy at the University Hospital Schleswig-Holstein Campus Lübeck, including 94 patients due to recurrent cancer. Within these, 18 patients were referred to our clinic because of early progressive disease following first- or second-line treatment failure. They received the new palliative regimen. A matched-pair analysis including recurrent tumor stage, status of resection margins, tissue invasion and previous therapy was performed to evaluate this treatment retrospectively. Overall survival (OS), disease-free survival (DFS), functional outcome and treatment toxicity was analyzed on the basis of medical records and follow-up data. DFS and OS of the study group were 8.7 and 14.8 months. Whereas, DFS and OS of the control group, treated only by function preserving tumor debulking and brachytherapy, was 3.9 and 6.1 months respectively. This demonstrates a positive trend through the additional use of the cetuximab-taxane protocol. Furthermore, no increase of therapy induced toxicities was displayed. Pre-treated patients with a further relapse benefit from the ‘cetuximab-taxane recurrency scheme’. It seems to be a valuable complement to interdisciplinary and multimodal tumor therapy, which improves OS and results in acceptable toxicity. The online version of this article (doi:10.1186/s13014-016-0583-0) contains supplementary material, which is available to authorized users

CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma: a novel therapeutic option for a deadly disease.

Science.gov (United States)

Kosovec, Juliann E; Zaidi, Ali H; Omstead, Ashten N; Matsui, Daisuke; Biedka, Mark J; Cox, Erin J; Campbell, Patrick T; Biederman, Robert W W; Kelly, Ronan J; Jobe, Blair A

2017-11-21

Esophageal adenocarcinoma (EAC) is a deadly disease with limited therapeutic options. In the present study, we determined the preclinical efficacy of CDK4/6 inhibitor abemaciclib for treatment of EAC. In vitro , apoptosis, proliferation, and pathway regulation were evaluated in OE19, OE33, and FLO1 EAC cell lines. In vivo , esophagojejunostomy was performed on rats to induce EAC. At 36 weeks post-surgery, MRI and endoscopic biopsy established baseline tumor volume and molecular correlates, respectively. Next, the study animals were randomized to 26mg/kg intraperitoneal abemaciclib treatment or vehicle control for 28 days. Pre and post treatment MRIs, histopathology, and qRT-PCR were utilized to determine response. Our results demonstrated treatment with abemaciclib lead to increased apoptosis, and decreased proliferation in OE19 (p=0.185), OE33 (p=0.048), and FLO1 (p=0.043) with anticipated downstream molecular inhibition. In vivo , 78.9% of treatment animals demonstrated >20% tumor volume decrease (placebo 0%). Mean tumor volume changed in the treatment arm by -65.5% (placebo +133.5%) (p<0.01), and prevalence changed by -37.5% (placebo +16.7%) (p<0.01). Pre vs post treatment qRT-PCR demonstrated significant inhibition of all downstream molecular correlates. Overall our findings suggest potent antitumor efficacy of abemaciclib against EAC with evident molecular pathway inhibition and reasonable safety, establishing the rationale for future clinical development.

Deep tissue imaging of microfracture and non-displaced fracture of bone using the second and third near-infrared therapeutic windows

Science.gov (United States)

Sordillo, Laura A.; Pu, Yang; Sordillo, P. P.; Budansky, Yury; Alfano, Robert R.

2014-03-01

Near-infrared (NIR) light in the wavelengths of 700 nm to 2,000 nm has three NIR optical, or therapeutic, windows, which allow for deeper depth penetration in scattering tissue media. Microfractures secondary to repetitive stress, particularly in the lower extremities, are an important problem for military recruits and athletes. They also frequently occur in the elderly, or in patients taking bisphosphonates or denosumab. Microfractures can be early predictors of a major bone fracture. Using the second and third NIR therapeutic windows, we investigated the results from images of chicken bone and human tibial bone with microfractures and non-displaced fractures with and without overlying tissues of various thicknesses. Images of bone with microfractures and non-displaced fractures with tissue show scattering photons in the third NIR window with wavelengths between 1,650 nm and 1,870 nm are diminished and absorption is increased slightly from and second NIR windows. Results from images of fractured bones show the attenuation length of light through tissue in the third optical window to be larger than in the second therapeutic window. Use of these windows may aid in the detection of bone microfractures, and thus reduce the incidence of major bone fracture in susceptible groups.

Ozone-augmented percutaneous discectomy: A novel treatment option for refractory discogenic sciatica

International Nuclear Information System (INIS)

Crockett, M.T.; Moynagh, M.; Long, N.; Kilcoyne, A.; Dicker, P.; Synnott, K.; Eustace, S.J.

2014-01-01

Aim: To assess the short and medium-term efficacy and safety of a novel, minimally invasive therapeutic option combining automated percutaneous lumbar discectomy, intradiscal ozone injection, and caudal epidural: ozone-augmented percutaneous discectomy (OPLD). Materials and methods: One hundred and forty-seven patients with a clinical and radiological diagnosis of discogenic sciatica who were refractory to initial therapy were included. Fifty patients underwent OPLD whilst 97 underwent a further caudal epidural. Outcomes were evaluated using McNab's score, improvement in visual analogue score (VAS) pain score, and requirement for further intervention. Follow-up occurred at 1 and 6 months, and comparison was made between groups. Results: OPLD achieved successful outcomes in almost three-quarters of patients in the short and medium term. OPLD achieved superior outcomes at 1 and 6 months compared to caudal epidural. There was a reduced requirement for further intervention in the OPLD group. No significant complications occurred in either group. Discussion: OPLD is a safe and effective treatment for patients with refractory discogenic sciatica in the short and medium term. OPLD has the potential to offer an alternative second-line minimally invasive treatment option that could reduce the requirement for surgery in this patient cohort. - Highlights: • Discogenic sciatica is a common condition which causes significant morbidity. • Ozone augmented percutaneous lumbar discectomy (OPLD) is a novel treatment. • Comparison was made to caudal epidural injection. • All outcomes were superior in the OPLD treatment group. • OPLD appears is an effective treatment for refractory discogenic sciatica

Prevalence of resistance to second-line tuberculosis drug among multidrug-resistant tuberculosis patients in Viet Nam, 2011.

Science.gov (United States)

Nguyen, Hoa Binh; Nguyen, Nhung Viet; Tran, Huong Thi Giang; Nguyen, Hai Viet; Bui, Quyen Thi Tu

2016-01-01

Extensively drug-resistant tuberculosis (XDR-TB) represents an emerging public health problem worldwide. According to the World Health Organization, an estimated 9.7% of multidrug-resistant TB (MDR-TB) cases are defined as XDR-TB globally. The objective of this study was to determine the prevalence of drug resistance to second-line TB drugs among MDR-TB cases detected in the Fourth National Anti-Tuberculosis Drug Resistance Survey in Viet Nam. Eighty clusters of TB cases were selected using a probability-proportion-to-size approach. To identify MDR-TB cases, drug susceptibility testing (DST) was performed for the four major first-line TB drugs. DST of second-line drugs (ofloxacin, amikacin, kanamycin, capreomycin) was performed on isolates from MDR-TB cases to identify pre-XDR and XDR cases. A total of 1629 smear-positive TB cases were eligible for culture and DST. Of those, DST results for first-line drugs were available for 1312 cases, and 91 (6.9%) had MDR-TB. Second-line DST results were available for 84 of these cases. Of those, 15 cases (17.9%) had ofloxacin resistance and 6.0% were resistant to kanamycin and capreomycin. Five MDR-TB cases (6.0%) met the criteria of XDR-TB. This survey provides the first estimates of the proportion of XDR-TB among MDR-TB cases in Viet Nam and provides important information for local policies regarding second-line DST. Local policies and programmes that are geared towards TB prevention, early diagnosis and treatment with effective regimens are of high importance.

On the use of dental ceramics as a possible second-line approach to accident irradiation dosimetry

International Nuclear Information System (INIS)

Davies, J.E.

1979-01-01

Recent development in dental ceramic production has resulted in natural or depleted uranium, used for over half a century to mimic the fluorescence of natural teeth, being substituted in such ceramics by non-radioactive fluorescent materials. This creates the possibility of using dental ceramics incorporating the latter as second-line dosimeters in cases of accidental irradiation. This pilot study shows the feasbility of such an approach using both thermally stimulated exoelectron and thermoluminescent techniques. In conclusion, it is considered that it would be of interest to continue this investigation of dental ceramic materials as second-line accident dosimeters

Advanced colorectal cancer, refractory to infusional fluorouracil treatment: efficacy of second line fluorouracil in combination with a different biochemical modulation

NARCIS (Netherlands)

van Halteren, H. K.; Wagener, D. J.; Vreugdenhil, G.; Punt, C. J.

1997-01-01

Currently there is no standard second line treatment for patients with advanced colorectal cancer (ACC). Previous reports have demonstrated that some patients may benefit from second line infusional 5-fluorouracil (5-FU) after failing 5-FU bolus treatment. We retrospectively studied the efficacy and

Is there a progression-free survival benefit of first-line crizotinib versus standard chemotherapy and second-line crizotinib in ALK-positive advanced lung adenocarcinoma? A retrospective study of Chinese patients.

Science.gov (United States)

Cui, Shaohua; Zhao, Yizhuo; Dong, Lili; Gu, Aiqin; Xiong, Liwen; Qian, Jialin; Zhang, Wei; Niu, Yanjie; Pan, Feng; Jiang, Liyan

2016-06-01

Although crizotinib has demonstrated promising efficacy and acceptable toxicity in patients with advanced non-small cell lung cancer (NSCLC), the available evidence in Chinese populations is currently limited. This study compared the progression-free survival (PFS) of Chinese patients with anaplastic lymphoma kinase (ALK)-positive, advanced lung adenocarcinoma who received first-line crizotinib therapy with that of patients who received first-line standard chemotherapy, and also the PFS benefit of first-line versus second-line crizotinib treatment. Data on 80 patients with ALK-positive, advanced lung adenocarcinoma who received crizotinib or standard chemotherapy as first-line treatments between June 2013 and December 2014 were retrospectively collected; 26 of the patients received crizotinib as second-line therapy after progressive disease (PD) occurred on first-line chemotherapy. Tumor responses were assessed using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The median PFS was 13.3 months (95% CI: 6.5-20.0 months) in patients who received first-line crizotinib as compared with 5.4 months (95% CI: 4.4-6.5 months) in patients who received first-line standard chemotherapy (adjusted hazard ratio for progression or death with crizotinib, 0.20; 95% CI: 0.11-0.36; P benefit of first-line crizotinib versus first-line standard chemotherapy in Chinese patients with ALK-positive lung adenocarcinoma. Additionally, crizotinib showed promising efficacy in patients who received it as second-line therapy after PD had occurred on first-line chemotherapy. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Training options for countering nuclear smuggling

International Nuclear Information System (INIS)

Ball, D Y; Erickson, S A

1999-01-01

The burden of stopping a nuclear smuggling attempt at the border rests most heavily on the front-line customs inspector. He needs to know how to use the technological tools at his disposal, how to discern tell-tale anomalies in export documents and manifests, how to notice psychological signs of a smuggler's tension, and how to search anything that might hide nuclear material. This means that assistance in the counter-nuclear smuggling training of customs officers is one of the most critical areas of help that the United States can provide. This paper discusses the various modes of specialized training, both in the field and in courses, as well as the types of assistance that can be provided. Training for nuclear customs specialists, and supervisors and managers of nuclear smuggling detection systems is also important, and differs from front-line inspector training in several aspects. The limitations of training and technological tools such as expert centers that will overcome these limitations are also discussed. Training assistance planned by DOE/NN-43 to Russia within the Second Line of Defense program is discussed in the light of these options, and future possibilities for such training are projected

Second Line of Defense Virtual Private Network Guidance for Deployed and New CAS Systems

Energy Technology Data Exchange (ETDEWEB)

Singh, Surya V.; Thronas, Aaron I.

2010-01-01

This paper discusses the importance of remote access via virtual private network (VPN) for the Second Line of Defense (SLD) Central Alarm System (CAS) sites, the requirements for maintaining secure channels while using VPN and implementation requirements for current and future sites.

Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes

NARCIS (Netherlands)

Falzon, Dennis; Gandhi, Neel; Migliori, Giovanni B.; Sotgiu, Giovanni; Cox, Helen S.; Holtz, Timothy H.; Hollm-Delgado, Maria-Graciela; Keshavjee, Salmaan; Deriemer, Kathryn; Centis, Rosella; D'Ambrosio, Lia; Lange, Christoph G.; Bauer, Melissa; Menzies, Dick; Ahuja, S. D.; Ashkin, D.; Avendaño, M.; Banerjee, R.; Bauer, M.; Becerra, M. C.; Benedetti, A.; Burgos, M.; Centis, R.; Chan, E. D.; Chiang, C. Y.; Cobelens, F.; Cox, H.; D'Ambrosio, L.; de Lange, W. C. M.; DeRiemer, K.; Enarson, D.; Falzon, D.; Flanagan, K. L.; Flood, J.; Gandhi, N.; Garcia-Garcia, M. L.; Granich, R. M.; Hollm-Delgado, M. G.; Holtz, T. H.; Hopewell, P.; Iseman, M. D.; Jarlsberg, L. G.; Keshavjee, S.; Kim, H. R.; Koh, W. J.; Lancaster, J. L.; Lange, C.; Leimane, V.; Leung, C. C.; Li, J.

2013-01-01

A meta-analysis for response to treatment was undertaken using individual data of multidrug-resistant tuberculosis (MDR-TB) (resistance to isoniazid and rifampicin) patients from 26 centres. The analysis assessed the impact of additional resistance to fluoroquinolones and/or second-line injectable

Therapeutic options for chronic myeloid leukemia: focus on imatinib (Glivec®, Gleevec™

Directory of Open Access Journals (Sweden)

Martin Henkes

2008-03-01

Full Text Available 1Martin Henkes, 2Heiko van der Kuip, 1Walter E Aulitzky12nd Department of Internal Medicine, Oncology and Hematology, Robert Bosch Hospital, Auerbachstr. 110, Stuttgart, Germany; 2Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, Stuttgart, and University of Tuebingen, GermanyAbstract: Treatment options for chronic myeloid leukemia (CML have changed dramatically during the last decades. Interferon-α treatment and stem cell transplantation (SCT clearly improved survival over conventional chemotherapy and offered the possibility of complete and durable responses. With the advent of the small molecule inhibitor imatinib mesylate (Glivec®, GleevecTM targeting the causative Bcr-Abl oncoprotein, the era of molecular cancer therapy began with remarkable success especially in chronic phase patients. Today, imatinib is the first-line treatment for CML. However, imatinib does not appear to be capable to eliminate all leukemia cells in the patients and pre-existing as well as acquired resistance to the drug has been increasingly recognized. To overcome these problems, several strategies involving dose escalation, combinations with other agents, and novel Bcr-Abl inhibitors have been developed.Keywords: CML therapy, imatinib, SCT, novel kinase inhibitors

Evaluation of MGIT 960 System for the Second-Line Drugs Susceptibility Testing of Mycobacterium tuberculosis

Directory of Open Access Journals (Sweden)

Hyejin Kim

2013-01-01

Full Text Available Many laboratories validate DST of the second-line drugs by BACTEC MGIT 960 system. The objective of this study is to evaluate the critical concentration and perform DST for the 2nd line drugs. We evaluated 193 clinical strains of M. tuberculosis isolated from patients in South Korea. Testing the critical concentration of six second-line drugs was performed by MGIT 960 and compared with L-J proportion method. The critical concentration was determined to establish the most one that gave the difference between drug resistance and susceptibility in MGIT960 system. Good agreement of the following concentrations was found: Concordance was 95% for 0.5 μg/mL of moxifloxacin; 93.6%, 1.0 μg/mL of levofloxacin; 97.5%, 2.5 μg/mL of kanamycin; 90.6%, 2.5 μg/mL of capreomycin; 86.2%, 5.0 μg/mL of ethionamide; and 90.8%, 2.0 μg/mL of ρ-aminosalicylic acid. The critical concentrations of the four drugs, moxifloxacin, levofloxacin, kanamycin, and capreomycin, were concordant and reliable for testing 2nd line drug resistance. Further study of ethionamide and ρ-aminosalicylic acid is required.

24 CFR 206.26 - Change in payment option.

Science.gov (United States)

2010-04-01

... 24 Housing and Urban Development 2 2010-04-01 2010-04-01 false Change in payment option. 206.26... in payment option. (a) General. The payment option may be changed as provided in this section. (b... credit payment option. Until the repairs are completed, the mortgagee shall make no line of credit...

Perceived adherence barriers among patients failing second-line antiretroviral therapy in Khayelitsha, South Africa

Directory of Open Access Journals (Sweden)

W Barnett

2013-11-01

Full Text Available Background. The recent scale-up of antiretroviral therapy (ART coverage in resource-limited settings has greatly improved access to treatment. However, increasing numbers of patients are failing first- and second-line ART. Objective. To examine factors affecting adherence to second-line ART from the perspective of clinic staff and patients, assessing both individual and structural perceived barriers. Methods. Research was conducted at a large primary care tuberculosis (TB/HIV clinic in Khayelitsha, a peri-urban township in Cape Town, South Africa. Participants were drawn from a Médecins Sans Frontières-run programme to support patients failing second-line ART. A qualitative research approach was used, combining multiple methodologies including key informant interviews with staff (n=11, in-depth interviews with patients (n=10 and a Photovoice workshop (n=11. Responses and photographs were coded by content; data were transformed into variables and analysed accordingly. Results. Staff identified drinking, non-disclosure, not using condoms and pill fatigue as barriers to ART adherence, while patients identified side-effects, not using condoms and a lack of understanding concerning medication timing. With respect to service delivery, staff identified a need for continued counselling and educational support following ART initiation. Patients were concerned about missing medical records and poor staff attitudes in the clinic. Conclusion. These findings identify discrepancies between provider and patient perceptions of barriers to, and facilitators of adherence, as well as of service delivery solutions. This highlights the need for on-going counselling and education following ART initiation, improved quality of counselling, and improved methods to identify and address specific barriers concerning medication adherence.

Therapeutic options to treat sulfur mustard poisoning--the road ahead.

Science.gov (United States)

Smith, William J

2009-09-01

For the past 15 years the international research community has conducted a basic and applied research program aimed at identifying a medical countermeasure against chemical threat vesicant, or blistering, agents. The primary emphasis of this program has been the development of therapeutic protection against sulfur mustard and its cutaneous pathology-blister formation. In addition to the work on a medical countermeasures, significant research has been conducted on the development of topical skin protectants and medical strategies for wound healing. This review will focus on the pharmacological strategies investigated, novel therapeutic targets currently under investigation and therapeutic approaches being considered for transition to advanced development. Additionally, we will review the expansion of our understanding of the pathophysiological mechanisms of mustard injury that has come from this research. While great strides have been made through these investigations, the complexity of the mustard insult demands that further studies extend the inroads made and point the way toward better understanding of cellular and tissue disruptions caused by sulfur mustard.

Congenitally missing mandibular second premolars: clinical options.

Science.gov (United States)

Kokich, Vincent G; Kokich, Vincent O

2006-10-01

Congenital absence of mandibular second premolars affects many orthodontic patients. The orthodontist must make the proper decision at the appropriate time regarding management of the edentulous space. These spaces can be closed or left open. If the space will be left open for an eventual restoration, the keys during orthodontic treatment are to create the correct amount of space and to leave the alveolar ridge in an ideal condition for a future restoration. If the space will be closed, the clinician must avoid any detrimental alterations to the occlusion and the facial profile. Some early decisions that the orthodontist makes for a patient whose mandibular second premolars are congenitally missing will affect his or her dental health for a lifetime. Therefore, the correct decision must be made at the appropriate time. In this article, we present and discuss various treatment alternatives for managing orthodontic patients with at least 1 congenitally missing mandibular second premolar.

A Phase II Study of Weekly Docetaxel as Second-Line Chemotherapy in Patients With Metastatic Urothelial Carcinoma.

Science.gov (United States)

Kim, Young Saing; Lee, Soon Il; Park, Se Hoon; Park, Silvia; Hwang, In Gyu; Lee, Sang-Cheol; Sun, Jong-Mu; Lee, Jeeyun; Lim, Ho Yeong

2016-02-01

The present multicenter phase II study evaluated the efficacy and safety of weekly docetaxel as second-line chemotherapy for metastatic urothelial carcinoma. Weekly docetaxel was well tolerated but demonstrated modest activity, with a response rate of 6%, a median progression-free survival (PFS) of 1.4 months, and a median overall survival (OS) of 8.3 months. The dichotomy between PFS and OS was likely associated with subsequent platinum-based chemotherapy received by 58% of the patients. Docetaxel is commonly used for second-line therapy for metastatic urothelial carcinoma (UC). However, myelosuppression is a substantial concern when the traditional 3-week docetaxel cycle is used. The present multicenter phase II study evaluated the efficacy and safety of weekly docetaxel as second-line chemotherapy for metastatic UC. Patients with progression after previous platinum-based chemotherapy for advanced or metastatic disease were treated with docetaxel 30 mg/m(2) on days 1 and 8 every 21 days. The primary endpoint was the response rate. The study enrolled 31 patients. Their median age was 64 years (range, 40-79 years). An Eastern Cooperative Oncology Group performance status of 1, liver metastasis, and a hemoglobin level chemotherapy had been administered for metastatic disease in 29 patients (94%). Although fatigue (13%) and anorexia (6%) were the most frequently observed grade 3 to 4 toxicities, the safety profiles were generally mild and manageable. Two patients (6%) achieved an objective response, which was maintained for 3.0 to 7.8 months. Eight patients experienced disease stabilization (disease control rate, 32%). The median progression-free survival (PFS) and overall survival (OS) were 1.4 months (95% confidence interval [CI], 1.3-1.6) and 8.3 months (95% CI, 5.9-10.6), respectively. A relatively long OS was associated with further salvage platinum-based chemotherapy (n = 18, 58%) showing an encouraging activity (response rate, 44%; median PFS, 4.0 months

Therapeutic hypothermia for acute stroke

DEFF Research Database (Denmark)

Olsen, Tom Skyhøj; Weber, Uno Jakob; Kammersgaard, Lars Peter

2003-01-01

Experimental evidence and clinical experience show that hypothermia protects the brain from damage during ischaemia. There is a growing hope that the prevention of fever in stroke will improve outcome and that hypothermia may be a therapeutic option for the treatment of stroke. Body temperature...... obvious therapeutic potential, hypothermia as a form of neuroprotection for stroke has been investigated in only a few very small studies. Therapeutic hypothermia is feasible in acute stroke but owing to serious side-effects--such as hypotension, cardiac arrhythmia, and pneumonia--it is still thought...

Evolving paradigms in clinical pharmacology and therapeutics for the treatment of Duchenne muscular dystrophy.

Science.gov (United States)

Huard, J; Mu, X; Lu, A

2016-08-01

Progressive muscle weakness and degeneration due to the lack of dystrophin eventually leads to the loss of independent ambulation by the middle of the patient's second decade, and a fatal outcome due to cardiac or respiratory failure by the third decade. More specifically, loss of sarcolemmal dystrophin and the dystrophin-associated glycoprotein (DAG) complex promotes muscle fiber damage during muscle contraction. This process results in an efflux of creatine kinase (CK), an influx of calcium ions, and the recruitment of T cells, macrophages, and mast cells to the damaged muscle, causing progressive myofiber necrosis. For the last 20 years, the major goal in the development of therapeutic approaches to alleviate muscle weakness in DMD has been centered on the restoration of dystrophin or proteins that are analogous to dystrophin, such as utrophin, through a variety of modalities including cell therapy, gene therapy, gene correction, and the highly promising techniques utilizing CRISPR/Cas9 technology. Despite the development of new therapeutic options, there still exist numerous challenges that we must face with regard to these new strategies and, consequently, we still do not have any feasible options available to ultimately slow the progression of this devastating disease. The purpose of this article is to highlight the current knowledge and advancements in the evolving paradigms in clinical pharmacology and therapeutics for this devastating musculoskeletal disease. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Astroglial networks and implications for therapeutic neuromodulation of epilepsy.

Science.gov (United States)

Witcher, Mark R; Ellis, Thomas L

2012-01-01

Epilepsy is a common chronic neurologic disorder affecting approximately 1% of the world population. More than one-third of all epilepsy patients have incompletely controlled seizures or debilitating medication side effects in spite of optimal medical management. Medically refractory epilepsy is associated with excess injury and mortality, psychosocial dysfunction, and significant cognitive impairment. Effective treatment options for these patients can be limited. The cellular mechanisms underlying seizure activity are incompletely understood, though we here describe multiple lines of evidence supporting the likely contribution of astroglia to epilepsy, with focus on individual astrocytes and their network functions. Of the emerging therapeutic modalities for epilepsy, one of the most intriguing is the field of neuromodulation. Neuromodulatory treatment, which consists of administering electrical pulses to neural tissue to modulate its activity leading to a beneficial effect, may be an option for these patients. Current modalities consist of vagal nerve stimulation, open and closed-loop stimulation, and transcranial magnetic stimulation. Due to their unique properties, we here present astrocytes as likely important targets for the developing field of neuromodulation in the treatment of epilepsy.

Refractory pulmonary sarcoidosis - proposal of a definition and recommendations for the diagnostic and therapeutic approach.

Science.gov (United States)

Korsten, Peter; Strohmayer, Katharina; Baughman, Robert P; Sweiss, Nadera J

2016-03-01

Patients with sarcoidosis undergo spontaneous remission or may be effectively controlled with glucocorticoids alone in many cases. Progressive and refractory pulmonary sarcoidoisis constitute more than 10% of patients seen at specialized centers. Pulmonary fibrosis and associated complications, such as infections and pulmonary hypertension are leading causes of mortality. No universal definition of refractoriness exists, we therefore propose classifying patients as having refractory disease when the following criteria are fulfilled: (1) progressive disease despite at least 10 mg of prednisolone or equivalent for at least three months and need for additional disease-modifying anti-sarcoid drugs due to lack of efficacy, drug toxicity or intolerability and (2) treatment started for significant impairment of life due to progressive pulmonary symptoms. Both criteria should be fulfilled. Treatment options in addition to or instead of glucocorticoids for these patients include second- (methotrexate, azathioprine, leflunomide) and third-line agents (infliximab, adalimumab). Other immunmodulating agents can be used, but the evidence is very limited. Newer agents with anti-fibrotic properties, such as pirfenidone or nintedanib, might hold promise also for the pulmonary fibrosis seen in sarcoidosis. Treating physicians have to actively look for potentially treatable complications, such as pulmonary hypertension, cardiac disease or infections before patients should be classified as treatment-refractory. Ultimately, lung transplantation has to be considered as treatment option for patients not responding to medical therapy. In this review, we aim to propose a new definition of refractoriness, describe the associated clinical features and suggest the therapeutic approach.

A Bayesian network meta-analysis on second-line systemic therapy in advanced gastric cancer.

Science.gov (United States)

Zhu, Xiaofu; Ko, Yoo-Joung; Berry, Scott; Shah, Keya; Lee, Esther; Chan, Kelvin

2017-07-01

It is unclear which regimen is the most efficacious among the available therapies for advanced gastric cancer in the second-line setting. We performed a network meta-analysis to determine their relative benefits. We conducted a systematic review of randomized controlled trials (RCTs) through the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases and American Society of Clinical Oncology abstracts up to June 2014 to identify phase III RCTs on advanced gastric cancer in the second-line setting. Overall survival (OS) data were the primary outcome of interest. Hazard ratios (HRs) were extracted from the publications on the basis of reported values or were extracted from survival curves by established methods. A Bayesian network meta-analysis was performed with WinBUGS to compare all regimens simultaneously. Eight RCTs (2439 patients) were identified and contained extractable data for quantitative analysis. Network meta-analysis showed that paclitaxel plus ramucirumab was superior to single-agent ramucirumab [OS HR 0.51, 95 % credible region (CR) 0.30-0.86], paclitaxel (OS HR 0.81, 95 % CR 0.68-0.96), docetaxel (OS HR 0.56, 95 % CR 0.33-0.94), and irinotecan (OS HR 0.71, 95 % CR 0.52-0.99). Paclitaxel plus ramucirumab also had an 89 % probability of being the best regimen among all these regimens. Single-agent ramucirumab, paclitaxel, docetaxel, and irinotecan were comparable to each other with respect to OS and were superior to best supportive care. This is the first network meta-analysis to compare all second-line regimens reported in phase III gastric cancer trials. The results suggest the paclitaxel plus ramucirumab combination is the most effective therapy and should be the reference regimen for future comparative trials.

CK1δ in lymphoma: gene expression and mutation analyses and validation of CK1δ kinase activity for therapeutic application

Directory of Open Access Journals (Sweden)

Brigitte Sophia Winkler

2015-02-01

Full Text Available The prognosis of lymphoid neoplasms has improved considerably during the last decades. However, treatment response for some lymphoid neoplasms is still poor, indicating the need for new therapeutic approaches. One promising new strategy is the inhibition of kinases regulating key signal transduction pathways, which are of central importance in tumorigenesis. Kinases of the CK1 family may represent an attractive drug target since CK1 expression and/or activity are associated with the pathogenesis of malignant diseases. Over the last years efforts were taken to develop highly potent and selective CK1-specific inhibitor compounds and their therapeutic potential has now to be proved in pre-clinical trials. Therefore, we analyzed expression and mutational status of CK1δ in several cell lines representing established lymphoma entities, and also measured the mRNA expression level in primary lymphoma tissue as well as non-neoplastic blood cells. For a selection of lymphoma cell lines we furthermore determined CK1δ kinase activity and demonstrated therapeutic potential of CK1-specific inhibitors as a putative therapeutic option in the treatment of lymphoid neoplasms.

Nelson Syndrome: Update on Therapeutic Approaches.

Science.gov (United States)

Azad, Tej D; Veeravagu, Anand; Kumar, Sunny; Katznelson, Laurence

2015-06-01

To review the pathophysiology and therapeutic modalities availble for Nelson syndrome. We reviewed the current literature including managment for Nelson syndrome. For patients with NS, surgical intervention is often the first-line therapy. With refractory NS or tumors with extrasellar involvement, radiosurgery offers an important alternative or adjuvant option. Pharmacologic interventions have demonstrated limited usefulness, although recent evidence supports the feasibility of a novel somatostatin analog for patients with NS. Modern neuroimaging, improved surgical techniques, and the advent of stereotactic radiotherapy have transformed the management of NS. An up-to-date understanding of the pathophysiology underlying Nelson Syndrome and evidence-based management is imperative. Early detection may allow for more successful therapy in patients with Nelson Syndrome. Improved radiotherapeutic interventions and rapidly evolving pharmacologic therapies offer an opportunity to create targeted, multifocal treatment regiments for patients with Nelson Syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.

Political Status of Puerto Rico: Options for Congress

Science.gov (United States)

2010-05-19

basis would voters select the status quo option during the second plebiscite? Second, could the inclusion of the commonwealth option on the second...Values and Institutions (Cambridge, Harvard University Press, 1969), p. 262. C. Arthur Borg, “The Problem of Puerto Rico’s Political Status, Revista ...University Press of Kansas, 1975), p. 185.] See also Roberta A. Johnson, “The 1967 Puerto Rican Plebiscite: The People Decide,” Revista /Review

Current treatment options for vulvovaginal candidiasis caused by azole-resistant Candida species.

Science.gov (United States)

Sobel, J D; Sobel, R

2018-06-22

Clinicians are increasingly challenged by patients with refractory vulvovaginal candidiasis (VVC) caused by azole-resistant Candida species. Fluconazole resistant C.albicans is a growing and perplexing problem following years of indiscriminate drug prescription and unnecessary drug exposure and for which there are few therapeutic alternatives. Regrettably, although the azole class of drugs has expanded, new classes of antifungal drugs have not been forthcoming, limiting effective treatment options in patients with azole resistant Candida vaginitis. Areas covered: This review covers published data on epidemiology, pathophysiology and treatment options for women with azole-resistant refractory VVC. Expert opinion: Fluconazole resistant C.albicans adds to the challenge of azole resistant non-albicans Candida spp. Both issues follow years of indiscriminate drug prescription and unnecessary fluconazole exposure. Although an understanding of azole resistance in yeast has been established, this knowledge has not translated into useful therapeutic advantage. Treatment options for such women with refractory symptoms are extremely limited. New therapeutic options and strategies are urgently needed to meet this challenge of azole drug resistance.

THERAPEUTIC OPTIONS FOR BREAST CANCER

Directory of Open Access Journals (Sweden)

Milena Georgescu

2011-12-01

Full Text Available Breast cancer remains a major public health problem, being the second cause of cancer death in women. There is a marked tendency to restrict the extension of surgical gesture, which directly leads to two different attitudes: radical surgery and conservative surgery, to which, at least in our country, there are still some delays. Prospective and retrospective studies have shown that, in 20 years, conservative and radical therapy had about the same rate of survival and disease-free interval, at least for stage I and II breast cancer, the only real counterargument against conservative surgery being that, in principle, the higher rate of recurrence local constraint can be solved by postoperative radiotherapy. Finally, the survival rate is the main parameter of evaluation, assessing the effectiveness of the treatment in breast cancer, and in all its other forms.

Characterization of HIV-1 antiretroviral drug resistance after second-line treatment failure in Mali, a limited-resources setting

Science.gov (United States)

Maiga, Almoustapha Issiaka; Fofana, Djeneba Bocar; Cisse, Mamadou; Diallo, Fodié; Maiga, Moussa Youssoufa; Traore, Hamar Alassane; Maiga, Issouf Alassane; Sylla, Aliou; Fofana, Dionke; Taiwo, Babafemi; Murphy, Robert; Katlama, Christine; Tounkara, Anatole; Calvez, Vincent; Marcelin, Anne-Geneviève

2012-01-01

Objectives We describe the outcomes of second-line drug resistance profiles and predict the efficacy of drugs for third-line therapy in patients monitored without the benefit of plasma HIV-1 RNA viral load (VL) or resistance testing. Methods We recruited 106 HIV-1-infected patients after second-line treatment failure in Mali. VL was determined by the Abbott RealTime system and the resistance by the ViroSeq HIV-1 genotyping system. The resistance testing was interpreted using the latest version of the Stanford algorithm. Results Among the 106 patients, 93 had isolates successfully sequenced. The median age, VL and CD4 cells were respectively 35 years, 72 000 copies/mL and 146 cells/mm3. Patients were exposed to a median of 4 years of treatment and to six antiretrovirals. We found 20% of wild-type viruses. Resistance to etravirine was noted in 38%, to lopinavir in 25% and to darunavir in 12%. The duration of prior nucleos(t)ide reverse transcriptase inhibitor exposure was associated with resistance to abacavir (P < 0.0001) and tenofovir (P = 0.0001), and duration of prior protease inhibitor treatment with resistance to lopinavir (P < 0.0001) and darunavir (P = 0.06). Conclusion Long duration of therapy prior to failure was associated with high levels of resistance and is directly related to limited access to VL monitoring and delayed switches to second-line treatment, precluding efficacy of drugs for third-line therapy. This study underlines the need for governments and public health organizations to recommend the use of VL monitoring and also the availability of darunavir and raltegravir for third-line therapies in the context of limited-resource settings. PMID:22888273

The state-of-play and future of antibody therapeutics.

Science.gov (United States)

Elgundi, Zehra; Reslan, Mouhamad; Cruz, Esteban; Sifniotis, Vicki; Kayser, Veysel

2017-12-01

It has been over four decades since the development of monoclonal antibodies (mAbs) using a hybridoma cell line was first reported. Since then more than thirty therapeutic antibodies have been marketed, mostly as oncology, autoimmune and inflammatory therapeutics. While antibodies are very efficient, their cost-effectiveness has always been discussed owing to their high costs, accumulating to more than one billion dollars from preclinical development through to market approval. Because of this, therapeutic antibodies are inaccessible to some patients in both developed and developing countries. The growing interest in biosimilar antibodies as affordable versions of therapeutic antibodies may provide alternative treatment options as well potentially decreasing costs. As certain markets begin to capitalize on this opportunity, regulatory authorities continue to refine the requirements for demonstrating quality, efficacy and safety of biosimilar compared to originator products. In addition to biosimilars, innovations in antibody engineering are providing the opportunity to design biobetter antibodies with improved properties to maximize efficacy. Enhancing effector function, antibody drug conjugates (ADC) or targeting multiple disease pathways via multi-specific antibodies are being explored. The manufacturing process of antibodies is also moving forward with advancements relating to host cell production and purification processes. Studies into the physical and chemical degradation pathways of antibodies are contributing to the design of more stable proteins guided by computational tools. Moreover, the delivery and pharmacokinetics of antibody-based therapeutics are improving as optimized formulations are pursued through the implementation of recent innovations in the field. Copyright © 2016 Elsevier B.V. All rights reserved.

Phase II study of biweekly cetuximab in combination with irinotecan as second-line treatment in patients with platinum-resistant gastro-oesophageal cancer

DEFF Research Database (Denmark)

Schønnemann, K R; Yilmaz, Mette Karen; Bjerregaard, J K

2012-01-01

The purpose of this phase II trial was to evaluate the efficacy and safety of cetuximab and irinotecan as second-line treatment in patients with gastro-oesophageal adenocarcinoma.......The purpose of this phase II trial was to evaluate the efficacy and safety of cetuximab and irinotecan as second-line treatment in patients with gastro-oesophageal adenocarcinoma....

Operative shortening of the sling as a second-line treatment after TVT failure

Science.gov (United States)

Matuszewski, Marcin; Michajłowski, Jerzy; Krajka, Kazimierz

2011-01-01

Introduction Stress urinary incontinence (SUI) is defined as an involuntary loss of urine during physical exertion, sneezing, coughing, laughing, or other activities that put pressure on the bladder. In some cases, recurrent or persistent SUI after sling operations may be caused by too loose placement of the sling. In the current study, we describe our method of shortening of the sling as a second-line treatment of tension-free vaginal tape (TVT) failure. Materials and methods Four women, aged 46-61, after initial TVT operation were treated for persistent SUI. The severity of SUI was estimated by: physical examinations, cough tests, 24-h pad tests, and King's Health Questionnaire. The shortening procedure, based on excising the fragment of tape and suturing it back, was performed in all patients. Results All cases achieved a good result, which was defined as restoration of full continence. No complications occurred. The 12-month follow-up showed no side-effects. The postoperative control tests: the cough and 24-h pad tests were negative in all women. The general health perceptions increased after the shortening procedure by a mean value 44.25%. The incontinence impact decreased by a mean value 44.6%. In all patients, role and physical limitations significantly decreased (by 88.5% and 80.5%, respectively). The negative emotions connected with SUI significantly decreased after the second procedure. Conclusions The operative shortening of the implanted sling is a simple, cheap, and effective method of second-line treatment in cases of TVT failure and may be offered to the majority of patients with insufficient urethral support after the first procedure. PMID:24578885

[Comparison of the Efficacy and Safety of Icotinib with Standard Second-line 
Chemotherapy in Previously Treated Advanced Non-small Cell Lung Cancer].

Science.gov (United States)

Yao, Shuyang; Qian, Kun; Wang, Ruotian; Li, Yuanbo; Zhang, Yi

2015-06-01

This study compared the efficacy and safety of icotinib with standard second-line chemotherapy (single-agent docetaxel or pemetrexed) in previously treated advanced non-small cell lung cancer (NSCLC). Thirty-two consecutive patients treated with icotinib and 33 consecutive patients treated with standard second-line chemotherapy in Xuanwu Hospital from January 2012 to July 2013 were enrolled in our retrospective research. The Response Evaluation Criteria in Solid Tumors were used to evaluate the tumor responses, and the progression-free survival (PFS) was evaluated by Kaplan-Meier method. Icotinib was comparable with standard second-line chemotherapy for advanced NSCLC in terms of overall response rate (ORR) (28.1% vs 18.2%, P=0.341), disease control rate (DFS)(43.8% vs 45.5%, P=0.890), and PFS (4.3 months vs 3.8 months, P=0.506). In the icotinib group, the ORR of epidermal growth factor receptor (EGFR) mutant was significantly higher than that of EGFR unknown or wild type (P=0.017). In multivariate analysis, age, gender, histology, and the optimum first-line treatment response were dependent prognostic factors based on the PFS of the icotinib group. The incidence of adverse events was significantly fewer in the icotinib group than in the chemotherapy group (P=0.001). Compared with the standard second-line chemotherapy, icotinib is active in the treatment of advanced NSCLC patients, especially with EGFR unknown in the second line, with an acceptable adverse event profile.

Arms Control and nonproliferation technologies: Technology options and associated measures for monitoring a Comprehensive Test Ban, Second quarter

Energy Technology Data Exchange (ETDEWEB)

Casey, Leslie A.

1994-01-01

This newsletter contains reprinted papers discussing technology options and associated measures for monitoring a Comprehensive Test Ban Treaty (CTBT). These papers were presented to the Conference on Disarmament (CD) in May and June 1994. An interagency Verification Monitoring Task Force developed the papers. The task force included participants from the Arms Control and Disarmament Agency, the Department of Defense, the Department of Energy, the Intelligence Community, the Department of Interior, and the Department of State. The purpose of this edition of Arms Control and Nonproliferation Technologies is to share these papers with the broad base of stakeholders in a CTBT and to facilitate future technology discussions. The papers in the first group discuss possible technology options for monitoring a CTBT in all environments (underground, underwater, atmosphere, and space). These technologies, along with on-site inspections, would facilitate CTBT monitoring by treaty participants. The papers in the second group present possible associated measures, e.g., information exchanges and transparency measures, that would build confidence among states participating in a CTBT.

Tadalafil - a therapeutic option in the management of BPH-LUTS.

Science.gov (United States)

Carson, C C; Rosenberg, M; Kissel, J; Wong, D G

2014-01-01

Men with signs of benign prostatic hyperplasia (BPH) may experience lower urinary tract symptoms (LUTS) such as urinary frequency, urgency, intermittence, nocturia, straining, incomplete emptying or a weak urinary stream. The effective management of LUTS suggestive of BPH (BPH-LUTS) requires careful consideration of several factors, including the severity of a patient's symptoms, concurrent or other coexisting medical conditions, the ability to improve symptoms and impact quality of life (QOL), as well as the potential side effects of available treatment options. Several clinical studies have assessed phosphodiesterase type 5 (PDE5) inhibitors in reducing LUTS; however, tadalafil is the only PDE5 inhibitor approved for the treatment of signs and symptoms of BPH, as well as in men with both erectile dysfunction (ED) and the signs and symptoms of BPH. This review examined articles that assessed tadalafil in patients with signs and symptoms of BPH, with or without erectile dysfunction (ED), which led to regulatory approval in the United States and Europe. In dose-ranging and confirmatory studies, results demonstrate that tadalafil significantly improved total International Prostate Symptom Score (IPSS) following 12 weeks of treatment with once daily tadalafil 5 mg. Statistically significant improvements in Benign Prostatic Hyperplasia Impact Index (BII), IPSS subscores, IPSS QOL and International Index of Erectile Function (IIEF) were also observed. Improvement in urinary symptoms occurred regardless of age, previous treatment with an α1 -adrenergic blocker, BPH-LUTS severity at baseline or ED status. While tadalafil is most frequently recognised as a standard treatment option for men with ED, it also represents a well-tolerated and effective treatment option in men with moderate to severe BPH-LUTS. © 2013 John Wiley & Sons Ltd.

Therapeutic Options in Idiopathic Burning Mouth Syndrome: Literature Review

OpenAIRE

Miziara, Ivan; Chagury, Azis; Vargas, Camila; Freitas, Ludmila; Mahmoud, Ali

2014-01-01

Introduction Burning mouth syndrome (BMS) is characterized by a burning sensation in the tongue, palate, lips, or gums of no well-defined etiology. The diagnosis and treatment for primary BMS are controversial. No specific laboratory tests or diagnostic criteria are well established, and the diagnosis is made by excluding all other possible disorders.Objective To review the literature on the main treatment options in idiopathic BMS and compare the best results of the main studies in 15 years....

Radiation induced expression of survivin in Ewing sarcoma cell-lines

International Nuclear Information System (INIS)

Sheikh-Mounessi, F.; Willich, N.; Greve, B.

2009-01-01

Full text: Introduction: Survivin belongs to the Inhibitor of Apoptosis Protein Family (IAP), is a protein of 16.5 kD and active as a homodimer. It is overexpressed in nearly all human tumors and has a vital function in cell division and apoptotic processes. Beside its role as a relevant prognostic and predictive factor it was described to be a molecular target to improve effectiveness of radiotherapy. We investigated the radiation induced survivin expression in Ewing sarcoma cell-lines. Methods: Ewing sarcoma cells were either irradiated with 10 Gy X-ray and harvested at different time points (0, 2, 4, 6, 10 and 24 h) or irradiated with different doses (0, 2, 5 and 10 Gy) and harvested 24 h later. Protein and mRNA expression was analysed by Westernblot or Real-Time PCR. Results: Directly after irradiation with 10 Gy X-ray survivin mRNA expression was increased in relation to the reference GAPDH. Protein expression was increased in a time dependent manner and reached a maximum after 24h. Three of four investigated cell-lines showed a significant dose dependent increase of survivin protein concentration 24h after irradiation. The same three cell-lines showed a LD50 of >30 Gy. The line with the lowest dose dependent survivin induction was investigated to be most radiosensitive (LD50 = 24 Gy). Discussion: Ewing sarcoma is a childhood tumor with relatively poor prognosis. This tumor often shows significant therapeutic resistance to chemo- and/or radiotherapy. It would be of high interest to find new therapeutic approaches for its treatment. We found a remarkable overexpression of survivin in untreated Ewing sarcoma and a time and dose dependent increase of survivin protein concentration after irradiation with X-ray. The cell-line with the lowest survivin induction showed the highest radiosensitivity. In conclusion, our results show that survivin is an inducible radioresistance factor in Ewing sarcoma. This may open new therapeutic options to treat this aggressive

Comparison of the Efficacy and Safety of Icotinib with Standard Second-line 
Chemotherapy in Previously Treated Advanced Non-small Cell Lung Cancer

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Shuyang YAO

2015-06-01

Full Text Available Background and objective This study compared the efficacy and safety of icotinib with standard second-line chemotherapy (single-agent docetaxel or pemetrexed in previously treated advanced non-small cell lung cancer (NSCLC. Methods Thirty-two consecutive patients treated with icotinib and 33 consecutive patients treated with standard second-line chemotherapy in Xuanwu Hospital from January 2012 to July 2013 were enrolled in our retrospective research. The Response Evaluation Criteria in Solid Tumors were used to evaluate the tumor responses, and the progression-free survival (PFS was evaluated by Kaplan-Meier method. Results Icotinib was comparable with standard second-line chemotherapy for advanced NSCLC in terms of overall response rate (ORR (28.1% vs 18.2%, P=0.341, disease control rate (DFS(43.8% vs 45.5%, P=0.890, and PFS (4.3 months vs 3.8 months, P=0.506. In the icotinib group, the ORR of epidermal growth factor receptor (EGFR mutant was significantly higher than that of EGFR unknown or wild type (P=0.017. In multivariate analysis, age, gender, histology, and the optimum first-line treatment response were dependent prognostic factors based on the PFS of the icotinib group. The incidence of adverse events was significantly fewer in the icotinib group than in the chemotherapy group (P=0.001. Conclusion Compared with the standard second-line chemotherapy, icotinib is active in the treatment of advanced NSCLC patients, especially with EGFR unknown in the second line, with an acceptable adverse event profile.

Translational nanomedicine--through the therapeutic window.

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Pierce, Robin L

2015-01-01

Translational nanomedicine occurs only through the successful integration of multiple inputs and iterative modifications. The therapeutic window plays a pivotal role in the trajectory of translational nanomedicine. Often defined in terms of the range of dosage for safe and effective therapeutic effect, a second definition of the therapeutic window refers to the often narrow temporal window in which a therapeutic effect can be obtained. Expanding the second definition to explicitly include the spatial dimension, this article explores aspects of the therapeutic spaces created by nanomedicine that shift the traditional dimensions of symptom, sign and pathology. This article analyzes three aspects of the therapeutic window in nanomedicine - temporal, spatial and manner of construction and their impact on the dimensions of modern medicine.

Continued efficacy of sulfadoxine-pyrimethamine as second line treatment for malaria in children in Guinea-Bissau

DEFF Research Database (Denmark)

Kofoed, Poul-Erik; Rodrigues, Amabelia; Aaby, Peter

2006-01-01

BACKGROUND: Sulfadoxine-pyrimethamine (S/P) is widely used for treatment of failures following the first line treatment for malaria in Africa. In Guinea-Bissau, it has been recommended as second line therapy by the National Malaria Programme since 1996. In order to monitor any change of the in vivo...... sensitivity, the efficacy of S/P was studied immediately before the introduction of the drug and 6-9 years later. METHODS: Children participating in clinical in vivo studies were given S/P if having late clinical treatment failure following the treatment with quinine, chloroquine, or amodiaquine...

Metastatic non-small-cell lung cancer: consensus on pathology and molecular tests, first-line, second-line, and third-line therapy: 1st ESMO Consensus Conference in Lung Cancer; Lugano 2010

DEFF Research Database (Denmark)

Felip, E; Gridelli, C; Baas, P

2011-01-01

the conference, the expert panel prepared clinically relevant questions concerning five areas: early and locally advanced non-small-cell lung cancer (NSCLC), first-line metastatic NSCLC, second-/third-line NSCLC, NSCLC pathology and molecular testing, and small-cell lung cancer to be addressed through discussion......The 1st ESMO Consensus Conference on lung cancer was held in Lugano, Switzerland on 21 and 22 May 2010 with the participation of a multidisciplinary panel of leading professionals in pathology and molecular diagnostics, medical oncology, surgical oncology and radiation oncology. Before...... at the Consensus Conference. All relevant scientific literature for each question was reviewed in advance. During the Consensus Conference, the panel developed recommendations for each specific question. The consensus agreement on three of these areas: NSCLC pathology and molecular testing, the treatment of first-line...

Astroglial networks and implications for therapeutic neuromodulation of epilepsy

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Mark R Witcher

2012-08-01

Full Text Available Epilepsy is a common chronic neurologic disorder affecting approximately 1 percent of the world population. More than one-third of all epilepsy patients have incompletely controlled seizures or debilitating medication side effects in spite of optimal medical management. Medically refractory epilepsy is associated with excess injury and mortality, psychosocial dysfunction, and significant cognitive impairment. Effective treatment options for these patients can be limited. The cellular mechanisms underlying seizure activity are incompletely understood, though we here describe multiple lines of evidence supporting the likely contribution of astroglia to epilepsy, with focus on individual astrocytes and their network functions. Of the emerging therapeutic modalities for epilepsy, one of the most intriguing is the field of neuromodulation. Neuromodulatory treatment, which consists of administering electrical pulses to neural tissue to modulate its activity leading to a beneficial effect, may be an option for these patients. Current modalities consist of vagal nerve stimulation, open and closed loop stimulation, and transcranial magnetic stimulation. Due to their unique properties, we here present astrocytes as likely important targets for the developing field of neuromodulation in the treatment of epilepsy.

Is it timing or backdating of option grants?

NARCIS (Netherlands)

van der Goot, T.

2010-01-01

Using a unique dataset from the Netherlands, we investigate three questions of interest. First, we explore the effects of a rule change in September 2002 on option grant dates. Second, we examine the retroactive backdating of option grant dates. Finally, we look at the timing of option grant dates

Anti-leukemic activity of bortezomib and carfilzomib on B-cell precursor ALL cell lines.

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Kazuya Takahashi

Full Text Available Prognosis of childhood acute lymphoblastic leukemia (ALL has been dramatically improved. However, prognosis of the cases refractory to primary therapy is still poor. Recent phase 2 study on the efficacy of combination chemotherapy with bortezomib (BTZ, a proteasome inhibitor, for refractory childhood ALL demonstrated favorable clinical outcomes. However, septic death was observed in over 10% of patients, indicating the necessity of biomarkers that could predict BTZ sensitivity. We investigated in vitro BTZ sensitivity in a large panel of ALL cell lines that acted as a model system for refractory ALL, and found that Philadelphia chromosome-positive (Ph+ ALL, IKZF1 deletion, and biallelic loss of CDKN2A were associated with favorable response. Even in Ph-negative ALL cell lines, IKZF1 deletion and bilallelic loss of CDKN2A were independently associated with higher BTZ sensitivity. BTZ showed only marginal cross-resistance to four representative chemotherapeutic agents (vincristine, dexamethasone, l-asparaginase, and daunorubicin in B-cell precursor-ALL cell lines. To improve the efficacy and safety of proteasome inhibitor combination chemotherapy, we also analyzed the anti-leukemic activity of carfilzomib (CFZ, a second-generation proteasome inhibitor, as a substitute for BTZ. CFZ showed significantly higher activity than BTZ in the majority of ALL cell lines except for the P-glycoprotein-positive t(17;19 ALL cell lines, and IKZF1 deletion was also associated with a favorable response to CFZ treatment. P-glycoprotein inhibitors effectively restored the sensitivity to CFZ, but not BTZ, in P-glycoprotein-positive t(17;19 ALL cell lines. P-glycoprotein overexpressing ALL cell line showed a CFZ-specific resistance, while knockout of P-glycoprotein by genome editing with a CRISPR/Cas9 system sensitized P-glycoprotein-positive t(17;19 ALL cell line to CFZ. These observations suggested that IKZF1 deletion could be a useful biomarker to predict good

Intermittent Massage as a Therapeutic Option for Compartment Syndrome after Embolectomy of the Lower Limbs

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José Maria Pereira de Godoy

2018-01-01

Full Text Available The case of a 54-year-old cardiac patient is reported, who was admitted to hospital with a complaint of sudden pain in the legs associated with edema, paresthesia, and coldness. Arterial embolism of the lower limbs was diagnosed and the patient was submitted to bilateral embolectomy. The patient evolved with a burning sensation, hypersensitivity in the right leg, swelling, and difficulty bending and stretching the sole of the foot and the knee. A physical examination detected edema and increased tension in the anterior, lateral, and posterior compartments. Treatment using intermittent massage of the leg during the evaluation of the patient was chosen in an attempt to stimulate lymphatic and venous drainage. After a few minutes of stimulation, there was significant improvement in the pain and edema. In 40 minutes, there was total reduction of the pain in the posterior and lateral compartments and improvement of over 50% in the anterior compartment. After this, the patient started to bend the knee without pain and bend the sole of the foot with slight pain. On the following day, the patient was walking around the hospital ward without difficulty. It seems that intermittent massage is a therapeutic option in selected cases of compartment syndrome.

Intravaginal boric acid: is it an alternative therapeutic option for vaginal trichomoniasis?

Science.gov (United States)

Thorley, Nicola; Ross, Jonathan

2017-12-09

Trichomoniasis, caused by Trichomonas vaginalis (TV), is the most common curable sexually transmitted infection worldwide. Current guidance in the UK is to treat TV with a nitroimidazole antibiotic. The high prevalence of TV, high rate of antibiotic resistance and limited tolerability to nitroimidazoles suggest that alternative treatment regimens are needed. Intravaginal boric acid (BA) has been used safely for the treatment of candida vulvovaginitis and bacterial vaginosis, and in vitro studies suggest BA is active against TV. We review the evidence for the efficacy of BA in patients with TV. MEDLINE, EMBASE, CINAHL, AMED, HMIC and BNI and Grey literature databases, The Cochrane Library, Trial Registers, conference abstracts and proceedings were searched. Inclusion criteria were women aged 16 years or over with microbiological confirmation of TV infection and using BA as treatment. There were no restrictions on language, publication date or study design. The in vitro evidence for BA activity against TV was also reviewed. No randomised controlled trials or case series were found. Four case reports demonstrated TV clearance with BA using a variety of dose regimens (dose 600 mg alternate nights to 600 mg two times per day; duration 1-5 months). In vitro studies suggest that BA has activity against TV which is independent of its effect on pH. Further evaluation of BA for the treatment of uncomplicated TV is required, but it may be useful when therapeutic options are limited. If shown to be safe and effective, intravaginal BA might provide a well-tolerated alternative anti-infective treatment which reduces community exposure to systemic antibiotics. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Where to Turn for Second-Line Cytoreduction After Hydroxyurea in Polycythemia Vera?

Science.gov (United States)

Nazha, Aziz; Gerds, Aaron T

2016-04-01

The goals of therapy in patients with polycythemia vera (PV) are to improve disease-related symptoms, prevent the incidence or recurrence of thrombosis, and possibly delay or prevent the transformation into myelofibrosis or acute myeloid leukemia (AML). Cytoreductive therapies have been used in older patients and those with a history of thrombosis to achieve these goals. Hydroxyurea (HU) remains the first-line cytoreductive choice; however, up to one in four patients treated with HU over time will develop resistance or intolerance to HU. More importantly, patients who fail HU have a 5.6-fold increase in mortality and a 6.8-fold increase risk of transformation to myelofibrosis or AML; therefore, alternative therapies are needed for these patients. Interferon-α has been used in PV and has shown significant activity in achieving hematologic responses and decreasing JAK2 V617F mutation allele burden. JAK inhibition has also been investigated and recently garnered regulatory approval for this indication. In this review, we will discuss the current treatment options that are available for patients after HU and the novel therapies that are currently under investigation. The outcomes of PV patients who fail or who are intolerant of hydroxyurea are poor. Although pegylated interferon can be considered in younger patients, currently, ruxolitinib is the only U.S. Food and Drug Administration-approved agent in this setting, representing a viable option, leading to hematocrit control and a reduction in spleen size and constitutional symptoms. Although a small number of patients will achieve a molecular response with continuous treatment, the implications of such response on the clinical outcomes are still unknown. Patients whose disease is not adequately controlled with ruxolitinib, or who lose their response, can be treated with low-dose busulfan or pipobroman; however, they should be encouraged to participate in trials with novel therapies. ©AlphaMed Press.

THERAPEUTIC DECISION-MAKING OF PHYSICIANS

NARCIS (Netherlands)

DENIG, P; HAAIJER-RUSKAMP, FM

1992-01-01

In this review the therapeutic decision-making process of physicians is described. This process is divided into two steps: the generation of a limited set of possible options (the 'evoked set') and the selection from this evoked set of a treatment for a specific patient. Factors that are important

Gene Therapy for Advanced Melanoma: Selective Targeting and Therapeutic Nucleic Acids

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Joana R. Viola

2013-01-01

Full Text Available Despite recent advances, the treatment of malignant melanoma still results in the relapse of the disease, and second line treatment mostly fails due to the occurrence of resistance. A wide range of mutations are known to prevent effective treatment with chemotherapeutic drugs. Hence, approaches with biopharmaceuticals including proteins, like antibodies or cytokines, are applied. As an alternative, regimens with therapeutically active nucleic acids offer the possibility for highly selective cancer treatment whilst avoiding unwanted and toxic side effects. This paper gives a brief introduction into the mechanism of this devastating disease, discusses the shortcoming of current therapy approaches, and pinpoints anchor points which could be harnessed for therapeutic intervention with nucleic acids. We bring the delivery of nucleic acid nanopharmaceutics into perspective as a novel antimelanoma therapeutic approach and discuss the possibilities for melanoma specific targeting. The latest reports on preclinical and already clinical application of nucleic acids in melanoma are discussed.

Low lopinavir plasma or hair concentrations explain second-line protease inhibitor failures in a resource-limited setting

NARCIS (Netherlands)

van Zyl, Gert Uves; van Mens, Thijs E.; McIlleron, Helen; Zeier, Michele; Nachega, Jean B.; Decloedt, Eric; Malavazzi, Carolina; Smith, Peter; Huang, Yong; van der Merwe, Lize; Gandhi, Monica; Maartens, Gary

2011-01-01

In resource-limited settings, many patients, with no prior protease inhibitor (PI) treatment on a second-line, high genetic barrier, ritonavir-boosted PI-containing regimen have virologic failure. We conducted a cross-sectional survey to investigate the aetiology of virologic failure in 2 public

Conservative therapeutic management of carpal tunnel syndrome

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Roberto Sérgio Martins

Full Text Available ABSTRACT Carpal tunnel syndrome is the most prevalent nerve compression and can be clinically or surgically treated. In most cases, the first therapeutic alternative is conservative treatment but there is still much controversy regarding the most effective modality of this treatment. In this study, we critically evaluated the options of conservative treatment for carpal tunnel syndrome, aiming to guide the reader through the conventional options used in this therapy.

Metastatic Urothelial Carcinoma with Glandular Differentiation That Confirmed the Response by Autopsy Specimen to Second-Line mFOLFOX6 (Fluorouracil, Oxaliplatin, and Leucovorin plus Bevacizumab Chemotherapy

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Taku Naiki

2017-11-01

Full Text Available The prognostic significance of glandular differentiation in urothelial carcinoma (UC is controversial, and thus far there is no established treatment strategy against metastasis of glandular component. We describe here a case of metastatic UC with glandular differentiation that had histological disappearance of adenocarcinoma components at autopsy after sequential chemotherapy with S-1 and cisplatin (CDDP and with mFOLFOX6 (fluorouracil, oxaliplatin, and leucovorin plus bevacizumab (mFOLFOX6+Bev. A 62-year-old Asian male was diagnosed with invasive UC with glandular differentiation (T2N0M0 by radical cystectomy and ileal conduit, and careful follow-up observation was made. Eight years after radical operation, peritoneal metastases occurred, and a biopsy specimen using colon fiber revealed high-grade adenocarcinomas with an immunohistochemical profile that included positivity for cytokeratin 7 (CK7 and negativity for cytokeratin 20 (CK20 and uroplakin, which was identical to the radical cystectomy specimen. Thus, he received combination chemotherapy consisting of S-1 and CDDP; however, the peritoneal metastasis worsened after 2 cycles. Therefore, second-line mFOLFOX6+Bev chemotherapy was performed for a total of 5 courses. In spite of this, the patient died, and the final diagnosis by autopsy was multiple metastases of infiltrating pure UC to the lung, bone, and peritoneum. Interestingly, there were no pathological findings of adenocarcinoma, and the immunohistochemical profile of the metastatic lesions was identical to that of the previous specimens from the bladder and colon. This suggests that sequential chemotherapy of S-1 and CDDP and second-line mFOLFOX6+Bev might be a feasible option in metastatic UC with glandular differentiation.

Cyclophosphamide-hydroxycamptothecin as second-line chemotherapy for advanced Ewing's sarcoma: experience of a single institution.

Science.gov (United States)

Han, Kun; Sun, Yuanjue; Zhang, Jianjun; He, Aina; Zheng, Shui'er; Shen, Zan; Yao, Yang

2014-06-01

To investigate the feasibility and efficacy of cyclophosphamide (CTX)-hydroxycamptothecin (HCPT) as second-line chemotherapy on advanced Ewing's sarcoma. From April 2009 to November 2010, 27 patients with advanced Ewing's sarcoma who had progressive disease after the first-line chemotherapy regimen of vincristine, dactinomycin and cyclophosphamide and ifosfamide and etoposide were retrospectively reviewed in this analysis. CTX was given (0.6 g/m(2), i.v. push day 1) and HCPT (6 mg/m(2), i.v. drip days 1-5) as second-line chemotherapy every 3 weeks. The primary end-point was overall response rate, the secondary end-point included progression-free, overall survival, disease control rate and toxicities. A total of 134 cycles were given, median four cycles per patient (range 2-6). Overall response rate was 30% and disease control rate was 82%, with two complete response (8%), six partial remission (22%) and 14 stable disease (52%). The median time to progression and overall survival time were 7 months (95% CI 3-10) and 11 months (95% CI 5-18), respectively. Major severe toxicities (grade 3 and 4) were: nausea/vomiting (17%), alopecia (17%); leukopenia (27%) in total cycles. Mild toxicities (grade 1 or 2) were leukopenia (73%), nausea/vomiting (83%), hepatic lesion (14%) and anemia (44%). A CTX-HCPT regimen can control disease progression effectively and the side effects can be tolerable for Chinese advanced Ewing's sarcoma patients. Further assessment is necessary to confirm the safety and efficacy of this treatment. © 2012 Wiley Publishing Asia Pty Ltd.

Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation.

Science.gov (United States)

Trevisani, Franco; Brandi, Giovanni; Garuti, Francesca; Barbera, Maria Aurelia; Tortora, Raffaella; Casadei Gardini, Andrea; Granito, Alessandro; Tovoli, Francesco; De Lorenzo, Stefania; Inghilesi, Andrea Lorenzo; Foschi, Francesco Giuseppe; Bernardi, Mauro; Marra, Fabio; Sacco, Rodolfo; Di Costanzo, Giovan Giuseppe

2018-02-01

Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5-11.6) vs 5.0 (4.2-5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8-12.9) vs. 5.8 (4.8-6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5-24.1) vs. 7.8 (5.2-10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.

Phytotherapy: emerging therapeutic option in urologic disease

Science.gov (United States)

2012-01-01

Phytotherapy belongs to the area of complementary and alternative medicine (CAM) and the definition of phytotherapy is the use of plants or plant extracts for medicinal uses. Interest in phytotherapy is growing in both Asian and western countries for its use in the prevention and management of disease, improvement of general health and anti-aging. And also, there are several studies about the efficacy of phytotherapy in urologic diseases like benign prostatic hyperplasia (BPH), erectile dysfunction (ED), late-onset hypogonadism (LOH) and infertility in males. Phytotherapy for BPH including saw palmetto, pygeum, and nettles, is under vigorous research for the therapeutic effect. No solid evidence showing better effective treatment modality for ED than placebo has been found yet for phytotherapy. Recently, a potent NO donor, L-arginine is under research with promising results. Phytotherapy is used by a number of patients with urological disease, and urologists need to have accurate knowledge about phytotherapy as well as keep a cautious approach. The possible effects and side effects should be defined and related to urologic patients by urologists. PMID:26816707

Novel treatment options in depression and psychosis

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Ceskova E

2018-03-01

Full Text Available Eva Ceskova, Petr Silhan Department of Psychiatry, University Hospital Ostrava, Ostrava, Czech Republic Abstract: In spite of tremendous development in central nervous system research, current treatment is suboptimal, especially in severe mental disorders. In medicine, there are two main methods of improving the health care provided: seeking new treatment procedures and perfecting (optimizing the existing ones. Optimization of treatment includes not only practical tools such as therapeutic drug monitoring but also implementation of general trends in the clinical practice. New pharmacological options include new more sophisticated forms of monoaminergic drugs, old drugs rediscovered on the base of a better understanding of pathophysiology of mental illnesses, and drugs aimed at new treatment targets. In depression, treatment resistance to antidepressive pharmacotherapy represents one of the most important clinical challenges. Switching to monotherapy with new multimodal/multifunctional antidepressants and augmentation with new atypical antipsychotics (aripiprazole and brexpiprazole may be promising options. Further, current evidence supports utility and safety of adjunctive treatment of nutraceuticals. Novel approaches being studied include ketamine and opioids. Recent advances in technology and emerging knowledge about dysfunctional brain circuits and neuroplasticity have led to the development of different new neuromodulation techniques usually used as add-on therapy. Antipsychotics are still the cornerstone of the current treatment of schizophrenia. Two new partial dopamine agonists, brexpiprazole and cariprazine, are now available in addition to aripiprazole. Although the mechanisms of action are similar, the two agents differ in terms of their pharmacodynamic profiles. Further, two new formulations of long-acting injections of second-generation antipsychotics (aripiprazole lauroxil and 3-month paliperidone palmitate were introduced into

Nintedanib plus docetaxel as second-line therapy in patients with non-small-cell lung cancer of adenocarcinoma histology

DEFF Research Database (Denmark)

Popat, Sanjay; Mellemgaard, Anders; Reck, Martin

2017-01-01

PATIENTS & METHODS: We provide an update to a network meta-analysis evaluating the relative efficacy of nintedanib + docetaxel versus other second-line agents in adenocarcinoma histology non-small-cell lung cancer. RESULTS: Overall similarity of nintedanib + docetaxel versus ramucirumab + docetaxel...

Is tetrahydrobiopterin a therapeutic option in diabetic hypertensive patients?

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Alberto Francisco Rubio-Guerra

2010-09-01

Full Text Available Alberto Francisco Rubio-Guerra1, Hilda Vargas-Robles2, Luz Maria Ramos-Brizuela1, Bruno Alfonso Escalante-Acosta21Metabolic Clinic, Hospital General de Ticomán SS DF, Mexico; 2Department of Molecular Biomedicine, Centro de Investigacion y de Estudios Avanzados del IPN, MexicoAbstract: Nitric oxide (NO is an important regulator of vascular tone, and is also an antithrombotic, anti-inflammatory, antiproliferative, and antiatherogenic factor. Endothelial function is altered in patients with coronary artery disease, stroke, and peripheral artery disease, and endothelial dysfunction correlates with the risk factor profile for a patient. Hypertension and type 2 diabetes are risk factors for vascular disease, and are both pathologies characterized by loss of NO activity. Indeed, endothelial dysfunction is usually present in diabetic and/or hypertensive patients. Tetrahydrobiopterin is an essential cofactor for the NO synthase enzyme, and insufficiency of this cofactor leads to uncoupling of the enzyme, release of superoxide, endothelial dysfunction, progression of hypertension, and finally, proatherogenic effects. Tetrahydrobiopterin is also an important mediator of NO synthase regulation in type 2 diabetes and hypertension, and may be a rational therapeutic target to restore endothelial function and prevent vascular disease in these patients. The aim of this paper is to review the rationale for therapeutic strategies directed to biopterins as a target for vascular disease in type 2 diabetic hypertensive patients.Keywords: tetrahydrobiopterin, endothelial dysfunction, diabetes, hypertension, oxidative stress, nitric oxide, eNOS synthase uncoupling

Helicobacter pylori first-line and rescue treatments in the presence of penicillin allergy.

Science.gov (United States)

Gisbert, Javier P; Barrio, Jesús; Modolell, Inés; Molina-Infante, Javier; Aisa, Angeles Perez; Castro-Fernández, Manuel; Rodrigo, Luis; Cosme, Angel; Gisbert, Jose Luis; Fernández-Bermejo, Miguel; Marcos, Santiago; Marín, Alicia C; McNicholl, Adrián G

2015-02-01

Helicobacter pylori eradication is a challenge in penicillin allergy. To assess the efficacy and safety of first-line and rescue treatments in patients allergic to penicillin. Prospective multicenter study. Patients allergic to penicillin were given a first-line treatment comprising (a) 7-day omeprazole-clarithromycin-metronidazole and (b) 10-day omeprazole-bismuth-tetracycline-metronidazole. Rescue treatments were as follows: (a) bismuth quadruple therapy; (b) 10-day PPI-clarithromycin-levofloxacin; and (c) 10-day PPI-clarithromycin-rifabutin. Eradication was confirmed by (13)C-urea breath test. Compliance was determined through questioning and recovery of empty medication envelopes. Adverse effects were evaluated by questionnaires. In total, 267 consecutive treatments were included. (1) First-line treatment: Per-protocol and intention-to-treat eradication rates with omeprazole-clarithromycin-metronidazole were 59 % (62/105; 95 % CI 49-62 %) and 57 % (64/112; 95 % CI 47-67 %). Respective figures for PPI-bismuth-tetracycline-metronidazole were 75 % (37/49; 95 % CI 62-89 %) and 74 % (37/50; 95 % CI (61-87 %) (p failure; compliance was 88-100 %, with 23-29 % adverse effects (all mild). (3) Third-/fourth-line treatment: Intention-to-treat eradication rate with PPI-clarithromycin-rifabutin was 22 %. In allergic to penicillin patients, a first-line treatment with a bismuth-containing quadruple therapy (PPI-bismuth-tetracycline-metronidazole) seems to be a better option than the triple PPI-clarithromycin-metronidazole regimen. A levofloxacin-based regimen (together with a PPI and clarithromycin) represents a second-line rescue option in the presence of penicillin allergy.

PREDICTORS OF OVERALL SURVIVAL IN PATIENTS WITH RECURRENT NON-SEMINOMATOUS GERMINAL TESTICULAR TUMORS ON CURRENT SECOND-LINE CHEMOTHERAPY

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M. Yu. Fedyanin

2010-01-01

Full Text Available Objective: to define predictors that influence longevity in patients with recurrent non-seminomatous germinal testicular tumors (NGTT on standard second-line chemotherapy (CT including cisplatin and iphosphamide. Statistical analysis was performed using the statistical packages Graph Pad Prism 4.00 for Windows and SPSS 15.0 for Windows. Subjects and methods. Case history data were analyzed in 693 patients with disseminated NGTT who had received current CT and followed up at the Department of Clinical Pharmacology and CT, N.N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences. The median follow-up was 32 (range 3-215 months. The disease progressed in 181 (26% patients. Detailed information was available on the nature of second-line CT in only 138 patients. Half (71 (51.7% of the 138 patients had second-line CT including iphosphamide. Uni- and multivariate analyses were made to identify predictors that influence longevity in patients with recurrent NGTT on standard secondline CT including cisplatin and iphosphamide. Results. Five-year overall survival (OS was 32% (95% confidence interval 25-41%. The multivariate analysis showed the morphological pattern of a primary tumor (a yolk sac tumor component, a pre-induction CT lactate dehydrogenase (LDH level of ?d1.5 units of the upper normal range, progression during induction CT, and a pre-second-line CT LDH level of ?d 1000 U/l to be negative predictors. According to the number of negative factors, the patients were classified into 3 groups: 1 good prognosis [n = 10 (14% of the 71 patients], 100% 3-year OS; 2 intermediate prognosis (one negative factor [n = 33 (46.5% of the 71 patients], 50.2% 3-year OS; 3 poor prognosis (?d 2 negative factors, 6.7% 3-year OS. Conclusion. Standard iphosphamide-containing therapy enables all patients to be treated in the good prognosis group of those with recurrent NGTT. That fails to achieve such striking results in the intermediate and

Indications and interventional options for non-resectable tracheal stenosis

Science.gov (United States)

Bacon, Jenny Louise; Patterson, Caroline Marie

2014-01-01

Non-specific presentation and normal examination findings in early disease often result in tracheal obstruction being overlooked as a diagnosis until patients present acutely. Once diagnosed, surgical options should be considered, but often patient co-morbidity necessitates other interventional options. Non-resectable tracheal stenosis can be successfully managed by interventional bronchoscopy, with therapeutic options including airway dilatation, local tissue destruction and airway stenting. There are common aspects to the management of tracheal obstruction, tracheomalacia and tracheal fistulae. This paper reviews the pathogenesis, presentation, investigation and management of tracheal disease, with a focus on tracheal obstruction and the role of endotracheal intervention in management. PMID:24624290

Targeting Angiogenesis and Tumor Microenvironment in Metastatic Colorectal Cancer: Role of Aflibercept

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Guido Giordano

2014-01-01

Full Text Available In the last decades, we have progressively observed an improvement in therapeutic options for metastatic colorectal cancer (mCRC treatment with a progressive prolongation of survival. mCRC prognosis still remains poor with low percentage of 5-year survival. Targeted agents have improved results obtained with standard chemotherapy. Angiogenesis plays a crucial role in colorectal cancer growth, proliferation, and metastasization and it has been investigated as a potential target for mCRC treatment. Accordingly, novel antiangiogenic targeted agents bevacizumab, regorafenib, and aflibercept have been approved for mCRC treatment as the result of several phase III randomized trials. The development of a tumor permissive microenvironment via the aberrant expression by tumor cells of paracrine factors alters the tumor-stroma interactions inducing an expansion of proangiogenic signals. Recently, the VELOUR study showed that addition of aflibercept to FOLFIRI regimen as a second-line therapy for mCRC improved significantly OS, PFS, and RR. This molecule represents a valid second-line therapeutic option and its peculiar ability to interfere with placental growth factor (PlGF/vascular endothelial growth factor receptor 1 (VEGFR1 axis makes it effective in targeting angiogenesis, inflammatory cells and in overcoming resistances to anti-angiogenic first-line treatment. Here, we discuss about Aflibercept peculiar ability to interfere with tumor microenvironment and angiogenic pathway.

Treatment paradigms for patients with metastatic non small cell lung cancer (NSCLC, squamous lung cancer: first, second and third-line

Directory of Open Access Journals (Sweden)

Abdulaziz eAl Farsi

2014-06-01

Full Text Available Historically, the treatment algorithm applied to non small cell lung cancer (NSCLC was the same for all histologic subtypes. However, recent advances in our understanding of the molecular profiles of squamous and non-squamous NSCLC have changed this perspective. Histologic subtype and the presence of specific molecular abnormalities have predictive value for response to and toxicity from therapy, as well as overall survival. For patients with squamous NSCLC, a platinum agent plus gemcitabine, or paclitaxel is recommended as first-line therapy. The role of EGFR monoclonal antibodies is uncertain. Maintenance therapy is not widely recommended, although data exist for the use of erlotinib. The standard recommendation for second-line therapy is docetaxel and erlotinib should be considered as second or third-line therapy. There is ongoing research identifying molecular targets in squamous NSCLC and many agents are in early phase clinical trials. Immunotherapeutic approaches targeting programmed death 1 receptor (PD-1 and its ligand (PD-L1 appear promising.

[Clinical features and therapeutic response of our anti-SRP positive patients with myositis].

Science.gov (United States)

Botos, Balázs; Nagy-Vincze, Melinda; Dankó, Katalin

2017-09-01

Idiopathic inflammatory myopathies are a group of clinically heterogeneous diseases, which have been classified by myositis specific antibodies recently. The anti-SRP positive subset of this group is characterized by more severe clinical prognosis than other myositis specific antibody positive types. Our goal was to compare 16 anti-SRP positive patients in the Division of Clinical Immunology, Department of Internal Medicine, University of Debrecen with 16 antibody negative ones. Muscle strength validated in both groups by the manual muscle test proved to be significantly decreased both before and after therapy (χ 2 = 0.006 and 0.019) in the anti-SRP positive group. Muscle-specific inflammatory laboratory parameters showed significant difference only in case of LDH-levels after therapy. Both groups showed good clinical response to first line steroid treatment, yet the significantly higher rate of second line administration suggests worse therapeutic response of the antibody positive group. Based on these facts we determined poor clinical prognosis and therapeutic response of the anti-SRP positive group. Orv Hetil. 2017; 158(35): 1382-1389.

Ifosfamide, mesna and epirubicin as second-line chemotherapy in advanced breast cancer.

Science.gov (United States)

Kiraz, S; Baltali, E; Güler, N; Barista, I; Benekli, M; Celik, I; Güllü, I H; Kars, A; Tekuzman, G; Firat, D

1996-08-01

The ifosfamide, mesna and epirubicin (IMEpi) combination is administered to 16 patients having advanced metastatic breast carcinoma as second-line chemotherapy. We observed complete response in 6%, partial response in 44% (total overall response rate of 50%), stable disease in 12% and progressive disease in the remaining 38% of the patients. The median remission duration in responders was calculated to be 9.6 months. IMEpi regimen had a tolerable toxicity profile including alopecia, nausea and vomiting, microscopic hematuria, leukopenia and neurotoxicity in which serious complications necessitating discontinuation of the chemotherapy were not encountered. It might be concluded that IMEpi chemotherapy combination is an effective alternative among schedules in the management of patients with stage IV breast carcinoma without serious side effects.

Higher-Order Finite Element Solutions of Option Prices

DEFF Research Database (Denmark)

Raahauge, Peter

2004-01-01

Kinks and jumps in the payoff function of option contracts prevent an effectiveimplementation of higher-order numerical approximation methods. Moreover, thederivatives (the greeks) are not easily determined around such singularities, even withstandard lower-order methods. This paper suggests...... for prices as well as for first and second order derivatives(delta and gamma). Unlike similar studies, numerical approximation errors aremeasured both as weighted averages and in the supnorm over a state space includingtime-to-maturities down to a split second.KEYWORDS: Numerical option pricing, Transformed...

Experience with second line drugs in frequently relapsing and steroid dependent childhood nephrotic syndrome in a large Saudi center

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Khalid Alsaran, M.D.

2017-06-01

Conclusion: All the second line drugs in our study were equally effective. However, we recommend that the initial treatment of FR/SD nephrotic syndrome should be chosen with the least toxic yet equally efficacious drug Levamisole.

Pain and endometriosis: Etiology, impact, and therapeutics

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Robert N. Taylor

2012-12-01

Full Text Available The association of pain and endometriosis was recognized with the first definitive published reports of this disorder. Unfortunately, the precise etiologies and pathways leading to nociception and pain symptoms in endometriosis remain poorly understood, and as a result, effective therapeutic interventions are lacking with consequent profound effects on affected women’s quality of life. In this opinion paper we summarize selected proceedings presented at the 28th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE in Istanbul, Turkey, and review the clinical and translational evidence of chronic pain, neurogenesis, and the pernicious impact of dyspareunia on women with symptomatic endometriosis. The effectiveness of medical treatments is critically assessed and the findings indicate that good therapeutic options are available with extant medications effective in some sub-groups of women with endometriosis, many of which are affordable globally. Nevertheless, new management strategies and drugs need to be developed to increase the options of all afflicted women to minimize and ideally eradicate painful symptoms of endometriosis. However, only by elucidating distinctions among sub-groups with specific symptoms, suggesting different mechanisms, are we likely to derive truly successful therapeutic strategies.

Use of anti-retroviral therapy in tuberculosis patients on second-line anti-TB regimens: a systematic review.

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Matthew Arentz

Full Text Available Use of antiretroviral therapy (ART during treatment of drug susceptible tuberculosis (TB improves survival. However, data from HIV infected individuals with drug resistant TB are lacking. Second line TB drugs when combined with ART may increase drug interactions and lead to higher rates of toxicity and greater noncompliance. This systematic review sought to determine the benefit of ART in the setting of second line drug therapy for drug resistant TB.We included individual patient data from studies that evaluated treatment of drug-resistant tuberculosis in HIV-1 infected individuals published between January 1980 and December of 2009. We evaluated the effect of ART on treatment outcomes, time to smear and culture conversion, and adverse events.Ten observational studies, including data from 217 subjects, were analyzed. Patients using ART during TB treatment had increased likelihood of cure (hazard ratio (HR 3.4, 95% CI 1.6-7.4 and decreased likelihood of death (HR 0.4, 95% CI 0.3-0.6 during treatment for drug resistant TB. These associations remained significant in patients with a CD4 less than 200 cells/mm(3 and less than 50 cells/mm(3, and when correcting for drug resistance pattern.We identified only observational studies from which individual patient data could be drawn. Limitations in study design, and heterogeneity in a number of the outcomes of interest had the potential to introduce bias.While there are insufficient data to determine if ART use increases adverse drug interactions when used with second line TB drugs, ART use during treatment of drug resistant TB appears to improve cure rates and decrease risk of death. All individuals with HIV appear to benefit from ART use during treatment for TB.

TDF and quantitative ultrasound bone quality in African patients on second line ART, ANRS 12169 2LADY sub-study.

Science.gov (United States)

Kabore, Firmin Nongodo; Eymard-Duvernay, Sabrina; Zoungrana, Jacques; Badiou, Stéphanie; Bado, Guillaume; Héma, Arsène; Diouf, Assane; Delaporte, Eric; Koulla-Shiro, Sinata; Ciaffi, Laura; Cournil, Amandine

2017-01-01

Bone demineralization, which leads to osteoporosis and increased fracture risk, is a common metabolic disorder in HIV-infected individuals. In this study, we aimed to assess the change in bone quality using quantitative ultrasound (QUS) over 96 weeks of follow-up after initiation of second-line treatment, and to identify factors associated with change in bone quality. In a randomized trial (ANRS 12169), TDF and PI-naïve participants failing standard first-line treatment, from Burkina Faso, Cameroon, and Senegal were randomized to receive either TDF/FTC/LPVr, ABC/ddI/LPVr or TDF/FTC/DRVr. Their bone quality was assessed using calcaneal QUS at baseline and every 24 weeks until week 96. Stiffness index (SI) was used to measure bone quality. Out of 228 participants, 168 (74%) were women. At baseline, median age was 37 years (IQR: 33-46 years) and median T-CD4 count was 199 cells/μl (IQR: 113-319 cells/μl). The median duration of first-line antiretroviral treatment (ART) was 52 months (IQR: 36-72 months) and the median baseline SI was 101 (IQR: 87-116). In multivariable analysis, factors associated with baseline SI were sex (β = -10.8 [-18.1,-3.5] for women), age (β = -8.7 [-12.4,-5.1] per 10 years), body mass index (BMI) (β = +0.8 [0.1,1.5] per unit of BMI), and study site (β = +12.8 [6.5,19.1] for Cameroon). After 96 weeks of second-line therapy, a reduction of 7.1% in mean SI was observed, as compared with baseline. Factors associated with SI during the follow-up were similar to those found at baseline. Exposure to TDF was not associated with a greater loss of bone quality over time. Bone quality decreased after second-line ART initiation in African patients independently of TDF exposure. Factors associated with bone quality include age, sex, baseline BMI, study site, and duration of follow-up.

New chondrosarcoma cell lines and mouse models to study the link between chondrogenesis and chemoresistance.

Science.gov (United States)

Monderer, David; Luseau, Alexandrine; Bellec, Amélie; David, Emmanuelle; Ponsolle, Stéphanie; Saiagh, Soraya; Bercegeay, Sylvain; Piloquet, Philippe; Denis, Marc G; Lodé, Laurence; Rédini, Françoise; Biger, Marine; Heymann, Dominique; Heymann, Marie-Françoise; Le Bot, Ronan; Gouin, François; Blanchard, Frédéric

2013-10-01

Chondrosarcomas are cartilage-forming, poorly vascularized tumors. They represent the second malignant primary bone tumor of adults after osteosarcoma, but in contrast to osteosarcoma they are resistant to chemotherapy and radiotherapy, surgical excision remaining the only therapeutic option. Few cell lines and animal models are available, and the mechanisms behind their chemoresistance remain largely unknown. Our goal was to establish new cell lines and animal cancer models from human chondrosarcoma biopsies to study their chemoresistance. Between 2007 and 2012, 10 chondrosarcoma biopsies were collected and used for cell culture and transplantation into nude mice. Only one transplanted biopsy and one injected cell line has engrafted successfully leading to conventional central high-grade chondrosarcoma similar to the original biopsies. In culture, two new stable cell lines were obtained, one from a dedifferentiated and one from a grade III conventional central chondrosarcoma biopsy. Their genetic characterization revealed triploid karyotypes, mutations in IDH1, IDH2, and TP53, deletion in CDKN2A and/or MDM2 amplification. These cell lines expressed mesenchymal membrane markers (CD44, 73, 90, 105) and were able to produce a hyaline cartilaginous matrix when cultured in chondrogenic three-dimensional (3D) pellets. Using a high-throughput quantitative RT-PCR approach, we observed that cell lines cultured in monolayer had lost expression of several genes implicated in cartilage development (COL2A1, COMP, ACAN) but restored their expression in 3D cultures. Chondrosarcoma cells in monolayer were sensitive to several conventional chemotherapeutic agents but became resistant to low doses of mafosfamide or doxorubicin when cultured in 3D pellets, in parallel with an altered nucleic accumulation of the drug. Our results indicate that the cartilaginous matrix produced by chondrosarcoma cells may impair diffusion of several drugs and thus contribute to chemoresistance

Cetuximab in first line treatment of metastatic colorectal cancer

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Carlo Barone

2012-07-01

Full Text Available The present health technology assessment report evaluates the clinical and economic profile of cetuximab in first-line metastatic colorectal cancer (mCRC in Italy. The first part of the report addresses the epidemiological, clinical, social and economic impact of mCRC. In the second part, evidence of efficacy, safety and cost-effectiveness of cetuximab and its available alternatives is shown. Finally, a model-based economic evaluation aimed at comparing cetuximab-based re­gimens vs. alternative therapeutic strategies indicated in mCRC in Italy is presented. The model estimates the incremental cost-effectiveness of adding cetuximab to FOLFOX-4 or FOLFIRI based on KRAS status, vs. adding bevacizumab to FOLFOX-4 or vs. FOLFOX-4 or FOLFIRI alone. A theoretical analysis vs. panitumumab has also been performed, despite panitumumab is not yet reimbursed in Italy in first-line mCRC. Survival outcomes, quality of life and costs of patient ma­nagement are estimated through a Markov model, using the Italian National Healthcare Service (NHS perspective, over a 10 year period, taking into account KRAS status of patients. The results of the pharmaco-economic analysis show that cetuximab + FOLFOX-4 and cetuximab + FOLFIRI are associated with increased survival, increased cost and increased quality adjusted survival, compared to all other treatments currently indicated and reimbursed in Italy. Adding cetuximab to FOLFOX-4 or FOLFIRI, based on KRAS status shows favorable incremental cost-effectiveness ratio (ICER vs. adding bevacizumab to FOLFIRI or vs. FOLFOX-4 or FOLFIRI alone. ICER of cetuximab (in combination with FOLFOX-4 or FOLFIRI, compared to currently reimbursed alternatives, is estimated between 6 and 13 thousand Euros per QALY gai­ned, depending on alternative treatment. These estimates are robust in extensive sensitivity analyses. As a final result, both clinical and economic evidence analyzed in this health technology assessment leads to

HIV multi-drug resistance at first-line antiretroviral failure and subsequent virological response in Asia

Science.gov (United States)

Jiamsakul, Awachana; Sungkanuparph, Somnuek; Law, Matthew; Kantor, Rami; Praparattanapan, Jutarat; Li, Patrick CK; Phanuphak, Praphan; Merati, Tuti; Ratanasuwan, Winai; Lee, Christopher KC; Ditangco, Rossana; Mustafa, Mahiran; Singtoroj, Thida; Kiertiburanakul, Sasisopin

2014-01-01

Introduction First-line antiretroviral therapy (ART) failure often results from the development of resistance-associated mutations (RAMs). Three patterns, including thymidine analogue mutations (TAMs), 69 Insertion (69Ins) and the Q151M complex, are associated with resistance to multiple-nucleoside reverse transcriptase inhibitors (NRTIs) and may compromise treatment options for second-line ART. Methods We investigated patterns and factors associated with multi-NRTI RAMs at first-line failure in patients from The TREAT Asia Studies to Evaluate Resistance – Monitoring study (TASER-M), and evaluated their impact on virological responses at 12 months after switching to second-line ART. RAMs were compared with the IAS-USA 2013 mutations list. We defined multi-NRTI RAMs as the presence of either Q151M; 69Ins; ≥2 TAMs; or M184V+≥1 TAM. Virological suppression was defined as viral load (VL) Malaysia and Philippines were included. There were 97/105 (92%) patients harbouring ≥1 RAMs at first-line failure, 39/105 with multi-NRTI RAMs: six with Q151M; 24 with ≥2 TAMs; and 32 with M184V+≥1 TAM. Factors associated with multi-NRTI RAMs were CD4 ≤200 cells/µL at genotyping (OR=4.43, 95% CI [1.59–12.37], p=0.004) and ART duration >2 years (OR=6.25, 95% CI [2.39–16.36], p<0.001). Among 87/105 patients with available VL at 12 months after switch to second-line ART, virological suppression was achieved in 85%. The median genotypic susceptibility score (GSS) for the second-line regimen was 2.00. Patients with ART adherence ≥95% were more likely to be virologically suppressed (OR=9.33, 95% CI (2.43–35.81), p=0.001). Measures of patient resistance to second-line ART, including the GSS, were not significantly associated with virological outcome. Conclusions Multi-NRTI RAMs at first-line failure were associated with low CD4 level and longer duration of ART. With many patients switching to highly susceptible regimens, good adherence was still crucial in achieving

Sporotrichosis: An Overview and Therapeutic Options

Science.gov (United States)

Mahajan, Vikram K.

2014-01-01

Sporotrichosis is a chronic granulomatous mycotic infection caused by Sporothrix schenckii, a common saprophyte of soil, decaying wood, hay, and sphagnum moss, that is endemic in tropical/subtropical areas. The recent phylogenetic studies have delineated the geographic distribution of multiple distinct Sporothrix species causing sporotrichosis. It characteristically involves the skin and subcutaneous tissue following traumatic inoculation of the pathogen. After a variable incubation period, progressively enlarging papulo-nodule at the inoculation site develops that may ulcerate (fixed cutaneous sporotrichosis) or multiple nodules appear proximally along lymphatics (lymphocutaneous sporotrichosis). Osteoarticular sporotrichosis or primary pulmonary sporotrichosis are rare and occur from direct inoculation or inhalation of conidia, respectively. Disseminated cutaneous sporotrichosis or involvement of multiple visceral organs, particularly the central nervous system, occurs most commonly in persons with immunosuppression. Saturated solution of potassium iodide remains a first line treatment choice for uncomplicated cutaneous sporotrichosis in resource poor countries but itraconazole is currently used/recommended for the treatment of all forms of sporotrichosis. Terbinafine has been observed to be effective in the treatment of cutaneous sporotrichosis. Amphotericin B is used initially for the treatment of severe, systemic disease, during pregnancy and in immunosuppressed patients until recovery, then followed by itraconazole for the rest of the therapy. PMID:25614735

Biweekly cetuximab and irinotecan as second-line therapy in patients with gastro-esophageal cancer previously treated with platinum

DEFF Research Database (Denmark)

Schoennemann, Katrine R; Bjerregaard, Jon K; Hansen, Tine P

2011-01-01

toxicities were: diarrhea (8%), fatigue (10%), neutropenia (16%), and febrile neutropenia (2%). CONCLUSION: Cetiri every two weeks is a convenient and well-tolerated second-line regimen in GEC patients. A promising effect was seen in patients with PS 0-1 and in patients who developed a rash....

Early antiretroviral therapy and potent second-line drugs could decrease HIV incidence of drug resistance.

Science.gov (United States)

Shen, Mingwang; Xiao, Yanni; Rong, Libin; Meyers, Lauren Ancel; Bellan, Steven E

2017-06-28

Early initiation of antiretroviral therapy (ART) reduces the risk of drug-sensitive HIV transmission but may increase the transmission of drug-resistant HIV. We used a mathematical model to estimate the long-term population-level benefits of ART and determine the scenarios under which earlier ART (treatment at 1 year post-infection, on average) could decrease simultaneously both total and drug-resistant HIV incidence (new infections). We constructed an infection-age-structured mathematical model that tracked the transmission rates over the course of infection and modelled the patients' life expectancy as a function of ART initiation timing. We fitted this model to the annual AIDS incidence and death data directly, and to resistance data and demographic data indirectly among men who have sex with men (MSM) in San Francisco. Using counterfactual scenarios, we assessed the impact on total and drug-resistant HIV incidence of ART initiation timing, frequency of acquired drug resistance, and second-line drug effectiveness (defined as the combination of resistance monitoring, biomedical drug efficacy and adherence). Earlier ART initiation could decrease the number of both total and drug-resistant HIV incidence when second-line drug effectiveness is sufficiently high (greater than 80%), but increase the proportion of new infections that are drug resistant. Thus, resistance may paradoxically appear to be increasing while actually decreasing. © 2017 The Author(s).

Therapeutic cloning in the mouse

Science.gov (United States)

Mombaerts, Peter

2003-01-01

Nuclear transfer technology can be applied to produce autologous differentiated cells for therapeutic purposes, a concept termed therapeutic cloning. Countless articles have been published on the ethics and politics of human therapeutic cloning, reflecting the high expectations from this new opportunity for rejuvenation of the aging or diseased body. Yet the research literature on therapeutic cloning, strictly speaking, is comprised of only four articles, all in the mouse. The efficiency of derivation of embryonic stem cell lines via nuclear transfer is remarkably consistent among these reports. However, the efficiency is so low that, in its present form, the concept is unlikely to become widespread in clinical practice. PMID:12949262

The therapeutic efficacy of propranolol in children with recurrent primary epistaxis

Science.gov (United States)

Bjelakovic, Bojko; Bojanovic, Mila; Lukic, Stevo; Saranac, Ljiljana; Vukomanovic, Vladislav; Prijic, Sergej; Zivkovic, Nikola; Randjelovic, Dusica

2013-01-01

We hypothesized that some characteristics of beta-blockers, including negative inotropic, peripheral vasoconstrictor, and antiangiogenic effects, might be potentially useful in treating children with epistaxis. From June 2010 to March 2012, a total of seven children with recurrent primary epistaxis resistant to conventional management were observed at our institution. An overall effectiveness of propranolol was noted in all seven children when given a dose of 1.5–2 mg/kg/day (divided into three doses) as a second line therapy for terminating epistaxis. Based on our first experience, we believe that propranolol could be a favorable treatment option for patients with primary epistaxis. PMID:23467483

Options for the solution of the problem of insulators contamination; Alternativas de solucion al problema de contaminacion en aisladores

Energy Technology Data Exchange (ETDEWEB)

Fierro Chavez, Jose Luis [Instituto de Investigaciones Electricas, Cuernavaca (Mexico)

1996-12-31

In accordance with Comision Federal de Electricidad (CFE) statistics, the insulators contamination is cataloged as the second cause of transmission power lines outages. In this article a revision of the different available options for the solution or diminution of this problem, is presented. The application of these options must be made within a technico-economic and cost-benefit frame. [Espanol] De acuerdo con estadisticas de la Comision Federal de Electricidad (CFE) la contaminacion del aislamiento esta catalogada como la segunda causa de salidas de las lineas de transmision. En este articulo se presenta una revision de las diferentes alternativas disponibles para solucionar o disminuir este problema. La aplicacion de estas alternativas debe hacerse dentro de un marco tecnicoeconomico y de costo-beneficio.

Options for the solution of the problem of insulators contamination; Alternativas de solucion al problema de contaminacion en aisladores

Energy Technology Data Exchange (ETDEWEB)

Fierro Chavez, Jose Luis [Instituto de Investigaciones Electricas, Cuernavaca (Mexico)

1997-12-31

In accordance with Comision Federal de Electricidad (CFE) statistics, the insulators contamination is cataloged as the second cause of transmission power lines outages. In this article a revision of the different available options for the solution or diminution of this problem, is presented. The application of these options must be made within a technico-economic and cost-benefit frame. [Espanol] De acuerdo con estadisticas de la Comision Federal de Electricidad (CFE) la contaminacion del aislamiento esta catalogada como la segunda causa de salidas de las lineas de transmision. En este articulo se presenta una revision de las diferentes alternativas disponibles para solucionar o disminuir este problema. La aplicacion de estas alternativas debe hacerse dentro de un marco tecnicoeconomico y de costo-beneficio.

Who will bear the torch tomorrow? Charismatic leadership and second-line leaders in development NGOs

OpenAIRE

M. Shameem Siddiqi

2001-01-01

Competent leadership has always been considered vital in every organisation and there has been considerable research on mainstream leadership issues in the corporate sector and in politics.1 But there has been very little research on leadership issues in the emerging sector of development NGOs. The issue of second-line leadership development2 is an important one not only for the NGOs themselves but also for the aid industry, the poor and vulnerable people for whom they work and for society as...

Therapeutic decisions in ALS patients: cross-cultural differences and clinical implications.

Science.gov (United States)

Andersen, Peter M; Kuzma-Kozakiewicz, Magdalena; Keller, Jürgen; Aho-Oezhan, Helena E A; Ciecwierska, Katarzyna; Szejko, Natalia; Vázquez, Cynthia; Böhm, Sarah; Badura-Lotter, Gisela; Meyer, Thomas; Petri, Susanne; Linse, Katharina; Hermann, Andreas; Semb, Olof; Stenberg, Erica; Nackberg, Simona; Dorst, Johannes; Uttner, Ingo; Häggström, Ann-Cristin; Ludolph, Albert C; Lulé, Dorothée

2018-05-04

Quantitative analysis of decision-making on therapeutic options in different sociocultural context in amyotrophic lateral sclerosis (ALS). ALS patients (n = 244) were consecutively recruited in Germany (n = 83), Poland (n = 83), and Sweden (n = 78) in a prospective cross-cultural study ( www.NEEDSinALS.com ). They were interviewed on preferences for therapeutic techniques including invasive (IV) and non-invasive ventilation (NIV), as well as percutaneous endoscopic gastrostomy (PEG) and on hypothetical termination of these using quantitative questions. Using standardized questionnaires, religiousness, personal values, quality of life, and depressiveness were assessed. NIV was most frequently used in Germany and PEG in Sweden. Swedish patients were most liberal on initiation and termination of PEG, NIV and IV. Polish patients were mostly undecided and were least likely to consider discontinuing supportive management. Current use was partly associated with age, gender and state of physical function; also, financial support explained some variance. Future preferences on therapeutic options from the patient's perspective were also closely associated with cultural factors. The more oriented towards traditional and conservative values, the less likely patients were to decide for invasive therapeutic devices (IV, PEG), the least likely to have ideations to discontinue any device and the more likely to have an undecided attitude. Current use of therapeutic options is determined by medical condition in analogy to clinical guidelines. For future considerations, other factors such as cultural background are crucial, yielding hurdles to be regarded in the implementation of advanced directives in a multicultural environment.

Options for modulation of drug resistance in ovarian cancer

NARCIS (Netherlands)

Arts, HJG; Van der Zee, AGJ; De Jong, S; De Vries, EGE

2000-01-01

The objective of this paper is to present an update of mechanisms responsible for drug resistance in ovarian cancer and the possible therapeutic options to modulate this resistance using literature review with emphasis on data acquired in studies comprising ovarian tumor samples. The classic

An LC-MS Assay with Isocratic Separation and On-Line Solid Phase Extraction to Improve the Routine Therapeutic Drug Monitoring of Busulfan in Plasma

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Ialongo Cristiano

2017-04-01

Full Text Available Background: Busulfan (Bu requires therapeutic drug monitoring (TDM in subjects undergoing a conditioning regimen for hematopoietic stem cell transplantation (HSCT. To speed up the procedure and increase reproducibility, we improved our routine LC-MS/MS assay using the on-line solid-phase extraction (SPE of samples.

Irinotecan and oxaliplatin: an overview of the novel chemotherapeutic options for the treatment of advanced colorectal cancer

Directory of Open Access Journals (Sweden)

I. Grivicich

2001-09-01

Full Text Available Colorectal cancer is one of the most frequent malignancies in humans and an important cause of cancer death. Metastatic colorectal cancer remains incurable with available systemic therapeutic options. The most active cytotoxic drug against this malignancy, the antimetabolite 5-fluorouracil, was developed more than forty years ago, and as a single agent produces responses in only 10 to 15% of patients which in general last less than one year. Efforts to ameliorate these poor results resulted in the 5-fluorouracil/leucovorin combination, which enhances response rates about two-fold, without, however, significantly improving survival rates. The recent emergence of a handful of new 5-fluorouracil analogues and folate antagonists, as well as the topoisomerase I inhibitor irinotecan, and the third-generation platinum compound oxaliplatin, is likely to alter this gloomy scenario. These agents are at least as effective as 5-fluorouracil in patients with advanced colorectal carcinoma, both untreated and previously treated with 5-fluorouracil-based regimens. This has led to the approval of irinotecan as second-line treatment for 5-fluorouracil-refractory disease, while the use of oxaliplatin has been suggested for patients having a defective 5-fluorouracil catabolism. Recently, FDA approved the combination of irinotecan with 5-fluorouracil and leucovorin for first-line treatment of advanced colon cancer. Based on the synergistic preclinical antitumor effects of some of these agents, their meaningful single-agent activity, distinct mechanisms of cytotoxicity and resistance, and only partially overlapping toxicity profiles, effective combination regimens are now being developed, which are likely to lead to a new, more hopeful era for patients suffering from advanced colorectal carcinoma.

Novel therapeutic options for relapsed hairy cell leukemia.

Science.gov (United States)

Jain, Preetesh; Polliack, Aaron; Ravandi, Farhad

2015-01-01

The majority of patients with hairy cell leukemia (HCL) achieve a response to therapy with cladribine or pentostatin with or without rituximab. However, late relapses can occur. Treatment of relapsed HCL can be difficult due to a poor tolerance to chemotherapy, increased risk of infections and decreased responsiveness to chemotherapy. The identification of BRAFV600E mutations and the role of aberrant MEK kinase and Bruton's tyrosine kinase (BTK) pathways in the pathogenesis of HCL have helped to develop novel targeted therapies for these patients. Currently, the most promising therapeutic strategies for relapsed or refractory HCL include recombinant immunoconjugates targeting CD22 (e.g. moxetumomab pasudotox), BRAF inhibitors such as vemurafenib and B cell receptor signaling kinase inhibitors such as ibrutinib. Furthermore, the VH4-34 molecular variant of classic HCL has been identified to be less responsive to chemotherapy. Herein, we review the results of the ongoing clinical trials and potential future therapies for relapsed/refractory HCL.

HIV multi-drug resistance at first-line antiretroviral failure and subsequent virological response in Asia.

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Jiamsakul, Awachana; Sungkanuparph, Somnuek; Law, Matthew; Kantor, Rami; Praparattanapan, Jutarat; Li, Patrick C K; Phanuphak, Praphan; Merati, Tuti; Ratanasuwan, Winai; Lee, Christopher K C; Ditangco, Rossana; Mustafa, Mahiran; Singtoroj, Thida; Kiertiburanakul, Sasisopin

2014-01-01

First-line antiretroviral therapy (ART) failure often results from the development of resistance-associated mutations (RAMs). Three patterns, including thymidine analogue mutations (TAMs), 69 Insertion (69Ins) and the Q151M complex, are associated with resistance to multiple-nucleoside reverse transcriptase inhibitors (NRTIs) and may compromise treatment options for second-line ART. We investigated patterns and factors associated with multi-NRTI RAMs at first-line failure in patients from The TREAT Asia Studies to Evaluate Resistance - Monitoring study (TASER-M), and evaluated their impact on virological responses at 12 months after switching to second-line ART. RAMs were compared with the IAS-USA 2013 mutations list. We defined multi-NRTI RAMs as the presence of either Q151M; 69Ins; ≥ 2 TAMs; or M184V+≥ 1 TAM. Virological suppression was defined as viral load (VL) failure and (2) factors associated with virological suppression after 12 months on second-line. A total of 105 patients from 10 sites in Thailand, Hong Kong, Indonesia, Malaysia and Philippines were included. There were 97/105 (92%) patients harbouring ≥ 1 RAMs at first-line failure, 39/105 with multi-NRTI RAMs: six with Q151M; 24 with ≥ 2 TAMs; and 32 with M184V+≥ 1 TAM. Factors associated with multi-NRTI RAMs were CD4 ≤ 200 cells/µL at genotyping (OR=4.43, 95% CI [1.59-12.37], p=0.004) and ART duration >2 years (OR=6.25, 95% CI [2.39-16.36], pfailure were associated with low CD4 level and longer duration of ART. With many patients switching to highly susceptible regimens, good adherence was still crucial in achieving virological response. This emphasizes the importance of continued adherence counselling well into second-line therapy.

Polymyxins: Antimicrobial susceptibility concerns and therapeutic options

Directory of Open Access Journals (Sweden)

V Balaji

2011-01-01

Full Text Available The increasing prevalence of multidrug-resistant nosocomial pathogens such as Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae poses a great challenge to the treating physicians. The paucity of newer effective antimicrobials has led to renewed interest in the polymyxin group of drugs, as a last resort for treatment of gram-negative bacterial infections. There is a dearth of information on the pharmacological properties of colistin, leading to difficulties in selecting the right dose, dosing interval, and route of administration for treatment, especially in critically-ill patients. The increasing use of colistin over the last few years necessitates the need for accurate and reliable in vitro susceptibility testing methods. Development of heteroresistant strains as a result of colistin monotherapy is also a growing concern. There is a compelling need from the clinicians to provide options for probable and possible colistin combination therapy for multidrug-resistant bacterial infections in the ICU setting. Newer combination drug synergy determination tests are being developed and reported. There are no standardized recommendations from antimicrobial susceptibility testing reference agencies for the testing and interpretation of these drug combinations. Comparison and analysis of these reported methodologies may help to understand and assist the microbiologist to choose the best method that produces accurate results at the earliest. This will help clinicians to select the appropriate combination therapy. In this era of multidrug resistance it is important for the microbiology laboratory to be prepared, by default, to provide timely synergistic susceptibility results in addition to routine susceptibility, if warranted. Not as a favour or at request, but as a responsibility.

SunLine Transit Agency Advanced Technology Fuel Cell Bus Evaluation: Second Results Report and Appendices

Energy Technology Data Exchange (ETDEWEB)

Eudy, L.; Chandler, K.

2011-10-01

This report describes operations at SunLine Transit Agency for their newest prototype fuel cell bus and five compressed natural gas (CNG) buses. In May 2010, SunLine began operating its sixth-generation hydrogen fueled bus, an Advanced Technology (AT) fuel cell bus that incorporates the latest design improvements to reduce weight and increase reliability and performance. The agency is collaborating with the U.S. Department of Energy's (DOE) National Renewable Energy Laboratory (NREL) to evaluate the bus in revenue service. This is the second results report for the AT fuel cell bus since it was placed in service, and it focuses on the newest data analysis and lessons learned since the previous report. The appendices, referenced in the main report, provide the full background for the evaluation. They will be updated as new information is collected but will contain the original background material from the first report.

Randomized Phase II trial of paclitaxel plus valproic acid vs paclitaxel alone as second-line therapy for patients with advanced gastric cancer

Directory of Open Access Journals (Sweden)

Fushida S

2015-04-01

Full Text Available Sachio Fushida,1 Masahide Kaji,2 Katsunobu Oyama,1 Yasuo Hirono,3 Hideaki Nezuka,4 Toshiya Takeda,5 Tomoya Tsukada,1 Daisuke Fujimoto,3 Shigekazu Ohyama,6 Takashi Fujimura,7 Tetsuo Ohta1 On behalf of the Digestive Disease Support Organization (DDSO 1Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, 2Department of Surgery, Toyama Prefectural Central Hospital, Toyama, 3First Department of Surgery, Fukui University Hospital, Fukui, 4Department of Surgery, Yatsuo General Hospital, Toyama, 5Department of Surgery, Ishikawa Matto Central Hospital, Hakusan, 6Department of Surgery, Kanazawa Medical Center, Kanazawa, 7Toyama City Hospital, Toyama, Japan Abstract: The standard regimen of second-line chemotherapy for patients with unresectable gastric cancer has not been established. However, weekly paclitaxel (wPTX has become the preferable second-line chemotherapy in Japan. Histone deacetylase (HDAC inhibitors have been shown to have antiproliferative activity through cell-cycle arrest, differentiation, and apoptosis in gastric cancer cells. One HDAC inhibitor, valproic acid (VPA, also inhibits tumor growth by inducing apoptosis, and enhances the efficacy of paclitaxel in a mouse xenograft model of gastric cancer. wPTX plus VPA as a second-line chemotherapy is expected to improve survival in gastric cancer patients. A multicenter randomized Phase II study was conducted to compare the effects of wPTX plus VPA and wPTX alone. A total of 66 patients participated in this study. The primary end point of the study was overall survival, and secondary end points were progression-free survival, response rate, and assessment of peripheral neuropathy. Keywords: valproic acid, paclitaxel, second-line therapy, advanced gastric cancer 

In chronic myeloid leukemia patients on second-line tyrosine kinase inhibitor therapy, deep sequencing of BCR-ABL1 at the time of warning may allow sensitive detection of emerging drug-resistant mutants.

Science.gov (United States)

Soverini, Simona; De Benedittis, Caterina; Castagnetti, Fausto; Gugliotta, Gabriele; Mancini, Manuela; Bavaro, Luana; Machova Polakova, Katerina; Linhartova, Jana; Iurlo, Alessandra; Russo, Domenico; Pane, Fabrizio; Saglio, Giuseppe; Rosti, Gianantonio; Cavo, Michele; Baccarani, Michele; Martinelli, Giovanni

2016-08-02

Imatinib-resistant chronic myeloid leukemia (CML) patients receiving second-line tyrosine kinase inhibitor (TKI) therapy with dasatinib or nilotinib have a higher risk of disease relapse and progression and not infrequently BCR-ABL1 kinase domain (KD) mutations are implicated in therapeutic failure. In this setting, earlier detection of emerging BCR-ABL1 KD mutations would offer greater chances of efficacy for subsequent salvage therapy and limit the biological consequences of full BCR-ABL1 kinase reactivation. Taking advantage of an already set up and validated next-generation deep amplicon sequencing (DS) assay, we aimed to assess whether DS may allow a larger window of detection of emerging BCR-ABL1 KD mutants predicting for an impending relapse. a total of 125 longitudinal samples from 51 CML patients who had acquired dasatinib- or nilotinib-resistant mutations during second-line therapy were analyzed by DS from the time of failure and mutation detection by conventional sequencing backwards. BCR-ABL1/ABL1%(IS) transcript levels were used to define whether the patient had 'optimal response', 'warning' or 'failure' at the time of first mutation detection by DS. DS was able to backtrack dasatinib- or nilotinib-resistant mutations to the previous sample(s) in 23/51 (45 %) pts. Median mutation burden at the time of first detection by DS was 5.5 % (range, 1.5-17.5 %); median interval between detection by DS and detection by conventional sequencing was 3 months (range, 1-9 months). In 5 cases, the mutations were detectable at baseline. In the remaining cases, response level at the time mutations were first detected by DS could be defined as 'Warning' (according to the 2013 ELN definitions of response to 2nd-line therapy) in 13 cases, as 'Optimal response' in one case, as 'Failure' in 4 cases. No dasatinib- or nilotinib-resistant mutations were detected by DS in 15 randomly selected patients with 'warning' at various timepoints, that later turned into optimal

An industry update: the latest news in therapeutic delivery.

Science.gov (United States)

Harris, Elaine

2017-11-01

The present industry update covers the period 1-31 July 2017. Information was sourced primarily from company press releases, regulatory and patent agencies, scientific literature and various news websites. There was positive approval news this month for GlaxoSmithKline for its new self-injecting treatment for systemic lupus erythematosus but less positive news for Ocular Therapeutix, a new drug application for its treatment for postoperative ocular pain, DEXTENZA™ was rejected for a second time. Endo Pharmaceuticals agreed to withdraw its opioid formulation Opana ® Er due to abuse concerns. Collaborations for novel therapeutic delivery research were announced this month by Takeda and BioSurfaces, Catelent and Rutgers University, Lilly and Purdue University and Titan Pharmaceuticals with Walter Reed and the Southwest Research Institute. A number of companies announced significant financing deals to allow for the clinical development of products with enhanced delivery options including Sebacia and Diasome.

Therapeutic cloning in individual parkinsonian mice

Science.gov (United States)

Tabar, Viviane; Tomishima, Mark; Panagiotakos, Georgia; Wakayama, Sayaka; Menon, Jayanthi; Chan, Bill; Mizutani, Eiji; Al-Shamy, George; Ohta, Hiroshi; Wakayama, Teruhiko; Studer, Lorenz

2009-01-01

Cell transplantation with embryonic stem (ES) cell progeny requires immunological compatibility with host tissue. ‘Therapeutic cloning’ is a strategy to overcome this limitation by generating nuclear transfer (nt)ES cells that are genetically matched to an individual. Here we establish the feasibility of treating individual mice via therapeutic cloning. Derivation of 187 ntES cell lines from 24 parkinsonian mice, dopaminergic differentiation, and transplantation into individually matched host mice showed therapeutic efficacy and lack of immunological response. PMID:18376409

Cost Effectiveness Analysis of Different Management Strategies between Best Supportive Care and Second-line Chemotherapy for Platinum-resistant or Refractory Ovarian Cancer.

Science.gov (United States)

Luealon, Phanida; Khempech, Nipon; Vasuratna, Apichai; Hanvoravongchai, Piya; Havanond, Piyalamporn

2016-01-01

There is no standard treatment for patients with platinum-resistant or refractory epithelial ovarian cancer. Single agent chemotherapies have evidence of more efficacy and less toxicity than combination therapy. Most are very expensive, with appreciable toxicity and minimal survival. Since it is difficult to make comparison between outcomes, economic analysis of single-agent chemotherapy regimens and best supportive care may help to make decisions about an appropriate management for the affected patients. To evaluate the cost effectiveness of second-line chemotherapy compared with best supportive care for patients with platinum-resistant or refractory epithelial ovarian cancer. A Markov model was used to estimate the effectiveness and total costs associated with treatments. The hypothetical patient population comprised women aged 55 with platinum-resistant or refractory epithelial ovarian cancer. Four types of alternative treatment options were evaluated: 1) gemcitabine followed by BSC; 2) pegylated liposomal doxorubicin (PLD) followed by BSC; 3) gemcitabine followed by topotecan; and 4) PLD followed by topotecan. Baseline comparator of alternative treatments was BSC. Time horizon of the analysis was 2 years. Health care provider perspective and 3% discount rate were used to determine the costs of medical treatment in this study. Quality-adjusted life-years (QALY) were used to measure the treatment effectiveness. Treatment effectiveness data were derived from the literature. Costs were calculated from unit cost treatment of epithelial ovarian cancer patients at various stages of disease in King Chulalongkorn Memorial Hospital (KCMH) in the year 2011. Parameter uncertainty was tested in probabilistic sensitivity analysis by using Monte Carlo simulation. One-way sensitivity analysis was used to explore each variable's impact on the uncertainty of the results. Approximated life expectancy of best supportive care was 0.182 years and its total cost was 26,862 Baht. All

[Female androgenetic alopecia, a survey of causes and therapeutic options].

Science.gov (United States)

Duchková, Hana; Hašková, Marta

2015-01-01

Mesotherapy is one of the options for the treatment of androgenetic alopecia. Testing 24 women with androgenetic alopecia has demonstrated a positive effect of mesotherapy on the hair growth, hair thickness, with only insignificant increase of hair density. It is known that androgenetic alopecia represents a localized aging of hair follicles. We therefore decided to examine the different effects of mesotherapy on hair density in younger and in elderly women. In younger women mesotherapy significantly increased hair density compared with older women. For mesotherapy we used a combination of micronutrients and antioxidants. Mesotherapy achievements were evident for 6-12 months. Treatment requires a long-term care.

Proposed inductive voltage adder based accelerator concepts for the second axis of DARHT

International Nuclear Information System (INIS)

Smith, D.L.; Johnson, D.L.; Boyes, J.D.

1997-01-01

As participants in the Technology Options Study for the second axis of the Dual Axis Radiographic HydroTest (DARHT) facility located at Los Alamos National Laboratories, the authors have considered several accelerator concepts based on the Inductive Voltage Adder (IVA) technology that is being used successfully at Sandia on the SABRE and HERMES-III facilities. The challenging accelerator design requirements for the IVA approach include: ≥12-MeV beam energy; ∼60-ns electrical pulse width; ≤40-kA electron beam current; ∼1-mm diameter e-beam; four pulses on the same axis or as close as possible to that axis; and an architecture that fits within the existing building envelope. To satisfy these requirements the IVA concepts take a modular approach. The basic idea is built upon a conservative design for eight ferromagnetically isolated 2-MV cavities that are driven by two 3 to 4-Ω water dielectric pulse forming lines (PFLs) synchronized with laser triggered gas switches. The 100-Ω vacuum magnetically insulated transmission line (MITL) would taper to a needle cathode that produces the electron beam(s). After considering many concepts the authors narrowed their study to the following options: (A) Four independent single pulse drivers powering four single pulse diodes; (B) Four series adders with interleaved cavities feeding a common MITL and diode; (C) Four stages of series PFLs, isolated from each other by triggered spark gap switches, with single-point feeds to a common adder, MITL, and diode; and (D) Isolated PFLs with multiple-feeds to a common adder using spark gap switches in combination with saturable magnetic cores to isolate the non-energized lines. The authors will discuss these options in greater detail identifying the challenges and risks associated with each

LONG-TERM RESULTS OF TARGET THERAPY WITH FIRST AND * SECOND-LINE TYROSINE KINASE INHIBITORS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA

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L. L. Vysotskaya

2015-01-01

Full Text Available Aim: To assess long-term efficacy of firstand second-line tyrosine kinase inhibitors in non-selected patients with chronic myeloid leukemia in a real-life clinical setting.Materials and methods: The assessment is based on long-term results of a prospective single center comparative clinical trial that was based on non-selected groups of 116 patients with various stages of chronic myeloid leukemia being treated with a first generation tyrosine kinase inhibitor imatinib, and of 44 patients being treated with a second generation tyrosine kinase inhibitor nilotinib. We analyzed all-cause mortality, progression-free survival from April 2005 to April 2013, with a median of the follow-up of 128 months.Results: In 116 patients with chronic myeloid leukemia treated with imatinib, the Kaplan-Meier survival estimate was 120 months. In 44 patients at an early chronic phase, 5-year overall survival and progression-free survival was 93.2% and 8-year overall and progression-free survival was 79.5%. In 44 patients at a late chronic stage, 5-year overall and progression-free survival was 95.5%, 8-year overall and progression-free survival, 72.7%. In 28 patients at acceleration phase, 5-years overall survival was 78.6% and 8-year overall survival, 46%. Median of overall survival in patients treated with nilotinib was not reached. During 78.6 months of combination treatment with cytotoxic agents, tyrosine kinase inhibitors of the first (imatinib and second line (nilotinib, overall survival was 100%.Conclusion: In clinical practice, inclusion of patients with chronic myeloid leukemia and imatinib resistance (disease relapse or imatinib intolerance into the treatment program with frontline therapy with general cytotoxic agents and thereafter with firstand second-line tyrosine kinase inhibitors significantly improves overall survival.

A cross-sectional study to evaluate second line virological failure and elevated bilirubin as a surrogate for adherence to atazanavir/ritonavir in two urban HIV clinics in Lilongwe, Malawi.

Science.gov (United States)

Ongubo, Dennis Miyoge; Lim, Robertino; Tweya, Hannock; Stanley, Christopher Chikhosi; Tembo, Petros; Broadhurst, Richard; Gugsa, Salem; Ngongondo, McNeil; Speight, Colin; Heller, Tom; Phiri, Sam; Hosseinipour, Mina C

2017-07-03

Malawi's national antiretroviral therapy program provides atazanavir/ritonavir-based second line regimens which cause concentration-dependent rise in indirect bilirubin. We sought to determine if elevated bilirubin, as a surrogate of atazanavir/ritonavir adherence, can aid in the evaluation of second line virological failure in Malawi. We conducted a cross-sectional study of HIV-infected patients ≥15 years who were on boosted protease inhibitor-based second line antiretroviral therapy for at least 6 months in two urban HIV clinics in Lilongwe, Malawi. Antiretroviral therapy history and adherence data were extracted from the electronic medical records and blood was drawn for viral load, complete blood count, total bilirubin, and CD4 cell count at a clinic visit. Factors associated with virological failure were assessed using multivariate logistic regression model. Out of 376 patients on second line antiretroviral therapy evaluated, 372 (98.9%) were on atazanavir/ritonavir-based therapy and 142 (37.8%) were male. Mean age was 40.9 years (SD ± 10.1), mean duration on second line antiretroviral therapy was 41.9 months (SD ± 27.6) and 256 patients (68.1%) had elevated bilirubin >1.3 mg/dL. Overall, 35 (9.3%) patients had viral load >1000 copies/ml (virological failure). Among the virologically failing vs. non-failing patients, bilirubin was elevated in 34.3% vs. 72.0% respectively (p bilirubin levels (aOR 5.4, p bilirubin levels better predicted virological failure than pill count adherence. Therefore, strategic use of bilirubin and viral load testing to target adherence counseling and support may be cost-effective in monitoring second line antiretroviral therapy adherence and virological failure. Drug resistance testing targeted for patients with virological failure despite elevated bilirubin levels would facilitate timely switch to third line antiretroviral regimens whenever available.

Therapeutic options in peripheral T cell lymphoma

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Yaping Zhang

2016-04-01

Full Text Available Abstract Peripheral T cell lymphoma (PTCL is a rare and heterogeneous group of non-Hodgkin lymphomas with a very poor prognosis. The standard first-line treatments have resulted in unsatisfactory patient outcomes. With the exception of low-risk anaplastic lymphoma kinase (ALK-positive anaplastic large cell lymphoma (ALCL, the majority of patients relapse rapidly; the current 5-year overall survival rates are only 10–30 %. Novel targeted therapies and combination chemotherapies are required for the treatment of patients with PTCL. In recent years, some retrospective and prospective studies have been performed concerning PTCL. Consequently, a number of novel agents and their relevant combination therapies have been identified, including histone deacetylase inhibitors, immunoconjugates, antifolates, monoclonal antibodies, immunomodulatory agents, nucleoside analogs, proteasome inhibitors, kinase inhibitors, bendamustine, l-asparaginase, and other targeted agents. It is hoped that these innovative approaches will finally improve outcomes in patients with PTCL. This review summarizes the currently available approaches for the treatment of PTCL with an emphasis on potential new agents, including the role of stem cell transplantation.

Metronomic capecitabine as second-line treatment in hepatocellular carcinoma after sorafenib failure.

Science.gov (United States)

Granito, Alessandro; Marinelli, Sara; Terzi, Eleonora; Piscaglia, Fabio; Renzulli, Matteo; Venerandi, Laura; Benevento, Francesca; Bolondi, Luigi

2015-06-01

No standard second-line treatments are available for hepatocellular carcinoma patients who fail sorafenib therapy. We assessed the safety and efficacy of metronomic capecitabine after first-line sorafenib failure. Retrospective analysis of consecutive hepatocellular carcinoma patients receiving metronomic capecitabine between January 2012 and November 2014. The primary end-point was safety, secondary end-point was efficacy, including time-to-progression and overall survival. Twenty-six patients (80% Child-Pugh A, 80% Barcelona Clinic Liver Cancer stage C) received metronomic capecitabine (500 mg/bid). Median treatment duration was 3.2 months (range 0.6-31). Fourteen (53%) patients experienced at least one adverse event. The most frequent drug-related adverse events were bilirubin elevation (23%), fatigue (15%), anaemia (11%), lymphoedema (11%), and hand-foot syndrome (7.6%). Treatment was interrupted in 19 (73%) for disease progression, in 4 (15%) for liver deterioration, and in 1 (3.8%) for adverse event. Disease control was achieved in 6 (23%) patients. Median time-to-progression was 4 months (95% confidence interval 3.2-4.7). Median overall survival was 8 months (95% confidence interval 3.7-12.3). Metronomic capecitabine was well tolerated in hepatocellular carcinoma patients who had been treated with sorafenib. Preliminary data show potential anti-tumour activity with long-lasting disease control in a subgroup of patients that warrants further evaluation in a phase III study. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Metabolic syndrome: nature, therapeutic solutions and options.

Science.gov (United States)

Onat, Altan

2011-08-01

Metabolic syndrome (MetS) defines the clustering in an individual of multiple metabolic abnormalities, based on central obesity and insulin resistance. In addition to its five components, prothrombotic and proinflammatory states are essential features. The significance of MetS lies in its close association with the risk of type 2 diabetes and cardiovascular disease (CVD). This field being an evolving one necessitated the current review. The areas covered in this review include the so far unproven concept that enhanced low-grade inflammation often leads to dysfunction of the anti-inflammatory and atheroprotective properties of apolipoprotein A-I (apoA-I) and HDL particles, which further increases the risk of diabetes and CVD. It was emphasized that lifestyle modification is essential in the prevention and management of MetS, which includes maintenance of optimal weight by caloric restriction, adherence to a diet that minimizes postprandial glucose and triglyceride fluctuations, restricting alcohol consumption, smoking cessation and engaging in regular exercise. Drug therapy should target the dyslipoproteinemia and the often associated hypertension or dysglycemia.Statins are the drugs of first choice, to be initiated in patients with MetS at high 10-year cardiovascular risk. Such treatment is inadequate if fasting serum triglycerides remain at > 150 mg/dl, when niacin should be combined. Fibrates, omega 3 fatty acids, metformin, angiotensin-converting enzyme inhibitors and pioglitazone are additional options in drug therapy. Research on MetS in subpopulations prone to impaired glucose tolerance and insulin resistance has indicated that proinflammatory state and oxidative stress are often prominently involved in MetS, to the extent that evidence of impaired function of HDL and apo A-I particles is discernible by biological evidence of functional defectiveness via outcomes studies and/or correlations with inflammatory and anti-inflammatory biomarkers. A sex difference

New therapeutic options for the metabolic syndrome: what's next?

Science.gov (United States)

Flordellis, Christodoulos S; Ilias, Ioannis; Papavassiliou, Athanasios G

2005-08-01

The metabolic syndrome (MSX), characterized by obesity, insulin resistance, dyslipidemia and hypertension, increases the risk of cardiovascular morbidity and mortality. It has recently been hypothesized that MSX and type 2 diabetes are caused by triglyceride and long-chain fatty acid accumulation in liver, muscle, pancreatic islets and selected brain areas. This lipocentric approach is integrated with analysis of inflammation associated with end-organ damage, including the vascular wall. Genes and proteins contributing to insulin resistance, beta cell dysfunction and vascular wall damage have been identified. Transcription factors and coactivators, including peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 are crucial in mediating insulin resistance and accelerating vascular wall inflammation, and represent promising therapeutic targets. New pharmacological strategies include dual PPARalpha/gamma agonists, drugs with pleiotropic effects or combination therapies.

Splenomegaly in myelofibrosis—new options for therapy and the therapeutic potential of Janus kinase 2 inhibitors

Directory of Open Access Journals (Sweden)

Randhawa Jasleen

2012-08-01

Full Text Available Abstract Splenomegaly is a common sign of primary myelofibrosis (PMF, post-polycythemia vera myelofibrosis (post-PV MF, and post-essential thrombocythemia myelofibrosis (post-ET MF that is associated with bothersome symptoms, which have a significant negative impact on patients’ quality of life. It may also be present in patients with advanced polycythemia vera (PV or essential thrombocythemia (ET. Until recently, none of the therapies used to treat MF were particularly effective in reducing splenomegaly. The discovery of an activating Janus kinase 2 (JAK2 activating mutation (JAK2V617F that is present in almost all patients with PV and in about 50-60 % of patients with ET and PMF led to the initiation of several trials investigating the clinical effectiveness of various JAK2 (or JAK1/JAK2 inhibitors for the treatment of patients with ET, PV, and MF. Some of these trials have documented significant clinical benefit of JAK inhibitors, particularly in terms of regression of splenomegaly. In November 2011, the US Food and Drug Administration approved the use of the JAK1- and JAK2-selective inhibitor ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and post-ET MF. This review discusses current therapeutic options for splenomegaly associated with primary or secondary MF and the treatment potential of the JAK inhibitors in this setting.

Membrana amniótica como alternativa de tratamiento en superficie ocular Amniotic membrane as a therapeutic option for the ocular surface

Directory of Open Access Journals (Sweden)

Keyly Fernández García

2012-12-01

Full Text Available Se realizó una revisión bibliográfica con el objetivo de conocer la utilidad de la membrana amniótica como alternativa de tratamiento en la superficie ocular. Son abordados tópicos como las diferentes formas de obtención, preparación y conservación de la misma, sus mecanismos de acción y aplicaciones. Se consultó una bibliografía que abarca un periodo de varios años para conocer los resultados publicados sobre el trasplante de membrana amniótica humana en la superficie ocular.A literature review was made to learn about the usefulness of the amniotic membrane as a therapeutic option for the ocular surface. The different ways for obtaining, preparing, and conserving this membrane, its mechanism of action and its applications were also addressed. Literature covering several years was reviewed in order to be acquainted with the published results of the human amniotic membrane transplantation on the ocular surface.

Electric and magnetic field reduction by alternative transmission line options

Energy Technology Data Exchange (ETDEWEB)

Stewart, J.R. (Power Technologies, Inc., Schenectady, NY (United States)); Dale, S.J. (Oak Ridge National Lab., TN (United States)); Klein, K.W. (Energetics, Inc., Columbia, MD (United States))

1991-01-01

Ground level electric, and more recently magnetic, fields from overhead power transmission lines are increasingly important considerations in right of way specification, with states setting or planning to set edge of right of way limits. Research has been conducted in high phase order power transmission wherein six of twelve phases are used to transmit power in less physical space and with reduced electrical environmental effects than conventional designs. The first magnetic field testing, as reported in this paper, has verified predictive methods for determination of magnetic fields from high phase order lines. Based on these analytical methods, field profiles have been determined for lines of different phase order of comparable power capacity. Potential advantages of high phase order as a means of field mitigation are discussed. 10 refs., 12 figs., 3 tabs.

Medical device for applying therapeutic radiation

International Nuclear Information System (INIS)

Tokita, K.M.; Haller, B.L.

1986-01-01

A device is described for applying therapeutic radiation from a preselected radiation source to a predetermined portion of a body comprising, in combination: a body member having: an external peripheral surface; a first end surface; and a second end surface spaced from the first end surface; the body member further comprising: at least first internal walls defining a first radiation source receiving channel means spaced a preselected distance from the peripheral surface, and having: a first portion extending from the second end surface to regions adjacent the first end surface; and a second portion extending from the first portion at the first end surface to the second end surface; and, the channel means communicating with regions external the body member at the second surface whereby the radiation source of a preselected intensity inserted at least along a preselected portion of the channel means is applied to the predetermined area of the body requiring therapeutic radiation treatment

Discontinuing VEGF-targeted Therapy for Progression Versus Toxicity Affects Outcomes of Second-line Therapies in Metastatic Renal Cell Carcinoma

DEFF Research Database (Denmark)

De Velasco, Guillermo; Xie, Wanling; Donskov, Frede

2017-01-01

BACKGROUND: A significant subgroup of metastatic renal cell carcinoma (mRCC) patients discontinue vascular endothelial growth factor-targeted therapies (VEGF-TT) because of toxicity. Whether clinical outcomes differ in patients who receive second-line (2L) targeted therapy on the basis of reason ...

Novel treatment options for portal hypertension

Science.gov (United States)

Laleman, Wim

2017-01-01

Abstract Portal hypertension is most frequently associated with cirrhosis and is a major driver for associated complications, such as variceal bleeding, ascites or hepatic encephalopathy. As such, clinically significant portal hypertension forms the prelude to decompensation and impacts significantly on the prognosis of patients with liver cirrhosis. At present, non-selective β-blockers, vasopressin analogues and somatostatin analogues are the mainstay of treatment but these strategies are far from satisfactory and only target splanchnic hyperemia. In contrast, safe and reliable strategies to reduce the increased intrahepatic resistance in cirrhotic patients still represent a pending issue. In recent years, several preclinical and clinical trials have focused on this latter component and other therapeutic avenues. In this review, we highlight novel data in this context and address potentially interesting therapeutic options for the future. PMID:28533907

Patterns of HIV-1 drug resistance after first-line antiretroviral therapy (ART) failure in 6 sub-Saharan African countries: implications for second-line ART strategies.

Science.gov (United States)

Hamers, Raph L; Sigaloff, Kim C E; Wensing, Annemarie M; Wallis, Carole L; Kityo, Cissy; Siwale, Margaret; Mandaliya, Kishor; Ive, Prudence; Botes, Mariette E; Wellington, Maureen; Osibogun, Akin; Stevens, Wendy S; Rinke de Wit, Tobias F; Schuurman, Rob

2012-06-01

Human immunodeficiency virus type 1 (HIV-1) drug resistance may limit the benefits of antiretroviral therapy (ART). This cohort study examined patterns of drug-resistance mutations (DRMs) in individuals with virological failure on first-line ART at 13 clinical sites in 6 African countries and predicted their impact on second-line drug susceptibility. A total of 2588 antiretroviral-naive individuals initiated ART consisting of different nucleoside reverse transcriptase inhibitor (NRTI) backbones (zidovudine, stavudine, tenofovir, or abacavir, plus lamivudine or emtricitabine) with either efavirenz or nevirapine. Population sequencing after 12 months of ART was retrospectively performed if HIV RNA was >1000 copies/mL. The 2010 International Antiviral Society-USA list was used to score major DRMs. The Stanford algorithm was used to predict drug susceptibility. HIV-1 sequences were generated for 142 participants who virologically failed ART, of whom 70% carried ≥1 DRM and 49% had dual-class resistance, with an average of 2.4 DRMs per sequence (range, 1-8). The most common DRMs were M184V (53.5%), K103N (28.9%), Y181C (15.5%), and G190A (14.1%). Thymidine analogue mutations were present in 8.5%. K65R was frequently selected by stavudine (15.0%) or tenofovir (27.7%). Among participants with ≥1 DRM, HIV-1 susceptibility was reduced in 93% for efavirenz/nevirapine, in 81% for lamivudine/emtricitabine, in 59% for etravirine/rilpivirine, in 27% for tenofovir, in 18% for stavudine, and in 10% for zidovudine. Early failure detection limited the accumulation of resistance. After stavudine failure in African populations, zidovudine rather than tenofovir may be preferred in second-line ART. Strategies to prevent HIV-1 resistance are a global priority.

The effect of resveratrol in combination with irradiation and chemotherapy. Study using Merkel cell carcinoma cell lines

International Nuclear Information System (INIS)

Heiduschka, G.; Lill, C.; Brunner, M.; Thurnher, D.; Seemann, R.; Schmid, R.; Houben, R.; Bigenzahn, J.

2014-01-01

Merkel cell carcinoma (MCC) is a rare, but highly malignant tumor of the skin. In case of systemic disease, possible therapeutic options include irradiation or chemotherapy. The aim of this study was to evaluate whether the flavonoid resveratrol enhances the effect of radiotherapy or chemotherapy in MCC cell lines. The two MCC cell lines MCC13 and MCC26 were treated with increasing doses of resveratrol. Combination experiments were conducted with cisplatin and etoposide. Colony forming assays were performed after sequential irradiation with 1, 2, 3, 4, 6, and 8 Gy and apoptosis was assessed with flow cytometry. Expression of cancer drug targets was analyzed by real-time PCR array. Resveratrol is cytotoxic in MCC cell lines. Cell growth is inhibited by induction of apoptosis. The combination with cisplatin and etoposide resulted in a partially synergistic inhibition of cell proliferation. Resveratrol and irradiation led to a synergistic reduction in colony formation compared to irradiation alone. Evaluation of gene expression did not show significant difference between the cell lines. Due to its radiosensitizing effect, resveratrol seems to be a promising agent in combination with radiation therapy. The amount of chemosensitizing depends on the cell lines tested. (orig.) [de

First-Line First? Trends in Thiazide Prescribing for Hypertensive Seniors

Directory of Open Access Journals (Sweden)

Morgan Steve

2005-01-01

effective and least costly therapeutic options are significant.

A new technique for on-line and off-line high speed computation

International Nuclear Information System (INIS)

Hartouni, E.P.; Jensen, D.A.; Klima, B.; Kreisler, M.N.; Rabin, M.S.Z.; Uribe, J.; Gottschalk, E.; Gara, A.; Knapp, B.C.

1989-01-01

A new technique for both on-line and off-line computation has been developed. With this technique, a reconstruction analysis in Elementary Particle Physics, otherwise prohibitively long, has been accomplished. It will be used on-line in an upcoming Fermilab experiment to reconstruct more than 100,000 events per second and to trigger on the basis of that information. The technique delivers 40 Giga operations per second, has a bandwidth on the order of Gigabytes per second and has a modest cost. An overview of the program, details of the system, and performance measurements are presented in this paper

Immunophenotyping of Waldenstroms macroglobulinemia cell lines reveals distinct patterns of surface antigen expression: potential biological and therapeutic implications.

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Aneel Paulus

Full Text Available Waldenströms macroglobulinemia (WM is a subtype of Non-Hodgkin's lymphoma in which the tumor cell population is markedly heterogeneous, consisting of immunoglobulin-M secreting B-lymphocytes, plasmacytoid lymphocytes and plasma cells. Due to rarity of disease and scarcity of reliable preclinical models, many facets of WM molecular and phenotypic architecture remain incompletely understood. Currently, there are 3 human WM cell lines that are routinely used in experimental studies, namely, BCWM.1, MWCL-1 and RPCI-WM1. During establishment of RPCI-WM1, we observed loss of the CD19 and CD20 antigens, which are typically present on WM cells. Intrigued by this observation and in an effort to better define the immunophenotypic makeup of this cell line, we conducted a more comprehensive analysis for the presence or absence of other cell surface antigens that are present on the RPCI-WM1 model, as well as those on the two other WM cell lines, BCWM.1 and MWCL-1. We examined expression of 65 extracellular and 4 intracellular antigens, comprising B-cell, plasma cell, T-cell, NK-cell, myeloid and hematopoietic stem cell surface markers by flow cytometry analysis. RPCI-WM1 cells demonstrated decreased expression of CD19, CD20, and CD23 with enhanced expression of CD28, CD38 and CD184, antigens that were differentially expressed on BCWM.1 and MWCL-1 cells. Due to increased expression of CD184/CXCR4 and CD38, RPCI-WM1 represents a valuable model in which to study the effects anti-CXCR4 or anti-CD38 targeted therapies that are actively being developed for treatment of hematologic cancers. Overall, differences in surface antigen expression across the 3 cell lines may reflect the tumor clone population predominant in the index patients, from whom the cell lines were developed. Our analysis defines the utility of the most commonly employed WM cell lines as based on their immunophenotype profiles, highlighting unique differences that can be further studied for

Organizational and technological compatibility of the technological processes of second and third line maintenance of KhTZ-3522 tractors

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Kyzminskyj Roman

2018-01-01

Full Text Available The work is devoted to systematic substantiation of productivity, production structure and specialization of service stations of KhTZ-3522 tractors. Based on the technical and economic comparative analysis of the results of the technological processes modeling of the second and third line maintenance of KhTZ-3522 tractors, the parametrical series of production structures of service stations both mono- and polytechnological specialization, which can work effectively in a wide range of the general annual program of orders, and in the conditions of seasonal fluctuations of orders for the maintenance of these tractors, are found. The results of calculations of the indicators system for organizational and technological compatibility of technological processes of the second and third line maintenance of KhTZ-3522 tractors in the joint technological flow are presented. The dependencies of these indicators on the total annual program of orders for service stations of different productivity are analyzed. According to the results of the analysis, the polytechnological specialization of such service stations is substantiated.

Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines.

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Yuki Haga

Full Text Available Despite recent advances in treatment strategies, it is still difficult to cure patients with hepatocellular carcinoma (HCC. Sorafenib is the only approved multiple kinase inhibitor for systemic chemotherapy in patients with advanced HCC. The majority of advanced HCC patients are resistant to sorafenib. The mechanisms of sorafenib resistance are still unknown.The expression of molecules involved in the mitogen-activated protein kinase (MAPK signaling pathway in human hepatoma cell lines was examined in the presence or absence of sorafenib. Apoptosis of human hepatoma cells treated with sorafenib was investigated, and the expression of Jun proto-oncogene (c-Jun was measured.The expression and phosphorylation of c-Jun were enhanced in human hepatoma cell lines after treatment with sorafenib. Inhibiting c-Jun enhanced sorafenib-induced apoptosis. The overexpression of c-Jun impaired sorafenib-induced apoptosis. The expression of osteopontin, one of the established AP-1 target genes, was enhanced after treatment with sorafenib in human hepatoma cell lines.The protein c-Jun plays a role in sorafenib resistance in human hepatoma cell lines. The modulation and phosphorylation of c-Jun could be a new therapeutic option for enhancing responsiveness to sorafenib. Modulating c-Jun may be useful for certain HCC patients with sorafenib resistance.

Second-order quadrupolar line shapes under molecular dynamics: An additional transition in the extremely fast regime.

Science.gov (United States)

Hung, Ivan; Wu, Gang; Gan, Zhehong

NMR spectroscopy is a powerful tool for probing molecular dynamics. For the classic case of two-site exchange, NMR spectra go through the transition from exchange broadening through coalescence and then motional narrowing as the exchange rate increases passing through the difference between the resonance frequencies of the two sites. For central-transition spectra of half-integer quadrupolar nuclei in solids, line shape change due to molecular dynamics occurs in two stages. The first stage occurs when the exchange rate is comparable to the second-order quadrupolar interaction. The second spectral transition comes at a faster exchange rate which approaches the Larmor frequency and generally reduces the isotropic quadrupolar shift. Such a two-stage transition phenomenon is unique to half-integer quadrupolar nuclei. A quantum mechanical formalism in full Liouville space is presented to explain the physical origin of the two-stage phenomenon and for use in spectral simulations. Variable-temperature 17 O NMR of solid NaNO 3 in which the NO 3 - ion undergoes 3-fold jumps confirms the two-stage transition process. The spectra of NaNO 3 acquired in the temperature range of 173-413K agree well with simulations using the quantum mechanical formalism. The rate constants for the 3-fold NO 3 - ion jumps span eight orders of magnitude (10 2 -10 10 s -1 ) covering both transitions of the dynamic 17 O line shape. Copyright © 2016 Elsevier Inc. All rights reserved.

Real Options Analysis of Electricity Investments

Energy Technology Data Exchange (ETDEWEB)

Heggedal, Ane Marte

2012-07-01

This thesis utilizes real options analysis for evaluating investment opportunities in the electricity sector. It also formally tests how investors in hydropower plants have included uncertainty when considering their investment opportunities. The real options method applies financial options theory to quantify the value of management flexibility and is chosen due to three important characteristics of investments in the electricity sector. First; the investment is completely or partially irreversible, second; the investor can choose when to invest in the facility, and third; there is uncertainty in several factors affecting the cash flows of the investments. Factors of uncertainty include the development of electricity prices, policies, technological advances, and macroeconomics measures.Four papers are included in this thesis. Paper 1, Upgrading hydropower plants with storage: Timing and capacity choice, presents a valuation framework for deciding when to upgrade an existing hydropower plant and which capacity to choose. The second paper, Transmission capacity between Norway and Germany: A real options analysis, sheds light on when two electricity markets, in this case Norway and Germany, should be connected through a sub sea cable. The investor can choose when to invest and the capacity of the cable, and may also choose to invest sequentially. Paper 3, Optimal timing and capacity choice for pumped hydropower storage, investigates when investment in a pumped hydropower plant with storage should be undertaken and what the capacity of the facility should be. Whereas the three first papers investigate investment opportunities, Paper 4, Uncertain climate policy decisions and investment timing: Evidence from small hydropower plants, studies when investors in small hydropower plants chose to invest. The analyses disclose whether the net present value approach or the real options method best describe the investment decisions made by the investors. Viewing investment

Intuition, subjectivity, and Le bricoleur: cancer patients' accounts of negotiating a plurality of therapeutic options.

Science.gov (United States)

Broom, Alex

2009-08-01

Cancer patients are now combining complementary and alternative medicine (CAM) with biomedical cancer treatments, reflecting an increasingly pluralistic health care environment. However, there has been little research done on the ways in which cancer patients juggle multiplicity in claims to expertise, models of disease, and therapeutic practice. Drawing on the accounts of cancer patients who use CAM, in this article I develop a conceptualization of therapeutic decision making, utilizing the notion of bricolage as a key point of departure. The patient accounts illustrate the "piecing together" (or bricolage) of therapeutic trajectories, drawing on intuitive, embodied knowledge, as well as formalized "objective" scientific expertise. Le bricoleur, as characterized here, actively mediates, rather than accepts or rejects CAM or biomedicine, and utilizes a combination of scientific expertise, embodied physicality, and social knowledge to make decisions and assess therapeutic effectiveness. Although these "border crossings" are potentially subversive of established biomedical expertise, the analysis also illustrates the structural constraints (and penalties) associated with bricolage, and furthermore, the interplay of a repositioning of responsibility with neoliberal forms of self-governance.

Analyzing the Risks Embedded in Option Prices with rndfittool

DEFF Research Database (Denmark)

Barletta, Andrea; Santucci de Magistris, Paolo

2018-01-01

This paper introduces a new computational tool for the analysis of the risks embedded in a set of prices of European-style options. The software enables the estimation of the risk-neutral density (RND) from the observed option prices by means of orthogonal polynomial expansions. Orthogonal...... polynomials offer a viable alternative to more standard techniques based on interpolation and estimation of the second-order derivatives of option prices. The app rndfittool is available on GitHub and its usage is illustrated with examples based on real data....

Mine Drainage Generation and Control Options.

Science.gov (United States)

Wei, Xinchao; Rodak, Carolyn M; Zhang, Shicheng; Han, Yuexin; Wolfe, F Andrew

2016-10-01

This review provides a snapshot of papers published in 2015 relevant to the topic of mine drainage generation and control options. The review is broken into 3 sections: Generation, Prediction and Prevention, and Treatment Options. The first section, mine drainage generation, focuses on the characterization of mine drainage and the environmental impacts. As such, it is broken into three subsections focused on microbiological characterization, physiochemical characterization, and environmental impacts. The second section of the review is divided into two subsections focused on either the prediction or prevention of acid mine drainage. The final section focuses on treatment options for mine drainage and waste sludge. The third section contains subsections on passive treatment, biological treatment, physiochemical treatment, and a new subsection on beneficial uses for mine drainage and treatment wastes.

Anti-tumor effect of bisphosphonate (YM529 on non-small cell lung cancer cell lines

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Date Hiroshi

2007-01-01

Full Text Available Abstract Background YM529 is a newly developed nitrogen-containing bisphosphonate (BP classified as a third-generation BP that shows a 100-fold greater potency against bone resorption than pamidronate, a second-generation BP. This agent is, therefore expected to be extremely useful clinically for the treatment of osteoporosis and hypercalcemia. Recently, YM529 as well as other third-generation BPs have also been shown to exert anti-tumor effects against various types of cancer cells both in vitro or/and in vivo. In this study, we investigate the anti-tumor effect of YM529 on non-small cell lung cancer (NSCLC. Methods Direct anti-tumor effect of YM529 against 8 NSCLC cell lines (adenocarcinoma: H23, H1299, NCI-H1819, NCI-H2009, H44, A549, adenosquamous cell carcinoma: NCI-H125, squamous cell carcinoma: NCI-H157 were measured by MTS assay and calculated inhibition concentration 50 % (IC50 values. YM529 induced apoptosis of NCI-H1819 was examined by DNA fragmentation of 2 % agarose gel electrophoresis and flowcytometric analysis (sub-G1 method. We examined where YM529 given effect to apoptosis of NSCLC cells in signaling pathway of the mevalonate pathway by western blotting analysis. Results We found that there was direct anti-tumor effect of YM529 on 8 NSCLC cell lines in a dose-dependent manner and their IC50 values were 2.1 to 7.9 μM and YM529 induced apoptosis and G1 arrest cell cycle with dose-dependent manner and YM529 caused down regulation of phospholyration of ERK1/2 in signaling pathways of NSCLC cell line (NCI-H1819. Conclusion Our study demonstrate that YM529 showed direct anti-tumor effect on NSCLC cell lines in vitro, which supports the possibility that third-generation BPs including YM529 can be one of therapeutic options for NSCLC.

Combination chemotherapy versus single-agent therapy as first- and second-line treatment in metastatic breast cancer

DEFF Research Database (Denmark)

Joensuu, H; Holli, K; Heikkinen, M

1998-01-01

PURPOSE: We report results of a randomized prospective study that compared single agents of low toxicity given both as the first-line and second-line chemotherapy with combination chemotherapy in advanced breast cancer with distant metastases. PATIENTS AND METHODS: Patients in the single-agent arm...... (n = 153) received weekly epirubicin (E) 20 mg/m2 until progression or until the cumulative dose of 1,000 mg/m2, followed by mitomycin (M) 8 mg/m2 every 4 weeks, and those in the combination chemotherapy arm (n = 150) were first given cyclophosphamide 500 mg/m2, E 60 mg/m2, and fluorouracil 500 mg/m2...... younger than 50. RESULTS: An objective response (complete [CR] or partial [PR]) was obtained in 55%, 48%, 16%, and 7% of patients treated with CEF, E, M, and MV, respectively. A response to CEF tended to last longer than a response to E (median, 12 v 10.5 months; P = .07). Treatment-related toxicity...

Left atrial appendage occlusion with Amplatzer Cardio Plug is an acceptable therapeutic option for prevention of stroke recurrence in patients with non-valvular atrial fibrillation and contraindication or failure of oral anticoagulation with acenocumarol

OpenAIRE

Hawkes, Maximiliano A.; Pertierra, Lucía; Rodriguez-Lucci, Federico; Pujol-Lereis, Virginia A.; Ameriso, Sebastián F.

2016-01-01

ABSTRACT Left atrial appendage occlusion (LAAO) appears as a therapeutic option for some atrial fibrillation patients not suitable for oral anticoagulation because an increased hemorrhagic risk or recurrent ischemic events despite anticoagulant treatment. Methods Report of consecutive atrial fibrillation patients treated with LAAO with Amplatzer Cardio Plug because contraindication or failure of oral anticoagulation with acenocumarol. CHA2DS2VASC, HAS-BLED, NIHSS, mRS, procedural complicati...

Polish Toxic Currency Options

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Waldemar Gontarski

2009-06-01

other hand issuing call options confers an absolute obligation to deliver to the other party to the option contract a specified amount in euro at exchange rate set in advance. This latter position (short call means unlimited loss in the case of appreciation of euro. This was the situation faced by some Polish exporters in the second half of 2008 who in the middle of 2008 issued the most risky call options for banks and, thus, they bought a currency risk from the banks. Issuing any option always means also buying someone other’s risk, in exchange for a relatively small option premium which might trigger a relatively huge and actually unlimited risk of losses, if the assumed forecast does not come true. This is not the economic analysis of law to be relied on any more in respect of the cost of preventing the risk of loss being higher or lower than the amount of damage. The manager of an exporting company, unlike the speculator who sells options (buys risk, usually has no knowledge of financial engineering, which is essential to safely manage such excessive risk through creating a hedging portfolio.

Applicability of line outage distribution factors to evaluate distribution network expansion options

NARCIS (Netherlands)

Grond, M.O.W.; Pouw, J.I.P.; Morren, J.; Slootweg, J.G.

2014-01-01

Distribution network operators require more advanced planning tools to deal with the challenges of future network planning. An appropriate planning and optimization tool can identify which option for network extension should be selected from available alternatives. However, the evaluation part in

Option Valuation with Volatility Components, Fat Tails, and Nonlinear Pricing Kernels

DEFF Research Database (Denmark)

Babaoglu, Kadir Gokhan; Christoffersen, Peter; Heston, Steven

We nest multiple volatility components, fat tails and a U-shaped pricing kernel in a single option model and compare their contribution to describing returns and option data. All three features lead to statistically significant model improvements. A second volatility factor is economically most i...

First and second line drug resistance among treatment naïve pulmonary tuberculosis patients in a district under Revised National Tuberculosis Control Programme (RNTCP in New Delhi

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Vithal Prasad Myneedu

2015-12-01

Full Text Available There is limited information of level of drug resistance to first-line and second line anti-tuberculosis agents in treatment naïve pulmonary tuberculosis (PTB patients from the Indian region. Therefore, the present prospective study was conducted to determine the antimicrobial susceptibility to first-line and second line anti-TB drug resistance in such patients. Sputum samples from consecutive treatment naïve PTB cases registered in Lala Ram Sarup (LRS district, under RNTCP containing 12 Directly Observed Treatment Centre’s (DOTS, were enrolled using cluster sampling technology. A total of 453 samples were received from July 2011 to June 2012. All samples were cultured on solid medium followed by drug susceptibility to first and second line anti-tubercular drugs as per RNTCP guidelines. Primary multi-drug resistance (MDR was found to be 18/453; (4.0%. Extensively drug resistance (XDR was found in one strain (0.2%, which was found to be resistant to other antibiotics. Data of drug resistant tuberculosis among treatment naïve TB patients are lacking in India. The presence of XDR-TB and high MDR-TB in small population studied, calls for conducting systematic multi-centric surveillance across the country.

Curcumin Nanomedicine: A Road to Cancer Therapeutics

Science.gov (United States)

Yallapu, Murali M.; Jaggi, Meena; Chauhan, Subhash C.

2013-01-01

Cancer is the second leading cause of death in the United States. Conventional therapies cause widespread systemic toxicity and lead to serious side effects which prohibit their long term use. Additionally, in many circumstances tumor resistance and recurrence is commonly observed. Therefore, there is an urgent need to identify suitable anticancer therapies that are highly precise with minimal side effects. Curcumin is a natural polyphenol molecule derived from the Curcuma longa plant which exhibits anticancer, chemo-preventive, chemo- and radio-sensitization properties. Curcumin’s widespread availability, safety, low cost and multiple cancer fighting functions justify its development as a drug for cancer treatment. However, various basic and clinical studies elucidate curcumin’s limited efficacy due to its low solubility, high rate of metabolism, poor bioavailability and pharmacokinetics. A growing list of nanomedicine(s) using first line therapeutic drugs have been approved or are under consideration by the Food and Drug Administration (FDA) to improve human health. These nanotechnology strategies may help to overcome challenges and ease the translation of curcumin from bench to clinical application. Prominent research is reviewed which shows that advanced drug delivery of curcumin (curcumin nanoformulations or curcumin nanomedicine) is able to leverage therapeutic benefits by improving bioavailability and pharmacokinetics which in turn improves binding, internalization and targeting of tumor(s). Outcomes using these novel drug delivery systems have been discussed in detail. This review also describes the tumor-specific drug delivery system(s) that can be highly effective in destroying tumors. Such new approaches are expected to lead to clinical trials and to improve cancer therapeutics. PMID:23116309

Review of therapeutic agents for burns pruritus and protocols for management in adult and paediatric patients using the GRADE classification

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Goutos Ioannis

2010-10-01

Full Text Available To review the current evidence on therapeutic agents for burns pruritus and use the Grading of Recommendations, Assessment, Development and Evaluation (GRADE classification to propose therapeutic protocols for adult and paediatric patients. All published interventions for burns pruritus were analysed by a multidisciplinary panel of burns specialists following the GRADE classification to rate individual agents. Following the collation of results and panel discussion, consensus protocols are presented. Twenty-three studies appraising therapeutic agents in the burns literature were identified. The majority of these studies (16 out of 23 are of an observational nature, making an evidence-based approach to defining optimal therapy not feasible. Our multidisciplinary approach employing the GRADE classification recommends the use of antihistamines (cetirizine and cimetidine and gabapentin as the first-line pharmacological agents for both adult and paediatric patients. Ondansetron and loratadine are the second-line medications in our protocols. We additionally recommend a variety of non-pharmacological adjuncts for the perusal of clinicians in order to maximise symptomatic relief in patients troubled with postburn itch. Most studies in the subject area lack sufficient statistical power to dictate a ′gold standard′ treatment agent for burns itch. We encourage clinicians to employ the GRADE system in order to delineate the most appropriate therapeutic approach for burns pruritus until further research elucidates the most efficacious interventions. This widely adopted classification empowers burns clinicians to tailor therapeutic regimens according to current evidence, patient values, risks and resource considerations in different medical environments.

First on-line survey of an international multidisciplinary working group (MightyMedic) on current practice in diagnosis, therapy and follow-up of dyslipidemias.

Science.gov (United States)

Stefanutti, C; D'Alessandri, G; Petta, A; Harada-Shiba, M; Julius, U; Soran, H; Moriarty, P M; Romeo, S; Drogari, E; Jaeger, B R

2015-05-01

The MightyMedic (Multidisciplinary International Group for Hemapheresis TherapY and MEtabolic DIsturbances Contrast) Working Group has been founded in 2013. The leading idea was to establish an international network of interdisciplinary nature aimed at working to cross national borders research projects, clinical trials, educational initiatives (meetings, workshops, summer schools) in the field of metabolic diseases, namely hyperlipidemias, and diabetes, preventive cardiology, and atherosclerosis. Therapeutic apheresis, its indications and techniques, is a parallel field of investigation. The first on-line survey of the Group has been completed in the first half of 2014. The survey included # 24 Centers in Italy, Germany, Greece, UK, Sweden, Japan and USA. Relevant data have been collected on current practice in diagnosis, therapy and follow-up of dyslipidemias. 240 subjects with hyperlipidemia and treated with lipoprotein apheresis have been reported in the survey, but a large percentage of patients (35%) who could benefit from this therapeutic option are still treated by conventional drug approach. Genetic molecular diagnosis is performed in only 33% of patients while Lipoprotein(a) (Lp(a)) is included in cardiovascular disease risk assessment in 71% of participating Centers. New detailed investigations and prospective multicenter studies are needed to evaluate changes induced by the impact of updated indications and strategies, as well as new treatment options, targeting standardization of therapeutic and diagnostic approaches. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Behaviour Recovery. Second Edition

Science.gov (United States)

Rogers, Bill

2004-01-01

This second edition of Behaviour Recovery puts emphasis on teaching behaviour concerning children with emotional and behavioural disorders (EBD). These children have many factors in their lives that affect their behaviour over which schools have limited control. This book acknowledges the challenge and explores the practical realities, options and…

Nuclear Power Options Viability Study. Volume 4. Bibliography

Energy Technology Data Exchange (ETDEWEB)

Trauger, D B; White, J D; Sims, J W [eds.

1986-09-01

Documents in the Nuclear Power Options Viability Study (NPOVS) bibliography are classified under one of four headings or categories as follows: nuclear options; light water reactors; liquid metal reactors; and high temperature reactors. The collection and selection of these documents, beginning early in 1984 and continuing through March of 1986, was carried out in support of the study's objective: to explore the viabilities of several nuclear electric power generation options for commercial deployment in the United States between 2000 and 2010. There are approximately 550 articles, papers, reports, and books in the bibliography that have been selected from some 2000 surveyed. The citations have been made computer accessible to facilitate rapid on-line retrieval by keyword, author, corporate author, title, journal name, or document number.

Nuclear Power Options Viability Study. Volume 4. Bibliography

International Nuclear Information System (INIS)

Trauger, D.B.; White, J.D.; Sims, J.W.

1986-09-01

Documents in the Nuclear Power Options Viability Study (NPOVS) bibliography are classified under one of four headings or categories as follows: nuclear options; light water reactors; liquid metal reactors; and high temperature reactors. The collection and selection of these documents, beginning early in 1984 and continuing through March of 1986, was carried out in support of the study's objective: to explore the viabilities of several nuclear electric power generation options for commercial deployment in the United States between 2000 and 2010. There are approximately 550 articles, papers, reports, and books in the bibliography that have been selected from some 2000 surveyed. The citations have been made computer accessible to facilitate rapid on-line retrieval by keyword, author, corporate author, title, journal name, or document number

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics.

Science.gov (United States)

Sparrow, Janet R

2016-04-26

Although currently available treatment options for age-related macular degeneration (AMD) are limited, particularly for atrophic AMD, the identification of predisposing genetic variations has informed clinical studies addressing therapeutic options such as complement inhibitors and anti-inflammatory agents. To lower risk of early AMD, recommended lifestyle interventions such as the avoidance of smoking and the intake of low glycemic antioxidant-rich diets have largely followed from the identification of nongenetic modifiable factors. On the other hand, the challenge of understanding the complex relationship between aging and cumulative damage leading to AMD has fueled investigations of the visual cycle adducts that accumulate in retinal pigment epithelial (RPE) cells and are a hallmark of aging retina. These studies have revealed properties of these compounds that provide insights into processes that may compromise RPE and could contribute to disease mechanisms in AMD. This work has also led to the design of targeted therapeutics that are currently under investigation.

THE REAL OPTIONS OF CAPITAL BUDGET

Directory of Open Access Journals (Sweden)

Antonio Lopo Martins

2008-07-01

Full Text Available The traditional techniques of capital budget, as the deducted cash flow and the net value present, do not incorporate existing flexibilities in an investment project, they tend to distort the value of certain investments, mainly those that are considered in scenes of uncertainty and risk. Therefore, this study intends to demonstrate that the Real Options Theory (TOR is a useful methodology to evaluate and to indicate the best option for project of expansion investment. To reach the considered objective the procedure method was used a case study, having as unit of case the Resort Praia Hotel do Litoral Norte of Salvador. This study was developed of the following form: first it identified the traditional net value present and later it was incorporated the volatileness of each analyzed uncertainty. Second, as the real options are analogous to the financial options, it was necessary to identify elements that composed the terminologies of the financial options with intention to get the value of the real option. For this model of options pricing of Black & Scholes jointly with a computational simulator was used (SLS to get the expanded net value present. As a result of this study it was possible to evidence that using the traditional tool of capital budget Net Value Present (VPL is negative, therefore the project of expansion of the Hotel would be rejected. While for the application of methodology TOR the project presents positive Expanded Present Value which would represent an excellent chance of investment. Key-word: Capital budget, Real options, Analysis of investments.

Avian Diagnostic and Therapeutic Antibodies

Energy Technology Data Exchange (ETDEWEB)

Bradley, David Sherman [UND SMHS

2012-12-31

A number of infectious agents have the potential of causing significant clinical symptomology and even death, but dispite this, the number of incidence remain below the level that supports producing a vaccine. Therapeutic antibodies provide a viable treatment option for many of these diseases. We proposed that antibodies derived from West Nile Virus (WNV) immunized geese would be able to treat WNV infection in mammals and potential humans. We demonstrated that WNV specific goose antibodies are indeed successful in treating WNV infection both prophylactically and therapeutically in a golden hamster model. We demonstrated that the goose derived antibodies are non-reactogenic, i.e. do not cause an inflammatory response with multiple exposures in mammals. We also developed both a specific pathogen free facility to house the geese during the antibody production phase and a patent-pending purification process to purify the antibodies to greater than 99% purity. Therefore, the success of these study will allow a cost effective rapidly producible therapeutic toward clinical testing with the necessary infrastructure and processes developed and in place.

EURISOL-DS Multi-MW Target Comparative Neutronic Performance of the Baseline Configuration vs. the Hg-Jet Option

CERN Document Server

Herrera-Martínez, A

2006-01-01

This technical report summarises the comparative study between several design options for the Multi-MW target station performed within Task #2 of the European Isotope Separation On-Line Radioactive Ion Beam Facility Design Study (EURISOL DS) [1]. Previous analyses were carried out, using the Monte Carlo code FLUKA [2], to determine optimal values for relevant parameters in the target design [3] and to analyse a preliminary Multi-MW target assembly configuration [4]. The second report showed that the aimed fission rates, i.e. ~1015 fissions/s, could be achieved with such a configuration. Nevertheless, a preliminary study of the target assembly integration [5] suggested reducing some of the dimensions. Moreover, the yields of specific isotopes have yet to be assessed and compared to other target configurations. This note presents a detailed comparison of the baseline configuration and the Hg-jet option, in terms of primary and neutron distribution, power densities and fission product yields. A scaled-down versi...

Threaded biliary inside stents are a safe and effective therapeutic option in cases of malignant hilar obstruction.

Science.gov (United States)

Inatomi, Osamu; Bamba, Shigeki; Shioya, Makoto; Mochizuki, Yosuke; Ban, Hiromitsu; Tsujikawa, Tomoyuki; Saito, Yasuharu; Andoh, Akira; Fujiyama, Yoshihide

2013-02-14

Although endoscopic biliary stents have been accepted as part of palliative therapy for cases of malignant hilar obstruction, the optimal endoscopic management regime remains controversial. In this study, we evaluated the safety and efficacy of placing a threaded stent above the sphincter of Oddi (threaded inside plastic stents, threaded PS) and compared the results with those of other stent types. Patients with malignant hilar obstruction, including those requiring biliary drainage for stent occlusion, were selected. Patients received either one of the following endoscopic indwelling stents: threaded PS, conventional plastic stents (conventional PS), or metallic stents (MS). Duration of stent patency and the incident of complication were compared in these patients. Forty-two patients underwent placement of endoscopic indwelling stents (threaded PS = 12, conventional PS = 17, MS = 13). The median duration of threaded PS patency was significantly longer than that of conventional PS patency (142 vs. 32 days; P = 0.04, logrank test). The median duration of threaded PS and MS patency was not significantly different (142 vs. 150 days, P = 0.83). Stent migration did not occur in any group. Among patients who underwent threaded PS placement as a salvage therapy after MS obstruction due to tumor ingrowth, the median duration of MS patency was significantly shorter than that of threaded PS patency (123 vs. 240 days). Threaded PS are safe and effective in cases of malignant hilar obstruction; moreover, it is a suitable therapeutic option not only for initial drainage but also for salvage therapy.

Small Molecule Targeting of a MicroRNA Associated with Hepatocellular Carcinoma.

Science.gov (United States)

Childs-Disney, Jessica L; Disney, Matthew D

2016-02-19

Development of precision therapeutics is of immense interest, particularly as applied to the treatment of cancer. By analyzing the preferred cellular RNA targets of small molecules, we discovered that 5"-azido neomycin B binds the Drosha processing site in the microRNA (miR)-525 precursor. MiR-525 confers invasive properties to hepatocellular carcinoma (HCC) cells. Although HCC is one of the most common cancers, treatment options are limited, making the disease often fatal. Herein, we find that addition of 5"-azido neomycin B and its FDA-approved precursor, neomycin B, to an HCC cell line selectively inhibits production of the mature miRNA, boosts a downstream protein, and inhibits invasion. Interestingly, neomycin B is a second-line agent for hepatic encephalopathy (HE) and bacterial infections due to cirrhosis. Our results provocatively suggest that neomycin B, or second-generation derivatives, may be dual functioning molecules to treat both HE and HCC. Collectively, these studies show that rational design approaches can be tailored to disease-associated RNAs to afford potential lead therapeutics.

Security option file - Exploitation (DOS-Expl)

International Nuclear Information System (INIS)

2016-01-01

This document aims at presenting functions performed by Cigeo during its exploitation phase, its main technical and security options which are envisaged with respect to different types of internal or external risks, and a first assessment of its impact on mankind and on the environment during its exploitation in normal operation as well as in incidental or accidental situations. A first volume addresses security principles, approach and management in relationship with the legal and regulatory framework. The second volume presents input data related to waste parcels and used for the installation sizing and operation, the main site characteristics, the main technical options regarding structures and equipment, and the main options regarding exploitation (parcel management, organisational and human aspects, and effluent management). The third volume describes how parcel are processed from their arrival to their setting in storage compartment, an inventory of internal and external risks, and a first assessment of consequences of scenarios on mankind and on the environment. The fourth volume presents options and operations which are envisaged regarding Cigeo closure, and inventory of associated risks

Alternative disposal options for transuranic waste

International Nuclear Information System (INIS)

Loomis, G.G.

1994-01-01

Three alternative concepts are proposed for the final disposal of stored and retrieved buried transuranic waste. These proposed options answer criticisms of the existing U.S. Department of Energy strategy of directly disposing of stored transuranic waste in deep, geological salt formations at the Waste Isolation Pilot Plant (WIPP) in Carlsbad, New Mexico. The first option involves enhanced stabilization of stored waste by thermal treatment followed by convoy transportation and internment in the existing WIPP facility. This concept could also be extended to retrieved buried waste with proper permitting. The second option involves in-state, in situ internment using an encapsulating lens around the waste. This concept applies only to previously buried transuranic waste. The third option involves sending stored and retrieved waste to the Nevada Test Site and configuring the waste around a thermonuclear device from the U.S. or Russian arsenal in a specially designed underground chamber. The thermonuclear explosion would transmute plutonium and disassociate hazardous materials while entombing the waste in a national sacrifice area

Micro - Focused Phototherapy Associated To Janus Kinase Inhibitor: A Promising Valid Therapeutic Option for Patients with Localized Vitiligo

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Serena Gianfaldoni

2018-01-01

Full Text Available BACKGROUND: Vitiligo is an acquired pigmentary cutaneous disease, characterised by the progressive loss of melanocytes, resulting in hypopigmented skin areas which progressively become amelanotic. Classically, vitiligo treatments are unsatisfactory and challenging. Despite the continuous introduction of new therapies, phototherapy is still the mainstay for vitiligo repigmentation. AIM: The aim of this multicenter observational retrospective study was to evaluate the efficacy and safety of the nb - UVB micro - phototherapy (BIOSKIN EVOLUTION®, used alone or in associations with an oral Janus kinase inhibitor (Tofacitinib citrate, in the treatment of stable or active forms of localised vitiligo. MATERIAL AND METHODS: Fifty eight patients had been treated with n-UVB micro-photootherapy (Group A; 9 patients had been treated with phototherapy plus Tofacitinb citrate (Group B. RESULTS: Among Group A, 42 patients (72% obtained a re-pigmentation rate higher than 75%, with a medium value of 77%. 11 patients (19% achieved a marked improvement of the clinical findings with a repigmentation rate between 50-75%; 4 patients (8% showed a moderate response with a lesional repigmentation of 25-50%. Only one patient (1% had a poor response to the phototherapeutic treatment CONCLUSION: Nb - UVB micro-focused phototherapy is one of the most effective therapeutic options for vitiligo treatment. The association of micro-focused phototherapy to Tofacitinib citrate seems to provide better clinical results in term of repigmentation rate.

Flexibility and Project Value: Interactions and Multiple Real Options

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Čulík, Miroslav

2010-06-01

This paper is focused on a project valuation with embedded portfolio of real options including their interactions. Valuation is based on the criterion of Net Present Value on the simulation basis. Portfolio includes selected types of European-type real options: option to expand, contract, abandon and temporarily shut down and restart a project. Due to the fact, that in reality most of the managerial flexibility takes the form of portfolio of real options, selected types of options are valued not only individually, but also in combination. The paper is structured as follows: first, diffusion models for forecasting of output prices and variable costs are derived. Second, project value is estimated on the assumption, that no real options are present. Next, project value is calculated with the presence of selected European-type options; these options and their impact on project value are valued first in isolation and consequently in different combinations. Moreover, intrinsic value evolution of given real options with respect to the time of exercising is analysed. In the end, results are presented graphically; selected statistics and risk measures (Value at Risk, Expected Shortfall) of the NPV's distributions are calculated and commented.

Second-line chemotherapy of disseminated malignant melanoma with cystemustine at 60 mg/m2: a phase II trial.

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Thivat, Emilie; Durando, Xavier; D'Incan, Michel; Cure, Hervé; Mouret-Reynier, Marie-Ange; Madelmont, Jean-Claude; Souteyrand, Pierre; Chollet, Philippe

2005-10-01

Nitrosoureas possess some anti-tumor activity as a single agent in metastatic melanoma (MM). In a phase II trial, we evaluated the anti-tumor effects of cystemustine chemotherapy, a new nitrosourea, as a second-line treatment. Patients were required to have histologic evidence of disseminated MM and had failed in first-line chemotherapy. Treatment comprised cystemustine given at a dose of 60 mg/m every 2 weeks by a 15-min infusion. From February 1997 to September 1999, 22 patients (median age 66 years) were enrolled and were assessable. Two complete responses, one partial response, three stable diseases and 16 progressions were observed, giving an overall response rate of 13.6%. Median duration of response was 10 months (range 4-63). Median survival of responders and non-responders was 11 and 4 months, respectively. However, hematological toxicity, particularly thrombopenia, was a limiting factor for one-third of patients. We conclude that cystemustine at 60 mg/m is active in patients who progressed after one line of chemotherapy in advanced disease, and offers the possibility of complete responses and long durations of these responses.

Efficacy and safety of sequential versus quadruple therapy as second-line treatment for helicobacter pylori infection-A randomized controlled trial.

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Daniela Munteanu

Full Text Available Quadruple therapy is recommended as second-line treatment for Helicobacter pylori eradication failure. However, high cost, multiple side effects, and low adherence rates are major drawbacks to its routine use. Our aim was to compare the efficacy and safety of sequential versus quadruple regimens as second line treatment for persistent Helicobacter pylori infection.Prospective, randomized, open label trial was conducted at a large academic, tertiary care center in Israel. Patients who previously failed a standard triple treatment eradication course were randomly assigned (1:1 to receive a 10-day sequential therapy course, or a 14-day quadruple regimen. Compliance and adverse events were evaluated by telephone questionnaires. The primary endpoint for analysis was the rate of Helicobacter pylori eradication as defined by either a negative 13C-urea breath-test, or stool antigen test, 4-16 weeks after treatment assessed under the non-inferiority hypothesis. The trial was terminated prematurely due to low recruitment rates. See S1 Checklist for CONSORT checklist.One hundred and one patients were randomized. Per modified intention-to-treat analysis, eradication rate was 49% in the sequential versus 42.5% in the quadruple regimen group (p-value for non-inferiority 0.02. Forty-two (84.0% versus 33 (64.7% patients completed treatment in the sequential and quadruple groups respectively (p 0.027. Gastrointestinal side effects were more common in the quadruple regimen group.Sequential treatment when used as a second line regimen, was non-inferior to the standard of care quadruple regimen in achieving Helicobacter pylori eradication, and was associated with better compliance and fewer adverse effects. Both treatment protocols failed to show an adequate eradication rate in the population of Southern Israel.ClinicalTrials.gov NCT01481844.

Comparative cost-effectiveness of Option B+ for prevention of mother-to-child transmission of HIV in Malawi.

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Tweya, Hannock; Keiser, Olivia; Haas, Andreas D; Tenthani, Lyson; Phiri, Sam; Egger, Matthias; Estill, Janne

2016-03-27

To estimate the cost-effectiveness of prevention of mother-to-child transmission (MTCT) of HIV with lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women ('Option B+') compared with ART during pregnancy or breastfeeding only unless clinically indicated ('Option B'). Mathematical modelling study of first and second pregnancy, informed by data from the Malawi Option B+ programme. Individual-based simulation model. We simulated cohorts of 10 000 women and their infants during two subsequent pregnancies, including the breastfeeding period, with either Option B+ or B. We parameterized the model with data from the literature and by analysing programmatic data. We compared total costs of antenatal and postnatal care, and lifetime costs and disability-adjusted life-years of the infected infants between Option B+ and Option B. During the first pregnancy, 15% of the infants born to HIV-infected mothers acquired the infection. With Option B+, 39% of the women were on ART at the beginning of the second pregnancy, compared with 18% with Option B. For second pregnancies, the rates MTCT were 11.3% with Option B+ and 12.3% with Option B. The incremental cost-effectiveness ratio comparing the two options ranged between about US$ 500 and US$ 1300 per DALY averted. Option B+ prevents more vertical transmissions of HIV than Option B, mainly because more women are already on ART at the beginning of the next pregnancy. Option B+ is a cost-effective strategy for PMTCT if the total future costs and lost lifetime of the infected infants are taken into account.

Therapeutic Applications of Interleukin 24 (IL24): A Review ...

African Journals Online (AJOL)

IL24 has growth suppressive properties in a wide variety of human cancer cell lines without inducing harmful effects in normal cells. This review is focused on the role of IL 24 on tumor cell biology and its potential therapeutic applications. Keywords: Melanoma differentiation, Protein, Therapeutics, Interleukin, ...

Novel Therapeutic Approaches to the Treatment of Chronic Abdominal Visceral Pain

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Franca Patrizi

2006-01-01

Full Text Available Chronic abdominal visceral pain (CAVP has a significant clinical impact and represents one of the most frequent and debilitating disorders in the general population. It also leads to a significant economic burden due to workdays lost, reduced productivity, and long-term use of medications with their associated side effects. Despite the availability of several therapeutic options, the management of patients with CAVP is often inadequate, resulting in frustration for both patients and physicians. This may in part be explained by the lack of understanding of the mechanisms underlying chronic pain; in contrast with acute pain in which the pathophysiology is relatively well known and has several satisfactory therapeutic options. Recently, the development of tools for brain investigation, such as functional magnetic resonance imaging, has provided new insights on the pathophysiology of chronic pain. These new data have shown that plastic changes in the central and peripheral nervous system might play an important role in the maintenance of chronic pain. Therefore, approaches aimed at the modulation of the nervous system, rather than the ones interfering with the inflammatory pathways, may be more effective for chronic pain treatment. We propose that noninvasive central nervous system stimulation, with transcranial magnetic stimulation (TMS, might be a novel therapeutic option for CAVP. This paper will present an overview of the pathophysiology and the available therapies for CAVP, focusing on the recent advances in the treatment of this pathology.

Complete spontaneous avascular necrosis of the adult navicula associated with Mee's growth arrest lines of the great and second toenails.

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Singh, Dishan; Ferrerro, Andrea

2014-03-01

Spontaneous total avascular necrosis of the tarsal navicula has been well documented in children (Kohler's disease) but is uncommon in adults where partial necrosis is usually seen after trauma or in Müller-Weiss disease. A case of spontaneous complete navicular osteonecrosis in a 46 year old female is described; she had accompanying Mee's leuchonychial lines in the toenails of the great and second toes only; the lines resolved after 9 months. She has been treated with an excision of the navicula and interpositional iliac crest bone graft talo-cuneiform fusion with resolution of her pain. It is postulated that the combination of the Mee's lines and avascular necrosis of the navicula indicates an occlusion of the dorsalis pedis in a predisposed individual. Copyright © 2013 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.

Testing of SNS-032 in a Panel of Human Neuroblastoma Cell Lines with Acquired Resistance to a Broad Range of Drugs12

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Löschmann, Nadine; Michaelis, Martin; Rothweiler, Florian; Zehner, Richard; Cinatl, Jaroslav; Voges, Yvonne; Sharifi, Mohsen; Riecken, Kristoffer; Meyer, Jochen; von Deimling, Andreas; Fichtner, Iduna; Ghafourian, Taravat; Westermann, Frank; Cinatl, Jindrich

2013-01-01

Novel treatment options are needed for the successful therapy of patients with high-risk neuroblastoma. Here, we investigated the cyclin-dependent kinase (CDK) inhibitor SNS-032 in a panel of 109 neuroblastoma cell lines consisting of 19 parental cell lines and 90 sublines with acquired resistance to 14 different anticancer drugs. Seventy-three percent of the investigated neuroblastoma cell lines and all four investigated primary tumor samples displayed concentrations that reduce cell viability by 50% in the range of the therapeutic plasma levels reported for SNS-032 (<754 nM). Sixty-two percent of the cell lines and two of the primary samples displayed concentrations that reduce cell viability by 90% in this concentration range. SNS-032 also impaired the growth of the multidrug-resistant cisplatin-adapted UKF-NB-3 subline UKF-NB-3rCDDP1000 in mice. ABCB1 expression (but not ABCG2 expression) conferred resistance to SNS-032. The antineuroblastoma effects of SNS-032 did not depend on functional p53. The antineuroblastoma mechanism of SNS-032 included CDK7 and CDK9 inhibition-mediated suppression of RNA synthesis and subsequent depletion of antiapoptotic proteins with a fast turnover rate including X-linked inhibitor of apoptosis (XIAP), myeloid cell leukemia sequence 1 (Mcl-1), baculoviral IAP repeat containing 2 (BIRC2; cIAP-1), and survivin. In conclusion, CDK7 and CDK9 represent promising drug targets and SNS-032 represents a potential treatment option for neuroblastoma including therapy-refractory cases. PMID:24466371

Diagnostic and therapeutic management of hepatocellular carcinoma

Science.gov (United States)

Bellissimo, Francesco; Pinzone, Marilia Rita; Cacopardo, Bruno; Nunnari, Giuseppe

2015-01-01

Hepatocellular carcinoma (HCC) is an increasing health problem, representing the second cause of cancer-related mortality worldwide. The major risk factor for HCC is cirrhosis. In developing countries, viral hepatitis represent the major risk factor, whereas in developed countries, the epidemic of obesity, diabetes and nonalcoholic steatohepatitis contribute to the observed increase in HCC incidence. Cirrhotic patients are recommended to undergo HCC surveillance by abdominal ultrasounds at 6-mo intervals. The current diagnostic algorithms for HCC rely on typical radiological hallmarks in dynamic contrast-enhanced imaging, while the use of α-fetoprotein as an independent tool for HCC surveillance is not recommended by current guidelines due to its low sensitivity and specificity. Early diagnosis is crucial for curative treatments. Surgical resection, radiofrequency ablation and liver transplantation are considered the cornerstones of curative therapy, while for patients with more advanced HCC recommended options include sorafenib and trans-arterial chemo-embolization. A multidisciplinary team, consisting of hepatologists, surgeons, radiologists, oncologists and pathologists, is fundamental for a correct management. In this paper, we review the diagnostic and therapeutic management of HCC, with a focus on the most recent evidences and recommendations from guidelines. PMID:26576088

Identification of the second mutation of BADH2 gene derived from rice mutant lines induced by gamma rays

International Nuclear Information System (INIS)

I Ishak

2016-01-01

The BADH2 gene acts as suppressor of 2-acetyl-1-pyrolline (2AP) biosynthesis in plants. 2AP is the volatile compound which provides fragrance in rice. Biosynthesis of 2AP occurs when BADH2 loses its function as suppressor gene. Aromatic rice cultivars naturally incur mutation of BADH2 gene at 8 bp. In this experiment, aromatic mutant rice lines derived from irradiation of Sintanur cultivar by gamma rays with dose of 100 Gy were studied in molecular level. These mutant lines were characterized at the M10 plantgeneration under the assumption that genetically these aromatic mutant rice lines were homozygotic. Several primers related to aroma in rice have been used for polymerase chain reaction (PCR) in a thermal cycler instrument. Gel electrophoreses were carried out using 1.5% agarose in TAE buffer. DNA fragments at 254 bp and 355 bp (base pair) were taken and amplified by primer for nucleotide sequencing of these fragments. Molecular identification and characterization after electrophoresis showed that the mutant line from AR1020 can be differentiated from AR.1080 at 254 bp. Nucleotide sequence data from of these DNA fragments showed that point mutations (deletions and substitutions) occurred at the BADH2 gene in exon 7; those are called second mutation and were caused by gamma rays effects. The Sintanur variety was used as check cultivar and its DNA sequence was compared to that of the AR.1020 mutant line. The results from both DNA sequences (from cv. Sintanur and AR.1020) derived from fragments at 254 bp show that point mutations occurred within exon 7 and earlier stop codon occurred in the AR.1020 mutant rice line. Further, the use of EA primer in PCR resulted in detection of deletion and substitution of nucleotides in the AR.1020 mutant line. (author)

Evaluation of the Sensititre MycoTB plate for susceptibility testing of the Mycobacterium tuberculosis complex against first- and second-line agents.

Science.gov (United States)

Hall, Leslie; Jude, Kurt P; Clark, Shirley L; Dionne, Kim; Merson, Ryan; Boyer, Ana; Parrish, Nicole M; Wengenack, Nancy L

2012-11-01

The Sensititre MycoTB plate (TREK Diagnostic Systems, Cleveland, OH) uses a microtiter plate MIC format for susceptibility testing of Mycobacterium tuberculosis complex isolates against first- and second-line antituberculosis agents. Categorical agreement versus the agar proportion method for 122 M. tuberculosis complex isolates was 94% to 100%.

A curative treatment option for Complex Regional Pain Syndrome (CRPS) Type I: dorsal root entry zone operation (report of two cases).

Science.gov (United States)

Kanpolat, Yucel; Al-Beyati, Eyyub; Ugur, Hasan Caglar; Akpinar, Gokhan; Kahilogullari, Gokmen; Bozkurt, Melih

2014-01-01

Complex Regional Pain Syndrome Type I (CRPS-I) is a debated health problem concerning its pathophysiology and treatment strategies. A 12-year-old boy and a 35-year-old woman were diagnosed with CRPS-I at different times. They had previously undergone various types of interventions with no success. After one year of follow-up and observation, DREZ lesioning operation was performed. Afterwards, both cases had transient lower extremity ataxia. The first case was followed for 60 months with no recurrence and total cure. The second case was pain-free until the 6th month, when she required psychological support; she was followed for 33 months with partial satisfactory outcome. Although not a first-line option, DREZ lesioning procedure can be chosen and may be a curative option in selected cases of CRPS-I who are unresponsive to conventional therapies.

Economic considerations of commercial tokamak options

International Nuclear Information System (INIS)

Dabiri, A.E.

1986-05-01

Systems studies have been performed to assess commercial tokamak options. Superconducting, as well as normal, magnet coils in either first or second stability regimes have been considered. A spherical torus (ST), as well as an elongated tokamak (ET), is included in the study. The cost of electricity (COE) is selected as the figure of merit, and beta and first-wall neutron wall loads are selected to represent the physics and technology characteristics of various options. The results indicate that an economical optimum for tokamaks is predicted to require a beta of around 10%, as predicted to be achieved in the second stability regime, and a wall load of about 5 MW/m 2 , which is assumed to be optimum technologically. This tokamak is expected to be competitive with fission plants if efficient, noninductive current drive is developed. However, if this regime cannot be attained, all other tokamaks operating in the first stability regime, including spherical torus and elongated tokamak and assuming a limiting wall load of 5 MW/m 2 , will compete with one another with a COE of about 50 mill/kWh. This 40% higher than the COE for the optimum reactor in the second stability regime with fast-wave current drive. The above conclusions pertain to a 1200-MW(e) net electric power plant. A comparison was also made between ST, ET, and superconducting magnets in the second stability regime with fast-wave current drive at 600 MW(e)

Simulation of a Narrowband Power Line Communications System over Medium Voltage

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Nikolaos Chiotellis

2016-03-01

Full Text Available Narrowband Power Line Communications (NB-PLCs are investigated as an alternative option for transferring low rate smart grid (SG data via Medium Voltage (MV power lines. In this framework, two variants of orthogonal frequency division multiplexing are examined, namely Filtered-OFDM (F-OFDM and Wavelet-OFDM (W-OFDM, in an attempt to determine which of them is capable of transmitting low rate SG data to greater distances over non-branched MV power lines. The reach of NB-PLC signals via MV power lines is estimated, taking into account the transfer function of the relevant PLC channels and noise mechanisms as well as the specific features of the two modulation options under consideration. Simulations show that NB-PLC transmission constitutes a technically feasible and economically affordable option for exchanging low rate data with remote SG nodes dispersed over the MV grid. Moreover, simulations show that F-OFDM allows low rate data transmission to considerably greater distances compared to W-OFDM.

The potential for emerging therapeutic options for Clostridium difficile infection

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Mathur, Harsh; Rea, Mary C; Cotter, Paul D; Ross, R Paul; Hill, Colin

2014-01-01

Clostridium difficile is mainly a nosocomial pathogen and is a significant cause of antibiotic-associated diarrhea. It is also implicated in the majority of cases of pseudomembranous colitis. Recently, advancements in next generation sequencing technology (NGS) have highlighted the extent of damage to the gut microbiota caused by broad-spectrum antibiotics, often resulting in C. difficile infection (CDI). Currently the treatment of choice for CDI involves the use of metronidazole and vancomycin. However, recurrence and relapse of CDI, even after rounds of metronidazole/vancomycin administration is a problem that must be addressed. The efficacy of alternative antibiotics such as fidaxomicin, rifaximin, nitazoxanide, ramoplanin and tigecycline, as well as faecal microbiota transplantation has been assessed and some have yielded positive outcomes against C. difficile. Some bacteriocins have also shown promising effects against C. difficile in recent years. In light of this, the potential for emerging treatment options and efficacy of anti-C. difficile vaccines are discussed in this review. PMID:25564777

Sensitivity Pattern of Second Line Anti-Tuberculosis Drugs against Clinical Isolates of Multidrug Resistant Mycobacterium Tuberculosis

International Nuclear Information System (INIS)

Ghafoor, T.; Ikram, A.; Abbasi, S. A.; Zaman, G.; Ayyub, M.; Palomino, J. C.; Vandamme, P.; Martin, A.

2015-01-01

Objective:To determine the current sensitivity pattern of second line anti-tuberculosis drugs against clinical isolates of Multidrug Resistant Mycobacterium tuberculosis (MDR-TB). Study Design: A cross-sectional study. Place and Duration of Study: Department of Microbiology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from November 2011 to April 2013. Methodology: Samples received during the study period were processed on BACTEC MGIT 960 system for Mycobacterium tuberculosis (MTB) culture followed by first line drugs susceptibility testing of culture proven MTB isolates. On the basis of resistance to rifampicin and isoniazid, 100 clinical isolates of MDR-TB were further subjected to susceptibility testing against amikacin (AMK), capreomycin (CAP), ofloxacin (OFL) and ethionamide (ETH) as per standard BACTEC MGIT 960 instructions. Results: Out of 100 MDR-TB isolates, 62% were from male patients and 38% from female patients. 97% were sensitive to AMK, 53% to OFL, 87% to CAP; and 87% were sensitive to ETH. Conclusion: The majority of the MDR-TB isolates showed excellent sensitivity against AMK, CAP and ETH. However, sensitivity of MDR-TB isolates against fluoroquinolones like OFL was not encouraging. (author)

Associations between deepness of response and clinical outcomes among Japanese patients with metastatic colorectal cancer treated with second-line FOLFIRI plus cetuximab

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Osumi H

2015-08-01

Full Text Available Hiroki Osumi, Satoshi Matsusaka, Mitsukuni Suenaga, Eiji Shinozaki, Nobuyuki Mizunuma Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan Background: In the FIRE-3 trial, overall survival (OS was significantly longer in patients treated with FOLFIRI plus cetuximab (C-mab than in those treated with FOLFIRI plus bevacizumab (Bev, but progression-free survival (PFS was not significantly different. This may be associated with the deepness of response (DpR in patients treated with FOLFIRI plus C-mab. We aimed to evaluate the relationship between clinical outcome and DpR in metastatic colorectal cancer (mCRC patients treated with second-line FOLFIRI plus C-mab.Methods: A total of 112 patients with histopathologically confirmed mCRC treated with second-line FOLFIRI in combination with C-mab (N=42 or Bev (N=70 were retrospectively enrolled between October 2008 and June 2013. The relationship between DpR and clinical outcome in patients treated with FOLFIRI plus C-mab or Bev was determined.Results: Forty-two patients treated with FOLFIRI plus C-mab had a mean DpR of 6.1% (interquartile range: -13.7%, 20.8% and a minimum DpR of -62.7%. On the other hand, 70 patients treated with FOLFIRI plus Bev had a mean DpR of 0% (interquartile range: -16%, 10% and a minimum DpR of -111%. DpR ≥30% was associated with significantly longer OS and PFS when compared with DpR ≤30% in patients given FOLFIRI plus C-mab. DpR (≥30% was independently associated with prolongation of OS and PFS. In patients treated with FOLFIRI plus C-mab, there was a moderate positive correlation between DpR and clinical outcomes (OS: r=0.51, P<0.001; PFS: r=0.54, P<0.001.Conclusion: FOLFIRI plus C-mab yielded a stronger correlation between DpR and clinical outcomes. These results indicate the potential of DpR as a new measure of efficacy in mCRC patients treated with second-line chemotherapy plus C-mab. Keywords: deepness of

Bone Marrow-Derived Cells as a Therapeutic Approach to Optic Nerve Diseases

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Louise A. Mesentier-Louro

2016-01-01

Full Text Available Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized.

Mouse-tracking evidence for parallel anticipatory option evaluation.

Science.gov (United States)

Cranford, Edward A; Moss, Jarrod

2017-12-23

In fast-paced, dynamic tasks, the ability to anticipate the future outcome of a sequence of events is crucial to quickly selecting an appropriate course of action among multiple alternative options. There are two classes of theories that describe how anticipation occurs. Serial theories assume options are generated and evaluated one at a time, in order of quality, whereas parallel theories assume simultaneous generation and evaluation. The present research examined the option evaluation process during a task designed to be analogous to prior anticipation tasks, but within the domain of narrative text comprehension. Prior research has relied on indirect, off-line measurement of the option evaluation process during anticipation tasks. Because the movement of the hand can provide a window into underlying cognitive processes, online metrics such as continuous mouse tracking provide more fine-grained measurements of cognitive processing as it occurs in real time. In this study, participants listened to three-sentence stories and predicted the protagonists' final action by moving a mouse toward one of three possible options. Each story was presented with either one (control condition) or two (distractor condition) plausible ending options. Results seem most consistent with a parallel option evaluation process because initial mouse trajectories deviated further from the best option in the distractor condition compared to the control condition. It is difficult to completely rule out all possible serial processing accounts, although the results do place constraints on the time frame in which a serial processing explanation must operate.

Cost-effectiveness of tenofovir instead of zidovudine for use in first-line antiretroviral therapy in settings without virological monitoring.

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Viktor von Wyl

Full Text Available BACKGROUND: The most recent World Health Organization (WHO antiretroviral treatment guidelines recommend the inclusion of zidovudine (ZDV or tenofovir (TDF in first-line therapy. We conducted a cost-effectiveness analysis with emphasis on emerging patterns of drug resistance upon treatment failure and their impact on second-line therapy. METHODS: We used a stochastic simulation of a generalized HIV-1 epidemic in sub-Saharan Africa to compare two strategies for first-line combination antiretroviral treatment including lamivudine, nevirapine and either ZDV or TDF. Model input parameters were derived from literature and, for the simulation of resistance pathways, estimated from drug resistance data obtained after first-line treatment failure in settings without virological monitoring. Treatment failure and cost effectiveness were determined based on WHO definitions. Two scenarios with optimistic (no emergence; base and pessimistic (extensive emergence assumptions regarding occurrence of multidrug resistance patterns were tested. RESULTS: In the base scenario, cumulative proportions of treatment failure according to WHO criteria were higher among first-line ZDV users (median after six years 36% [95% simulation interval 32%; 39%] compared with first-line TDF users (31% [29%; 33%]. Consequently, a higher proportion initiated second-line therapy (including lamivudine, boosted protease inhibitors and either ZDV or TDF in the first-line ZDV user group 34% [31%; 37%] relative to first-line TDF users (30% [27%; 32%]. At the time of second-line initiation, a higher proportion (16% of first-line ZDV users harboured TDF-resistant HIV compared with ZDV-resistant viruses among first-line TDF users (0% and 6% in base and pessimistic scenarios, respectively. In the base scenario, the incremental cost effectiveness ratio with respect to quality adjusted life years (QALY was US$83 when TDF instead of ZDV was used in first-line therapy (pessimistic scenario: US$ 315

Tuberculosis drug issues: prices, fixed-dose combination products and second-line drugs.

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Laing, R O; McGoldrick, K M

2000-12-01

Access to tuberculosis drugs depends on multiple factors. Selection of a standard list of TB drugs to procure is the first step. This paper reviews the advantages and disadvantages of procuring and using fixed-dose combination (FDC) products for both the intensive and continuation phases of treatment. The major advantages are to prevent the emergence of resistance, to simplify logistic management and to reduce costs. The major disadvantage is the need for the manufacturers to assure the quality of these FDCs by bioavailability testing. The paper reports on the inclusion of second-line TB drugs in the 1999 WHO Essential Drug List (EDL). The need to ensure that these drugs are used within established DOTS-Plus programs is stressed. The price of TB drugs is determined by many factors, including producer prices, local taxes and duties as well as mark-ups and fees. TB drug prices for both the public and private sectors from industrialized and developing countries are reported. Price trends over time are also reported. The key findings of this study are that TB drug prices have generally declined in developing countries while they have increased in developed countries, both for the public and private sectors. Prices vary between countries, with the US paying as much as 95 times the price paid in a specific developing country. The prices of public sector first-line TB drugs vary little between countries, although differences do exist due to the procurement methods used. The price of tuberculin, a diagnostic agent, has increased dramatically in the US, with substantial inter-country variations in price. The paper suggests that further research is necessary to identify the reasons for the price disparities and changes over time, and suggests methods which can be used by National Tuberculosis Programme managers to ensure availability of quality assured TB drugs at low prices.

Energy options

International Nuclear Information System (INIS)

Hampton, Michael

1999-01-01

This chapter focuses on energy options as a means of managing exposure to energy prices. An intuitive approach to energy options is presented, and traditional definitions of call and put options are given. The relationship between options and swaps, option value and option exercises, commodity options, and option pricing are described. An end-user's guide to energy option strategy is outlined, and straight options, collars, participating swaps and collars, bull and bear spreads, and swaption are examined. Panels explaining the defining of basis risk, and discussing option pricing and the Greeks, delta hedging, managing oil options using the Black-Scholes model, caps, floors and collars, and guidelines on hedging versus speculation with options are included in the paper

Therapeutic compliance of first line disease-modifying therapies in patients with multiple sclerosis. COMPLIANCE Study.

Science.gov (United States)

Saiz, A; Mora, S; Blanco, J

2015-05-01

Non-adherence to disease-modifying therapies (DMTs) in multiple sclerosis may be associated with reduced efficacy. We assessed compliance, the reasons for non-compliance, treatment satisfaction, and quality of life (QoL) of patients treated with first-line therapies. A cross-sectional, multicenter study was conducted that included relapsing multiple sclerosis patients. Compliance in the past month was assessed using Morisky-Green test. Seasonal compliance and reasons for non-compliance were assessed by an ad-hoc questionnaire. Treatment satisfaction and QoL were evaluated by means of TSQM and PRIMUS questionnaires. A total of 220 patients were evaluated (91% relapsing-remitting); the mean age was 39.1 years, 70% were female, and the average time under treatment was 5.4 years. Subcutaneous interferon (IFN) β-1b was used in 23% of the patients, intramuscular IFN β-1a in 21%, subcutaneous IFN β-1a in 37%, and with glatiramer acetate in 19%. The overall compliance was 75%, with no significant differences related to the therapy, and 81% did not report any seasonal variation. Compliant patients had significantly lower disability scores and time of diagnosis, and greater satisfaction with treatment and its effectiveness. Discomfort and flu-like symptoms were the most frequent reasons for non-compliance. The satisfaction and QoL were associated with less disability and number of therapeutic switches. The rate of compliance, satisfaction and QoL in multiple sclerosis patients under DMTs is high, especially for those newly diagnosed, less disabled, and with fewer therapeutic switches. Discomfort and flu-like symptoms associated with injected therapies significantly affect adherence. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Update on neuropathic pain treatment for trigeminal neuralgia

Science.gov (United States)

Al-Quliti, Khalid W.

2015-01-01

Trigeminal neuralgia is a syndrome of unilateral, paroxysmal, stabbing facial pain, originating from the trigeminal nerve. Careful history of typical symptoms is crucial for diagnosis. Most cases are caused by vascular compression of the trigeminal root adjacent to the pons leading to focal demyelination and ephaptic axonal transmission. Brain imaging is required to exclude secondary causes. Many medical and surgical treatments are available. Most patients respond well to pharmacotherapy; carbamazepine and oxcarbazepine are first line therapy, while lamotrigine and baclofen are considered second line treatments. Other drugs such as topiramate, levetiracetam, gabapentin, pregabalin, and botulinum toxin-A are alternative treatments. Surgical options are available if medications are no longer effective or tolerated. Microvascular decompression, gamma knife radiosurgery, and percutaneous rhizotomies are most promising surgical alternatives. This paper reviews the medical and surgical therapeutic options for the treatment of trigeminal neuralgia, based on available evidence and guidelines. PMID:25864062

Severe hepatocytolisis syndrome - a challenge in medical therapy of Cushing’s disease

Directory of Open Access Journals (Sweden)

Valea Ana

2015-08-01

Full Text Available Introduction Cushing’s disease is a rare endocrine disorder characterized by persistent hypercortisolism due to excessive, autonomous ACTH secretion by a pituitary adenoma. Transsphenoidal adenomectomy is the main therapeutic option in Cushing’s disease. When imaging studies are unable to demonstrate an obvious pituitary mass complete tumor resection is difficult and often encumbered by risk of relapse. Medical therapy is a second-line option or the first-line treatment for patients with high surgical risk, incomplete surgical resection or relapse. Rarely classic clinical manifestations limit the selection of medical therapy for Cushing’s disease. Case presentation We present the case of a male patient with Cushing’s disease complicated with diabetes mellitus and severe hepatocytolisis syndrome with no visible pituitary adenoma on MRI studies. In the absence of technical equipment petrosal sinus sampling could not be performed in order to improve surgery outcome

Experience with ibrutinib for first-line use in patients with chronic lymphocytic leukemia.

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Itchaki, Gilad; Brown, Jennifer R

2018-01-01

Ibrutinib is the first in-class, orally administered, Bruton's tyrosine kinase (BTK) inhibitor that abrogates the critical signaling downstream of the B-cell receptor (BCR). This signaling is required for B-cell survival, proliferation and interaction with the microenvironment. Ibrutinib proved active in preclinical models of lymphoproliferative diseases and achieved impressive response rates in heavily pretreated relapsed and refractory (R/R) patients with chronic lymphocytic leukemia (CLL). Ibrutinib prolonged survival compared to standard therapy and mitigated the effect of most poor prognostic factors in CLL, thus becoming the main therapeutic option in high-risk populations. Moreover, compared with standard chemoimmunotherapy (CIT) for adults, ibrutinib causes fewer cytopenias and infections, while having its own unique toxicity profile. Its efficacy in relapsed patients as well as its tolerability have led to its increased use in previously untreated patients, especially in those with poor prognostic markers and/or the elderly. This review elaborates on ibrutinib's unique toxicity profile and the mechanisms of acquired resistance leading to progression on ibrutinib, since both are critical for understanding the obstacles to its first-line use. We will further evaluate the data from ongoing clinical trials in this setting and explore future options for combination therapy.

Effect of Some Therapeutic Agents on the Radionuclides Excretion from Internally Contaminated Rats

International Nuclear Information System (INIS)

Aziz, M.; Mangood, Sh.A.; Sohsah, M.A.

2009-01-01

The present work was oriented to investigate the effectiveness of Prussian blue (PB), vermiculite and diethylenetriaminepentaacetic acid (CaDTPA) as therapeutic agents for the elimination of either 134 Cs or 60 Co from contaminated rats after intake of one of the isotopes. The study was performed by using 48 adult rats divided into 8 identical groups each of six rats having approximately the same body weight. The groups included a reference group, without isotope or therapeutic agent administration, four groups given one of the isotopes and four groups given the isotopes and treated with different therapeutic regimes. The isotope content of the treated and untreated contaminated rats were followed by daily whole body radiometric counting for three weeks. On plotting log % radionuclide retained as a function of time, elapsed between radionuclide administration and radiometric counting, straight lines were obtained. The results indicate that excretion can mostly be represented by two stages; the first is fast followed by a second slow stage. The % radionuclide excreted, the corresponding rate constant and the biological half-life of each stage was estimated. It was found that the application of PB + vermiculite is more efficient, to remove 134 Cs, from contaminated rats, than PB only and CaDTPA is more efficient to remove 60Co. Therefore, it is recommended to use the three therapeutic agents to remove both isotopes when taken simultaneously

Interferon-gamma sensitizes colonic epithelial cell lines to physiological and therapeutic inducers of colonocyte apoptosis.

LENUS (Irish Health Repository)

O'Connell, J

2012-02-03

Homeostasis in the colonic epithelium is achieved by a continuous cycle of proliferation and apoptosis, in which imbalances are associated with disease. Inflammatory bowel disease (IBD) and colon cancer are associated with either excessive or insufficient apoptosis of colonic epithelial cells, respectively. By using two colonic epithelial cell lines, HT29 and SW620, we investigated how the epithelial cell\\'s sensitivity to apoptosis was regulated by the proinflammatory cytokine interferon-gamma (IFN-gamma). We found that IFN-gamma sensitized HT29 cells, and to a lesser extent SW620, to diverse inducers of apoptosis of physiologic or therapeutic relevance to the colon. These apoptosis inducers included Fas (CD95\\/APO-1) ligand (FasL), short-chain fatty acids, and chemotherapeutic drugs. The extent of IFN-gamma-mediated apoptosis sensitization in these two cell lines correlated well with the degree of IFN-gamma-mediated upregulation of the proapoptotic protease caspase-1. Although IFN-gamma alone effectively sensitized HT29 cells to apoptosis, inclusion of the protein synthesis inhibitor cyclohexamide (CHX) during apoptotic challenge was necessary for maximal sensitization of SW620. The requirement of CHX to sensitize SW620 cells to apoptosis implies a need to inhibit translation of antiapoptotic proteins absent from HT29. In particular, the antiapoptotic protein Bcl-2 was strongly expressed in SW620 cells but absent from HT29. Our results indicate that IFN-gamma increases the sensitivity of colonic epithelial cells to diverse apoptotic stimuli in concert, via upregulation of caspase-1. Our findings implicate caspase-1 and Bcl-2 as important central points of control determining the general sensitivity of colonic epithelial cells to apoptosis.

Extracellular vesicles derived from mesenchymal stromal cells: a therapeutic option in respiratory diseases?

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Abreu, Soraia C; Weiss, Daniel J; Rocco, Patricia R M

2016-04-14

Extracellular vesicles (EVs) are plasma membrane-bound fragments released from several cell types, including mesenchymal stromal cells (MSCs), constitutively or under stimulation. EVs derived from MSCs and other cell types transfer molecules (such as DNA, proteins/peptides, mRNA, microRNA, and lipids) and/or organelles with reparative and anti-inflammatory properties to recipient cells. The paracrine anti-inflammatory effects promoted by MSC-derived EVs have attracted significant interest in the regenerative medicine field, including for potential use in lung injuries. In the present review, we describe the characteristics, biological activities, and mechanisms of action of MSC-derived EVs. We also review the therapeutic potential of EVs as reported in relevant preclinical models of acute and chronic respiratory diseases, such as pneumonia, acute respiratory distress syndrome, asthma, and pulmonary arterial hypertension. Finally, we discuss possible approaches for potentiating the therapeutic effects of MSC-derived EVs so as to enable use of this therapy in clinical practice.

A population-based study of first and second-line drug-resistant tuberculosis in a high-burden area of the Mexico/United States border

Directory of Open Access Journals (Sweden)

Pola Becerril-Montes

2013-04-01

Full Text Available The resistance of 139 Mycobacterium tuberculosis (MTB isolates from the city of Monterrey, Northeast Mexico, to first and second-line anti-TB drugs was analysed. A total of 73 isolates were susceptible and 66 were resistant to anti-TB drugs. Monoresistance to streptomycin, isoniazid (INH and ethambutol was observed in 29 cases. Resistance to INH was found in 52 cases and in 29 cases INH resistance was combined with resistance to two or three drugs. A total of 24 isolates were multidrug-resistant (MDR resistant to at least INH and rifampicin and 11 MDR cases were resistant to five drugs. The proportion of MDR-TB among new TB cases in our target population was 0.72% (1/139 cases. The proportion of MDR-TB among previously treated cases was 25.18% (35/139 cases. The 13 polyresistant and 24 MDR isolates were assayed against the following seven second-line drugs: amikacin (AMK, kanamycin (KAN, capreomycin (CAP, clofazimine (CLF, ethionamide (ETH, ofloxacin (OFL and cycloserine (CLS. Resistance to CLF, OFL or CLS was not observed. Resistance was detected to ETH (10.80% and to AMK (2.70%, KAN (2.70% and CAP (2.70%. One isolate of MDR with primary resistance was also resistant to three second-line drugs. Monterrey has a high prevalence of MDR-TB among previously treated cases and extensively drug-resistant-MTB strains may soon appear.

Breast cancer. Nuclear medicine in diagnosis and therapeutic options

International Nuclear Information System (INIS)

Bombardieri, E.; Bonadonna, G.; Gianni, L.

2008-01-01

Brings up-to-date nuclear medical knowledge in breast cancer. Includes vital information on advances in the field of diagnosis. Supplies data on the development of some new modalities. Offers a general overview of the available tools for breast cancer treatment. There can never be enough material in the public domain about cancers, and particularly breast cancer. This book adds much to the literature. It provides general information on breast cancer management and considers all new methods of diagnosis and therapy. It focuses on nuclear medicine modalities by comparing their results with other diagnostic and therapeutic approaches. The coverage provides readers with up-to-date knowledge on breast cancer as well as information on the advances in the field of diagnosis. It also details data on the development of some new modalities and provides a general overview of the available tools for breast cancer treatment. In sum, it is a hugely useful text that performs a dual function. Not only does it provide practitioners of all descriptions with a vital overview of the current state of play in breast cancer treatment, but it also lays out in a beautifully structured way the latest diagnostic methodologies. (orig.)

Overview of magnet design options: Deliverable D5.1

CERN Document Server

AUTHOR|(CDS)2069265; Toral, Fernando

2016-01-01

This document describes the design options for 16 T superconducting dipole magnets for the FCC hadron collider explored in the frame of the activities of WP5. All options have been considered under comparable assumptions and managed using the same tools to ensure a correct judgement and comparison of their relevant pros and cons. Three baseline design configurations have been explored: 1) block-coils, 2) cosine-theta and 3) common-coils. A fourth option, the canted cosine-theta, has been initiated by Swiss (PSI, not part of EuroCirCol) and US (LBNL, EuroCirCol partner) laboratories. The studies show that, adopting a reference margin to the load line of 14 % and with reasonable assumptions on the conductor performance, the total amount of conductor needed for the entire collider is between 7.5 and 10 ktons. depending on the option. The cosine-theta uses less conductor and the canted cosine-theta uses the largest amount. The characterisation of the magnet design options is complete and the work to finalize and ...

Effects of Help Options in a Multimedia Listening Environment on L2 Vocabulary Acquisition

Science.gov (United States)

Mohsen, Mohammed Ali

2016-01-01

Several types of help options have been incorporated into reading and listening comprehension activities to aid second language (L2) vocabulary acquisition. Textbook authors, teachers, and sometimes even students may pick and choose which help options they wish to use. In this paper, I investigate the effects of two help options in a multimedia…

Nail Psoriasis: A Review of Treatment Options.

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Pasch, Marcel C

2016-04-01

Nail involvement affects 80-90 % of patients with plaque psoriasis, and is even more prevalent in patients with psoriatic arthritis. This review is the result of a systemic approach to the literature and covers topical, intralesional, conventional systemic, and biologic systemic treatments, as well as non-pharmacological treatment options for nail psoriasis. The available evidence suggests that all anti-tumor necrosis factor-α, anti-interleukin (IL)-17, and anti-IL-12/23 antibodies which are available for plaque psoriasis and psoriatic arthritis are highly effective treatments for nail psoriasis. Conventional systemic treatments, including methotrexate, cyclosporine, acitretin, and apremilast, as well as intralesional corticosteroids, can also be effective treatments for nail psoriasis. Topical treatments, including corticosteroids, calcipotriol, tacrolimus, and tazarotene, have also been shown to have a position in the treatment of nail psoriasis, particularly in mild cases. Finally, non-pharmacological treatment options, including phototherapy, photodynamic therapy, laser therapy, and several radiotherapeutic options, are also reviewed but cannot be advised as first-line treatment options. Another conclusion of this review is that the lack of a reliable core set of outcomes measures for trials in nail psoriasis hinders the interpretation of results, and is urgently needed.

Assessment of Extracorporeal Shock Wave Lithotripsy (ESWL) Therapeutic Efficiency in Urolithiasis.

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Tomescu, P; Pănuş, A; Mitroi, G; Drăgoescu, O; Stoica, L; Dena, S; Enache, E

2009-01-01

Extracorporeal shock wave lithotripsy (ESWL) revolutionized the treatment of urolithiasis and gradually became the favorite treatment option so that today it is considered to be the first line of treatment for more than 75% of the patients with urolithiasis. The purpose of this study was the assessment of the therapeutic efficiency, complications and limitations of ESWL in urolithiasis in the initial experience using a third generation electromagnetic lithotripter.  Between 2007 and 2008 we performed ESWL for 167 patients with urolithiasis. We recorded 92 patients with single stone (55.1%) and 72 with multiple lithiasis (44.9%). Stone size varied between 7 and 24 mm with an average of 12.3±7.1 mm. Radioopac stones were found in 104 patients (62.3%) while radiolucent stones in 63 only (37.6%).    Complete stone disintegration and clearance was achieved in most cases (86.2%). Complications were mostly minor and rare (transitory haematuria, renal colic). Severe complications (renal hematoma, steinstrasse) were diagnosed for a limited number of patients (3.6%) and their management was mostly nonsurgical or minimally invasive (retrograde ureteroscopy). ESWL is therefore the first line of treatment for urolithiasis with stone size smaller than 2.5 cm. It has an efficiency rate above 85%, low procedure time, high safety and good tolerability (new generation lithotripters do not require anesthesia) and minimal complications.

Influence of in-plane field on vertical Bloch line in the walls of the second kind of dumbbell domains at various temperatures

International Nuclear Information System (INIS)

Xu, J.P.; Liu, S.P.; Guo, G.X.; Zhen, C.M.; Tang, G.D.; Sun, H.Y.; Nie, X.F.

2004-01-01

The stability of vertical Bloch lines (VBLs) in the second kind of dumbbell domain (IIDs) walls in liquid phase epitaxy garnet bubble films subjected to an in-plane field at various temperatures is studied experimentally. It is found that there exists a critical in-plane field range depending on temperature, in which vertical Bloch lines (VBLs) in the second kind of IIDs walls are unstable, i.e., [Hip(1)(T),Hip(2)(T)]. Here, Hip(1)(T) is the initial critical in-plane field at which VBLs in the walls of IIDs annihilate; while Hip(2)(T) is the lowest in-plane field at which all VBLs in the walls of IIDs have annihilated completely. Also, the critical in-plane field range [Hip(1)(T),Hip(2)(T)],Hip(1)(T) and Hip(2)(T) all decrease with the temperature increasing. Hip(1)(T) and Hip(2)(T) reach zero at T0' and T0, respectively

Management options for recycling radioactive scrap metals

Energy Technology Data Exchange (ETDEWEB)

Dehmel, J.C.; MacKinney, J.; Bartlett, J.

1997-02-01

The feasibility and advantages of recycling radioactive scrap metals (RSM) have yet to be assessed, given the unique technical, regulatory, safety, and cost-benefit issues that have already been raised by a concerned recycling industry. As is known, this industry has been repeatedly involved with the accidental recycling of radioactive sources and, in some cases, with costly consequences. If recycling were deemed to be a viable option, it might have to be implemented with regulatory monitoring and controls. Its implementation may have to consider various and complex issues and address the requirements and concerns of distinctly different industries. There are three basic options for the recycling of such scraps. They are: (1) recycling through the existing network of metal-scrap dealers and brokers, (2) recycling directly and only with specific steelmills, or (3) recycling through regional processing centers. Under the first option, scrap dealers and brokers would receive material from RSM generators and determine at which steelmills such scraps would be recycled. For the second option, RSM generators would deal directly with selected steelmills under specific agreements. For the third option, generators would ship scraps only to regional centers for processing and shipment to participating steelmills. This paper addresses the potential advantages of each option, identifies the types of arrangements that would need to be secured among all parties, and attempts to assess the receptivity of the recycling industry to each option.

Second-line Treatment of Stage III/IV Non-Small-Cell Lung Cancer (NSCLC with pemetrexed in routine clinical practice: Evaluation of performance status and health-related quality of life

Directory of Open Access Journals (Sweden)

Schuette Wolfgang

2012-01-01

Full Text Available Abstract Background Second-line treatment of advanced non-small-cell lung cancer (NSCLC improves overall survival. There is a lack of data regarding the impact on patients' overall health condition. This prospective, non-interventional study evaluated performance status (PS and health-related quality of life (HR-QoL during second-line pemetrexed treatment in routine clinical practice. Methods Stage III/IV NSCLC patients who initiated second-line pemetrexed (standard vitamin and dexamethasone supplementation were observed for a maximum of 9 treatment cycles. The primary objective was to evaluate the proportion of patients achieving improvement of Karnofsky Index (KI of ≥ 10% (absolute or maintaining KI ≥ 80% after the second treatment cycle ("KI benefit response". HR-QoL was self-rated using the EuroQoL-5D questionnaire (EQ-5D. Factors potentially associated with KI benefit response were evaluated using logistic regression models. Results Of 521 eligible patients (73.5% Stage IV, median age 66.3 yrs, 36.1% ≥ 70 yrs, 62.0% with KI ≥ 80%, 471 (90.4% completed at least 2 treatment cycles. 58.0% (95%CI 53.6%;62.2% achieved KI benefit response after the second cycle. Patients with baseline KI ≥ 80%, no Grade 3/4 toxicities during the first 2 cycles, or combination regimen as prior first-line therapy were more likely to achieve a KI benefit response. EQ-5D scores improved over time. Grade 3/4 toxicities were reported in 23.8% of patients (mainly fatigue/asthenia 15.9%, neutropenia 8.7%. Conclusions In this large prospective, non-interventional study of second-line pemetrexed treatment in patients with advanced NSCLC, including 36% elderly patients ( ≥ 70 years, physician-rated PS and self-rated HR-QoL were maintained or improved in the majority of patients. Trial registration Registered on ClinicalTrials.gov (NCT00540241 on October 4, 2007

48 CFR 552.217-71 - Notice Regarding Option(s).

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 4 2010-10-01 2010-10-01 false Notice Regarding Option(s... Notice Regarding Option(s). As prescribed in 517.208(b), insert the following provision: Notice Regarding Option(s) (NOV 1992) The General Services Administration (GSA) has included an option to [Insert...

An Overall Investigation of Direct Vessel Injection Line Break Accidents of the ATLAS Facility

International Nuclear Information System (INIS)

Kim, Yeon-Sik; Choi, Ki-Yong; Cho, Seok; Kim, Bok-Deuk

2015-01-01

For parametric evaluations of direct vessel injection (DVI) line break scenarios, the pressurizer (PZR) pressure, core collapsed water level, and peak cladding temperature were investigated between the analyses and tests. The PZR pressure was mainly dependent upon the break flow model, e.g., discharge coefficient of the Henry-Fauske critical model. The core collapsed water level and peak cladding temperature were mainly dependent on the counter-current flow limit (CCFL) option of the fuel alignment plate (FAP). The CCFL option of the cross-over leg (COL) affected the PZR pressure owing to the loop seal clearings and seemed to have little effect on the core collapsed water level. Proper C d values and applicable CCFL options were summarized. C d values seemed to be dependent on the sizes of the DVI line break. The PZR pressure was mainly dependent on the break flow model, e.g., the discharge coefficient of the Henry-Fauske critical model. The core collapsed water level and peak cladding temperature were mainly dependent on the CCFL option of the FAP. The CCFL option of the COL affected the PZR pressure owing to loop seal clearings and seemed to have little effect on the core collapsed water level. From parametric evaluations, proper C d values and applicable CCFL options were suggested. The C d values seemed to be dependent on the sizes of the DVI line break. Although there was little difference in the CCFL options of the COL, the Ku-option was the preferred one for COLs' CCFL option. The CCFL options of the FAP appeared sensitive to the core collapsed water level and peak cladding temperature. The Ku-option of the FAP tended to negatively exaggerate the core behavior and showed excessively conservative results, especially on the peak cladding temperature. For smaller breaks, e.g., 25%, NA- and Wa-options would be applicable for the FAP. However, for larger breaks, e.g., 50%, the Wa-option of the FAP was the preferred one. Comparisons between the tests and

Economic evaluation of therapeutic sequences in the treatment of patients with chronic lymphocytic leukemia and coexisting conditions

Directory of Open Access Journals (Sweden)

Antonio Cuneo

2017-10-01

Full Text Available Economic evaluation of therapeutic sequences in the treatment of patients with chronic lymphocytic leukemia and coexisting conditionsIntroductionChronic lymphocytic leukemia (CLL is a chronic lymphoproliferative syndrome and it is the most common hematological malignancy in Western countries. It has a tendency to develop subsequent relapses, so affected patients are likely to undergo more than one line of treatment.MethodsRather than evaluating the cost-effectiveness of individual therapeutic agents, it becomes therefore recommendable for decision-makers to identify an optimal sequencing of such agents. A four-year cost-consequence analysis was conducted, comparing three alternative strategies for the first-line treatment of patients with previously untreated CLL and coexisting conditions: i obinutuzumab with chlorambucil (Obi-Clb, ii rituximab with chlorambucil (Rtx-Clb, and iii ofatumumab with chlorambucil (Ofa-Clb. Only drug costs were considered in the analysis.ResultsIn two trials, median time to next treatment (TTNT was longer in Obi-Clb (51.1 months as compared to Rtx-Clb (38.2 months or to Ofa-Clb (39.8 months. Therefore, during a 48-month time horizon, patients treated with Obi-Clb would maintain on average the first line treatment; on the contrary, patients treated with Rtx-Clb or with Ofa-Clb would receive on average a second line treatment consisting in the majority of cases of ibrutinib monotherapy, or rituximab with idelalisib or rituximab with bendamustine. The sequence using Obi-Clb regimen in first line showed the lower mean cost of treatment: €22,958 over the 48-month time horizon. Sensitivity analyses on a couple of scenarios provided similar conclusions in terms of overall costs.ConclusionObi-Clb as first-line treatment appears a recommendable strategy in terms of drug costs in the treatment of patients with previously untreated CLL and coexisting conditions.

Busulfan is effective second-line therapy for older patients with Philadelphia-negative myeloproliferative neoplasms intolerant of or unresponsive to hydroxyurea.

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Douglas, Genevieve; Harrison, Claire; Forsyth, Cecily; Bennett, Michael; Stevenson, William; Hounsell, John; Ratnasingam, Sumita; Ritchie, David; Ross, David M; Grigg, Andrew

2017-01-01

Hydroxyurea (Hu) is widely used as first-line cytoreductive therapy for patients with high-risk Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPN), but a small proportion of patients have refractory disease or experience adverse effects. Studies have demonstrated busulfan (Bu) to be an active first-line agent, but data on its role as second-line or later therapy are minimal. To evaluate its efficacy and safety in this context, we undertook a multicenter audit of Ph-neg MPN patients who had received Bu as therapy for Hu intolerance or failure. Of 51 patients identified, 38 (75%) achieved either complete or partial hematological response following at least one Bu cycle. Bu was generally well tolerated, with only 21/135 (15%) cycles complicated by adverse effects, predominantly cytopenia; only 6% of cycles were ceased due to treatment complications. Bu is an effective and well-tolerated agent in patients with Ph-neg MPN in the setting of Hu intolerance or unresponsiveness.

Bayesian comparative effectiveness study of four consensus treatment plans for initial management of systemic juvenile idiopathic arthritis: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST).

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Nigrovic, Peter A; Beukelman, Timothy; Tomlinson, George; Feldman, Brian M; Schanberg, Laura E; Kimura, Yukiko

2018-03-01

Systemic juvenile idiopathic arthritis is a rare febrile arthritis of childhood characterized by a potentially severe course, including prolonged glucocorticoid exposure, growth failure, destructive arthritis, and life-threatening macrophage activation syndrome. Early cytokine-blocking biologic therapy may improve long-term outcomes, although some systemic juvenile idiopathic arthritis patients respond well to non-biologic treatment, leaving optimal management undefined. Consequently, treatment of new-onset systemic juvenile idiopathic arthritis by expert clinicians varies widely. To describe a pragmatic, observational comparative effectiveness study that takes advantage of diversity in the management of a rare disease: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST), comparing non-biologic and biologic consensus treatment plans for new-onset systemic juvenile idiopathic arthritis within the 60-center Childhood Arthritis and Rheumatology Research Alliance Registry (CARRA). FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) is a multicenter, prospective, non-randomized study that compares four Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans for new-onset systemic juvenile idiopathic arthritis: (1) glucocorticoids alone, (2) methotrexate, (3) interleukin-1 blockade, and (4) interleukin-6 blockade. Patients consenting to participation in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry are started on one of four Consensus Treatment Plans at the discretion of the treating physician. The outcome of primary interest is clinically inactive disease off glucocorticoids at 9 months, comparing non-biologic (Consensus Treatment Plans 1 + 2) versus biologic (Consensus Treatment Plans 3 + 4) strategies. Bayesian analytic methods will be employed to evaluate response rates, using propensity scoring to balance treatment groups for potential

Imaging enabled platforms for development of therapeutics

Science.gov (United States)

Celli, Jonathan; Rizvi, Imran; Blanden, Adam R.; Evans, Conor L.; Abu-Yousif, Adnan O.; Spring, Bryan Q.; Muzikansky, Alona; Pogue, Brian W.; Finkelstein, Dianne M.; Hasan, Tayyaba

2011-03-01

Advances in imaging and spectroscopic technologies have enabled the optimization of many therapeutic modalities in cancer and noncancer pathologies either by earlier disease detection or by allowing therapy monitoring. Amongst the therapeutic options benefiting from developments in imaging technologies, photodynamic therapy (PDT) is exceptional. PDT is a photochemistry-based therapeutic approach where a light-sensitive molecule (photosensitizer) is activated with light of appropriate energy (wavelength) to produce reactive molecular species such as free radicals and singlet oxygen. These molecular entities then react with biological targets such as DNA, membranes and other cellular components to impair their function and lead to eventual cell and tissue death. Development of PDT-based imaging also provides a platform for rapid screening of new therapeutics in novel in vitro models prior to expensive and labor-intensive animal studies. In this study we demonstrate how an imaging platform can be used for strategizing a novel combination treatment strategy for multifocal ovarian cancer. Using an in vitro 3D model for micrometastatic ovarian cancer in conjunction with quantitative imaging we examine dose and scheduling strategies for PDT in combination with carboplatin, a chemotherapeutic agent presently in clinical use for management of this deadly form of cancer.

GSK3α/β: A Novel Therapeutic Target for Neuroendocrine Tumors?

Science.gov (United States)

Aristizabal Prada, Elke Tatjana; Weis, Carla; Orth, Michael; Lauseker, Michael; Spoettl, Gerald; Maurer, Julian; Grabowski, Patricia; Grossman, Ashley; Auernhammer, Christoph Josef; Nölting, Svenja

2017-10-02

Introduction: GSK3α/β is a serine/threonine-kinase that plays a critical role in cancer. In this study, we evaluated the effects of the specific GSK3α/β inhibitor AR-A014418 in vitro to gain novel insights into GSK3α/β signaling in NETs. Human NET cell lines (BON1, QGP1, H727 and GOT1) were treated with different concentrations of AR-A014418 alone and in combination with lovastatin, everolimus, 5-fluorouracil (5-FU) and γ-irradiation. AR-A014418 significantly dose- and time-dependently decreased cell viability in all four NET cell lines through inhibition of EGFR- and mTORC1/p70S6K signaling, as well as Cyclin D3 downregulation and induction of pChk1. In all cell lines tested, FACS analysis showed an AR-A014418-induced increase in the sub-G1 phase, reflecting cell death. However, apoptosis induction was only observed in H727 cells. Furthermore, significant anti-migratory effects upon GSK3α/β inhibition were found and were associated with β-catenin downregulation in all cell lines tested. Compensatory up-regulation of pAkt and pERK in response to GSK3α/β inhibition was prevented by combining AR-A014418 with the ERK- and Akt-inhibitor lovastatin. Accordingly, the lovastatin/AR-A014418 combination was synergistic in BON1 and QGP1 cells. Moreover, AR-A014418 displayed promising chemo-sensitizing effects to 5-FU in QGP1 and slight radio-sensitizing properties in BON1 and QGP1 cells. Our data provide new insights into the role of GSK3α/β in NETs and suggest that GSK3α/β-inhibition could be a novel therapeutic option in NETs, especially in combination with lovastatin or 5-FU, depending on tumor entity. ©2017S. Karger AG, Basel.

Vinorelbine as first-line or second-line therapy for advanced breast cancer

DEFF Research Database (Denmark)

Langkjer, Sven T; Ejlertsen, Bent; Mouridsen, Henning

2008-01-01

INTRODUCTION: This study was conducted to establish the maximum tolerated dose (MTD) of intravenous vinorelbine and on the determined dose to assess efficacy and safety in patients with metastatic breast cancer previously treated with epirubicin. PATIENTS AND METHODS: Patients had histologically...... proven breast cancer and had received a prior epirubicin based regimen either adjuvant or as first line therapy for advanced disease. Vinorelbine was administered intravenously day 1 and 8 in a 3 weeks' schedule. Subsequently 48 additional patients were treated at one dose-level below MTD. RESULTS: Fifty...

Comparison of erlotinib and pemetrexed as second-/third-line treatment for lung adenocarcinoma patients with asymptomatic brain metastases

Directory of Open Access Journals (Sweden)

He YY

2016-04-01

Full Text Available Yayi He,1,* Wenwen Sun,2,* Yan Wang,3,* Shengxiang Ren,1 Xuefei Li,3 Jiayu Li,3 Christopher J Rivard,4 Caicun Zhou,1 Fred R Hirsch4 1Department of Oncology, Shanghai Pulmonary Hospital, 2Clinic and Research Center of Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, 3Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, People’s Republic of China; 4Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO, USA *These authors contributed equally to this work Objective: Brain metastases occur in one-third of all non-small-cell lung cancer patients. Due to restrictive transport at the blood–brain barrier, many drugs provide poor control of metastases in the brain. The aim of this study was to compare erlotinib with pemetrexed as second-/third-line treatment in patients with lung adenocarcinoma with asymptomatic brain metastases.Methods: From January 2012 to June 2014, all lung adenocarcinoma patients with asymptomatic brain metastases who received treatment with erlotinib or pemetrexed as second-/third-line treatment were retrospectively reviewed. Chi-square and log-rank tests were used to perform statistical analysis.Results: The study enrolled 99 patients, of which 44 were positive for EGFR mutation. Median progression-free survival (PFS in months was not significantly different between the erlotinib- and pemetrexed-treated groups (4.2 vs 3.4 months; 95% confidence interval [CI]: 2.01–6.40 vs 2.80–5.00, respectively; P=0.635. Median PFS was found to be significantly longer in EGFR mutation–positive patients in the erlotinib-treated group (8.0 months; 95% CI 5.85–10.15 compared to the pemetrexed group (3.9 months; 95% CI: 1.25–6.55; P=0.032. The most common treatment-related side effect was mild-to-moderate rash and the most common drug-related side

Investigation of Susceptibility of Mycobacterium tuberculosis Complex Strains Isolated from Clinical Samples Against the First and Second-Line Anti-tuberculosis Drugs by the Sensititre MycoTB Plate Method

Directory of Open Access Journals (Sweden)

Figen KAYSERİLİ ORHAN

2018-03-01

Full Text Available Introduction: Phenotypic methods for drug susceptibility testing of Mycobacterium tuberculosis complex (MTC to second-line drugs are not yet standardized. The Sensititre MycoTB Plate is a microtiter plate containing lyophilized antibiotics and configured for determination of MIC to first and second-line anti-tuberculosis drugs. The purpose of this study is to detect the susceptibility rates of MTC strains isolated from patients’ specimens for first and second-line anti-tuberculosis drugs. Materials and Methods: This study included 50 MTC strains isolated from various clinical specimens. Out of the 50 strains, 38 were isolated from sputum, three from cerebrospinal fluid, three from bronchoalveolar lavage, and six from other samples in this study. The susceptibility of strains to anti-tuberculosis drugs were determined by the Sensititre MycoTB Plate Method. Thawed isolates were subcultured, and dilutions were inoculated into MycoTB wells. The results were read at days 7, 14 and 21. Results: At the end of study, out of 50 MTC isolates, 7 (14% showed resistance to Isoniazid (INH, 5 (10% to streptomycin (SM, 4 (8% to ethambutol (EMB, 4 (8% to ethionamide (ETH, 3 (6% to rifampicin (RIF, 3 (6% to rifabutin (RFB, 2 (4% to kanamycin (KAN, 2 (4% to ofloxacin (OFL, 2 (4% to P-aminosalicyclic acid (PAS, 1 (2% to moxiflocacin (MOX, and 1 (2% to cycloserine (CYC. All strains were found sensitive to amikacin while 2 strains (4% were identified as multidrug-resistant tuberculosis (MDR-TB. Thirty-five strains (70% were sensitive to all drugs. Extensively drug resistant tuberculosis (XDR-TB was not determined in this study. Conclusion: This is the first study that tests second line anti-tuberculosis drugs in our location and provides us valuable data regarding MDR-TB and XDR-TB rates. The Sensititre MycoTB Plate Method is a fast, reliable and practical method and can be used to determine the susceptibility of first and second-line anti-tuberculosis drugs.

Second Line of Defense Megaports Initiative Operational Testing and Evaluation Plan Colon Container Terminal (CCT) Panama

Energy Technology Data Exchange (ETDEWEB)

Newhouse, Robert N.

2010-01-01

Report on the Operational Testing and Evaluation to validate and baseline an operable system that meets the Second Line of Defense (SLD) mission requirements. An SLD system is defined as the detection technology and associated equipment, the system operators from the host country, the standard operating procedures (SOPs), and other elements such as training and maintenance which support long-term system sustainment. To this end, the activities conducted during the OT&E phase must demonstrate that the Megaports System can be operated effectively in real-time by Panama Direccion General de Aduanas (DGA Panama Customs) personnel to the standards of the U.S. Department of Energy/National Nuclear Security Administration (DOE/NNSA).

Payout phase in DC pension funds – policy option - Theoretical considerations and Albanian available options

Directory of Open Access Journals (Sweden)

Enkeleda Shehi

2015-11-01

Full Text Available The aim of this paper is to provide a brief overview of the third pillar of pensions in Albania and what are the different alternatives related to the payout. Referring to the actual development of this market in Albania, experience of the actors involved, I find it indispensable and necessary to provide some theoretical background and considerations, and then build up a simple model of projection of a pension scheme cost and a model for payout alternatives for the Albanian pension funds. A great deal of importance is shown towards posing the assumptions. Also, the paper gives an explanation about the differences among different payout options and suggests the best option for the existing pension funds in Albania. The best option represents my conclusion and recommendation for the actual third pillar of pensions and the others that might join latter. To sum up, the first conclusion of the paper is that the annuity option is the best alternative for the payout phase of the pensions. It has the advantage of providing the highest protection against the risk of longevity. The second conclusion is that based on other countries experiences, the annuity market have to be developed hand in hand with the pension system development. Therefore Albania should rely on and follow this experience.

An oncofetal glycosaminoglycan modification provides therapeutic access to Cisplatin-resistant bladder cancer

DEFF Research Database (Denmark)

Seiler, Roland; Oo, Htoo Zarni; Tortora, Davide

2017-01-01

the malaria parasite Plasmodium falciparum, we can target these sugar chains, and our results showed a significant antitumor effect in cisplatin-resistant bladder cancer. This novel treatment paradigm provides therapeutic access to bladder cancers not responding to cisplatin.......BACKGROUND: Although cisplatin-based neoadjuvant chemotherapy (NAC) improves survival of unselected patients with muscle-invasive bladder cancer (MIBC), only a minority responds to therapy and chemoresistance remains a major challenge in this disease setting. OBJECTIVE: To investigate the clinical...... significance of oncofetal chondroitin sulfate (ofCS) glycosaminoglycan chains in cisplatin-resistant MIBC and to evaluate these as targets for second-line therapy. DESIGN, SETTING, AND PARTICIPANTS: An ofCS-binding recombinant VAR2CSA protein derived from the malaria parasite Plasmodium falciparum (rVAR2...

Progressive Supranuclear Palsy and Corticobasal Degeneration: Pathophysiology and Treatment Options

OpenAIRE

Lamb, Ruth; Rohrer, Jonathan D.; Lees, Andrew J.; Morris, Huw R.

2016-01-01

Opinion statement There are currently no disease-modifying treatments for progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD), and no approved pharmacological or therapeutic treatments that are effective in controlling their symptoms. The use of most pharmacological treatment options are based on experience in other disorders or from non-randomized historical controls, case series, or expert opinion. Levodopa may provide some improvement in symptoms of Parkinsonism (specif...

Progressive Supranuclear Palsy and Corticobasal Degeneration: Pathophysiology and Treatment Options

OpenAIRE

Lamb, R.; Rohrer, J. D.; Lees, A. J.; Morris, H. R.

2016-01-01

There are currently no disease-modifying treatments for progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD), and no approved pharmacological or therapeutic treatments that are effective in controlling their symptoms. The use of most pharmacological treatment options are based on experience in other disorders or from non-randomized historical controls, case series, or expert opinion. Levodopa may provide some improvement in symptoms of Parkinsonism (specifically bradykinesi...

Economic analysis of the TAX 317 trial: docetaxel versus best supportive care as second-line therapy of advanced non-small-cell lung cancer.

Science.gov (United States)

Leighl, Natasha B; Shepherd, Frances A; Kwong, Rita; Burkes, Ronald L; Feld, Ronald; Goodwin, Pamela J

2002-03-01

To determine the cost-effectiveness (CE) of second-line docetaxel compared with best supportive care (BSC) in the TAX 317 trial, a randomized clinical trial of second-line chemotherapy in non-small-cell lung cancer. A retrospective CE analysis of the TAX 317 trial was undertaken, evaluating direct medical costs of therapy from the viewpoint of Canada's public health care system. Costs were derived in 1999 Canadian dollars, and resource use was determined through prospective trial data. The incremental survival benefit in the docetaxel arm over BSC was 2 months (P =.047). The CE of docetaxel was $57,749 per year of life gained. For patients treated with docetaxel 75 mg/m(2), the CE was $31,776 per year of life gained. In univariate sensitivity analyses, CE estimates were most sensitive to changes in survival, ranging from $18,374 to $117,434 with 20% variation in survival at the recommended dose. The largest cost center in both arms was hospitalization, followed by the cost of drugs, investigations, radiotherapy, and community care. BSC patients had fewer hospitalizations than patients in the chemotherapy arm and were more often palliated at home. Although the decision to treat should not be based on economic considerations alone, our CE estimate of $31,776 per year of life gained (at the currently recommended dose of docetaxel) is within an acceptable range of health care expenditures, and the total costs of therapy are similar to those of second-line palliative chemotherapy for other solid tumors.

Comparison of second-order impact line shifts

International Nuclear Information System (INIS)

Griem, H.R.; Iglesias, C.A.; Boercker, D.B.

1991-01-01

The second-order impact shifts in hydrogen obtained from the Baranger formalism are compared with those from a kinetic theory approach. The resulting Δn=0 contributions to the shift from the two theories are shown to be identical, except for the neglect of electron-electron correlations in the Baranger formalism. It is also shown that some care is required in taking the classical limit for the perturbing electrons, or else the shift from Δn=0 interactions vanishes

Train turn restrictions and line plan performance

DEFF Research Database (Denmark)

Burggraeve, Sofie; Bull, Simon Henry; Lusby, Richard Martin

In this paper we study the impact of the `turn conditions' in end stations on the performance of a line plan. If trains have to turn on their platform in an end station, the yoccupy the platform for several minutes. A more preferred option, from a timetabling point of view, would be that a train...... in a exible and large enough shunt. Starting from a given line plan, we compare two timetables, one where trains have to turn on their platform and one where trains can turn in a shunt. We evaluate the impact on the performance of the line plan by its feasibility for timetabling,the minimum overall buffer...... disappears from the platform in its end station after dwelling and only appears again when departing for a subsequent trip. In this case, the train will not interfere with other trains that dwell on the platform during the time between these events. However, this option is only possible if the train can stay...

Current options for the treatment of pathological scarring.

Science.gov (United States)

Poetschke, Julian; Gauglitz, Gerd G

2016-05-01

Scarring is the consequence of surgery, trauma or different skin diseases. Apart from fresh, immature scars,that transform into mature scars over the course of would healing and that do not require further treatment,linear hypertrophic scars, widespread hypertrophic scars, keloids and atrophic scars exist. Symptoms like pruritusand pain, stigmatization as well as functional and aesthetic impairments that are very disturbing for the affected patients can bethe basis for the desire for treatment. Today, a multitude of options for the treatment and prevention of scars exists. Topical agents based on silicone or onion extract, intralesional injections of cristalline glucocorticoids (oftentimes in combinationwith cryotherapy) or 5-Fluorouracil as well as ablative and nonablative laser treatment are used. Current guidelines summarize the multitude of available treatment options and the currently available datafor the treating physicians, allowing them to make clear therapy recommendations for every single scar type. Relieving patients of their discomfort and doing their aesthetic demands justice is thus possible. Apart from scar prevention becoming more and more important, the increased use of modernlaser treatment options constitutes a key point in clinical scar treatment. At the same time the attention is turned to evaluating current therapeutic options with the help of contemporary study designs so as to graduallyimprove the level of evidence in scar treatment. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

Cost-effectiveness of HIV drug resistance testing to inform switching to second line antiretroviral therapy in low income settings

DEFF Research Database (Denmark)

Phillips, Andrew; Cambiano, Valentina; Nakagawa, Fumiyo

2014-01-01

BACKGROUND: To guide future need for cheap resistance tests for use in low income settings, we assessed cost-effectiveness of drug resistance testing as part of monitoring of people on first line ART - with switching from first to second line ART being conditional on NNRTI drug resistance mutations...... being identified. METHODS: An individual level simulation model of HIV transmission, progression and the effect of ART which accounts for adherence and resistance development was used to compare outcomes of various potential monitoring strategies in a typical low income setting in sub-Saharan Africa....... Underlying monitoring strategies considered were based on clinical disease, CD4 count or viral load. Within each we considered a strategy in which no further measures are performed, one with a viral load measure to confirm failure, and one with both a viral load measure and a resistance test. Predicted...

Evidence Based Digoxin Therapeutic Monitoring - A Lower and Narrower Therapeutic Range

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Amine BENLMOUDEN

2016-06-01

Full Text Available Cardiac glycosides have been used for congestive heart failure and certain cardiac arrhythmias for more than 200 years. Despite the introduction of a variety of new classes of drugs for the management of heart failure, specifically angiotensin-converting enzyme (ACE inhibitors, b-adrenergic antagonists (bblockers, and the aldosterone antagonist spironolactone, digoxin continues to have an important role in long-term outpatient management. However, a narrow margin exists between therapeutic and toxic doses of digoxin, resulting in a high incidence of digoxin toxicity in clinical practice.A wide variety of placebo-controlled clinical trials have unequivocally shown that treatment with digoxin can improve symptoms, quality of life, and exercise tolerance in patients with mild, moderate, or severe heart failure. The clinical relevance of digoxin therapeutic monitoring is also proved but the SDC (Serum Digoxin Conentrations required for optimal clinical efficacy and acceptable toxicity remains controversial. In the last years, international guidelines recommend 1.2 ng/mL as acceptable high level.In this bibliographic synthesis, we aim to collect pertinent informations from MedLine database about exposure-effect relationship in order to assess the evidence level scientific of new digoxin therapeutic monitoring. 

Targeting Glutathione-S Transferase Enzymes in Musculoskeletal Sarcomas: A Promising Therapeutic Strategy

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Michela Pasello

2011-01-01

Full Text Available Recent studies have indicated that targeting glutathione-S-transferase (GST isoenzymes may be a promising novel strategy to improve the efficacy of conventional chemotherapy in the three most common musculoskeletal tumours: osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. By using a panel of 15 drug-sensitive and drug-resistant human osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma cell lines, the efficay of the GST-targeting agent 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthiohexanol (NBDHEX has been assessed and related to GST isoenzymes expression (namely GSTP1, GSTA1, GSTM1, and MGST. NBDHEX showed a relevant in vitro activity on all cell lines, including the drug-resistant ones and those with higher GSTs levels. The in vitro activity of NBDHEX was mostly related to cytostatic effects, with a less evident apoptotic induction. NBDHEX positively interacted with doxorubicin, vincristine, cisplatin but showed antagonistic effects with methotrexate. In vivo studies confirmed the cytostatic efficay of NBDHEX and its positive interaction with vincristine in Ewing's sarcoma cells, and also indicated a positive effect against the metastatisation of osteosarcoma cells. The whole body of evidence found in this study indicated that targeting GSTs in osteosarcoma, Ewing's sarcoma and rhabdomyosarcoma may be an interesting new therapeutic option, which can be considered for patients who are scarcely responsive to conventional regimens.

The Second Workshop on Lineshape Code Comparison: Isolated Lines

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Spiros Alexiou

2014-05-01

Full Text Available In this work, we briefly summarize the theoretical aspects of isolated line broadening. We present and discuss test run comparisons from different participating lineshape codes for the 2s-2p transition for LiI, B III and NV.

Athabasca caribou landscape management options report : executive summary

Energy Technology Data Exchange (ETDEWEB)

NONE

2009-05-15

The woodland caribou are listed as threatened under Alberta's Wildlife Act and the federal Species at Risk Act. The key factors that directly or indirectly affect the population size and distribution of woodland caribou population include habitat change due to wildfire or human land-use activities, predation and hunting. The Alberta Woodland Caribou Recovery Plan outlines a time line to progressively improve conditions for caribou in Alberta. The 2 main goals are to achieve self-sustaining woodland caribou populations and maintain the distribution of caribou in Alberta; and ensure that long-term habitat requirements for woodland caribou are met within Alberta's caribou range. The Athabasca Landscape Team conducted 2 analyses from which it developed management options. The first was a rating or relative risk to caribou persistence within 4 Athabasca ranges based on a series of 8 risk criteria, including both biological and land use factors. The second analysis conducted for each planning area involved simulation modeling using ALCES to forecast likely caribou populations and habitat conditions under 3 scenarios, including non-industrial, business and usual, and alternative futures. 1 tab.

Preliminary study of possible ORELA replacement options

International Nuclear Information System (INIS)

Olsen, D.K.; Martin, J.A.; Horen, D.J.

1984-06-01

Based on two conceptual design studies performed by the LANL Accelerator Technology Division, the possibilities in terms of accelerator systems for replacing ORELA with a more intense Maxwellian-type continuous-energy neutron source are summarized and discussed. The neutron intensities from ORELA are compared with those from existing or potential accelerator systems used for cross-section and condensed-matter studies. The best replacement options seem to involve a spallation source from 200- to 400-MeV protons on an ORELA-like target. Pulsing and intensity desiderata with such a source are discussed which correspond to a spectrum-averaged 100-fold improved figure of merit over ORELA for TOF measurements with only a tenfold increased source strength. Existing accelerator designs seem to be inadequate for such a source. Consequently, two conceptual designs were developed for this study by the LANL Accelerator Technology Division. The first conceptual design is for a 200-MeV large linac capable of accelerating 1.3 A during a macropulse; this linac standing alone could serve as an ORELA replacement source. The second conceptual design is for a much smaller 250-MeV PIGMI linac with a 28-mA macropulse current which feeds a proton accumulator ring and bunch-compressor transport line. This linac-ring-compressor (LIRIC) option would give a more cost-effective neutron source for cross-section measurements, whereas the large linac, or a modified version of it, would give a much simpler system more suitable for expansion. In particular, both conceptual designs would incorporate the present ORELA building and would provide approximately 100-fold improved neutron sources over ORELA for cross-section measurements. The total estimated cost of the LIRIC system would be $43M (1984), whereas the cost of the large linac would be about a factor of two more. 55 references, 11 figures, 19 tables

Therapeutic Options for the Treatment of Hypertension in Children and Adolescents

Directory of Open Access Journals (Sweden)

Mary M. Stephens MD, MPH

2012-01-01

Full Text Available Primary hypertension in children is increasing in prevalence with many cases likely going undiagnosed. The prevalence is currently estimated at between 3%-5% in the United States and may be higher in certain ethnic groups. Primary hypertension, once felt to be rare in children, is now considered to be about five times more common than secondary hypertension. This review provides information to guide physicians through an organized approach to: 1 screening children and adolescents for hypertension during routine visits; 2 using normative percentile data for diagnosis and classification; 3 performing a clinical evaluation to identify the presence of co-morbidities; 4 initiating a plan of care including subsequent follow-up blood pressure measurements, therapeutic lifestyle changes and pharmacologic therapies.

Energy exotic options

International Nuclear Information System (INIS)

Kaminski, V.; Gibner, S.; Pinnamaneni, K.

1999-01-01

This chapter with 88 references focuses on the use of exotic options to control exposure to energy prices. Exotic options are defined, and the conversion of a standard option into an exotic option and pricing models are examined. Pricing and hedging exotic options, path-dependent options, multi-commodity options, options on the minimum-or-maximum of two commodities, compound options, digital options, hybrid and complex structures, and natural gas daily options are described. Formulas for option pricing for vanilla, barrier, compound, options on minimum or maximum of two assets, and look back options are given in an appendix

Reducing the number of options on multiple-choice questions: response time, psychometrics and standard setting.

Science.gov (United States)

Schneid, Stephen D; Armour, Chris; Park, Yoon Soo; Yudkowsky, Rachel; Bordage, Georges

2014-10-01

Despite significant evidence supporting the use of three-option multiple-choice questions (MCQs), these are rarely used in written examinations for health professions students. The purpose of this study was to examine the effects of reducing four- and five-option MCQs to three-option MCQs on response times, psychometric characteristics, and absolute standard setting judgements in a pharmacology examination administered to health professions students. We administered two versions of a computerised examination containing 98 MCQs to 38 Year 2 medical students and 39 Year 3 pharmacy students. Four- and five-option MCQs were converted into three-option MCQs to create two versions of the examination. Differences in response time, item difficulty and discrimination, and reliability were evaluated. Medical and pharmacy faculty judges provided three-level Angoff (TLA) ratings for all MCQs for both versions of the examination to allow the assessment of differences in cut scores. Students answered three-option MCQs an average of 5 seconds faster than they answered four- and five-option MCQs (36 seconds versus 41 seconds; p = 0.008). There were no significant differences in item difficulty and discrimination, or test reliability. Overall, the cut scores generated for three-option MCQs using the TLA ratings were 8 percentage points higher (p = 0.04). The use of three-option MCQs in a health professions examination resulted in a time saving equivalent to the completion of 16% more MCQs per 1-hour testing period, which may increase content validity and test score reliability, and minimise construct under-representation. The higher cut scores may result in higher failure rates if an absolute standard setting method, such as the TLA method, is used. The results from this study provide a cautious indication to health professions educators that using three-option MCQs does not threaten validity and may strengthen it by allowing additional MCQs to be tested in a fixed amount

[Extracorporeal shockwave therapy (ESWT) as therapeutic option in supraspinatus tendon syndrome? One year results of a placebo controlled study].

Science.gov (United States)

Schmitt, J; Tosch, A; Hünerkopf, M; Haake, M

2002-07-01

Extracorporeal shock wave therapy (ESWT) is seen as a therapeutic option in the treatment of chronic supraspinatus tendinitis by some authors. To test whether ESWT comprising 3 x 2000 pulses with the positive energy flux density ED+ of 0.33 mJ/mm2 is clinically superior to a sham ESWT treatment, a prospective, randomized, single-blinded, placebo-controlled study with an independent observer was performed. Forty patients were treated either by verum ESWT or sham ESWT under local anesthesia. Target criteria were the age-corrected Constant score, pain at rest and during activity on a visual analogue scale, and subjective improvement. Patients who reported no subjective improvement after 12 weeks were deblinded and received verum ESWT if they had belonged to the placebo group (partial crossover). The results of the verum group lie within the range of results for ESWT published by other authors. Patients in the placebo group with local anesthetic showed equally good results. At 12 weeks, and 1 year after intervention, no difference could be found between the verum and placebo groups regarding Constant score, pain, shoulder function, or subjective improvement. The nonresponders to the placebo ESWT continued to show no improvement after receiving verum ESWT. This contradicts a specific ESWT effect. Based on the results of this placebo-controlled study, ESWT appears to have no clinically relevant effect on supraspinatus tendinitis. The study underlines the importance of a control group in evaluating new treatment methods for diseases with unknown natural history.

The Effects of Framing Vocational Choices on Young Adults' Sets of Career Options

Science.gov (United States)

Feldman, Daniel C.; Whitcomb, Kathleen M.

2005-01-01

Purpose: The present paper examines the effects of two decision-framing inductions on young adults' set of career options: first, whether young adults use abilities or interests as the grounds for their vocational choices and, second, whether young adults approach the decision-making task by including all career options to which they feel…

Microneedle physical contact as a therapeutic for abnormal scars

OpenAIRE

Yeo, David C.; Balmayor, Elizabeth R.; Schantz, Jan-Thorsten; Xu, Chenjie

2017-01-01

Background Abnormal (keloid and hypertrophic) scars are a significant affliction with no satisfactory single modality therapy to-date. Available options are often ineffective, painful, potentially hazardous, and require healthcare personnel involvement. Herein a self-administered microneedle device based on drug-free physical contact for inhibiting abnormal scars is reported. Its therapeutic activity through microneedle contact eliminates hazards associated with toxic anti-scarring drugs whil...

Cyclic peptides as potential therapeutic agents for skin disorders.

Science.gov (United States)

Namjoshi, Sarika; Benson, Heather A E

2010-01-01

There is an increasing understanding of the role of peptides in normal skin function and skin disease. With this knowledge, there is significant interest in the application of peptides as therapeutics in skin disease or as cosmeceuticals to enhance skin appearance. In particular, antimicrobial peptides and those involved in inflammatory processes provide options for the development of new therapeutic directions in chronic skin conditions such as psoriasis and dermatitis. To exploit their potential, it is essential that these peptides are delivered to their site of action in active form and in sufficient quantity to provide the desired effect. Many polymers permeate the skin poorly and are vulnerable to enzymatic degradation. Synthesis of cyclic peptide derivatives can substantially alter the physicochemical characteristics of the peptide with the potential to improve its skin permeation. In addition, cyclization can stabilize the peptide structure and thereby increase its stability. This review describes the role of cyclic peptides in the skin, examples of current cyclic peptide therapeutic products, and the potential for cyclic peptides as dermatological therapeutics and cosmeceuticals.

Comparative cost-effectiveness of Option B+ for prevention of mother to child transmission of HIV in Malawi: Mathematical modelling study

Science.gov (United States)

Tweya, Hannock; Keiser, Olivia; Haas, Andreas D.; Tenthani, Lyson; Phiri, Sam; Egger, Matthias; Estill, Janne

2016-01-01

Objective To estimate the cost-effectiveness of prevention of mother to child transmission (MTCT) of HIV with lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women (‘Option B+’) compared to ART during pregnancy or breastfeeding only unless clinically indicated (‘Option B’). Design Mathematical modelling study of first and second pregnancy, informed by data from the Malawi Option B+ programme. Methods Individual-based simulation model. We simulated cohorts of 10,000 women and their infants during two subsequent pregnancies, including the breastfeeding period, with either Option B+ or B. We parameterised the model with data from the literature and by analysing programmatic data. We compared total costs of ante-natal and post-natal care, and lifetime costs and disability-adjusted life-years (DALYs) of the infected infants between Option B+ and Option B. Results During the first pregnancy, 15% of the infants born to HIV-infected mothers acquired the infection. With Option B+, 39% of the women were on ART at the beginning of the second pregnancy, compared to 18% with Option B. For second pregnancies, the rates MTCT were 11.3% with Option B+ and 12.3% with Option B. The incremental cost-effectiveness ratio comparing the two options ranged between about US$ 500 and US$ 1300 per DALY averted. Conclusion Option B+ prevents more vertical transmissions of HIV than Option B, mainly because more women are already on ART at the beginning of the next pregnancy. Option B+ is a cost-effective strategy for PMTCT if the total future costs and lost lifetime of the infected infants are taken into account. PMID:26691682

Dry needling in lateral epicondylitis: a prospective controlled study.

Science.gov (United States)

Uygur, Esat; Aktaş, Birol; Özkut, Afşar; Erinç, Samet; Yilmazoglu, Emime Gül

2017-11-01

Lateral epicondylitis (LE), a common disease, especially in middle age, causes decreased productivity and economic losses. The first-line treatment for LE is conservative and consists of topical and oral anti-inflammatory drugs, ice application, and brace use. If the first-line treatment fails, second-line treatment modalities, which are generally invasive, are offered. Second-line therapeutic regimens include saline, corticosteroid, or platelet-rich plasma injections. Dry needling is relatively new. We hypothesized that dry needling would be at least as effective as first-line treatment for LE. We compared the outcomes of first-line treatment and dry needling. The study allocated 110 patients into groups using online randomization software. After completing the Patient-rated Tennis Elbow Evaluation (PRTEE), patients in group I received dry needling, whereas those in group II received first-line treatment, consisting of ibuprofen 100 mg twice a day and a proximal forearm brace. The patients were evaluated after three weeks and six months. The study ultimately analyzed 92 patients. Although both treatment methods were effective at three weeks, dry needling was significantly more effective than the first-line treatment at six months. Because of the low complication rate, dry needling is a safe method, and it might be an effective treatment option for LE.

A Kramers-Moyal approach to the analysis of third-order noise with applications in option valuation.

Science.gov (United States)

Popescu, Dan M; Lipan, Ovidiu

2015-01-01

We propose the use of the Kramers-Moyal expansion in the analysis of third-order noise. In particular, we show how the approach can be applied in the theoretical study of option valuation. Despite Pawula's theorem, which states that a truncated model may exhibit poor statistical properties, we show that for a third-order Kramers-Moyal truncation model of an option's and its underlier's price, important properties emerge: (i) the option price can be written in a closed analytical form that involves the Airy function, (ii) the price is a positive function for positive skewness in the distribution, (iii) for negative skewness, the price becomes negative only for price values that are close to zero. Moreover, using third-order noise in option valuation reveals additional properties: (iv) the inconsistencies between two popular option pricing approaches (using a "delta-hedged" portfolio and using an option replicating portfolio) that are otherwise equivalent up to the second moment, (v) the ability to develop a measure R of how accurately an option can be replicated by a mixture of the underlying stocks and cash, (vi) further limitations of second-order models revealed by introducing third-order noise.

Therapeutic Options for Controlling Fluids in the Visual System

Science.gov (United States)

Curry, Kristina M.; Wotring, Virginia E.

2014-01-01

Visual Impairment/Intracranial Pressure (VIIP) is a newly recognized risk at NASA. The VIIP project examines the effect of long-term exposure to microgravity on vision of crewmembers before and after they return to Earth. Diamox (acetazolamide) is a medication which is used to decrease intraocular pressure; however, it carries a 3% risk of kidney stones. Astronauts are at a higher risk of kidney stones during spaceflight and the use Diamox would only increase the risk; therefore alternative therapies were investigated. Histamine 2 (H2) antagonist acid blockers such as cimetidine, ranitidine, famotidine and nizatidine are typically used to relieve the symptoms of gastroesophageal reflux disease (GERD). H2 receptors have been found in the human visual system, which has led to research on the use of H2 antagonist blockers to control fluid production in the human eye. Another potential therapeutic strategy is targeted at aquaporins, which are water channels that help maintain fluid homeostasis. Aquaporin antagonists are also known to affect intracranial pressure which can in turn alter intraocular pressure. Studies on aquaporin antagonists suggest high potential for effective treatment. The primary objective of this investigation is to review existing research on alternate medications or therapy to significantly reduce intracranial and intraocular pressure. A literature review was conducted. Even though we do not have all the answers quite yet, a considerable amount of information was discovered, and findings were narrowed, which should allow for more conclusive answers to be found in the near future.

Internet privacy options for adequate realisation

CERN Document Server

2013-01-01

A thorough multidisciplinary analysis of various perspectives on internet privacy was published as the first volume of a study, revealing the results of the achatech project "Internet Privacy - A Culture of Privacy and Trust on the Internet." The second publication from this project presents integrated, interdisciplinary options for improving privacy on the Internet utilising a normative, value-oriented approach. The ways in which privacy promotes and preconditions fundamental societal values and how privacy violations endanger the flourishing of said values are exemplified. The conditions which must be fulfilled in order to achieve a culture of privacy and trust on the internet are illuminated. This volume presents options for policy-makers, educators, businesses and technology experts how to facilitate solutions for more privacy on the Internet and identifies further research requirements in this area.

ROCK as a therapeutic target for ischemic stroke.

Science.gov (United States)

Sladojevic, Nikola; Yu, Brian; Liao, James K

2017-12-01

Stroke is a major cause of disability and the fifth leading cause of death. Currently, the only approved acute medical treatment of ischemic stroke is tissue plasminogen activator (tPA), but its effectiveness is greatly predicated upon early administration of the drug. There is, therefore, an urgent need to find new therapeutic options for acute stroke. Areas covered: In this review, we summarize the role of Rho-associated coiled-coil containing kinase (ROCK) and its potential as a therapeutic target in stroke pathophysiology. ROCK is a major regulator of cell contractility, motility, and proliferation. Many of these ROCK-mediated processes in endothelial cells, vascular smooth muscle cells, pericytes, astrocytes, glia, neurons, leukocytes, and platelets are important in stroke pathophysiology, and the inhibition of such processes could improve stroke outcome. Expert commentary: ROCK is a potential therapeutic target for cardiovascular disease and ROCK inhibitors have already been approved for human use in Japan and China for the treatment of acute stroke. Further studies are needed to determine the role of ROCK isoforms in the pathophysiology of cerebral ischemia and whether there are further therapeutic benefits with selective ROCK inhibitors.

Final Report on Two-Stage Fast Spectrum Fuel Cycle Options

International Nuclear Information System (INIS)

Yang, Won Sik; Lin, C. S.; Hader, J. S.; Park, T. K.; Deng, P.; Yang, G.; Jung, Y. S.; Kim, T. K.; Stauff, N. E.

2016-01-01

This report presents the performance characteristics of two ''two-stage'' fast spectrum fuel cycle options proposed to enhance uranium resource utilization and to reduce nuclear waste generation. One is a two-stage fast spectrum fuel cycle option of continuous recycle of plutonium (Pu) in a fast reactor (FR) and subsequent burning of minor actinides (MAs) in an accelerator-driven system (ADS). The first stage is a sodium-cooled FR fuel cycle starting with low-enriched uranium (LEU) fuel; at the equilibrium cycle, the FR is operated using the recovered Pu and natural uranium without supporting LEU. Pu and uranium (U) are co-extracted from the discharged fuel and recycled in the first stage, and the recovered MAs are sent to the second stage. The second stage is a sodium-cooled ADS in which MAs are burned in an inert matrix fuel form. The discharged fuel of ADS is reprocessed, and all the recovered heavy metals (HMs) are recycled into the ADS. The other is a two-stage FR/ADS fuel cycle option with MA targets loaded in the FR. The recovered MAs are not directly sent to ADS, but partially incinerated in the FR in order to reduce the amount of MAs to be sent to the ADS. This is a heterogeneous recycling option of transuranic (TRU) elements

Final Report on Two-Stage Fast Spectrum Fuel Cycle Options

Energy Technology Data Exchange (ETDEWEB)

Yang, Won Sik [Purdue Univ., West Lafayette, IN (United States); Lin, C. S. [Purdue Univ., West Lafayette, IN (United States); Hader, J. S. [Purdue Univ., West Lafayette, IN (United States); Park, T. K. [Purdue Univ., West Lafayette, IN (United States); Deng, P. [Purdue Univ., West Lafayette, IN (United States); Yang, G. [Purdue Univ., West Lafayette, IN (United States); Jung, Y. S. [Purdue Univ., West Lafayette, IN (United States); Kim, T. K. [Argonne National Lab. (ANL), Argonne, IL (United States); Stauff, N. E. [Argonne National Lab. (ANL), Argonne, IL (United States)

2016-01-30

This report presents the performance characteristics of two “two-stage” fast spectrum fuel cycle options proposed to enhance uranium resource utilization and to reduce nuclear waste generation. One is a two-stage fast spectrum fuel cycle option of continuous recycle of plutonium (Pu) in a fast reactor (FR) and subsequent burning of minor actinides (MAs) in an accelerator-driven system (ADS). The first stage is a sodium-cooled FR fuel cycle starting with low-enriched uranium (LEU) fuel; at the equilibrium cycle, the FR is operated using the recovered Pu and natural uranium without supporting LEU. Pu and uranium (U) are co-extracted from the discharged fuel and recycled in the first stage, and the recovered MAs are sent to the second stage. The second stage is a sodium-cooled ADS in which MAs are burned in an inert matrix fuel form. The discharged fuel of ADS is reprocessed, and all the recovered heavy metals (HMs) are recycled into the ADS. The other is a two-stage FR/ADS fuel cycle option with MA targets loaded in the FR. The recovered MAs are not directly sent to ADS, but partially incinerated in the FR in order to reduce the amount of MAs to be sent to the ADS. This is a heterogeneous recycling option of transuranic (TRU) elements

Our Experiences with Erlotinib in Second and Third Line Treatment Patients with Advanced Stage Iiib/ Iv Non-Small Cell Lung Cancer

Directory of Open Access Journals (Sweden)

Bakir Mehić

2008-11-01

Full Text Available HeadHER1/EGFR is known to play a pivotal role in tumorigenesis and is overexpressed in up to 80% of NSCLCs. The study of an Expanded Access Clinical Program of Erlotinib in NSCLC is a phase IV openlabel, non-randomized, multicenter trial in patients with advanced (inoperable stage IIIb/IV NSCLC who were eligible for treatment with erlotinib but had no access to trial participation. Patients for the study from Bosnia and Herzegovina (B&H were selected from two Clinical centres (Sarajevo and Banja Luka. The aim of study was to evaluated efficacy and tolerability of erlotinib monotherapy in this setting. All patients who received at least one dose of erlotinib and data were entered in the database as of the CRF cut-off date of 14th May 2008 were included in analysis of data (n = 19. This population is defined as the Intent to Treat (ITT population and includes all patients who had at least one dose of erlotinib regardless of whether major protocol violations were incurred. The findings are consistent with the results of the randomized, placebo-controlled BR.21 study. Indicating that erlotinib is an effective option for patients with advanced NSCLC who are unsuitable for, or who have previously failed standard chemotherapy. In B&H group of patients DCR was almost 84%, and PFS was approximately 24,7 weeks (compared with 44% and 9,7 weeks for erlotinib reported in phase III. Almost three quarter of the patients received erlotinib as their second line of therapy. Overall, erlotinib was well tolerated; there were no patients who withdrew due to a treatment-related AE (mainly rash and there were few dose reductions. 24% of patients experienced an SAE (most commonly gastrointestinal (GI disorders.

Composite Materials in Overhead Lines

DEFF Research Database (Denmark)

Sørensen, Thomas Kjærsgaard; Holbøll, Joachim

2009-01-01

towers and recently conductors based on composite materials are available at transmission levels. In this paper it is investigated which composite based solutions are available in connection with complete overhead line systems including insulators, towers and conductors. The components are reviewed......The use of composite materials, e.g. fibreglass materials, in overhead transmission line systems is nothing new. Composite based insulators have been applied to transmission lines for over 30 years, mainly as suspension and post insulators and often as an option for special applications. Also...... with respect to solved and persisting known failures/problems of both mechanical and electrical nature. Major challenges related to extensive use of composite materials in an overhead line system are identified, as are possible benefits - both when using standard as well as customised composite components, e...

Recovering Risk-Neutral Densities from Brazilian Interest Rate Options

Directory of Open Access Journals (Sweden)

José Renato Haas Ornelas

2011-03-01

Full Text Available Building Risk-Neutral Density (RND from options data is one useful way for extracting market expectations about a financial variable. For a sample of IDI (Brazilian Interbank Deposit Rate Index options from 1998 to 2009, this paper estimates the option-implied Risk-Neutral Densities for the Brazilian short rate using three methods: Shimko, Mixture of Two Log-Normals and Generalized Beta of Second Kind. Our in-sample goodness-of-fit evaluation shows that the Mixture of Log-Normals method provides better fitting to option’s data than the other two methods. The shape of log-normal distributions seems to fit well to the mean-reversal dynamics of Brazilian interest rates. We have also calculated the RND implied Skewness, showing how it could have provided market early-warning signals of the monetary policy outcomes in 2002 and 2003. Overall, Risk-Neutral Densities implied on IDI options showed to be a useful tool for extracting market expectations about future outcomes of the monetary policy.

Performance of some numerical Laplace inversion methods on American put option formula

Science.gov (United States)

Octaviano, I.; Yuniar, A. R.; Anisa, L.; Surjanto, S. D.; Putri, E. R. M.

2018-03-01

Numerical inversion approaches of Laplace transform is used to obtain a semianalytic solution. Some of the mathematical inversion methods such as Durbin-Crump, Widder, and Papoulis can be used to calculate American put options through the optimal exercise price in the Laplace space. The comparison of methods on some simple functions is aimed to know the accuracy and parameters which used in the calculation of American put options. The result obtained is the performance of each method regarding accuracy and computational speed. The Durbin-Crump method has an average error relative of 2.006e-004 with computational speed of 0.04871 seconds, the Widder method has an average error relative of 0.0048 with computational speed of 3.100181 seconds, and the Papoulis method has an average error relative of 9.8558e-004 with computational speed of 0.020793 seconds.

Molecular characterization of mutations associated with resistance to second-line tuberculosis drug among multidrug-resistant tuberculosis patients from high prevalence tuberculosis city in Morocco.

Science.gov (United States)

Oudghiri, Amal; Karimi, Hind; Chetioui, Fouad; Zakham, Fathiah; Bourkadi, Jamal Eddine; Elmessaoudi, My Driss; Laglaoui, Amin; Chaoui, Imane; El Mzibri, Mohammed

2018-02-27

The emergence of extensively drug-resistant tuberculosis (XDR-TB) has raised public health concern for global TB control. Although multi drug-resistant tuberculosis (MDR- TB) prevalence and associated genetic mutations in Morocco are well documented, scarce information on XDR TB is available. Hence, the evaluation of pre-XDR and XDR prevalence, as well as the mutation status of gyrA, gyrB, rrs, tlyA genes and eis promoter region, associated with resistance to second line drugs, is of great value for better management of M/XDR TB in Morocco. To evaluate pre-XDR and XDR prevalence, as well as the mutation status of gyrA, gyrB, rrs, tlyA genes and eis promoter region, associated with resistance to second line drug resistance, in 703 clinical isolates from TB patients recruited in Casablanca, and to assess the usefulness of molecular tools in clinical laboratories for better management of M/XDR TB in Morocco. Drug susceptibility testing (DST) was performed by the proportional method for first line drugs, and then the selected MDR isolates were tested for second line drugs (Ofloxacin, Kanamycin, Amikacin and Capreomycin). Along with DST, all samples were subjected to rpoB, katG and p-inhA mutation analysis by PCR and DNA sequencing. MDR isolates as well as 30 pan-susceptible strains were subjected to PCR and DNA sequencing of gyrA, gyrB, rrs, tlyA genes and eis promoter, associated with resistance to fluoroquinolones and injectable drugs. Among the 703 analysed strains, 12.8% were MDR; Ser531Leu and Ser315Thr being the most common recorded mutations within rpoB and katG genes associated with RIF and INH resistance respectively. Drug susceptibility testing for second line drugs showed that among the 90 MDR strains, 22.2% (20/90) were resistant to OFX, 2.22% (2/90) to KAN, 3.33% (3/90) to AMK and 1.11% (1/90) to CAP. Genotypic analysis revealed that 19 MDR strains harbored mutations in the gyrA gene; the most recorded mutation being Asp91Ala accounting for 47.6% (10

Using therapeutic cloning to fight human disease: a conundrum or reality?

Science.gov (United States)

Hall, Vanessa J; Stojkovic, Petra; Stojkovic, Miodrag

2006-07-01

The development and transplantation of autologous cells derived from nuclear transfer embryonic stem cell (NT-ESC) lines to treat patients suffering from disease has been termed therapeutic cloning. Human NT is still a developing field, with further research required to improve somatic cell NT and human embryonic stem cell differentiation to deliver safe and effective cell replacement therapies. Furthermore, the implications of transferring mitochondrial heteroplasmic cells, which may harbor aberrant epigenetic gene expression profiles, are of concern. The production of human NT-ESC lines also remains plagued by ethical dilemmas, societal concerns, and controversies. Recently, a number of alternate therapeutic strategies have been proposed to circumvent the moral implications surrounding human nuclear transfer. It will be critical to overcome these biological, legislative, and moral restraints to maximize the potential of this therapeutic strategy and to alleviate human disease.

Analysis of the cytotoxicity of carbon-based nanoparticles, diamond and graphite, in human glioblastoma and hepatoma cell lines

DEFF Research Database (Denmark)

Zakrzewska, Karolina Ewa; Samluk, Anna; Wierzbicki, Mateusz

2015-01-01

carbon based nanoparticles, diamond and graphite, on glioblastoma and hepatoma cells were compared. First, we confirmed previous results that diamond nanoparticles are practically nontoxic. Second, graphite nanoparticles exhibited a negative impact on glioblastoma, but not on hepatoma cells. The studied...... carbon nanoparticles could be a potentially useful tool for therapeutics delivery to the brain tissue with minimal side effects on the hepatocytes. Furthermore, we showed the influence of the nanoparticles on the stable, fluorescently labeled tumor cell lines and concluded that the labeled cells...

20 CFR 416.2035 - Optional supplementation: Additional State options.

Science.gov (United States)

2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Optional supplementation: Additional State options. 416.2035 Section 416.2035 Employees' Benefits SOCIAL SECURITY ADMINISTRATION SUPPLEMENTAL... § 416.2035 Optional supplementation: Additional State options. (a) Residency requirement. A State or...

Controlling the spread of carbapenemase-producing Gram-negatives: therapeutic approach and infection control.

Science.gov (United States)

Carmeli, Y; Akova, M; Cornaglia, G; Daikos, G L; Garau, J; Harbarth, S; Rossolini, G M; Souli, M; Giamarellou, H

2010-02-01

Although the rapid spread of carbapenemase-producing Gram-negatives (CPGNs) is providing the scientific community with a great deal of information about the molecular epidemiology of these enzymes and their genetic background, data on how to treat multidrug-resistant or extended drug-resistant carbapenemase-producing Enterobacteriaceae and how to contain their spread are still surprisingly limited, in spite of the rapidly increasing prevalence of these organisms and of their isolation from patients suffering from life-threatening infections. Limited clinical experience and several in vitro synergy studies seem to support the view that antibiotic combinations should be preferred to monotherapies. But, in light of the data available to date, it is currently impossible to quantify the real advantage of drug combinations in the treatment of these infections. Comprehensive clinical studies of the main therapeutic options, broken down by pathogen, enzyme and clinical syndrome, are definitely lacking and, as carbapenemases keep spreading, are urgently needed. This spread is unveiling the substantial unpreparedness of European public health structures to face this worrisome emergency, although experiences from different countries-chiefly Greece and Israel-have shown that CPGN transmission and cross-infection can cause a substantial threat to the healthcare system. This unpreparedness also affects the treatment of individual patients and infection control policies, with dramatic scarcities of both therapeutic options and infection control measures. Although correct implementation of such measures is presumably cumbersome and expensive, the huge clinical and public health problems related to CPGN transmission, alongside the current scarcity of therapeutic options, seem to fully justify this choice.

Analysis of Options Contract, Option Pricing in Agricultural Products

Directory of Open Access Journals (Sweden)

H. Tamidy

2016-03-01

Full Text Available Introduction: Risk is an essential component in the production and sale of agricultural products. Due to the nature of agricultural products, the people who act in this area including farmers and businesspersons encounter unpredictable fluctuations of prices. On the other hand, the firms that process agricultural products also face fluctuation of price of agricultural inputs. Given that the Canola is considered as one of the inputs of product processing factories, control of unpredictable fluctuations of the price of this product would increase the possibility of correct decision making for farmers and managers of food processing industries. The best available tool for control and management of the price risk is the use of future markets and options. It is evident that the pricing is the main pillar in every trade. Therefore, offering a fair price for the options will be very important. In fact, options trading in the options market create cost insurance stopped. In this way, which can reduce the risks of deflation created in the future, if the person entitled to the benefits of the price increase occurs in the future. Unlike the futures, market where the seller had to deliver the product on time, in the options market, there is no such compulsion. In addition, this is one of the strengths of this option contract, because if there is not enough product for delivery to the futures market as result of chilling, in due course, the farmers suffer, but in the options market there will be a loss. In this study, the setup options of rape, as a product, as well as inputs has been paid for industry. Materials and Methods: In this section. The selection criteria of the disposal of asset base for valuation of European put options and call option is been introduced. That for obtain this purpose, some characteristics of the goods must considered: 1-Unpredictable fluctuations price of underlying asset 2 -large underlying asset cash market 3- The possibility

Evaluation of design feature No.20 -- Ground support options

International Nuclear Information System (INIS)

Duan, F.

2000-01-01

Ground support options are primarily evaluated for emplacement drifts while ground support systems for non-emplacement openings such as access mains and ventilation drifts are not evaluated against LADS evaluation criteria in this report. Considerations include functional requirements for ground support, the use of a steel-lined system, and the feasibility of using an unlined ground support system principally with grouted rock bolts for permanent ground support. The feature evaluation also emphasizes the postclosure effects of ground support materials on waste isolation and the preclosure aspects such as durability, maintainability, constructibility, safety, engineering acceptability, and cost. This evaluation is to: (A) Review the existing analyses, reports, and studies regarding this design feature, and compile relevant information on performance characteristics. (B) Develop an appropriate evaluation approach for evaluating ground support options against evaluation criteria provided by the LADS team. (C) Evaluate ground support options not only for their preclosure performance in terms of drift stability, material durability, maintenance, constructibility, and cost, but also for their postclosure performance in terms of chemical effects of ground support materials (i.e., concrete, steel) on waste isolation and radionuclide transport. Specifically, the scope for ground support options evaluation include: (1) all steel-lined drifts (no cementitious materials), (2) unlined drifts with minimum cementitious materials (e.g., grout for rockbolts), and (3) concrete-lined drifts, with the focus on the postclosure acceptability evaluation. In addition, unlined drifts with zero cementitious materials (e.g., use of frictional bolts such as split sets, Swellex bolts) are briefly discussed. (D) Identify candidate ground support systems that have the potential to enhance the repository performance based on the feature evaluation. and (E) Provide conclusions and recommendations

Should CA-125 response criteria be preferred to response evaluation criteria in solid tumors (RECIST) for prognostication during second-line chemotherapy of ovarian carcinoma?

DEFF Research Database (Denmark)

Gronlund, Bo; Høgdall, Claus; Hilden, Jørgen

2004-01-01

-line chemotherapy. PATIENTS AND METHODS: From a single-institution registry of 527 consecutive patients with primary ovarian carcinoma, 131 records satisfied the inclusion criteria: ovarian carcinoma of International Federation of Gynecology and Obstetrics stage IC to IV, first-line chemotherapy with paclitaxel...... and a platinum compound, refractory or recurrent disease, and second-line chemotherapy consisting of topotecan or paclitaxel plus carboplatin. Univariate and multivariate analyses of survival were performed using the landmark method. RESULTS: In patients with measurable disease by RECIST and with assessable...... sites (solitary v multiple; hazard ratio, 0.47; P = .020) were identified as contributory prognostic factors for survival, whereas the parameters of RECIST (responders v nonresponders), as well as the remaining variables, had nonsignificant prognostic impact. CONCLUSION: The GCIG CA-125 response...

Pre-treatment prediction of chemoresistance in second-line chemotherapy of ovarian carcinoma: value of serological tumor marker determination (tetranectin, YKL-40, CASA, CA 125)

DEFF Research Database (Denmark)

Grønlund, B; Høgdall, E V S; Christensen, Ib Jarle

2006-01-01

for the biochemical tumor markers tetranectin, YKL-40, CASA (cancer-associated serum antigen), and CA 125. The serum tumor marker levels at time of relapse were correlated with response status at landmark time after 4 cycles of second-line chemotherapy. Univariate and multivariate logistic regression analyses...... (OR 1.8; 95% CI: 1.0-3.3; p=0.045), and CASA (OR 1.8; 95% CI: 1.2-2.7; p=0.007) had predictive value for second-line chemoresistance, whereas serum CA 125 had no predictive value. In a multivariate logistic regression analysis, serum tetranectin and CASA both had independent predictive value...... for chemoresistance. The combined determination of tetranectin and CASA had a specificity of 90% with 33% sensitivity for the prediction of chemoresistance (area under the receiver operating characteristic curve = 0.78; 95% CI: 0.66-0.91; p=0.001). CONCLUSION: Low serum levels of tetranectin, or high serum levels...

Hypothyroidism during second-line treatment of multidrug-resistant tuberculosis: a prospective study.

Science.gov (United States)

Bares, R; Khalid, N; Daniel, H; Dittmann, H; Reimold, M; Gallwitz, B; Schmotzer, C

2016-07-01

Hypothyroidism is an adverse effect of certain anti-tuberculosis drugs. This is a prospective study of the frequency and possible pathomechanisms associated with hypothyroidism due to second-line treatment of multidrug-resistant tuberculosis. Fifty human immunodeficiency virus negative patients and 20 controls were included. All participants underwent ultrasonography of the thyroid and measurement of thyroid stimulating hormone (TSH). TSH levels were checked every 3 months. If hypothyroidism was present, T3, T4 and thyroid peroxidase autoantibodies were measured, and imaging extended to scintigraphy and repeated ultrasonography. Before treatment, 7 patients (14%) and 1 control (5%) were hypothyreotic. During the first 6 months of treatment, TSH levels increased in 41 patients (82%), 39 (78%) had values above the normal range and 19 (38%) had overt hypothyroidism. As none of the patients had signs of autoimmune thyroiditis, interaction with anti-tuberculosis drugs was assumed to be the cause of hypothyroidism. Nine patients died during treatment, all of whom had developed hypothyroidism. In seven, the metabolic situation at their death was known, and they had become euthyreotic following levothyroxine substitution. TSH levels should be checked before initiating anti-tuberculosis treatment and after 3 and 6 months to start timely replacement of levothyroxine. Further studies are needed to elucidate the exact pathomechanism involved in hypothyroidism and whether hypothyroidism can be used as predictor of treatment failure.

Lysosomal storage diseases: current diagnostic and therapeutic options

International Nuclear Information System (INIS)

Malinova, V.; Honzik, T.

2013-01-01

Lysosomal storage diseases are rare genetic diseases caused by insufficient activity of some of the lysosomal enzymes and/or transport proteins. Initial symptoms may appear any time from the neonatal period to late adulthood; early forms tend to have a severe course with rapid progression and unfavorable prognosis. There is multisystem involvement with continuous progression of symptoms and involvement of metabolically active organs or tissues – the bone marrow, liver, bones, skeletal muscles, myocardium, or CNS. The diagnosis is definitively confirmed by demonstration of reduced activity of the particular enzyme and by mutation analysis. Some of the storage diseases can be effectively treated by intravenous administration of recombinant enzymes or by limiting the amount of the substrate stored. In a small number of lysosomal storage diseases, bone marrow transplantation is successful. Multidisciplinary collaboration, including genetic counselling and prenatal diagnosis in patient families, is required. The first part of the paper deals with general characteristics of lysosomal storage diseases and the most common diseases that are currently treatable in the Czech Republic (Gaucher’s disease, Pompe disease, Fabry disease, Niemann–Pick disease, cholesterol ester storage disease). The second part of the paper deals with mucopolysaccharidase, another group of rare lysosomal storage diseases. (author)

International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: VI. Trends in recommendations for the pharmacotherapy of anxiety disorders, 1992-1997.

Science.gov (United States)

Uhlenhuth, E H; Balter, M B; Ban, T A; Yang, K

1999-01-01

To assemble expert clinical experience and judgment regarding the treatment of anxiety disorders in a systematic, quantitative manner, particularly with respect to changes during the preceding five years. A panel of 73 internationally recognized experts in the pharmacotherapy of anxiety and depression was constituted by multistage peer nomination. Sixty-six completed a questionnaire in 1992, and 51 of those completed a follow-up questionnaire in 1997. This report focuses on the experts' responses to questions about therapeutic options relevant to seven vignettes describing typical cases of different anxiety disorders. The preferred initial treatment strategy in 1992 was a combination of medication with a psychological therapy for all vignettes except simple phobia, where a psychological procedure alone was favored. There was little change in 1997, primarily some decrease in the choice of psychological therapy and some increase in the choice of medication for social phobia. Experts recommending a medication in 1992 most often chose as first-line treatment a benzodiazepine anxiolytic (BZ) for panic disorder (PD), generalized anxiety disorder (GAD), simple phobia, and adjustment disorder. They recommended a beta-blocker most often for social phobia and a tricyclic anti-depressant (TCA) for agoraphobia and obsessive-compulsive disorder (OCD). Nearly a fourth chose a combination of medications, usually a TCA plus a BZ. In 1997, the expert panel's most frequent recommendation for agoraphobia, PD, and OCD changed to a specific serotonin reuptake inhibitor (SSRI); and they also recommended these compounds more often for GAD, social phobia, and simple phobia. Fewer experts chose BZs or TCAs. However, in 1997 many again chose a combination of medications, often a BZ plus a SSRI, so that, overall, there was only a small decline in recommendations for BZs. As second-line medications (1997 only), the experts recommended SSRIs most often for most vignettes, but a TCA for PD and

Helicobacter pylori second-line rescue therapy with levofloxacin- and bismuth-containing quadruple therapy, after failure of standard triple or non-bismuth quadruple treatments.

Science.gov (United States)

Gisbert, J P; Romano, M; Gravina, A G; Solís-Muñoz, P; Bermejo, F; Molina-Infante, J; Castro-Fernández, M; Ortuño, J; Lucendo, A J; Herranz, M; Modolell, I; Del Castillo, F; Gómez, J; Barrio, J; Velayos, B; Gómez, B; Domínguez, J L; Miranda, A; Martorano, M; Algaba, A; Pabón, M; Angueira, T; Fernández-Salazar, L; Federico, A; Marín, A C; McNicholl, A G

2015-04-01

The most commonly used second-line Helicobacter pylori eradication regimens are bismuth-containing quadruple therapy and levofloxacin-containing triple therapy, both offering suboptimal results. Combining bismuth and levofloxacin may enhance the efficacy of rescue eradication regimens. To evaluate the efficacy and tolerability of a second-line quadruple regimen containing levofloxacin and bismuth in patients whose previous H. pylori eradication treatment failed. This was a prospective multicenter study including patients in whom a standard triple therapy (PPI-clarithromycin-amoxicillin) or a non-bismuth quadruple therapy (PPI-clarithromycin-amoxicillin-metronidazole, either sequential or concomitant) had failed. Esomeprazole (40 mg b.d.), amoxicillin (1 g b.d.), levofloxacin (500 mg o.d.) and bismuth (240 mg b.d.) was prescribed for 14 days. Eradication was confirmed by (13) C-urea breath test. Compliance was determined through questioning and recovery of empty medication envelopes. Incidence of adverse effects was evaluated by questionnaires. 200 patients were included consecutively (mean age 47 years, 67% women, 13% ulcer). Previous failed therapy included: standard clarithromycin triple therapy (131 patients), sequential (32) and concomitant (37). A total of 96% took all medications correctly. Per-protocol and intention-to-treat eradication rates were 91.1% (95%CI = 87-95%) and 90% (95%CI = 86-94%). Cure rates were similar regardless of previous (failed) treatment or country of origin. Adverse effects were reported in 46% of patients, most commonly nausea (17%) and diarrhoea (16%); 3% were intense but none was serious. Fourteen-day bismuth- and levofloxacin-containing quadruple therapy is an effective (≥90% cure rate), simple and safe second-line strategy in patients whose previous standard triple or non-bismuth quadruple (sequential or concomitant) therapies have failed. © 2015 John Wiley & Sons Ltd.

Acquired hemophilia A: a review of recent data and new therapeutic options.

Science.gov (United States)

Franchini, Massimo; Vaglio, Stefania; Marano, Giuseppe; Mengoli, Carlo; Gentili, Sara; Pupella, Simonetta; Liumbruno, Giancarlo Maria

2017-10-01

Acquired hemophilia A (AHA) is a rare, but potentially life-threatening, bleeding disorder caused by an autoantibody against factor VIII that interferes with its coagulant function. We performed a narrative review focusing on the diagnostic aspects of AHA and on the current treatment strategies with particular regard to new data and therapeutic developments. The management of this severe hemorrhagic disorder is based on the control of bleeding with the use of bypassing agents and on the utilization of a variety of immunosuppressant agents with the goal of eliminating the autoantibody permanently. The optimal management of AHA should be multidisciplinary and requires a close collaboration between physicians from various specialties.

U.S. second line of defense: preventing nuclear smuggling across Russia's borders

International Nuclear Information System (INIS)

Ball, D. Y.

1998-01-01

Preventing the theft of weapons-usable highly enriched uranium and plutonium in Russia is one of the central security concerns facing the US today. The dissolution of the highly centralized USSR and the resulting societal crisis has endangered Russia's ability to protect its more than 200 metric tons of plutonium and 1000 tons of highly enriched uranium (roughly 8 kg Pu or 25 kg HEU is sufficient to make a bomb). Producing this fissile material is the most difficult and expensive part of nuclear weapons production and the US must make every effort to ensure that fissile material (and nuclear-related technologies) does not reach the hands of terrorist groups, rogue states or other potential proliferators. In response to this concern, the US has undertaken a number of initiatives in partnership with Russia and other FSU states to prevent the theft of fissile material. The Material Protection, Control and Accounting Program (MPC and A) was begun in 1993 to prevent the theft of nuclear materials from Russian civilian complexes, that is facilities not under control of the Ministry of Defense, which is largely responsible for possession and oversight of nuclear weapons. The MPC and A program is considered the first line of defense against theft of nuclear material because its goal is to prevent theft of material at production and storage facilities. This year the Department of Energy (DOE) initiated a new program called the Second Line of Defense (SLD), the goal of which is to assist Russia in preventing the smuggling of nuclear material and weapons at its borders, either by land, sea or air. The SLD program represents an important phase in the overall effort to ensure the security of nuclear material and weapons in Russia. However, as the US engages Russian customs officials in this important project, Americans should keep in mind that providing equipment--even indigenous equipment--is insufficient by itself; material aid must be accompanied by rigorous inspection and

Engineering Multi-Walled Carbon Nanotube Therapeutic Bionanofluids to Selectively Target Papillary Thyroid Cancer Cells.

Directory of Open Access Journals (Sweden)

Idit Dotan

Full Text Available The incidence of papillary thyroid carcinoma (PTC has risen steadily over the past few decades as well as the recurrence rates. It has been proposed that targeted ablative physical therapy could be a therapeutic modality in thyroid cancer. Targeted bio-affinity functionalized multi-walled carbon nanotubes (BioNanofluid act locally, to efficiently convert external light energy to heat thereby specifically killing cancer cells. This may represent a promising new cancer therapeutic modality, advancing beyond conventional laser ablation and other nanoparticle approaches.Thyroid Stimulating Hormone Receptor (TSHR was selected as a target for PTC cells, due to its wide expression. Either TSHR antibodies or Thyrogen or purified TSH (Thyrotropin were chemically conjugated to our functionalized Bionanofluid. A diode laser system (532 nm was used to illuminate a PTC cell line for set exposure times. Cell death was assessed using Trypan Blue staining.TSHR-targeted BioNanofluids were capable of selectively ablating BCPAP, a TSHR-positive PTC cell line, while not TSHR-null NSC-34 cells. We determined that a 2:1 BCPAP cell:α-TSHR-BioNanofluid conjugate ratio and a 30 second laser exposure killed approximately 60% of the BCPAP cells, while 65% and >70% of cells were ablated using Thyrotropin- and Thyrogen-BioNanofluid conjugates, respectively. Furthermore, minimal non-targeted killing was observed using selective controls.A BioNanofluid platform offering a potential therapeutic path for papillary thyroid cancer has been investigated, with our in vitro results suggesting the development of a potent and rapid method of selective cancer cell killing. Therefore, BioNanofluid treatment emphasizes the need for new technology to treat patients with local recurrence and metastatic disease who are currently undergoing either re-operative neck explorations, repeated administration of radioactive iodine and as a last resort external beam radiation or chemotherapy, with

Comparison of second-echelon treatments for Ménière's disease.

Science.gov (United States)

Basura, Gregory J; Lin, Giant C; Telian, Steven A

2014-08-01

To compare the efficacy of treatments commonly offered to patients with Ménière's disease who fail conservative medical therapy including diuretics and a sodium-restricted diet. This study compared three second-echelon treatments: the Meniett device, endolymphatic sac decompression, and intratympanic gentamicin injections to determine their comparative effectiveness and capacity to mitigate against the necessity of a surgical labyrinthectomy. Retrospective observational study at an academic tertiary care center. Patients with Ménière's disease who failed primary medical management were evaluated after treatment with a Meniett device (n=20), endolymphatic sac decompression (n=23) or intratympanic gentamicin injections (n=17). Cases were included if auditory and vertigo control data were available before and a minimum of two years after treatment, in patients without previous otologic surgery or intratympanic injections. Average age ranged from 54 to 75 years. Use of the Meniett device, endolymphatic sac shunt decompression surgery or intratympanic gentamicin injections using variable doses and injection schedules. Proportion of patients with vertigo control and hearing preservation by a modified version of the AAO-HNS criteria after second-echelon treatment, thus not requiring definitive labyrinthectomy. Despite endolymphatic sac surgery demonstrating a longer duration (61 months) prior to labyrinthectomy, no differences were found between the 3 treatment options in terms of patients going on to definitive labyrinthectomy or in the number of months of symptom relief following treatment. There was also no difference in residual auditory perception across the 3 groups. No significant therapeutic differences were found between the studied second-echelon treatments for symptom relief of Ménière's disease.

Comparison between three option, four option and five option multiple choice question tests for quality parameters: A randomized study.

Science.gov (United States)

Vegada, Bhavisha; Shukla, Apexa; Khilnani, Ajeetkumar; Charan, Jaykaran; Desai, Chetna

2016-01-01

Most of the academic teachers use four or five options per item of multiple choice question (MCQ) test as formative and summative assessment. Optimal number of options in MCQ item is a matter of considerable debate among academic teachers of various educational fields. There is a scarcity of the published literature regarding the optimum number of option in each item of MCQ in the field of medical education. To compare three options, four options, and five options MCQs test for the quality parameters - reliability, validity, item analysis, distracter analysis, and time analysis. Participants were 3 rd semester M.B.B.S. students. Students were divided randomly into three groups. Each group was given one set of MCQ test out of three options, four options, and five option randomly. Following the marking of the multiple choice tests, the participants' option selections were analyzed and comparisons were conducted of the mean marks, mean time, validity, reliability and facility value, discrimination index, point biserial value, distracter analysis of three different option formats. Students score more ( P = 0.000) and took less time ( P = 0.009) for the completion of three options as compared to four options and five options groups. Facility value was more ( P = 0.004) in three options group as compared to four and five options groups. There was no significant difference between three groups for the validity, reliability, and item discrimination. Nonfunctioning distracters were more in the four and five options group as compared to three option group. Assessment based on three option MCQs is can be preferred over four option and five option MCQs.

Applying Real Options for Evaluating Investments in ERP Systems

Science.gov (United States)

Nakagane, Jun; Sekozawa, Teruji

This paper intends to verify effectiveness of real options approach for evaluating investments in Enterprise Resource Planning systems (ERP) and proves how important it is to disclose shadow options potentially embedded in ERP investment. The net present value (NPV) method is principally adopted to evaluate the value of ERP. However, the NPV method assumes no uncertainties exist in the object. It doesn't satisfy the current business circumstances which are filled with dynamic issues. Since the 1990s the effectiveness of option pricing models for Information System (IS) investment to solve issues in the NPV method has been discussed in the IS literature. This paper presents 3 business cases to review the practical advantages of such techniques for IS investments, especially ERP investments. The first case is EDI development. We evaluate the project by a new approach with lighting one of shadow options, EDI implementation. In the second case we reveal an ERP investment has an “expanding option” in a case of eliminating redundancy. The third case describes an option to contract which is deliberately slotted in ERP development to prepare transferring a manufacturing facility.

Therapeutic inertia amongst general practitioners with interest in diabetes.

Science.gov (United States)

Seidu, Samuel; Than, Tun; Kar, Deb; Lamba, Amrit; Brown, Pam; Zafar, Azhar; Hussain, Rizwan; Amjad, Ahmed; Capehorn, Mathew; Martin, Elizabeth; Fernando, Kevin; McMoran, Jim; Millar-Jones, David; Kahn, Shahzada; Campbell, Nigel; Brice, Richard; Mohan, Rahul; Mistry, Mukesh; Kanumilli, Naresh; St John, Joan; Quigley, Richard; Kenny, Colin; Khunti, Kamlesh

2018-02-01

As the therapeutic options in the management of type 2 diabetes increase, there is an increase confusion among health care professionals, thus leading to the phenomenon of therapeutic inertia. This is the failure to escalate or de-escalate treatment when the clinical need for this is required. It has been studied extensively in various settings, however, it has never been reported in any studies focusing solely on primary care physicians with an interest in diabetes. This group is increasingly becoming the focus of managing complex diabetes care in the community, albeit with the support from specialists. In this retrospective audit, we assessed the prevalence of the phenomenon of therapeutic inertia amongst primary care physicians with an interest in diabetes in UK. We also assessed the predictive abilities of various patient level characteristics on therapeutic inertia amongst this group of clinicians. Out of the 240 patients reported on, therapeutic inertia was judged to have occurred in 53 (22.1%) of patients. The full model containing all the selected variables was not statistically significant, p=0.59. So the model was not able to distinguish between situations in which therapeutic inertia occurred and when it did not occur. None of the patient level characteristics on its own was predictive of therapeutic inertia. Therapeutic inertia was present only in about a fifth of patient patients with diabetes being managed by primary care physicians with an interest in diabetes. Copyright © 2017 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

Quality of Life in Second-Line Treatment of Metastatic Castration-Resistant Prostate Cancer Using Cabazitaxel or Other Therapies After Previous Docetaxel Chemotherapy: Swiss Observational Treatment Registry.

Science.gov (United States)

Stenner, Frank; Rothschild, Sacha I; Betticher, Daniel; Caspar, Clemens; Morant, Rudolf; Popescu, Razvan; Rauch, Daniel; Huber, Urs; Zenhäusern, Reinhard; Rentsch, Cyrill; Cathomas, Richard

2017-08-24

The aim was to evaluate quality of life (QoL), pain, and fatigue in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with different regimens after first-line docetaxel, as well as disease progression. Patients with mCRPC having received first-line chemotherapy with docetaxel were eligible. Second-line treatment choice was at the discretion of the local investigator. All patients had regular assessments of QoL with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, of fatigue with the Brief Fatigue Inventory, and of pain with the McGill Pain Questionnaire-Short Form. The primary end point was QoL maintenance defined as having a maximum decrease in 2 functional domains of the FACT-P. One hundred thirty-eight patients were included in 36 oncology centers across Switzerland. QoL analysis was available for all patients (59 who received cabazitaxel; 79 who received other therapy [OT] including 75 who received abiraterone). No significant differences for any of the end points were found between groups. A numerically higher number of patients had QoL maintenance with OT (25 of 79 patients, 32%) compared with cabazitaxel (8 of 59 patients, 14%). QoL improvement was found in 20% of patients (12 of 59) who received cabazitaxel and 24% (19 of 79) who received OT. Mean FACT-P score did not change in a clinically relevant manner over time in either group. Pain was present in 70% of patients (96 of 138), and a pain response to treatment was noted in 22% (13 of 59) who received cabazitaxel and 29% (23 of 79) who received OT. A similar but minor improvement of fatigue was noted in both groups. Some degree of QoL decrease was seen in most patients regardless of second-line treatment. No significant differences in QoL parameters between cabazitaxel or other second line treatments were found. Copyright © 2017 Elsevier Inc. All rights reserved.

SESOTHO trial ("Switch Either near Suppression Or THOusand") - switch to second-line versus WHO-guided standard of care for unsuppressed patients on first-line ART with viremia below 1000 copies/mL: protocol of a multicenter, parallel-group, open-label, randomized clinical trial in Lesotho, Southern Africa.

Science.gov (United States)

Amstutz, Alain; Nsakala, Bienvenu Lengo; Vanobberghen, Fiona; Muhairwe, Josephine; Glass, Tracy Renée; Achieng, Beatrice; Sepeka, Mamorena; Tlali, Katleho; Sao, Lebohang; Thin, Kyaw; Klimkait, Thomas; Battegay, Manuel; Labhardt, Niklaus Daniel

2018-02-12

The World Health Organization (WHO) recommends viral load (VL) measurement as the preferred monitoring strategy for HIV-infected individuals on antiretroviral therapy (ART) in resource-limited settings. The new WHO guidelines 2016 continue to define virologic failure as two consecutive VL ≥1000 copies/mL (at least 3 months apart) despite good adherence, triggering switch to second-line therapy. However, the threshold of 1000 copies/mL for defining virologic failure is based on low-quality evidence. Observational studies have shown that individuals with low-level viremia (measurable but below 1000 copies/mL) are at increased risk for accumulation of resistance mutations and subsequent virologic failure. The SESOTHO trial assesses a lower threshold for switch to second-line ART in patients with sustained unsuppressed VL. In this multicenter, parallel-group, open-label, randomized controlled trial conducted in Lesotho, patients on first-line ART with two consecutive unsuppressed VL measurements ≥100 copies/mL, where the second VL is between 100 and 999 copies/mL, will either be switched to second-line ART immediately (intervention group) or not be switched (standard of care, according to WHO guidelines). The primary endpoint is viral resuppression (VL < 50 copies/mL) 9 months after randomization. We will enrol 80 patients, giving us 90% power to detect a difference of 35% in viral resuppression between the groups (assuming two-sided 5% alpha error). For our primary analysis, we will use a modified intention-to-treat set, with those lost to care, death, or crossed over considered failure to resuppress, and using logistic regression models adjusted for the prespecified stratification variables. The SESOTHO trial challenges the current WHO guidelines, assessing an alternative, lower VL threshold for patients with unsuppressed VL on first-line ART. This trial will provide data to inform future WHO guidelines on VL thresholds to recommend switch to second-line ART

Trans-species Engineering of Glycosylated Therapeutic Proteins

DEFF Research Database (Denmark)

Yang, Zhang

important to address. Whenever glycosylation has been found to be an important PTM for function or bioactivity, human therapeutics have generally been produced in mammalian Chinese hamster ovary (CHO) cell line. Oglycosylation is one of the most complex regulated PTMs of proteins but also one of the least...... understood. Currently, mammalian cells are required for human O-glycosylation. Increasing efforts have been devoted to engineering non-mammalian cells for production of recombinant proteins with “human-like” glycosylation. Substantial success has been achieved with designed N-glycosylation in both lower......Recombinant expression of therapeutic proteins is one of the major tasks in modern biomedicine. One of the most important factors with respect to therapeutic use in human is posttranslational modifications (PTMs) of the recombinant proteins, of which protein glycosylation is by far the most...

High expression of CD109 antigen regulates the phenotype of cancer stem-like cells/cancer-initiating cells in the novel epithelioid sarcoma cell line ESX and is related to poor prognosis of soft tissue sarcoma.

Directory of Open Access Journals (Sweden)

Makoto Emori

Full Text Available Epithelioid sarcoma (ES is a relatively rare, highly malignant soft tissue sarcoma. The mainstay of treatment is resection or amputation. Currently other therapeutic options available for this disease are limited. Therefore, a novel therapeutic option needs to be developed. In the present study, we established a new human ES cell line (ESX and analyzed the characteristics of its cancer stem-like cells/cancer-initiating cells (CSCs/CICs based on ALDH1 activity. We demonstrated that a subpopulation of ESX cells with high ALDH1 activity (ALDH(high cells correlated with enhanced clonogenic ability, sphere-formation ability, and invasiveness in vitro and showed higher tumorigenicity in vivo. Next, using gene expression profiling, we identified CD109, a GPI-anchored protein upregulated in the ALDH(high cells. CD109 mRNA was highly expressed in various sarcoma cell lines, but weakly expressed in normal adult tissues. CD109-positive cells in ESX predominantly formed spheres in culture, whereas siCD109 reduced ALDH1 expression and inhibited the cell proliferation in vitro. Subsequently, we evaluated the expression of CD109 protein in 80 clinical specimens of soft tissue sarcoma. We found a strong correlation between CD109 protein expression and the prognosis (P = 0.009. In conclusion, CD109 might be a CSC/CIC marker in epithelioid sarcoma. Moreover, CD109 is a promising prognostic biomarker and a molecular target of cancer therapy for sarcomas including ES.

Effect of Primary Tumor Location on Second- or Later-line Treatment Outcomes in Patients With RAS Wild-type Metastatic Colorectal Cancer and All Treatment Lines in Patients With RAS Mutations in Four Randomized Panitumumab Studies.

Science.gov (United States)

Boeckx, Nele; Koukakis, Reija; Op de Beeck, Ken; Rolfo, Christian; Van Camp, Guy; Siena, Salvatore; Tabernero, Josep; Douillard, Jean-Yves; André, Thierry; Peeters, Marc

2018-03-08

The primary tumor location has a prognostic impact in metastatic colorectal cancer (mCRC). We report the results from retrospective analyses assessing the effect of tumor location on prognosis and efficacy of second- and later-line panitumumab treatment in patients with RAS wild-type (WT) mCRC and on prognosis in all lines of treatment in patients with RAS mutant (MT) mCRC. RAS WT data (n = 483) from 2 randomized phase III panitumumab trials (ClinicalTrials.gov identifiers, NCT00339183 and NCT00113763) were analyzed for treatment outcomes stratified by tumor location. The second analysis assessed the effect of tumor location in RAS MT patients (n = 1205) from 4 panitumumab studies (ClinicalTrials.gov identifiers, NCT00364013, NCT00819780, NCT00339183, and NCT00113763). Primary tumors located in the cecum to transverse colon were coded as right-sided; those located from the splenic flexure to the rectum were coded as left-sided. Of all patients, the tumor location was ascertained for 83% to 88%; 71% to 77% of patients had left-sided tumors. RAS WT patients with right-sided tumors did worse for all efficacy parameters compared with those with left-sided tumors. The patients with left-sided tumors had better outcomes with panitumumab than with the comparator treatment. Because of the low patient numbers, no conclusions could be drawn for right-sided mCRC. The prognostic effect of tumor location on survival was unclear for RAS MT patients. These retrospective analyses have confirmed that RAS WT right-sided mCRC is associated with a poor prognosis, regardless of the treatment. RAS WT patients with left-sided tumors benefitted from the addition of panitumumab in second or later treatment lines. Further research is warranted to determine the optimum management of right-sided mCRC and RAS MT tumors. Copyright © 2018 Elsevier Inc. All rights reserved.

Stock Options Economic Determinants of Brazilian Listed Companies

Directory of Open Access Journals (Sweden)

Isaac Gezer Silva de Oliveira

2018-01-01

Full Text Available It aim to identify the economic determinants that influence the use of stock options plans in Brazilian public companies listed on the Brazilian Securities, Commodities, and Futures Exchange (BM&FBovespa. Theoretically, the study relies on agency theory and corporate governance and executive compensation body of knowledge. Four research hypotheses were drawn concerning financial performance and corporate value; indebtedness; ownership concentration; and size. The sample was comprised of 100 companies with greater liquidity shares and volume for six years (from 2010 to2015.Data were examined from the logistic regression panel. The results lead to the rejection of the first and the fourth hypo the sesindicating, in the case of H1, that the higher financial performance the lower is probability of use stock options and, in the case of H4, that the higher size is related the lower is probability of use of stock options in their incentive plans for executives. The third hypothesis (H3 was not rejected, indicating that the ownership concentration relates negatively with the use of stock options. Regarding the second hypothesis (H2, the results did not present statistical significance indicating the absence of a relationship between indebtedness and the use of stock options. As a summary of the results it was found that the use of stock options tend to be used by lower companies, with lower ownership concentration and lower financial performance.

Limited-Sampling Strategies for Therapeutic Drug Monitoring of Moxifloxacin in Patients With Tuberculosis

NARCIS (Netherlands)

Pranger, Arianna D.; Kosterink, Jos G. W.; van Altena, Richard; Aarnoutse, Rob E.; van der Werf, Tjip S.; Uges, Donald R. A.; Alffenaar, Jan-Willem C.

Background: Moxifloxacin (MFX) is a potent drug for multidrug resistant tuberculosis(TB) treatment and is also useful if first-line agents are not tolerated. Therapeutic drug monitoring may help to prevent treatment failure. Obtaining a full concentration-time curve of MFX for therapeutic drug

Limited-sampling strategies for therapeutic drug monitoring of moxifloxacin in patients with tuberculosis

NARCIS (Netherlands)

Pranger, A.D.; Kosterink, J.G.W.; Altena, R. van; Aarnoutse, R.E.; Werf, T.S. van der; Uges, D.R.A.; Alffenaar, J.W.C.

2011-01-01

BACKGROUND: Moxifloxacin (MFX) is a potent drug for multidrug resistant tuberculosis(TB) treatment and is also useful if first-line agents are not tolerated. Therapeutic drug monitoring may help to prevent treatment failure. Obtaining a full concentration-time curve of MFX for therapeutic drug

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

Asthma & COPD--IQPC's Second Conference.

Science.gov (United States)

Catley, Matthew C

2010-09-01

The International Quality & Productivity Center's (IQPC) Second Asthma & COPD conference, held in Philadelphia, included topics covering new therapeutic developments in the field of asthma and COPD. This conference report highlights selected presentations on mAb treatments for asthma, including targeting IL-5, IL-13, IL-9 and TNFa, CCR3 inhibitors, histamine H4 receptor inhibition, novel mouse models of COPD and inhaled antisense asthma therapies. Investigational drugs discussed include mepolizumab (GlaxoSmithKline plc), benralizumab (BioWa Inc/Kyowa Hakko Kirin Co Ltd/MedImmune LLC), AMG-317 (Amgen Inc/Takeda Bio Development Center Ltd), TPI-ASM-8 (Pharmaxis Ltd) and AIR-645 (Altair Therapeutics Inc).

Biologic activity of the novel orally bioavailable selective inhibitor of nuclear export (SINE) KPT-335 against canine melanoma cell lines

Science.gov (United States)

2014-01-01

Background Exportin 1 (XPO1, also known as CRM1), is a chaperone protein responsible for the export of over 200 target proteins out of the nucleus. The expression and activity of XPO1 is upregulated in several human cancers and its expression is also linked to the development of chemotherapy resistance. Recent studies using both human and murine cancer cell lines have demonstrated that XPO1 is a relevant target for therapeutic intervention. The present study sought to characterize the biologic activity of an orally bioavailable selective inhibitor of nuclear export (SINE), KPT-335, against canine melanoma cell lines as a prelude to future clinical trials in dogs with melanoma. Results We evaluated the effects of KPT-335 on 4 canine malignant melanoma cell lines and found that KPT-335 inhibited proliferation, blocked colony formation, and induced apoptosis of treated cells at biologically relevant concentrations of drug. Additionally, KPT-335 downregulated XPO1 protein while inducing a concomitant increase in XPO1 messenger RNA. Lastly, KPT-335 treatment of cell lines upregulated the expression of both protein and mRNA for the tumor suppressor proteins p53 and p21, and promoted their nuclear localization. Conclusions KPT-335 demonstrates biologic activity against canine melanoma cell lines at physiologically relevant doses, suggesting that KPT-335 may represent a viable treatment option for dogs with malignant melanoma. PMID:25022346

[Orthodontic Management of the Impacted Mandibular Second Molar Tooth].

Science.gov (United States)

Mah, Michael; Takada, Kenji

2016-09-01

When the mandibular permanent second molar becomes impacted, it is identified as a malocclusion that needs treatment as it often leads to unwanted complications such as caries and periodontitis of the adjacent permanent first molar. Other less common complications include root resorption of the adjacent first molar root or continued root development to be in close proximity to the inferior dental alveolar nerve. This paper seeks to differentiate various levels of severity of impaction and review treatment options that are considered clinically available for the proper management of the impacted mandibular permanent second molar. Treatment options that will be discussed in this article include timing of second molar removal for replacement by the third molar, relief of impaction via second premolar removal, surgical repositioning and the combination of third molar removal, surgical exposure and orthodontic uprighting of the impacted tooth. Depending on the severity of the impaction, most impactions can be easily and predictably corrected with nickel titanium archwires or auxillary open coil springs or uprighting springs. Uncommonly, the mandibular permanent second molar can become severely impacted and in close proximity to the inferior dentoalveolar nerve. In these instances, the use of temporary anchorage devices such as microimplants has shown to be successful in uprighting the severely impacted mandibular permanent second molars. © EDP Sciences, SFODF, 2016.

Therapeutic options for lymphangioleiomyomatosis (LAM): where we are and where we are going

Science.gov (United States)

Steagall, Wendy K; Moss, Joel

2009-01-01

Lymphangioleiomyomatosis (LAM), a multisystem disease affecting predominantly premenopausal and middle-aged women, causes progressive respiratory failure due to cystic lung destruction and is associated with lymphatic and kidney tumors. In the past, the treatment of LAM comprised exclusively anti-estrogen and related hormonal therapies. These treatments, however, have not been proven effective. In this article, we discuss new findings regarding the molecular mechanisms involved in the regulation of LAM cell growth, which may offer opportunities to develop effective and targeted therapeutic agents. PMID:20948684

Second Malignant Neoplasms and Cause of Death in Patients With Germ Cell Cancer

DEFF Research Database (Denmark)

Kier, Maria G; Hansen, Merete K; Lauritsen, Jakob

2016-01-01

radiotherapy (RT); bleomycin, etoposide, and cisplatin (BEP); or more than 1 line of treatment (MTOL). Main Outcomes and Measures: Cumulative incidence and hazard ratios (HRs) for SMN and death calculated by the Cox proportional hazards model were compared with those of age-matched controls. Results: The study......Importance: Patients given systemic treatment for testicular germ cell cancer (GCC) are at increased risk for a second malignant neoplasm (SMN). Previous studies on SMN and causes of death lacked information on the exact treatment applied or were based on patients receiving former treatment options....... Objective: To evaluate the treatment-specific risks for SMN and death in a nationwide population-based cohort of patients with GCC treated with current standard regimens. Design, Setting, and Participants: This study examined a Danish nationwide cohort of 5190 men with GCC who entered the Danish Testicular...

Surgical Options for the Refractive Correction of Keratoconus: Myth or Reality

Directory of Open Access Journals (Sweden)

L. Fernández-Vega-Cueto

2017-01-01

Full Text Available Keratoconus provides a decrease of quality of life to the patients who suffer from it. The treatment used as well as the method to correct the refractive error of these patients may influence on the impact of the disease on their quality of life. The purpose of this review is to describe the evidence about the conservative surgical treatment for keratoconus aiming to therapeutic and refractive effect. The visual rehabilitation for keratoconic corneas requires addressing three concerns: halting the ectatic process, improving corneal shape, and minimizing the residual refractive error. Cross-linking can halt the disease progression, intrastromal corneal ring segments can improve the corneal shape and hence the visual quality and reduce the refractive error, PRK can correct mild-moderate refractive error, and intraocular lenses can correct from low to high refractive error associated with keratoconus. Any of these surgical options can be performed alone or combined with the other techniques depending on what the case requires. Although it could be considered that the surgical option for the refracto-therapeutic treatment of the keratoconus is a reality, controlled, randomized studies with larger cohorts and longer follow-up periods are needed to determine which refractive procedure and/or sequence are most suitable for each case.

Second-line chemotherapy with dacarbazine and fotemustine in nitrosourea-pretreated patients with recurrent glioblastoma multiforme.

Science.gov (United States)

Fazeny-Dörner, Barbara; Veitl, Mario; Wenzel, Catharina; Piribauer, Maria; Rössler, Karl; Dieckmann, Karin; Ungersböck, Karl; Marosi, Christine

2003-07-01

The aim of this study was to assess the efficacy and toxicity of a combination of dacarbazine (D) and fotemustine (F) administered to a homogenous group of patients with recurrent or progressive glioblastoma multiforme (GBM). Thirty-one patients with computed tomography or magnetic resonance imaging scan evidence of recurrent or progressive GBM after first-line chemotherapy with nitrosoureas as well as radiation therapy were given a combination of D (200 mg/m2) and F (100 mg/m2). At 30 min after termination of D administration, F was given over 60 min. Treatment was performed in an outpatient setting every 21 days. A total of 140 cycles (range 1-12 cycles; median 4 cycles) was administered. One partial response (3%) lasting for 11 weeks was observed. Sixteen (52%) patients reached stable disease lasting between 7 and 94 weeks. Median survival from start of the D/F combination was 45 (range 10-150) weeks. Median time to progression was 17 (3-101) weeks for all patients. Major toxicity was myelosuppression resulting in exclusion from study in seven (23%) patients [due to thrombocytopenia common toxicity criteria (CTC) grade 2 persisting longer than 3 weeks in three patients, due to thrombocytopenia CTC grade >/=3 in three and due to leukopenia CTC grade 3 in one patient]. No other toxicity than alopecia occurred. We conclude that the D/F combination is a well-tolerated second-line regimen and can be administered in a complete outpatient setting. D/F shows efficacy even in nitrosourea-pretreated patients and justifies further investigation.

Second malignancies after radiotherapy for testicular seminoma: 2 cases; Seconds cancers apres radiotherapie pour seminome testiculaire: a propos de deux cas

Energy Technology Data Exchange (ETDEWEB)

Servagi-Vernat, S.; Crehange, G.; Lorchel, F.; Bontemps, P.; Bosset, J.F. [Centre Hospitalier Universitaire Jean Minjoz, Service de Radiotherapie, 25 - Besancon (France)

2006-05-15

Orchidectomy with adjuvant radiotherapy of retroperitoneal paraaortic and ipsilateral iliac nodes is the standard treatment for localized testicular seminoma (I, IIA, IIB). Post therapeutic follow-up allows to detect local relapse and radio-induced second cancer. Nevertheless, evaluation of risk of second malignancy still remains difficult. We report 2 cases of rectal cancer after radiotherapy for testicular seminoma. (authors)

Date Palm Tree (Phoenix dactylifera L.: Natural Products and Therapeutic Options

Directory of Open Access Journals (Sweden)

Reem A. Al-Alawi

2017-05-01

Full Text Available Many plants, including some of the commonly consumed herbs and spices in our daily food, can be safely and effectively used to prevent and/or treat some health concerns. For example, caffeine the active ingredient found in coffee beans (Coffea, shows biological activity in the treatment of the central nervous system (CNS disorders, indole-3-carbinol, and 3,3′-diindolylmethane are both broccoli (Brassica oleracea derived phytochemicals with potential anti-cancer activity, and resveratrol, isolated from grape (Vitis vinifera, is reported to extend lifespan and provide cardio-neuro-protective, anti-diabetic, and anti-cancer effects. Date palm fruits possess high nutritional and therapeutic value with significant antioxidant, antibacterial, antifungal, and anti-proliferative properties. This review focuses on the date fruit extracts and their benefits in individual health promoting conditions and highlights their applications as useful to the pharmaceutical and nutraceutical industries in the development of natural compound-based industrial products.

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

year were $34,141, $19,371, and $17,506 higher, respectively. Everolimus had similar OS and lower costs compared with axitinib. The additional cost per month of OS was $48,773 for cabozantinib and $24,214 for nivolumab versus everolimus. The additional treatment cost with cabozantinib, nivolumab, or axitinib versus everolimus for each additional month of PFS was estimated at $21,338, $64,570, and $35,012, respectively. Over 2 years, the additional costs per additional month of OS for nivolumab and axitinib versus everolimus were similar to the 1-year analysis; for cabozantinib, the cost was lower. Results were sensitive to changes in mean OS, mean PFS, therapy duration, and drug costs estimates. Everolimus for second-line mRCC was associated with similar OS and lower costs compared with axitinib over 1- and 2-year horizons. The additional cost per additional month of OS and PFS associated with cabozantinib or nivolumab versus everolimus creates a metric for evaluating the cost of second-line therapies in relation to their respective treatment effects. Funding for this research was provided by Novartis, which was involved in all stages of study research and manuscript preparation. Ghate and Perez are employees of Novartis and own stock/stock options. Swallow, Messali, McDonald, and Duchesneau are employees of Analysis Group, which has received consultancy fees from Novartis. Study concept and design were contributed by Swallow, Messali, Ghate, and Perez, along with McDonald and Duchesneau. Swallow, Messali, McDonald, and Duchesneau collected the data, and all authors participated in data interpretation. The manuscript was written by Swallow, Messali, and Ghate, along with the other authors, and revised by Swallow, Messali, Ghate, and Perez. A synopsis of the current research was presented in poster format at the 15th International Kidney Cancer Symposium on November 4-5, 2016, in Miami, Florida.

The efficacy and safety of Oxaliplatin-Vinorelbine as a second-line chemotherapy combination in patients with platinum-resistant pretreated epithelial ovarian cancer: A retrospective study

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Fidia Mumtahana

2014-12-01

Full Text Available Purpose: The main purpose of this study was to analyze the effects and tolerability of Oxaliplatin-Vinorelbine combination on Platinum-resistant epithelial ovarian carcinoma (EOC patients.Methods: A single centered retrospective study comprising of 34 patients was conducted, and all 34 patients were treated with Vinorelbine 30 mg/m2 on day 1 and 8 along with Oxaliplatin 100 mg/m2 on day 1 of 3 weeks treatment cycle following progressive platinum-resistant EOC. Results: The combination showed an overall response rate (ORR of 18% (95% CI, 4.4 - 31.6 where 2 (6% patients had complete response and 4 (12% patients had partial response. Stable disease was observed in 9 (26% patients and progressive disease in 19 (56% patients. Median diseases free survival, median relapse free survival and median time to progression was 17.05 months, 4.4 months, and 1.25 months, respectively. Hematological toxicities were mild; only 1 (2.9% patient had G3 anemia and major non-hematological toxicities include nausea-vomiting, diarrhea, constipation, hepatotoxicity, fatigueness and alopecia, which are mainly limited to G1-G2 and reversible. Conclusion: The effect of this combination is moderate as a second line treatment of platinum resistant EOC; however, in comparison with other regimens of Vinorelbine and Oxaliplatin, the activity is substandard but the toxicity profile is well tolerable. Further multicenter evaluation is needed for the better understanding of the therapeutic efficacy of the combination.

Renal Artery Embolization - A First Line Treatment Option For End-Stage Hydronephrosis

International Nuclear Information System (INIS)

Mitra, Kakali; Prabhudesai, Vikramaditya; James, R. Lester; Jones, Robert W. A.; French, Michael E.; Cowling, Mark; West, David J.

2004-01-01

Conventionally poorly functioning hydronephrotic kidneys have been removed if they are symptomatic. In our unit, patients are offered renal artery embolization as an alternative treatment option. Patients and Methods: Fifteen patients (11 male, 4 female) with a mean age of 32.9 yr (20-51 yrs) have undergone renal artery embolization for symptomatic hydronephrosis with poor function. Mean follow-up was 64.13 weeks (range 14-200). All patients had loin pain and hydronephrosis. Twelve patients had primary pelvi-ureteric junction obstruction (PUJO). Two patients had poorly functioning hydronephrotic kidneys secondary to chronic calculous obstruction. One patient had chronic pain in an obstructed but reasonably functioning kidney following a previous pyeloplasty for PUJO which demanded intervention. Mean split function on renography was 11% (range 0-46%). Selective renal artery embolization was carried out under antibiotic cover using a 7 Fr balloon occlusion catheter and absolute alcohol, steel coils, and polyvinyl alcohol particles.Results: Nine patients developed post-embolization syndrome of self-limiting pain and pyrexia with no evidence of sepsis. One patient required readmission with this condition. One patient developed a hematoma at the puncture site. Mean hospital stay was 2.3 days. Fourteen patients are happy with the result and are completely pain free. One patient has minor discomfort but is delighted with the result. Nine patients have had follow-up ultrasound confirming resolution of the hydronephrosis. Conclusion: Renal artery embolization is an effective, safe, well-tolerated minimally invasive treatment option in end-stage hydronephrosis and we routinely offer it as an alternative to nephrectomy

Do follow-on therapeutic substitutes induce price competition between hospital medicines? Evidence from the Danish hospital sector

DEFF Research Database (Denmark)

Hostenkamp, Gisela

2013-01-01

Objective The pricing of follow-on drugs, that offer only limited health benefits over existing therapeutic alternatives, is a recurring health policy debate. This study investigates whether follow-on therapeutic substitutes create price competition between branded hospital medicines. Methods New...... pioneer products were significantly reduced as a reaction to competition from follow-on drugs. Conclusion Competition between patented therapeutic substitutes did not seem to increase price competition and containment of pharmaceutical expenditures in the Danish hospital market. Strengthening hospitals......’ incentives to consider the price of alternative treatment options paired with a more active formulary management may increase price competition between therapeutic substitutes in the Danish hospital sector in the future....

Quantitative Analysis of Therapeutic Drugs in Dried Blood Spot Samples by Paper Spray Mass Spectrometry: An Avenue to Therapeutic Drug Monitoring

Science.gov (United States)

Manicke, Nicholas Edward; Abu-Rabie, Paul; Spooner, Neil; Ouyang, Zheng; Cooks, R. Graham

2011-09-01

A method is presented for the direct quantitative analysis of therapeutic drugs from dried blood spot samples by mass spectrometry. The method, paper spray mass spectrometry, generates gas phase ions directly from the blood card paper used to store dried blood samples without the need for complex sample preparation and separation; the entire time for preparation and analysis of blood samples is around 30 s. Limits of detection were investigated for a chemically diverse set of some 15 therapeutic drugs; hydrophobic and weakly basic drugs, such as sunitinib, citalopram, and verapamil, were found to be routinely detectable at approximately 1 ng/mL. Samples were prepared by addition of the drug to whole blood. Drug concentrations were measured quantitatively over several orders of magnitude, with accuracies within 10% of the expected value and relative standard deviation (RSD) of around 10% by prespotting an internal standard solution onto the paper prior to application of the blood sample. We have demonstrated that paper spray mass spectrometry can be used to quantitatively measure drug concentrations over the entire therapeutic range for a wide variety of drugs. The high quality analytical data obtained indicate that the technique may be a viable option for therapeutic drug monitoring.

Second-line therapy with levofloxacin after failure of treatment to eradicate helicobacter pylori infection: time trends in a Spanish Multicenter Study of 1000 patients.

Science.gov (United States)

Gisbert, Javier P; Pérez-Aisa, Angeles; Bermejo, Fernando; Castro-Fernández, Manuel; Almela, Pedro; Barrio, Jesús; Cosme, Angel; Modolell, Inés; Bory, Felipe; Fernández-Bermejo, Miguel; Rodrigo, Luis; Ortuño, Jesús; Sánchez-Pobre, Pilar; Khorrami, Sam; Franco, Alejandro; Tomas, Albert; Guerra, Iván; Lamas, Eloisa; Ponce, Julio; Calvet, Xavier

2013-02-01

Second-line bismuth-containing quadruple therapy is complex and frequently induces adverse effects. A triple rescue regimen containing levofloxacin is a potential alternative; however, resistance to quinolones is rapidly increasing. To evaluate the efficacy and tolerability of a second-line triple-regimen-containing levofloxacin in patients whose Helicobacter pylori eradication treatment failed and to assess whether the efficacy of the regimen decreases with time. Prospective multicenter study. In whom treatment with a regimen comprising a proton-pump inhibitor, clarithromycin, and amoxicillin had failed. Levofloxacin (500 mg bid), amoxicillin (1 g bid), and omeprazole (20 mg bid) for 10 days. Eradication was confirmed using the C-urea breath test 4 to 8 weeks after therapy. Compliance/tolerance: Compliance was determined through questioning and recovery of empty medication envelopes. Incidence of adverse effects was evaluated by means of a questionnaire. The study sample comprised 1000 consecutive patients (mean age, 49 ± 15 y, 42% men, 33% peptic ulcer) of whom 97% took all medications correctly. Per-protocol and intention-to-treat eradication rates were 75.1% (95% confidence interval, 72%-78%) and 73.8% (95% confidence interval, 71%-77%). Efficacy (intention-to-treat) was 76% in the year 2006, 68% in 2007, 70% in 2008, 76% in 2009, 74% in 2010, and 81% in 2011. In the multivariate analysis, none of the studied variables (including diagnosis and year of treatment) were associated with success of eradication. Adverse effects were reported in 20% of patients, most commonly nausea (7.9%), metallic taste (3.9%), myalgia (3.1%), and abdominal pain (2.9%). Ten-day levofloxacin-containing therapy is an encouraging second-line strategy, providing a safe and simple alternative to quadruple therapy in patients whose previous standard triple therapy has failed. The efficacy of this regimen remains stable with time.

Clinically Relevant Anticancer Polymer Paclitaxel Therapeutics

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Danbo Yang

2010-12-01

Full Text Available The concept of utilizing polymers in drug delivery has been extensively explored for improving the therapeutic index of small molecule drugs. In general, polymers can be used as polymer-drug conjugates or polymeric micelles. Each unique application mandates its own chemistry and controlled release of active drugs. Each polymer exhibits its own intrinsic issues providing the advantage of flexibility. However, none have as yet been approved by the U.S. Food and Drug Administration. General aspects of polymer and nano-particle therapeutics have been reviewed. Here we focus this review on specific clinically relevant anticancer polymer paclitaxel therapeutics. We emphasize their chemistry and formulation, in vitro activity on some human cancer cell lines, plasma pharmacokinetics and tumor accumulation, in vivo efficacy, and clinical outcomes. Furthermore, we include a short review of our recent developments of a novel poly(L-g-glutamylglutamine-paclitaxel nano-conjugate (PGG-PTX. PGG-PTX has its own unique property of forming nano-particles. It has also been shown to possess a favorable profile of pharmacokinetics and to exhibit efficacious potency. This review might shed light on designing new and better polymer paclitaxel therapeutics for potential anticancer applications in the clinic.

Clinically Relevant Anticancer Polymer Paclitaxel Therapeutics

International Nuclear Information System (INIS)

Yang, Danbo; Yu, Lei; Van, Sang

2010-01-01

The concept of utilizing polymers in drug delivery has been extensively explored for improving the therapeutic index of small molecule drugs. In general, polymers can be used as polymer-drug conjugates or polymeric micelles. Each unique application mandates its own chemistry and controlled release of active drugs. Each polymer exhibits its own intrinsic issues providing the advantage of flexibility. However, none have as yet been approved by the U.S. Food and Drug Administration. General aspects of polymer and nano-particle therapeutics have been reviewed. Here we focus this review on specific clinically relevant anticancer polymer paclitaxel therapeutics. We emphasize their chemistry and formulation, in vitro activity on some human cancer cell lines, plasma pharmacokinetics and tumor accumulation, in vivo efficacy, and clinical outcomes. Furthermore, we include a short review of our recent developments of a novel poly(l-γ-glutamylglutamine)-paclitaxel nano-conjugate (PGG-PTX). PGG-PTX has its own unique property of forming nano-particles. It has also been shown to possess a favorable profile of pharmacokinetics and to exhibit efficacious potency. This review might shed light on designing new and better polymer paclitaxel therapeutics for potential anticancer applications in the clinic

Clinically Relevant Anticancer Polymer Paclitaxel Therapeutics

Energy Technology Data Exchange (ETDEWEB)

Yang, Danbo [Biomedical Engineering and Technology Institute, Institutes for Advanced Interdisciplinary Research, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062 (China); Yu, Lei, E-mail: yu-lei@gg.nitto.co.jp [Biomedical Engineering and Technology Institute, Institutes for Advanced Interdisciplinary Research, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062 (China); Biomedical Group, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92058 (United States); Van, Sang [Biomedical Group, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92058 (United States)

2010-12-23

The concept of utilizing polymers in drug delivery has been extensively explored for improving the therapeutic index of small molecule drugs. In general, polymers can be used as polymer-drug conjugates or polymeric micelles. Each unique application mandates its own chemistry and controlled release of active drugs. Each polymer exhibits its own intrinsic issues providing the advantage of flexibility. However, none have as yet been approved by the U.S. Food and Drug Administration. General aspects of polymer and nano-particle therapeutics have been reviewed. Here we focus this review on specific clinically relevant anticancer polymer paclitaxel therapeutics. We emphasize their chemistry and formulation, in vitro activity on some human cancer cell lines, plasma pharmacokinetics and tumor accumulation, in vivo efficacy, and clinical outcomes. Furthermore, we include a short review of our recent developments of a novel poly(l-γ-glutamylglutamine)-paclitaxel nano-conjugate (PGG-PTX). PGG-PTX has its own unique property of forming nano-particles. It has also been shown to possess a favorable profile of pharmacokinetics and to exhibit efficacious potency. This review might shed light on designing new and better polymer paclitaxel therapeutics for potential anticancer applications in the clinic.

Pharmacophore-based screening of differentially-expressed PGF, DDIT4, COMP and CHI3L1 from hMSC cell lines reveals five novel therapeutic compounds for primary osteoporosis

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Catherine Jessica Lai

2016-06-01

Full Text Available As many societies age, primary osteoporosis (PO is increasingly a major health problem. Current drug treatments such as alendronate and risedronate have known side effects. We took an agnostic empirical approach to find PO therapeutic compounds. We examined 13,548,960 probe data-points from mesenchymal stromal cell (hMSC lines and found that PGF, DDIT4, and COMP to be up-regulated, and CHI3L1, down-regulated. We then identified their druggable domains. For the up-regulated differentially-expressed genes, we used protein–protein interactions to find residue clusters as binding surfaces. We then employed pharmacophore models to screen 15,407,096 conformations of 22,723,923 compounds, which identified (6R,9R-6-(2-furyl-9-(1H-indol-3-yl-2-(trifluoromethyl-5,6,7, 9-tetrahydro-4H[1,2,4]triazolo[5,1],(2S-N1-[2-[2-(methylamino-2-oxo-ethyl]phenyl]-N2-phenylpyrrolidine-1,2-dicarboxamide, and 2-furyl-(1H-indol-3-yl-methyl-BLAHone as candidate compounds. For the down-regulated CH13L1, we relied on genome-wide disease signatures to identify (11alpha-9-fluoro-11,17,21-trihydroxypregn-4-ene-3,20-dione and Genistein as candidate compounds. Our approach differs from previous research as we did not confine our drug targets to hypothesized compounds in the existing literature. Instead, we allowed the full expression profile of PO cell lines to reveal the most desirable targets. Second, our differential gene analysis revealed both up- and down-regulated genes, in contrast to the literature, which has focused on inhibiting only up-regulated genes. Third, our virtual screening universe of 22,723,923 compounds was more than 100 times larger than those in the known literature.

Pricing Vulnerable Options with Market Prices of Common Jump Risks under Regime-Switching Models

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Miao Han

2018-01-01

Full Text Available This paper investigates the valuation of vulnerable European options considering the market prices of common systematic jump risks under regime-switching jump-diffusion models. The way of regime-switching Esscher transform is adopted to identify an equivalent martingale measure for pricing vulnerable European options. Explicit analytical pricing formulae for vulnerable European options are derived by risk-neutral pricing theory. For comparison, the other two cases are also considered separately. The first case considers all jump risks as unsystematic risks while the second one assumes all jumps risks to be systematic risks. Numerical examples for the valuation of vulnerable European options are provided to illustrate our results and indicate the influence of the market prices of jump risks on the valuation of vulnerable European options.

Novel therapeutic approaches in chondrosarcoma.

Science.gov (United States)

Polychronidou, Genovefa; Karavasilis, Vasilios; Pollack, Seth M; Huang, Paul H; Lee, Alex; Jones, Robin L

2017-03-01

Chondrosarcoma is a malignant tumor of bones, characterized by the production of cartilage matrix. Due to lack of effective treatment for advanced disease, the clinical management of chondrosarcomas is exceptionally challenging. Current research focuses on elucidating the molecular events underlying the pathogenesis of this rare bone malignancy, with the goal of developing new molecularly targeted therapies. Signaling pathways suggested to have a role in chondrosarcoma include Hedgehog, Src, PI3k-Akt-mTOR and angiogenesis. Mutations in IDH1/2, present in more than 50% of primary conventional chondrosarcomas, make the development of IDH inhibitors a promising treatment option. The present review discusses the preclinical and early clinical data on novel targeted therapeutic approaches in chondrosarcoma.

Biofeedback as complementary treatment in patients with epilepsy – an underestimated therapeutic option? Review, results, discussion

Directory of Open Access Journals (Sweden)

Uhlmann Carmen

2016-12-01

Full Text Available Background. Biofeedback methods represent side effect free complementary options in the treatment of epilepsy. In this paper we review the current status of these methods in terms of clinical study results and their evaluation by systematic review papers. Possible mechanisms of action in biofeedback methods are discussed.

Split high-dose oral levothyroxine treatment as a successful therapy option in myxedema coma.

Science.gov (United States)

Charoensri, Suranut; Sriphrapradang, Chutintorn; Nimitphong, Hataikarn

2017-10-01

High-dose intravenous thyroxine (T4) is the preferable treatment for myxedema coma. We describe the clinical course of a 69-year-old man who presented with myxedema coma and received oral levothyroxine (LT4) therapy (1 mg) in a split dose. This suggests split high-dose oral LT4 as a therapeutic option in myxedema coma.

Harnessing natural product assembly lines: structure, promiscuity, and engineering.

Science.gov (United States)

Ladner, Christopher C; Williams, Gavin J

2016-03-01

Many therapeutically relevant natural products are biosynthesized by the action of giant mega-enzyme assembly lines. By leveraging the specificity, promiscuity, and modularity of assembly lines, a variety of strategies has been developed that enables the biosynthesis of modified natural products. This review briefly summarizes recent structural advances related to natural product assembly lines, discusses chemical approaches to probing assembly line structures in the absence of traditional biophysical data, and surveys efforts that harness the inherent or engineered promiscuity of assembly lines for the synthesis of non-natural polyketides and non-ribosomal peptide analogues.

Process to identify and evaluate restoration options

International Nuclear Information System (INIS)

Strand, J.; Senner, S.; Weiner, A.; Rabinowitch, S.; Brodersen, M.; Rice, K.; Klinge, K.; MacMullin, S.; Yender, R.; Thompson, R.

1993-01-01

The restoration planning process has yielded a number of possible alternatives for restoring resources and services injured by the Exxon Valdez oil spill. They were developed by resource managers, scientists, and the public, taking into consideration the results of damage assessment and restoration studies and information from the scientific literature. The alternatives thus far identified include no action natural recovery, management of human uses, manipulation of resources, habitat protection and acquisition, acquisition of equivalent resources, and combinations of the above. Each alternative consists of a different mix of resource- or service-specific restoration options. To decide whether it was appropriate to spend restoration funds on a particular resource or service, first criteria had to be developed that evaluated available evidence for consequential injury and the adequacy and rate of natural recovery. Then, recognizing the range of effective restoration options, a second set of criteria was applied to determine which restoration options were the most beneficial. These criteria included technical feasibility, potential to improve the rate or degree of recovery, the relationship of expected costs to benefits, cost effectiveness, and the potential to restore the ecosystem as a whole. The restoration options considered to be most beneficial will be grouped together in several or more of the above alternatives and presented in a draft restoration plan. They will be further evaluated in a companion draft environmental impact statement

Second-Line Intraperitoneal Chemotherapy for Recurrent Epithelial Ovarian, Tubal and Peritoneal Cancer: A Propensity Score-Matching Study.

Science.gov (United States)

Lu, Chien-Hsing; Chang, Yen-Hou; Lee, Wai-Hou; Chang, Yi; Peng, Chia-Wen; Chuang, Chi-Mu

2016-01-01

The superiority of frontline intraperitoneal (IP) over intravenous (IV) chemotherapy is well established in the treatment of epithelial ovarian cancer. However, the role of IP chemotherapy in the second-line setting has rarely been investigated. Consecutive patients diagnosed with recurrent epithelial, tubal and peritoneal cancers between January 2000 and December 2012 were recruited using a propensity score-matching technique to adjust relevant risk factors. In total, 310 patients were included in the final analysis (94 for platinum-refractory/resistant disease and 216 for platinum-sensitive disease). IP chemotherapy demonstrated significantly longer median progression-free survival than IV chemotherapy (4.9 vs. 2.4 months, p chemotherapy confers longer progression-free survival than IV chemotherapy. Large-scale clinical trials should be conducted to validate the true efficacy. © 2016 S. Karger AG, Basel.

Therapeutic effects of different durations of acupuncture on rats with middle cerebral artery occlusion

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Chao Zhang

2015-01-01

Full Text Available Acupuncture is regarded as an effective therapy for cerebral ischemia. Different acupuncture manipulations and durations may result in different therapeutic effects. In the present study, the Neiguan (PC6 acupoint of rats with occluded middle cerebral arteries was needled at a fixed frequency (3 Hz with different durations, i.e., 5, 60 and 180 seconds under a twisting-rotating acupuncture method. Results showed that different durations of acupuncture had different therapeutic effects, with 60 seconds yielding a better therapeutic effect than the other two groups. This duration of treatment demonstrated rapid cerebral blood flow, encouraging recovery of neurological function, and small cerebral infarct volume. Experimental findings indicated that under 3 Hz frequency, the treatment of needling Neiguan for 60 seconds is effective for ischemic stroke

Topical kanamycin: an effective therapeutic option in aerobic vaginitis.

Science.gov (United States)

Tempera, G; Abbadessa, G; Bonfiglio, G; Cammarata, E; Cianci, A; Corsello, S; Raimondi, A; Ettore, G; Nicolosi, D; Furneri, P M

2006-08-01

Eighty-one patients with clinical diagnosis of aerobic vaginitis (AV) were included in the study. The patients were randomized for treatment, 45 with kanamycin (100 mg vaginal ovules for 6 days, consecutively) and 36 with meclocycline (35 mg vaginal ovules for 6 days, consecutively). The patients were examined before starting the study, 1-2 days after treatment and 30 days after the end of the study. At the first follow-up the patients showed different levels of symptom reduction. Reduction in the presence of leukocytes, vaginal mucosa burning and itching were statistically significant in the group treated with kanamycin with respect to the group treated with meclocycline. Moreover, there was also reduced isolation of Enterobacteriaeae (97%) in the group treated with kanamycin versus those treated with meclocycline (76%). At the second follow-up, vaginal homeostasis (normalization of pH and presence of lactobacilli) was more evident in the kanamycin-treated group. In conclusion, our data suggest that the topical use of kanamycin could be considered a specific antibiotic for the therapy of this new pathology.

Binge-eating disorder: Clinical and therapeutic advances.

Science.gov (United States)

Hutson, Peter H; Balodis, Iris M; Potenza, Marc N

2018-02-01

Binge-eating disorder (BED) is the most prevalent eating disorder with estimates of 2-5% of the general adult population. Nonetheless, its pathophysiology is poorly understood. Furthermore, there exist few therapeutic options for its effective treatment. Here we review the current state of binge-eating neurobiology and pharmacology, drawing from clinical therapeutic, neuroimaging, cognitive, human genetic and animal model studies. These studies, which are still in their infancy, indicate that while there are many gaps in our knowledge, several key neural substrates appear to underpin binge-eating and may be conserved between human and animals. This observation suggests that behavioral intermediate phenotypes or endophenotypes relevant to BED may be modeled in animals, facilitating the identification and testing of novel pharmacological targets. The development of novel, safe and effective pharmacological therapies for the treatment of BED will enhance the ability of clinicians to provide optimal care for people with BED. Copyright © 2017 Elsevier Inc. All rights reserved.

Dry eye syndrome. Etiological and therapeutic aspects.

Science.gov (United States)

Apostol, Silvia; Filip, M; Dragne, Carmen; Filip, A

2003-01-01

"Dry eye syndrome" is a common disorder of the tear film that results from inadequate tear production, excessive tear evaporation or abnormality in mucin or lipid components of the tear film. A number of 53 patients suffering from dry eye syndrome were followed up for a period of 18 months. The study group was heterogeneous, including a lot of conditions accompanied by dry eye syndrome: Syogren's syndrome, lupus erythematous, ocular rosacea, patients with systemic treatments with antidepressants, betablockers, diuretics, oral contraceptives, glaucomatous patients with topical beta-blockers, postmenopausal women, aging people, computer users and long-term contact lens wearers. The therapeutical options were dictated by the severity of the syndrome: substitution therapy, treatment of the underlying eyelid diseases, modifying of the environmental conditions and treatment of the complications in the most severe cases. The new pathological approach is innovative and it may provide a real therapeutical measure for this condition: topical A Cyclosporine and androgen drops.

A Proposed Solution for the Chicken-Egg Dilemma in Pricing Currency Options

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Ariful Hoque

2013-06-01

Full Text Available The implied volatility (IV estimation process suffers from an obvious chicken-egg dilemma: obtaining an unbiased IV requires the options to be priced correctly and calculating an accurate option price (OP requires an unbiased IV. We address this critical issue in two steps. First, the Granger causality test is employed, whichconfirms the chicken-and-egg problem in the IV computing process. Secondly, the concept of “moneyness volatility (MV” is introduced as an alternative to IV. MV is modelled based on an option’s moneyness (OM during the life of the option’s contract. The F-test, Granger-Newbold test and Diebold-Mariano test results consistently show that MV outperforms IV in estimating the exchange rate volatility for pricing options. Further, these series of tests across six major currency options substantiate the validity as well as the reliability of the results. We posit that MV offers a unique solution for pricing currency options accurately.

SGLT2 inhibitors provide an effective therapeutic option for diabetes complicated with insulin antibodies.

Science.gov (United States)

Hayashi, Akinori; Takano, Koji; Kawai, Sayuki; Shichiri, Masayoshi

2016-01-01

Diabetes mellitus complicated with insulin antibodies is rare in clinical practice but usually difficult to control. A high amount of insulin antibodies, especially with low affinity and high binding capacity, leads to unstable glycemic control characterized by hyperglycemia unresponsive to large volume of insulin and unanticipated hypoglycemia. There are several treatment options, such as changing insulin preparation, immunosupression with glucocorticoids, and plasmapheresis, most of which are of limited efficacy. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of drug which decrease renal glucose reabsorption and lowers plasma glucose level independent of insulin action. We report here a case with diabetes complicated with insulin antibodies who was effectively controlled by an SGLT2 inhibitor. A 47-year-old man with type 2 diabetes treated with insulin had very poor glycemic control characterized by postprandial hyperglycemia unresponsive to insulin therapy and repetitive hypoglycemia due to insulin antibodies. Treatment with ipragliflozin, an SGLT2 inhibitor, improved HbA1c from 8.4% to 6.0% and glycated albumin from 29.4% to 17.9%. Continuous glucose monitoring revealed improvement of glycemic profile (average glucose level from 212 mg/dL to 99 mg/dL and glycemic standard deviation from 92 mg/dL to 14 mg/dL) with disappearance of hypoglycemic events. This treatment further ameliorated the characteristics of insulin antibodies and resulted in reduced insulin requirement. SGLT2 inhibitors may offer an effective treatment option for managing the poor glycemic control in diabetes complicated with insulin antibodies.

Options for rural electrification in Arua District, Uganda

International Nuclear Information System (INIS)

Onzia, Joseph; Núñez Bosch, Osvaldo Manuel

2015-01-01

This study proposed a power generation system suitable for rural area application. The electrification options were proposed for secondary schools, health centres, households and trading centre loads using solar PV system, diesel fired generators, biogas co-fired diesel generators and grid extension. The study is based on simulation, modeling and optimization of renewable energy system. Designs for the options considered were based on the electricity demand and environmental conditions of Arua district. From the designs, capital costs for each option were determined. This was used in carrying out simulations in HOMER computer program to come up with the most cost effective options. Sensitivity analysis was carried out to determine the effects of variation in costs such as diesel price and capital cost of solar PV system.Based on simulation results, it has been found that the trading centre, with 500 kW of electrical demand, must be electrified using the grid extension. The breakeven grid distance is 75.1 km. Grid extension become cost effective compared to diesel generators and solar PV system within this distance. The load at household level ranges from as low as 16 W to 5 kW. For 103 W peak load, the most cost effective option was solar PV system. The second best option was biogas co-fired diesel generator. For schools and health centres with load of up to 15 kW, biogas co-fired generator is the best compared to the total cost of 18 kW diesel fired generator which is higher. Therefore, where biogas cannot be generated, diesel generators should be used. Based on the amount of pollutants produced, a biogas co-fired diesel generator is the best option. (full text)

Trend of extensively drug-resistant Acinetobacter baumannii and the remaining therapeutic options: a multicenter study in Tehran, Iran over a 3-year period.

Science.gov (United States)

Jasemi, S; Douraghi, M; Adibhesami, H; Zeraati, H; Rahbar, M; Boroumand, M A; Aliramezani, A; Ghourchian, S; Mohammadzadeh, M

2016-12-01

Comprehensive data on drug-resistant patterns of Acinetobacter baumannii isolates in developing countries is limited. We conducted a multihospital study to assess the rate and trend of drug-resistant phenotypes in Ac. baumannii using standardized definitions and to determine the remaining therapeutic options against resistant phenotypes. The 401 nonduplicate isolates were collected from six hospitals which are geographically distributed across Tehran, Iran over a 3-year period. Following PCR of bla OXA -51-like gene, susceptibility testing was performed against nine antimicrobial agent categories. Three hundred and ninety (97%) isolates were resistant to least two carbapenems; carbapenem-resistant Ac. baumannii. The majority of isolates (366, 91·3%) were extensively drug resistant (XDR) and the rest of the isolates were classified as multidrug resistant (26, 6·8%) and susceptible (9, 2·2%). The rate of XDR-AB slightly decreased from 93·8% in 2011 to 89·8% in 2013. A considerable decrease in resistance to doxycycline, minocycline and tigecycline was demonstrated. The XDR-AB isolates showed susceptibility to gentamicin (10·4%), tobramycin (23%), ampicilin-sulbactam (30·1%), minocycline (32·8%), tigecycline (10·7%), doxycycline (21·6%), colistin (100%) and polymixin B (100%). We demonstrated the rising trend of resistance to all antibiotic categories except tetracyclines and folate pathway inhibitors. We found that the treatment options against XDR-AB are extremely limited and each treatment alternative including even old, but safe, antibiotics might be considered. The high frequency of drug-resistant phenotypes including carbapenem-resistant Acinetobacter baumannii, multidrug-resistant, and extensively resistant has been demonstrated in Ac. baumannii isolates tested here. As the antibiotic resistance pattern of isolates varies in different geographical regions, this study can provide comprehensive information about the antibiotic resistance profile of Ac

Impact of Nuclear Energy Futures on Advanced Fuel Cycle Options

International Nuclear Information System (INIS)

Dixon, B.W.; Piet, S.J.

2004-01-01

The Nuclear Waste Policy Act requires the Secretary of Energy to inform Congress before 2010 on the need for a second geologic repository for spent nuclear fuel. By that time, the spent fuel discharged from current commercial reactors will exceed the statutory limit of the first repository. There are several approaches to eliminate the need for another repository in this century. This paper presents a high-level analysis of these spent fuel management options in the context of a full range of possible nuclear energy futures. The analysis indicates the best option to implement varies depending on the nuclear energy future selected

Innovative thin silicon detectors for monitoring of therapeutic proton beams: preliminary beam tests

Science.gov (United States)

Vignati, A.; Monaco, V.; Attili, A.; Cartiglia, N.; Donetti, M.; Fadavi Mazinani, M.; Fausti, F.; Ferrero, M.; Giordanengo, S.; Hammad Ali, O.; Mandurrino, M.; Manganaro, L.; Mazza, G.; Sacchi, R.; Sola, V.; Staiano, A.; Cirio, R.; Boscardin, M.; Paternoster, G.; Ficorella, F.

2017-12-01

To fully exploit the physics potentials of particle therapy in delivering dose with high accuracy and selectivity, charged particle therapy needs further improvement. To this scope, a multidisciplinary project (MoVeIT) of the Italian National Institute for Nuclear Physics (INFN) aims at translating research in charged particle therapy into clinical outcome. New models in the treatment planning system are being developed and validated, using dedicated devices for beam characterization and monitoring in radiobiological and clinical irradiations. Innovative silicon detectors with internal gain layer (LGAD) represent a promising option, overcoming the limits of currently used ionization chambers. Two devices are being developed: one to directly count individual protons at high rates, exploiting the large signal-to-noise ratio and fast collection time in small thicknesses (1 ns in 50 μm) of LGADs, the second to measure the beam energy with time-of-flight techniques, using LGADs optimized for excellent time resolutions (Ultra Fast Silicon Detectors, UFSDs). The preliminary results of first beam tests with therapeutic beam will be presented and discussed.

[Immune checkpoint inhibitors (antibodies to PD1 and PD-L1), a new therapeutic weapon against non-small cell bronchial carcinoma].

Science.gov (United States)

Berghmans, T; Grigoriu, B; Sculier, J P; Meert, A P

2018-02-01

Classical therapeutic strategy for advanced and metastatic non-small cell lung cancer, without activable oncogenic driver mutation, has been based mainly on cytotoxic chemotherapy with modest benefits in terms of increased survival. A better understanding of the mechanisms involved in the regulation of the immune system led to the development of antibodies directed against immune checkpoints such as PD-L1. The first encouraging clinical data from phase I studies assessing anti-PD1 and anti-PD-L1 antibodies have been confirmed in randomised phase III trials. These new drugs now constitute a standard second-line treatment for metastatic tumours and in the future, at least for pembrolizumab, in the first line. Their adjuvant role after locoregional treatment with curative intent is currently under investigation. Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Myocardial Energetics and Heart Failure: a Review of Recent Therapeutic Trials.

Science.gov (United States)

Bhatt, Kunal N; Butler, Javed

2018-06-01

Several novel therapeutics being tested in patients with heart failure are based on myocardial energetics. This review will provide a summary of the recent trials in this area, including therapeutic options targeting various aspects of cellular and mitochondrial metabolism. Agents that improve the energetic balance in myocardial cells have the potential to improve clinical heart failure status. The most promising therapies currently under investigation in this arena include (1) elamipretide, a cardiolipin stabilizer; (2) repletion of iron deficiency with intravenous ferrous carboxymaltose; (3) coenzyme Q10; and (4) the partial adenosine receptor antagonists capadenoson and neladenosone. Myocardial energetics-based therapeutics are groundbreaking in that they utilize novel mechanisms of action to improve heart failure symptoms, without causing the adverse neurohormonal side effects associated with current guideline-based therapies. The drugs appear likely to be added to the heart failure therapy armamentarium as adjuncts to current regimens in the near future.

Exotic Options: a Chooser Option and its Pricing

Directory of Open Access Journals (Sweden)

Raimonda Martinkutė-Kaulienė

2012-12-01

Full Text Available Financial instruments traded in the markets and investors’ situation in such markets are getting more and more complex. This leads to more complex derivative structures used for hedging that are harder to analyze and which risk is harder managed. Because of the complexity of these instruments, the basic characteristics of many exotic options may sometimes be not clearly understood. Most scientific studies have been focused on developing models for pricing various types of exotic options, but it is important to study their unique characteristics and to understand them correctly in order to use them in proper market situations. The paper examines main aspects of options, emphasizing the variety of exotic options and their place in financial markets and risk management process. As the exact valuation of exotic options is quite difficult, the article deals with the theoretical and practical aspects of pricing of chooser options that suggest a broad range of usage and application in different market conditions. The calculations made in the article showed that the price of the chooser is closely correlated with the choice time and low correlated with its strike price. So the first mentioned factor should be taken into consideration when making appropriate hedging and investing decisions.

Split high‐dose oral levothyroxine treatment as a successful therapy option in myxedema coma

OpenAIRE

Charoensri, Suranut; Sriphrapradang, Chutintorn; Nimitphong, Hataikarn

2017-01-01

Key Clinical Message High‐dose intravenous thyroxine (T4) is the preferable treatment for myxedema coma. We describe the clinical course of a 69‐year‐old man who presented with myxedema coma and received oral levothyroxine (LT4) therapy (1 mg) in a split dose. This suggests split high‐dose oral LT4 as a therapeutic option in myxedema coma.

Treatment options for diabetic foot osteomyelitis.

Science.gov (United States)

Senneville, Eric; Robineau, Olivier

2017-06-01

Diabetic foot osteomyelitis therapeutical options are based on antibiotic therapy and surgical resection of the infected bone(s). Surgical and medical approaches of patients suffering from a diabetic foot osteomyelitis do not oppose but are complementary and need to be discussed as a tailored manner. Areas covered: The aim of the present article is to discuss data issued from the most recent guidelines of the Infectious Diseases Society of America and the International Working Group on the Diabetic Foot on the management of the diabetic foot infection and from a search in the current literature using the terms diabetic foot osteomyelitis and treatment/therapy/therapeutical in both PubMed and Medline, restricted to the last five years. Expert opinion: Surgical removal of the entire infected bone(s) has been considered in the past as the standard treatment but medical approach of these patients has now proven efficacy in selected situations. The current emergence of bacteria, especially among Gram negative rods, resistant to almost all the available antibiotics gradually augments the complexity of the management of these patients and is likely to decrease the place of the medical approach and to worsen the outcome of these infections in the next future.

The Novel IκB Kinase β Inhibitor, IMD-0560, Has Potent Therapeutic Efficacy in Ovarian Cancer Xenograft Model Mice.

Science.gov (United States)

Sawada, Ikuko; Hashimoto, Kae; Sawada, Kenjiro; Kinose, Yasuto; Nakamura, Koji; Toda, Aska; Nakatsuka, Erika; Yoshimura, Akihiko; Mabuchi, Seiji; Fujikawa, Tomoyuki; Itai, Akiko; Kimura, Tadashi

2016-05-01

Aberrant activation of nuclear factor-kappa β (NF-κB) signaling has been correlated with poor outcome among patients with ovarian cancer. Although the therapeutic potential of NF-κB pathway disruption in cancers has been extensively studied, most classical NF-κB inhibitors are poorly selective, exhibit off-target effects, and have failed to be applied in clinical use. IMD-0560, N-[2,5-bis (trifluoromethyl) phenyl]-5-bromo-2-hydroxybenzamide, is a novel low-molecular-weight compound that selectively inhibits the IκB kinase complex and works as an inhibitor of NF-κB signaling. The aim of this study was to assess the therapeutic potential of IMD-0560 against ovarian cancer in vitro and in vivo. NF-κB activity (phosphorylation) was determined in 9 ovarian cancer cell lines and the inhibitory effect of IMD-0560 on NF-κB activation was analyzed by Western blotting. Cell viability, cell cycle, vascular endothelial growth factor (VEGF) expression, and angiogenesis were assessed in vitro to evaluate the effect of IMD-0560 on ovarian cancer cells. In vivo efficacy of IMD-0560 was also investigated using an ovarian cancer xenograft mouse model. The NF-κB signaling pathway was constitutively activated in 8 of 9 ovarian cancer cell lines. IMD-0560 inhibited NF-κB activation and suppressed ovarian cancer cell proliferation by inducing G1 phase arrest. IMD-0560 decreased VEGF secretion from cancer cells and inhibited the tube formation of human umbilical vein endothelial cells. IMD-0560 significantly inhibited peritoneal metastasis and prolonged the survival in an ovarian cancer xenograft mice model. Immunohistochemical staining of excised tumors revealed that IMD-0560 suppressed VEGF expression, tumor angiogenesis, and cancer cell proliferation. IMD-0560 showed promising therapeutic efficacy against ovarian cancer xenograft mice by inducing cell cycle arrest and suppressing VEGF production from cancer cells. IMD-0560 may be a potential future option in regimens for the

Novel strategies and therapeutic options for the management of primary biliary cholangitis.

Science.gov (United States)

Khanna, Amardeep; Jones, David E

2017-10-01

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease. It has a varied course of progression ranging from being completely asymptomatic to aggressive disease leading to cirrhosis and resulting in liver transplantation. In addition, symptoms can be debilitating and can have a major impact on quality of life. For decades, there was only one anti-cholestatic agent available to target this disease and that was only effective in around half of patients, with little or no effect on symptoms. With increasing understanding of the pathogenic mechanisms of PBC and potential targets for drug treatment, pharmaceutical companies have shown a greater interest in this rare disease. A large number of novel therapeutic molecules have been developed and are currently being evaluated. In this review article all the novel molecules in use and in trials targeting cholestasis and symptoms in PBC are discussed.

Cost-effectiveness of sunitinib as second-line treatment for gastrointestinal stromal tumor in the People’s Republic of China

Directory of Open Access Journals (Sweden)

Li J

2017-01-01

Full Text Available Jian Li,1 Hong Ye Ren,2 Juanjuan Zhang,2 Peng Dong,2 Yan Wang,3 Andrea L Stevens,3 Yi Han,3 Min Huang4 1Laboratory of Carcinogenesis and Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, 2Pfizer Inc., Beijing, People’s Republic of China; 3WG Consulting, New York, NY, USA; 4School of Pharmacy, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China Objective: To evaluate the cost-effectiveness of sunitinib as a second-line treatment in patients with advanced gastrointestinal stromal tumors that no longer respond to imatinib 400 mg/d, compared with imatinib 600 mg/d, 800 mg/d, or best supportive care (BSC in the People’s Republic of China. Methods: This study was conducted from the government payer’s perspective with a time horizon of 5 years. Three health states were considered: progression-free survival, disease progression survival, and death, with a cycle length of 6 weeks. Probabilities of disease progression and death were estimated based on survival functions using exponential distribution and progression survival data in the clinical trials. Drug costs were based on drug retail prices and the patient assistance program in the People’s Republic of China, and adverse event management costs were based on published data and/or expert opinion. Uncertainties for parameters in the study were addressed through one-way deterministic and probabilistic sensitivity analysis. Results: When sunitinib was compared with imatinib 600 mg/d and BSC, the incremental cost-effectiveness ratio was RMB75,715 with RMB121,080 per quality-adjusted life-year (QALY gained. Sunitinib demonstrated lower costs and higher QALYs than imatinib 800 mg/d. In the probabilistic sensitivity analysis, the willingness-to-pay per QALY gained was set to be three times the per capita gross domestic product of the People’s Republic of

Second Line of Defense, Port of Buenos Aires and Exolgan Container Terminal Operational Testing and Evaluation Plan, Buenos Aires, Argentina

Energy Technology Data Exchange (ETDEWEB)

Roberts, Bryan W.

2012-08-23

The Office of the Second Line of Defense (SLD) Megaports project team for Argentina will conduct operational testing and evaluation (OT&E) at Exolgan Container Terminal at the Port of Dock Sud from July 16-20, 2012; and at the Port of Buenos Aires from September 3-7, 2012. SLD is installing radiation detection equipment to screen export, import, and transshipment containers at these locations. The purpose of OT&E is to validate and baseline an operable system that meets the SLD mission and to ensure the system continues to perform as expected in an operational environment with Argentina Customs effectively adjudicating alarms.

COMBINATION THERAPIES OR STANDALONE INTERVENTIONS? INNOVATION OPTIONS FOR PHARMACEUTICAL FIRMS FIGHTING CANCER

OpenAIRE

GUNJAN BHARDWAJ; ANSHIT AGRAWAL; RUPESH TYAGI

2015-01-01

Innovation is key to the pharma model, from an initial discovery to the final development of a marketable drug. Here, we explore the innovation options in the fiercely contested therapeutic area of Oncology. We studied clinical development of drugs targeting PD-1 and PD-L1 pathway. In this interesting contest, companies seem to be focusing on standalone interventions (exploratory innovation) and combination therapy (exploitative innovation) in clinical development. Merck Sharp and Dohme, havi...

Policy options to improve the effectiveness of the EU emissions trading system: A multi-criteria analysis

International Nuclear Information System (INIS)

Clò, Stefano; Battles, Susan; Zoppoli, Pietro

2013-01-01

This paper considers several policy options which have been proposed to improve the functioning of the ETS. These options require an intervention either on the ETS cap (−30% target, set-aside, carbon central bank, long-term target) or on the carbon price (European and national price floor). We analyse the impact of each policy on the ETS carbon price and emissions. A multi-criteria evaluation method is applied to compare the policy options against a plurality of environmental, economic and procedural criteria. We find that the final ranking depends on the goals to be achieved, i.e., the relative weights attributed to the criteria. When policymakers want mainly to support the carbon price both in the short and long-run, while improving ETS flexibility and harmonization, the CCB and the EU price floor are, respectively ranked as first and second-best options. As the preference for environmental and implementation goals gradually increases, the position of the EU price floor and CCB options tend to invert. The −30% target should be adopted when reducing emissions is the priority goal, while a national price floor is the worst option, in this case. Nevertheless, self-interested States looking for a relatively quick, feasible solution, may find it optimal. - Highlights: ► A multi-criteria analysis is adopted to compare policy options to improve the ETS effectiveness. ► An ETS cap reversible adjustment by a carbon central bank is the first-best option. ► The establishment of a EU-wide price floor would represent a second-best solution. ► A national price floor is the worst option but self-interest states may find it optimal. ► A post-2020 target is not a mutually exclusive option and should be set

Advancing treatment options for chronic idiopathic constipation.

Science.gov (United States)

Quigley, Eamonn M M; Neshatian, Leila

2016-01-01

Chronic constipation is a global problem affecting all ages and associated with considerable morbidity and significant financial burden for society. Though formerly defined on the basis of a single symptom, infrequent defecation; constipation is now viewed as a syndrome encompassing several complaints such as difficulty with defecation, a sense of incomplete evacuation, hard stools, abdominal discomfort and bloating. The expanded concept of constipation has inevitably led to a significant change in outcomes in clinical trials, as well as in patient expectations from new therapeutic interventions. The past decades have also witnessed a proliferation in therapeutic targets for new agents. Foremost among these have been novel prokinetics, a new category, prosecretory agents and innovative approaches such as inhibitors of bile salt transport. In contrast, relatively few effective therapies exist for the management of those anorectal and pelvic floor problems that result in difficult defecation. Though constipation is a common and often troublesome disorder, many of those affected can resolve their symptoms with relatively simple measures. For those with more resistant symptoms a number of novel, effective and safe options now exist. Those with defecatory difficulty (anismus, pelvic floor dysfunction) continue to represent a significant management challenge.

An update on adjunctive treatment options for bipolar disorder.

Science.gov (United States)

Dean, Olivia M; Gliddon, Emma; Van Rheenen, Tamsyn E; Giorlando, Francesco; Davidson, Sandra K; Kaur, Manreena; Ngo, Trung T; Williams, Lana J

2018-03-01

Bipolar disorder is a complex illness often requiring combinations of therapies to successfully treat symptoms. In recent years, there have been significant advancements in a number of therapies for bipolar disorder. It is therefore timely to provide an overview of current adjunctive therapeutic options to help treating clinicians to inform their patients and work towards optimal outcomes. Publications were identified from PubMed searches on bipolar disorder and pharmacotherapy, nutraceuticals, hormone therapy, psychoeducation, interpersonal and social rhythm therapy, cognitive remediation, mindfulness, e-Health and brain stimulation techniques. Relevant articles in these areas were selected for further review. This paper provides a narrative review of adjunctive treatment options and is not a systematic review of the literature. A number of pharmacotherapeutic, psychological and neuromodulation treatment options are available. These have varying efficacy but all have shown benefit to people with bipolar disorder. Due to the complex nature of treating the disorder, combination treatments are often required. Adjunctive treatments to traditional pharmacological and psychological therapies are proving useful in closing the gap between initial symptom remission and full functional recovery. Given that response to monotherapy is often inadequate, combination regimens for bipolar disorder are typical. Correspondingly, psychiatric research is working towards a better understanding of the disorder's underlying biology. Therefore, treatment options are changing and adjunctive therapies are being increasingly recognized as providing significant tools to improve patient outcomes. Towards this end, this paper provides an overview of novel treatments that may improve clinical outcomes for people with bipolar disorder. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Second-line rescue triple therapy with levofloxacin after failure of non-bismuth quadruple "sequential" or "concomitant" treatment to eradicate H. pylori infection.

Science.gov (United States)

Gisbert, Javier P; Molina-Infante, Javier; Marin, Alicia C; Vinagre, Gemma; Barrio, Jesus; McNicholl, Adrian Gerald

2013-06-01

Non-bismuth quadruple "sequential" and "concomitant" regimens, including a proton pump inhibitor (PPI), amoxicillin, clarithromycin and a nitroimidazole, are increasingly used as first-line treatments for Helicobacter pylori infection. Eradication with rescue regimens may be challenging after failure of key antibiotics such as clarithromycin and nitroimidazoles. To evaluate the efficacy and tolerability of a second-line levofloxacin-containing triple regimen (PPI-amoxicillin-levofloxacin) in the eradication of H. pylori after non-bismuth quadruple-containing treatment failure. prospective multicenter study. in whom a non-bismuth quadruple regimen, administered either sequentially (PPI + amoxicillin for 5 days followed by PPI + clarithromycin + metronidazole for 5 more days) or concomitantly (PPI + amoxicillin + clarithromycin + metronidazole for 10 days) had previously failed. levofloxacin (500 mg b.i.d.), amoxicillin (1 g b.i.d.) and PPI (standard dose b.i.d.) for 10 days. eradication was confirmed with (13)C-urea breath test 4-8 weeks after therapy. Compliance and tolerance: compliance was determined through questioning and recovery of empty medication envelopes. Incidence of adverse effects was evaluated by means of a questionnaire. 100 consecutive patients were included (mean age 50 years, 62% females, 12% peptic ulcer and 88% dyspepsia): 37 after "sequential", and 63 after "concomitant" treatment failure. All patients took all medications correctly. Overall, per-protocol and intention-to-treat H. pylori eradication rates were 75.5% (95% CI 66-85%) and 74% (65-83%). Respective intention-to-treat cure rates for "sequential" and "concomitant" failure regimens were 74.4% and 71.4%, respectively. Adverse effects were reported in six (6%) patients; all of them were mild. Ten-day levofloxacin-containing triple therapy constitutes an encouraging second-line strategy in patients with previous non-bismuth quadruple "sequential" or "concomitant" treatment failure.

Therapeutic touch is not therapeutic for procedural pain in very preterm neonates: a randomized trial.

Science.gov (United States)

Johnston, Celeste; Campbell-Yeo, Marsha; Rich, Bonnie; Whitley, Julie; Filion, Francoise; Cogan, Jennifer; Walker, Claire-Dominique

2013-09-01

Preterm neonates below 30 weeks' gestational age undergo numerous painful procedures. Many management approaches are not appropriate for this population. Therapeutic Touch, an alternative approach based on the theory of energy medicine, has been shown to promote physiological stability in preterm neonates and reduce pain in some adult studies. The objective was to determine whether Therapeutic Touch is efficacious in decreasing pain in preterm neonates. Infants Touch (n = 27) with infant behind curtains, leaving the curtained area for the heel lance, performed by another. In the sham condition (n = 28), the therapist stood by the incubator with hands by her side. The Premature Infant Pain Profile was used for pain response and time for heart rate to return to baseline for recovery. Heart rate variability and stress response were secondary outcomes. There were no group differences in any of the outcomes. Mean Premature Infant Pain Profile scores across 2 minutes of heel lance procedure in 30-second blocks ranged from 7.92 to 8.98 in the Therapeutic Touch group and 7.64 to 8.46 in the sham group. Therapeutic Touch given immediately before and after heel lance has no comforting effect in preterm neonates. Other effective strategies involving actual touch should be considered.

Comparing On-Line to In-Person Course Delivery: An Empirical Study

OpenAIRE

Jammie Price; Leslie Hossfeld

2007-01-01

Web-based technologies have been used in the classroom for over 15 years, including websites, email, listserves, library reserves, and text books. Among these options, social scientists range widely in their web usage – from simply posting syllabi on-line to delivering a course fully on-line in asynchronous learning networks. Use of web-based technology for instructional purposes is increasing, as is enrollment in distance education courses and on-line course offerings. Many administrators ...

Meta-analysis of published efficacy and safety data for docetaxel in second-line treatment of patients with advanced non-small-cell lung cancer.

Science.gov (United States)

Stroh, Mark; Green, Michelle; Cha, Edward; Zhang, Nancy; Wada, Russ; Jin, Jin

2016-03-01

To gain a better understanding of the impact of dose and other prognostic factors on safety and efficacy of docetaxel in second-line non-small-cell lung cancer patients. A model-based meta-analysis (MBMA) of a published docetaxel monotherapy data in 6085 second-line non-small-cell lung cancer patients from 46 trials was conducted. The logit of grade 3/4 neutropenia incidence was a linear function of dose, with a 5% increase in the odds of neutropenia per mg/m(2) increase in dose [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.04-1.06], and a Japanese study effect (OR 17.1, 95% CI 6.05-48.4). The logit of overall response rate (ORR) was a linear function of cumulative dose (0.4% increase in the odds of response per mg/m(2) increase; OR 1.004, 95% CI 1.001-1.008) and median population age (OR 1.08 per year, 95% CI 1.02-1.15). A Japanese study effect was identified for overall survival (OS) in addition to prognostic factors identified by a previous meta-analysis. This current MBMA identified docetaxel dose-response relationships for both neutropenia and ORR, an effect of age on ORR, and Japanese study effects on both neutropenia and OS.

Influence of rotating in-plane field on vertical Bloch lines in the walls of second kind of dumbbell domains

International Nuclear Information System (INIS)

Sun, H.Y.; Hu, H.N.; Sun, Y.P.; Nie, X.F.

2004-01-01

Influence of rotating in-plane field on vertical Bloch lines in the walls of second kind of dumbbell domains (IIDs) was investigated, and a critical in-plane field range [H ip 1 ,H ip 2 ] of which vertical-Bloch lines (VBLs) annihilated in IIDs is found under rotating in-plane field (H ip 1 is the maximal critical in-plane-field of which hard domains remain stable, H ip 2 is the minimal critical in-plane-field of which all of the hard domains convert to soft bubbles (SBs, without VBLs)). It shows that the in-plane field range [H ip 1 , H ip 2 ] changes with the change of the rotating angle Δφ H ip 1 maintains stable, while H ip 2 decreases with the decreasing of rotating angle Δφ. Comparing it with the spontaneous shrinking experiment of IIDs under both bias field and in-plane field, we presume that under the application of in-plane field there exists a direction along which the VBLs in the domain walls annihilate most easily, and it is in the direction that domain walls are perpendicular to the in-plane field

The Challenge of Interfacing the Primary Beam Lines for the AWAKE Project at CERN

CERN Document Server

Bracco, C; Gschwendtner, E; Meddahi, M; Petrenko, A; Velotti, FM

2014-01-01

The Proton Driven Plasma Wakefield Acceleration Experiment (AWAKE) at CERN foresees the simultaneous operation of a proton, a laser and an electron beam. The first stage of the experiment will consist in proving the self-modulation, in the plasma, of a long proton bunch into micro-bunches. The success of this experiment requires an almost perfect concentricity of the proton and laser beam, over the full length of the plasma cell. The complexity of integrating the laser into the proton beam line and fulfilling the strict requirements in terms of pointing precision of the proton beam at the plasma cell are described. The second stage of the experiment foresees also the injection of electron bunches to probe the accelerating wakefields driven by the proton beam. Studies were performed to evaluate the possibility of injecting the electron beam parallel and with an offset to the beam axis. This option would imply that protons and electrons will have to share the last few meters of a common beam line. Issues and po...

Development of a second-harmonic buncher for the RILAC

International Nuclear Information System (INIS)

Kohara, S.; Goto, A.; Miyazawa, Y.; Chiba, T.; Hemmi, M.; Chiba, Y.; Ikezawa, E.; Kase, M.; Yano, Y.

1994-01-01

A second-harmonic buncher has been constructed and installed on the injection beam line of the RIKEN variable-frequency heavy-ion linac (RILAC) to increase beam intensity. It has a good impedance matching to power feed line without adjusting device in the required wide frequency range. Beam intensity was increased by 50% with both the fundamental-frequency and the second-harmonic bunchers. Its structure, rf characteristics and beam test are described. (author)

Australian Asian Options

OpenAIRE

Manuel Moreno; Javier F. Navas

2003-01-01

We study European options on the ratio of the stock price to its average and viceversa. Some of these options are traded in the Australian Stock Exchange since 1992, thus we call them Australian Asian options. For geometric averages, we obtain closed-form expressions for option prices. For arithmetic means, we use different approximations that produce very similar results.

Targeting tissue factor as a novel therapeutic oncotarget for eradication of cancer stem cells isolated from tumor cell lines, tumor xenografts and patients of breast, lung and ovarian cancer.

Science.gov (United States)

Hu, Zhiwei; Xu, Jie; Cheng, Jijun; McMichael, Elizabeth; Yu, Lianbo; Carson, William E

2017-01-03

Targeting cancer stem cell (CSC) represents a promising therapeutic approach as it can potentially fight cancer at its root. The challenge is to identify a surface therapeutic oncotarget on CSC. Tissue factor (TF) is known as a common yet specific surface target for cancer cells and tumor neovasculature in several solid cancers. However, it is unknown if TF is expressed by CSCs. Here we demonstrate that TF is constitutively expressed on CD133 positive (CD133+) or CD24-CD44+ CSCs isolated from human cancer cell lines, tumor xenografts from mice and breast tumor tissues from patients. TF-targeted agents, i.e., a factor VII (fVII)-conjugated photosensitizer (fVII-PS for targeted photodynamic therapy) and fVII-IgG1Fc (Immunoconjugate or ICON for immunotherapy), can eradicate CSC via the induction of apoptosis and necrosis and via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, respectively. In conclusion, these results demonstrate that TF is a novel surface therapeutic oncotarget for CSC, in addition to cancer cell TF and tumor angiogenic vascular endothelial TF. Moreover, this research highlights that TF-targeting therapeutics can effectively eradicate CSCs, without drug resistance, isolated from breast, lung and ovarian cancer with potential to translate into other most commonly diagnosed solid cancer, in which TF is also highly expressed.

The effect of shadow lines on a low concentrating photovoltaic system

NARCIS (Netherlands)

Janssen, H.J.J.; Sonneveld, P.J.; Swinkels, G.L.A.M.; Tuijl, van B.A.J.; Zwart, de H.F.

2011-01-01

In order to reduce the energy losses caused by shadow lines, three options are investigated. These are: 1. the use of two types of diodes; 2. the use of an ”ideal” diode based an active bypass by using MOS-FET’s [4] and 3. parallel switching of a number of cells between two shadow lines. The first

Product line design

Czech Academy of Sciences Publication Activity Database

Anderson, S. P.; Celik, Levent

2015-01-01

Roč. 157, May (2015), s. 517-526 ISSN 0022-0531 Institutional support: RVO:67985998 Keywords : product line design * product differentiation * second-degree price discrimination Subject RIV: AH - Economics Impact factor: 1.097, year: 2015

Model of directed lines for square ice with second-neighbor and third-neighbor interactions

Science.gov (United States)

Kirov, Mikhail V.

2018-02-01

The investigation of the properties of nanoconfined systems is one of the most rapidly developing scientific fields. Recently it has been established that water monolayer between two graphene sheets forms square ice. Because of the energetic disadvantage, in the structure of the square ice there are no longitudinally arranged molecules. The result is that the structure is formed by unidirectional straight-lines of hydrogen bonds only. A simple but accurate discrete model of square ice with second-neighbor and third-neighbor interactions is proposed. According to this model, the ground state includes all configurations which do not contain three neighboring unidirectional chains of hydrogen bonds. Each triplet increases the energy by the same value. This new model differs from an analogous model with long-range interactions where in the ground state all neighboring chains are antiparallel. The new model is suitable for the corresponding system of point electric (and magnetic) dipoles on the square lattice. It allows separately estimating the different contributions to the total binding energy and helps to understand the properties of infinite monolayers and finite nanostructures. Calculations of the binding energy for square ice and for point dipole system are performed using the packages TINKER and LAMMPS.

Terahertz in-line digital holography of human hepatocellular carcinoma tissue

Science.gov (United States)

Rong, Lu; Latychevskaia, Tatiana; Chen, Chunhai; Wang, Dayong; Yu, Zhengping; Zhou, Xun; Li, Zeyu; Huang, Haochong; Wang, Yunxin; Zhou, Zhou

2015-02-01

Terahertz waves provide a better contrast in imaging soft biomedical tissues than X-rays, and unlike X-rays, they cause no ionisation damage, making them a good option for biomedical imaging. Terahertz absorption imaging has conventionally been used for cancer diagnosis. However, the absorption properties of a cancerous sample are influenced by two opposing factors: an increase in absorption due to a higher degree of hydration and a decrease in absorption due to structural changes. It is therefore difficult to diagnose cancer from an absorption image. Phase imaging can thus be critical for diagnostics. We demonstrate imaging of the absorption and phase-shift distributions of 3.2 mm × 2.3 mm × 30-μm-thick human hepatocellular carcinoma tissue by continuous-wave terahertz digital in-line holography. The acquisition time of a few seconds for a single in-line hologram is much shorter than that of other terahertz diagnostic techniques, and future detectors will allow acquisition of meaningful holograms without sample dehydration. The resolution of the reconstructions was enhanced by sub-pixel shifting and extrapolation. Another advantage of this technique is its relaxed minimal sample size limitation. The fibrosis indicated in the phase distribution demonstrates the potential of terahertz holographic imaging to obtain a more objective, early diagnosis of cancer.

Terahertz in-line digital holography of human hepatocellular carcinoma tissue.

Science.gov (United States)

Rong, Lu; Latychevskaia, Tatiana; Chen, Chunhai; Wang, Dayong; Yu, Zhengping; Zhou, Xun; Li, Zeyu; Huang, Haochong; Wang, Yunxin; Zhou, Zhou

2015-02-13

Terahertz waves provide a better contrast in imaging soft biomedical tissues than X-rays, and unlike X-rays, they cause no ionisation damage, making them a good option for biomedical imaging. Terahertz absorption imaging has conventionally been used for cancer diagnosis. However, the absorption properties of a cancerous sample are influenced by two opposing factors: an increase in absorption due to a higher degree of hydration and a decrease in absorption due to structural changes. It is therefore difficult to diagnose cancer from an absorption image. Phase imaging can thus be critical for diagnostics. We demonstrate imaging of the absorption and phase-shift distributions of 3.2 mm × 2.3 mm × 30-μm-thick human hepatocellular carcinoma tissue by continuous-wave terahertz digital in-line holography. The acquisition time of a few seconds for a single in-line hologram is much shorter than that of other terahertz diagnostic techniques, and future detectors will allow acquisition of meaningful holograms without sample dehydration. The resolution of the reconstructions was enhanced by sub-pixel shifting and extrapolation. Another advantage of this technique is its relaxed minimal sample size limitation. The fibrosis indicated in the phase distribution demonstrates the potential of terahertz holographic imaging to obtain a more objective, early diagnosis of cancer.

The results of therapeutic plasma exchange in patients with severe hyperthyroidism: a retrospective multicenter study.

Science.gov (United States)

Keklik, Muzaffer; Kaynar, Leylagul; Yilmaz, Mehmet; Sivgin, Serdar; Solmaz, Musa; Pala, Cigdem; Aribas, Sulbiye; Akyol, Gulsah; Unluhizarci, Kursat; Cetin, Mustafa; Eser, Bulent; Unal, Ali

2013-06-01

Hyperthyroidism characterized by elevated serum levels of circulating thyroid hormones. The aim of hyperthyroidism treatment is to achieve a euthyroid state as soon as possible and to maintain euthyroid status. However, drug withdrawal and utilization of alternative therapies are needed in cases in which leucopenia or impairment in liver functions is observed during medical therapy. In the present study, we aimed to present our cases which underwent therapeutic plasma exchange (TPE) due to severe hyperthyroidism. The results of 22 patients who underwent therapeutic plasma exchange due to hyperthyroidism in Apheresis Units of Erciyes University and Gaziantep University, between 2006 and 2012, were retrospectively reviewed. These cases had severe thyrotoxic values despite anti-thyroid drug use. After TPE, we observed a significant decrease in free thyroxin (FT4) (phyperthyroidism by TPE in 20 cases (91%). Both FT3 and FT4 levels remained above the normal limits in two of 22 patients. TPE should be considered as an effective and safe therapeutic option to achieve euthyroid state before surgery or radioactive iodine treatment. TPE is a useful option in cases with severe hyperthyroidism unresponsive to anti-thyroid agents and in those with clinical manifestations of cardiac failure and in patients with severe adverse events during anti-thyroid therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1)

DEFF Research Database (Denmark)

Machiels, Jean-Pascal H; Haddad, Robert I; Fayette, Jérôme

2015-01-01

BACKGROUND: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting......%]), and neutropenia (1 [... provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC. FUNDING: Boehringer Ingelheim....

New innovations: therapeutic opportunities for intellectual disabilities.

Science.gov (United States)

Picker, Jonathan D; Walsh, Christopher A

2013-09-01

Intellectual disability is common and is associated with significant morbidity. Until the latter half of the 20th century, there were no efficacious treatments. Following initial breakthroughs associated with newborn screening and metabolic corrections, little progress was made until recently. With improved understanding of genetic and cellular mechanisms, novel treatment options are beginning to appear for a number of specific conditions. Fragile X and tuberous sclerosis offer paradigms for the development of targeted therapeutics, but advances in understanding of other disorders such as Down syndrome and Rett syndrome, for example, are also resulting in promising treatment directions. In addition, better understanding of the underlying neurobiology is leading to novel developments in enzyme replacement for storage disorders and adjunctive therapies for metabolic disorders, as well as potentially more generalizable approaches that target dysfunctional cell regulation via RNA and chromatin. Physiologic therapies, including deep brain stimulation and transcranial magnetic stimulation, offer yet another direction to enhance cognitive functioning. Current options and evolving opportunities for the intellectually disabled are reviewed and exemplified. Copyright © 2013 American Neurological Association.

Investigation of Neptunium Precipitator Cleanout Options

International Nuclear Information System (INIS)

Hill, B.C.

2003-01-01

Oxalate precipitation followed by filtration is used to prepare plutonium oxalate. Historically, plutonium oxalate has tended to accumulate in the precipitation tanks. These solids are periodically removed by flushing with concentrated (64 percent) nitric acid. The same precipitation tanks will now be used in the processing of neptunium. Literature values indicate that neptunium oxalate may not be as soluble as plutonium oxalate in nitric acid. Although a wide variety of options is available to improve neptunium oxalate solubility for precipitator flushing, most of these options are not practical for use. Many of these options require the use of incompatible or difficult to handle chemicals. Other options would require expensive equipment modifications or are likely to lead to product contamination. Based on review of literature and experimental results, the two best options for flushing the precipitator are (1) 64 percent nitric acid and (2) addition of sodium permanganate follow ed by sodium nitrite. Nitric acid is the easiest option to implement. It is already used in the facility and will not lead to product contamination. Experimental results indicate that neptunium oxalate can be dissolved in concentrated nitric acid (64 percent) at 60 degree C to a concentration of 2.6 to 5.6 grams of Np/liter after at least three hours of heating. A lower concentration (1.1 grams of Np/liter) was measured at 60 degree C after less than two hours of heating. These concentrations are acceptable for flushing if precipitator holdup is low (approximately 100-250 grams), but a second method is required for effective flushing if precipitator holdup is high (approximately 2 kilograms). The most effective method for obtaining higher neptunium concentrations is the use of sodium permanganate followed by the addition of sodium nitrite. There is concern that residual manganese from these flushes could impact product purity. Gas generation during permanganate addition is also a concern

Real Options in Capital Budgeting. Pricing the Option to Delay and the Option to Abandon a Project

Directory of Open Access Journals (Sweden)

Nicoleta Vintila

2007-07-01

Full Text Available Traditional discounted cash-flows method for assessing projects assumes that investment decision is an irreversible one, which is not correct. Managers can and must reconsider their initial decision as the new information arises during the project life. This is managerial flexibility and it creates strategic value for a project, only if management takes advantage of the opportunities associated with an analyzed project. Real options represent a new approach in capital budgeting, using the theory of pricing financial options for investments in real assets. In this paper, we emphasize the characteristics and valuation methodologies of real options. The objective in the last section is pricing the option to delay and the option to abandon a project in construction materials field.

Therapeutic advancement of chronic lymphocytic leukemia

Directory of Open Access Journals (Sweden)

Lu Kang

2012-09-01

Full Text Available Abstract Despite the combinations of chemotherapy with monoclonal antibodies have further improved response rates, chronic lymphocytic leukemia (CLL remains an incurable disease with an extremely variable course. This article reviews the ongoing clinical advances in the treatment of CLL in both previously untreated and relapsed disease and focuses on the benefit of different therapeutic strategies, the most effective therapy combinations and the potential activity of novel agents. Novel agents and combination therapies have been investigated by several studies in both the upfront and relapsed setting, particularly for patients with 17p deletion, TP53 mutation and fludarabine-refractory CLL. While these agents and combination therapies have improved initial response rates, ongoing studies are continued to determine and improve the efficacy and safety. Despite advancements in the treatment of CLL have led to high response rates, allogeneic hematopoietic stem cell transplantation (allo-HSCT remains the only curative option and reduced-intensity conditioning (RIC allo-HSCT must be strongly considered whenever feasible. As such, ongoing studies of these agents and other novel approaches in clinical development are needed to expand and improve treatment options for CLL patients.

Stata 8 Graphics: Options, sub-options and sub-sub-options

OpenAIRE

Tim Collier

2005-01-01

Stata 8 graphics have changed out of all recognition from that available in earlier versions. It was not just that a whole new array of options and sub-options were introduced, but the graph syntax itself completely changed. Just trying to produce a simple plot of x against y using Stata 7 syntax (graph x y) produced bewildering error messages e.g. xgraph_g.new y: class member function not found r(4023) and the like. If you did succeed in working out the new syntax (graph twoway scatter x y) ...

Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer.

Science.gov (United States)

Sanoff, Hanna K; Goldberg, Richard M; Ivanova, Anastasia; O'Reilly, Seamus; Kasbari, Samer S; Kim, Richard D; McDermott, Ray; Moore, Dominic T; Zamboni, William; Grogan, William; Cohn, Allen Lee; Bekaii-Saab, Tanios S; Leonard, Gregory; Ryan, Theresa; Olowokure, Olugbenga O; Fernando, Nishan H; McCaffrey, John; El-Rayes, Bassel F; Horgan, Anne M; Sherrill, Gary Bradley; Yacoub, George Hosni; O'Neil, Bert H

2018-06-15

Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double-blind, placebo-controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer. Patients with metastatic colorectal cancer who progressed on first-line oxaliplatin and fluoropyrimidine enrolled at 45 sites in the United States and Ireland. Patients, stratified by prior bevacizumab use, were randomized 2:1 to regorafenib or placebo. The treatment consisted of FOLFIRI on days 1 and 2 and days 15 and 16 with 160 mg of regorafenib or placebo on days 4 to 10 and days 18 to 24 of every 28-day cycle. Crossover was not allowed. The primary endpoint was progression-free survival (PFS). Under the assumption of a 75% event rate, 180 patients were required for 135 events to achieve 90% power to detect a hazard ratio (HR) of 0.65 with a 1-sided α value of .1. One hundred eighty-one patients were randomized (120 to regorafenib-FOLFIRI and 61 to placebo-FOLFIRI) with a median age of 62 years. Among these, 117 (65%) received prior bevacizumab or aflibercept. PFS was longer with regorafenib-FOLFIRI than placebo-FOLFIRI (median, 6.1 vs 5.3 months; HR, 0.73; 95% confidence interval [CI], 0.53-1.01; log-rank P = .056). The median overall survival was not longer (HR, 1.01; 95% CI, 0.71-1.44). The response rate was higher with regorafenib-FOLFIRI (34%; 95% CI, 25%-44%) than placebo-FOLFIRI (21%; 95% CI, 11%-33%; P = .07). Grade 3/4 adverse events with a >5% absolute increase from regorafenib included diarrhea, neutropenia, febrile neutropenia, hypophosphatemia, and hypertension. The addition of regorafenib to FOLFIRI as second-line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer

Medical Student Interest in Flexible Residency Training Options.

Science.gov (United States)

Piotrowski, Madison; Stulberg, Debra; Egan, Mari

2018-05-01

Medical residents continue to experience high rates of burnout during residency training even after implementation of the 2003 Accreditation Council for Graduate Medical Education duty-hour restrictions. The purpose of this study is to determine medical student interest in flexible residency training options. Researchers developed an 11-question survey for second through fourth-year medical students. The populations surveyed included medical students who were: (1) attending the 2015 American Academy of Family Physicians National Conference, the 2015 Family Medicine Midwest Conference, and (2) enrolled at University of Chicago Pritzker School of Medicine, University of Illinois College of Medicine at Chicago, Drexel University College of Medicine, and Case Western Reserve University School of Medicine. The survey was completed by 789 medical students. Over half of medical students surveyed indicated that they would be interested in working part-time during some portion of their residency training (51%), and that access to part-time training options would increase their likelihood of applying to a particular residency program (52%). When given the option of three residency training schedules of varying lengths, 41% of male students and 60% of female students chose a 60-hour workweek, even when that meant extending the residency length by 33% and reducing their yearly salary to $39,000. There is considerable interest among medical students in access to part-time residency training options and reduced-hour residency programs. This level of interest indicates that offering flexible training options could be an effective recruitment tool for residency programs and could improve students' perception of their work-life balance during residency.

Perspectives for Preventive and Therapeutic HPV Vaccines

Science.gov (United States)

Lin, Ken; Doolan, Kimberley; Hung, Chien-Fu; Wu, T-C

2010-01-01

Cervical cancer is the second most common cause of female cancer death worldwide. Persistent infection with `high risk' HPV genotypes is the major etiological factor in cervical cancer and thus effective vaccination against HPV provides an opportunity to reduce the morbidity and mortality associated with HPV. The FDA has approved two preventive vaccines to limit the spread of HPV. However, these are unlikely to impact upon HPV prevalence and cervical cancer rates for many years. Furthermore, preventive vaccines do not exert therapeutic effects on pre-existing HPV infections and HPV-associated lesions. In order to further impact upon the burden of HPV infections worldwide, therapeutic vaccines are being developed. These vaccines aim to generate a cell-mediated immune response to infected cells. This review discusses current preventive and therapeutic HPV vaccines and their future directions. PMID:20123582

Automated (Centrifugal) therapeutic plasma exchange option for guillain-barre syndrome: A report from Calabar, Nigeria.

Science.gov (United States)

Iheanacho, O E; Chimeziem, C; Sachais, B S; Shi, P A

2017-10-01

Therapeutic plasma exchange (TPE) is performed frequently and effectively in developed countries, whereas the reverse is the case in developing countries. Guillain-Barre syndrome (GBS), synonymous with acute inflammatory demyelinating polyneuropathy, is an important indication for TPE, but this is rarely administered in the treatment of such patients in Nigeria due to lack of such automated facility, limited expertise, and high cost. This report therefore presents an uncommon case of GBS in which automated TPE was utilized in the management, with the aims of highlighting the current status and challenges of therapeutic apheresis services in Nigeria. A 42-year-old male presented with rapidly progressive (in an ascending fashion) paralysis of all four limbs within 24 h without any preceding history of fever or other symptoms. Clinical examination revealed a young man, afebrile, not pale, and also not dehydrated. Central nervous system examination showed a conscious man, alert, and oriented in time, person, and place. There were no signs of meningeal irritation and the cranial nerves were grossly intact. There was no power in the limbs: global hypotonia and areflexia were noted on examination. However, he had intact sensory perceptions to touch and pain. Following a diagnosis of GBS, he was treated with four sessions of plasmapheresis and TPE. The TPE session was done using a discontinuous flow apheresis machine which exchanged one plasma volume (3 L of plasma) and 5% albumin used for replacement. The patient made gradual but steady recovery as return of power to the upper limbs and trunk started by the 2nd week of treatment. TPE is an important treatment modality in the management of GBS as well as several other conditions, and it is becoming increasingly available in Nigeria. However, it is still grossly underutilized, thus the need for more therapeutic apheresis facilities and trained personnel, in addition to concerted efforts to subsidize the cost of accessing

The Impact of Endometriosis across the Lifespan of Women: Foreseeable Research and Therapeutic Prospects

Directory of Open Access Journals (Sweden)

C. L. Hughes

2015-01-01

Full Text Available In addition to estrogen dependence, endometriosis is characterized by chronic pelvic inflammation. The impact of the chronic pelvic inflammatory state on other organ systems and women’s health is unclear. Endometriosis associated chronic inflammation and potential adverse health effects across the lifespan render it imperative for renewed research vigor into the identification of novel biomarkers of disease and therapeutic options. Herein we propose a number of opportunities for research and development of new therapeutics to address the unmet needs in the treatment of endometriosis per se and its ancillary risks for other diseases in women across the lifespan.

Human Cell Line-Derived Monoclonal IgA Antibodies for Cancer Immunotherapy

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Felix Hart

2017-05-01

Full Text Available IgA antibodies have great potential to improve the functional diversity of current IgG antibody-based cancer immunotherapy options. However, IgA production and purification is not well established, which can at least in part be attributed to the more complex glycosylation as compared to IgG antibodies. IgA antibodies possess up to five N-glycosylation sites within their constant region of the heavy chain as compared to one site for IgG antibodies. The human GlycoExpress expression system was developed to produce biotherapeutics with optimized glycosylation and used here to generate a panel of IgA isotype antibodies directed against targets for solid (TA-mucin 1, Her2, EGFR, Thomsen–Friedenreich and hematological (CD20 cancer indications. The feasibility of good manufacturing practice was shown by the production of 11 g IgA within 35 days in a one liter perfusion bioreactor, and IgA antibodies in high purity were obtained after purification. The monoclonal IgA antibodies possessed a high sialylation degree, and no non-human glycan structures were detected. Kinetic analysis revealed increased avidity antigen binding for IgA dimers as compared to monomeric antibodies. The IgA antibodies exhibited potent Fab- and Fc-mediated functionalities against cancer cell lines, whereby especially granulocytes are recruited. Therefore, for patients who do not sufficiently benefit from therapeutic IgG antibodies, IgA antibodies may complement current regiment options and represent a promising strategy for cancer immunotherapy. In conclusion, a panel of novel biofunctional IgA antibodies with human glycosylation was successfully generated.

Process Alternatives for Second Generation Ethanol Production from Sugarcane Bagasse

DEFF Research Database (Denmark)

F. Furlan, Felipe; Giordano, Roberto C.; Costa, Caliane B. B.

2015-01-01

on the economic feasibility of the process. For the economic scenario considered in this study, using bagasse to increase ethanol production yielded higher ethanol production costs compared to using bagasse for electric energy production, showing that further improvements in the process are still necessary.......In ethanol production from sugarcane juice, sugarcane bagasse is used as fuel for the boiler, to meet the steam and electric energy demand of the process. However, a surplus of bagasse is common, which can be used either to increase electric energy or ethanol production. While the first option uses...... already established processes, there are still many uncertainties about the techno-economic feasibility of the second option. In this study, some key parameters of the second generation ethanol production process were analyzed and their influence in the process feasibility assessed. The simulated process...

Managing first-line failure.

Science.gov (United States)

Cooper, David A

2014-01-01

WHO standard of care for failure of a first regimen, usually 2N(t)RTI's and an NNRTI, consists of a ritonavir-boosted protease inhibitor with a change in N(t)RTI's. Until recently, there was no evidence to support these recommendations which were based on expert opinion. Two large randomized clinical trials, SECOND LINE and EARNEST both showed excellent response rates (>80%) for the WHO standard of care and indicated that a novel regimen of a boosted protease inhibitor with an integrase inhibitor had equal efficacy with no difference in toxicity. In EARNEST, a third arm consisting of induction with the combined protease and integrase inhibitor followed by protease inhibitor monotherapy maintenance was inferior and led to substantial (20%) protease inhibitor resistance. These studies confirm the validity of the current recommendations of WHO and point to a novel public health approach of using two new classes for second line when standard first-line therapy has failed, which avoids resistance genotyping. Notwithstanding, adherence must be stressed in those failing first-line treatments. Protease inhibitor monotherapy is not suitable for a public health approach in low- and middle-income countries.

Psycholinguistically Oriented Second Language Research.

Science.gov (United States)

Juffs, Alan

2001-01-01

Reviews recent research that investigates second language performance from the perspective of sentence processing (on-line comprehension studies) and word recognition. Concentrates on describing methods that employ reaction time measures as correlates of processing difficulty or knowledge representation. (Author/VWL)

High level of viral suppression and low switch rate to second-line antiretroviral therapy among HIV-infected adult patients followed over five years: retrospective analysis of the DART trial.

Directory of Open Access Journals (Sweden)

Cissy Kityo

Full Text Available In contrast to resource-rich countries, most HIV-infected patients in resource-limited countries receive treatment without virological monitoring. There are few long-term data, in this setting, on rates of viral suppression or switch to second-line antiretroviral therapy. The DART trial compared clinically driven monitoring (CDM versus routine laboratory (CD4/haematology/biochemistry and clinical monitoring (LCM in HIV-infected adults initiating therapy. There was no virological monitoring in either study group during follow-up, but viral load was measured in Ugandan participants at trial closure. Two thousand three hundred and seventeen (2317 participants from this country initiated antiretroviral therapy with zidovudine/lamivudine plus tenofovir (n = 1717, abacavir (n = 300, or nevirapine (n = 300. Of 1896 (81.8% participants who were alive and in follow-up at trial closure (median 5.1 years after therapy initiation, 1507 (79.5% were on first-line and 389 (20.5% on second-line antiretroviral therapy. The overall switch rate after the first year was 5.6 per 100 person-years; the rate was substantially higher in participants with low baseline CD4 counts (<50 cells/mm3. Among 1207 (80.1% first-line participants with viral load measured, HIV RNA was <400 copies/ml in 963 (79.8%, 400-999 copies/ml in 37 (3.1%, 1,000-9,999 copies/ml in 110 (9.1%, and ≥10,000 copies/ml in 97 (8.0%. The proportion with HIV RNA <400 copies/ml was slightly lower (difference 7.1%, 95% CI 2.5 to 11.5% in CDM (76.3% than in LCM (83.4%. Among 252 (64.8% second-line participants with viral load measured (median 2.3 years after switch, HIV RNA was <400 copies/ml in 226 (89.7%, with no difference between monitoring strategies. Low switch rates and high, sustained levels of viral suppression are achievable without viral load or CD4 count monitoring in the context of high-quality clinical care.ISRCTN13968779.

Therapeutic High-Density Barium Enema in a Case of Presumed Diverticular Hemorrhage

Directory of Open Access Journals (Sweden)

Nonthalee Pausawasdi

2011-02-01

Full Text Available Many patients with lower gastrointestinal bleeding do not have an identifiable source of bleeding at colonoscopy. A significant percentage of these patients will have recurrent bleeding. In many patients, the presence of multiple diverticula leads to a diagnosis of presumed diverticular bleeding. Current treatment options include therapeutic endoscopy, angiography, or surgical resection, all of which depend on the identification of the diverticular source of bleeding. This report describes a case of recurrent bleeding in an elderly patient with diverticula but no identifiable source treated successfully with barium impaction therapy. This therapeutic modality does not depend on the identification of the bleeding diverticular lesion and was well tolerated by our 86-year-old patient.

The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: a critical analysis.

Science.gov (United States)

Heijman, Jordi; Algalarrondo, Vincent; Voigt, Niels; Melka, Jonathan; Wehrens, Xander H T; Dobrev, Dobromir; Nattel, Stanley

2016-04-01

Atrial fibrillation (AF) is an extremely common clinical problem associated with increased morbidity and mortality. Current antiarrhythmic options include pharmacological, ablation, and surgical therapies, and have significantly improved clinical outcomes. However, their efficacy remains suboptimal, and their use is limited by a variety of potentially serious adverse effects. There is a clear need for improved therapeutic options. Several decades of research have substantially expanded our understanding of the basic mechanisms of AF. Ectopic firing and re-entrant activity have been identified as the predominant mechanisms for arrhythmia initiation and maintenance. However, it has become clear that the clinical factors predisposing to AF and the cellular and molecular mechanisms involved are extremely complex. Moreover, all AF-promoting and maintaining mechanisms are dynamically regulated and subject to remodelling caused by both AF and cardiovascular disease. Accordingly, the initial presentation and clinical progression of AF patients are enormously heterogeneous. An understanding of arrhythmia mechanisms is widely assumed to be the basis of therapeutic innovation, but while this assumption seems self-evident, we are not aware of any papers that have critically examined the practical contributions of basic research into AF mechanisms to arrhythmia management. Here, we review recent insights into the basic mechanisms of AF, critically analyse the role of basic research insights in the development of presently used anti-AF therapeutic options and assess the potential value of contemporary experimental discoveries for future therapeutic innovation. Finally, we highlight some of the important challenges to the translation of basic science findings to clinical application. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Use of Third Line Antiretroviral Therapy in Latin America

Science.gov (United States)

Cesar, Carina; Shepherd, Bryan E.; Jenkins, Cathy A.; Ghidinelli, Massimo; Castro, Jose Luis; Veloso, Valdiléa Gonçalves; Cortes, Claudia P.; Padgett, Denis; Crabtree-Ramirez, Brenda; Gotuzzo, Eduardo; Fink, Valeria; Duran, Adriana; Sued, Omar; McGowan, Catherine C.; Cahn, Pedro

2014-01-01

Background Access to highly active antiretroviral therapy (HAART) is expanding in Latin America. Many patients require second and third line therapy due to toxicity, tolerability, failure, or a combination of factors. The need for third line HAART, essential for program planning, is not known. Methods Antiretroviral-naïve patients ≥18 years who started first HAART after January 1, 2000 in Caribbean, Central and South America Network (CCASAnet) sites in Argentina, Brazil, Honduras, Mexico, and Peru were included. Clinical trials participants were excluded. Third line HAART was defined as use of darunavir, tipranavir, etravirine, enfuvirtide, maraviroc or raltegravir. Need for third line HAART was defined as virologic failure while on second line HAART. Results Of 5853 HAART initiators followed for a median of 3.5 years, 310 (5.3%) failed a second line regimen and 44 (0.8%) received a third line regimen. Cumulative incidence of failing a 2nd or starting a 3rd line regimen was 2.7% and 6.0% three and five years after HAART initiation, respectively. Predictors at HAART initiation for failing a second or starting a third line included female sex (hazard ratio [HR] = 1.54, 95% confidence interval [CI] 1.18–2.00, p = 0.001), younger age (HR = 2.76 for 20 vs. 40 years, 95% CI 1.86–4.10, p<0.001), and prior AIDS (HR = 2.17, 95% CI 1.62–2.90, p<0.001). Conclusions Third line regimens may be needed for at least 6% of patients in Latin America within 5 years of starting HAART, a substantial proportion given the large numbers of patients on HAART in the region. Improved accessibility to third line regimens is warranted. PMID:25221931

Use of third line antiretroviral therapy in Latin America.

Directory of Open Access Journals (Sweden)

Carina Cesar

Full Text Available Access to highly active antiretroviral therapy (HAART is expanding in Latin America. Many patients require second and third line therapy due to toxicity, tolerability, failure, or a combination of factors. The need for third line HAART, essential for program planning, is not known.Antiretroviral-naïve patients ≥18 years who started first HAART after January 1, 2000 in Caribbean, Central and South America Network (CCASAnet sites in Argentina, Brazil, Honduras, Mexico, and Peru were included. Clinical trials participants were excluded. Third line HAART was defined as use of darunavir, tipranavir, etravirine, enfuvirtide, maraviroc or raltegravir. Need for third line HAART was defined as virologic failure while on second line HAART.Of 5853 HAART initiators followed for a median of 3.5 years, 310 (5.3% failed a second line regimen and 44 (0.8% received a third line regimen. Cumulative incidence of failing a 2nd or starting a 3rd line regimen was 2.7% and 6.0% three and five years after HAART initiation, respectively. Predictors at HAART initiation for failing a second or starting a third line included female sex (hazard ratio [HR] = 1.54, 95% confidence interval [CI] 1.18-2.00, p = 0.001, younger age (HR = 2.76 for 20 vs. 40 years, 95% CI 1.86-4.10, p<0.001, and prior AIDS (HR = 2.17, 95% CI 1.62-2.90, p<0.001.Third line regimens may be needed for at least 6% of patients in Latin America within 5 years of starting HAART, a substantial proportion given the large numbers of patients on HAART in the region. Improved accessibility to third line regimens is warranted.

An optimal algorithm for configuring delivery options of a one-dimensional intensity-modulated beam

International Nuclear Information System (INIS)

Luan Shuang; Chen, Danny Z; Zhang, Li; Wu Xiaodong; Yu, Cedric X

2003-01-01

The problem of generating delivery options for one-dimensional intensity-modulated beams (1D IMBs) arises in intensity-modulated radiation therapy. In this paper, we present an algorithm with the optimal running time, based on the 'rightmost-preference' method, for generating all distinct delivery options for an arbitrary 1D IMB. The previously best known method for generating delivery options for a 1D IMB with N left leaf positions and N right leaf positions is a 'brute-force' solution, which first generates all N! possible combinations of the left and right leaf positions and then removes combinations that are not physically allowed delivery options. Compared with the brute-force method, our algorithm has several advantages: (1) our algorithm runs in an optimal time that is linearly proportional to the total number of distinct delivery options that it actually produces. Note that for a 1D IMB with multiple peaks, the total number of distinct delivery options in general tends to be considerably smaller than the worst case N!. (2) Our algorithm can be adapted to generating delivery options subject to additional constraints such as the 'minimum leaf separation' constraint. (3) Our algorithm can also be used to generate random subsets of delivery options; this feature is especially useful when the 1D IMBs in question have too many delivery options for a computer to store and process. The key idea of our method is that we impose an order on how left leaf positions should be paired with right leaf positions. Experiments indicated that our rightmost-preference algorithm runs dramatically faster than the brute-force algorithm. This implies that our algorithm can handle 1D IMBs whose sizes are substantially larger than those handled by the brute-force method. Applications of our algorithm in therapeutic techniques such as intensity-modulated arc therapy and 2D modulations are also discussed

ACCOUNTING FOR OPTIONS AND ANALYSIS OF USE OF OPTION COMBINATION STRATEGIES

Directory of Open Access Journals (Sweden)

I. Derun

2016-08-01

Full Text Available The article deals with problems of accounting for options in Ukraine, namely: value expression of initial cost of options, their revaluation, accounting of premiums, financial assets and financial liabilities and variation margin. The paper offers ways of solution of these problems which based on harmonization with IAS 32, IAS 39, IFRS 7 and IFRS 9. The study considers option combination strategies (straddle, strangle, strap, strip and approaches of identification of possible financial results for investors which use these strategies. Examples of possible financial results are provided for buyers and sellers of options which use option combination strategies.

Therapeutic nanomedicine surmounts the limitations of pharmacotherapy

Directory of Open Access Journals (Sweden)

Odiba Arome

2017-09-01

Full Text Available Science always strives to find an improved way of doing things and nanoscience is one such approach. Nanomaterials are suitable for pharmaceutical applications mostly because of their size which facilitates absorption, distribution, metabolism and excretion of the nanoparticles. Whether labile or insoluble nanoparticles, their cytotoxic effect on malignant cells has moved the use of nanomedicine into focus. Since nanomedicine can be described as the science and technology of diagnosing, treating and preventing diseases towards ultimately improving human health, a lot of nanotechnology options have received approval by various regulatory agencies. Nanodrugs also have been discovered to be more precise in targeting the desired site, hence maximizing the therapeutic effects, while minimizing side-effects on the rest of the body. This unique property and more has made nanomedicine popular in therapeutic medicine employing nanotechnology in genetic therapy, drug encapsulation, enzyme manipulation and control, tissue engineering, target drug delivery, pharmacogenomics, stem cell and cloning, and even virus-based hybrids. This review highlights nanoproducts that are in development and have gained approval through one clinical trial stage or the other.

Japan's patent issues relating to life science therapeutic inventions.

Science.gov (United States)

Tessensohn, John A

2014-09-01

Japan has made 'innovation in science and technology' as one of its central pillars to ensure high growth in its next stage of economic development and its life sciences market which hosts regenerative medicine was proclaimed to be 'the best market in the world right now.' Although life science therapeutic inventions are patentable subject matter under Japanese patent law, there are nuanced obviousness and enablement challenges under Japanese patent law that can be surmounted in view of some encouraging Japanese court developments in fostering a pro-patent applicant environment in the life sciences therapeutic patent field. Nevertheless, great care must be taken when drafting and prosecuting such patent applications in the world's second most important life sciences therapeutic market.