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Sample records for first-line antiglaucomatous monotherapy

  1. Patient persistence with first-line antiglaucomatous monotherapy

    PubMed Central

    Arias, Alfonso; Schargel, Konrad; Ussa, Fernando; Canut, Maria I; Robles, Amelia y Belén; Sánchez, Belén Martí

    2010-01-01

    Purpose To identify the extent of persistence (period of time of continuous therapy with the drug prescribed) of glaucoma patients treated with prostaglandins (latanoprost, bimatoprost, or travoprost), or β-blocker (timolol) monotherapy. Methods An observational retrospective study of a 24-month follow-up in 191 patients (from four centers) was done to identify the time elapsed until patients discontinued their antiglaucomatous treatment. The relevant information was extracted from patients’ medical charts. A descriptive analysis, a Kaplan–Meier survival analysis, and a Cox regression model were used to determine which drug was associated with greater patient persistence and to detect variables significantly influencing persistence. Results Descriptive analysis and survival curves showed that after 24 months, latanoprost was associated with a higher persistence in glaucoma treatment than the alternative agents: 81.6% versus 22.9% for bimatoprost, 65.4% for travoprost, and 60.5% for timolol (P < 0.0001). Persistence was significantly influenced by the antiglaucoma agent used as monotherapy (with a six-fold higher risk of treatment discontinuation during the follow-up period due to receiving bimatoprost instead of latanoprost; P < 0.0001) and patient age (P = 0.001). Even though comorbidities could not be directly related to persistence, their occurrence was related to patient age. The main reasons for treatment discontinuation were lack of efficacy, development of intolerance and/or adverse events, which were significant in the bimatoprost group, 28.6% (P < 0.001) and 48.6% (P < 0.001), respectively. Conclusions Latanoprost shows higher patient persistence compared with travoprost, bimatoprost, and timolol in routine clinical practice, and could lead to better control of intraocular pressure and lower associated economic costs. PMID:20463793

  2. First-line combination therapy versus first-line monotherapy for primary hypertension.

    PubMed

    Garjón, Javier; Saiz, Luis Carlos; Azparren, Ana; Elizondo, José J; Gaminde, Idoia; Ariz, Mª José; Erviti, Juan

    2017-01-13

    Starting with one drug and starting with a combination of two drugs are strategies suggested in clinical guidelines as initial treatment of hypertension. The recommendations are not based on evidence about clinically relevant outcomes. Some antihypertensive combinations have been shown to be harmful. The actual harm-to-benefit balance of each strategy is unknown. To determine if there are differences in clinical outcomes between monotherapy and combination therapy as initial treatment for primary hypertension. We searched the Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 2), Ovid MEDLINE, Ovid Embase, LILACS, ClinicalTrials.gov, Current Controlled Trials, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to February 2016. We searched in clinical studies repositories of pharmaceutical companies, reviews of combination drugs in Food and Drug Administration and European Medicines Agency, and lists of references in reviews and clinical practice guidelines. Randomized, double-blind trials with at least 12 months' follow-up in adults with primary hypertension (systolic blood pressure/diastolic blood pressure 140/90 mmHg or higher, or 130/80 mmHg or higher if participants had diabetes), which compared combination of two first-line antihypertensive drug with monotherapy as initial treatment. Trials had to include at least 50 participants per group and report mortality, cardiovascular mortality, cardiovascular events or serious adverse events. Two authors independently selected trials for inclusion, evaluated the risk of bias and entered the data. Primary outcomes were mortality, serious adverse events, cardiovascular events and cardiovascular mortality. Secondary outcomes were withdrawals due to drug-related adverse effects, reaching blood pressure control (as defined in each trial) and blood pressure change from baseline. Analyses were based on the intention

  3. Capecitabine Monotherapy: Review of Studies in First-Line HER-2-Negative Metastatic Breast Cancer

    PubMed Central

    Kaufmann, Manfred; Siedentopf, Friederike; Dalivoust, Philippe; Debled, Marc; Robert, Nicholas J.; Harbeck, Nadia

    2012-01-01

    The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta-analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first-line anthracycline-based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first-line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first-line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel agents. First-line capecitabine monotherapy has a favorable safety profile, lacking myelosuppression and alopecia, and does not compromise the administration of further lines of chemotherapy. Capecitabine is suitable for long-term administration without the cumulative toxicity that can limit the prolonged use of other chemotherapy agents. Here, we review the available data on capecitabine as a single agent for first-line treatment of patients with human epidermal growth factor receptor 2–negative MBC. PMID:22418569

  4. Nivolumab Monotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer.

    PubMed

    Gettinger, Scott; Rizvi, Naiyer A; Chow, Laura Q; Borghaei, Hossein; Brahmer, Julie; Ready, Neal; Gerber, David E; Shepherd, Frances A; Antonia, Scott; Goldman, Jonathan W; Juergens, Rosalyn A; Laurie, Scott A; Nathan, Faith E; Shen, Yun; Harbison, Christopher T; Hellmann, Matthew D

    2016-09-01

    Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has demonstrated improved survival over docetaxel in previously treated advanced non-small-cell lung cancer (NSCLC). First-line monotherapy with nivolumab for advanced NSCLC was evaluated in the phase I, multicohort, Checkmate 012 trial. Fifty-two patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity; postprogression treatment was permitted per protocol. The primary objective was to assess safety; secondary objectives included objective response rate (ORR) and 24-week progression-free survival (PFS) rate; overall survival (OS) was an exploratory end point. Any-grade treatment-related adverse events (AEs) occurred in 71% of patients, most commonly: fatigue (29%), rash (19%), nausea (14%), diarrhea (12%), pruritus (12%), and arthralgia (10%). Ten patients (19%) reported grade 3 to 4 treatment-related AEs; grade 3 rash was the only grade 3 to 4 event occurring in more than one patient (n = 2; 4%). Six patients (12%) discontinued because of a treatment-related AE. The confirmed ORR was 23% (12 of 52), including four ongoing complete responses. Nine of 12 responses (75%) occurred by first tumor assessment (week 11); eight (67%) were ongoing (range, 5.3+ to 25.8+ months) at the time of data lock. ORR was 28% (nine of 32) in patients with any degree of tumor PD-ligand 1 expression and 14% (two of 14) in patients with no PD-ligand 1 expression. Median PFS was 3.6 months, and the 24-week PFS rate was 41% (95% CI, 27 to 54). Median OS was 19.4 months, and the 1-year and 18-month OS rates were 73% (95% CI, 59 to 83) and 57% (95% CI, 42 to 70), respectively. First-line nivolumab monotherapy demonstrated a tolerable safety profile and durable responses in first-line advanced NSCLC. © 2016 by American Society of Clinical Oncology.

  5. Effectiveness of first-line pegvisomant monotherapy in acromegaly: an ACROSTUDY analysis.

    PubMed

    Tritos, Nicholas A; Chanson, Philippe; Jimenez, Camilo; King, Donna; Jönsson, Peter J; Klibanski, Anne; Biller, Beverly M K

    2017-02-01

    To examine the effectiveness and safety of primary pegvisomant monotherapy. Retrospective analysis of data extracted from ACROSTUDY (global observational outcomes study of patients with acromegaly treated with pegvisomant). The earliest time to insulin-like growth factor 1 (IGF-1) normalization on pegvisomant monotherapy was determined. Both the proportion of patients who achieved IGF-1 normalization and the time to IGF-1 normalization on pegvisomant monotherapy were assessed. Eligible patients included 28 subjects on primary medical therapy (PT) and 176 controls on adjunctive pegvisomant therapy treated postoperatively, including 43 who were naïve to medical therapy (NMT) and 133 who were previously treated medically and were washed out (WASH). IGF-1 normalization occurred in 76.9% (PT), 85.2% (NMT) and 78.3% (WASH) patients (P = NS). Median times to IGF-1 normalization were 0.5 year (PT), 0.7 year (NMT) and 0.6 year (WASH), P = NS. On survival analysis, the fraction of patients controlled on pegvisomant monotherapy was not different between groups. Higher baseline IGF-1 levels, obtained at study entry, predicted a lower likelihood of IGF-1 normalization on monotherapy (P = 0.012). Safety data include low prevalence of skin rashes, injection site reactions and reversible transaminase elevations. There was one patient (NMT) with a verified increase in tumor size. Pegvisomant monotherapy, administered either as primary medical therapy or as adjunctive therapy according to local practice, led to IGF-1 normalization in >75% of patients. Pegvisomant monotherapy had a favorable safety profile, consistent with previous observations. Prospective data are needed to further evaluate the role of primary pegvisomant monotherapy in acromegaly. © 2017 European Society of Endocrinology.

  6. Clinical evidence for caspofungin monotherapy in the first-line and salvage therapy of invasive Aspergillus infections.

    PubMed

    Heinz, Werner J; Buchheidt, Dieter; Ullmann, Andrew J

    2016-08-01

    In 2001, caspofungin received market authorisation by the FDA and EMA and is globally licensed for several indications, including candidiasis, empirical antifungal therapy in patients with neutropenic fever of unknown origin and treatment of invasive aspergillosis in patients refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B or itraconazole. Despite the lack of phase III data in first-line treatment of invasive aspergillosis, increasing evidence supports the use of first-line therapy. Here, we analyse the evidence of therapeutic activity, represented by favourable response rates, of caspofungin for invasive aspergillosis. A systematic literature search was conducted to identify international presentations and papers reporting monotherapy with caspofungin. Efficacy data are summarised separately for first-line and salvage therapy. Thirty-one papers and published abstracts reported caspofungin therapy for aspergillosis. Fifteen full papers and two abstracts fulfilled the criteria of reporting significant outcome data for caspofungin monotherapy for invasive aspergillosis. Consistent with other analyses and the known safety profile, few adverse events and associated terminations of caspofungin medication have been reported. Although a randomised, comparative, prospective study using caspofungin in this indication is still lacking, growing evidence supports the efficacy of this echinocandin not only for salvage but also for first-line therapy.

  7. Cost Effectiveness of First-Line Treatment with Doxorubicin/Ifosfamide Compared to Trabectedin Monotherapy in the Management of Advanced Soft Tissue Sarcoma in Italy, Spain, and Sweden

    PubMed Central

    Guest, Julian F.; Sladkevicius, Erikas; Gough, Nicholas

    2013-01-01

    Background. Doxorubicin/ifosfamide is a first-line systemic chemotherapy for the majority of advanced soft tissue sarcoma (ASTS) subtypes. Trabectedin is indicated for the treatment of ASTS after failure of anthracyclines and/or ifosfamide; however it is being increasingly used off-label as a first-line treatment. This study estimated the cost effectiveness of these two treatments in the first-line management of ASTS in Italy, Spain, and Sweden. Methods. A Markov model was constructed to estimate the cost effectiveness of doxorubicin/ifosfamide compared to trabectedin monotherapy, defined as the cost per QALY gained, in each country. Results. First-line treatment with doxorubicin/ifosfamide resulted in lower two-year healthcare costs and more QALYs than first-line treatment with trabectedin monotherapy in all three countries. Probabilistic sensitivity analysis showed that at a cost per QALY threshold of €35,000, >90% of a cohort would be cost effectively treated with doxorubicin/ifosfamide compared to trabectedin monotherapy in all three countries. Conclusion. Within the model's limitations, first-line treatment of patients with ASTS with doxorubicin/ifosfamide instead of trabectedin monotherapy affords a cost-effective use of publicly funded healthcare resources in Italy, Spain, and Sweden and is therefore the preferred treatment in all three countries. These findings support the recommendation that trabectedin should remain a second-line treatment. PMID:24302852

  8. Necessity of re-evaluation of estramustine phosphate sodium (EMP) as a treatment option for first-line monotherapy in advanced prostate cancer.

    PubMed

    Kitamura, T

    2001-02-01

    Estramustine phosphate sodium (EMP) was first introduced in the early 1970s for the treatment of prostate cancer, when EMP was supposed to have the dual effect of estrogenic activity and cytotoxicity. For the following decades, it was used mainly in hormone-refractory cases, with a conventional dosage of 4-9 capsules/day, which showed a 30-35% objective response rate. However, a very limited number of cases have been reported that used EMP as a first-line monotherapy in the conventional dosage. One study showed a response rate of 82%, which is at least as effective as conventional estrogen (diethylstilbestrol; DES) monotherapy. Nevertheless, EMP was almost abandoned for the treatment of prostate cancer because of severe adverse side-effects, especially in the cardiovascular system and gastrointestinal tract. Recently, two facts have become evident. First, EMP interferes with cellular microtubule dynamics but does not show alkylating effects. Second, EMP is able to produce a complex with calcium when dairy products are taken concomitantly with EMP, resulting in a decrease in the absorption rate of EMP from the gut. Many clinical trials have been undertaken without warning against concomitant dairy product intake since the introduction of EMP. This fact will jeopardize almost all the clinical trials performed before 1990. It is considered that response rates have been underestimated and better results could have been obtained because side-effects decrease dose-dependently. Low-dose EMP monotherapy (2 capsules/day) has been performed infrequently in previously untreated advanced prostate cancer. The only large trial by the European Organization for Research and Treatment of Cancer in 1984 was biased in selecting patients. Nevertheless, the response rate of EMP is comparable to that of DES. In this study, the adverse side-effects of EMP were less than that of DES. Recently, a study was conducted at the University of Tokyo of 11 patients with advanced prostate cancer on

  9. Combined sildenafil with vacuum erection device therapy in the management of diabetic men with erectile dysfunction after failure of first-line sildenafil monotherapy.

    PubMed

    Sun, Lu; Peng, Fang-Li; Yu, Zhi-Ling; Liu, Cai-Ling; Chen, Jun

    2014-12-01

    To evaluate the efficacy and safety of combination therapy of sildenafil plus vacuum erection devices in men with type 2 diabetes mellitus with moderate to severe erectile dysfunction who are dissatisfied with the results of using sildenafil alone. The study included 66 diabetes mellitus patients presenting erectile dysfunction for at least 6 months and dissatisfied with the use of 100 mg sildenafil monotherapy. The patients were randomized in two groups. Those in group A (n = 33) were instructed to use a vacuum erection device only, whereas those in group B (n = 33) were treated with combination therapy, including sildenafil 100 mg and a vacuum erection device. Erectile function was evaluated subjectively using the International Index of Erectile Function, Sexual Encounter Profile questionnaire questions 2 and 3 at visit 1 (baseline; study entry), visit 2 (4 weeks after baseline), and visit 3 (12 weeks after baseline; study end). There were no significant differences in average patient age, duration of diabetes, duration of erectile dysfunction, baseline International Index of Erectile Function scores, hypertension, blood testosterone, smoking and alcohol consumption between two groups. Mean International Index of Erectile Function scores were significantly higher for group B at the 1-month (14.86 ± 2.17 vs 12.41 ± 2.63; P < 0.0001) and 3-months (17.53 ± 2.95 vs 14.29 ± 2.81; P < 0.0001) visits. Men in group B had better successful penetration (73.3% vs 46.6%) and successful intercourse (70% vs 46.6%) at 3 months compared with group A. Combined use of sildenafil and vacuum erection device therapy significantly enhances erectile function, and it is well tolerated by diabetes mellitus patients not responding to first-line sildenafil alone. © 2014 The Japanese Urological Association.

  10. [The circadian effects of antiglaucomatous drugs].

    PubMed

    Bron, A

    2004-09-01

    To collect data reflecting the current knowledge on the interactions of medical antiglaucomatous therapy and circadian variations. Review of the available literature published on this topic in common electronic databases. The IOP-reducing effect of a molecule throughout the day depends on many parameters and still remains poorly investigated. It is well known that beta-blockers have a poor efficacy at night, while prostaglandins prevent nocturnal IOP variations because of their original mechanism. The lack of a 24-hour IOP recording device limits our ability to track the effect of antiglaucomatous drugs over 24 hours, an important point because these antiglaucomatous drugs vary in terms of their capacity to reduce IOP over a 24-hour period. Assessing the effect of antiglaucomatous therapy on a 24-hour basis remains very difficult. However, in the next few Years, this could become an emerging focus point in the management of glaucoma. Copyright 2004 Masson

  11. Protease Inhibitor Resistance Analysis in the MONARK Trial Comparing First-Line Lopinavir-Ritonavir Monotherapy to Lopinavir-Ritonavir plus Zidovudine and Lamivudine Triple Therapy▿

    PubMed Central

    Delaugerre, Constance; Flandre, Philippe; Chaix, Marie Laure; Ghosn, Jade; Raffi, François; Dellamonica, Pierre; Jaeger, H.; Shürmann, D.; Cohen-Codar, Isabelle; Ngo Van, Philippe; Norton, Michael; Taburet, Anne-Marie; Delfraissy, Jean-François; Rouzioux, Christine

    2009-01-01

    The MONARK study was a pilot randomized trial comparing the safety and efficacy of lopinavir-ritonavir (LPV/r) monotherapy to those of LPV/r-zidovudine-lamivudine triple therapy for antiretroviral-naïve human immunodeficiency virus type 1 (HIV-1)-infected patients. Resistance testing was performed at the time of initial screening and at the time of virological failure (defined to include low-level viremia with >50 and <400 HIV-1 virus RNA copies/ml of plasma). Changes from the baseline sequences, including mutations noted on the 2008 International AIDS Society—USA list of resistance-associated protease mutations, were considered. Drug resistance testing was performed for 38 patients (5 of 53 on triple therapy and 33 of 83 on monotherapy). By week 96 (W96), virus samples from 18 of 33 patients in the monotherapy arm showed changes from baseline sequences, and 5 of these patients had viruses with major protease inhibitor (PI) resistance-associated mutations (M46I at W40, L76V at W48, M46I and L76V at W48, L10F and V82A at W72, and L76V at W84). Data on virus phenotypes detected at the time of initial screening and the time of virological failure were available for four patients in whom major PI resistance mutations developed, and these data revealed a mean increase of 2.2-fold (range, 0.75- to 4.6-fold) in the LPV 50% inhibitory concentration. All three patients in whom the L76V PI resistance mutation developed were infected with HIV-1 subtype CRF02_AG. In the triple-therapy group, no major PI resistance mutation was selected among the three patients with protease changes by W48. No association between the baseline CD4 cell count and the viral load, the W4 and final viral loads, or the final LPV trough concentration and the emergence of a major PI resistance mutation was found. Major PI resistance-associated mutations were detected in 5 (6%) of 83 patients treated with LPV/r monotherapy, suggesting that LPV/r monotherapy is an inappropriate first option. The

  12. Cost-Effectiveness of Nivolumab-Ipilimumab Combination Therapy Compared with Monotherapy for First-Line Treatment of Metastatic Melanoma in the United States.

    PubMed

    Oh, Anna; Tran, Dang M; McDowell, Leann C; Keyvani, Dor; Barcelon, Jay Andrew; Merino, Oscar; Wilson, Leslie

    2017-06-01

    The approval of new immunotherapies has dramatically changed the treatment landscape of metastatic melanoma. These survival gains come with trade-offs in side effects and costs, as well as important considerations for third-party payer systems, physicians, and patients. To develop a Markov model to determine the cost-effectiveness of nivolumab, ipilimumab, and nivolumab-ipilimumab combination as firstline therapy in metastatic melanoma, while accounting for differential effectiveness in programmed death-ligand 1 (PD-L1) positive and negative patients. A 3-state Markov model (PD-L1 positive stable disease, PD-L1 negative stable disease, and progression and/or death) was developed using a U.S. societal perspective with a lifetime time horizon of 14.5 years. Transition probabilities were calculated from progression-free (PF) survival data reported in the CheckMate-067 trial. Costs were expressed in 2015 U.S. dollars and were determined using national sources. Adverse event (AE) management was determined using immune-related AE (irAE) data from CheckMate-067, irAE management guides for nivolumab and ipilimumab, and treatment guidelines. Utilities were obtained from published literature, using melanoma-specific studies when available, and were weighted based on incidence and duration of irAEs. Base case, one-way sensitivity, and probabilistic sensitivity analyses were conducted. Nivolumab-ipilimumab combination therapy was not the cost-effective choice ($454,092 per PF quality-adjusted life-year [QALY]) compared with nivolumab monotherapy in a base case analysis at a willingness-to-pay threshold of $100,000 per PFQALY. Combination therapy and nivolumab monotherapy were cost-effective choices compared with ipilimumab monotherapy. PD-L1 positive status, utility of nivolumab and combination therapy, and medication costs contributed the most uncertainty to the model. In a population of 100% PD-L1 negative patients, nivolumab was still the optimal treatment, but combination

  13. The Effect of Long-term Antiglaucomatous Drug Administration on Central Corneal Thickness.

    PubMed

    Schrems, Wolfgang A; Schrems-Hoesl, Laura M; Mardin, Christian Y; Horn, Folkert K; Juenemann, Anselm G M; Kruse, Friedrich E; Braun, Joachim M; Laemmer, Robert

    2016-03-01

    To evaluate rates of changes per year of central corneal thickness after antiglaucomatous drug administration with β-blockers, prostaglandin analogs, and carbonic anhydrase inhibitors monotherapy and combined topical antiglaucomatous therapy, in a cohort of patients with ocular hypertension, glaucoma suspects, and patients with perimetric glaucoma as compared with normal controls. This retrospective single-center study included 130 eyes as healthy controls, 121 eyes of ocular hypertensive patients, 105 eyes of glaucoma suspects, and 49 eyes of perimetric glaucoma patients. All patients underwent standard automated perimetry, 24-hour intraocular pressure profile, optic disc photography, and optical coherence pachymetry (OCP; Heidelberg Engineering). The cohort was divided into 8 groups on the basis of topical antiglaucomatous medication. Linear regression analysis was conducted to analyze the relationship between central corneal thickness and exposure to antiglaucomatous medication during the follow-up. Central corneal thickness did not change during the follow-up for investigated diagnostic subgroups. There was a statistically significant decrease in central corneal thickness for eyes treated with prostaglandin monotherapy (-3.1 μm/y for left eye), and a combined therapy with prostaglandins, carbonic anhydrase inhibitors, and β-blockers (-5.8 and -3.8 μm/y for right and left eye, respectively). We recommend regular measurements before and during therapy with prostaglandin monotherapy and a combined therapy with prostaglandins, carbonic anhydrase inhibitors, and β-blockers. Follow-up intraocular pressure measurements may be underestimated for eyes treated with the aforementioned treatment regimens if central corneal thickness is not measured on a regular basis.

  14. Valproic Acid versus Lamotrigine as First-line Monotherapy in Newly Diagnosed Idiopathic Generalized Tonic –Clonic Seizures in Adults – A Randomized Controlled Trial

    PubMed Central

    Giri, Om Prakash; Khan, Farhan Ahmad; Kumar, Narendra; Kumar, Ajay; Haque, Ataul

    2016-01-01

    Introduction Idiopathic Generalized Tonic-Clonic Seizures (GTCS) are frequently encountered in adults. Their successful control is necessary to improve the quality of life of these patients. Valproic acid is a simple branched-chain carboxylic acid and lamotrigine is a phenyltriazine derivative. Opinions differ in regards to their effectiveness in idiopathic GTCS. Aim To compare the effectiveness of valproic acid and lamotrigine in newly diagnosed adults with idiopathic generalized tonic-clonic seizures. Materials and Methods The present prospective randomized study was conducted on 60 patients suffering from idiopathic GTCS. Thirty patients received valproic acid and rest 30 patients received lamotrigine. All patients were followed regularly monthly for one year for treatment response and adverse effects. Results After 12 months follow-up, 76.67% patients taking valproic acid and 56.67% patients taking lamotrigine were seizure-free. Common adverse effects recorded were nausea, dyspepsia, headache and skin rash. Conclusion Valproic acid is more effective than lamotrigine as first-line drug in the treatment of adults with newly diagnosed idiopathic generalized tonic-clonic seizures. PMID:27630862

  15. Managing first-line failure.

    PubMed

    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.

  16. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: a randomised, phase 3 trial.

    PubMed

    Yang, James Chih-Hsin; Kang, Jin Hyoung; Mok, Tony; Ahn, Myung-Ju; Srimuninnimit, Vichien; Lin, Chia-Chi; Kim, Dong-Wan; Tsai, Chun-Ming; Barraclough, Helen; Altug, Sedat; Orlando, Mauro; Park, Keunchil

    2014-09-01

    In the Iressa Pan-ASia Study (IPASS), gefitinib claimed improved progression-free survival (PFS) versus carboplatin-paclitaxel in clinically selected lung cancer patients. The primary objective of this study was to assess the PFS of pemetrexed-cisplatin (PC) followed by gefitinib maintenance versus gefitinib monotherapy in an IPASS-like population. In this open-label, randomised, phase 3 trial, eligible patients were ⩾18 years, chemonaïve, East Asian, light ex-smokers/never-smokers with advanced non-squamous non-small cell lung cancer, an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and unknown epidermal growth factor receptor (EGFR) mutation status who enrolled at 12 sites in Asia. Patients randomly received (1:1) pemetrexed (500 mg/m(2)) plus cisplatin (75mg/m(2)) for six 21-day cycles, followed by gefitinib maintenance or gefitinib monotherapy (250 mg/day). Patient tissue was retrospectively analysed for EGFR mutations. This study is registered with ClinicalTrials.gov, NCT01017874. Between 23rd November 2009 and 27th April 2012, 253 patients entered, and 236 patients were randomly assigned to and treated with PC therapy (N=114) and gefitinib monotherapy (N=118). Between-arm baseline characteristics were balanced. PFS was not significantly different between treatment arms (p=0.217). The unadjusted hazard ratio (HR) was 0.85 (95% confidence interval (CI) 0.63-1.13). The HR should be cautiously interpreted as it was not constant. EGFR mutation status was determined for 74 tissue samples; 50 (67.6%) had mutations. In a pre-specified subgroup analysis, only the treatment-by-EGFR mutation interaction was significant (p=0.008) for PFS. For the entire treatment period, a higher proportion of patients in the PC/gefitinib arm versus gefitinib experienced possibly drug-related grade 3-4 treatment-emergent adverse events (39 of 114 [34%] versus 19 of 118 [16%]; p=0.002). In the intention-to-treat (ITT) population, PFS was not significantly different

  17. Dutasteride plus tamsulosin fixed-dose combination first-line therapy versus tamsulosin monotherapy in the treatment of benign prostatic hyperplasia: a budget impact analysis in the Greek healthcare setting.

    PubMed

    Geitona, Maria; Karabela, Pinelopi; Katsoulis, Ioannis A; Kousoulakou, Hara; Lyberopoulou, Eleni; Bitros, Eleftherios; Xaplanteris, Loukas; Papanicolaou, Sotiria

    2014-09-26

    The purpose of this study was to explore the budget impact of dutasteride plus tamsulosin fixed-dose combination (DUT + TAM FDC) versus tamsulosin monotherapy, in the treatment of patients with benign prostatic hyperplasia (BPH) from the perspective of the Greek healthcare insurance system. A Microsoft Excel-based model was developed to estimate the financial consequences of adopting DUT + TAM FDC within the Greek healthcare setting. The model, compared six mutually exclusive health states in two alternative treatment options: current standard of care and the introduction of DUT + TAM FDC in the market. The model used clinical inputs from the CombAT study; data on resource use associated with the management of BPH in Greece were derived from expert panel, and unit cost data were derived from official reimbursement tariffs. A payer perspective was taken into account. As patient distribution data between public and private sectors are not available in Greece two scenarios were investigated, considering the whole eligible population in each scenario. A 4 year time horizon was taken into account and included treatment costs, number of transurethral resections of the prostate (TURPs) and acute urinary retention (AUR) episodes avoided. The clinical benefit from the market adoption of DUT + TAM FDC in Greece was 1,758 TURPs and 972 episodes of AUR avoided cumulatively in a four year period. The increase in total costs from the gradual introduction of DUT + TAM FDC to the Greek healthcare system ranges from €1.3 million in the first year to €5.8 million in the fourth year, for the public sector, and €1.2 million to €4.0 million, for the private sector. This represents an increase of 1.91% to 7.94% for the public sector and 1.10% 3.29% in the private sector, during the 4-year time horizon. Budget impact analysis (BIA) results indicated that the gradual introduction of DUT + TAM FDC, would increase the overall budget of the disease, however providing

  18. Dutasteride plus Tamsulosin fixed-dose combination first-line therapy versus Tamsulosin Monotherapy in the treatment of benign prostatic hyperplasia: a budget impact analysis in the Greek healthcare setting

    PubMed Central

    2014-01-01

    Background The purpose of this study was to explore the budget impact of dutasteride plus tamsulosin fixed-dose combination (DUT + TAM FDC) versus tamsulosin monotherapy, in the treatment of patients with benign prostatic hyperplasia (BPH) from the perspective of the Greek healthcare insurance system. Methods A Microsoft Excel-based model was developed to estimate the financial consequences of adopting DUT + TAM FDC within the Greek healthcare setting. The model, compared six mutually exclusive health states in two alternative treatment options: current standard of care and the introduction of DUT + TAM FDC in the market. The model used clinical inputs from the CombAT study; data on resource use associated with the management of BPH in Greece were derived from expert panel, and unit cost data were derived from official reimbursement tariffs. A payer perspective was taken into account. As patient distribution data between public and private sectors are not available in Greece two scenarios were investigated, considering the whole eligible population in each scenario. A 4 year time horizon was taken into account and included treatment costs, number of transurethral resections of the prostate (TURPs) and acute urinary retention (AUR) episodes avoided. Results The clinical benefit from the market adoption of DUT + TAM FDC in Greece was 1,758 TURPs and 972 episodes of AUR avoided cumulatively in a four year period. The increase in total costs from the gradual introduction of DUT + TAM FDC to the Greek healthcare system ranges from €1.3 million in the first year to €5.8 million in the fourth year, for the public sector, and €1.2 million to €4.0 million, for the private sector. This represents an increase of 1.91% to 7.94% for the public sector and 1.10% 3.29% in the private sector, during the 4-year time horizon. Conclusions Budget impact analysis (BIA) results indicated that the gradual introduction of DUT + TAM FDC, would increase the overall

  19. Assessment of the Anterior Chamber Flare and Macular Thickness in Patients Treated with Topical Antiglaucomatous Drugs.

    PubMed

    Selen, Fırat; Tekeli, Oya; Yanık, Özge

    2017-04-01

    To determine the changes in the anterior chamber flare and central macular thickness (CMT) under topical antiglaucomatous therapy. This study included 121 eyes of 73 patients and 36 eyes of 18 controls. Glaucoma patients were divided into 3 groups (timolol maleate, latanoprost, and bimatoprost). Control eyes did not receive any medications. Flare and CMT measurements were performed at baseline and follow-up visits (15th day, and 1st, 3rd, 6th, and 12th month). Statistically significant increases were detected in the flare values in the bimatoprost and latanoprost groups (P < 0.001, P = 0.011, respectively). Significant increases were also found in CMT values measured in these 2 groups (P < 0.001, P = 0.002, respectively). However, increased flare and CMT values were not clinically manifested as uveitis and macular edema. Flare and CMT values did not change statistically in the timolol maleate and control groups. Although the use of prostaglandin (PG) analogs was found to be associated with increased flare and CMT, these increases were not clinically significant. PG analog monotherapy may be safely and effectively used in the treatment of glaucoma.

  20. A phase I followed by a randomized phase II trial of two cycles carboplatin-olaparib followed by olaparib monotherapy versus capecitabine in BRCA1- or BRCA2-mutated HER2-negative advanced breast cancer as first line treatment (REVIVAL): study protocol for a randomized controlled trial.

    PubMed

    Schouten, Philip C; Dackus, Gwen M H E; Marchetti, Serena; van Tinteren, Harm; Sonke, Gabe S; Schellens, Jan H M; Linn, Sabine C

    2016-06-21

    Preclinical studies in breast cancer models showed that BRCA1 or BRCA2 deficient cell lines, when compared to BRCA proficient cell lines, are extremely sensitive to PARP1 inhibition. When combining the PARP1 inhibitor olaparib with cisplatin in a BRCA1-mutated breast cancer mouse model, the combination induced a larger response than either of the two compounds alone. Several clinical studies have investigated single agent therapy or combinations of both drugs, but no randomized clinical evidence exists for the superiority of carboplatin-olaparib versus standard of care therapy in patients with BRCA1- or BRCA2--mutated metastatic breast cancer. This investigator-initiated study contains two parts. Part 1 is a traditional 3 + 3 dose escalation study of the carboplatin-olaparib combination followed by olaparib monotherapy. The carboplatin dose will be escalated from area under the curve (AUC) 3 to AUC 4 with an olaparib dose of 25 mg BID. Olaparib is subsequently escalated to 50, 75, and 100 mg BID until >1/6 of patients develop dose-limiting toxicity (DLT). The dose level below will be the maximum tolerable dose (MTD). It is expected that 15-20 patients are needed in Part I. In Part 2 BRCA1- or BRCA2-mutated HER2-negative breast cancer patients will be randomized between standard capecitabine 1250 mg/m(2) BID day 1-14 q day 22, versus 2 cycles carboplatin-olaparib followed by olaparib monotherapy 300 mg BID. In total 104 events in 110 patients need to be observed to detect a 75 % clinically meaningful improvement in progression-free survival (PFS), from a median of 4 months (control) to 7 months (experimental) assuming a 2-year accrual and ≥6 months of follow-up with 80 % power (5 %, two-sided significance level). After progression on first line treatment, patients will receive physician's best choice of paclitaxel, vinorelbine, eribulin, or capecitabine (experimental arm only) at standard dose. A compassionate use program of olaparib is available

  1. The clinical effectiveness and cost-effectiveness of cetuximab (mono- or combination chemotherapy), bevacizumab (combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal No.150 and part review of technology appraisal No. 118): a systematic review and economic model.

    PubMed

    Hoyle, M; Crathorne, L; Peters, J; Jones-Hughes, T; Cooper, C; Napier, M; Tappenden, P; Hyde, C

    2013-04-01

    Colorectal cancer is the third most commonly diagnosed cancer in the UK after breast and lung cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Recently, targeted agents have become available including anti-epidermal growth factor receptor (EGFR) agents, for example cetuximab and panitumumab, and anti-vascular endothelial growth factor (VEGF) receptor agents, for example bevacizumab. To investigate the clinical effectiveness and cost-effectiveness of panitumumab monotherapy and cetuximab (mono- or combination chemotherapy) for Kirsten rat sarcoma (KRAS) wild-type (WT) patients, and bevacizumab in combination with non-oxaliplatin chemotherapy, for the treatment of metastatic colorectal cancer after first-line chemotherapy. The assessment comprises a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions and a de novo cohort-based economic analysis. For the assessment of effectiveness, a literature search was conducted in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library, from 2005 to November 2010. Studies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab, bevacizumab or panitumumab in participants with EGFR-expressing metastatic colorectal cancer with KRAS WT status that has progressed after first-line chemotherapy (for cetuximab and panitumumab) or participants with metastatic colorectal cancer that has progressed after first-line chemotherapy (bevacizumab). All steps in the review were performed by one reviewer and checked independently by a second. Synthesis was mainly narrative. An economic model was developed focusing on third-line and subsequent lines of treatment. Costs and benefits were discounted at 3.5% per annum. Probabilistic and univariate deterministic sensitivity analyses were performed. The searches

  2. First-Line Pemetrexed plus Cisplatin followed by Gefitinib Maintenance Therapy versus Gefitinib Monotherapy in East Asian Never-Smoker Patients with Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer: Final Overall Survival Results from a Randomized Phase 3 Study.

    PubMed

    Yang, James Chih-Hsin; Srimuninnimit, Vichien; Ahn, Myung-Ju; Lin, Chia-Chi; Kim, Sang-We; Tsai, Chun-Ming; Mok, Tony; Orlando, Mauro; Puri, Tarun; Wang, Xin; Park, Keunchil

    2016-03-01

    The primary analysis of this open-label, randomized, multicenter phase 3 study revealed no significant difference in progression-free survival between pemetrexed plus cisplatin followed by maintenance gefitinib (PC/G) and gefitinib monotherapy (G) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) and unknown epidermal growth factor receptor gene (EGFR) mutation status; however, the hazard ratio favored PC/G. This report describes the final overall survival (OS) results. Chemonaive, East Asian light ex-smokers/never-smokers with advanced nonsquamous NSCLC and unknown EGFR mutation status were randomized (1:1) to PC/G (n = 118) or G (n = 118). EGFR mutation status was retrospectively determined for 76 patients, 52 (68.4%) of whom had EGFR-mutated tumors (exon 19 deletions in 26 and L858R point mutation in 24). OS was analyzed by the Kaplan-Meier method. The study was registered at ClinicalTrials.gov (NCT01017874). Median OS was similar in the PC/G (26.9 months) and G (27.9 months) groups (hazard ratio = 0.94, 95% confidence interval: 0.68-1.31, p = 0.717). Median OS was longer with PC/G than with G in patients with EGFR wild-type tumors (28.4 versus 8.9 months) and longer with G than with PC/G in patients with EGFR-mutated tumors (45.7 versus 32.4 months), especially those with exon 19 deletions. Second-line postdiscontinuation therapy was common and included chemotherapy (PC/G, 41 of 118 [34.7%]; G, 73 of 118 [61.9%]) and rechallenge with an EGFR tyrosine kinase inhibitor (PC/G, 27 of 118 [22.9%]; G, 9 of 118 [7.6%]). The progression-free survival and OS results from this study further demonstrate the importance of determining EGFR mutation status to select the most appropriate first-line treatment for patients with advanced NSCLC. Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  3. Systemic first-line phenotyping.

    PubMed

    Gailus-Durner, Valérie; Fuchs, Helmut; Adler, Thure; Aguilar Pimentel, Antonio; Becker, Lore; Bolle, Ines; Calzada-Wack, Julia; Dalke, Claudia; Ehrhardt, Nicole; Ferwagner, Barbara; Hans, Wolfgang; Hölter, Sabine M; Hölzlwimmer, Gabriele; Horsch, Marion; Javaheri, Anahita; Kallnik, Magdalena; Kling, Eva; Lengger, Christoph; Mörth, Corinna; Mossbrugger, Ilona; Naton, Beatrix; Prehn, Cornelia; Puk, Oliver; Rathkolb, Birgit; Rozman, Jan; Schrewe, Anja; Thiele, Frank; Adamski, Jerzy; Aigner, Bernhard; Behrendt, Heidrun; Busch, Dirk H; Favor, Jack; Graw, Jochen; Heldmaier, Gerhard; Ivandic, Boris; Katus, Hugo; Klingenspor, Martin; Klopstock, Thomas; Kremmer, Elisabeth; Ollert, Markus; Quintanilla-Martinez, Leticia; Schulz, Holger; Wolf, Eckhard; Wurst, Wolfgang; de Angelis, Martin Hrabé

    2009-01-01

    With the completion of the mouse genome sequence an essential task for biomedical sciences in the twenty-first century will be the generation and functional analysis of mouse models for every gene in the mammalian genome. More than 30,000 mutations in ES cells will be engineered and thousands of mouse disease models will become available over the coming years by the collaborative effort of the International Mouse Knockout Consortium. In order to realize the full value of the mouse models proper characterization, archiving and dissemination of mouse disease models to the research community have to be performed. Phenotyping centers (mouse clinics) provide the necessary capacity, broad expertise, equipment, and infrastructure to carry out large-scale systemic first-line phenotyping. Using the example of the German Mouse Clinic (GMC) we will introduce the reader to the different aspects of the organization of a mouse clinic and present selected methods used in first-line phenotyping.

  4. Modified by air plasma polymer tack membranes as drainage material for antiglaucomatous operations

    NASA Astrophysics Data System (ADS)

    Ryazantseva, T. V.; Kravets, L. I.; Elinson, V. M.

    2014-06-01

    The morphological and clinical studies of poly(ethylene terephthalate) track membranes modified by air plasma as drainage materials for antiglaucomatous operations were performed. It was demonstrated their compatibility with eye tissues. Moreover, it was shown that a new drainage has a good lasting hypotensive effect and can be used as operation for refractory glaucoma surgery.

  5. Tolerability and Outcomes of First-Line Pemetrexed-Cisplatin Followed by Gefitinib Maintenance Therapy Versus Gefitinib Monotherapy in Korean Patients with Advanced Nonsquamous Non-small Cell Lung Cancer: A Post Hoc Descriptive Subgroup Analysis of a Randomized, Phase 3 Trial.

    PubMed

    Kang, Jin Hyoung; Ahn, Myung-Ju; Kim, Dong-Wan; Cho, Eun Kyung; Kim, Joo-Hang; Shin, Sang Won; Wang, Xin; Kim, Jong Seok; Orlando, Mauro; Park, Keunchil

    2016-04-01

    We recently reported on a randomized, open-label, phase 3 trial comparing pemetrexed-cisplatin chemotherapy followed by gefitinib maintenance therapy (PC/G) with gefitinib monotherapy in patients with non-small cell lung cancer (NSCLC). Here, we report on a post hoc subgroup analysis of that study assessing the demographics and disposition of the Korean patient subgroup, and comparing the tolerability of PC/G and gefitinib monotherapy and the tumor response with respect to epidermal growth factor receptor (EGFR) status. Patients, who were ≥ 18 years, chemonaïve, Korean, light ex-smokers/never-smokers with advanced NSCLC, were randomly assigned (1:1) to PC/G or gefitinib monotherapy. Treatment-emergent adverse events (TEAEs) were graded, and tumor response was measured as change in lesion sum from baseline at best response. The study was registered with ClinicalTrials. gov, NCT01017874. Overall, 111 Korean patients were treated (PC/G, 51; gefitinib, 60). Between-arm characteristics were balanced and similar to those of the overall population. Treatment discontinuations due to adverse events were low (PC/G: 1, 2.0%; gefitinib: 7, 11.7%). Overall, 92 patients (82.9%) reported ≥ 1 TEAE (PC/G, 44; gefitinib, 48); few patients (PC/G, 16; gefitinib, 7) reported severe TEAEs; the most frequent was neutropenia (PC/G arm) and elevated alanine aminotransferase (gefitinib arm). The lesion sum was decreased by PC/G treatment in most patients, regardless of EGFR mutation status, while gefitinib monotherapy reduced the lesion sum in EGFR-positive patients but had no effect in EGFR-negative patients. Our results confirm that both PC/G and gefitinib were well tolerated in Korean patients, regardless of EGFR status; however, patients with EGFR wild-type NSCLC may not benefit from gefitinib monotherapy.

  6. A decrease of the rabbit's physiologic IOP after the application of specific amino acids and double combination of antiglaucomatics mixture.

    PubMed

    Olah, Z; Veselovsky, J

    2013-01-01

    To compare the effect of amino acids mixtures to a double combination of antiglaucomatics on the physiologic intraocular pressure (IOP) in rabbits. Experimental evaluations were performed on 5 female rabbits of the New Zealand White species. 1) After instillation of 10 % L-arginine. HCl in the double combination of antiglaucomatics: a) 0.5 % Timolol with 0.005 % Xalatan mixture, the biphasic IOP decrease was measured. The mean decrease in 24 hours was - 2.9 torr; b) 2 % Trusopt with 0.005 % Xalatane mixture in 24 hours, the biphasic decrease of the IOP was measured. The mean decrease in 24 hours was - 4.2 torr; c) Fixed combination COSOPT the mean IOP value decrease was - 1.8 torr. 2) The IOP decrease achieved during 24 hours by instillation of the amino acid 10 % L-taurine.HCl and the double combination of antiglaucomatics: 0.5% Timolol with 0.005% Xalatane mixture was in average - 2.8 torr. The pupilar diameter was not changed. We assume that after the interaction of the selected amino acids 10 % L-arginin or 10 % L-taurin with the double combination of antiglaucomatics (Trusopt and Xalatan, COSOPT or Timoptol and Xalatan) a new substance was formed. The effect of this substance is not separate or additive but acts as a newly formed substance. In vivo, it is only a weak interaction with the free amino acids of the conjunctival sac and the antiglaucomatics. The amino acids interacted in vitro with the double combination of antiglaucomatics resulting in a new "bio-antiglaucomatic" better penetrating into the target area. This new substance was responsible for a more significant decrease and regulation IOP after the mixture application compared to the antiglaucomatics alone (Fig. 1, Ref. 23).

  7. Do antiglaucomatous prostaglandins induce melanogenesis in human conjunctiva?: an impression cytology pilot study.

    PubMed

    Cagigrigoriu, Andrea; Boero, Elena; Carenini, Alessandra Boles; Rolle, Teresa; Cappia, Susanna; Bacillo, Elisa; Papotti, Mauro; Gregori, Dario; Brovarone, Filippo Vitale; Grignolo, Federico Maria

    2010-01-01

    To determine the effect of antiglaucomatous prostaglandin analogs on conjunctival melanogenesis. For this pilot study, 30 glaucomatous patients treated with prostaglandin drops (alone and in association to beta-blockers) and 30 control subjects (15 healthy volunteers and 15 patients treated with beta-blockers) were included in this transversal, single masked, case-control, observational study. Skin complexion, eye color, conjunctival pigmentation, lacrimal tests, and corneal fluorescein staining were evaluated. Immunoreactivity for Tyrosinase was assayed on conjunctival imprints. Twenty percent of patients treated with prostaglandins and 10% of the control subjects clinically manifested conjunctival pigmentation (P=0.279). Only 4% (8/198) of the conjunctival specimens were positive to Tyrosinase immunostaining, with no statistically significant difference among the groups (P=0.449). In all cases, the proportion of positive cells was below 4%. When compared with subjects having negative specimens, those with positive immunostains did not show any statistically significant difference in skin complexion, eye color or exposure to irritants, and ultraviolet (P>0.05). According to our preliminary results, prostaglandin antiglaucomatous analogs do not significantly enhance pigmentation in the superficial layers of the conjunctiva. The existence of the Tyrosinase enzyme in the superficial layers of the conjunctiva suggests that basal melanocytes may transfer their melanogenic apparatus to superficial epithelial cells.

  8. [Results of the IOP decrease after application of some mixtures of amino acids and antiglaucomatics in rabbits (a review of experimental publications)].

    PubMed

    Oláh, Z; Veselovský, J

    2011-01-01

    To summarise of experimental results performed on rabbit eyes focused to influence the physiological intraocular pressure (lOP) after application of some amino acids mixture with some regularly used antiglaucomatics. The experiments were performed on adult rabbits (female of the New Zealand White species). The applicated substances were: 10% solution of amino acids (L-lysin.2HCl.2H2O, L-arginine.HCL or L-glycine.HCL) in antiglau-comatics 0.5% timolol (Timoptol) or 0.005% latanoprost (Xalatan). This mixture was applicated to the left eye; right eye was used as control. The measurement of IOP and pupil diameter was performed before instillation, in 15th, 30th, 60th, 180th, 240th minute and 24 hours after application. Functional bioactivity of the used antiglaucomatics in case of decreased lOP is rising after interaction with the relevant specific amino acid. Glycine in timolol showed the highest effect on average decrease of the lOP physiological values (lOP decrease reached - 5,5 torr) followed by arginine in timolol (lOP decrease reached - 3,3 torr). The lOP decrease after other combinations of amino acids and antiglaucomatics was in average lower or nonsignificant. Through interaction between in vitro prepared mixture free amino acids and antiglaucomatics a new, biologically active substance (metabolite) is created. After instillation in experimental condition achieving stronger and longer decrease of the lOP compared with a single antiglaucomatic or amino acid.

  9. The AMBITION trial: tocilizumab monotherapy for rheumatoid arthritis.

    PubMed

    Jones, Graeme

    2010-03-01

    Recent years have seen many exciting developments in the treatment of inflammatory arthritis. Tocilizumab (TCZ) is a compound that inhibits the IL-6 receptor. Following initial studies in Japan, it has been extensively studied in five multicenter clinical trials. This report concentrates on the Actemra Versus Methotrexate Double-blind Investigative Trial in Monotherapy (AMBITION), which compared TCZ monotherapy (8 mg/kg every 4 weeks) with methotrexate monotherapy over 24 weeks. TCZ was shown to be the first biologic agent that is superior to methotrexate across a whole range of clinical outcomes measures with a rapid onset of effect. Significant liver toxicity was less common in the TCZ group. However, increases in lipids and decreases in neutrophils and skin infections were more common in the TCZ arm. Long-term efficacy and safety follow-up is ongoing. This trial supports the use of TCZ as monotherapy and suggests it should be regarded as a first-line biologic therapy.

  10. Sulthiame monotherapy for epilepsy.

    PubMed

    Milburn-McNulty, Philip; Powell, Graham; Sills, Graeme J; Marson, Anthony G

    2014-03-09

    Epilepsy is a common neurological condition characterised by recurrent seizures. Sulthiame (STM) is widely used as an antiepileptic drug in Europe and Israel. In this review, we present a summary of evidence for the use of STM as monotherapy in epilepsy. To examine the efficacy and side effect profile of STM as monotherapy when compared with placebo or another antiepileptic drug. We searched the Cochrane Epilepsy Group Specialised Register (24 October 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 9), MEDLINE Ovid (1946 to 24 October 2013), SCOPUS (1823 to 24 October 2013), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (28 October 2013) and ClinicalTrials.gov (28 October 2013). We imposed no language restrictions. We contacted the manufacturers of STM and researchers in the field to ask about ongoing and unpublished studies. Randomised controlled monotherapy trials of STM in people of any age with epilepsy of any aetiology. Two review authors independently selected trials for inclusion and extracted the relevant data.The following outcomes were assessed: (1) time to treatment failure; (2) time to 12-month remission; (3) proportion seizure free at 12 months; (4) adverse effects; and (5) quality of life scoring. Primary analyses were intention-to-treat when possible. A narrative analysis of the data was presented. Two studies representing 100 participants with a diagnosis of benign epilepsy of childhood with centrotemporal spikes (BECTS) and one study representing 146 participants with a diagnosis of generalised tonic-clonic seizures (GTCS) were included. STM was given as monotherapy compared with placebo in the BECTS studies and compared with phenytoin in the GTCS study. An English translation of the full text of one of the BECTS studies could not be found, and analysis of this study was based solely on the English translation of the abstract. No data were reported for

  11. Efficacy of indomethacin 0.1% and fluorometholone 0.1% on conjunctival inflammation following chronic application of antiglaucomatous drugs.

    PubMed

    Baudouin, Christophe; Nordmann, Jean-Philippe; Denis, Philippe; Creuzot-Garcher, Catherine; Allaire, Catherine; Trinquand, Claude

    2002-11-01

    Subclinical conjunctival inflammation has been shown to have a deleterious effect on the outcome of filtering surgery. The study was designed to assess the efficacy and safety of a non-steroidal anti-inflammatory ophthalmic solution (preservative-free indomethacin 0.1%) on conjunctival inflammation following chronic application of antiglaucomatous drugs, in comparison with a steroidal ophthalmic solution (preserved fluorometholone). Eighty-nine glaucomatous patients were included in a randomised, multicentre study comparing two parallel groups of treatment given on the basis of 1 drop 4 times daily for 1 month before filtering surgery. Patients had been treated with one or more antiglaucomatous drugs for at least 3 years. The routine antiglaucomatous treatment was continued during the study. Evaluations were carried out at baseline and after 30 days of treatment. Conjunctival inflammation was assessed under masked conditions by means of conjunctival impression analysis which determined the percentage of cells expressing HLA-DR. The ocular surface was also examined using the fluorescein test and lissamine green staining. Paired conjunctival impression specimens available both on day 0 (D0) and day 30 (D30) involved 49 patients. Among them, 34 eyes had a positive expression of HLA-DR at inclusion. On D30, in patients positive to HLA-DR on D0, the percentage of cells expressing HLA-DR had significantly decreased in both treatment groups: the mean reduction was 29.7% from a baseline value of 51.4% in the indomethacin group ( P=0.019) and 32.5% from a baseline value of 48.7% in the fluorometholone group ( P<0.001). There was no significant difference between groups. Seven cases of drug-related superficial punctate keratitis were observed on D30 by means of a fluorescein test: one in the indomethacin group and six in the fluorometholone group. Both anti-inflammatory eyedrops were effective in reducing subclinical conjunctival inflammation before filtering surgery

  12. Tailored first-line biologic therapy in patients with rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis.

    PubMed

    Cantini, Fabrizio; Niccoli, Laura; Nannini, Carlotta; Cassarà, Emanuele; Kaloudi, Olga; Giulio Favalli, Ennio; Becciolini, Andrea; Biggioggero, Martina; Benucci, Maurizio; Li Gobbi, Francesca; Grossi, Valentina; Infantino, Maria; Meacci, Francesca; Manfredi, Mariangela; Guiducci, Serena; Bellando-Randone, Silvia; Matucci-Cerinic, Marco; Foti, Rosario; Di Gangi, Marcella; Mosca, Marta; Tani, Chiara; Palmieri, Fabrizio; Goletti, Delia

    2016-04-01

    A multidisciplinary expert panel, the Italian board for the TAilored BIOlogic therapy (ITABIO), was constituted to formulate evidence-based decisional statements for the first-line tailored biologic therapy in patient with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA). Systematic review of the literature to identify English-language articles on the variables influencing the first-line biologic choice, including the efficacy and safety of the drug, the route of administration, the availability of response predictor biomarkers, the need of monotherapy, the patient socio-economic status, lifestyle, cultural level, personality, fertility and childbearing potential in women, the presence of comorbidities, the host-related risk factors for infection and latent tuberculosis infection (LTBI) reactivation, the cardiovascular (CV) risk, and costs. Some variables, including the patients' preference, the indication for anti-TNF monotherapy in potential childbearing women, and the intravenous route with dose titration in obese subjects resulted valid for all the three rheumatic conditions. Further, evidence of a better cost-effectiveness profile for etanercept (ETN) and biosimilar infliximab (IFX) in RA was found. Any biologic may be employed in absence of choice driving factors in RA. Otherwise, a high infection risk or LTBI positivity drive the choice toward abatacept (ABA), tocilizumab (TCZ), or ETN. TCZ should be the first choice if monotherapy is required. High rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) titers should drive the choice toward TCZ or ABA, while in patients at high CVD risk anti-TNF choice, with preference for ETN, seems appropriate. Presence of anterior uveitis or inflammatory bowel disease drives the choice to monoclonal antibody anti-TNFs (MoAb anti-TNFs). In PsA, ustekinumab (UTK), and to a lesser extent ETN, represents the first choice in patients at high infection and TB risk. Anti-TNFs or

  13. Monotherapy trials: presurgical studies.

    PubMed

    Pledger, G

    2001-05-01

    Presurgical evaluation of patients with refractory partial seizures provides a unique opportunity to perform a placebo-controlled, monotherapy trial. Some patients undergoing presurgical evaluations must have all of their antiepileptic drugs (AEDs) tapered in order to induce seizures and therefore such patients are possible candidates for a placebo-controlled monotherapy trial. Often, EEG monitoring is continued throughout the trial period, thus patients either receiving placebo or whose seizures do not completely respond to the active drug are still evaluated to determine whether or not surgery is feasible, supporting the validity of a trial in this setting. In addition, all patients are, in general, eligible to receive the study drug after the blinded period of the trial, and can therefore be assured of the possible therapeutic benefits of the study. Presurgical inpatients studies have been carried out using felbamate, gabapentin and oxcarbazepine. All patients randomised in these trials were refractory to previous treatment and the studies themselves were short-term and placebo-controlled. These presurgical studies are designed to elucidate AED activity and show statistically significant differences between active and control treatments during short-term therapy, and are therefore of use in fulfilling regulatory requirements. However, these measures of efficacy are distinctly different from those determined during chronic treatment and are therefore not necessarily predictive of clinical usefulness.

  14. Ixabepilone alone or with cetuximab as first-line treatment for advanced/metastatic triple-negative breast cancer.

    PubMed

    Trédan, Olivier; Campone, Mario; Jassem, Jacek; Vyzula, Rostislav; Coudert, Bruno; Pacilio, Carmen; Prausova, Jana; Hardy-Bessard, Anne-Claire; Arance, Ana; Mukhopadhyay, Pralay; Aloe, Alessandra; Roché, Henri

    2015-02-01

    Despite high initial sensitivity to chemotherapy, TNBC is associated with a poor prognosis, highlighting the need for novel therapeutic strategies. The aim of this multicenter, randomized, open-label phase II trial was to assess the efficacy of ixabepilone as monotherapy, and the combination of ixabepilone with cetuximab, as first-line treatment in patients with triple-negative locally advanced nonresectable and/or metastatic breast cancer. Women were randomly assigned to receive either ixabepilone (40 mg/m(2)) every 21 days (n = 40), or ixabepilone (40 mg/m(2)) every 21 days with cetuximab (400 mg/m(2) loading dose, followed by 250 mg/m(2)) once weekly (n = 39). The primary end point of the trial was to estimate the response rates of ixabepilone monotherapy and ixabepilone with cetuximab combination therapy. Of 79 randomized patients, 77 were treated. Based on an intent-to-treat analysis, an objective response rate of 30% (95% confidence interval [CI], 16.6-46.5) was observed in the monotherapy arm, and 35.9% (95% CI, 21.2-52.8) in the combination arm. Median progression-free survival was 4.1 months in both treatment groups. Safety findings were consistent with the known individual toxicity profiles of ixabepilone and cetuximab. Skin and subcutaneous tissue disorders were more common with combination therapy, as were discontinuations because of adverse events. Ixabepilone monotherapy and the ixabepilone and cetuximab combination demonstrated similar levels of clinical activity in first-line treatment of advanced TNBC, with a predictable safety profile. Further investigation of novel therapies for TNBC is required to improve patient outcomes. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Ribociclib as First-Line Treatment for Metastatic Breast Cancer

    Cancer.gov

    A summary of interim results from a phase III trial testing ribociclib plus letrozole (Femara®) as a first-line treatment for postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.

  16. Survival with first-line bosentan in patients with primary pulmonary hypertension.

    PubMed

    McLaughlin, V V; Sitbon, O; Badesch, D B; Barst, R J; Black, C; Galiè, N; Rainisio, M; Simonneau, G; Rubin, L J

    2005-02-01

    Primary pulmonary hypertension (PPH) is a progressive disease with high mortality. Administration of i.v. epoprostenol has demonstrated improved exercise tolerance, haemodynamics, and survival. The orally active, dual endothelin receptor antagonist bosentan improves exercise endurance, haemodynamics, and functional class over the short term. To determine the effect of first-line bosentan therapy on survival, this study followed 169 patients with PPH treated with bosentan in two placebo-controlled trials and their extensions. Data on survival and alternative treatments were collected from September 1999 (start of the first placebo-controlled study) to December 31, 2002. Observed survival up to 36 months was reported as Kaplan-Meier estimates and compared with predicted survival as determined for each patient by the National Institutes of Health Registry formula. Kaplan-Meier survival estimates were 96% at 12 months and 89% at 24 months. In contrast, predicted survival was 69% and 57%, respectively. In addition, at the end of 12 and 24 months, 85% and 70% of patients, respectively, remained alive and on bosentan monotherapy. Factors that predicted a worse outcome included World Health Organization Functional Class IV and 6-min walk distance below the median (358 m) at baseline. First-line bosentan therapy was found to improve survival in patients with advanced primary pulmonary hypertension.

  17. A first-line nurse manager's goal-profile.

    PubMed

    Johansson, Gunilla; Pörn, Ingmar; Theorell, Töres; Gustafsson, Barbro

    2007-01-01

    The aim of this case study was to acquire understanding concerning the first-line nurse manager's goal-profile, i.e. prioritization of goals in her work as a first-line nurse manager, through use of an action-theoretic and confirmatory theory. The first-line nurse manager's pivotal role regarding quality of care and development in relation to on-going changes in the health care sector is stressed by many researchers and the transition from nurse to manager is described as a demanding challenge for the first-line nurse manager. The case study described in this paper concerns a first-line nurse manager in an actual working environment in care of older people. Data collection comprised interviews, observations, a job description and policy documents. A hermeneutic interpretation was used for data analysis. The results showed that the first-line nurse manager had three goals in her goal-profile, in the following order of priority: (i) a nurse goal that she had strongly accepted and in which she had excellent control, (ii) an administrator goal that she had accepted and in which she had control, (iii) a leadership goal that she had not accepted and in which she did not have control. Both the administrator and leadership goals were based on her job description, but the nurse goal was a personally chosen goal based on her own self-relation/goal-fulfillment. The first-line nurse manager's prioritized self-identity, based on successful realization of goals in her goal-profile, was decisive in the manifestation of her work. This study contributes to a new understanding of the first-line nurse manager's self-identity related to work in terms of goal acceptance and goal control of prioritized goals. This action-theoretic approach could be a valuable 'key' for understanding leadership (or lack of leadership) in clinical practice.

  18. Drug Susceptibility and Resistance Mutations After First-Line Failure in Resource Limited Settings

    PubMed Central

    Wallis, Carole L.; Aga, Evgenia; Ribaudo, Heather; Saravanan, Shanmugam; Norton, Michael; Stevens, Wendy; Kumarasamy, Nagalingeswaran; Bartlett, John; Katzenstein, David

    2014-01-01

    Background. The development of drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been associated with baseline human immunodeficiency virus (HIV)-1 RNA level (VL), CD4 cell counts (CD4), subtype, and treatment failure duration. This study describes drug resistance and levels of susceptibility after first-line virologic failure in individuals from Thailand, South Africa, India, Malawi, Tanzania. Methods. CD4 and VL were captured at AIDs Clinical Trial Group (ACTG) A5230 study entry, a study of lopinavir/ritonavir (LPV/r) monotherapy after first-line virologic failure on an NNRTI regimen. HIV drug-resistance mutation associations with subtype, site, study entry VL, and CD4 were evaluated using Fisher exact and Kruskall–Wallis tests. Results. Of the 207 individuals who were screened for A5230, sequence data were available for 148 individuals. Subtypes observed: subtype C (n = 97, 66%) AE (n = 27, 18%), A1 (n = 12, 8%), and D (n = 10, 7%). Of the 148 individuals, 93% (n = 138) and 96% (n = 142) had at least 1 reverse transcriptase (RT) mutation associated with NRTI and NNRTI resistance, respectively. The number of NRTI mutations was significantly associated with a higher study screening VL and lower study screening CD4 (P < .001). Differences in drug-resistance patterns in both NRTI and NNRTI were observed by site. Conclusions. The degree of NNRTI and NRTI resistance after first-line virologic failure was associated with higher VL at study entry. Thirty-two percent of individuals remained fully susceptible to etravirine and rilpivirine, protease inhibitor resistance was rare. Some level of susceptibility to NRTI remained; however, VL monitoring and earlier virologic failure detection may result in lower NRTI resistance. PMID:24795328

  19. Detail of insulator array at first line structure showing historic ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Detail of insulator array at first line structure showing historic porcelain suspension insulators in strings of eight, porcelain jumper support insulators in strings of six, arch rings and ball weights - Morony Hydroelectric Facility, Morony-to-Rainbow 100 kV Transmission Line, West bank of the Missouri River, Great Falls, Cascade County, MT

  20. Pancreatic cancer: New hopes after first line treatment

    PubMed Central

    Aroldi, Francesca; Bertocchi, Paola; Savelli, Giordano; Rosso, Edoardo; Zaniboni, Alberto

    2016-01-01

    Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. Extensive research has yielded advances in first-line treatment strategies, but there is no standardized second-line therapy. In this review, we examine the literature trying to establish a possible therapeutic algorithm. PMID:27672426

  1. Bilingual Cancer Information: Access Is the First Line of Defense

    ERIC Educational Resources Information Center

    Boudreault, Patrick; Palmer, Christina

    2015-01-01

    Information about cancer, the disease that kills more Americans than any other except heart disease, is essential. In some ways, information is our first line of defense. It allows us to identify individual risk factors, to note when a problem means we should see a professional, and to avoid activities that might put us at risk. However,…

  2. Moxifloxacin plus standard first-line therapy in the treatment of pulmonary tuberculosis: A meta-analysis.

    PubMed

    Chen, Zhi; Liang, Jian-Qin; Wang, Jin-He; Feng, Shi-Sheng; Zhang, Guang-Yu

    2015-07-01

    The fluoroquinolone moxifloxacin has potent activity against Mycobacterium tuberculosis and has been recommended by the guidelines for the treatment of pulmonary tuberculosis (TB). Monotherapy is not recommended by the guidelines and only a few studies have evaluated the efficacy and safety of moxifloxacin plus standard first-line therapy in treating TB. The purpose of this meta-analysis was to further investigate the efficacy and safety of moxifloxacin plus standard therapy compared with standard therapy alone in treating patients with pulmonary TB. Medline, Cochrane, EMBASE and Google Scholar (until February 12, 2015) were searched for studies that evaluated the clinical efficacy and tolerability of moxifloxacin in the treatment of pulmonary TB. Rate of culture conversion and serious adverse events (SAEs) were assessed. Risk of bias and sensitivity analysis, using the leave-one-out approach, was used to assess the robustness of the findings. Six studies were included in the meta-analysis which covered 2056 patients with pulmonary TB. For all included studies, the drug regimens at least contained rifampicin and pyrazinamide and the length of treatment was at least eight weeks. The odds ratio (OR) for the negative culture rate for moxifloxacin plus first-line medications compared first-line medications alone (the control group) was 1.60 with 95% CI in 0.93-2.74 (P = 0.089), indicating the moxifloxacin plus first-line medications had no significantly greater rate of culture conversion compared with first-line medication alone. The odds ratio of SAEs for moxifloxacin plus first-line medications compared with first-line medications alone found no difference in rate of SAEs between treatment groups (OR = 0.94, P = 0.862). In conclusion, our meta-analysis suggests that there was a trend for the addition of moxifloxacin to standard first-line therapy for non-drug resistant TB resulted to increase the rate of culture conversion but this effect requires confirmation

  3. First-line drugs inhibiting the renin angiotensin system versus other first-line antihypertensive drug classes for hypertension.

    PubMed

    Xue, Hao; Lu, Zhuang; Tang, Wen Lu; Pang, Lu Wei; Wang, Gan Mi; Wong, Gavin W K; Wright, James M

    2015-01-11

    Renin-angiotensin system (RAS) inhibitors are widely prescribed for treatment of hypertension, especially for diabetic patients on the basis of postulated advantages for the reduction of diabetic nephropathy and cardiovascular morbidity and mortality. Despite widespread use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for hypertension in both diabetic and non-diabetic patients, the efficacy and safety of RAS inhibitors compared to other antihypertensive drug classes remains unclear. To evaluate the benefits and harms of first-line RAS inhibitors compared to other first-line antihypertensive drugs in patients with hypertension. We searched the Cochrane Hypertension Group's Specialised Register, MEDLINE, MEDLINE In-Process, EMBASE and ClinicalTrials.gov for randomized controlled trials up to November 19, 2014 and the Cochrane Central Register of Controlled Trials (CENTRAL) up to October 19, 2014. The WHO International Clinical Trials Registry Platform (ICTRP) is searched for inclusion in the Cochrane Hypertension Group's Specialised Register. We included randomized, active-controlled, double-blinded studies with at least six months follow-up in people with primary elevated blood pressure (≥130/85 mmHg), which compared first-line RAS inhibitors with other first-line antihypertensive drug classes and reported morbidity and mortality or blood pressure outcomes. Patients with proven secondary hypertension were excluded. Two authors independently selected the included trials, evaluated the risk of bias and entered the data for analysis. We included 42 studies, involving 65,733 participants, with a mean age of 66 years. Much of the evidence for our key outcomes is dominated by a small number of large studies at a low risk of bias for most sources of bias. Imbalances in the added second-line antihypertensive drugs in some of the studies were important enough for us to downgrade the quality of the evidence.Primary outcomes were

  4. Beta-Blockers and Calcium Channel Blockers: First Line Agents.

    PubMed

    Pascual, Isaac; Moris, Cesar; Avanzas, Pablo

    2016-08-01

    Beta-blockers and calcium channel blockers (CCB) are milestones in the treatment of stable coronary ischaemic disease. Their main effects are particularly suited for the management of effort-induced angina because of the reduction of oxygen demand they achieve. The clinical benefits of these drugs are highly reproducible and have been shown to improve overall clinical outcomes. Despite the availability of other, and newer antianginal drugs, treatment guidelines continue to recommend the use of beta-blockers and calcium channel blockers as first line therapies.

  5. Successful monotherapy of pemphigus vegetans with minocycline and nicotinamide.

    PubMed

    von Köckritz, A; Ständer, S; Zeidler, C; Metze, D; Luger, T; Bonsmann, G

    2017-01-01

    Pemphigus vegetans is a rare variant of pemphigus vulgaris, accounting for 1-2% of all pemphigus diseases. Systemic corticosteroids are the therapy of first choice in combination with immunosuppressants as steroid-sparing agents. To highlight the exceptional but successful use of minocycline/nicotinamide monotherapy in pemphigus vegetans. A review of the literature to date about pemphigus vegetans with special emphasis on therapy was performed. Due to its rarity, multiple anecdotal reports without long-term follow-up are available and prospective controlled trials are lacking. Only one retrospective study from Tunisia includes 17 patients with pemphigus vegetans. We present a 76-year-old woman with pemphigus vegetans achieving complete response to a minocycline/nicotinamide monotherapy at onset and at relapse of the disease. Treatment has been discontinued after repeated direct immunofluorescence (DIF) of previously affected normal skin and anti-desmoglein 3 antibodies had become negative. In addition, DIF of previously involved oral mucosa was negative. During long-term follow-up clinical remission has been maintained for more than 5 years. Up to now, negative results of serial performed indirect immunofluorescence and desmoglein ELISA testing also predict immunological remission. In our patient and in a case with oesophageal involvement, published more than 20 years ago, clearly the benefit of minocycline/nicotinamide monotherapy was demonstrated. We propose to consider minocycline/nicotinamide as first-line monotherapy in pemphigus vegetans, especially in elderly patients with comorbidities and contraindications to standard therapy, as it avoids the toxicities of systemic corticosteroids and immunosuppressants. © 2016 European Academy of Dermatology and Venereology.

  6. Conversion to eslicarbazepine acetate monotherapy

    PubMed Central

    French, Jacqueline; Jacobson, Mercedes P.; Pazdera, Ladislav; Gough, Mallory; Cheng, Hailong; Grinnell, Todd; Blum, David

    2016-01-01

    Objective: To assess the efficacy and safety of eslicarbazepine acetate (ESL) monotherapy. Methods: This post hoc pooled analysis of 2 randomized double-blind studies (093-045 and -046) included adults with partial-onset seizures medically uncontrolled by 1 or 2 antiepileptic drugs (AEDs). Following the baseline period (8 weeks), eligible patients were randomized 2:1 to receive ESL 1,600 mg or 1,200 mg once daily for 18 weeks; the primary endpoint was study exit by meeting predefined exit criteria (signifying worsening seizure control). In each study, treatment was considered effective if the upper 95% confidence limit for exit rate was lower than the historical control threshold (65.3%). Results: Pooled exit rates were as follows: ESL 1,600 mg = 20.6% (95% confidence interval: 15.6%–26.8%); ESL 1,200 mg = 30.8% (23.0%–40.5%). Use of 2 baseline AEDs or rescue medication, US location, epilepsy duration ≥20 years, and higher maximum baseline seizure frequency were associated with higher exit risks. Median percent reductions in standardized seizure frequency between baseline and the 18-week double-blind period were as follows: ESL 1,600 mg = 43.2%; ESL 1,200 mg = 35.7%; baseline carbamazepine use was associated with smaller reductions. Safety profiles were similar between ESL doses. Conclusions: Exit rates for ESL monotherapy (1,600 mg and 1,200 mg once daily) were lower than the historical control threshold, irrespective of baseline AED use and region, with no additional safety concerns identified. Clinical factors and location clearly influence treatment responses in conversion-to-monotherapy trials. Classification of evidence: This pooled analysis provides Class IV evidence that for adults with medically uncontrolled partial-onset seizures, ESL monotherapy is well tolerated and effective. PMID:26911639

  7. First-line antiretroviral drug discontinuations in children

    PubMed Central

    Fortuin-de Smidt, Melony; de Waal, Reneé; Cohen, Karen; Technau, Karl-Günter; Stinson, Kathryn; Maartens, Gary; Boulle, Andrew; Igumbor, Ehimario U.; Davies, Mary-Ann

    2017-01-01

    Introduction There are a limited number of paediatric antiretroviral drug options. Characterising the long term safety and durability of different antiretrovirals in children is important to optimise management of HIV infected children and to determine the estimated need for alternative drugs in paediatric regimens. We describe first-line antiretroviral therapy (ART) durability and reasons for discontinuations in children at two South African ART programmes, where lopinavir/ritonavir has been recommended for children <3 years old since 2004, and abacavir replaced stavudine as the preferred nucleoside reverse transcriptase inhibitor in 2010. Methods We included children (<16 years at ART initiation) who initiated ≥3 antiretrovirals between 2004–2014 with ≥1 follow-up visit on ART. We estimated the incidence of first antiretroviral discontinuation using Kaplan-Meier analysis. We determined the reasons for antiretroviral discontinuations using competing risks analysis. We used Cox regression to identify factors associated with treatment-limiting toxicity. Results We included 3579 children with median follow-up duration of 41 months (IQR 14–72). At ART initiation, median age was 44 months (IQR 13–89) and median CD4 percent was 15% (IQR 9–21%). At three and five years on ART, 72% and 26% of children respectively remained on their initial regimen. By five years on ART, the most common reasons for discontinuations were toxicity (32%), treatment failure (18%), treatment simplification (5%), drug interactions (3%), and other or unspecified reasons (18%). The incidences of treatment limiting toxicity were 50.6 (95% CI 46.2–55.4), 1.6 (0.5–4.8), 2.0 (1.2–3.3), and 1.3 (0.6–2.8) per 1000 patient years for stavudine, abacavir, efavirenz and lopinavir/ritonavir respectively. Conclusions While stavudine was associated with a high risk of treatment-limiting toxicity, abacavir, lopinavir/ritonavir and efavirenz were well-tolerated. This supports the World Health

  8. Using adjunctive treatments when first-line antidepressants fail.

    PubMed

    Thase, Michael E

    2012-01-01

    Treatment-resistant depression is a common challenge for clinicians, as the majority of patients with depression do not achieve remission after an initial antidepressant trial. Major strategies for managing treatment-resistant depression include switching to another antidepressant or augmenting the initial antidepressant with another medication. Switching may be appropriate for patients experiencing little or no symptom relief or intolerable side effects with the initial antidepressant. For patients who experience partial response from the first-line antidepressant, adjunctive therapies avoid the loss of this response and the wash-out and cross-titration that are required when switching antidepressants. Several effective antidepressant augmentation agents are available, including lithium, thyroid hormone, anti-anxiety medications, and atypical antipsychotics. The evidence for the efficacy and risks of these strategies is discussed. © Copyright 2012 Physicians Postgraduate Press, Inc.

  9. Dilemma of first line regimens in metastatic pancreatic adenocarcinoma

    PubMed Central

    Ghosn, Marwan; Ibrahim, Tony; Assi, Tarek; El Rassy, Elie; Kourie, Hampig Raphael; Kattan, Joseph

    2016-01-01

    Pancreatic cancer is one of the deadliest cancers, ranking fourth among cancer-related deaths. Despite all the major molecular advances and treatment breakthroughs, mainly targeted therapies, the cornerstone treatment of metastatic pancreatic cancer (mPC) remains cytotoxic chemotherapy. In 2016, more than 40 years after the introduction of gemcitabine in the management of mPC, the best choice for first-line treatment has not yet been fully elucidated. Two main strategies have been adopted to enhance treatment efficacy. The first strategy is based on combining non-cross resistant drugs, while the second option includes the development of newer generations of chemotherapy. More recently, two new regimens, FOLFIRINOX and gemcitabine/nab-paclitaxel (GNP), have both been shown to improve overall survival in comparison with gemcitabine alone, at the cost of increased toxicity. Therefore, the best choice for first line therapy is a matter of debate. For some authors, FOLFIRINOX should be the first choice in patients with an Eastern Cooperative Oncology Group score (0-1) given its lower hazard ratio. However, others do not share this opinion. In this paper, we review the main comparison points between FOLFIRINOX and GNP. We analyze the two pivotal trials to determine the similarities and differences in study design. In addition, we compare the toxicity profile of the two regimens as well as the impact on quality of life. Finally, we present studies revealing real life experiences and review the advantages and disadvantages of possible second-line therapies including their cost effectiveness. PMID:28028360

  10. [First-line anti-infective treatment in sepsis].

    PubMed

    Burgmann, H

    2014-11-01

    The Surviving Sepsis Campaign strongly recommends that intravenous antibiotic therapy should be started as early as possible, ideally within the first hour of recognition of severe sepsis or septic shock. There is ample evidence that failure to initiate early antimicrobial treatment correlates with increased morbidity and mortality. The purpose of this work was to review the recent literature regarding optimal initial antimicrobial treatment in patients with severe sepsis and sepsis shock. A literature review was performed. The most frequently quoted papers claiming the overriding prognostic importance of early administered antibiotics are retrospective data analyses. However, an equivalent number of studies report that a group of septic patients do not benefit from early administration of antibiotics, but can also be harmed. In these patients, watchful waiting with administration of a targeted antibiotic can be used, thus, avoiding the possible collateral damage from excessive treatment with antibiotics. Treatment with monotherapy is adequate in most cases. The administration of antibiotics based on the local epidemiology should be initiated quickly in critically ill patients with severe sepsis and septic shock. In patients who are not in septic shock, treatment can be withheld, while awaiting further studies or clinical assessment to confirm the suspicion of infection.

  11. Effectiveness of sotalol as first-line therapy for fetal supraventricular tachyarrhythmias.

    PubMed

    Shah, Amee; Moon-Grady, Anita; Bhogal, Neil; Collins, Kathryn K; Tacy, Theresa; Brook, Michael; Hornberger, Lisa K

    2012-06-01

    Fetal supraventricular tachycardia (SVT) and atrial flutter (AF) can be associated with significant morbidity and mortality. Digoxin is often used as first-line therapy but can be ineffective and is poorly transferred to the fetus in the presence of fetal hydrops. As an alternative to digoxin monotherapy, we have been using sotalol at presentation in fetuses with SVT or AF with, or at risk of, developing hydrops to attempt to achieve more rapid control of the arrhythmia. The present study was a retrospective review of the clinical, echocardiographic, and electrocardiographic data from all pregnancies with fetal tachycardia diagnosed and managed at a single center from 2004 to 2008. Of 29 affected pregnancies, 21 (16 SVT and 5 AF) were treated with sotalol at presentation, with or without concurrent administration of digoxin. Of the 21, 11 (6 SVT and 5 AF) had resolution of the tachycardia within 5 days (median 1). Six others showed some response (less frequent tachycardia, rate slowing, resolution of hydrops) without complete conversion. In 1 fetus with a slow response, the mother chose pregnancy termination. The 5 survivors with a slow response were all difficult to treat postnatally, including 1 requiring radiofrequency ablation as a neonate. One fetus developed blocked atrial extrasystoles after 1 dose of sotalol and was prematurely delivered for fetal bradycardia. Three grossly hydropic fetuses with SVT showed no response and died within 1 to 3 days of treatment. In conclusion, transplacental sotalol, alone or combined with digoxin, is effective for the treatment of fetal SVT and AF, with an 85% complete or partial response rate in our series.

  12. [First line therapy for Helicobacter pylori eradication in France].

    PubMed

    Dupas, Jean-Louis

    2003-03-01

    The available results of triple therapy for the eradication of Helicobacter pylori (H. pylori), as recommended in European countries--i.e. combination of proton pump inhibitor (PPI) and two antibiotics among amoxicillin, clarithromycin, metronidazole for 7 days--lead to rates of failure of about 30%. Several clinical studies have been recently conducted to distinguish factors influencing effectiveness of therapy and to evaluate results of new regimens. Comparative trials have demonstrated the equivalence of omeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, rabeprazole 20 mg and esomeprazole 20 mg, twice daily in these 7-days triple therapies. Efficacy of treatment is not affected by metronidazole resistance (44% in France) when amoxicillin-clarithromycin-based triple therapy is prescribed. The impact of clarithromycin resistance (14%) is much more important with failure of eradication in all cases treated by clarithromycin-based triple therapy. The eradication rate could be slightly improved by increasing the dose of clarithromycin but with more frequent side effects. To prolong the duration treatment improve also slightly the cure rate with a gain of less than 10%, but with an increasing rate of side effects. To date, the PPI-based triple therapies, as recommended in France, have not to be modified. The treatment of H. pylori infection has to be globally considered, with a first-line treatment leading to eradication in 70% of patients and a second-line treatment needed for the resting 30% of patients.

  13. First-line pharmacotherapy approaches for generalized anxiety disorder.

    PubMed

    Davidson, Jonathan R

    2009-01-01

    Many patients with generalized anxiety disorder (GAD) do not receive adequate treatment. Several classes of drugs, including benzodiazepines, azapirones, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antihistamines, alpha(2)delta Ca++ channel modulators, and atypical antipsychotics are consistently beneficial in patients with GAD. Cognitive therapy is also effective as a first-line treatment. When individualizing treatment, drug dose ranges and side effect profiles need to be considered, as well as the patient's comorbid conditions. Doses may need to be reduced for elderly or medically ill patients or those taking other medications. Doses may need to be increased for refractory cases. Common comorbid conditions with GAD include depression, alcohol or drug abuse, social anxiety disorder, and panic disorder. In patients with significant depression, an antidepressant is more likely to succeed than a benzodiazepine. Generalized anxiety disorder is a chronic illness that requires long-term treatment. Remission is attainable but can take several months, and stopping medication increases the risk of relapse within the first year of initiating treatment.

  14. Dasatinib first-line: Multicentric Italian experience outside clinical trials.

    PubMed

    Breccia, Massimo; Stagno, Fabio; Luciano, Luigiana; Abruzzese, Elisabetta; Annunziata, Mario; D'Adda, Mariella; Maggi, Alessandro; Sgherza, Nicola; Russo-Rossi, Antonella; Pregno, Patrizia; Castagnetti, Fausto; Iurlo, Alessandra; Latagliata, Roberto; Cedrone, Michele; Di Renzo, Nicola; Sorà, Federica; Rege-Cambrin, Giovanna; La Nasa, Giorgio; Scortechini, Anna Rita; Greco, Giovanna; Franceschini, Luca; Sica, Simona; Bocchia, Monica; Crugnola, Monica; Orlandi, Esther; Guarini, Attilio; Specchia, Giorgina; Rosti, Gianantonio; Saglio, Giuseppe; Alimena, Giuliana

    2016-01-01

    Dasatinib was approved for the treatment of chronic phase (CP) chronic myeloid leukemia (CML) patients in first line therapy based on the demonstration of efficacy and safety reported in patients enrolled in clinical trials. We describe a multicentric Italian "real-life" experience of dasatinib used as frontline treatment outside clinical trials. One hundred and nine patients (median age 54 years) were treated from January 2012 to December 2013. Increased incidence of high risk patients were detected according to stratification (26% according to Sokal score, 19% according to Euro score and 16% according to EUTOS) when compared to company sponsored studies. Median time from diagnosis to start of dasatinib was 18 days. Ten patients received unscheduled starting dose (6 patients 50mg and 4 patients 80 mg QD), whereas 99 patients started with 100mg QD. At 3 months, 92% of patients achieved a BCR-ABL ratio less than 10%. At 6 months, the rate of CCyR was 91% and the rate of MR3 was 40%, with 8% of the patients reaching MR4.5. Ninety-three patients were evaluable at 12 months: the rate of MR3 was 62%, with MR4.5 being achieved by 19% of the patients. At a median follow-up of 12 months, 27 patients (24.7%) were receiving the drug at reduced dose. Two patients (1.8%) experienced a lymphoid blast crisis and the overall incidence of resistance was 8%. As regards safety, the major side effects recorded were thrombocytopenia, neutropenia and pleural effusions, which occurred in 22%, 10% and 8% of patients, respectively. Present results, achieved in a large cohort of patients treated outside clinical trials, further confirm the efficacy and safety of dasatinib as firstline treatment in CML.

  15. Cost and resource utilization associated with fluconazole as first-line therapy for invasive candidiasis: a retrospective database analysis.

    PubMed

    Craver, Christopher W; Tarallo, Miriam; Roberts, Craig S; Blanchette, Christopher M; Ernst, Frank R

    2010-12-01

    Fluconazole is a standard first-line therapy for candidemia/invasive candidiasis (C/IC), based on its efficacy, safety profile, and comparatively low acquisition cost. However, little is known about the total costs associated with fluconazole treatment for this indication, particularly in cases of clinical failure. The aim of this study was to examine overall costs, resource use, and treatment outcomes associated with fluconazole as first-line therapy for invasive Candida infections in the United States. A retrospective analysis of data from a US hospital-based (>500 hospitals), service-level database was performed. All patients aged >16 years with primary or secondary International Classification of Diseases, Ninth Revision, Clinical Modification codes for IC or septicemia, receiving intravenous fluconazole treatment, and discharged between October 1, 2004 and September 30, 2005 were selected. Costs and resource use were calculated from the start of antifungal therapy until discharge. Two groups were analyzed: patients who received fluconazole only and those who required a second-line antifungal. Separate analyses for the survivor subpopulations were also conducted. A total of 7170 patients met the inclusion criteria; 21.2% required an additional antifungal agent. Overall mortality was 27.1%, and total mean treatment cost for all patients was $44,482 (in 2005 US dollars). Patients treated with fluconazole alone incurred mean costs of $36,319. Mean hospital and intensive care unit stays in the fluconazole monotherapy group were 17.9 days and 7.1 days, respectively. Patients requiring additional therapy had a mortality rate of 34.5% and a mean treatment cost of $76,329; in this group, the mean hospital and intensive care unit stays were 31.7 days and 14.8 days, respectively. The overall resource use associated with fluconazole as first-line treatment for C/IC was high, especially in patients who required additional antifungal therapy. Future studies should examine

  16. Prescription practices and availability of artemisinin monotherapy in India: where do we stand?

    PubMed Central

    2011-01-01

    monotherapy in retail market and an inadequate supply of recommended drugs in the public sector health facilities promoted its prescription. This study resulted in notifications to all state drug controllers in India to withdraw the oral artemisinin formulations from the market. In 2010, artesunate + sulphadoxine-pyrimethamine became the universal first-line treatment for confirmed Plasmodium falciparum malaria and was deployed at full scale. PMID:22166073

  17. Efficacy of monotherapies and artesunate-based combination therapies in children with uncomplicated malaria in Somalia.

    PubMed

    Warsame, Marian; Atta, Hoda; Klena, John D; Waqar, Butt Ahmed; Elmi, Hussein Haji; Jibril, Ali Mohamed; Hassan, Hassan Mohamed; Hassan, Abdullahi Mohamed

    2009-02-01

    In order to guide the antimalarial treatment policy of Somalia, we conducted therapeutic efficacy studies of routinely used antimalarial monotherapies as well as artemisinin-based combination therapies (ACTs) for uncomplicated malaria in three sentinel sites during 2003-2006. Therapeutic efficacy of chloroquine (CQ), amodiaquine (AQ) and sulfadoxine/pyrimetahmine (SP) monotherapies, and artesunate plus SP (AS+SP) or AQ (AS+AQ) were evaluated in children 6 months to 10 years old with uncomplicated malaria. For the assessment of the monotherapies, 2003 WHO protocol with 14-day follow-up was used while the 2005 WHO protocol with 28-day follow-up was used for testing the ACTs. Of the monotherapies, CQ performed very poorly with treatment failures varying from 76.5% to 88% between the sites. AQ treatment failure was low except for Janale site with treatment failure of 23.4% compared to 2.8% and 8% in Jamame and Jowhar, respectively. For SP, treatment failures from 7.8% to 12.2% were observed. A 28-day test of artemisinin-based combinations, AS+SP and AS+AQ, proved to be highly efficacious with cure rates of 98-100% supporting the choice of AS+SP combination as first line treatment for uncomplicated malaria for Somalia.

  18. Factors that facilitate registered nurses in their first-line nurse manager role.

    PubMed

    Cziraki, Karen; McKey, Colleen; Peachey, Gladys; Baxter, Pamela; Flaherty, Brenda

    2014-11-01

    To determine the factors that attract and retain Registered Nurses in the first-line nurse manager role. The first-line nurse manger role is pivotal in health-care organisations. National demographics suggest that Canada will face a first-line nurse manager shortage because of retirement in the next decade. Determination of factors that attract and retain Registered Nurses will assist organisations and policy makers to employ strategies to address this shortage. The study used an exploratory, descriptive qualitative approach, consisting of semi-structured individual interviews with 11 Registered Nurses in first-line nurse manager roles. The findings revealed a discrepancy between the factors that attract and retain Registered Nurses in the first-line nurse manager role, underscored the importance of the mentor role and confirmed the challenges encountered by first-line nurse managers practicing in the current health-care environment. The first-line nurse manager role has been under studied. Further research is warranted to understand which strategies are most effective in supporting first-line nurse managers. Strategies to support nurses in the first-line nurse manager role are discussed for the individual, programme, organisation and health-care system/policy levels. © 2013 John Wiley & Sons Ltd.

  19. Second monotherapy in childhood absence epilepsy.

    PubMed

    Cnaan, Avital; Shinnar, Shlomo; Arya, Ravindra; Adamson, Peter C; Clark, Peggy O; Dlugos, Dennis; Hirtz, Deborah G; Masur, David; Glauser, Tracy A

    2017-01-10

    To determine optimal second monotherapy for children with childhood absence epilepsy (CAE) experiencing initial treatment failure. Children with CAE experiencing treatment failure during the double-blind phase of a randomized controlled trial comparing ethosuximide, valproic acid, and lamotrigine were randomized to open-label second monotherapy with one of the 2 other study therapies. Primary study outcome was freedom from failure proportion at week 16-20 and month 12 visits after randomization. Secondary study outcome was percentage of participants experiencing attentional dysfunction at these visits. A total of 208 children were enrolled, randomized, and received second therapy. At both week 16-20 visit and month 12 visit, ethosuximide's (63%, 57%) and valproic acid's (65%, 49%) freedom from failure proportions were similar to each other and higher than lamotrigine's (45%, 36%, p = 0.051 and p = 0.062). At both time points, ethosuximide and valproic acid had superior seizure control compared to lamotrigine (p < 0.0001). At both the week 16-20 and month 12 visits, attentional dysfunction was numerically more common with valproic acid than with ethosuximide or lamotrigine. For each medication, second monotherapy freedom from failure proportions demonstrated noninferiority to initial monotherapy freedom from failure proportions. As second monotherapy, ethosuximide and valproic acid, demonstrated higher freedom from failure proportions and greater efficacy than lamotrigine; valproic acid was associated with more attentional dysfunction. Ethosuximide is the optimal second monotherapy for children with CAE not responding to initial therapy with other medications. NCT00088452. This study provides Class III evidence that for children with CAE experiencing initial treatment failure, second monotherapy with ethosuximide or valproic acid is superior to lamotrigine. © 2016 American Academy of Neurology.

  20. The Represented Consciousness in the First Line: A Phenomenological Approach to How a Poem Begins.

    ERIC Educational Resources Information Center

    Mathis, Jerry W.

    The successful oral reading of poetry requires that oral interpreters conduct phenomenological investigations of the first lines of the poems, not merely to make these lines happen properly but to suggest what has preceded the first line. Individual word meanings in the opening lines of a poem establish "structures of intentionality"--the…

  1. Exfoliative dermatitis to all four first line oral anti-tubercular drugs.

    PubMed

    Dua, Ruchi; Sindhwani, Girish; Rawat, Jagdish

    2010-01-01

    Exfoliative dermatitis to all four first line drugs singly or rarely in combination has been reported. Here we report a rare case of pulmonary tuberculosis with exfoliative dermatitis to all four oral first line antitubercular drugs. (Rifampicin, Isoniazid, Ethambutol, Pyrazinamide). To the best of our knowledge, this is the first such case.

  2. The Represented Consciousness in the First Line: A Phenomenological Approach to How a Poem Begins.

    ERIC Educational Resources Information Center

    Mathis, Jerry W.

    The successful oral reading of poetry requires that oral interpreters conduct phenomenological investigations of the first lines of the poems, not merely to make these lines happen properly but to suggest what has preceded the first line. Individual word meanings in the opening lines of a poem establish "structures of intentionality"--the…

  3. Caring behaviour perceptions from nurses of their first-line nurse managers.

    PubMed

    Peng, Xiao; Liu, Yilan; Zeng, Qingsong

    2015-12-01

    Nursing is acknowledged as being the art and science of caring. According to the theory of nursing as caring, all persons are caring but not every behaviour of a person is caring. Caring behaviours in the relationship between first-line nurse managers and Registered Nurses have been studied to a lesser extent than those that exist between patients and nurses. Caring behaviour of first-line nurse managers from the perspective of Registered Nurses is as of yet unknown. Identifying caring behaviours may be useful as a reference for first-line nurse managers caring for nurses in a way that nurses prefer. To explore first-line nurse managers' caring behaviours from the perspective of Registered Nurses in mainland China. Qualitative study, using descriptive phenomenological approach. Fifteen Registered Nurses recruited by purposive sampling method took part in in-depth interviews. Data were analysed according to Colaizzi's technique. Three themes of first-line nurse managers' caring behaviours emerged: promoting professional growth, exhibiting democratic leadership and supporting work-life balance. A better understanding of the first-line nurse managers' caring behaviours is recognised. The three kinds of behaviours have significant meaning to nurse managers. Future research is needed to describe what first-line nurse managers can do to promote nurses' professional growth, increase the influence of democratic leadership, as well as support their work-life balance. © 2015 Nordic College of Caring Science.

  4. Predictors of first line antiretroviral therapy failure and burden of second line antiretroviral therapy.

    PubMed

    Patrikar, Seema; Shankar, Subramanian; Kotwal, Atul; Basannar, D R; Bhatti, Vijay; Verma, Rajesh; Mukherji, Sandip

    2017-01-01

    As HIV steps into the third decade, there are more number of patients living on lifelong (antiretroviral therapy) ART and facing the threat of drug resistance with subsequent treatment failure. The aim of this study was to determine predictors of first-line ART failure with the objectives to estimate the burden of 2nd line ART. A retrospective 5-year cohort of HIV patients who were initiated on first line ART in 2008-09 was studied. Patients were followed from the time of ART initiation. Kaplan-Meier methods and Cox proportional hazards regression models were used to estimate probabilities and predictors of first line ART failure. Of the total of 195 patients initiated on first line ART, 15 patients were switched to second line ART yielding 7.69% failure rate. During the 7178 person-years of follow-up, the incidence of first line ART failure was 2.09 per 1000 person-years. The Kaplan-Meier survival analysis gave a mean survival time of 55.6 months. BMI, CD4 count at ART initiation and presence of opportunistic infections were significant predictors of first line ART failure. The burden of second line ART patients by the end of 5 years of first line ART is expected to be 151 patients. Though the first line ART failure is quite low in this study, we still need to be vigilant for lower BMI, low baseline CD4 count and occurrence of opportunistic infections to efficiently manage failures on first line ART.

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

    PubMed Central

    2005-01-01

    Background Evidence of reduced cardiovascular morbidity and mortality as well as cost support thiazide diuretics as the first-line choice for treatment of hypertension. The purpose of this study was to determine the proportion of senior hypertensives that received thiazide diuretics as first-line treatment, and to determine if cardiovascular and other potentially relevant comorbidities predict the choice of first-line therapy. Methods and Findings British Columbia PharmaCare data were used to determine the cohort of seniors (residents aged 65 or older) who received their first reimbursed hypertension drug during the period 1993 to 2000. These individual records were linked to medical and hospital claims data using the British Columbia Linked Health Database to find the subset that had diagnoses indicating the presence of hypertension as well as cardiovascular and other relevant comorbidities. Rates of first-line thiazide prescribing as proportion of all first-line treatment were analysed, accounting for patient age, sex, overall clinical complexity, and potentially relevant comorbidities. For the period 1993 to 2000, 82,824 seniors who had diagnoses of hypertension were identified as new users of hypertension drugs. The overall rate at which thiazides were used as first-line treatment varied from 38% among senior hypertensives without any potentially relevant comorbidity to 9% among hypertensives with previous acute myocardial infarction. The rate of first-line thiazide diuretic prescribing for patients with and without potentially relevant comorbidities increased over the study period. Women were more likely than men, and older patients were more likely than younger, to receive first-line thiazide therapy. Conclusions Findings indicate that first-line prescribing practices for hypertension are not consistent with the evidence from randomized control trials measuring morbidity and mortality. The health and financial cost of not selecting the most effective and

  6. Caspofungin first-line therapy for invasive aspergillosis in allogeneic hematopoietic stem cell transplant patients: an European Organisation for Research and Treatment of Cancer study.

    PubMed

    Herbrecht, R; Maertens, J; Baila, L; Aoun, M; Heinz, W; Martino, R; Schwartz, S; Ullmann, A J; Meert, L; Paesmans, M; Marchetti, O; Akan, H; Ameye, L; Shivaprakash, M; Viscoli, C

    2010-07-01

    Caspofungin at standard dose was evaluated as first-line monotherapy of mycologically documented probable/proven invasive aspergillosis (IA) (unmodified European Organisation for Research and Treatment of Cancer/Mycosis Study Group criteria) in allogeneic hematopoietic SCT patients. The primary efficacy end point was complete or partial response at end of caspofungin treatment. Response at week 12, survival and safety were additional end points. Enrollment was stopped prematurely because of low accrual, with 42 enrolled and 24 eligible, giving the study a power of 85%. Transplant was from unrelated donors in 16 patients; acute or chronic GVHD was present in 15. In all, 12 patients were neutropenic (<500/microl) at baseline, 10 received steroids and 16 calcineurin inhibitors or sirolimus. Median duration of caspofungin treatment was 24 days. At the end of caspofungin therapy, 10 (42%) patients had complete or partial response (95% confidence interval: 22-63%); 1 (4%) and 12 (50%) had stable and progressing disease, respectively; one was not evaluable. At week 12, eight patients (33%) had complete or partial response. Survival rates at week 6 and 12 were 79 and 50%, respectively. No patient had a drug-related serious adverse event or discontinued because of toxicity. Caspofungin first-line therapy was effective and well tolerated in allogeneic hematopoietic SCT patients with mycologically documented IA.

  7. Should sulfonylureas remain an acceptable first-line add-on to metformin therapy in patients with type 2 diabetes? No, it's time to move on!

    PubMed

    Genuth, Saul

    2015-01-01

    Since their introduction to clinical practice in the 1950s, sulfonylureas have been widely prescribed for use in patients with type 2 diabetes. Of all the other medications currently available for clinical use, only metformin has been used more frequently. However, several new drug classes have emerged that are reported to have equal glucose-lowering efficacy and greater safety when added to treatment of patients in whom metformin monotherapy is no longer sufficient. Moreover, current arguments also suggest that the alternative drugs may be superior to sulfonylureas with regard to the risk of cardiovascular complications. Thus, while there is universal agreement that metformin should remain the first-line pharmacologic therapy for those in whom lifestyle modification is insufficient to control hyperglycemia, there is no consensus as to which drug should be added to metformin. Therefore, given the current controversy, we provide a Point-Counterpoint on this issue. In the preceding point narrative, Dr. Abrahamson provides his argument suggesting that avoiding use of sulfonylureas as a class of medication as an add-on to metformin is not appropriate as there are many patients whose glycemic control would improve with use of these drugs with minimal risk of adverse events. In the counterpoint narrative below, Dr. Genuth suggests there is no longer a need for sulfonylureas to remain a first-line addition to metformin for those patients whose clinical characteristics are appropriate and whose health insurance and/or financial resources make an alternative drug affordable.

  8. Should sulfonylureas remain an acceptable first-line add-on to metformin therapy in patients with type 2 diabetes? Yes, they continue to serve us well!

    PubMed

    Abrahamson, Martin J

    2015-01-01

    Since their introduction to clinical practice in the 1950s, sulfonylureas have been widely prescribed for use in patients with type 2 diabetes. Of all the other medications currently available for clinical use, only metformin has been used more frequently. However, several new drug classes have emerged that are reported to have equal glucose-lowering efficacy and greater safety when added to treatment of patients in whom metformin monotherapy is no longer sufficient. Moreover, current arguments also suggest that the alternative drugs may be superior to sulfonylureas with regard to the risk of cardiovascular complications. Thus, while there is universal agreement that metformin should remain the first-line pharmacologic therapy for those in whom lifestyle modification is insufficient to control hyperglycemia, there is no consensus as to which drug should be added to metformin. Therefore, given the current controversy, we provide a Point-Counterpoint on this issue. In the point narrative presented below, Dr. Abrahamson provides his argument suggesting that avoiding use of sulfonylureas as a class of medication as an add-on to metformin is not appropriate as there are many patients whose glycemic control would improve with use of these drugs with minimal risk of adverse events. In the following counterpoint narrative, Dr. Genuth suggests there is no longer a need for sulfonylureas to remain a first-line addition to metformin for those patients whose clinical characteristics are appropriate and whose health insurance and/or financial resources make an alternative drug affordable.

  9. Ukrain monotherapy in malignant melanoma (case report).

    PubMed

    Hamler, F; Hiesmayr, W; Korsh, O; Melnyk, A

    1996-01-01

    A patient with a metastasizing malignant melanoma (stage III) was treated with Ukrain monotherapy. Before and during the first Ukrain course of treatment the patient excreted melanin in the urine. After the third course melanin was no more detectable and the patient has been without any symptoms of disease for the last 12 years.

  10. An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients.

    PubMed

    Viscoli, C; Herbrecht, R; Akan, H; Baila, L; Sonet, A; Gallamini, A; Giagounidis, A; Marchetti, O; Martino, R; Meert, L; Paesmans, M; Ameye, L; Shivaprakash, M; Ullmann, A J; Maertens, J

    2009-12-01

    Caspofungin was evaluated as first-line monotherapy of invasive aspergillosis (IA) in patients with haematological malignancies and undergoing autologous transplants. Adults with proven or probable IA, defined strictly according to EORTC-MSG criteria, were eligible. Those with possible IA were enrolled, but were not evaluable for efficacy unless upgraded to proven/probable disease within 7 days of registration based on investigations performed within 48 h after enrolment. Caspofungin dosage was 70 mg (day 1) followed by 50 mg/day. The primary endpoint was the proportion of patients with complete or partial response at the end of caspofungin therapy in the modified intention to treat (MITT) group; secondary endpoints were response and survival at day 84 and safety. In the MITT group (n = 61), 75% of patients had cancer not in remission (relapsing or refractory), 85% were neutropenic at enrolment and 49% had a Karnofsky score of < or =50. At end of treatment, 1 and 19 patients had complete and partial response, respectively [success rate 33% (20/61)], 9 (15%) achieved stabilization and 31 (51%) had disease progression. One patient was not evaluable. The 6 and 12 week survival rates were 66% (40/61) and 53% (32/60), respectively. Baseline characteristics associated with survival at day 84 were an underlying disease in remission (not relapsing or refractory) and Karnofsky score. Recovery from neutropenia at the end of treatment was also significantly associated with survival. No serious drug-related adverse events or discontinuations due to drug-related adverse events were observed. Caspofungin provided an observed response rate compatible with the null hypothesis of a true response rate of < or =35%. Underlying disease-related factors had a major impact on results.

  11. Treatment patterns, healthcare resource utilization, and costs following first-line antidepressant treatment in major depressive disorder: a retrospective US claims database analysis.

    PubMed

    Gauthier, Geneviève; Guérin, Annie; Zhdanava, Maryia; Jacobson, William; Nomikos, George; Merikle, Elizabeth; François, Clément; Perez, Vanessa

    2017-06-19

    Although the symptoms of major depressive disorder (MDD) are often manageable with pharmacotherapy, response to first-line antidepressant treatment is often less than optimal. This study describes long-term treatment patterns in MDD patients in the United States and quantifies the economic burden associated with different treatment patterns following first-line antidepressant therapy. MDD patients starting first-line antidepressant monotherapy and having continuous enrollment ≥12 months before and ≥24 months following the index date (i.e., the first documented prescription fill) were selected from the Truven Health Analytics MarketScan (2003-2014) database. Based on the type of first treatment change following initiation, six treatment cohorts were defined a priori ("persistence"; "discontinuation"; "switch"; "dose escalation"; "augmentation"; and "combination"). Treatment patterns through the fourth line of therapy within each cohort, healthcare resource utilization (HCRU), and cost analyses were restricted to patients with adequate treatment duration (defined as ≥42 days) in each line (analysis sub-sample, N = 21,088). HCRU and costs were described at the cohort and pattern levels. Treatment cohorts representing <5% of the analysis sub-sample were decided a priori not to be analyzed due to limited sample size. 39,557 patients were included. Mean age was 42.1 years, 61.1% of patients were female, and mean follow-up was 4.1 years. Among the analysis sub-sample, the discontinuation (49.1%), dose escalation (37.4%), and switch (6.6%) cohorts were the most common of all treatment cohorts. First-line antidepressant discontinuation without subsequent MDD pharmacotherapy (22.9%) and cycling between discontinuation and resumption (11.2%) were the two most common treatment patterns. Median time to discontinuation was 23 weeks. The switch cohort exhibited the highest HCRU (18.9 days with medical visits per-patient-per-year) and greatest healthcare costs ($11

  12. Tyrosine kinase inhibitor combination therapy in first-line treatment of non-small-cell lung cancer: systematic review and network meta-analysis

    PubMed Central

    Batson, Sarah; Mitchell, Stephen A; Windisch, Ricarda; Damonte, Elisabetta; Munk, Veronica C; Reguart, Noemi

    2017-01-01

    Introduction The introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has improved the outlook for patients with advanced non-small-cell lung cancer (NSCLC) with EGFR+ mutations. However, most patients develop resistance, with the result that median progression-free survival (PFS) iŝ12 months. Combining EGFR-TKIs with other agents, such as bevacizumab, is a promising approach to prolonging remission. This systematic review and network meta-analysis (NMA) were undertaken to assess available evidence regarding the benefits of first-line combination therapy involving EGFR-TKIs in patients with advanced NSCLC. Methods Literature searches were performed using relevant search terms. Study-level pseudo-individual patient-level data (IPD) were recreated from digitized Kaplan–Meier curve data, using a published algorithm. Study IPD were analyzed using both the proportional hazards and the acceleration failure time (AFT) survival models, and it was concluded that the AFT model was most appropriate. An NMA was performed based on acceleration factors (AFs) using a Bayesian framework to compare EGFR-TKIs and chemotherapy. Results Nine randomized controlled trials were identified that provided data for EGFR-TKI therapy in patients with EGFR+ tumors. These included studies of afatinib (n=3), erlotinib (n=3), erlotinib plus bevacizumab (n=1) and gefitinib (n=2). Erlotinib plus bevacizumab produced the greatest increase in PFS compared with chemotherapy, with 1/AF being 0.24 (95% credible interval [CrI] 0.17, 0.34). This combination also produced greater increases in PFS compared with EGFR-TKI monotherapy: 1/AF versus afatinib, 0.51 (95% CrI 0.35, 0.73); versus erlotinib, 0.53 (95% CrI 0.39, 0.72) and versus gefitinib, 0.46 (95% CrI 0.32, 0.66). All three EGFR-TKI monotherapies prolonged PFS compared with chemotherapy; estimates of treatment effect ranged from 1/AF 0.53 (95% CrI 0.48, 0.60) for gefitinib to 1/AF 0.46 (95% CrI 0.40, 0.53) for

  13. First-Line Nursing Home Managers in Sweden and their Views on Leadership and Palliative Care

    PubMed Central

    Håkanson, Cecilia; Cronfalk, Berit Seiger; Henriksen, Eva; Norberg, Astrid; Ternestedt, Britt-Marie; Sandberg, Jonas

    2015-01-01

    The aim of this study was to investigate first-line nursing home managers’ views on their leadership and related to that, palliative care. Previous research reveals insufficient palliation, and a number of barriers towards implementation of palliative care in nursing homes. Among those barriers are issues related to leadership quality. First-line managers play a pivotal role, as they influence working conditions and quality of care. Nine first-line managers, from different nursing homes in Sweden participated in the study. Semi-structured interviews were conducted and analysed using qualitative descriptive content analysis. In the results, two categories were identified: embracing the role of leader and being a victim of circumstances, illuminating how the first-line managers handle expectations and challenges linked to the leadership role and responsibility for palliative care. The results reveal views corresponding to committed leaders, acting upon demands and expectations, but also to leaders appearing to have resigned from the leadership role, and who express powerlessness with little possibility to influence care. The first line managers reported their own limited knowledge about palliative care to limit their possibilities of taking full leadership responsibility for implementing palliative care principles in their nursing homes. The study stresses that for the provision of high quality palliative care in nursing homes, first-line managers need to be knowledgeable about palliative care, and they need supportive organizations with clear expectations and goals about palliative care. Future action and learning oriented research projects for the implementation of palliative care principles, in which first line managers actively participate, are suggested. PMID:25628769

  14. First-Line Nursing Home Managers in Sweden and their Views on Leadership and Palliative Care.

    PubMed

    Håkanson, Cecilia; Cronfalk, Berit Seiger; Henriksen, Eva; Norberg, Astrid; Ternestedt, Britt-Marie; Sandberg, Jonas

    2014-01-01

    The aim of this study was to investigate first-line nursing home managers' views on their leadership and related to that, palliative care. Previous research reveals insufficient palliation, and a number of barriers towards implementation of palliative care in nursing homes. Among those barriers are issues related to leadership quality. First-line managers play a pivotal role, as they influence working conditions and quality of care. Nine first-line managers, from different nursing homes in Sweden participated in the study. Semi-structured interviews were conducted and analysed using qualitative descriptive content analysis. In the results, two categories were identified: embracing the role of leader and being a victim of circumstances, illuminating how the first-line managers handle expectations and challenges linked to the leadership role and responsibility for palliative care. The results reveal views corresponding to committed leaders, acting upon demands and expectations, but also to leaders appearing to have resigned from the leadership role, and who express powerlessness with little possibility to influence care. The first line managers reported their own limited knowledge about palliative care to limit their possibilities of taking full leadership responsibility for implementing palliative care principles in their nursing homes. The study stresses that for the provision of high quality palliative care in nursing homes, first-line managers need to be knowledgeable about palliative care, and they need supportive organizations with clear expectations and goals about palliative care. Future action and learning oriented research projects for the implementation of palliative care principles, in which first line managers actively participate, are suggested.

  15. Association of First-Line and Second-Line Antiretroviral Therapy Adherence

    PubMed Central

    Ramadhani, Habib O.; Bartlett, John A.; Thielman, Nathan M.; Pence, Brian W.; Kimani, Stephen M.; Maro, Venance P.; Mwako, Mtumwa S.; Masaki, Lazaro J.; Mmbando, Calvin E.; Minja, Mary G.; Lirhunde, Eileen S.; Miller, William C.

    2014-01-01

    Background  Adherence to first-line antiretroviral therapy (ART) may be an important indicator of adherence to second-line ART. Evaluating this relationship may be critical to identify patients at high risk for second-line failure, thereby exhausting their treatment options, and to intervene and improve patient outcomes. Methods  Adolescents and adults (n = 436) receiving second-line ART were administered standardized questionnaires that captured demographic characteristics and assessed adherence. Optimal and suboptimal cumulative adherence were defined as percentage adherence of ≥90% and <90%, respectively. Bivariable and multivariable binomial regression models were used to assess the prevalence of suboptimal adherence percentage by preswitch adherence status. Results  A total of 134 of 436 (30.7%) participants reported suboptimal adherence to second-line ART. Among 322 participants who had suboptimal adherence to first-line ART, 117 (36.3%) had suboptimal adherence to second-line ART compared with 17 of 114 (14.9%) who had optimal adherence to first-line ART. Participants who had suboptimal adherence to first-line ART were more likely to have suboptimal adherence to second-line ART (adjusted prevalence ratio, 2.4; 95% confidence interval, 1.5–3.9). Conclusions  Adherence to first-line ART is an important predictor of adherence to second-line ART. Targeted interventions should be evaluated in patients with suboptimal adherence before switching into second-line therapy to improve their outcomes. PMID:25734147

  16. Capsule endoscopy or push enteroscopy for first-line exploration of obscure gastrointestinal bleeding?

    PubMed

    de Leusse, Antoine; Vahedi, Kouroche; Edery, Joël; Tiah, Djamel; Fery-Lemonnier, Elisabeth; Cellier, Christophe; Bouhnik, Yoram; Jian, Raymond

    2007-03-01

    The position of capsule endoscopy (CE) relative to push enteroscopy (PE) in the diagnostic algorithm of obscure gastrointestinal bleeding is unclear, as previous studies involved the use of both techniques in all patients. We therefore conducted a trial in which patients were randomized to undergo one or other exploration. All consecutive patients referred for obscure gastrointestinal bleeding were randomized between CE and PE as the first-line exploration. The alternative method was only used if the first-line method revealed no definite bleeding source, or if required for clinical reasons during follow-up. CE and PE, used as the first-line exploration, identified a bleeding source in 20 of 40 patients and 9 of 38 patients, respectively (50% vs 24%; P = .02). CE missed lesions in 8% of patients, and all these lesions were located in sites accessible to standard endoscopy. PE missed lesions in 26% of patients. At the end of the 12-month follow-up period, the strategy based on CE as first-line exploration followed by PE if necessary only was similar to PE followed by CE in terms of diagnostic yield, clinical outcome, and therapeutic impact, but reduced the percentage of patients needing the alternative exploration (25% vs 79%; P < .001). CE has a higher diagnostic yield than PE in obscure gastrointestinal bleeding, and a strategy based on CE as first-line exploration avoids unnecessary explorations.

  17. Association of first-line and second-line antiretroviral therapy adherence.

    PubMed

    Ramadhani, Habib O; Bartlett, John A; Thielman, Nathan M; Pence, Brian W; Kimani, Stephen M; Maro, Venance P; Mwako, Mtumwa S; Masaki, Lazaro J; Mmbando, Calvin E; Minja, Mary G; Lirhunde, Eileen S; Miller, William C

    2014-09-01

    Adherence to first-line antiretroviral therapy (ART) may be an important indicator of adherence to second-line ART. Evaluating this relationship may be critical to identify patients at high risk for second-line failure, thereby exhausting their treatment options, and to intervene and improve patient outcomes. Adolescents and adults (n = 436) receiving second-line ART were administered standardized questionnaires that captured demographic characteristics and assessed adherence. Optimal and suboptimal cumulative adherence were defined as percentage adherence of ≥90% and <90%, respectively. Bivariable and multivariable binomial regression models were used to assess the prevalence of suboptimal adherence percentage by preswitch adherence status. A total of 134 of 436 (30.7%) participants reported suboptimal adherence to second-line ART. Among 322 participants who had suboptimal adherence to first-line ART, 117 (36.3%) had suboptimal adherence to second-line ART compared with 17 of 114 (14.9%) who had optimal adherence to first-line ART. Participants who had suboptimal adherence to first-line ART were more likely to have suboptimal adherence to second-line ART (adjusted prevalence ratio, 2.4; 95% confidence interval, 1.5-3.9). Adherence to first-line ART is an important predictor of adherence to second-line ART. Targeted interventions should be evaluated in patients with suboptimal adherence before switching into second-line therapy to improve their outcomes.

  18. The Optimal First-Line Therapy of Helicobacter pylori Infection in Year 2012.

    PubMed

    Kuo, Chao-Hung; Kuo, Fu-Chen; Hu, Huang-Ming; Liu, Chung-Jung; Wang, Sophie S W; Chen, Yen-Hsu; Hsieh, Ming-Chia; Hou, Ming-Feng; Wu, Deng-Chyang

    2012-01-01

    This paper reviews the literature about first-line therapies for H. pylori infection in recent years. First-line therapies are facing a challenge because of increasing treatment failure due to elevated antibiotics resistance. Several new treatment strategies that recently emerged to overcome antibiotic resistance have been surveyed. Alternative first-line therapies include bismuth-containing quadruple therapy, sequential therapy, concomitant therapy, and hybrid therapy. Levofloxacin-based therapy shows impressive efficacy but might be employed as rescue treatment due to rapidly raising resistance. Rifabutin-based therapy is also regarded as a rescue therapy. Several factors including antibiotics resistance, patient compliance, and CYP 2C19 genotypes could influence the outcome. Clinicians should use antibiotics according to local reports. It is recommended that triple therapy should not be used in areas with high clarithromycin resistance or dual clarithromycin and metronidazole resistance.

  19. Pediatric multiple sclerosis: Conventional first-line treatment and general management.

    PubMed

    Ghezzi, Angelo; Amato, Maria Pia; Makhani, Naila; Shreiner, Teri; Gärtner, Jutta; Tenembaum, Silvia

    2016-08-30

    Many disease-modifying therapies are currently available for adults with relapsing-remitting multiple sclerosis (MS) but none of them has been tested in pediatric MS in randomized placebo-controlled trials. At present, as suggested by observational studies and experts' guidelines, interferon-β and glatiramer acetate continue to be the standard first-line treatments for pediatric MS. Observational studies and some controlled unblinded trials have shown a positive effect of these meditations in reducing relapse rate and delaying disease progression, with an acceptable safety profile. The goal of this article is to provide an overview of current knowledge with regard to safety, tolerability, and efficacy of first-line treatment options for MS in the pediatric age group, with the aim of providing guidance for planning first-line treatment of MS in children and adolescents.

  20. Clinically relevant transmitted drug resistance to first line antiretroviral drugs and implications for recommendations.

    PubMed

    Monge, Susana; Guillot, Vicente; Alvarez, Marta; Chueca, Natalia; Stella, Natalia; Peña, Alejandro; Delgado, Rafael; Córdoba, Juan; Aguilera, Antonio; Vidal, Carmen; García, Federico

    2014-01-01

    The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007-2011. Using the Stanford algorithm "Low-level resistance", "Intermediate resistance" and "High-level resistance" categories were considered as "Resistant". 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8-7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9-9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8-2.9) vs. 3.6% (2.9-4.3) by the WHO list] and PIs [0.8% (0.4-1.1) vs. 1.7% (1.2-2.2)], while it was higher for NNRTIs [4.6% (3.8-5.3) vs. 3.7% (3.0-4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02). Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations.

  1. Role of First-Line Noninvasive Ventilation in Non-COPD Subjects With Pneumonia.

    PubMed

    Rialp, Gemma; Forteza, Catalina; Muñiz, Daniel; Romero, Maria

    2017-09-01

    The use of noninvasive ventilation (NIV) in non-COPD patients with pneumonia is controversial due to its high rate of failure and the potentially harmful effects when NIV fails. The purpose of the study was to evaluate outcomes of the first ventilatory treatment applied, NIV or invasive mechanical ventilation (MV), and to identify predictors of NIV failure. Historical cohort study of 159 non-COPD patients with pneumonia admitted to the ICU with ventilatory support. Subjects were divided into 2 groups: invasive MV or NIV. Univariate and multivariate analyses with demographic and clinical data were performed. Analysis of mortality was adjusted for the propensity of receiving first-line invasive MV. One hundred and thirteen subjects received first-line invasive MV and 46 received first-line NIV, of which 27 needed intubation. Hospital mortality was 35, 37 and 56%, respectively, with no significant differences among groups. In the propensity-adjusted analysis (expressed as OR [95% CI]), hospital mortality was associated with age (1.05 [1.02-1.08]), SAPS3 (1.03 [1.00-1.07]), immunosuppression (2.52 [1.02-6.27]) and NIV failure compared to first-line invasive MV (4.3 [1.33-13.94]). Compared with invasive MV, NIV failure delayed intubation (p=.004), and prolonged the length of invasive MV (p=.007) and ICU stay (p=.001). NIV failure was associated with need for vasoactive drugs (OR 7.8 [95% CI, 1.8-33.2], p=.006). In non-COPD subjects with pneumonia, first-line NIV was not associated with better outcome compared with first-line invasive MV. NIV failure was associated with longer duration of MV and hospital stay, and with increased hospital mortality. The use of vasoactive drugs predicted NIV failure. Copyright © 2016 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Developing a predictive risk model for first-line antiretroviral therapy failure in South Africa

    PubMed Central

    Rohr, Julia K; Ive, Prudence; Horsburgh, C Robert; Berhanu, Rebecca; Shearer, Kate; Maskew, Mhairi; Long, Lawrence; Sanne, Ian; Bassett, Jean; Ebrahim, Osman; Fox, Matthew P

    2016-01-01

    Introduction A substantial number of patients with HIV in South Africa have failed first-line antiretroviral therapy (ART). Although individual predictors of first-line ART failure have been identified, few studies in resource-limited settings have been large enough for predictive modelling. Understanding the absolute risk of first-line failure is useful for patient monitoring and for effectively targeting limited resources for second-line ART. We developed a predictive model to identify patients at the greatest risk of virologic failure on first-line ART, and to estimate the proportion of patients needing second-line ART over five years on treatment. Methods A cohort of patients aged ≥18 years from nine South African HIV clinics on first-line ART for at least six months were included. Viral load measurements and baseline predictors were obtained from medical records. We used stepwise selection of predictors in accelerated failure-time models to predict virologic failure on first-line ART (two consecutive viral load levels >1000 copies/mL). Multiple imputations were used to assign missing baseline variables. The final model was selected using internal-external cross-validation maximizing model calibration at five years on ART, and model discrimination, measured using Harrell's C-statistic. Model covariates were used to create a predictive score for risk group of ART failure. Results A total of 72,181 patients were included in the analysis, with an average of 21.5 months (IQR: 8.8–41.5) of follow-up time on first-line ART. The final predictive model had a Weibull distribution and the final predictors of virologic failure were men of all ages, young women, nevirapine use in first-line regimen, low baseline CD4 count, high mean corpuscular volume, low haemoglobin, history of TB and missed visits during the first six months on ART. About 24.4% of patients in the highest quintile and 9.4% of patients in the lowest quintile of risk were predicted to experience

  3. Advances in first-line treatment of chronic lymphocytic leukemia: current recommendations on management and first-line treatment by the German CLL Study Group (GCLLSG).

    PubMed

    Cramer, Paula; Langerbeins, Petra; Eichhorst, Barbara; Hallek, Michael

    2016-01-01

    The management of patients with CLL is undergoing significant changes; during the last decade, the outcome of first-line therapies has been markedly improved with the addition of anti-CD20 antibodies to chemotherapy. Today, chemoimmunotherapy for physically fit patients ≤ 65 years should consist of fludarabine, cyclophosphamide, and rituximab (FCR). The combination of bendamustine and rituximab (BR) should be considered in physically fit patients > 65 years and in patients with a higher risk of infections. Patients with reduced fitness and/or relevant comorbidity should receive chlorambucil with a CD20 antibody, preferably obinutuzumab. Regardless of their fitness, patients with CLL carrying genetic aberrations such as del(17p) and/or TP53 mutation poorly respond to chemoimmunotherapy and therefore require different therapeutic approaches. An increasing understanding of the disease biology has led to the development of targeted drugs for the treatment of CLL, such as the BTK inhibitor ibrutinib and PI3K inhibitor idelalisib. These agents have shown efficacy in high-risk and relapsed/refractory patients and are currently being evaluated in clinical trials for first-line therapy. It is anticipated that these compounds and further other novel agents will profoundly change the therapy of CLL.

  4. Efficacy and Safety of Switching Latanoprost Monotherapy to Bimatoprost Monotherapy or Combination of Brinzolamide and Latanoprost

    PubMed Central

    Imasawa, Mitsuhiro; Tanabe, Joji; Kashiwagi, Fumiko; Kashiwagi, Kenji

    2016-01-01

    Purpose: To prospectively assess the efficacy and safety of switching to bimatoprost monotherapy or brinzolamide and latanoprost combination therapy in patients who had been receiving latanoprost monotherapy. Methods: A prospective, open-label study was conducted. Patients with primary open-angle glaucoma or ocular hypertension who had been receiving latanoprost monotherapy for three months or more were enrolled. Bimatoprost was substituted for latanoprost in one eye (BIM group), and brinzolamide was added to the latanoprost in the other eye (BRZ group) simultaneously. The patients underwent examinations at 6 weeks (visit 1) and 12 weeks (visit 2) after changing therapies. Subsequently, the treatments were returned to latanoprost monotherapy. The patients underwent another examination 6 weeks (visit 3) after the return to latanoprost. The parameters examined were intraocular pressure (IOP), conjunctival hyperemia, and corneal epithelial damage. Results: Twenty-six patients (13 men and 13 women) completed the protocol. Both groups showed a significant IOP reduction at visits 1 and 2 compared with the baseline, with a similar magnitude (BIM group: P = 0.016 at visit 1, P = 0.025 at visit 2, BRZ group: P = 0.0006 at visit 1, P = 0.028 at visit 2). The IOPs at the baseline and on visit 3 were similar in both groups (P = 0.7). The two groups showed no changes in either conjunctival hyperemia or corneal epithelial damage compared with the baseline. Conclusion: Bimatoprost monotherapy and brinzolamide adjunctive to latanoprost similarly reduced the IOP, with no additive adverse effects, compared with latanoprost monotherapy. PMID:27073587

  5. The Community College First-Line Dean: Management and Leadership Skills for Instructional Innovation.

    ERIC Educational Resources Information Center

    Kurzet, Reuel

    This qualitative dissertation examines how first-line "area" or "division" deans at community colleges promote instructional innovation among faculty. Community colleges must find ways to provide innovative instruction to a diverse student body, to train working students in new technologies for community economic development, and to be accountable…

  6. A Method of Determining Desirable Task Experiences for First Line Supervisors.

    ERIC Educational Resources Information Center

    Stacy, William J.; Hazel, Joe T.

    Air Force research has identified 254 highly rated journeyman-level tasks, out of a potential 683, in the career field of Accounting and Finance, and has evaluated the extent to which 1,261 first line supervisors in this area have had experience in these tasks. Two seven-skill level specialties within the career field, General Accounting…

  7. Use of bevacizumab as a first-line treatment for metastatic breast cancer

    PubMed Central

    Manso, L.; Moreno, F.; Márquez, R.; Castelo, B.; Arcediano, A.; Arroyo, M.; Ballesteros, A.I.; Calvo, I.; Echarri, M.J.; Enrech, S.; Gómez, A.; González del Val, R.; López–Miranda, E.; Martín–Angulo, M.; Martínez–Jañez, N.; Olier, C.; Zamora, P.

    2015-01-01

    Objective During clinical practice, it can be challenging, given the lack of response biomarkers, to identify the patients with metastatic breast cancer (mbca) who would benefit most from the addition of bevacizumab to first-line standard chemotherapy. The aim of the present review was to summarize the relevant scientific evidence and to discuss the experience of a group of experts in using bevacizumab to treat mbca. Methods A panel of 17 Spanish oncology experts met to discuss the literature and their experience in the use of bevacizumab as first-line treatment for mbca. During the meeting, discussions focused on three main issues: the profile of the patients who could benefit most from bevacizumab, the optimal bevacizumab treatment duration, and the safety profile of bevacizumab. Results The subset of mbca patients who would benefit the most from the addition of bevacizumab to first-line standard chemotherapy are those with clinically defined aggressive disease. Treatment with bevacizumab should be maintained until disease progression or the appearance of unacceptable toxicity. In the mbca setting, the toxicity profile of bevacizumab is well known and can be managed in clinical practice after adequate training. Conclusions This expert group recommends administering bevacizumab as first-line treatment in patients with clinically aggressive disease. PMID:25908921

  8. Male first-line managers' experiences of the work situation in elderly care: an empowerment perspective.

    PubMed

    Hagerman, Heidi; Engström, Maria; Häggström, Elisabeth; Wadensten, Barbro; Skytt, Bernice

    2015-09-01

    To describe male first-line managers' experiences of their work situation in elderly care. First-line managers' work is challenging. However, less attention has been paid to male managers' work situation in health care. Knowledge is needed to empower male managers. Fourteen male first-line managers were interviewed. The interview text was subjected to qualitative content analysis. Work situations were described as complex and challenging; challenges were the driving force. They talked about 'Being on one's own but not feeling left alone', 'Having freedom within set boundaries', 'Feeling a sense of satisfaction and stimulation', 'Feeling a sense of frustration' and 'Having a feeling of dejection and resignation'. Although the male managers report deficiencies in the support structure, they largely experience their work as a positive challenge. To meet increasing challenges, male first-line managers need better access to supportive structural conditions. Better access to resources is needed in particular, allowing managers to be more visible for staff and to work with development and quality issues instead of administrative tasks. Regarding organisational changes and the scrutiny of management and the media, they lack and thus need support and information from superiors. © 2013 John Wiley & Sons Ltd.

  9. Immunoadsorption in patients with chronic inflammatory demyelinating polyradiculoneuropathy with unsatisfactory response to first-line treatment.

    PubMed

    Galldiks, Norbert; Burghaus, Lothar; Dohmen, Christian; Teschner, Sven; Pollok, Manfred; Leebmann, Josef; Frischmuth, Nikolaus; Hollinger, Peter; Nazli, Nahed; Fassbender, Cordula; Klingel, Reinhard; Benzing, Thomas; Fink, Gereon R; Haupt, Walter F

    2011-01-01

    First-line treatment options for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are corticosteroids, intravenous immunoglobulin, and plasma exchange. In a significant number of patients, first-line therapy fails, and long-term maintenance treatment still remains a therapeutic challenge. Immunoadsorption (IA) may be an alternative to classical plasma exchange in the therapy of immune-mediated neurologic diseases. The aim of this investigation was to evaluate efficacy and safety of IA in patients with CIDP with unsatisfactory response to first-line treatment options. CIDP patients received adjunct IA treatment using tryptophan-immune adsorbers. The inflammatory neuropathy cause and treatment disability (INCAT) score was used to grade disability and monitor treatment effects. In total, 14 CIDP patients were analyzed. Ten patients were treated in hospital. After one IA treatment series, the INCAT score decreased significantly in all 10 patients. Four of these 14 patients were treated in outpatient clinics using long-term maintenance IA with 1-2 treatments per week. In these 4 patients, effects of long-term maintenance IA resulted in an improvement of overall disability. In all patients, IA was safe, well tolerated, and no severe adverse effects occurred. IA could be an effective and safe option for CIDP patients with unsatisfactory response to first-line treatment options and for long-term maintenance treatment. Copyright © 2011 S. Karger AG, Basel.

  10. Keeping the Bosses off My Back: Power and Knowledge in First Line Management Discourse.

    ERIC Educational Resources Information Center

    Reid, Zoe

    Since many first line managers (FLMs) have not participated in formal learning, how they make sense of their roles and the training they are doing is significant. A relationship between inadequate literacy skills and ability to do a job is assumed. Language, literacy, and numeracy must be understood in terms of social practice and creation of…

  11. Endoscopic internal drainage as first-line treatment for fistula following gastrointestinal surgery: a case series

    PubMed Central

    Donatelli, Gianfranco; Dumont, Jean-Loup; Cereatti, Fabrizio; Dhumane, Parag; Tuszynski, Thierry; Vergeau, Bertrand Marie; Meduri, Bruno

    2016-01-01

    Background and study aims: Leaks following gastrointestinal surgery are a dreadful complication burdened by high morbidity and not irrelevant mortality. Endoscopic internal drainage (EID) has showed optimal results in the treatment of leaks following bariatric surgery. We report our experience with EID as first-line treatment for fistulas following surgery along all gastrointestinal tract. PMID:27556072

  12. Undetected multidrug-resistant tuberculosis amplified by first-line therapy in mixed infection.

    PubMed

    Hingley-Wilson, Suzanne M; Casey, Rosalyn; Connell, David; Bremang, Samuel; Evans, Jason T; Hawkey, Peter M; Smith, Grace E; Jepson, Annette; Philip, Stuart; Kon, Onn Min; Lalvani, Ajit

    2013-07-01

    Infections with >1 Mycobacterium tuberculosis strain(s) are underrecognized. We show, in vitro and in vivo, how first-line treatment conferred a competitive growth advantage to amplify a multidrug-resistant M. tuberculosis strain in a patient with mixed infection. Diagnostic techniques that identify mixed tubercle bacilli populations are needed to curb the spread of multidrug resistance.

  13. Rituximab Plus Chlorambucil As First-Line Treatment for Chronic Lymphocytic Leukemia: Final Analysis of an Open-Label Phase II Study

    PubMed Central

    Hillmen, Peter; Gribben, John G.; Follows, George A.; Milligan, Donald; Sayala, Hazem A.; Moreton, Paul; Oscier, David G.; Dearden, Claire E.; Kennedy, Daniel B.; Pettitt, Andrew R.; Nathwani, Amit; Varghese, Abraham; Cohen, Dena; Rawstron, Andy; Oertel, Stephan; Pocock, Christopher F.E.

    2014-01-01

    Purpose Most patients with chronic lymphocytic leukemia (CLL) are elderly and/or have comorbidities that may make them ineligible for fludarabine-based treatment. For this population, chlorambucil monotherapy is an appropriate therapeutic option; however, response rates with chlorambucil are low, and more effective treatments are needed. This trial was designed to assess how the addition of rituximab to chlorambucil (R-chlorambucil) would affect safety and efficacy in patients with CLL. Patients and Methods Patients with first-line CLL were treated with rituximab (375 mg/m2 on day 1, cycle one, and 500 mg/m2 thereafter) plus chlorambucil (10 mg/m2/d all cycles; day 1 through 7) for six 28-day cycles. For patients not achieving complete response (CR), six additional cycles of chlorambucil alone could be administered. The primary end point of the study was safety. Results A total of 100 patients were treated with R-chlorambucil, with a median follow-up of 30 months. Median age of patients was 70 years (range, 43 to 86 years), with patients having a median of seven comorbidities. Hematologic toxicities accounted for most grade 3/4 adverse events reported, with neutropenia and lymphopenia both occurring in 41% of patients and leukopenia in 23%. Overall response rates were 84%, with CR achieved in 10% of patients. Median progression-free survival was 23.5 months; median overall survival was not reached. Conclusion These results compare favorably with previously published results for chlorambucil monotherapy, suggesting that the addition of rituximab to chlorambucil may improve efficacy with no unexpected adverse events. R-chlorambucil may improve outcome for patients who are ineligible for fludarabine-based treatments. PMID:24638012

  14. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study.

    PubMed

    Hillmen, Peter; Gribben, John G; Follows, George A; Milligan, Donald; Sayala, Hazem A; Moreton, Paul; Oscier, David G; Dearden, Claire E; Kennedy, Daniel B; Pettitt, Andrew R; Nathwani, Amit; Varghese, Abraham; Cohen, Dena; Rawstron, Andy; Oertel, Stephan; Pocock, Christopher F E

    2014-04-20

    Most patients with chronic lymphocytic leukemia (CLL) are elderly and/or have comorbidities that may make them ineligible for fludarabine-based treatment. For this population, chlorambucil monotherapy is an appropriate therapeutic option; however, response rates with chlorambucil are low, and more effective treatments are needed. This trial was designed to assess how the addition of rituximab to chlorambucil (R-chlorambucil) would affect safety and efficacy in patients with CLL. Patients with first-line CLL were treated with rituximab (375 mg/m(2) on day 1, cycle one, and 500 mg/m(2) thereafter) plus chlorambucil (10 mg/m(2)/d all cycles; day 1 through 7) for six 28-day cycles. For patients not achieving complete response (CR), six additional cycles of chlorambucil alone could be administered. The primary end point of the study was safety. A total of 100 patients were treated with R-chlorambucil, with a median follow-up of 30 months. Median age of patients was 70 years (range, 43 to 86 years), with patients having a median of seven comorbidities. Hematologic toxicities accounted for most grade 3/4 adverse events reported, with neutropenia and lymphopenia both occurring in 41% of patients and leukopenia in 23%. Overall response rates were 84%, with CR achieved in 10% of patients. Median progression-free survival was 23.5 months; median overall survival was not reached. These results compare favorably with previously published results for chlorambucil monotherapy, suggesting that the addition of rituximab to chlorambucil may improve efficacy with no unexpected adverse events. R-chlorambucil may improve outcome for patients who are ineligible for fludarabine-based treatments.

  15. Mycobacterium tuberculosis resistance pattern against first-line drugs in patients from urban area.

    PubMed

    Cucunawangsih; Wiwing, Veronica; Widysanto, Allen; Lugito, Nata Pratama Hardjo

    2015-12-01

    Tuberculosis (TB) infection is still a major public health burden in Indonesia. TB cases in Indonesia constitute 35% of all the TB cases detected worldwide and the prevalence of TB drug resistance in this country is approximately 3%. The aim of this study was to evaluate the resistance of Mycobacterium tuberculosis to first-line TB drugs among isolates from clinical specimens from a hospital in an urban area. This laboratory-based study was conducted in Tangerang District, Indonesia, from January 2011 to December 2014. Sputum and other clinical specimens were obtained from patients with pulmonary and extrapulmonary TB. The specimens were stained with Ziehl-Neelsen, inoculated on Löwenstein-Jensen media for 6-8 weeks, and tested for sensitivity against first-line TB drugs [isoniazid (INH), rifampicin (RIF), ethambutol (EMB), and streptomycin (SM)]. All TB patients in this study lived in urban areas with male preponderance. Of the 127 M. tuberculosis isolates collected, 22% showed resistance to first-line TB drugs. Among these resistant isolates, 20.5% showed resistance to at least one of the first-line TB drugs and 0.8% showed multidrug resistance (MDR). Resistance to EMB, INH, RIF, and SM was seen in 6.3% 6.3%, 4.7%, and 1.6% of isolates, respectively. Polyresistance to EMB and INH, EMB and RIF, and EMB, INH, and RIF was seen in 0.8% of the isolates, respectively. Our study confirms that drug resistance, including MDR, observed against all first-line TB drugs was a real threat in the management of TB infection in Indonesia. The resistance pattern identified in this study could assist clinicians in providing appropriate treatment regimen to TB patients and improve their clinical outcome. Copyright © 2015 Asian-African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.

  16. Real-world use of Permixon® in benign prostatic hyperplasia--determining appropriate monotherapy and combination treatment.

    PubMed

    Perry, Richard; Milligan, Gary; Anderson, Peter; Gillon, Andrew; White, Maren

    2012-06-01

    Benign prostatic hyperplasia (BPH) is a major health concern for aging men. The resulting lower urinary tract symptoms may have a profound effect on a patient's quality of life and it is recognized that patient acceptability of treatment is key to decreasing the human and economic burden of the condition. Alphaadrenergic antagonists (alpha-blockers), 5-alphareductase inhibitors (5-ARIs), and phytotherapy as monotherapy or in combination, form the mainstay of medical treatment. The Adelphi Permixon Study, a cross-sectional study of representative consulting patients with BPH in two European countries, was undertaken to examine the reasons for choice of medication. Physicians completed patient record forms, and data were analyzed for clinical outcomes and their relationship with the choice of appropriate therapy. Patients receiving combination therapies for BPH are likely to be older and are more likely to be retired than those on monotherapy. Combination therapy is adopted in the real-world setting as first-line therapy on a not-infrequent basis. The analyses demonstrated an association between choice of Permixon® (Pierre Fabre Medicament, Castres, France) as appropriate monotherapy or in combination with alpha-blockers, and the following: BPH severity; treatment of general urinary symptoms, including storage and voiding symptoms; improvement of urinary flow rate; lack of a risk of sexual problems; and reduction of inflammation. Permixon combination with an alpha-blocker is associated with benefits in terms of speed of onset of action, reduction of inflammation, and a positive benefit regarding sexual problems when compared with use of alpha-blocker monotherapy. In the real clinical world, Permixon is considered an appropriate treatment for BPH as both monotherapy and in combination with alpha-blockers. Prescribing Permixon in combination with alpha-blockers can be demonstrated to provide benefits beyond use of either therapy alone.

  17. Cabergoline versus levodopa monotherapy: a decision analysis.

    PubMed

    Smala, Antje M; Spottke, E Annika; Machat, Olaf; Siebert, Uwe; Meyer, Dieter; Köhne-Volland, Rudolf; Reuther, Martin; DuChane, Janeen; Oertel, Wolfgang H; Berger, Karin B; Dodel, Richard C

    2003-08-01

    We evaluated the incremental cost-effectiveness of cabergoline compared with levodopa monotherapy in patients with early Parkinson's disease (PD) in the German healthcare system. The study design was based on cost-effectiveness analysis using a Markov model with a 10-year time horizon. Model input data was based on a clinical trial "Early Treatment of PD with Cabergoline" as well as on cost data of a German hospital/office-based PD network. Direct and indirect medical and nonmedical costs were included. Outcomes were costs, disease stage, cumulative complication incidence, and mortality. An annual discount rate of 5% was applied and the societal perspective was chosen. The target population included patients in Hoehn and Yahr Stages I to III. It was found that the occurrence of motor complications was significantly lower in patients on cabergoline monotherapy. For patients aged >/=60 years of age, cabergoline monotherapy was cost effective when considering costs per decreased UPDRS score. Each point decrease in the UPDRS (I-IV) resulted in costs of euro;1,031. Incremental costs per additional motor complication-free patient were euro;104,400 for patients <60 years of age and euro;57,900 for patients >/=60 years of age. In conclusion, this decision-analytic model calculation for PD was based almost entirely on clinical and observed data with a limited number of assumptions. Although costs were higher in patients on cabergoline, the corresponding cost-effectiveness ratio for cabergoline was at least as favourable as the ratios for many commonly accepted therapies.

  18. Transitional polytherapy: tricks of the trade for monotherapy to monotherapy AED conversions.

    PubMed

    Garnett, William R; St Louis, Erik K; Henry, Thomas R; Bramley, Thomas

    2009-06-01

    The goal of epilepsy therapy is to help patients achieve seizure freedom without adverse effects. While monotherapy is preferable in epilepsy treatment, many patients fail a first drug due to lack of efficacy or failure to tolerate an initial medication, necessitating an alteration in therapy. Sudden changes between monotherapies are rarely feasible and sometimes deleterious given potential hazards of acute seizure exacerbation or intolerable adverse effects. The preferred method for converting between monotherapies is transitional polytherapy, a process involving initiation of a new antiepileptic drug (AED) and adjusting it toward a target dose while maintaining or reducing the dose of the baseline medication. A fixed-dose titration strategy of maintaining the baseline drug dose while titrating the new medication is preferable when breakthrough seizures are occurring and no adverse effects are present. However, a flexible titration strategy involving reduction of the baseline drug dose to ensure adequate tolerability of the new adjunctive medication is preferred when patients are already experiencing adverse effects. This article reviews pharmacokinetic considerations pertinent for ensuring successful transitional polytherapy with the standard and newer antiepileptic drugs. Practical consensus recommendations "from an expect panel (SPECTRA, Study by a Panel of Experts Considerations for Therapy Replacement and Antiepileptics) for a successful monotherapy" AED conversions are then summarized. Transitional polytherapy is most successful when clinicians appropriately manage the titration strategy and consider pharmacokinetic factors germane to the baseline and new adjunctive medication.

  19. Clinically Relevant Transmitted Drug Resistance to First Line Antiretroviral Drugs and Implications for Recommendations

    PubMed Central

    Monge, Susana; Guillot, Vicente; Alvarez, Marta; Chueca, Natalia; Stella, Natalia; Peña, Alejandro; Delgado, Rafael; Córdoba, Juan; Aguilera, Antonio; Vidal, Carmen; García, Federico; CoRIS

    2014-01-01

    Background The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. Methods We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007–2011. Using the Stanford algorithm “Low-level resistance”, “Intermediate resistance” and “High-level resistance” categories were considered as “Resistant”. Results 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8–7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9–9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8–2.9) vs. 3.6% (2.9–4.3) by the WHO list] and PIs [0.8% (0.4–1.1) vs. 1.7% (1.2–2.2)], while it was higher for NNRTIs [4.6% (3.8–5.3) vs. 3.7% (3.0–4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02). Conclusions Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations. PMID:24637804

  20. Latest advances in the efficacy, tolerability, and monotherapy of integrase inhibitors.

    PubMed

    Tang, Qi; Lu, Hongzhou

    2017-01-01

    More than 30 drugs for antiretroviral therapy (ART), including integrase inhibitors (INIs), have been approved by the U.S. Food and Drug Administration (FDA) as of 2017. Integrase is the third essential enzyme in the cycle of human immunodeficiency virus (HIV) replication. INIs can effectively inhibit the replication of HIV and HIV is less prone to develop resistance to INIs clinically. Previous studies based on 7 phase III clinic trials indicate that INIs have satisfactory efficacy and tolerability in patients infected with HIV. The latest advances in INIs indicate that: i) dolutegravir (DTG)-based regimens are more efficacious, tolerable, and safer forms of first-, second-, and third-Line ART; ii) current studies have indicated that DTG monotherapy fails both virologically and clinically; and iii) whether the most cost-effective treatment for DTG is to replace efavirenz (EFV) as a first-line ART, to replace protease inhibitors (PIs) in second-line ART, or to replace both as a monotherapy is unclear. Given these circumstances, further study of INIs in terms of drug interactions, dose reduction, drug convenience, and drug costs is warranted.

  1. Combining bosentan and sildenafil in pulmonary arterial hypertension patients failing monotherapy: real-world insights.

    PubMed

    Dardi, Fabio; Manes, Alessandra; Palazzini, Massimiliano; Bachetti, Cristina; Mazzanti, Gaia; Rinaldi, Andrea; Albini, Alessandra; Gotti, Enrico; Monti, Enrico; Bacchi Reggiani, Maria Letizia; Galiè, Nazzareno

    2015-08-01

    Pulmonary arterial hypertension is a severe disease with a complex pathogenesis, for which combination therapy is an attractive option.This study aimed to assess the impact of sequential combination therapy on both short-term responses and long-term outcomes in a real-world setting.Patients with idiopathic/heritable pulmonary arterial hypertension, or pulmonary arterial hypertension associated with congenital heart disease or connective tissue disease and who were not meeting treatment goals on either first-line bosentan or sildenafil monotherapy, were given additional sildenafil or bosentan and assessed after 3-4 months. Double combination therapy significantly improved clinical and haemodynamic parameters, independent of aetiology or the order of drug administration. Significant improvements in functional class were observed in patients with idiopathic/heritable pulmonary arterial hypertension. The 1-, 3- and 5-year overall survival estimates were 91%, 69% and 59%, respectively. Patients with pulmonary arterial hypertension associated with connective tissue disease had significantly poorer survival rates compared to other aetiologies (p<0.003).The favourable short-term haemodynamic results and good survival rates, observed in patients receiving both bosentan and sildenafil, supports the use of sequential combination therapy in patients failing on monotherapy in a real-world setting.

  2. [Case of MMF monotherapy for membranous nephropathy].

    PubMed

    Kobayashi, Mioko; Kojima, Chiari; Sugiura, Hidekazu; Aoki, Asuka; Itabashi, Mitsuyo; Tsukada, Misao; Takei, Takashi; Uchida, Keiko; Nitta, Kosaku

    2010-01-01

    We report the case of a 58-year-old male patient who visited our hospital for the management of edema and proteinuria. He was diagnosed as having nephrotic syndrome, with serum total protein and albumin levels of 4.6 g/dL and 2.1 g/dL, respectively, and a urinary protein excretion level of 6.0 g/day. A percutaneous renal biopsy showed features of membranous glomerulonephritis, with capillary-wall granular deposits of IgG and C3 on immunofluorescence and subepithelial immune complex deposits on electron microscopy. No other secondary cause of membranous glomerulopathy was found even after extensive investigations. The patient was started on mycophenolate mofetil (MMF) monotherapy (1,500 mg/day), and 18 months after the start of this therapy, the proteinuria decreased to 0.5 g/day, with return to a normal serum albumin level. No digestive symptoms, kidney function worsening or increase in blood pressure were noted during treatment. These findings suggest that MMF monotherapy is effective and safe for the treatment of membranous nephropathy.

  3. Monotherapy comparative trials: placebos and suboptimal comparators.

    PubMed

    Schwabe, S

    2001-05-01

    The superiority of a drug can be demonstrated using several comparative designs against either placebo, or a low dose of the study drug or standard anti-epileptic drug (AED). Firstly, the population could consist of inpatients admitted for presurgical monitoring. Although these trials are scientifically interpretable, and involve direct comparison of the study drug against placebo, they are, in general, too short in duration to be able to define clinical relevance. Secondly, patients with refractory epilepsy can participate in monotherapy substitution studies during which patients are randomised to one of at least two arms with the baseline AED subsequently tapered and discontinued. These patients are maintained on monotherapy for the rest of the trial. An enriched design can also be used in which patients successfully converted to a high dose of the study drug, are then randomised to either the high or low dose of the treatment. The ethics of such enriched designs is questionable. More recently, studies have been carried out in patients with new onset seizures. In such designs, patients are randomised to the study drug (possibly at different dosages), versus a placebo or pseudo-placebo control. Comparative trials in patients with newly-diagnosed epilepsy makes it more difficult to obtain significant differences due to the high number of patients needed and the usually lengthy time course of the study.

  4. Zonisamide monotherapy for idiopathic epilepsy in dogs.

    PubMed

    Chung, J Y; Hwang, C Y; Chae, J S; Ahn, J O; Kim, T H; Seo, K W; Lee, S Y; Youn, H Y

    2012-11-01

    To evaluate the efficacy of zonisamide as a monotherapy in dogs with idiopathic epileptic seizure. The experiment was conducted on 10 dogs with idiopathic epilepsy that were treated at the Seoul National University Hospital for Animals. A diagnosis was conducted based on physical and neurologic examination, complete blood count and chemical analysis, magnetic resonance imaging and cerebrospinal fluid analyses. Idiopathic epilepsy was diagnosed when all of these examinations were normal. Oral zonisamide was administrated to 10 dogs with idiopathic epilepsy at 5-15 mg/kg per os every 12 h to achieve a concentration of zonisamide in serum of 10-40 μg/mL. The frequency of seizures before and after the administration of zonisamide therapy was recorded and the concentrations of zonisamide in serum were measured. Six (60%) of the dogs were favourable responders to treatment, showing a ≥50% reduction in monthly frequency of seizures. Of the remaining four, two dogs did not show a reduction and the other two showed an increase in frequency of seizures. The mean dosage of zonisamide for favourable responders was 7.92 (SD 3.79) mg/kg, which was administered orally twice a day. Only one dog, which was one of the unfavourable responders in the whole study, experienced mild side effects. Among the dogs treated with oral zonisamide, 60% responded favourably. The effect of zonisamide as an anticonvulsant drug was demonstrated in this study. Based on these results, zonisamide monotherapy is effective in some dogs with idiopathic epilepsy.

  5. Optimal First-Line Treatment for Helicobacter pylori Infection: Recent Strategies

    PubMed Central

    2016-01-01

    A new treatment strategy is needed, as the efficacy of triple therapy containing clarithromycin—the current standard treatment for Helicobacter pylori infection—is declining. Increasing antibiotic resistance of H. pylori is the most significant factor contributing to eradication failure. Thus, selecting the most appropriate regimen depending on resistance is optimal, but identifying resistance to specific antibiotics is clinically challenging. In a region suspected to have high clarithromycin resistance, bismuth quadruple therapy and so-called nonbismuth quadruple therapies (sequential, concomitant, and sequential-concomitant hybrid) are some first-line regimen options. However, more research is needed regarding appropriate second-line treatments after first-line treatment failure. Tailored therapy, which is based on antibiotic sensitivity testing, would be optimal but has several limitations for clinical use, and an alternative technique is required. A novel potassium-competitive acid blocker-based eradication regimen could be a valuable eradication option in the near future. PMID:28070184

  6. Carpal tunnel syndrome diagnosed using ultrasound as a first-line exam by the surgeon.

    PubMed

    Lange, J

    2013-07-01

    This study evaluates the diagnostic value of ultrasound as a first-line exam in carpal tunnel syndrome. In 16 patients with carpal tunnel syndrome and 32 matched controls, evaluation of the median nerve was performed by the cross-sectional area at wrist level and wrist-forearm ratio. This study found statistically significant differences between patients and controls by both methods, and both showed high specificity and positive predictive values. Optimal cut-off values were identified at a 14 mm(2) cross-sectional area and a 1.6 wrist-forearm ratio. This study implies that ultrasound evaluation of the median nerve is a valuable tool as a first-line diagnostic test used by the surgeon for examination of patients with presumed carpal tunnel syndrome. Owing to the high positive predictive value of ultrasound, the need for referral to nerve conduction study may be limited.

  7. Bevacizumab-Based Therapies in the First-Line Treatment of Metastatic Colorectal Cancer

    PubMed Central

    Hurwitz, Herbert I.

    2012-01-01

    Since its approval for the first-line treatment of metastatic colorectal cancer (mCRC), bevacizumab has become a standard treatment option in combination with chemotherapy for patients with mCRC. Bevacizumab has demonstrated efficacy in combination with a number of different backbone chemotherapy regimens, and its widespread use has introduced several important questions regarding the selection and optimization of bevacizumab-based treatment regimens, its use in various patient populations, and the identification of associated adverse events. This review discusses the results of several phase II and phase III clinical trials, as well as large observational studies, to address the use of bevacizumab in the treatment of patients with mCRC in the first-line setting. PMID:22477726

  8. Hormonal therapy for acne: why not as first line therapy? facts and controversies.

    PubMed

    Katsambas, Andreas D; Dessinioti, Clio

    2010-01-01

    Standard systemic therapeutic agents used in acne include oral antimicrobials, isotretinoin, and hormonal agents. Appropriate patient selection is the key to decide when to use hormonal agents as first-line therapy as well as to achieve optimal results. Indications of hormonal therapy in acne in girls and women include proven ovarian or adrenal hyperandrogenism, recalcitrant acne, acne not responding to repeated courses of oral isotretinoin, acne tarda, polycystic ovary syndrome, or the presence of clinical signs of hyperandrogenism such as androgenic alopecia or the presence of the seborrhea, acne, hirsutism, alopecia syndrome. We describe the hormonal agents currently available for acne treatment, discuss their indications and contraindications, and address the question of whether they may be used as a first-line therapy in acne.

  9. Power in health care organizations: contemplations from the first-line management perspective.

    PubMed

    Isosaari, Ulla

    2011-01-01

    The aim of this paper is to examine health care organizations' power structures from the first-line management perspective. What liable power structures derive from the theoretical bases of bureaucratic, professional and result based organizations, and what power type do health care organizations represent, according to the empirical data? The paper seeks to perform an analysis using Mintzberg's power configurations of instrument, closed system, meritocracy and political arena. The empirical study was executed at the end of 2005 through a survey in ten Finnish hospital districts in both specialized and primary care. Respondents were all first-line managers in the area and a sample of staff members from internal disease, surgical and psychiatric units, as well as out-patient and primary care units. The number of respondents was 1,197 and the response percentage was 38. The data were analyzed statistically. As a result, it can be seen that a certain kind of organization structure supports the generation of a certain power type. A bureaucratic organization generates an instrument or closed system organization, a professional organization generates meritocracy and also political arena, and a result-based organization has a connection to political arena and meritocracy. First line managers regarded health care organizations as instruments when staff regarded them mainly as meritocracies having features of political arena. Managers felt their position to be limited by rules, whereas staff members regarded their position as having lots of space and influence potential. If the organizations seek innovative and active managers at the unit level, they should change the organizational structure and redistribute the work so that there could be more space for meaningful management. This research adds to the literature and gives helpful suggestions that will be of interest to those in the position of first-line management in health care.

  10. First-line managers' experiences of alternative modes of funding in elderly care in Sweden.

    PubMed

    Antonsson, Helen; Korjonen, Susanne Eriksson; Rosengren, Kristina

    2012-09-01

    The aim of this study was to describe first-line managers' experiences of alternative modes of funding elderly care in two communities in western Sweden. A growing elderly population demands alternative modes of funding elderly care for better outcomes for patients and better efficiency as it is publicly funded through taxation. The study comprised a total of eight semi-structured interviews with first-line managers working within elderly care. The interviews were analysed using manifest qualitative content analysis. Respect for the individuals was a main concern in the study. One category, quality improvement, and four subcategories freedom of choice, organisational structure, quality awareness and market forces effects were identified to describe first-line managers' experiences of the operation of elderly care. Quality improvement was an important factor to deal with when elderly care was operated in different organisational perspectives, either private or public. The first-line manager is a key person for developing a learning organisation that encourages both staff, clients and their relatives to improve the organisation. Moreover, person-centred care strengthens the client's role in the organisation, which is in line with the government's goal for the quality improvement of elderly care. However, further research is needed on how quality improvement could be developed when different caregivers operate in the same market in order to improve care from the elderly perspective. This study highlights alternative modes of funding elderly care. The economical perspectives should not dominate without taking care of quality improvement when the operation of elderly care is planned and implemented. Strategies such as a learning organisational structure built on person-centred care could create quality improvement in elderly care. © 2012 Blackwell Publishing Ltd.

  11. First-line tracheal resection and primary anastomosis for postintubation tracheal stenosis

    PubMed Central

    Mostafa, AM; Soliman, S; Shoukry, T; El-Nori, AA; El-Bawab, HY

    2016-01-01

    Introduction Tracheal stenosis following intubation is the most common indication for tracheal resection and reconstruction. Endoscopic dilation is almost always associated with recurrence. This study investigated first-line surgical resection and anastomosis performed in fit patients presenting with postintubation tracheal stenosis. Methods Between February 2011 and November 2014, a prospective study was performed involving patients who underwent first-line tracheal resection and primary anastomosis after presenting with postintubation tracheal stenosis. Results A total of 30 patients (20 male) were operated on. The median age was 23.5 years (range: 13–77 years). Seventeen patients (56.7%) had had previous endoscopic tracheal dilation, four (13.3%) had had tracheal stents inserted prior to surgery and one (3.3%) had undergone previous tracheal resection. Nineteen patients (63.3%) had had a tracheostomy. Eight patients (26.7%) had had no previous tracheal interventions. The median time of intubation in those developing tracheal stenosis was 20.5 days (range: 0–45 days). The median length of hospital stay was 10.5 days (range: 7–21 days). The success rate for anastomoses was 96.7% (29/30). One patient needed a permanent tracheostomy. The in-hospital mortality rate was 3.3%: 1 patient died from a chest infection 21 days after surgery. There was no mortality or morbidity in the group undergoing first-line surgery for de novo tracheal lesions. Conclusions First-line tracheal resection with primary anastomosis is a safe option for the treatment of tracheal stenosis following intubation and obviates the need for repeated dilations. Endoscopic dilation should be reserved for those patients with significant co-morbidities or as a temporary measure in non-equipped centres. PMID:27138847

  12. A population-based study of chronic myeloid leukemia patients treated with imatinib in first line.

    PubMed

    Castagnetti, Fausto; Di Raimondo, Francesco; De Vivo, Antonio; Spitaleri, Antonio; Gugliotta, Gabriele; Fabbiano, Francesco; Capodanno, Isabella; Mannina, Donato; Salvucci, Marzia; Antolino, Agostino; Marasca, Roberto; Musso, Maurizio; Crugnola, Monica; Impera, Stefana; Trabacchi, Elena; Musolino, Caterina; Cavazzini, Francesco; Mineo, Giuseppe; Tosi, Patrizia; Tomaselli, Carmela; Rizzo, Michele; Siragusa, Sergio; Fogli, Miriam; Ragionieri, Riccardo; Zironi, Alessandro; Soverini, Simona; Martinelli, Giovanni; Cavo, Michele; Vigneri, Paolo; Stagno, Fabio; Rosti, Gianantonio; Baccarani, Michele

    2017-01-01

    Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapy. These studies included patients selected according to many inclusion-exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real-life), inclusion-exclusion criteria do not exist, and the treatment outcome does not only depend on the choice of first-line TKI but also on second- and third-line TKIs. To investigate in a real-life setting the response and the outcome on first-line imatinib, with switch to second generation TKIs in case of unsatisfying response or intolerance, we analyzed all newly diagnosed patients (N = 236), living in two Italian regions, registered in a prospective study according to population-based criteria and treated front-line with imatinib. A switch from imatinib to second-generation TKIs was reported in 14% of patients for side effects and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively; the 4-year rates of MR(3.0) and MR(4.0) were 75% and 48%, respectively. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients receiving nilotinib as second-line. Older age (≥70 years) affected OS, but not LRS. These data provide an unbiased reference on the CML management and on the results of TKI treatment in real-life, according to ELN recommendations, using imatinib as first-line treatment and second-generation TKIs as second-line therapy. Am. J. Hematol. 92:82-87, 2017. © 2016 Wiley Periodicals, Inc.

  13. Is zidovudine first-line therapy virologically comparable to tenofovir in resource-limited settings?

    PubMed

    Labhardt, Niklaus D; Bader, Joëlle; Lejone, Thabo Ismael; Ringera, Isaac; Puga, Daniel; Glass, Tracy R; Klimkait, Thomas

    2015-07-01

    To compare virologic success between adult patients on tenofovir (TDF) and zidovudine (AZT)-containing first-line antiretroviral (ART) regimens in 10 rural clinics in Lesotho, Southern Africa. Multicentre cross-sectional study, patients ≥16 years, on first-line ART ≥6 months, receiving AZT/lamivudine (3TC) or TDF/3TC combined with efavirenz (EFV) or nevirapine (NVP). Patient characteristics and clinical/therapeutic history were collected on the day of blood draw for viral load (VL). Analysis was stratified for non-nucleoside reverse transcriptase inhibitor (EFV or NVP). A logistic regression model weighted for patients' baseline characteristics was used to assess the likelihood of virologic success (<80 copies/ml) in patients with TDF- as compared to AZT-backbones. In total 1539 patients were included in the analysis. Most were clinically and immunologically stable (clinical failure: 2.7% (AZT) and 2.8% (TDF); immunological failure: 4.6% (AZT) and 4.8% (TDF)). In EFV-based regimens (n = 1162), TDF was significantly associated with higher rates of virologic suppression than AZT (93.8% vs. 88.1%; weighted odds ratio: 2.15 (95% CI: 1.29-3.58; P = 0.003)). In NVP-based regimens, a similar trend was observed, but not significant (89.4% vs. 86.7%; 1.99 (0.83-4.75, P = 0.121)). These findings support the WHO recommendation to use TDF/3TC/EFV as first-line regimen. They do, however, not support the recommendation that patients who are clinically stable on AZT should continue on this first-line regimen. © 2015 John Wiley & Sons Ltd.

  14. First line chemotherapy plus trastuzumab in metastatic breast cancer HER2 positive - Observational institutional study

    PubMed Central

    Aitelhaj, Meryem; Lkhoyaali, Siham; Rais, Ghizlane; Boutayeb, Saber; Errihani, Hassan

    2016-01-01

    Breast cancer is the most common malignant disease and among the most frequent causes of cancer mortality in females worldwide. Metastatic breast cancer (MBC) is conventionally considered to be incurable. In first-line treatment of HER-2 positive MBC, randomized trials have demonstrated that trastuzumab when combined with chemotherapy significantly improves progression free survival and overall survival. To evaluate survival and toxicity of chemotherapy with Trastuzumab as first line therapy of human epithermal growth factor receptor 2 positive metastatic breast cancer, in Moroccan population. It is a phase IV observational institutional monocentric study. Including patients with metastatic breast cancer HER2 positive, as first-line chemotherapy combined with Trastuzumab from March 2009 until March 2010. Primary end point: progression free survival, secondary end point response rate and overall survival. A total of 20 patients were enrolled between March 2009 and March 2010. The lung was the first metastatic site in 60% of the cases, followed by bone, liver, nodes, skin and brain. All patients received chemotherapy with Trastuzumab: 9 of them with Docetaxel, 8 with vinorelbine, and 3 with capecitabine. The progression free survival was estimated by the Kaplan-Meier method, from the date of first cycle to the date of progression or at the last consultation, and the median was 12.8 months. Trastuzumab based chemotherapy was generally well tolerated; 5 patients (25%) presented cardiotoxicity. The results of this study join the literature and show the benefit of Trastuzumab to chemotherapy in first line metastatic breast cancer HER-2 positive. PMID:28154679

  15. First-line treatment in lymphomatoid papulosis: a retrospective multicentre study.

    PubMed

    Fernández-de-Misa, R; Hernández-Machín, B; Servitje, O; Valentí-Medina, F; Maroñas-Jiménez, L; Ortiz-Romero, P L; Sánchez Schmidt, J; Pujol, R M; Gallardo, F; Pau-Charles, I; García Muret, M P; Pérez Gala, S; Román, C; Cañueto, J; Blanch Rius, L; Izu, R; Ortiz-Brugués, A; Martí, R M; Blanes, M; Morillo, M; Sánchez, P; Peñate, Y; Bastida, J; Pérez Gil, A; Lopez-Lerma, I; Muniesa, C; Estrach, T

    2017-10-10

    Data regarding response to treatment in lymphomatoid papulosis (LyP) are scarce. To assess the daily clinical practice approach to LyP and the response to first-line treatments. This was a retrospective study enrolling 252 patients with LyP. Topical steroids, methotrexate and phototherapy were the most common first-line treatments, prescribed for 35%, 20% and 14% of the patients, respectively. Complete response (CR) was achieved in 48% of treated patients. Eczematous lesions significantly increased relative risk (RR) of not achieving CR (RR = 1.76; 95% CI 1.16-2.11). Overall median time to CR was 10 months (95% CI 6-13 months), and 78% of complete responders showed cutaneous relapse; both results were similar for all treatment groups (P > 0.05). Overall estimated median disease-free survival (DFS) was 11 months (95% CI 9-13 months) but DFS for patients treated with phototherapy was 23 months (95% CI 10-36 months; P < 0.03). Having the Type A LyP variant (RR = 2.04; 95% CI 0.96-4.30) and receiving a first-line treatment other than phototherapy (RR = 5.33; 95% CI 0.84-33.89) were significantly associated with cutaneous early relapse. Of the 252 patients, 31 (13%) had associated mycosis fungoides unrelated to therapeutic approach, type of LyP or T-cell receptor clonality. Current epidemiological, clinical and pathological data support previous results. Topical steroids, phototherapy and methotrexate are the most frequently prescribed first-line treatments. Although CR and cutaneous relapse rates do not differ between them, phototherapy achieves a longer DFS. Presence of Type A LyP and use of topical steroid or methotrexate were associated with an increased risk of early relapse. © 2017 British Association of Dermatologists.

  16. Integrating first-line treatment options into clinical practice: what's new in advanced melanoma?

    PubMed

    Dummer, Reinhard; Schadendorf, Dirk; Ascierto, Paolo A; Larkin, James; Lebbé, Celeste; Hauschild, Axel

    2015-12-01

    Melanoma remains a serious form of skin cancer in Europe and worldwide. Localized, early-stage melanomas can usually be treated with surgical excision. However, the prognosis is poorer for patients with advanced disease. Before 2011, treatment for advanced melanoma included palliative surgery and/or radiotherapy, and chemotherapy with or without immunotherapy, such as interleukin-2. As none of these treatments had shown survival benefits in patients with advanced melanoma, European guidelines had recommended that patients be entered into clinical trials. The lack of approved first-line options and varying access to clinical trials meant that European clinicians relied on experimental regimens and chemotherapy-based treatments when no other options were available. Since 2011, ipilimumab, an immuno-oncology therapy, and vemurafenib and dabrafenib, targeted agents that inhibit mutant BRAF, have been approved by the European Medicines Agency for the treatment of advanced melanoma. More recently, the MEK inhibitor, trametinib, received European marketing authorization for use in patients with BRAF mutation-positive advanced melanoma. In 2014, the anti-PD-1 antibody nivolumab was approved as a first-line therapy in Japan. Whereas nivolumab and another anti-PD-1 antibody, pembrolizumab, were approved as second-line therapies in the USA, their recent approval in Europe are for first-line use based on new clinical trial data in this setting. Together these agents are changing clinical practice and making therapeutic decisions more complex. Here, we discuss current and emerging therapeutic options for the first-line treatment of advanced melanoma, and how these therapies can be optimized to provide the best possible outcomes for patients.

  17. Job Analysis of U.S. Army Civilian First-Line Supervisors

    DTIC Science & Technology

    1988-05-01

    found in depots, training centers, hospitals, command headquarters, and a variety of other activities in the United States and throughout the world. Their...first-line supervisors working at 155 locations both within and outside the Continental United States . The number of surveys distributed ensured that...Office of Personnel Management, Equal Employment Opportunity Commission, and U.S. Department of Labor (1978). Uniform guidelines on employee selection

  18. The Country Team: Restructuring America’s First Line of Engagement

    DTIC Science & Technology

    2007-09-01

    Embassy staffs—our Country Teams—are ideally positioned as the first lines of engagement to face challenges to U.S. national interests. Yet effective ...resources. The Ambassador is not sufficiently empowered to act effectively as the Country Team’s leader. Despite longstanding policy to the contrary...and personalities all come together. The Coun- try Team builds the American image abroad and implements strategy. Without an effective Country Team

  19. [Indications for methotrexate in gynecology outside the first-line treatment of ectopic tubal pregnancies].

    PubMed

    Misme, H; Agostini, A; Dubernard, G; Tourette, C

    2015-03-01

    The objective of this work is to discuss the indications for methotrexate in gynecology outside the first-line treatment of tubal ectopic pregnancy. In tubal ectopic pregnancy, the prophylactic use of systemic methotrexate can be discussed when performing laparoscopic salpingotomy. In case of failure of salpingotomy, administration seems justified especially if it avoids re-intervention. The combination of methotrexate with other therapies such as mifepristone, potassium chloride or gefitinib is not recommended in the treatment of ectopic pregnancy. For non-tubal ectopic pregnancy, the intramuscular or local administration of methotrexate is an acceptable treatment for uncomplicated interstitial pregnancies. For uncomplicated cervical or cesarean scar pregnancies, the local administration of methotrexate should be considered as a first-line treatment. For ovarian pregnancies, methotrexate should not be a first-line treatment, surgical treatment remains the standard. Asymptomatic women presenting with a pregnancy of unknown location and plateauing serum hCG concentration<2000 UI/L can be managed expectantly: it is recommended to take an additional quantitative hCG serum level after 48 hours. Thus, methotrexate is not recommended in the first intention. Other gynecological indications were discussed: methotrexate is not recommended in the management of first-trimester miscarriages or in the management of placenta accreta.

  20. First-line urological evaluation in multiple sclerosis: validation of a specific decision-making algorithm.

    PubMed

    Amarenco, Gérard; Chartier-Kastler, Emmanuel; Denys, Pierre; Jean, Jacques Labat; de Sèze, Marianne; Lubetzski, Catherine

    2013-12-01

    Urinary disorders that lead to urological complications are frequent in multiple sclerosis, resulting in diminished quality of life. Urinary management guidelines are scarce and targeted to neuro-urology specialists. This study aimed to construct and validate an algorithm dedicated to neurologists and general practitioners to facilitate first-line evaluation and treatment of urinary disorders associated with multiple sclerosis. 49 items concerning urological symptom evaluation and therapeutic strategies were derived from literature analysis and evaluated by an expert panel. The Delphi method established consensus between the experts and allowed development of the First-Line Urological Evaluation in Multiple Sclerosis (FLUE-MS) algorithm. Two questions from the Urinary Bothersome Questionnaire in Multiple Sclerosis were included and their validation to verify comprehensiveness and acceptability was also conducted. Three rounds of expert review obtained consensus of all 49 items and allowed finalisation of the algorithm. Comprehension and acceptability of two Urinary Bothersome Questionnaire in Multiple Sclerosis questions were verified (mean comprehensiveness score: 1.99/2 [99.7% total comprehensiveness], mean acceptability score: 1.99/2 [99.1% complete acceptability]). The FLUE-MS algorithm was designed for neurologists and general practitioners, enabling identification of 'red flags', timely patient referral to specialist neuro-urology units, and appropriate first-line therapy.

  1. Cost-effectiveness of novel first-line treatment regimens for tuberculosis.

    PubMed

    Owens, J P; Fofana, M O; Dowdy, D W

    2013-05-01

    To evaluate the cost-effectiveness of novel first-line treatment regimens for tuberculosis (TB). Using decision analysis, we projected the costs and effectiveness, from the health care perspective, of treating a patient cohort in the public sector for active TB without known or suspected resistance to first-line drugs. We compared standard (6-month) treatment to hypothetical regimens of equal efficacy, higher cost and shorter duration. For every 100 TB patients treated, replacing standard treatment with shorter-course regimens would avert an estimated 2-4 failures/relapses, 0.2-0.4 deaths and 8-14 disability-adjusted life years (DALYs), or 6-11% of all DALYs suffered. We identified three primary determinants of cost-effectiveness: drug price, continuation phase treatment delivery costs and deaths averted through fewer relapses. In a high treatment cost scenario (similar to Brazil), averted delivery costs outweighed higher drug costs, making novel regimens cost-saving. In a low treatment cost scenario (similar to the Philippines), a 4-month regimen with a drug price of $1/day cost $66 per patient, or $840 per DALY averted, and became cost-saving if the drug price dropped below $0.37/day. Although they avert a small proportion of total DALYs, novel, shorter-course first-line regimens for TB are likely to be cost-effective or cost-saving in most settings.

  2. Resilience and work-life balance in first-line nurse manager.

    PubMed

    Kim, Miyoung; Windsor, Carol

    2015-03-01

    The aim of this study was to explore how first-line nurse managers constructed the meaning of resilience and its relationship to work-life balance for nurses in Korea. Participants were 20 first-line nurse managers working in six university hospitals. Data were collected through in-depth interviews from December 2011 to August 2012, and analyzed using Strauss and Corbin's grounded theory method. Analysis revealed that participants perceived work-life balance and resilience to be shaped by dynamic, reflective processes. The features consisting resilience included "positive thinking", "flexibility", "assuming responsibility", and "separating work and life". This perception of resilience has the potential to facilitate a shift in focus from negative to positive experiences, from rigidity to flexibility, from task-centered to person-centered thinking, and from the organization to life. Recognizing the importance of work-life balance in producing and sustaining resilience in first-line nurse managers could increase retention in the Korean nursing workforce. Copyright © 2015. Published by Elsevier B.V.

  3. Outcomes in achalasia from a surgical unit where pneumatic dilatation is first-line therapy.

    PubMed

    Howard, J M; Mongan, A-M; Manning, B J; Byrne, P; Lawler, P; Ravi, N; Reynolds, J V

    2010-08-01

    The management of achalasia remains controversial, with little consensus on the optimal patient treatment pathway. In our own esophageal unit, we offer pneumatic dilatation as the initial therapy in most patients as first-line therapy. In this study, we aimed to examine the safety and efficacy of our own approach to the management of patients with a diagnosis of achalasia, examining symptomatic outcomes, patient satisfaction, and need for further intervention, as well as examining patient factors associated with treatment failure. Sixty-seven consecutive patients underwent pneumatic dilatation as first-line therapy (53% male, mean age 46 years). All attended regular outpatient follow-up (mean 37, range 3-132 months). Twenty-five percent of patients required a second intervention because of symptom recurrence, at a median period of 4.5 months. Symptomatic outcomes were excellent or good in 80%. Significant predictors of treatment failure and poor symptom score included a younger age at the time of diagnosis and increased esophageal diameter on barium swallow. This study suggests that pneumatic dilatation is a safe and effective approach as first-line therapy in patients with newly diagnosed achalasia.

  4. First-line treatment of chronic hepatitis B with entecavir or tenofovir in 'real-life' settings: from clinical trials to clinical practice.

    PubMed

    Pol, S; Lampertico, P

    2012-06-01

    Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are potent nucleos(t)ide analogues (NUCs) recommended as first-line monotherapies for chronic hepatitis B. In Phase III trials, ETV and TDF demonstrated superior efficacy, and comparable safety compared with other NUCs. In long-term clinical studies, both drugs achieved virologic response rates of around 95%, with very low rates of resistance development and good safety profiles. Clinical trials are conducted under standardized conditions with strict enrolment criteria that limit the heterogeneity of study populations. 'Real-life' populations tend to be composed of a wider range of patients, often older and with different morbidities, comorbidities that may impact treatment efficacy and co-factors, such as smoking and alcohol intake, which can have a direct impact on disease progression. Real-life studies provide better representations of everyday clinical practice and are important to confirm the results reported in clinical studies and to identify rare or late-emerging adverse events. In five 'real-life' studies of ETV in more than 1000 patients, up to 4 years of treatment resulted in virologic responses in 76-96% of patients. Two real-life studies of TDF reported response rates of 71-92% after up to 21 months of treatment. Low incidences of drug resistance and favourable tolerabilities were reported for both drugs, thus confirming the results from registration trials. © 2012 Blackwell Publishing Ltd.

  5. Ofatumumab plus chlorambucil as a first-line therapy in less fit patients with chronic lymphocytic leukemia: analysis of COMPLEMENT1 and other monoclonal antibodies association data

    PubMed Central

    Frustaci, Anna Maria; Tedeschi, Alessandra; Picardi, Paola; Mazzucchelli, Maddalena; Cairoli, Roberto; Montillo, Marco

    2016-01-01

    The management of patients with chronic lymphocytic leukemia (CLL) has radically improved over the last few years with the addition of anti-CD20 monoclonal antibodies (MoAbs) to chemotherapy. Chlorambucil has been considered for decades as a suitable therapeutic option for frail patients. Taking into account the advantage offered by the addition of MoAbs to chemotherapy, different studies up to now have explored the feasibility of chlorambucil-based chemoimmunotherapies in treatment-naïve CLL. COMPLEMENT1 is a prospective, randomized, open-label trial evaluating the efficacy and safety of ofatumumab added to chlorambucil, compared with chlorambucil in monotherapy, in the setting of untreated patients with CLL considered unsuitable for a fludarabine-based approach. Progression-free survival was significantly longer in the chemoimmunotherapy arm when compared with the single-agent chlorambucil (22.4 months versus 13.1 months). Response rate and quality were also improved in the combination arm. Furthermore, the addition of ofatumumab did not lead to an unmanageable toxicity. While the employment of anti-CD20 antibodies represents an advantage in the treatment of the CLL symptomatic population, at present different patient selection and treatment schedules do not allow a reliable comparison between chlorambucil-based regimens. The addition of ofatumumab to chlorambucil represents a further therapeutic gain in CLL. Longer follow up and direct comparison with other MoAbs are warranted to establish the preferred first-line treatment in elderly and unfit patients. PMID:27493712

  6. Current Prospects for the Fluoroquinolones as First-Line Tuberculosis Therapy ▿

    PubMed Central

    Takiff, Howard; Guerrero, Elba

    2011-01-01

    While fluoroquinolones (FQs) have been successful in helping cure multidrug-resistant tuberculosis (MDR TB), studies in mice have suggested that if used as first-line agents they might reduce the duration of therapy required to cure drug-sensitive TB. The results of phase II trials with FQs as first-line agents have been mixed, but in at least three studies where moxifloxacin substituted for ethambutol, there was an increase in the early percentage of sputa that converted to negative for bacilli. Phase III trials are in progress to test the effectiveness of 4-month FQ-containing regimens, but there is concern that the widespread use of FQs for other infections could engender a high prevalence of FQ-resistant TB. However, several studies suggest that despite wide FQ use, the prevalence of FQ-resistant TB is low, and the majority of the resistance is low-level. The principal risk for resistance may be when FQs are used to treat nonspecific respiratory symptoms that are in fact TB, so curtailing this use of FQs could reduce the development of resistance and also the delays in TB diagnosis and treatment that have been documented when an FQ is given in this setting. While the future of FQs as first-line therapy will likely depend upon the results of the ongoing phase III trials, if they are to be effectively employed in high-TB-burden regions their use for community-acquired pneumonias should be restricted, the prevalence of FQ-resistant TB should be monitored, and the cost of the treatment should be comparable to that of current standard drug regimens. PMID:21876059

  7. Impact of First-Line Antifungal Agents on the Outcomes and Costs of Candidemia

    PubMed Central

    Ha, Young Eun; Joo, Eun-Jeong; Kim, Shin Woo; Jung, Sook-In; Chang, Hyun Ha; Park, Kyong Hwa; Han, Sang Hoon

    2012-01-01

    Candida species are the leading causes of invasive fungal infection among hospitalized patients and are responsible for major economic burdens. The goals of this study were to estimate the costs directly associated with the treatment of candidemia and factors associated with increased costs, as well as the impact of first-line antifungal agents on the outcomes and costs. A retrospective study was conducted in a sample of 199 patients from four university-affiliated tertiary care hospitals in Korea over 1 year. Only costs attributable to the treatment of candidemia were estimated by reviewing resource utilization during treatment. Risk factors for increased costs, treatment outcome, and hospital length of stay (LOS) were analyzed. Approximately 65% of the patients were treated with fluconazole, and 28% were treated with conventional amphotericin B. The overall treatment success rate was 52.8%, and the 30-day mortality rate was 47.9%. Hematologic malignancy, need for mechanical ventilation, and treatment failure of first-line antifungal agents were independent risk factors for mortality. The mean total cost for the treatment of candidemia was $4,743 per patient. Intensive care unit stay at candidemia onset and antifungal switch to second-line agents were independent risk factors for increased costs. The LOS was also significantly longer in patients who switched antifungal agents to second-line drugs. Antifungal switch to second-line agents for any reasons was the only modifiable risk factor of increased costs and LOS. Choosing an appropriate first-line antifungal agent is crucial for better outcomes and reduced hospital costs of candidemia. PMID:22526315

  8. First-Line Anti-Tubercular Drug Resistance of Mycobacterium tuberculosis in IRAN: A Systematic Review

    PubMed Central

    Pourakbari, Babak; Mamishi, Setareh; Mohammadzadeh, Mona; Mahmoudi, Shima

    2016-01-01

    Background: The spread of drug-resistant tuberculosis (TB) is one of the major public health problems through the world. Surveillance of anti-TB drug resistance is essential for monitoring of TB control strategies. The occurrence of drug resistance, particularly multi-drug resistance Mycobacterium tuberculosis (MDR), defined as resistance to at least rifampicin (RIF) and isoniazid (INH), has become a significant public health dilemma. The status of drug-resistance TB in Iran, one of the eastern Mediterranean countries locating between Azerbaijan and Armenia and high-TB burden countries (such as Afghanistan and Pakistan) has been reported inconsistently. Therefore, the aim of this study was to summarize reports of first-line anti-tubercular drug resistance in M. tuberculosis in Iran. Material and Methods: We systematically reviewed published studies on drug-resistant M. tuberculosis in Iran. The search terms were “Mycobacterium tuberculosis susceptibility” or “Mycobacterium tuberculosis resistant” and Iran. Results: Fifty-two eligible articles, published during 1998–2014, were included in this review. Most of the studies were conducted in Tehran. The most common used laboratory method for detecting M. tuberculosis drug resistant was Agar proportion. The highest resistance to first-line drugs was seen in Tehran, the capital city of Iran. The average prevalence of isoniazid (INH), rifampin (RIF), streptomycin (SM), and ethambotol (EMB) resistance via Agar proportion method in Tehran was 26, 23, 22.5, and 16%, respectively. In general, resistance to INH was more common than RIF, SM, and EMB in Tehran Conclusions: In conclusion, this systematic review summarized the prevalence and distribution of first-line anti-tubercular drug resistance of M. tuberculosis in Iran. Our results suggested that effective strategies to minimize the acquired drug resistance, to control the transmission of resistance and improve the diagnosis measures for TB control in Iran. PMID

  9. First-Line Anti-Tubercular Drug Resistance of Mycobacterium tuberculosis in IRAN: A Systematic Review.

    PubMed

    Pourakbari, Babak; Mamishi, Setareh; Mohammadzadeh, Mona; Mahmoudi, Shima

    2016-01-01

    The spread of drug-resistant tuberculosis (TB) is one of the major public health problems through the world. Surveillance of anti-TB drug resistance is essential for monitoring of TB control strategies. The occurrence of drug resistance, particularly multi-drug resistance Mycobacterium tuberculosis (MDR), defined as resistance to at least rifampicin (RIF) and isoniazid (INH), has become a significant public health dilemma. The status of drug-resistance TB in Iran, one of the eastern Mediterranean countries locating between Azerbaijan and Armenia and high-TB burden countries (such as Afghanistan and Pakistan) has been reported inconsistently. Therefore, the aim of this study was to summarize reports of first-line anti-tubercular drug resistance in M. tuberculosis in Iran. We systematically reviewed published studies on drug-resistant M. tuberculosis in Iran. The search terms were "Mycobacterium tuberculosis susceptibility" or "Mycobacterium tuberculosis resistant" and Iran. Fifty-two eligible articles, published during 1998-2014, were included in this review. Most of the studies were conducted in Tehran. The most common used laboratory method for detecting M. tuberculosis drug resistant was Agar proportion. The highest resistance to first-line drugs was seen in Tehran, the capital city of Iran. The average prevalence of isoniazid (INH), rifampin (RIF), streptomycin (SM), and ethambotol (EMB) resistance via Agar proportion method in Tehran was 26, 23, 22.5, and 16%, respectively. In general, resistance to INH was more common than RIF, SM, and EMB in Tehran Conclusions: In conclusion, this systematic review summarized the prevalence and distribution of first-line anti-tubercular drug resistance of M. tuberculosis in Iran. Our results suggested that effective strategies to minimize the acquired drug resistance, to control the transmission of resistance and improve the diagnosis measures for TB control in Iran.

  10. Comparison between guideline-preferred and nonpreferred first-line HIV antiretroviral therapy.

    PubMed

    Johnston, Stephen S; Juday, Timothy; Farr, Amanda M; Chu, Bong-Chul; Hebden, Tony

    2014-06-01

    To compare antiretroviral therapy (ART) adherence and persistence and total healthcare expenditures in Medicaid-insured patients with human immunodeficiency virus (HIV) initiating preferred or nonpreferred first-line ART based on March 2012 HHS HIV treatment guidelines. Retrospective observational study using Medicaid administrative healthcare claims from 15 states. Subjects were HIV patients 18 to 64 years who initiated first-line HIV-related ART between January 1, 2007, and September 30, 2011, with continuous enrollment for 6 months prior to and at least 3 months following ART initiation. Patients were classified as having initiated preferred or nonpreferred ART based on March 2012 HHS HIV treatment guidelines. Outcomes were: ART adherence (proportion of days covered dichotomized at ≥80% and ≥95%), time to ART nonpersistence, and per patient per month (PPPM) total healthcare expenditures. Outcomes were evaluated using multivariable regressions. Sample included 1979 patients initiating preferred ART regimens and 1614 patients initiating nonpreferred ART; overall mean age was 41 years; 48% of subjects were female. In the multivariable analyses, patients initiating preferred ART regimens had significantly greater odds of adherence ≥80% (odds ratio [OR], 1.38; 95% CI, 1.07-1.77) and adherence ≥95% (OR, 1.26; 95% CI, 1.05-1.51), and a significantly lower hazard of nonpersistence (HR, 0.48; 95% CI, 0.44-0.52). PPPM total healthcare expenditures were numerically lower for patients initiating preferred ART regimens (-$341; 95% CI, -$888 to $255) but the difference was not deemed significant. This study reinforces the value of HHS recommendations for first-line ART. The potential impact of these findings will grow as more HIV patients become Medicaid-eligible under the Patient Protection and Affordable Care Act.

  11. Factors Impacting Treatment Choice in the First-Line Treatment of Colorectal Cancer.

    PubMed

    Bloem, Lourens T; De Abreu Lourenço, Richard; Chin, Melvin; Ly, Brett; Haas, Marion

    2016-01-01

    To investigate the factors that affect the choice of 5-fluorouracil (5-FU) or its oral alternative, capecitabine, as first-line treatment in patients with colorectal cancer (CRC). Patients treated with 5-FU or capecitabine for CRC between January 1, 2011 and December 31, 2013 in a teaching hospital in the Sydney metropolitan area, Australia were identified using the hospital's database MOSAIQ(®). The electronic medical record of each patient was manually reviewed to extract factors potentially affecting treatment choice. Logistic regression was used to assess which patient and/or treatment factors could explain the choice between 5-FU or capecitabine. Where it was available in the medical correspondence, the explicit reason for the choice made was extracted. 170 CRC patients were included; 119 on 5-FU, and 51 on capecitabine. The odds of receiving capecitabine as a first-line treatment were positively associated with giving patients a choice in the decision (OR = 17.51, 95% CI: 5.37-57.08). Qualitative data suggest treatment choices were motivated by convenience (oral administration) and tolerability. Time from diagnosis to treatment commencement (OR = 1.02 per month, 95% CI 1.00-1.04) was also found to be positively associated with the choice of capecitabine. The odds of being treated with capecitabine were lower for patients who lived further from the treating hospital (OR = 0.22, 95% CI 0.05-0.94). This study suggests that patient choice, favoring oral capecitabine over i.v. 5-FU, was a key factor influencing first-line treatment for CRC in this cohort. To respect their autonomy, patients should be involved in the clinical decision making process.

  12. First-line targeted therapies in the treatment of metastatic colorectal cancer – role of cetuximab

    PubMed Central

    Tonini, Giuseppe; Calvieri, Alice; Vincenzi, Bruno; Santini, Daniele

    2009-01-01

    Worldwide, colorectal cancer (CRC) is the fourth most commonly diagnosed malignant disease and the second leading cause of cancer-related death in Western nations. In 2008 there were an estimated 148,810 new cases and 49,960 deaths in the US. For several years different chemotherapeutic regimens, based on fluoropyrimidines, irinotecan and oxaliplatin, have been used in advanced CRC, but survival is still unsatisfactory. New targeted therapies, including drugs and monoclonal antibodies (MoABs), show great promise in the fight against CRC and have shown activity in different disease settings. Cetuximab, a chimeric IgG1 monoclonal antibody that binds to the extracellular domain of epidermal growth factor receptor (EGFR), is active in metastatic colorectal cancer (mCRC). As an IgG1 antibody, cetuximab may exert its antitumor efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity. The combination of this drug with classical chemotherapies has shown better clinical profiles reflected in an improvement in overall and progression-free survival. Clinical trials established the role of cetuximab, particularly with irinotecan, in irinotecan-refractory/heavily pretreated patients. Whereas cetuximab has a clear indication in the salvage setting, its role in first-line therapy remains investigational. It is particularly encouraging that cetuximab may enhance curative opportunities in patients with early metastatic disease, suggesting that adding cetuximab in first-line therapy may downstage disease in some patients, and, as a result, allow potentially curative resection of previously unresectable metastases. In this review we will focus on the main epidermal growth factor receptor inhibitors demonstrating clinical benefit, and the role of cetuximab in first-line treatment of metastatic CRC. PMID:20616896

  13. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion.

    PubMed

    Strati, Paolo; Keating, Michael J; O'Brien, Susan M; Ferrajoli, Alessandra; Burger, Jan; Faderl, Stefan; Tambaro, Francesco Paolo; Jain, Nitin; Wierda, William G

    2014-08-01

    Although uncommon in treatment-naive patients with chronic lymphocytic leukemia, deletion 17p is a high-risk disease characteristic. We analyzed and reported outcomes for 63 patients with deletion 17p chronic lymphocytic leukemia who received first-line therapy at our institution; at time of first treatment, 81% had unmutated immunoglobulin heavy chain variable gene and 58% had complex karyotype. Forty-nine patients (76%) received first-line fludarabine, cyclophosphamide, rituximab-based therapy, 6 (11%) received rituximab-based and 8 (13%) received lenalidomide-based treatment. Overall, the complete plus nodular partial remission rate was 33%; on multivariable model, higher complete plus nodular partial remission rate was observed in patients with less than 50% cells positive for deletion 17p, and a higher probability of achieving at least a partial remission was observed with fludarabine, cyclophosphamide, rituximab-based treatment. After a median follow up of 33 months (range 1-89 months), the estimated median progression-free survival was 14 months (95% confidence interval 10-18) and estimated median overall survival was 63 months (95% confidence interval 43-83). In multivariable analysis, factors independently associated with longer progression-free survival were response to treatment and absence of complex karyotype. Achievement of complete plus nodular partial remission rate and mutated immunoglobulin heavy chain variable gene were independently associated with longer overall survival in multivariable model. Complex karyotype was associated with increased risk for Richter's transformation. New first-line strategies and agents must aim at both improving response and maintaining remission in patients with deletion 17p, particularly in the presence of complex karyotype.

  14. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion

    PubMed Central

    Strati, Paolo; Keating, Michael J.; O’Brien, Susan M.; Ferrajoli, Alessandra; Burger, Jan; Faderl, Stefan; Tambaro, Francesco Paolo; Jain, Nitin; Wierda, William G.

    2014-01-01

    Although uncommon in treatment-naive patients with chronic lymphocytic leukemia, deletion 17p is a high-risk disease characteristic. We analyzed and reported outcomes for 63 patients with deletion 17p chronic lymphocytic leukemia who received first-line therapy at our institution; at time of first treatment, 81% had unmutated immunoglobulin heavy chain variable gene and 58% had complex karyotype. Forty-nine patients (76%) received first-line fludarabine, cyclophosphamide, rituximab-based therapy, 6 (11%) received rituximab-based and 8 (13%) received lenalidomide-based treatment. Overall, the complete plus nodular partial remission rate was 33%; on multivariable model, higher complete plus nodular partial remission rate was observed in patients with less than 50% cells positive for deletion 17p, and a higher probability of achieving at least a partial remission was observed with fludarabine, cyclophosphamide, rituximab-based treatment. After a median follow up of 33 months (range 1–89 months), the estimated median progression-free survival was 14 months (95% confidence interval 10–18) and estimated median overall survival was 63 months (95% confidence interval 43–83). In multivariable analysis, factors independently associated with longer progression-free survival were response to treatment and absence of complex karyotype. Achievement of complete plus nodular partial remission rate and mutated immunoglobulin heavy chain variable gene were independently associated with longer overall survival in multivariable model. Complex karyotype was associated with increased risk for Richter’s transformation. New first-line strategies and agents must aim at both improving response and maintaining remission in patients with deletion 17p, particularly in the presence of complex karyotype. PMID:24859876

  15. Primary HIV drug resistance and efficacy of first-line antiretroviral therapy guided by resistance testing.

    PubMed

    Oette, Mark; Kaiser, Rolf; Däumer, Martin; Petch, Ruth; Fätkenheuer, Gerd; Carls, Horst; Rockstroh, Jürgen Kurt; Schmalöer, Dirk; Stechel, Jürgen; Feldt, Torsten; Pfister, Herbert; Häussinger, Dieter

    2006-04-15

    Primary HIV drug resistance has been associated with poor treatment outcome of first-line highly active antiretroviral therapy (HAART) in several trials. The aim of the study was to assess the efficacy of first-line HAART guided by resistance testing. In a prospective multicenter study in the state of Nordrhein-Westfalen, Germany, chronically HIV-infected patients underwent genotypic resistance testing and were monitored for 48 weeks after initiation of HAART. Primary drug resistance was found in 30 of 269 patients entering the study between January 2001 and December 2003 [11.2%; 95% confidence interval, 7.4-14.9]. In intent-to-treat analysis, the proportion of patients with viral load below 50 copies/mL after 24 and 48 weeks was 70.0% and 66.7%, respectively, in patients with resistance and 74.1% and 73.6%, respectively, in patients without (P = 0.66 and 0.51). In on-treatment analysis, the proportions were 80.8% and 83.3%, respectively, in patients with resistance and 81.9% and 85.0%, respectively, in patients without (P= 0.79 and 0.77). These results were also valid considering a detection limit of 400 copies/mL. The prevalence of primary drug resistance was 11.2% in chronically HIV-infected patients. HAART guided by resistance testing had similar efficacy in patients with primary drug resistance as compared with patients with wild-type virus. Based on these facts, resistance-adapted first-line HAART is suggested as routine practice.

  16. Nab-paclitaxel/bevacizumab/carboplatin chemotherapy in first-line triple negative metastatic breast cancer.

    PubMed

    Hamilton, Erika; Kimmick, Gretchen; Hopkins, Judith; Marcom, P Kelly; Rocha, Gloria; Welch, Renee; Broadwater, Gloria; Blackwell, Kimberly

    2013-12-01

    Triple negative metastatic breast cancer can be difficult to treat with primarily cytotoxic options. Nab-paclitaxel has demonstrated improved PFS and tolerability compared with standard cremophor-solubilized paclitaxel; based on this, we examined the efficacy and safety of combining weekly nab-paclitaxel with carboplatin and bevacizumab in TNMBC. In this phase II, multicenter trial, patients with first-line TNMBC received nab-paclitaxel (100 mg/m(2)) and carboplatin (area under the curve = 2) on days 1, 8, 15, and bevacizumab (10 mg/kg) on days 1 and 15 of a 28-day cycle. The primary end point was safety and tolerability and secondary end points included PFS, ORR, and CBR. PFS was calculated using the Kaplan-Meier method. Between July 16, 2007, and October 3, 2011, 34 patients were enrolled at 4 centers. Median age was 50.0 (range, 30-76) years and 77% (n = 26) of patients received previous adjuvant therapy. Median PFS was 9.2 months (95% confidence interval [CI], 7.8-25.1 months). The CBR was 94% (95% CI, 80%-99%), and ORR was 85% (95% CI, 69%-95%) for the combination. The regimen was well tolerated with the most common grade 3/4 adverse events being neutropenia (n = 18; 53%) and thrombocytopenia (n = 6; 18%), with other serous events including 1 grade 3 and 1 grade 4 thrombotic event and 1 febrile neutropenia. The combination of nab-paclitaxel, bevacizumab, and carboplatin as first-line treatment for TNMBC was efficacious and well tolerated. The PFS, CBR, and ORR, and tolerability of the regimen, compares favorably with other standard first-line therapies. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Autologous stem cell transplantation as first line treatment after incomplete excision of pancreatoblastoma.

    PubMed

    Meneses, Clarice Franco; Osório, Carolina Dame; de Castro Junior, Claudio Galvão; Brunetto, Algemir Lunardi

    2013-01-01

    Pancreatoblastoma is a rare tumor and surgery with complete resection is the main treatment approach. Prognosis for patients with residual disease after surgery is usually dismal. A 14-year-old girl with pancreatoblastoma in the pancreatic body and tail was submitted to preoperative chemotherapy. She underwent surgery and the tumor was resected with microscopic margins. Postoperative chemotherapy was followed by high dose chemotherapy and autologous hematopoietic stem cell transplantation. After four years she remains very well with no evidence of disease. This is the first case reported of pancreatoblastoma that was treated with autologous hematopoietic stem cell transplantation as first line treatment without radiotherapy at the site of the microscopic disease.

  18. Is Resistance to Dolutegravir Possible When This Drug Is Used in First-Line Therapy?

    PubMed Central

    Mesplède, Thibault; Wainberg, Mark A.

    2014-01-01

    Dolutegravir (DTG) is an HIV integrase inhibitor that was recently approved for therapy by the Food and Drug Administration in the United States. When used as part of first-line therapy, DTG is the only HIV drug that has not selected for resistance mutations in the clinic. We believe that this is due to the long binding time of DTG to the integrase enzyme as well as greatly diminished replication capacity on the part of viruses that might become resistant to DTG. We further speculate that DTG might be able to be used in strategies aimed at HIV eradication. PMID:25166745

  19. PET/CT: First-Line Examination to Assess Disease Extent of Disseminated Coccidioidomycosis.

    PubMed

    Foerter, Jason; Sundell, John; Vroman, Penny

    2016-09-01

    Coccidioidomycosis is an infection caused by inhalation of the Coccidioides fungus. Most infections remain subclinical or are confined to the pulmonary system. Disseminated disease is rare. Traditionally, a combination of imaging modalities has been used to determine disease extent. We suggest (18)F-FDG PET/CT as a single first-line imaging examination to assess disease extent. We present a case of disseminated coccidioidomycosis to the lung, mediastinum, soft tissues, and skeletal system. To our knowledge, no prior case reports demonstrate such widespread disease using PET/CT. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  20. Leukotriene antagonists as first-line or add-on asthma-controller therapy.

    PubMed

    Price, David; Musgrave, Stanley D; Shepstone, Lee; Hillyer, Elizabeth V; Sims, Erika J; Gilbert, Richard F T; Juniper, Elizabeth F; Ayres, Jon G; Kemp, Linda; Blyth, Annie; Wilson, Edward C F; Wolfe, Stephanie; Freeman, Daryl; Mugford, H Miranda; Murdoch, Jamie; Harvey, Ian

    2011-05-05

    Most randomized trials of treatment for asthma study highly selected patients under idealized conditions. We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score ≤6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score ≥1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial. Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups. Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack

  1. First-line nurse leaders' health-care change management initiatives.

    PubMed

    Macphee, Maura; Suryaprakash, Nitya

    2012-03-01

    To examine nurse leaders' change management projects within British Columbia, Canada. British Columbia Nursing Leadership Institute 2007-10 attendees worked on year-long change management initiatives/projects of importance to their respective health-care institutions. Most leaders were in first-line positions with <3 years' experience. Consenting leaders' project reports (N = 133) were content analysed for specific themes: types of projects; scope of projects (e.g. unit or local level, departmental, institutional); influence targets or key stakeholder groups targeted by the projects; leadership successes and challenges. Of study participants, 77% successfully completed their projects. Staff tool and resource development and existing services improvement were major project types. Care delivery teams were the major influence targets. Only 25% of projects were at the unit level. Many projects had broader scopes, such as institutional levels. Participants cited multiple leadership successes, including enhanced leadership styles and organizational skills. First-line nurse leaders were able to successfully manage projects beyond their traditional scope of responsibilities. The majority of projects dealt with staff needs and healthcare restructuring initiatives. Constant change is a global reality. Change management, a universal competency, must be included in leadership development programmes. © 2011 Blackwell Publishing Ltd.

  2. Thalidomide: new indication. For elderly myeloma patients: some improvement in first-line treatment.

    PubMed

    2009-04-01

    (1) First-line treatment with the melphalan-prednisone combination increases median overall survival time by at least 3 years in half of myeloma patients over 65 years of age; (2) Thalidomide, an immunodepressant, is now approved in the European Union as an adjunct to this treatment in elderly myeloma patients; (3) Clinical evaluation is based on 5 trials. One unblinded controlled trial included 447 patients. The addition of thalidomide to the melphalan-prednisone combination increased survival time by at least 1.5 years in half of the patients (median survival time: 51.6 months versus 33.2 months). Another trial in 255 patients that was published in detail showed an increase in progression-free survival, but did not show an overall survival advantage, after more than 3 years of follow-up. Three similar trials have been reported as conference abstracts. One trial showed a survival advantage of 1.5 years, but the other two did not. These 3 trials also showed an increase in progression-free survival; (4) Thalidomide has frequent and sometimes severe adverse effects, including neuropathy, venous thrombosis and pulmonary embolism, cutaneous disorders and bradycardia; (5) Thalidomide is highly teratogenic. As it enters semen, men who have partners of child-bearing age must use very effective methods of birth control; (6) In practice, provided treatment is closely monitored, thalidomide can be added to the melphalan-prednisone combination as first-line treatment for myeloma patients over 65 years of age.

  3. Choice of nasal nitric oxide technique as first-line test for primary ciliary dyskinesia.

    PubMed

    Marthin, J K; Nielsen, K G

    2011-03-01

    Nasal nitric oxide (nNO) has a well-known potential as an indirect discriminative marker between patients with primary ciliary dyskinesia (PCD) and healthy subjects, but real-life experience and usefulness in young children is sparsely reported. Three nNO sampling methods were examined and compared as first-line tests for PCD. Healthy subjects, confirmed PCDs, consecutive referrals with PCD-like symptoms and patients with cystic fibrosis (CF) had nNO sampled during breath hold (BH-nNO), oral exhalation against resistance (OE-R-nNO) and tidal breathing (TB-nNO) aiming to expand age range into infancy. 282 subjects, 117 consecutive referrals, 59 PCDs, 49 CF patients and 57 healthy subjects, were included. All methods separated significantly between PCD and non-PCD, including CF with reliability, in ranking order BH-nNO>OE-R-nNO>TB-nNO. Acceptability in children ranked in reverse order. A problematic high fraction (39%) of false positive TB-nNO was found in young children. An unexpected large fraction (6.8%) of PCDs had nNO values above cut-off. nNO is a helpful first-line tool in real-life PCD work-up in all age groups if the sampling method is chosen according to age. nNO can be misleading in a few patients with true PCD. Further studies are strongly needed in young children.

  4. Evaluation of intravenous 6-thioguanine as first-line chemotherapy in women with metastatic breast cancer.

    PubMed

    Ingle, J N; Twito, D I; Suman, V J; Krook, J E; Maillard, J A; Windschitl, H E; Marschke, R F

    1997-02-01

    6-Thioguanine (6-TG) is a purine analog that has marked variability in plasma concentration after oral administration. Following the development of a multiple-day i.v. regimen, we performed a phase II trial of this agent as first-line chemotherapy in women with metastatic breast cancer. Forty-one patients with measurable (31 patients) or evaluable (10 patients) disease were entered into this trial. 6-TG was administered i.v. over a 10 min period daily for 5 consecutive days, with a planned cycle length of 35 days. The daily dosage level was 55 mg/m2 in the first 15 patients, but this was increased to 65 mg/m2 in the remaining patients due to inadequate myelosuppression at the lower dose. Six patients, all with measurable disease, achieved a complete response (CR) (two patients) or a partial response (PR) (four patients). Three responses occurred at the 55 mg/m2 level and three at the 65 mg/m2 level. The 95% confidence interval (CI) for the true response rate among patients with measurable disease was 6-39%. The median time to progression was 140 days and median survival time was 460 days. The regimen was well tolerated. We conclude that 6-TG, as given in this study, has limited activity as first-line chemotherapy for women with metastatic breast cancer.

  5. Complete and sustained response of adult medulloblastoma to first-line sonic hedgehog inhibition with vismodegib.

    PubMed

    Lou, Emil; Schomaker, Matthew; Wilson, Jon D; Ahrens, Mary; Dolan, Michelle; Nelson, Andrew C

    2016-08-12

    Medulloblastoma is an aggressive primitive neuroectodermal tumor of the cerebellum that is rare in adults. Medulloblastomas fall into 4 prognostically significant molecular subgroups that are best defined by experimental gene expression profiles: the WNT pathway, sonic hedgehog (SHH) pathway, and subgroups 3 and 4 (non-SHH/WNT). Medulloblastoma of adults belong primarily to the SHH category. Vismodegib, an SHH-pathway inhibitor FDA-approved in 2012 for treatment of basal cell carcinoma, has been used successfully in the setting of chemorefractory medulloblastoma, but not as a first-line therapy. In this report, we describe a sustained response of an unresectable multifocal form of adult medulloblastoma to vismodegib. Molecular analysis in this case revealed mutations in TP53 and a cytogenetic abnormality, i17q, that is prevalent and most often associated with subgroup 4 rather than the SHH-activated form of medulloblastoma. Our findings indicate that vismodegib may also block alternate, non-canonical forms of downstream SHH pathway activation. These findings provide strong impetus for further investigation of vismodegib in clinical trials in the first-line setting for pediatric and adult forms of medulloblastoma.

  6. The Case for Using Higher Doses of First Line Anti-Tuberculosis Drugs to Optimize Efficacy.

    PubMed

    Goutelle, Sylvain; Bourguignon, Laurent; Maire, Pascal; Jelliffe, Roger W; Neely, Michael N

    2014-01-01

    Apart from new anti-tuberculosis drug development, another approach for tuberculosis (TB) treatment optimization is to derive maximum benefit from current agents. However, the dosage of current anti-TB drug regimens has never been optimized according to the exposure-effect relationships of each drug. The objective of this article is to review the latest pharmacokinetic, pharmacodynamic, experimental, and clinical data concerning the use of higher doses of first-line anti-TB drugs to improve the efficacy of pulmonary tuberculosis treatment. Exposure-effect relationships have been described for all first-line anti-TB agents. There is convincing evidence that patients would benefit from higher rifamycin exposure. This could be achieved by using higher daily doses of rifampin, or more frequent dosing of rifapentine. The dose-dependent activity of pyrazinamide observed in hollow-fiber and animal models suggests that higher doses of pyrazimamide might be more efficacious, but the tolerability of such higher doses needs to be investigated in humans. It is likely that higher doses of ethambutol would be associated with higher antibacterial effect, but the dose-related ocular toxicity of the drug precludes such practice. For isoniazid, dose individualization is required to optimize patient care. The use of higher than standard doses of isoniazid in fast acetylators should result in greater early bactericidal activity. To conclude, the use of higher doses for some of the firstline anti-TB agents has definite potential for shortening or improving TB treatment.

  7. A prospective, open-label noncomparative study with piperacillin-tazobactam monotherapy as management of fever in patients with acute leukemia.

    PubMed

    Fanci, R; Bartolozzi, B; Longo, G; Bosi, A

    2008-08-01

    We evaluated the efficacy of piperacillin-tazobactam monotherapy as empiric therapy of fever in acute leukemia patients in a total of 80 consecutive febrile episodes. The overall success rate was 75% with success without modification in 34% (afebrile at 72 h) and an overall death rate of 10%. No significant differences were seen in correlation between clinical outcome and phases of underlying disease. The success without modification was higher in patients with fever of unknown origin (FUO) than in those with documented infections (47% and 25% respectively). There were no significant differences in correlations between clinical response and degree of neutropenia. Our study suggests that empirical first-line monotherapy with piperacillin-tazobactam may be a reasonable option in patients with acute leukaemia, although in documented infections the response is frequently inadequate.

  8. Monotherapy for partial epilepsy: focus on levetiracetam

    PubMed Central

    Gambardella, Antonio; Labate, Angelo; Colosimo, Eleonora; Ambrosio, Roberta; Quattrone, Aldo

    2008-01-01

    Levetiracetam (LEV), the S-enantiomer of alpha-ethyl-2-oxo-1-pyrollidine acetamide, is a recently licensed antiepileptic drug (AED) for adjunctive therapy of partial seizures. Its mechanism of action is uncertain but it exhibits a unique profile of anticonvulsant activity in models of chronic epilepsy. Five randomized, double-blind, placebo-controlled trials enrolling adult or pediatric patients with refractory partial epilepsy have demonstrated the efficacy of LEV as adjunctive therapy, with a responder rate (≥50% reduction in seizure frequency) of 28%–45%. Long-term efficacy studies suggest retention rates of 60% after one year, with 13% of patients seizure-free for 6 months of the study and 8% seizure-free for 1 year. More recent studies illustrated successful conversion to monotherapy in patients with refractory epilepsy, and its effectiveness as a single agent in partial epilepsy. LEV has also efficacy in generalized epilepsies. Adverse effects of LEV, including somnolence, lethargy, and dizziness, are generally mild and their occurrence rate seems to be not significantly different from that observed in placebo groups. LEV also has no clinically significant pharmacokinetic interactions with other AEDs, or with commonly prescribed medications. The combination of effective antiepileptic properties with a relatively mild adverse effect profile makes LEV an attractive therapy for partial seizures. PMID:18728811

  9. Network Meta-analysis for Clinical Practice Guidelines: A Case Study on First-Line Medical Therapies for Primary Open-Angle Glaucoma.

    PubMed

    Rouse, Benjamin; Cipriani, Andrea; Shi, Qiyuan; Coleman, Anne L; Dickersin, Kay; Li, Tianjing

    2016-05-17

    Network meta-analysis compares multiple treatment options for the same condition and may be useful for developing clinical practice guidelines. To compare treatment recommendations for first-line medical therapy for primary open angle-glaucoma (POAG) from major updates of American Academy of Ophthalmology (AAO) guidelines with the evidence available at the time, using network meta-analysis. MEDLINE, Embase, and the Cochrane Library were searched on 11 March 2014 for randomized, controlled trials (RCTs) of glaucoma monotherapies compared with placebo, vehicle, or no treatment or other monotherapies. The AAO Web site was searched in August 2014 to identify AAO POAG guidelines. Eligible RCTs were selected by 2 independent reviewers, and guidelines were selected by 1 person. One person abstracted recommendations from guidelines and a second person verified. Two people independently abstracted data from included RCTs. Guidelines were grouped together on the basis of literature search dates, and RCTs that existed at 1991, 1995, 1999, 2004, and 2009 were analyzed. The outcome of interest was intraocular pressure (IOP) at 3 months. Only the latest guideline made a specific recommendation: prostaglandins. Network meta-analyses showed that all treatments were superior to placebo in decreasing IOP at 3 months. The mean reductions (95% credible intervals [CrIs]) for the highest-ranking class compared with placebo were as follows: 1991: β-blockers, 4.01 (CrI, 0.48 to 7.43); 1995: α2-adrenergic agonists, 5.64 (CrI, 1.73 to 9.50); 1999: prostaglandins, 5.43 (CrI, 3.38 to 7.38); 2004: prostaglandins, 4.75 (CrI, 3.11 to 6.44); 2009: prostaglandins, 4.58 (CrI, 2.94 to 6.24). When comparisons are informed by a small number of studies, the treatment effects and rankings may not be stable. For timely recommendations when multiple treatment options are available, guidelines developers should consider network meta-analysis. National Eye Institute, National Institutes of Health.

  10. Network Meta-analysis for Clinical Practice Guidelines: A Case Study on First-Line Medical Therapies for Primary Open-Angle Glaucoma

    PubMed Central

    Rouse, Benjamin; Cipriani, Andrea; Shi, Qiyuan; Coleman, Anne L.; Dickersin, Kay; Li, Tianjing

    2016-01-01

    Background Network meta-analysis compares multiple treatment options for the same condition and may be useful for developing clinical practice guidelines. Purpose To compare treatment recommendations for first-line medical therapy for primary open angle-glaucoma (POAG) from major updates of American Academy of Ophthalmology (AAO) guidelines with the evidence available at the time, using network meta-analysis. Data Sources MEDLINE, Embase, and the Cochrane Library were searched on 11 March 2014 for randomized, controlled trials (RCTs) of glaucoma monotherapies compared with placebo, vehicle, or no treatment or other monotherapies. The AAO Web site was searched in August 2014 to identify AAO POAG guidelines. Study Selection Eligible RCTs were selected by 2 independent reviewers, and guidelines were selected by 1 person. Data Extraction One person abstracted recommendations from guidelines and a second person verified. Two people independently abstracted data from included RCTs. Data Synthesis Guidelines were grouped together on the basis of literature search dates, and RCTs that existed at 1991, 1995, 1999, 2004, and 2009 were analyzed. The outcome of interest was intraocular pressure (IOP) at 3 months. Only the latest guideline made a specific recommendation: prostaglandins. Network meta-analyses showed that all treatments were superior to placebo in decreasing IOP at 3 months. The mean reductions (95% credible intervals [CrIs]) for the highest-ranking class compared with placebo were as follows: 1991: β-blockers, 4.01 (CrI, 0.48 to 7.43); 1995: α2-adrenergic agonists, 5.64 (CrI, 1.73 to 9.50); 1999: prostaglandins, 5.43 (CrI, 3.38 to 7.38); 2004: prostaglandins, 4.75 (CrI, 3.11 to 6.44); 2009: prostaglandins, 4.58 (CrI, 2.94 to 6.24). Limitation When comparisons are informed by a small number of studies, the treatment effects and rankings may not be stable. Conclusion For timely recommendations when multiple treatment options are available, guidelines developers

  11. Development of a G118R mutation in HIV-1 integrase following a switch to dolutegravir monotherapy leading to cross-resistance to integrase inhibitors.

    PubMed

    Brenner, Bluma G; Thomas, Réjean; Blanco, José Luis; Ibanescu, Ruxandra-Ilinca; Oliveira, Maureen; Mesplède, Thibault; Golubkov, Olga; Roger, Michel; Garcia, Federico; Martinez, Esteban; Wainberg, Mark A

    2016-07-01

    Dolutegravir shows a high barrier to resistance with no previously reported cases of acquired integrase mutations during first-line therapy. In this study, rapid development of the G118R mutation arose following a switch from first-line elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine to dolutegravir monotherapy. The G118R mutation also arose in a treatment-experienced patient switched to dolutegravir monotherapy. The genetic basis for G118R selection and potential phenotypic outcome was ascertained. Genotypic analysis was performed on patients with virological failure (<1000 copies/mL) on dolutegravir-containing regimens. The Los Alamos database was queried for glycine codon 118 polymorphisms. Cell culture selections and phenotypic drug susceptibility assays assessed resistance via the G118R pathway. We report on two patients who developed viral failure while on dolutegravir monotherapy. Both patients had been on a current or previous regimen containing integrase inhibitors. Virological failure (<1000 copies/mL) emerged early within 2 months following the dolutegravir switch. The appearance of G118R in these two cases and subtype C and CRF02_AG in vitro selections were related to a rare GGA natural polymorphism at codon 118 (1.5% prevalence), facilitating a GGA to AGA transition. Cell culture selections were used to assess the in vitro progression of the G118R pathway leading to cross-resistance to all integrase inhibitors. Although resistance to dolutegravir is typically rare, genetic polymorphisms and monotherapy can facilitate the acquisition of G118R. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  12. Durable response of breast cancer leptomeningeal metastasis to capecitabine monotherapy

    PubMed Central

    Rogers, Lisa R.; Remer, Sandra E.; Tejwani, Sheela

    2004-01-01

    We report a durable (12-month) response to capecitabine monotherapy, shown clinically, by MRI, and by cerebrospinal fluid analysis, in a patient with leptomeningeal metastasis from breast cancer. PMID:14769142

  13. Refractory autoimmune disease: an overview of when first-line therapy is not enough.

    PubMed

    Neunert, Cindy; Farah, Roula; Yacobovich, Joanne; Neufeld, Ellis

    2016-04-01

    A recent Intercontinental Cooperative ITP Study Group (ICIS) meeting in September 2015 focused on immunomodulation across the spectrum of autoimmune conditions. It became clear to the attendees that in this wide range of conditions, there is a subset of patients that remain highly refractory to first line therapy. Therapeutic approaches to these patients vary greatly and while many different immunomodulatory agents have been investigated, few have seen universal success. We outline here the landscape of immunomodulation therapy for refractory patients across a variety of autoimmune conditions in order to highlight the variety of agents that have been studied, the lack of overall consensus about management, and the need for ongoing research in this area.

  14. Voriconazole as a first-line treatment against potentially pathogenic Acanthamoeba strains from Peru.

    PubMed

    Cabello-Vílchez, Alfonso Martín; Martín-Navarro, Carmen M; López-Arencibia, Atteneri; Reyes-Batlle, María; Sifaoui, Ines; Valladares, Basilio; Piñero, José E; Lorenzo-Morales, Jacob

    2014-02-01

    Pathogenic strains of Acanthamoeba genus are the causative agents of fatal granulomatous amoebic encephalitis and a serious sight-threatening infection of the eye known as Acanthamoeba keratitis. In a previous study, Acanthamoeba strains were isolated from nasal swabs collected from healthy individuals in Peru. In the present study, the pathogenic potential of the isolated strains was established based on temperature and osmotolerance assays as well as the secretion rate of extracellular proteases. Based on these experiments, four strains that showed the highest pathogenic potential were selected for sensitivity assays against two molecules (voriconazole and chlorhexidine) which are currently used for the treatment of Acanthamoeba infections. After performing sensitivity and activity assays, it was found that both drugs were active against the tested strains. However, voriconazole showed higher activity against the studied strains compared to chlorhexidine. Therefore, voriconazole should be established as a first-line treatment against Acanthamoeba infections at least in the studied region of Peru.

  15. Targeted therapy in first line treatment of RAS wild type colorectal cancer.

    PubMed

    Formica, Vincenzo; Roselli, Mario

    2015-03-14

    The debate on the optimal drug combination for treating chemotherapy-naïve patients with metastatic colorectal cancer has recently become particularly heated. The present editorial will review recent data on this topic. The FIRE-3 and PEAK trials have shown a 7.5 to 12 mo survival advantage with the use anti-epidermal growth factor receptor (anti-EGFR) antibodies. The CALGB 80405 has shown no difference between anti-EGFR and anti-vascular endothelial growth factor agents. All three trials have consistently shown a significant increase in objective response rate. These data suggest that there is a subset of metastatic colorectal cancer patients, rigorously selected by molecular profiling, who particularly benefit from an anti-EGFR-based regimen in the first-line setting.

  16. Assessment of coronary bypass graft patency by first-line multi-detector computed tomography.

    PubMed

    Pesenti-Rossi, D; Baron, N; Georges, J-L; Augusto, S; Gibault-Genty, G; Livarek, B

    2014-11-01

    The purpose of the study was to assess whether a strategy based on a MDCT performed routinely before CA can reduce the radiation dose during the CA, without increased global exposure in patients who need imaging of CABG. A total of 147 consecutive patients were included. The radiation dose during CA (KAP 12.1 vs 22.0 Gy/cm(2), P<.01) and the volume of iodinated contrast (155 vs 200 mL, P<.02) were reduced when preceded by a MDCT. Patients' cumulative exposures were not different in the 2 strategies (5.0 vs 5.1 mSv, P=.76). MDCT performed in first line is a valuable strategy for the assessment of CABG.

  17. Recommendations Concerning the First-Line Treatment of Children with Tuberculosis.

    PubMed

    Principi, Nicola; Galli, Luisa; Lancella, Laura; Tadolini, Marina; Migliori, Giovanni Battista; Villani, Alberto; Esposito, Susanna

    2016-02-01

    This document describes the recommendations of a group of scientific societies concerning the first-line therapeutic approach to paediatric tuberculosis (TB). The treatment of pulmonary TB should be based on the existence of parenchymal involvement and the risk of antibiotic resistance. The treatment of extra-pulmonary TB is based on the regimens used for severe pulmonary TB. The administration of corticosteroids is recommended only in cases of miliary TB, tuberculous meningitis and tuberculous pericarditis. Vitamin B6 may be indicated in the case of isoniazid-treated TB in breastfeeding infants, severely malnourished subjects, or patients with other diseases at high risk of vitamin deficiency. Once having started treatment, children with TB should be carefully followed up in order to evaluate compliance, the response to treatment, the need for treatment changes, and the presence of drug-related adverse events. Primary care paediatricians can support reference centres in providing family healthcare education and encouraging treatment compliance.

  18. First-line Bismuth-containing Five-day Concomitant Quintuple Therapy for Helicobacter Pylori Eradication.

    PubMed

    Dolapcioglu, Can; Sayiner, Mehmet; Akkus, Esra Elif; Kural, Abdulaziz; Dolapcioglu, Hatice; Dabak, Resat; Ahishali, Emel

    2016-04-01

    Widespread use of antibiotics has resulted in increased rates of antibiotic resistance and decreased rates of Helicobacter pylori (H. pylori) eradication, leading to a search for newer therapeutic options. This study aimed to examine the efficacy, tolerability, and patient compliance of a first-line bismuth-containing 5-day concomitant quintuple therapy. This prospective study included 144 eradication treatment naïve H. pylori positive patients with dyspeptic complaints. Patients received the following concomitant quintuple therapy for 5 days: bismuth subcitrate 300 mg q.i.d, omeprazole 20 mg b.i.d, clarithromycin 500 mg b.i.d., amoxicillin 1 g b.i.d., and metronidazole 500 mg t.i.d. Eradication was assessed with H. pylori stool antigen test or urea-breath test 6 weeks after the completion of therapy. Treatment compliance rate in this study was 97.2%. Intention to treat and per-protocol eradication rates were 134/144 (93.1%, 95% CI, 88.9-97.2) and 134/140 (95.7%, 95% CI, 92.2-98.6), respectively. Side effect was reported by 8.5% of the patients that attended follow-up visits, including epigastric pain (2.8%), nausea/vomiting (2.1%), diarrhea (1.4%), taste disturbance (1.4%), and fatigue (0.7%). Bismuth-containing, short course, quintuple concomitant therapy appears to be an effective and safe therapeutic option for the first-line H. pylori eradication, particularly in populations with high resistance. © 2015 John Wiley & Sons Ltd.

  19. Metastatic colorectal cancer first-line treatment with bevacizumab: the impact of K-ras mutation.

    PubMed

    Rossi, Luigi; Veltri, Enzo; Zullo, Angelo; Zoratto, Federica; Colonna, Maria; Longo, Flavia; Mottolese, Marcella; Giannarelli, Diana; Ruco, Luigi; Marchetti, Paolo; Romiti, Adriana; Barucca, Viola; Giannini, Giuseppe; Bianchi, Loredana; Tomao, Silverio

    2013-01-01

    Bevacizumab plus chemotherapy prolongs progression-free survival (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC). Although there is strong evidence to suggest that the mutational status of the K-ras oncogene has a role as a predictive factor for activity in patients treated with cetuximab and panitumumab, few data have been obtained in patients treated with bevacizumab. We conducted an additional retrospective analysis to investigate the prognostic value of K-ras mutation relative to mCRC first-line treatment with bevacizumab. A total of 108 patients were retrospectively reviewed. K-ras status was assessed in the overall population by sequencing. Statistical association for PFS and OS was analyzed using the Kaplan-Meier method, and the prognostic role of K-ras was determined using the logrank test. Median PFS was 10 months both for patients with wild-type (WT) K-ras and mutated (MT) K-ras (hazard ratio [HR] 0.94, P=0.75); neither difference in median OS was significant (27 months WT K-ras versus 26 months MT K-ras, HR 0.92; P=0.70). A further analysis was carried out in the two groups according to metastatic sites. No statistically significant difference in terms of PFS and OS was demonstrated between WT K-ras and MT K-ras with liver metastases only and in those with extrahepatic disease. Although further study is required, our results seem to confirm that K-ras mutation does not have a prognostic role in mCRC patients receiving first-line treatment with bevacizumab.

  20. [Failure of first-line antiretroviral therapy in HIV-infected children in Ouagadougou, Burkina Faso].

    PubMed

    Kouéta, F; Yé, D; Zoungrana, A; Sacko, A; Ouédraogo-Traoré, R; Kafando, E; Ouédraogo, S

    2010-12-01

    Approximately one-fourth of the estimated 10,000 HIV-infected children in Burkina Faso are undergoing antiretroviral (ARV) therapy. At the Charles de Gaulle Pediatric Hospital Center in Ouagadougou, Burkina Faso, Support for ARV therapy began in July 2003 and a total of 250 children were undergoing treatment in late 2007. The purpose of this retrospective case-control study conducted over a period of 54 months from July 2003 to December 2007 was to investigate cases involving failure of first-line ARV therapy in particular with regard to cause. All patients (n = 32) showing poor virological, immunological, and/or clinical response to ARV therapy were considered as failures and thus included in the case group. The control group (n = 160) consisted of patients with good responses to treatment. Cases and controls were compared using the Chi-square test and odds ratio (OR) technique with a confidence interval at 95%. The failure rate was 12.8%. Failure was significantly correlated with low socioeconomic level (OR = 3), orphan status (OR = 4), age over 10 years (OR = 5), male gender (OR = 3), baseline viral load > or = 1,000,000 copies/mL (OR = 9), and poor compliance (OR = 37). Mortality in children who failed to respond to first-line ARV therapy was 25% due to the unavailability of a national second-line ARV therapy program. This study underlines the need for patient education to promote compliance and for creation of reference centers to prescribe ARV therapy to HIV-infected children including second-line ARV and genotyping.

  1. Should radioiodine be the first-line treatment for paediatric Graves' disease?

    PubMed

    West, James D; Cheetham, Timothy D; Dane, Carole; Natarajan, Anuja

    2015-07-01

    Debate exists regarding the optimal treatment strategy for paediatric Graves' disease with radioiodine (RAI), and surgery, usually reserved for failure of medical therapy. We present our own experience to introduce a review of the published literature focussing on the predictors of remission after antithyroid drug (ATD) therapy from diagnosis, and discuss whether RAI should be considered as a first-line therapy. A retrospective analysis of all diagnosed cases of paediatric Graves' disease presenting to a large District General Hospital. Thirteen patients were diagnosed with Graves' disease between February 2004 and May 2013. The median age at diagnosis was 13.7 years (range 7.2-17.1 years) with a female:male ratio of 11:2. Some nine patients completed a 2-year course of carbimazole out of which 8 relapsed after a mean duration of 0.82 years (range 0.08-1.42 years); the ninth currently remains in remission. Of the eight patients who relapsed, three have undergone RAI treatment. Two patients failed to tolerate carbimazole treatment, one of whom received RAI treatment because surgery was contraindicated and one patient with severe autism proceeded to RAI treatment due to poor compliance and persistent hyperthyroidism. Prognostic factors at presentation predicting a low likelihood of remission following ATD treatment include younger age, non-Caucasian ethnicity, and severe clinical and/or biochemical markers of hyperthyroidism. Psycho-social factors including compliance also influence management decisions. In specifically selected patients presenting with paediatric Graves' disease, the benefits and risks of radioactive iodine as a potential first-line therapy should be communicated allowing families to make informed decisions.

  2. Economic appraisal of dabigatran as first-line therapy for stroke prevention in atrial fibrillation.

    PubMed

    Bergh, M; Marais, C A; Miller-Jansön, H; Salie, F; Stander, M P

    2013-02-15

    Dabigatran is an oral anticoagulant direct thrombin inhibitor recently registered in South Africa (SA) to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation (AF). Owing to the price disparity between warfarin (the current gold standard for treatment of patients with AF) and dabigatran, we conducted an economic appraisal of the use of dabigatran compared with warfarin from a payer perspective in the South African private healthcare setting. To estimate the cost-effectiveness (CE) and budget impact of dabigatran compared with warfarin for the prevention of stroke in AF patients. Methods. A previously published Markov model was populated with SA cost and mortality data to estimate the CE and budget impact analysis of dabigatran over a lifetime horizon. The model population consisted of a cohort of patients of whom those aged younger than 80 years used dabigatran 150 mg twice daily and those older than 80 years 110 mg twice daily. Modelled outcomes included total cost, quality-adjusted life years (QALYs) and incremental CE ratio (ICER), with the effectiveness measured by QALYs gained. Dabigatran compared with warfarin as first-line treatment was estimated to have an ICER of R93 290 and an average incremental cost per beneficiary per month of R0.39 over a 5-year period. Conservative assumptions were made regarding the number of international normalised ratio monitoring tests for patients on warfarin, and the ICER is estimated to decrease by as much as 15.7% under less stringent assumptions. A robust sensitivity analysis was also performed. Dabigatran as first-line treatment compared with warfarin for the use of stroke prevention in patients with AF is deemed cost-effective when used in accordance with its registered indication in the SA private sector.

  3. Radiofrequency ablation for single hepatocellular carcinoma 3 cm or less as first-line treatment

    PubMed Central

    Gao, Jun; Wang, Shao-Hong; Ding, Xue-Mei; Sun, Wen-Bing; Li, Xiao-Long; Xin, Zong-Hai; Ning, Chun-Min; Guo, Shi-Gang

    2015-01-01

    AIM: To evaluate long-term outcomes of radiofrequency (RF) ablation as first-line therapy for single hepatocellular carcinoma (HCC) ≤ 3 cm and to determine survival and prognostic factors. METHODS: We included all 184 patients who underwent RF ablation as a first-line treatment for single HCC ≤ 3 cm between April 2005 and December 2013. According to the criteria of Livraghi, the 184 patients were divided into two groups: those suitable for surgical resection (84 cases) and those unsuitable for surgical resection (100 cases). The primary endpoints were the overall survival (OS) rate and safety; the secondary endpoints were primary technique effectiveness and recurrence rate. RESULTS: There were 19 (10.3%) cases of ablation related minor complications. The complete tumor ablation rate after one RF session was 97.8% (180/184). The rate of local tumor progression, extrahepatic metastases and intrahepatic distant recurrence were 4.9% (9/184), 9.8% (18/184) and 37.5% (69/184), respectively. In the 184 patients, the 1-, 3-, and 5-year OS rates were 99.5%, 81.0%, and 62.5%, respectively. The 1-, 3-, and 5-year OS rates were 100%, 86.9%, and 71.4%, respectively, in those suitable for surgical resection and 99.0%, 76.0%, and 55.0%, respectively, in those unsuitable for surgical resection (P = 0.021). On univariate and multivariate analyses, poorer OS was associated with Child-Pugh B class and portal hypertension (P < 0.05). CONCLUSION: RF ablation is a safe and effective treatment for single HCC ≤ 3 cm. The OS rate of patients suitable for surgical resection was similar to those reported in surgical series. PMID:25954102

  4. [Afatinib as first-line therapy in mutation-positive EGFR. Results by type of mutation].

    PubMed

    Vidal, Óscar Juan

    2016-04-01

    The discovery of endothelial growth factor receptor (EGFR) mutations has laid the foundations for personalized medicine in non-small cell lung carcinoma (NSCLC). In phase III trials, the first-generation tyrosine kinase inhibitors (TKI), gefitinib and erlotinib, demonstrated greater efficacy compared with chemotherapy in patients with EGFR mutations, achieving progression-free survival of 8-13.5 months. Afatinib, a second-generation irreversible pan-ErbB inhibitor, is the first TKI that has shown a benefit in overall survival (OS) compared with chemotherapy in EGFR mutation-positive NSCLC when used as first-line treatment. Exon 19 deletion (Del19) and the single-point substitution mutation (L858R) in exon 21, called activating mutations due to their ability to confer sensitivity to TKI, represent approximately 90% of the EGFR mutations in NSCLC. Distinct sensitivity to TKI has been observed depending on the type of mutation, with greater progression-free survival in patients with the Del19 mutation. The analysis of OS in the LUX-Lung 3 and LUX-Lung 6 trials showed a statistically significant increase in survival in afatinib-treated patients with the Del 19 mutation, but no significant increase in that of patients with the L858R mutation. Direct comparison of afatinib and gefitinib as first-line therapy (LUX-Lung 7 trial) showed a statistically-significant increase in progression-free survival (hazard ratio: 0.73; 95% confidence interval, 0.57-0.95; p=0.0165) with afatinib. In the analysis by type of mutation, this benefit was observed for both the Del19 and the L858R mutations.

  5. Resistance to first-line antituberculosis drugs in Spain, 2010-2011. RETUBES Study.

    PubMed

    Blanquer, Rafael; Rodrigo, Teresa; Casals, Martí; Ruiz Manzano, Juan; García-García, José María; Calpe, José Luís; Valencia, Eulalia; Pascual, Teresa; Mir, Isabel; Jiménez, María Ángeles; Cañas, Fernando; Vidal, Rafael; Penas, Antón; Caylà, Joan A

    2015-01-01

    The magnitude of current resistance to antituberculosis drugs in Spain is unknown. The objective of this study is to describe resistance to first-line antituberculosis drugs and determine the associated factors. Prospective multicenter study of adult tuberculosis patients with positive Mycobacterium tuberculosis culture and antibiogram including first-line drugs in 32 hospitals and one out-patient center of the Spanish Health System between 2010 and 2011. A total of 519 patients, 342 Spanish nationals and 177 (34.1%) foreigners were studied. Drug resistance was found in 48 (9.2%), of which 35 (6.7%) were isoniazid-resistant. There were 10 (1.9%) multiresistant cases and no strain was extremely resistant. Initial isoniazid resistance was detected in 28 of the 487 (5.7%) antituberulosis-naïve patients, most of whom were foreigners (P<.01). Acquired resistance was seen in 7 (22.6%) previously treated cases. Multiresistance was initial in 6 cases (1.2%) and acquired in another 4 (12.9%). Factors associated with initial isoniazid resistance were immigrant status and group cohabitation OR=2.3; 95%CI: .98-5.67 and OR=2.2; 95%CI: 1.05-7.07 respectively). The factor associated with acquired resistance to isoniazid was age below 50 years (P=.03). The rate of initial isoniazid resistance is greater than estimated, probably due to the increase in immigration during recent years, suggesting that systematic national monitoring is required. Immigrants and those who cohabit in groups have a higher risk of isoniazid resistance. Copyright © 2014. Published by Elsevier Espana.

  6. Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.

    PubMed

    Nevitt, Sarah J; Sudell, Maria; Weston, Jennifer; Tudur Smith, Catrin; Marson, Anthony G

    2017-06-29

    Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices. To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus). We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016. We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types). This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary

  7. Testing drug additivity based on monotherapies.

    PubMed

    Yang, Harry; Novick, Steven J; Zhao, Wei

    2015-01-01

    Under the Loewe additivity, constant relative potency between two drugs is a sufficient condition for the two drugs to be additive. Implicit in this condition is that one drug acts like a dilution of the other. Geometrically, it means that the dose-response curve of one drug is a copy of another that is shifted horizontally by a constant over the log-dose axis. Such phenomenon is often referred to as parallelism. Thus, testing drug additivity is equivalent to the demonstration of parallelism between two dose-response curves. Current methods used for testing parallelism are usually based on significance tests for differences between parameters in the dose-response curves of the monotherapies. A p-value of less than 0.05 is indicative of non-parallelism. The p-value-based methods, however, may be fundamentally flawed because an increase in either sample size or precision of the assay used to measure drug effect may result in more frequent rejection of parallel lines for a trivial difference. Moreover, similarity (difference) between model parameters does not necessarily translate into the similarity (difference) between the two response curves. As a result, a test may conclude that the model parameters are similar (different), yet there is little assurance on the similarity between the two dose-response curves. In this paper, we introduce a Bayesian approach to directly test the hypothesis that the two drugs have a constant relative potency. An important utility of our proposed method is in aiding go/no-go decisions concerning two drug combination studies. It is illustrated with both a simulated example and a real-life example. Copyright © 2015 John Wiley & Sons, Ltd.

  8. Differential prognosis of metastatic colorectal cancer patients post-progression to first-line triplet chemotherapy plus bevacizumab, FIr-B/FOx, according to second-line treatment and KRAS genotype

    PubMed Central

    BRUERA, GEMMA; CANNITA, KATIA; GIORDANO, ALDO VICTOR; VICENTINI, ROBERTO; FICORELLA, CORRADO; RICEVUTO, ENRICO

    2014-01-01

    Clinical outcome post-progression to first-line triplet chemotherapy (CT) plus bevacizumab (FIr-B/FOx) was evaluated in metastatic colorectal cancer (MCRC) patients (pts). Second-line treatment was selected according to fitness, KRAS genotype, previous efficacy and safety. Efficacy was evaluated and compared according to treatment or KRAS genotype, using log-rank analysis. Among 54 pts, median overall survival (OS) post-progression was 12 months, significantly better in 40 (74.1%) treated compared to 14 (25.9%) who died without further treatment. Second-line surgical treatment, 4 pts (7.4%), medical treatment, 36 pts (66.7%): triplet CT plus targeted agent, 10 (18.5%); triplet regimens, 19 (35.2%); doublet/monotherapy, 7 (13%). At follow-up of 14 months, objective response rate (ORR) was 38%, metastasectomies 12.5%, progression-free survival (PFS) 10 months, OS 14 months. According to treatment, ORR, metastasectomies, PFS and OS were significantly favourable in triplet CT plus targeted agent compared to triplet, respectively: 80%, 40%, 13 months, not reached; 28%, 6%, 8 months, 11 months. PFS and OS were significantly worse in c.35 G>A mutant compared to wild-type and/or other mutant patients. Prognosis after progression to first-line FIr-B/FOx may be significantly favourable in MCRC pts re-challenged with intensive regimens, and unfavourable in c.35 G>A KRAS mutant patients. PMID:24247407

  9. Long-term response to first-line trabectedin in an elderly female patient with a metastatic leiomyosarcoma unfit for anthracycline

    PubMed Central

    Maruzzo, Marco; Brunello, Antonella; Diminutto, Alberto; Rastrelli, Marco

    2016-01-01

    Systemic chemotherapy comprising anthracycline monotherapy is the standard regimen for metastatic soft tissue sarcomas, particularly leiomyosarcomas, which have limited sensitivity to ifosfamide. However, the optimal chemotherapy regimen for elderly patients, especially those considered unfit for anthracyclines, is undefined. Trabectedin is a potent marine-derived antineoplastic drug with documented activity in liposarcomas and leiomyosarcomas. It is registered in Europe for the treatment of adult patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. We report the long-term response to first-line trabectedin therapy in an elderly patient with metastatic leiomyosarcoma unfit for standard therapy. A 66-year-old woman underwent resection of a pelvic epithelioid leiomyosarcoma with positive margins in December 2002, followed by postoperative radiotherapy. In February 2012, she was diagnosed with multiple lung lesions and local relapse in the pelvis. As she was considered unsuitable for both anthracycline and ifosfamide because of cardiovascular comorbidities and because she was highly anxious at the prospect of developing alopecia, vomiting, and fatigue, we commenced treatment with trabectedin at 75% of the standard dose of 1.5 mg/m2 every 3 weeks. Treatment was well tolerated, and the patient continued treatment for 25 cycles, with disease stabilization according to the RECIST criteria and a partial response according to the Choi criteria. Disease progression was observed in November 2013 and the patient died 20 months after the diagnosis of metastases. Trabectedin may represent an alternative option for highly selected elderly patients with metastatic sarcoma and unfit for anthracyclines; careful monitoring of toxicities is strongly recommended. PMID:26629769

  10. Phase I dose-finding study of sorafenib with FOLFOX4 as first-line treatment in patients with unresectable locally advanced or metastatic gastric cancer

    PubMed Central

    Chi, Yihebali; Yang, Jianliang; Yang, Sheng; Sun, Yongkun; Jia, Bo

    2015-01-01

    Objective To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and efficacy of sorafenib in combination with FOLFOX4 (oxaliplatin/leucovorin (LV)/5-fluorouracil) as first-line treatment for advanced gastric cancer, we performed a phase I dose-finding study in nine evaluable patients with unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. Methods According to modified Fibonacci method, the design of this study was to guide elevation of the sorafenib dosage to the next level (from 200 mg twice daily to 400 mg twice daily and then, if tolerated, 600 mg twice daily). If the patient achieved complete response (CR), partial response (PR) or stable disease (SD) after eight cycles of treatment, combination chemotherapy was scheduled to be discontinued and sorafenib monotherapy continued at the original dose until either disease progression or unacceptable toxicity. Results In sorafenib 200 mg twice daily group, DLT was observed in 1 of 6 patients, and in 400 mg twice daily group, it was observed in 2 of 3 patients. Seven of 9 (77.8%) evaluable patients achieved PR, with a median overall survival (OS) of 11.8 [95% confidence interval (CI): 8.9-14.7] months. Common adverse effects include hand-foot syndrome, leukopenia, neutropenia, anorexia, and nausea. Conclusions Twice-daily dosing of sorafenib 200 mg in combination with FOLFOX4 was proven effective and safe for the treatment of advanced gastric cancer, and could be an appropriate dosage for subsequent phase II clinical studies. PMID:26157320

  11. Phase I Study of Sunitinib in Combination With Gemcitabine and Capecitabine for First-Line Treatment of Metastatic or Unresectable Renal Cell Carcinoma

    PubMed Central

    Suarez, Cristina; Gallardo, Enrique; Rodon, Jordi; Pons, Francesc; Bonfill, Teresa; Beltran, Marta; Moya, Irene; Galtes, Susana; Albanell, Joan; Carles, Joan

    2014-01-01

    Background. The combination of gemcitabine plus capecitabine and sunitinib (GCS) shows activity in metastatic renal cell carcinoma (mRCC). We tested the multitargeted “chemo-switch” regimen as first-line treatment in patients with mRCC. Methods. We assessed the maximum tolerated dose and antitumor activity of GCS in treatment-naïve, advanced mRCC patients. Treatment consisted of intravenous gemcitabine on days 1 and 8, oral capecitabine twice daily on days 1–14, and oral sunitinib daily for six 21-day cycles, followed by sunitinib monotherapy at the investigator’s discretion. Dose level 0 (DL0) was gemcitabine 1,000 mg/m2 per day plus capecitabine 650 mg/m2 per 12 hours plus sunitinib 37.5 mg/day; DL1 was gemcitabine 1,000 mg/m2 per day plus capecitabine 850 mg/m2 per 12 hours plus sunitinib 37.5 mg/day. Results. Sixteen patients were enrolled. At DL1, two of four patients had dose-limiting toxicity (DLT; grade 3 diarrhea and grade 4 thrombocytopenia). The dose was reduced to DL0 when only 1 of 12 patients experienced DLT (grade 3 diarrhea, grade 3 mucositis, and grade 3 thrombocytopenia). Dose reductions were frequent (58% of patients), and only seven patients were able to receive the three drugs for more than three cycles. One patient achieved a complete response, three had partial responses, and the best response for four was stable disease. Conclusion. The safety profile of the combination does not seem manageable in this patient population. No further development of the combination is recommended. PMID:25142843

  12. Long-term response to first-line trabectedin in an elderly female patient with a metastatic leiomyosarcoma unfit for anthracycline.

    PubMed

    Maruzzo, Marco; Brunello, Antonella; Diminutto, Alberto; Rastrelli, Marco; Basso, Umberto

    2016-03-01

    Systemic chemotherapy comprising anthracycline monotherapy is the standard regimen for metastatic soft tissue sarcomas, particularly leiomyosarcomas, which have limited sensitivity to ifosfamide. However, the optimal chemotherapy regimen for elderly patients, especially those considered unfit for anthracyclines, is undefined. Trabectedin is a potent marine-derived antineoplastic drug with documented activity in liposarcomas and leiomyosarcomas. It is registered in Europe for the treatment of adult patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. We report the long-term response to first-line trabectedin therapy in an elderly patient with metastatic leiomyosarcoma unfit for standard therapy. A 66-year-old woman underwent resection of a pelvic epithelioid leiomyosarcoma with positive margins in December 2002, followed by postoperative radiotherapy. In February 2012, she was diagnosed with multiple lung lesions and local relapse in the pelvis. As she was considered unsuitable for both anthracycline and ifosfamide because of cardiovascular comorbidities and because she was highly anxious at the prospect of developing alopecia, vomiting, and fatigue, we commenced treatment with trabectedin at 75% of the standard dose of 1.5 mg/m every 3 weeks. Treatment was well tolerated, and the patient continued treatment for 25 cycles, with disease stabilization according to the RECIST criteria and a partial response according to the Choi criteria. Disease progression was observed in November 2013 and the patient died 20 months after the diagnosis of metastases. Trabectedin may represent an alternative option for highly selected elderly patients with metastatic sarcoma and unfit for anthracyclines; careful monitoring of toxicities is strongly recommended.

  13. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study.

    PubMed

    Van Cutsem, E; Rivera, F; Berry, S; Kretzschmar, A; Michael, M; DiBartolomeo, M; Mazier, M-A; Canon, J-L; Georgoulias, V; Peeters, M; Bridgewater, J; Cunningham, D

    2009-11-01

    Bevacizumab significantly improves survival when added to chemotherapy for metastatic colorectal cancer (mCRC). The Bevacizumab Expanded Access Trial (BEAT) evaluated the safety and efficacy of bevacizumab plus first-line chemotherapy in a general cohort of patients with mCRC. Patients with unresectable mCRC received chemotherapy (physician's choice) plus bevacizumab [5 mg/kg every 2 weeks (5-fluorouracil regimens) or 7.5 mg/kg every 3 weeks (capecitabine regimens)]. The primary end point was safety, including prospective data collection in patients receiving unanticipated surgery during the study. Secondary objectives were progression-free survival (PFS) and overall survival (OS). The final analysis comprised 1914 assessable patients (male 58%; median age 59 years). Chemotherapy included 5-fluorouracil/leucovorin (5-FU/LV) + oxaliplatin (29%), irinotecan plus 5-FU/LV (26%), capecitabine plus oxaliplatin (18%) and monotherapy (16%). Serious/grade 3-5 adverse events of interest for bevacizumab included bleeding (3%), gastrointestinal perforation (2%), arterial thromboembolism (1%), hypertension (5.3%), proteinuria (1%) and wound-healing complications (1%). Sixty-day mortality was 3%. Median PFS was 10.8 months [95% confidence interval (CI) 10.4-11.3 months] and median OS reached 22.7 months (95% CI 21.7-23.8 months). The BEAT study shows that the efficacy and safety profile of bevacizumab in routine clinical practice is consistent with results observed in prospective randomised clinical trials and another large observational study in the United States (BRiTE study).

  14. First Line Anti-TB Drug Resistance in an Urban Area of Odisha, India.

    PubMed

    Das, Dasarathi; Satapathy, Prakasini; Murmu, Biswanath

    2016-11-01

    Drug resistance is a major cause for increasing the global burden of Tuberculosis (TB). However in countries with larger geographical areas and different climatic conditions like India the prevalence of drug resistance varies from place to place. Information on anti-TB drug resistance patterns particularly among newly diagnosed cases is crucial for planning an effective TB control program. To determine the prevalence of resistance against first line anti-TB drugs and Multi Drug Resistance (MDR) in Mycobacterium tuberculosis isolates. The prospective study was carried out in National Reference Laboratory (NRL) of Regional Medical Research Centre (RMRC), Bhubaneswar. During this period from January to September 2014, sputum specimens were collected from 850 suspected pulmonary TB patients attending Designated Microscopy Center (DMC) of Capital Hospital, Bhubaneswar, Odisha. Sputum specimens were subjected to Acid Fast Bacilli (AFB) smear microscopy and further processed for isolation on solid Lowenstein Jensen (LJ) medium. Drug Susceptibility Testing (DST) on isolates with first line anti-TB drugs was performed as per Revised National Tuberculosis Control Programe (RNTCP) guidelines. Out of all the 850 suspected pulmonary TB patients subjected to AFB microscopy and solid LJ culture, isolation of Mycobacterium tuberculosis was successful only in 161 (117 new and 44 previously treated) pulmonary TB patients. On DST by the RNTCP approved proportion method, prevalence of MDR- TB among 0.85% new and 4.54% previously treated cases was observed. Prevalence of mono resistance to streptomycin, isoniazid, rifampicin and ethambutol observed among new and previously treated cases were 3.41%, 2.56%, 0, 0.85% and 2.27%, 13.6%, 2.27%, 0 respectively. Only one patient from each category showed resistance to both streptomycin and isoniazid in previously treated as well as in new case. The study reports an unchanged low level of MDR-TB prevalence among new cases in an urban area of

  15. Economic evaluation for first-line anti-hypertensive medicines: applications for the Philippines

    PubMed Central

    2012-01-01

    Background Medicines to control hypertension, a leading cause of morbidity and mortality, are a major component of health expenditures in the Philippines. This study aims to review economic studies for first line anti-hypertensive medical treatment without co-morbidities; and discuss practical, informational and policy implications on the use of economic evaluation in the Philippines. Methods A systematic literature review was performed using the following databases: MEDLINE, EMBASE, BIOSIS, PubMed, The Cochrane Library, Health Economics Evaluations Database (HEED) and the Centre for Reviews and Dissemination – NHS NICE. Six existing economic analytical frameworks were reviewed and one framework for critical appraisal was developed. Results Out of 1336 searched articles, 12 fulfilled the inclusion criteria. The studies were summarized according to their background characteristics (year, journal, intervention and comparators, objective/study question, target audience, economic study type, study population, setting and country and source of funding/conflict of interest) and technical characteristics (perspective, time horizon, methodology/modeling, search strategy for parameters, costs, effectiveness measures, discounting, assumptions and biases, results, cost-effectiveness ratio, endpoints, sensitivity analysis, generalizability, strengths and limitations, conclusions, implications and feasibility and recommendations). The studies represented different countries, perspectives and stakeholders. Conclusions Diuretics were the most cost-effective drug class for first-line treatment of hypertension without co-morbidities. Although the Philippine Health Insurance Corporation may apply the recommendations given in previous studies (i.e. to subsidize diuretics, ACE inhibitors and calcium channel blockers), it is uncertain how much public funding is justified. There is an information gap on clinical data (transition probabilities, relative risks and risk reduction) and

  16. Resistance of uropathogenic bacteria to first-line antibiotics in mexico city: A multicenter susceptibility analysis

    PubMed Central

    Arredondo-García, José Luis; Soriano-Becerril, Diana; Solórzano-Santos, Fortino; Arbo-Sosa, Antonio; Coria-Jiménez, Rafael; Arzate-Barbosa, Patricia

    2007-01-01

    Abstract Background Growing antibiotic resistance demands the constant reassessment of antimicrobial efficacy, particularly in countries with wide antibiotic abuse, where higher resistance prevalence is often found. Knowledge of resistance trends is particularly important when prescribing antibiotics empirically, as is usually the case for urinary tract infections (UTIs). Currently, in Mexico City, ampicillin, cotrimoxazole (trimethoprim/sulfamethoxazole), and ciprofloxacin are used as “first-line” antibiotic treatment for UTI. Objective The aim of this study was to analyze the resistance of bacterial isolates to antibiotics, with a focus on first-line antibiotics, in Mexican pediatric patients and sexually active or pregnant female outpatients. Methods In this multicenter susceptibility analysis, bacterial isolates from urine samples collected from pediatric patients and sexually-active or pregnant female outpatients presenting with acute, uncomplicated UTIs in Mexico City from January 2006 through June 2006, were included in the study. Samples were tested for susceptibility to 10 antibiotics by the disk-diffusion method. Results Four-hundred and seventeen bacterial isolates were derived from sexually active or pregnant female outpatients (324 Escherichia coli) and pediatric patients (93 Klebsiella pneumoniae). We found a high prevalence of resistance towards the drugs used as “first-line” when treating UTIs: ampicillin, cotrimoxazole, and ciprofloxacin (79%, 60%, and 24% resistance, respectively). Ninety-eight percent of K pneumoniae isolates were resistant to ampicillin, whereas 66% of the E coli isolates were resistant to cotrimoxazole. Resistance towards third-generation cephalosporins was also high (6%–8% of E coli and 10%–28% of K pneumoniae). This was possibly caused by chromosomal β-lactamases, as 30% of all isolates were also resistant to amoxicillin/clavulanate. In contrast, 98% of the E coli isolates and 84% of the K pneumoniae strains (96

  17. Bivalirudin versus Heparin Monotherapy in Myocardial Infarction.

    PubMed

    Erlinge, David; Omerovic, Elmir; Fröbert, Ole; Linder, Rikard; Danielewicz, Mikael; Hamid, Mehmet; Swahn, Eva; Henareh, Loghman; Wagner, Henrik; Hårdhammar, Peter; Sjögren, Iwar; Stewart, Jason; Grimfjärd, Per; Jensen, Jens; Aasa, Mikael; Robertsson, Lotta; Lindroos, Pontus; Haupt, Jan; Wikström, Helena; Ulvenstam, Anders; Bhiladvala, Pallonji; Lindvall, Bo; Lundin, Anders; Tödt, Tim; Ioanes, Dan; Råmunddal, Truls; Kellerth, Thomas; Zagozdzon, Leszek; Götberg, Matthias; Andersson, Jonas; Angerås, Oskar; Östlund, Ollie; Lagerqvist, Bo; Held, Claes; Wallentin, Lars; Scherstén, Fredrik; Eriksson, Peter; Koul, Sasha; James, Stefan

    2017-09-21

    infarction, the rate of the composite of death from any cause, myocardial infarction, or major bleeding was not lower among those who received bivalirudin than among those who received heparin monotherapy. (Funded by the Swedish Heart-Lung Foundation and others; VALIDATE-SWEDEHEART ClinicalTrialsRegister.eu number, 2012-005260-10 ; ClinicalTrials.gov number, NCT02311231 .).

  18. Electrochemotherapy as First Line Cancer Treatment: Experiences from Veterinary Medicine in Developing Novel Protocols.

    PubMed

    Spugnini, E P; Azzarito, T; Fais, S; Fanciulli, M; Baldi, A

    2016-01-01

    Tumor microenvironment is one of the major obstacles to the efficacy of chemotherapy in cancer patients. The abnormal blood flow within the tumor results in uneven drug distribution. Electrochemotherapy (ECT) is a tumor treatment that adopts the systemic or local delivery of anticancer drugs with the application of permeabilizing electric pulses having appropriate amplitude and waveforms. This allows the use of lipophobic drugs that frequently have a narrow therapeutic index maintaining at the same time a reduced patient morbidity and preserving appropriate anticancer efficacy. Its use in humans is addressed to the treatment of cutaneous neoplasms or the palliation of skin tumor metastases, and a standard operating procedure has been devised. On the other hand, in veterinary oncology this approach is gaining popularity, thus becoming a first line treatment for different cancer histotypes, in a variety of clinical conditions due to its high efficacy and low toxicity. This review summarizes the state of the art in veterinary oncology as a preclinical model and reports the new protocols in terms of drugs and therapy combination that have been developed.

  19. Rituximab as a first-line preventive treatment in pediatric NMOSDs

    PubMed Central

    Longoni, Giulia; Banwell, Brenda; Filippi, Massimo

    2014-01-01

    Objective: No established therapeutic protocol has been proposed to date for childhood-onset neuromyelitis optica (NMO) spectrum disorders (NMOSDs). We report the response of 5 NMO immunoglobulin (Ig)G–positive pediatric cases to a standardized B-cell–targeted first-line immunosuppressive protocol with rituximab for prevention of relapses. Methods: Retrospective observational cohort study. Results: All patients included in the study showed disease remission after rituximab induction. Relapses always occurred in conjunction with CD19+ B-cell repopulation and appeared less severe than prior to treatment. At the end of follow-up, neurologic disability and MRI findings stabilized or improved in all the patients, with only minor and transient side effects. Oral steroid discontinuation was possible in all the patients. Conclusions: Our protocol is well-tolerated and has provided encouraging results in terms of control of relapses and progression of disability. An early intervention with rituximab might affect the disease course in pediatric NMO-IgG–positive NMOSDs. Classification of evidence: This study provides Class IV evidence that for children with NMOSDs, rituximab is well-tolerated and stabilizes or improves neurologic disability. PMID:25520954

  20. High Dose Ilaprazole/Amoxicillin as First-Line Regimen for Helicobacter pylori Infection in Korea

    PubMed Central

    Graham, David Y.

    2016-01-01

    Objective. The eradication rate of Helicobacter pylori (H. pylori) following standard triple therapy has declined over the past few decades. This study has determined whether high dose dual therapy (PPI and amoxicillin) is adequate for eradicating H. pylori in Korea. Methods. This was an open-labeled study of H. pylori infected treatment-naive patients. Subjects received dual therapy for 14 days: ilaprazole 40 mg tablets given twice a day and amoxicillin 750 mg tablets given 4 times a day. At the end of the therapy, the subjects visited the clinic to confirm compliance and monitor for any side effects. Subjects visited again after 4–6 weeks to confirm H. pylori status through a urea breath test. Results. The cure rate of H. pylori was 79.3% (23 of 29) (95% confidence interval: 61.6–90.2) in the intention-to-treat analysis and 82.1% (23 of 28) in the per-protocol analysis. Compliance rates were high (96.6%) and side effects were minimal and tolerable. Conclusion. A high dose of ilaprazole + amoxicillin was ineffective as the first-line therapy for eradicating H. pylori in Korea. Future studies should focus on intragastric pH measurements and assess amoxicillin resistance. PMID:27413365

  1. Leadership and management skills of first-line managers of elderly care and their work environment.

    PubMed

    Abdelrazek, Fathya; Skytt, Bernice; Aly, Magda; El-Sabour, Mona Abd; Ibrahim, Naglaa; Engström, Maria

    2010-09-01

    To study the leadership and management skills of first-line managers (FLMs) of elderly care and their work environment in Egypt and Sweden. FLMs in Egypt and Sweden are directly responsible for staff and quality of care. However, FLMs in Sweden, in elderly care, have smaller units/organizations to manage than do their colleagues in Egypt. Furthermore, family care of the elderly has been the norm in Egypt, but in recent years institutional care has increased, whereas in Sweden, residential living homes have existed for a longer period. A convenience sample of FLMs, 49 from Egypt and 49 from Sweden, answered a questionnaire measuring leadership and management skills, structural and psychological empowerment, job satisfaction and psychosomatic health. In both countries, FLMs' perceptions of their leadership and management skills and psychological empowerment were quite high, whereas scores for job satisfaction and psychosomatic health were lower. FLMs had higher values in several factors/study variables in Egypt compared with in Sweden. The work environment, both in Egypt and Sweden, needs to be improved to increase FLMs' job satisfaction and decrease stress. The cultural differences and levels of management have an effect on the differences between the two countries. © 2010 The Authors. Journal compilation © 2010 Blackwell Publishing Ltd.

  2. Interchangeability between first-line generic antiretroviral products prequalified by WHO using adjusted indirect comparisons.

    PubMed

    Gwaza, Luther; Gordon, John; Welink, Jan; Potthast, Henrike; Leufkens, Hubert; Stahl, Matthias; García-Arieta, Alfredo

    2017-01-01

    The scaling-up of access to antiretroviral therapy, particularly in low- to middle-income countries, was facilitated by the introduction and widespread use of generic antiretroviral medicines and fixed-dose combinations. Generic medicines are approved by regulatory authorities based on the demonstration of bioequivalence with the innovator or reference product, as well as meeting quality standards. In clinical practice, however, it is not unusual for generics to be interchanged between each other. This study investigated the differences in bioavailability between WHO-prequalified first-line antiretroviral generics by means of adjusted indirect comparisons to ensure interchangeability between these generics. Data on 34 products containing emtricitabine, tenofovir disoproxil fumarate, lamivudine and efavirenz in single formulations or fixed-dose combinations were included in the analysis. The 90% CI for the adjusted indirect comparisons was calculated using the homoscedastic method that uses the conventional t-test, and assumes homogeneity of variances between the studies and small sample sizes. The combined standard deviation of both bioequivalence studies was calculated from the variability of each individual study. The adjusted indirect comparisons between generics showed that the differences, expressed as 90% CIs, are less than 30%. Confidence in the interchangeability of two generic products was reduced if the mean difference between the test and reference in the original studies is more than 10%. From a bioequivalence perspective, the generic antiretroviral medicines prequalified by WHO are interchangeable with the reference, as well as between each other without safety or efficacy concerns.

  3. Introduction of dermatome shaving as first line treatment of chronic tattoo reactions.

    PubMed

    Sepehri, Mitra; Jørgensen, Bo; Serup, Jørgen

    2015-10-01

    Chronic tattoo reactions requiring treatment have increased. Laser removal is not ideal for removal of allergic reactions. Surgical removal of culprit pigment situated in the outer dermis by dermatome shaving is rational and need to be revisited. Fifty four tattoos with chronic reactions in 50 patients were treated with dermatome shaving. Tattoos with red/red nuances dominated the material. In total, 52 operations were performed in infiltration and 2 in general anaesthesia. Shaving was performed to the level in the dermis free of tattoo pigment as assessed visually by the surgeon. Operative complications were few. Healing occurred over weeks as normal for this procedure. On a rating scale from 0 to 4, 4 as most severe, the patient's severity rating of symptoms in their tattoo declined from 3.2 pre-operatively to 1.0, 0.8 and 0.7 after 3, 6 and 12 months, respectively. Burden of operation was rated low. Patient satisfaction was high. Dermatome shaving is efficient and with few complications, and is proposed as first line treatment of chronic tattoo reactions. Shaving of such reactions apparently has been neglected during enthusiastic introduction of laser approaches, which in the treatment of allergic tattoo reactions may be relatively contra indicated and of special risk.

  4. Intravenous Levetiracetam as first-line treatment of status epilepticus in the elderly.

    PubMed

    Fattouch, J; Di Bonaventura, C; Casciato, S; Bonini, F; Petrucci, S; Lapenta, L; Manfredi, M; Prencipe, M; Giallonardo, A T

    2010-06-01

    Status epilepticus is a condition of prolonged/repetitive seizures that often occurs in the elderly. Treatment in the elderly can be complicated by serious side effects associated with traditional drugs. The aim of this pilot study was to evaluate the short-term efficacy/safety of intravenously administered LEV (IVLEV) as the treatment of choice for SE in the elderly. We enrolled nine elderly patients (five female/four male; median age 78 years) with SE. Two patients had a previous diagnosis of epilepsy; in the remaining seven, SE was symptomatic. SE was convulsive in five and non-convulsive in four. All the patients presented concomitant medical conditions (arrhythmias/respiratory distress/hepatic diseases). As the traditional therapy for SE was considered unsafe, IVLEV was used as first-line therapy (loading dose of 1500 mg/100 ml/15 min, mean maintenance daily dose of 2500 mg/24 h) administered during video-EEG monitoring. In all the patients but one, IVLEV was effective in the treatment of SE and determined either the disappearance of (7/8), or significant reduction in (1/8), epileptic activity; no patient relapsed in the subsequent 24 h. No adverse events or changes in the ECG/laboratory parameters were observed. These data suggest that IVLEV may be an effective/safe treatment for SE in the elderly.

  5. Why do you need to move beyond first-line therapy for major depression?

    PubMed

    Culpepper, Larry

    2010-01-01

    Primary care clinicians need to move beyond first-line therapy for major depression. While initial treatment is ineffective in about two-thirds of patients, patients who have not responded to such initial treatments can be managed effectively. The severity of depression is as high in primary care as in specialty care settings. The risk of depression is currently elevated because economic hardship, job insecurity, and low socioeconomic status increase the likelihood of depression and treatment resistance. Depression worsens outcomes for medical comorbidities, such as cardiac disease, chronic obstructive pulmonary disease, and diabetes mellitus, and it increases the risk of rehospitalization. When depression is treatment-resistant (generally defined as not responding to 2 courses of treatment of adequate dose and duration), morbidity and mortality are increased, quality of life and function are reduced, and long-term brain changes may occur. Opportunities for change in care are available. Screening for depression in primary care settings with staff-assisted support, adopting the concepts of the patient-centered medical home and stepped care, and using new treatment options such as atypical antipsychotics and other treatment modalities can improve outcomes for these patients. Now is the time to make these moves because new tools, systems, and treatments offer ways to help these patients. © Copyright 2010 Physicians Postgraduate Press, Inc.

  6. Population pharmacokinetics and limited sampling strategy for first-line tuberculosis drugs and moxifloxacin.

    PubMed

    Magis-Escurra, C; Later-Nijland, H M J; Alffenaar, J W C; Broeders, J; Burger, D M; van Crevel, R; Boeree, M J; Donders, A R T; van Altena, R; van der Werf, T S; Aarnoutse, R E

    2014-09-01

    Therapeutic drug monitoring (TDM) of tuberculosis (TB) drugs currently focuses on peak plasma concentrations, yet total exposure [area under the 24-h concentration-time curve (AUC₀₋₂₄)] is probably most relevant to the efficacy of these drugs. We therefore assessed population AUC₀₋₂₄ data for all four first-line TB drugs (rifampicin, isoniazid, pyrazinamide and ethambutol) as well as moxifloxacin and developed limited sampling strategies to estimate AUC₀₋₂₄ values conveniently. AUC₀₋₂₄ and other pharmacokinetic (PK) parameters were determined following intensive PK sampling in two Dutch TB referral centres. Best subset selection multiple linear regression was performed to derive limited sampling equations. Median percentage prediction error and median absolute percentage prediction error were calculated via jackknife analysis to evaluate bias and imprecision of the predictions. Geometric mean AUC₀₋₂₄ values for rifampicin, isoniazid, pyrazinamide, ethambutol and moxifloxacin were 41.1, 15.2, 380, 25.5 and 33.6 hmg/L, respectively. Limited sampling at various fixed sampling points enabled an accurate and precise prediction of AUC₀₋₂₄ values of all drugs separately and simultaneously. In the absence of clinically validated target values for AUC₀₋₂₄, average AUC₀₋₂₄ values can be used as reference values in TDM. Limited sampling of AUC₀₋₂₄ is feasible in many settings and allows for TDM to be performed at a larger scale.

  7. First-line treatment with cephalosporins in spontaneous bacterial peritonitis provides poor antibiotic coverage.

    PubMed

    Novovic, Srdan; Semb, Synne; Olsen, Henrik; Moser, Claus; Knudsen, Jenny Dahl; Homann, Christian

    2012-02-01

    Spontaneous bacterial peritonitis is a common infection in cirrhosis, associated with a high mortality. Third-generation cephalosporins are recommended as first-line treatment. The aim was to evaluate the epidemiology of microbiological ascitic fluid findings and antimicrobial resistance in Denmark. All patients with cirrhosis and a positive ascitic fluid culture, at three university hospitals in the Copenhagen area during a 7-year period, were retrospectively evaluated. Patients with apparent secondary peritonitis were excluded from the study. One hundred and forty cases with 187 microbiological isolates were identified. The findings were: Gram-positive cocci, n = 86 (45.9%); Enterobacteriaceae, n = 59 (31.7%), with Escherichia coli identified in 31 cases; anaerobes, n = 14 (7.5%); yeast, n = 12 (6.4%); and cutaneous flora, n = 15 (8.0%). One case of Listeria monocytogenes was identified (0.5%). Overall antibiotic coverage was 57% for cephalosporins, 73% for piperacillin-tazobactam, and 72% for meropenem. Mortality rates in patients with isolates susceptible or resistant to the initial antibiotic treatment at 30 days follow-up were 35% and 55%, respectively (p = 0.017, Log-rank test). Almost half of the isolates were Gram-positive cocci, and as the overall antibiotic coverage with a cephalosporin was only 57%, and survival significantly dependent on whether the microbial etiology was susceptible to initial antibiotic treatment or not, a change of standard empiric antibiotic regime should be considered. Piperacillin-tazobactam could be a favorable choice.

  8. Beyond first-line chemotherapy for advanced pancreatic cancer: An expanding array of therapeutic options?

    PubMed Central

    Walker, Evan J; Ko, Andrew H

    2014-01-01

    While an increasing number of therapeutic options are now available for the first-line treatment of locally advanced or metastatic pancreatic cancer, the optimal choice for treatment in the second-line setting and beyond is less well defined. A variety of cytotoxic agents, either alone or in combination, have been evaluated, although primarily in the context of small single-arm or retrospective studies. Most regimens have been associated with median progression-free survival rates in the range of 2-4 mo and overall survival rates between 4-8 mo, highlighting the very poor prognosis of patients who are candidates for such treatment. Targeted therapies studied in this chemotherapy-refractory setting, meanwhile, have produced even worse efficacy results. In the current article, we review the clinical evidence for treatment of refractory disease, primarily in patients who have progressed on front-line gemcitabine-based chemotherapy. In the process, we highlight the limitations of the available data to date as well as some of the challenges in designing appropriate clinical trials in this salvage setting, including how to select an appropriate control arm given the absence of a well-established reference standard, and the importance of incorporating predictive biomarkers and quality of life measures whenever possible into study design. PMID:24605022

  9. Phenotypically Adapted Mycobacterium tuberculosis Populations from Sputum Are Tolerant to First-Line Drugs

    PubMed Central

    Turapov, Obolbek; O'Connor, Benjamin D.; Sarybaeva, Asel A.; Williams, Caroline; Patel, Hemu; Kadyrov, Abdullaat S.; Sarybaev, Akpay S.; Woltmann, Gerrit; Barer, Michael R.

    2016-01-01

    Tuberculous sputum contains multiple Mycobacterium tuberculosis populations with different requirements for isolation in vitro. These include cells that form colonies on solid media (plateable M. tuberculosis), cells requiring standard liquid medium for growth (nonplateable M. tuberculosis), and cells requiring supplementation of liquid medium with culture supernatant (SN) for growth (SN-dependent M. tuberculosis). Here, we describe protocols for the cryopreservation and direct assessment of antimicrobial tolerance of these M. tuberculosis populations within sputum. Our results show that first-line drugs achieved only modest bactericidal effects on all three populations over 7 days (1 to 2.5 log10 reductions), and SN-dependent M. tuberculosis was more tolerant to streptomycin and isoniazid than the plateable and nonplateable M. tuberculosis strains. Susceptibility of plateable M. tuberculosis to bactericidal drugs was significantly increased after passage in vitro; thus, tolerance observed in the sputum samples from the population groups was likely associated with mycobacterial adaptation to the host environment at some time prior to expectoration. Our findings support the use of a simple ex vivo system for testing drug efficacies against mycobacteria that have phenotypically adapted during tuberculosis infection. PMID:26883695

  10. Pertuzumab: in the first-line treatment of HER2-positive metastatic breast cancer.

    PubMed

    Keating, Gillian M

    2012-02-12

    The humanized monoclonal antibody pertuzumab is the first in a new class of drugs, the human epidermal growth factor receptor (HER) dimerization inhibitors. Given that pertuzumab binds to a different epitope of the HER2 extracellular domain than trastuzumab, combination therapy with pertuzumab plus trastuzumab may result in more comprehensive blockade of HER2 signalling than can be achieved with trastuzumab alone. The efficacy of adding pertuzumab to trastuzumab plus docetaxel for the first-line treatment of HER2-positive metastatic breast cancer was demonstrated in the randomized, double-blind, multinational, phase III CLEOPATRA trial. Both independently assessed progression-free survival (primary endpoint) and investigator-assessed progression-free survival were significantly improved in patients receiving pertuzumab plus trastuzumab and docetaxel compared with those receiving placebo plus trastuzumab and docetaxel. The prespecified interim analysis of survival revealed a strong trend towards a survival benefit associated with pertuzumab, although this was not considered statistically significant. The objective response rate was higher with pertuzumab than with placebo. Intravenous pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel in the CLEOPATRA trial.

  11. A First Line of Stress Defense: Small Heat Shock Proteins and their function in protein homeostasis

    PubMed Central

    Haslbeck, Martin; Vierling, Elizabeth

    2015-01-01

    Small heat shock proteins (sHsps) are virtually ubiquitous molecular chaperones that can prevent the irreversible aggregation of denaturing proteins. To maintain protein homeostasis, sHsps complex with a variety of nonnative proteins in an ATP-independent manner and, in the context of the stress response, form a first line of defense against protein aggregation. In vertebrates they act to maintain the clarity of the eye lens, and in humans sHsp mutations are linked to myopathies and neuropathies. Although found in all domains of life, sHsps are quite diverse and have evolved independently in metazoans, plants and fungi. sHsp monomers range in size from approximately 12 to 42 kDa and are defined by a conserved β-sandwich α-crystallin domain, flanked by variable N- and C-terminal sequences. Most sHsps form large oligomeric ensembles with a broad distribution of different, sphere- or barrel like oligomers, with the size and structure of the oligomers dictated by features of the N- and C-termini. The activity of sHsps is regulated by mechanisms that change the equilibrium distribution in tertiary features and/or quaternary structure of the sHsp ensembles. Cooperation and/or coassembly between different sHsps in the same cellular compartment adds an underexplored level of complexity to sHsp structure and function. PMID:25681016

  12. Bladder surgery as first-line treatment of complete duplex system complicated with ureterocele.

    PubMed

    Yoo, Eunsang; Kim, Hyuntae; Chung, Sungkwang

    2007-08-01

    We retrospectively analyzed our experience to determine the optimum management of complete duplex system complicated with ureterocele. Between 1994 and 2003, we reviewed 15 patients treated with bladder surgery for complete duplex system complicated with ureterocele. The associated anomalies were seven vesicoureteral reflux (VUR) of the lower pole ureter and one of both poles. All patients had ureterocele (11 intravesical, 4 extravesical) and a functioning upper moiety. Initial treatment was transurethral incision of ureterocele (TUI) (14) or common sheath reimplantation (1). The median follow-up was 30 (13-48) months. There were no requirements for secondary procedures, with a significant improvement or conservation of ipsilateral renal function and no reflux, in 10 patients (67%). Five patients (33%) with ureterocele (1 intravesical, 4 extravesical) who initially underwent TUI required additional operative management due to moderate to severe VUR, recurrent urinary tract infection or decreased function of upper moiety. The secondary operation performed was lower pole nephrectomy with ureteral reimplantation (1), ureteroureterostomy with ureteral reimplantation (2) or common sheath reimplantation (2). One patient who underwent common sheath reimplantation as secondary operation needed a nephrectomy due to breakthrough febrile urinary tract infection and decreased renal function. TUI is recommended as the first-line treatment of complete duplex system with intravesical ureterocele and well-conserved renal function.

  13. Comparison of automated treponemal and nontreponemal test algorithms as first-line syphilis screening assays.

    PubMed

    Huh, Hee Jin; Chung, Jae Woo; Park, Seong Yeon; Chae, Seok Lae

    2016-01-01

    Automated Mediace Treponema pallidum latex agglutination (TPLA) and Mediace rapid plasma reagin (RPR) assays are used by many laboratories for syphilis diagnosis. This study compared the results of the traditional syphilis screening algorithm and a reverse algorithm using automated Mediace RPR or Mediace TPLA as first-line screening assays in subjects undergoing a health checkup. Samples from 24,681 persons were included in this study. We routinely performed Mediace RPR and Mediace TPLA simultaneously. Results were analyzed according to both the traditional algorithm and reverse algorithm. Samples with discordant results on the reverse algorithm (e.g., positive Mediace TPLA, negative Mediace RPR) were tested with Treponema pallidum particle agglutination (TPPA). Among the 24,681 samples, 30 (0.1%) were found positive by traditional screening, and 190 (0.8%) by reverse screening. The identified syphilis rate and overall false-positive rate according to the traditional algorithm were lower than those according to the reverse algorithm (0.07% and 0.05% vs. 0.64% and 0.13%, respectively). A total of 173 discordant samples were tested with TPPA by using the reverse algorithm, of which 140 (80.9%) were TPPA positive. Despite the increased false-positive results in populations with a low prevalence of syphilis, the reverse algorithm detected 140 samples with treponemal antibody that went undetected by the traditional algorithm. The reverse algorithm using Mediace TPLA as a screening test is more sensitive for the detection of syphilis.

  14. Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer.

    PubMed

    Feliu, J; Safont, M J; Salud, A; Losa, F; García-Girón, C; Bosch, C; Escudero, P; López, R; Madroñal, C; Bolaños, M; Gil, M; Llombart, A; Castro-Carpeño, J; González-Barón, M

    2010-05-11

    The efficacy and safety of capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer (mCRC) considered unsuitable for receiving first-line chemotherapy with an irinotecan or oxaliplatin-based combination were assessed in a phase II, open, multicentre, uncontrolled study. Treatment consisted of capecitabine 1250 mg m(-2) (or 950 mg m(-2) for patients with a creatinine clearance of 30-50 ml min(-1)) twice daily on days 1-14 and bevacizumab (7.5 mg kg(-1)) on day 1 every 3 weeks. A total of 59 patients aged >or=70 years with mCRC were enrolled. In an intention-to-treat analysis, the overall response rate was 34%, with 71% of patients achieving disease control. Median progression-free survival and overall survival were 10.8 months and 18 months, respectively. In all, 32 patients (54%) had grade 3/4 adverse events (AEs), the most common being hand-foot syndrome (19%), diarrhoea (9%) and deep venous thrombosis (7%). Four patients died because of treatment-related AEs. A relationship was detected between creatinine clearance

  15. First line fertility treatment strategies regarding IUI and IVF require clinical evidence.

    PubMed

    Bahadur, G; Homburg, R; Muneer, A; Racich, P; Alangaden, T; Al-Habib, A; Okolo, S

    2016-06-01

    The advent of intracytoplasmic sperm injection (ICSI) has contributed to a significant growth in the delivery of assisted conception technique, such that IVF/ICSI procedures are now recommended over other interventions. Even the UK National Institute for Health Care Excellence (NICE) guidelines controversially recommends against intrauterine insemination (IUI) procedures in favour of IVF. We reflect on some of the clinical, economic, financial and ethical realities that have been used to selectively promote IVF over IUI, which is less intrusive and more patient friendly, obviates the need for embryo storage and has a global application. The evidence strongly favours IUI over IVF in selected couples and national funding strategies should include IUI treatment options. IUI, practised optimally as a first line treatment in up to six cycles, would also ease the pressures on public funds to allow the provision of up to three IVF cycles for couple who need it. Fertility clinics should also strive towards ISO15189 accreditation standards for basic semen diagnosis for male infertility used to triage ICSI treatment, to reduce the over-diagnosis of severe male factor infertility. Importantly, there is a need to develop global guidelines on inclusion policies for IVF/ICSI procedures. These suggestions are an ethically sound basis for constructing the provision of publicly funded fertility treatments.

  16. A first line of stress defense: small heat shock proteins and their function in protein homeostasis.

    PubMed

    Haslbeck, Martin; Vierling, Elizabeth

    2015-04-10

    Small heat shock proteins (sHsps) are virtually ubiquitous molecular chaperones that can prevent the irreversible aggregation of denaturing proteins. sHsps complex with a variety of non-native proteins in an ATP-independent manner and, in the context of the stress response, form a first line of defense against protein aggregation in order to maintain protein homeostasis. In vertebrates, they act to maintain the clarity of the eye lens, and in humans, sHsp mutations are linked to myopathies and neuropathies. Although found in all domains of life, sHsps are quite diverse and have evolved independently in metazoans, plants and fungi. sHsp monomers range in size from approximately 12 to 42kDa and are defined by a conserved β-sandwich α-crystallin domain, flanked by variable N- and C-terminal sequences. Most sHsps form large oligomeric ensembles with a broad distribution of different, sphere- or barrel-like oligomers, with the size and structure of the oligomers dictated by features of the N- and C-termini. The activity of sHsps is regulated by mechanisms that change the equilibrium distribution in tertiary features and/or quaternary structure of the sHsp ensembles. Cooperation and/or co-assembly between different sHsps in the same cellular compartment add an underexplored level of complexity to sHsp structure and function. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Economic Analysis of First-Line Treatment with Erlotinib in an EGFR-Mutated Population with Advanced NSCLC.

    PubMed

    Vergnenegre, Alain; Massuti, Bartomeu; de Marinis, Filippo; Carcereny, Enric; Felip, Enriqueta; Do, Pascal; Sanchez, Jose Miguel; Paz-Arez, Luis; Chouaid, Christos; Rosell, Rafael

    2016-06-01

    The cost-effectiveness of first-line tyrosine kinase inhibitor therapy in epidermal growth factor receptor gene (EGFR)-mutated advanced-stage non-small cell lung cancer (NSCLC) is poorly documented. We therefore conducted a cost-effectiveness analysis of first-line treatment with erlotinib versus standard chemotherapy in European patients with advanced-stage EGFR-mutated NSCLC who were enrolled in the European Erlotinib versus Chemotherapy trial. The European Erlotinib versus Chemotherapy study was a multicenter, open-label, randomized phase III trial performed mainly in Spain, France, and Italy. We based our economic analysis on clinical data and data on resource consumption (drugs, drug administration, adverse events, and second-line treatments) collected during this trial. Utility values were derived from the literature. Incremental cost-effectiveness ratios were calculated for the first-line treatment phase and for the overall strategy from the perspective of the three participating countries. Sensitivity analyses were performed by selecting the main cost drivers. Compared with standard first-line chemotherapy, the first-line treatment with erlotinib was cost saving (€7807, €17,311, and €19,364 for Spain, Italy and France, respectively) and yielded a gain of 0.117 quality-adjusted life-years. A probabilistic sensitivity analysis indicated that, given a willingness to pay at least €90,000 for 1 quality-adjusted life-year, the probability that a strategy of first-line erlotinib would be cost-effective was 100% in France, 100% in Italy, and 99.8% in Spain. This economic analysis shows that first-line treatment with erlotinib, versus standard chemotherapy, is a dominant strategy for EGFR-mutated advanced-stage NSCLC in three European countries. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  18. Cost-effectiveness of endoscopic sphenopalatine artery ligation versus nasal packing as first-line treatment for posterior epistaxis.

    PubMed

    Dedhia, Raj C; Desai, Shamit S; Smith, Kenneth J; Lee, Stella; Schaitkin, Barry M; Snyderman, Carl H; Wang, Eric W

    2013-07-01

    The advent of endoscopic sphenopalatine artery ligation (ESPAL) for the control of posterior epistaxis provides an effective, low-morbidity treatment option. In the current practice algorithm, ESPAL is pursued after failure of posterior packing. Given the morbidity and limited effectiveness of posterior packing, we sought to determine the cost-effectiveness of first-line ESPAL compared to the current practice model. A standard decision analysis model was constructed comparing first-line ESPAL and current practice algorithms. A literature search was performed to determine event probabilities and published Medicare data largely provided cost parameters. The primary outcomes were cost of treatment and resolution of epistaxis. One-way sensitivity analysis was performed for key parameters. Costs for the first-line ESPAL arm and the current practice arm were $6450 and $8246, respectively. One-way sensitivity analyses were performed for key variables including duration of packing. The baseline difference of $1796 in favor of the first-line ESPAL arm was increased to $6263 when the duration of nasal packing was increased from 3 to 5 days. Current practice was favored (cost savings of $437 per patient) if posterior packing duration was decreased from 3 to 2 days. This study demonstrates that ESPAL is cost-saving as first-line therapy for posterior epistaxis. Given the improved effectiveness and patient comfort of ESPAL compared to posterior packing, ESPAL should be offered as an initial treatment option for medically stable patients with posterior epistaxis. © 2013 ARS-AAOA, LLC.

  19. Establishment of a first-line second-line treatment model for human pulmonary adenocarcinoma

    PubMed Central

    Wang, Lining; Wang, Yu; Guan, Qi; Liu, Yong; He, Tianyi; Wang, Jiaru

    2016-01-01

    Lung cancer is one of the most prevalent types of cancer in the world. Surgery, chemotherapy and radiotherapy are used clinically as treatments for numerous cancers. Due to the appearance of drug resistance, the remission rate is limited to 40–50%. Docetaxel and pemetrexed are two drugs commonly used, and their effects in single-phase cell culture are well known. From the pharmacological point of view, it appears rational to hypothesize that sequential therapy effects can show better outcomes compared with traditional single-phase experiments. Considering this, the present study aimed to establish a first-line second-line adenocarcinoma treatment model, using the combination of cisplatin with docetaxel or pemetrexed in vitro in different sequential therapy timings. To test this, the human lung cancer A549 cell line was used. The inhibitory effect was determined by adding docetaxel following treatment with cisplatin and pemetrexed (Pem-Doc group) and comparing this with a group in which pemetrexed was added subsequent to treatment with cisplatin and docetaxel (Doc-Pem group). Additionally, the differences in the gene and protein expression levels of excision repair cross-completion gene 1 (ERCC1), a gene that promotes drug resistance to cisplatin, were compared between the two groups. The present results showed that the inhibitory effect of cell proliferation in the Pem-Doc group was increased compared with that of Doc-Pem group, while the gene expression and protein levels of ERCC1 in the Pem-Doc group were decreased compared with those of Doc-Pem group. The Pem-Doc treatment plan is more effective in inhibiting cell proliferation and in lowering the expression of the ERCC1 gene. Therefore, Pem-Doc may be a more effective adenocarcinoma treatment. PMID:28105156

  20. Melanocytes and melanin represent a first line of innate immunity against Candida albicans.

    PubMed

    Tapia, Cecilia V; Falconer, Maryanne; Tempio, Fabián; Falcón, Felipe; López, Mercedes; Fuentes, Marisol; Alburquenque, Claudio; Amaro, José; Bucarey, Sergio A; Di Nardo, Anna

    2014-07-01

    Melanocytes are dendritic cells located in the skin and mucosae that synthesize melanin. Some infections induce hypo- or hyperpigmentation, which is associated with the activation of Toll-like receptors (TLRs), especially TLR4. Candida albicans is an opportunist pathogen that can switch between blastoconidia and hyphae forms; the latter is associated with invasion. Our objectives in this study were to ascertain whether C. albicans induces pigmentation in melanocytes and whether this process is dependent on TLR activation, as well as relating this with the antifungal activity of melanin as a first line of innate immunity against fungal infections. Normal human melanocytes were stimulated with C. albicans supernatants or with crude extracts of the blastoconidia or hyphae forms, and pigmentation and TLR2/TLR4 expression were measured. Expression of the melanosomal antigens Melan-A and gp100 was examined for any correlation with increased melanin levels or antifungal activity in melanocyte lysates. Melanosomal antigens were induced earlier than cell pigmentation, and hyphae induced stronger melanization than blastoconidia. Notably, when melanocytes were stimulated with crude extracts of C. albicans, the cell surface expression of TLR2/TLR4 began at 48 h post-stimulation and peaked at 72 h. At this time, blastoconidia induced both TLR2 and TLR4 expression, whereas hyphae only induced TLR4 expression. Taken together, these results suggest that melanocytes play a key role in innate immune responses against C. albicans infections by recognizing pathogenic forms of C. albicans via TLR4, resulting in increased melanin content and inhibition of infection.

  1. Best practice guidelines on first-line laboratory testing for porphyria.

    PubMed

    Woolf, Jacqueline; Marsden, Joanne T; Degg, Timothy; Whatley, Sharon; Reed, Paul; Brazil, Nadia; Stewart, M Felicity; Badminton, Michael

    2017-03-01

    The porphyrias are disorders of haem biosynthesis which present with acute neurovisceral attacks or disorders of sun-exposed skin. Acute attacks occur mainly in adults and comprise severe abdominal pain, nausea, vomiting, autonomic disturbance, central nervous system involvement and peripheral motor neuropathy. Cutaneous porphyrias can be acute or chronic presenting at various ages. Timely diagnosis depends on clinical suspicion leading to referral of appropriate samples for screening by reliable biochemical methods. All samples should be protected from light. Investigation for an acute attack: • Porphobilinogen (PBG) quantitation in a random urine sample collected during symptoms. Urine concentration must be assessed by measuring creatinine, and a repeat requested if urine creatinine <2 mmol/L. • Urgent porphobilinogen testing should be available within 24 h of sample receipt at the local laboratory. Urine porphyrin excretion (TUP) should subsequently be measured on this urine. • Urine porphobilinogen should be measured using a validated quantitative ion-exchange resin-based method or LC-MS. • Increased urine porphobilinogen excretion requires confirmatory testing and clinical advice from the National Acute Porphyria Service. • Identification of individual acute porphyrias requires analysis of urine, plasma and faecal porphyrins. Investigation for cutaneous porphyria: • An EDTA blood sample for plasma porphyrin fluorescence emission spectroscopy and random urine sample for TUP. • Whole blood for porphyrin analysis is essential to identify protoporphyria. • Faeces need only be collected, if first-line tests are positive or if clinical symptoms persist. Investigation for latent porphyria or family history: • Contact a specialist porphyria laboratory for advice. Clinical, family details are usually required.

  2. First line of defence: the role of sloughing in the regulation of cutaneous microbes in frogs

    PubMed Central

    Cramp, Rebecca L.; McPhee, Rebecca K.; Meyer, Edward A.; Ohmer, Michel E.; Franklin, Craig E.

    2014-01-01

    Amphibian populations worldwide are currently experiencing unprecedented declines due to the combined effects of emerging infectious disease and climate change. The skin is the first line of defence in preventing establishment of pathogens and associated infections. Although amphibians undergo regular sloughing of the outer layer of the skin, the potential for regular sloughing to play a role in influencing cutaneous microbial populations and pathogens has been largely overlooked. In the present study, we assessed the effect of skin sloughing on cultivable cutaneous bacterial abundance in the green tree frog (Litoria caerulea). We also examined the effects of temperature and hydric environment on sloughing frequency and microbial re-establishment rates. Our data showed that cultivable cutaneous bacterial abundance was significantly reduced by sloughing events, and frogs kept at ‘summer’ temperatures (23–33°C) sloughed almost twice as frequently as those maintained at ‘winter’ temperatures (13–23°C). No effect of hydric environment on sloughing frequency was observed, but we did find that sloughing in L. caerulea appeared to be linked to ambient light cycles. Examination of the effect of sloughing on microbial recolonization indicated that at cool temperatures, an extended intermoult interval allowed microbial abundance to reach higher levels than at warmer ‘summer’ temperatures (when the intermoult interval was significantly reduced). Our data suggest that sloughing may significantly influence the establishment and/or maintenance of cutaneous bacterial populations (pathogenic, mutualistic and/or commensal) and this, in turn, may be affected by environmental factors, such as ambient light and temperature. These findings are likely to be important for our understanding of the ecology of skin-based pathogens, such as the amphibian chytrid fungus, Batrachochytrium dendrobatidis. PMID:27293633

  3. Cost-Effectiveness Analysis of Isavuconazole vs. Voriconazole as First-Line Treatment for Invasive Aspergillosis.

    PubMed

    Harrington, Rachel; Lee, Edward; Yang, Hongbo; Wei, Jin; Messali, Andrew; Azie, Nkechi; Wu, Eric Q; Spalding, James

    2017-01-01

    Invasive aspergillosis (IA) is associated with a significant clinical and economic burden. The phase III SECURE trial demonstrated non-inferiority in clinical efficacy between isavuconazole and voriconazole. No studies have evaluated the cost-effectiveness of isavuconazole compared to voriconazole. The objective of this study was to evaluate the costs and cost-effectiveness of isavuconazole vs. voriconazole for the first-line treatment of IA from the US hospital perspective. An economic model was developed to assess the costs and cost-effectiveness of isavuconazole vs. voriconazole in hospitalized patients with IA. The time horizon was the duration of hospitalization. Length of stay for the initial admission, incidence of readmission, clinical response, overall survival rates, and experience of adverse events (AEs) came from the SECURE trial. Unit costs were from the literature. Total costs per patient were estimated, composed of drug costs, costs of AEs, and costs of hospitalizations. Incremental costs per death avoided and per additional clinical responders were reported. Deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted. Base case analysis showed that isavuconazole was associated with a $7418 lower total cost per patient than voriconazole. In both incremental costs per death avoided and incremental costs per additional clinical responder, isavuconazole dominated voriconazole. Results were robust in sensitivity analysis. Isavuconazole was cost saving and dominant vs. voriconazole in most DSA. In PSA, isavuconazole was cost saving in 80.2% of the simulations and cost-effective in 82.0% of the simulations at the $50,000 willingness to pay threshold per additional outcome. Isavuconazole is a cost-effective option for the treatment of IA among hospitalized patients. Astellas Pharma Global Development, Inc.

  4. GENETIC MUTATIONS AFFECTING THE FIRST LINE ERADICATION THERAPY OF Helicobacter pylori-INFECTED EGYPTIAN PATIENTS

    PubMed Central

    RAMZY, Iman; ELGAREM, Hassan; HAMZA, Iman; GHAITH, Doaa; ELBAZ, Tamer; ELHOSARY, Waleed; MOSTAFA, Gehan; ELZAHRY, Mohammad A. Mohey Eldin

    2016-01-01

    SUMMARY Introduction: Several genetic mutations affect the first-line triple therapy for Helicobacter pylori. We aimed to study the most common genetic mutations affecting the metronidazole and clarithromycin therapy for H. pylori-infected Egyptian patients. Patients and Methods: In our study, we included 100 successive dyspeptic patients scheduled for diagnosis through upper gastroscopy at Cairo's University Hospital, Egypt. Gastric biopsies were tested for the presence of H. pylori by detection of the 16S rRNA gene. Positive biopsies were further studied for the presence of the rdxA gene deletion by Polymerase Chain Reaction (PCR), while clarithromycin resistance was investigated by the presence of nucleotide substitutions within H. pylori 23S rRNA V domain using MboII and BsaI to carry out a Restricted Fragment Length Polymorphism (RFLP) assay. Results: Among 70 H. pylori positive biopsies, the rdxA gene deletion was detected in 44/70 (62.9%) samples, while predominance of the A2142G mutations within the H. pylori 23S rRNA V domain was evidenced in 39/70 (55.7%) of the positive H. pylori cases. No statistically significant difference was found between the presence of gene mutations and different factors such as patients 'age, gender, geographic distribution, symptoms and endoscopic findings. Conclusion: Infection with mutated H. pylori strains is considerably high, a finding that imposes care in the use of the triple therapy to treat H. pylori in Egypt, since the guidelines recommend to abandon the standard triple therapy when the primary clarithromycin resistance rate is over 20%1. PMID:27982354

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

    PubMed

    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.

  6. Fosfomycin: A First-Line Oral Therapy for Acute Uncomplicated Cystitis

    PubMed Central

    Zhanel, George G.; Walkty, Andrew J.; Karlowsky, James A.

    2016-01-01

    Fosfomycin is a new agent to Canada approved for the treatment of acute uncomplicated cystitis (AUC) in adult women infected with susceptible isolates of E. coli and Enterococcus faecalis. We reviewed the literature regarding the use of oral fosfomycin for the treatment of AUC. All English-language references from 1975 to October 2015 were reviewed. In Canada, fosfomycin tromethamine is manufactured as Monurol® and is available as a 3-gram single dose sachet. Fosfomycin has a unique chemical structure, inhibiting peptidoglycan synthesis at an earlier site compared to β-lactams with no cross-resistance with other agents. Fosfomycin displays broad-spectrum activity against ESBL-producing, AmpC-producing, carbapenem-non-susceptible, and multidrug-resistant (MDR) E. coli. Resistance to fosfomycin in E. coli is rare (<1%). Fosfomycin is excreted unchanged in the urine by glomerular filtration with peak urinary concentration ~4000 µg/mL and remains at concentrations >100 µg/mL for 48 hours after a single 3-gram oral dose. No dosage adjustments are required in elderly patients, in pregnant patients, or in either renal or hepatic impairment. Fosfomycin demonstrates a favorable safety profile, and clinical trials have demonstrated efficacy in AUC that is comparable to ciprofloxacin, nitrofurantoin, and trimethoprim-sulfamethoxazole. Fosfomycin's in vitro activity against common uropathogens, including MDR isolates, its favorable safety profile including pregnancy patients, drug interactions, and clinical trials data demonstrating efficacy in AUC, has resulted in Canadian, US, and European guidelines/authorities recommending fosfomycin as a first line agent for the treatment of AUC. PMID:27366158

  7. First line anti-tuberculosis induced hepatotoxicity: incidence and risk factors

    PubMed Central

    Bouazzi, Omaima El; Hammi, Sanaa; Bourkadi, Jamal Eddine; Tebaa, Amina; Tanani, Driss Soussi; Soulaymani-Bencheikh, Rachida; Badrane, Narjis; Bengueddour, Rachid

    2016-01-01

    In our days, tuberculosis, whet ever its localization, became a curable disease. The cornerstone is a 6 month course of isoniazid, rifampicine and pyrazinamide. All of the three first line antituberculosis drugs may induce hepatic damage which may have negative consequences for treatment outcome. Several risk factors were associated with the development of antituberculosis- drug-induced hepatotoxicity (ATDH). A retrospective study was conducted from July 2014 to March 2015 regarding all therapeutic drug-monitoring requests sent to the Laboratory of Poison Control and Pharmacovigilance Centre of Morocco. 142 patients diagnosed with active tuberculosis were included in study. Plasma peak levels of isoniazid, rifampicin and pyrazinamide were analyzed in plasma samples after 2 to 3 hours of administration of anti-tuberculosis treatment. Logistic regression was used to identify the ATDH risk factors. The incidence of ATDH was found 24.6% (35 patients out of 142). Intergroup differences in the plasma levels were statistically significant for isoniazid (p=0.036). ATDH was found to be associated with combined form of anti-TB drugs (p=0.002, COR=13.1, AOR= 13.5) and plasma concentration of INH superior to 2mg/l (p=0.045, COR=1.3, AOR= 1.4).age, gender, alcohol intake and smoking status were not significantly associated with ATDH. The finding of 24.6% incidence of hepatotoxicity is extremely high. Many factors can be associated with the development of ATDH such as genetic factors, combined forms of treatment and plasma peak levels. PMID:28292129

  8. Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer

    PubMed Central

    Feliu, J; Safont, M J; Salud, A; Losa, F; García-Girón, C; Bosch, C; Escudero, P; López, R; Madroñal, C; Bolaños, M; Gil, M; Llombart, A; Castro-Carpeño, J; González-Barón, M

    2010-01-01

    Background: The efficacy and safety of capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer (mCRC) considered unsuitable for receiving first-line chemotherapy with an irinotecan or oxaliplatin-based combination were assessed in a phase II, open, multicentre, uncontrolled study. Methods: Treatment consisted of capecitabine 1250 mg m−2 (or 950 mg m−2 for patients with a creatinine clearance of 30–50 ml min−1) twice daily on days 1–14 and bevacizumab (7.5 mg kg−1) on day 1 every 3 weeks. Results: A total of 59 patients aged ⩾70 years with mCRC were enrolled. In an intention-to-treat analysis, the overall response rate was 34%, with 71% of patients achieving disease control. Median progression-free survival and overall survival were 10.8 months and 18 months, respectively. In all, 32 patients (54%) had grade 3/4 adverse events (AEs), the most common being hand–foot syndrome (19%), diarrhoea (9%) and deep venous thrombosis (7%). Four patients died because of treatment-related AEs. A relationship was detected between creatinine clearance ⩽50 ml min−1 and the development of non-bevacizumab-related grade 3/4 AEs. The incidence of bevacizumab-associated AEs (hypertension, thromboembolic events and proteinuria) was consistent with that of previous reports in elderly patients. Conclusion: Bevacizumab combined with capecitabine represents a valid therapeutic alternative in elderly patients considered to be unsuitable for receiving polychemotherapy. PMID:20424611

  9. Proteinuria with first-line therapy of metastatic renal cell cancer.

    PubMed

    Land, Josiah D; Chen, Adrienne H; Atkinson, Bradley J; Cauley, Diana H; Tannir, Nizar M

    2016-04-01

    Vascular endothelial growth factor receptor inhibitors, mammalian target of rapamycin inhibitors, and tyrosine kinase inhibitors are approved for metastatic renal cell cancer. Proteinuria can occur, but there is limited data regarding the incidence, monitoring, and management in metastatic renal cell cancer patients. Our primary objective was to describe the incidence and severity of proteinuria in metastatic renal cell cancer patients treated in the first-line setting with pazopanib, bevacizumab, or everolimus. We conducted a retrospective review of patients with metastatic renal cell cancer enrolled from January 2011-April 2013 in a phase II trial. Baseline and toxicity data were extracted from the electronic medical record. Descriptive statistics were used. In all, 129 patients were eligible for analysis. The overall incidence of proteinuria was 81%, with most events being Grade 1 or 2. The incidence of proteinuria was 80% (n = 35) for pazopanib, 64% (n = 25) for bevacizumab, and 96% (n = 44) for everolimus. At peak proteinuria, 80% (n = 28), 64% (n = 16), and 80% (n = 35) of patients on pazopanib, bevacizumab, and everolimus, respectively, were managed with continued monitoring at the same dose. The overall incidence of Grades 3 and 4 events was 24% (n = 6) and found in the bevacizumab group. A high incidence of proteinuria with minor severity within each class was demonstrated. It may be reasonable to continue therapy at the same dose for Grade 1 or 2 proteinuria. Treatment modification or discontinuation of therapy may be warranted with Grade 3 or 4 proteinuria. © The Author(s) 2014.

  10. Cost Effectiveness of Ofatumumab Plus Chlorambucil in First-Line Chronic Lymphocytic Leukaemia in Canada.

    PubMed

    Herring, William; Pearson, Isobel; Purser, Molly; Nakhaipour, Hamid Reza; Haiderali, Amin; Wolowacz, Sorrel; Jayasundara, Kavisha

    2016-01-01

    Our objective was to estimate the cost effectiveness of ofatumumab plus chlorambucil (OChl) versus chlorambucil in patients with chronic lymphocytic leukaemia for whom fludarabine-based therapies are considered inappropriate from the perspective of the publicly funded healthcare system in Canada. A semi-Markov model (3-month cycle length) used survival curves to govern progression-free survival (PFS) and overall survival (OS). Efficacy and safety data and health-state utility values were estimated from the COMPLEMENT-1 trial. Post-progression treatment patterns were based on clinical guidelines, Canadian treatment practices and published literature. Total and incremental expected lifetime costs (in Canadian dollars [$Can], year 2013 values), life-years and quality-adjusted life-years (QALYs) were computed. Uncertainty was assessed via deterministic and probabilistic sensitivity analyses. The discounted lifetime health and economic outcomes estimated by the model showed that, compared with chlorambucil, first-line treatment with OChl led to an increase in QALYs (0.41) and total costs ($Can27,866) and to an incremental cost-effectiveness ratio (ICER) of $Can68,647 per QALY gained. In deterministic sensitivity analyses, the ICER was most sensitive to the modelling time horizon and to the extrapolation of OS treatment effects beyond the trial duration. In probabilistic sensitivity analysis, the probability of cost effectiveness at a willingness-to-pay threshold of $Can100,000 per QALY gained was 59 %. Base-case results indicated that improved overall response and PFS for OChl compared with chlorambucil translated to improved quality-adjusted life expectancy. Sensitivity analysis suggested that OChl is likely to be cost effective subject to uncertainty associated with the presence of any long-term OS benefit and the model time horizon.

  11. Transmitted HIV Resistance to First-Line Antiretroviral Therapy in Lima, Peru

    PubMed Central

    Soria, Jaime; Bull, Marta; Mitchell, Caroline; La Rosa, Alberto; Dross, Sandra; Kraft, Kelli; Coombs, Robert; Ticona, Eduardo

    2012-01-01

    Abstract Transmission of drug-resistant HIV (TDR) has been associated with virologic failure of “first-line,” nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART). A national ART program began in Peru in 2004. We evaluated the prevalence of TDR in individuals initiating ART and their virologic outcome during 2 years of ART. HIV-infected, ARV-naive subjects who met criteria to start ART in Lima, Peru were enrolled in a longitudinal observational study between July 2007 and February 2009. Blood plasma and cells obtained prior to ART initiation were assessed for antiretroviral (ARV) resistance by an oligonucleotide ligation assay (OLA) sensitive to 2% mutant at reverse transcriptase (RT) codons K103N, Y181C, G190A, and M184V and a subset by consensus sequencing. A total of 112 participants were enrolled; the mean CD4 was 134±89 cells/μl and the median plasma HIV RNA was 93,556 copies/ml (IQR 62,776–291,364). Drug resistance mutations conferring high-level resistance to ARV were rare, detected in one of 96 (1%) evaluable participants. This subject had the Y181C mutation detected in both plasma and peripheral blood mononuclear cells (PBMCs) at a concentration of 100% by OLA and consensus sequencing; nevertheless nevirapine-ART suppressed her viral replication. Consensus sequencing of 37 (19%) participants revealed multiple polymorphisms that occasionally have been associated with low-level reductions in ARV susceptibility. A low prevalence of TDR was detected among Peruvians initiating ART. Given the increasing availability of ART, continuing surveillance is needed to determine if TDR increases and the mutant codons associated with virologic failure. PMID:21819256

  12. Transmitted HIV resistance to first-line antiretroviral therapy in Lima, Peru.

    PubMed

    Soria, Jaime; Bull, Marta; Mitchell, Caroline; La Rosa, Alberto; Dross, Sandra; Kraft, Kelli; Coombs, Robert; Ticona, Eduardo; Frenkel, Lisa

    2012-04-01

    Transmission of drug-resistant HIV (TDR) has been associated with virologic failure of "first-line," nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART). A national ART program began in Peru in 2004. We evaluated the prevalence of TDR in individuals initiating ART and their virologic outcome during 2 years of ART. HIV-infected, ARV-naive subjects who met criteria to start ART in Lima, Peru were enrolled in a longitudinal observational study between July 2007 and February 2009. Blood plasma and cells obtained prior to ART initiation were assessed for antiretroviral (ARV) resistance by an oligonucleotide ligation assay (OLA) sensitive to 2% mutant at reverse transcriptase (RT) codons K103N, Y181C, G190A, and M184V and a subset by consensus sequencing. A total of 112 participants were enrolled; the mean CD4 was 134 ± 89 cells/μl and the median plasma HIV RNA was 93,556 copies/ml (IQR 62,776-291,364). Drug resistance mutations conferring high-level resistance to ARV were rare, detected in one of 96 (1%) evaluable participants. This subject had the Y181C mutation detected in both plasma and peripheral blood mononuclear cells (PBMCs) at a concentration of 100% by OLA and consensus sequencing; nevertheless nevirapine-ART suppressed her viral replication. Consensus sequencing of 37 (19%) participants revealed multiple polymorphisms that occasionally have been associated with low-level reductions in ARV susceptibility. A low prevalence of TDR was detected among Peruvians initiating ART. Given the increasing availability of ART, continuing surveillance is needed to determine if TDR increases and the mutant codons associated with virologic failure.

  13. First line of defence: the role of sloughing in the regulation of cutaneous microbes in frogs.

    PubMed

    Cramp, Rebecca L; McPhee, Rebecca K; Meyer, Edward A; Ohmer, Michel E; Franklin, Craig E

    2014-01-01

    Amphibian populations worldwide are currently experiencing unprecedented declines due to the combined effects of emerging infectious disease and climate change. The skin is the first line of defence in preventing establishment of pathogens and associated infections. Although amphibians undergo regular sloughing of the outer layer of the skin, the potential for regular sloughing to play a role in influencing cutaneous microbial populations and pathogens has been largely overlooked. In the present study, we assessed the effect of skin sloughing on cultivable cutaneous bacterial abundance in the green tree frog (Litoria caerulea). We also examined the effects of temperature and hydric environment on sloughing frequency and microbial re-establishment rates. Our data showed that cultivable cutaneous bacterial abundance was significantly reduced by sloughing events, and frogs kept at 'summer' temperatures (23-33°C) sloughed almost twice as frequently as those maintained at 'winter' temperatures (13-23°C). No effect of hydric environment on sloughing frequency was observed, but we did find that sloughing in L. caerulea appeared to be linked to ambient light cycles. Examination of the effect of sloughing on microbial recolonization indicated that at cool temperatures, an extended intermoult interval allowed microbial abundance to reach higher levels than at warmer 'summer' temperatures (when the intermoult interval was significantly reduced). Our data suggest that sloughing may significantly influence the establishment and/or maintenance of cutaneous bacterial populations (pathogenic, mutualistic and/or commensal) and this, in turn, may be affected by environmental factors, such as ambient light and temperature. These findings are likely to be important for our understanding of the ecology of skin-based pathogens, such as the amphibian chytrid fungus, Batrachochytrium dendrobatidis.

  14. [Susceptibility of 36 Helicobacter pylori clinical isolates to four first-line antibiotics and virulence factors].

    PubMed

    Díaz-Reganon, J; Alarcón, T; Domingo, D; López-Brea, M

    2006-03-01

    Helicobacter pylori possess various virulence factors, including cagA and vacA genes, that are associated with more aggressive symptoms such as bleed-ing ulcer and gastric cancer. Although there are different treatment regimens, there is still a failure rate of up to 20% due to antibiotic resistance, among other causes. In our country resistance to metronidazole and clarithromycin is increasing, especially in children, although they are still susceptible to amoxicillin and tetracycline. In order to determine the susceptibility pattern to these antibiotics 36 H. pylori clinical isolates were studied. MIC was determined by agar diffusion and agar dilution, and vacA and cagA genes were detected by conventional PCR. All isolates were susceptible to amoxicillin and tetracycline. Resistance to metronidazole by diffusion or dilution tests was 35.7% and 36.1%, respectively, and to clarithromycin, 21.4% and 22.3%, respectively. There was one strain that showed intermediate resistance to clarithromycin (MIC 0.38 mg/l), using agar diffusion, and that was included among the resistant strains. Three discrepancies were observed between the diffusion and dilution methods. The vacA s1 allele was detected in 17.2% of the strains, and vacA s2 in 82.8%; 51.7% of the total were cagA+. In conclusion, all strains tested in our study were susceptible to amoxicillin and tetracycline, allowing them to be considered as first-line antibiotics, while clarithromycin and metronidazole maintain a slight increase in their resistance level. The cagA+ strains were detected in expected quantities, while the s1 allele of the vacA gene was detected in lower quantities.

  15. Pitted keratolysis: successful management with mupirocin 2% ointment monotherapy.

    PubMed

    Greywal, Tanya; Cohen, Philip R

    2015-08-15

    Pitted keratolysis is a benign dermatosis that occurs on plantar skin. We describe a man with pitted keratolysis that was successfully treated with mupirocin 2% ointment monotherapy. We reviewed PubMed for the following terms: mupirocin, ointment, pitted keratolysis, treatment. We also reviewed papers containing these terms and their references. Complete resolution of pitted keratolysis occurred following monotherapy with twice daily application of mupirocin 2% ointment for a duration of three weeks. There was no recurrence at a follow-up visit eight weeks later. Several topical and oral treatments are available to successfully manage pitted keratolysis. Our patient confirms previous reports of pitted keratolysis resolving with mupirocin 2% ointment treatment. Monotherapy with mupirocin 2% ointment should be considered as a primary treatment alternative for pitted keratolysis.

  16. Economic Outcomes of First-Line Regimen Switching Among Stable Patients with HIV.

    PubMed

    Rosenblatt, Lisa; Buikema, Ami R; Seare, Jerry; Bengtson, Lindsay G S; Johnson, Jonathan; Cao, Feng; Villasis-Keever, Angelina

    2017-07-01

    Although switching of antiretroviral therapy (ART) is a valid approach for addressing treatment failure in patients with human immunodeficiency virus (HIV), ART changes among those who are well maintained on their current regimens may lead to the development of new side effects or resistance. To examine the effect of first-line regimen switching on subsequent health care utilization and cost among stable HIV patients. This was a retrospective claims data study of adult patients with HIV who initiated ART between 2007 and 2013 and had been treated with their initial regimens for at least 6 continuous months. Those with evidence of pregnancy or HIV-2 were excluded. Patients who underwent an ART change were assigned to a switcher cohort; a nonswitcher cohort was then generated by matching up to 20 nonswitchers for each switcher, with replacement. The index date was the date of the first ART change for switchers and was the claim date closest to the corresponding switcher's switch date for nonswitchers. Patient characteristics at baseline and post-index annualized health care utilization and costs were analyzed descriptively and with multivariable models. Analyses were performed in the full population and among patients designated as virologically stable (had undetectable viral ribonucleic acid [RNA] for 90 days pre-index) and virologically and clinically stable (had undetectable viral RNA and no apparent clinical reason for switching ART). The study population consisted of 6,983 individuals, which included 927 switchers (168 virologically stable; 55 virologically+clinically stable), who were matched with replacement with 18,511 nonswitcher comparators. The switcher cohort was 88.8% male (mean age 43.8 years). Mean preindex and follow-up treatment durations for switchers and nonswitchers were 1.8 years and 1.5 years, respectively; demographic characteristics, pre-index treatment duration, and follow-up duration were similar between cohorts. Significantly more

  17. First-line chemotherapy in low-risk gestational trophoblastic neoplasia

    PubMed Central

    Alazzam, Mo’iad; Tidy, John; Hancock, Barry W; Osborne, Raymond; Lawrie, Theresa A

    2014-01-01

    Background This is an update of a Cochrane review that was first published in Issue 1, 2009. Gestational trophoblastic neoplasia (GTN) is a rare but curable disease arising in the fetal chorion during pregnancy. Most women with low-risk GTN will be cured by evacuation of the uterus with or without single-agent chemotherapy. However, chemotherapy regimens vary between treatment centres worldwide and the comparable benefits and risks of these different regimens are unclear. Objectives To determine the efficacy and safety of first-line chemotherapy in the treatment of low-risk GTN. Search methods In September 2008, we electronically searched the Cochrane Gynaecological Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL Issue 3, 2008), MEDLINE and EMBASE. In addition, we searched online trial registers, conference proceedings and reference lists of identified studies. We re-ran these searches in February 2012 for this updated review. Selection criteria For the original review, we included randomised controlled trials (RCTs), quasi-RCTs and non-RCTs that compared first-line chemotherapy for the treatment of low-risk GTN. For this updated version of the review, we included only RCTs. Data collection and analysis Two review authors independently assessed studies for inclusion and extracted data to a pre-designed data extraction form. Meta-analysis was performed by pooling the risk ratio (RR) of individual trials. Main results We included five moderate to high quality RCTs (517 women) in the updated review. These studies all compared methotrexate with dactinomycin. Three studies compared weekly intramuscular (IM) methotrexate with bi-weekly pulsed intravenous (IV) dactinomycin (393 women), one study compared five-day IM methotrexate with bi-weekly pulsed IV dactinomycin (75 women) and one study compared eight-day IM methotrexate-folinic acid (MTX-FA) with five-day IV dactinomycin (49 women). Overall, dactinomycin was associated

  18. Polymorphisms and pharmacogenomics for the toxicity of methotrexate monotherapy in patients with rheumatoid arthritis

    PubMed Central

    Qiu, Qi; Huang, Jing; Lin, Yang; Shu, Xiaoming; Fan, Huizheng; Tu, Zhihua; Zhou, Youwen; Xiao, Cheng

    2017-01-01

    Abstract Background: Methotrexate (MTX) is widely used and considered a first-line disease modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). However, 10% to 30% of patients discontinue therapy within a year of starting the treatment, usually because of undesirable side effects. Many of the relevant genes have been investigated to estimate the association between gene polymorphisms and MTX toxicity in RA patients, although inconsistent results have been reported. Methods: We searched EMBASE and PubMed in February 2016 for polymorphisms and pharmacogenomics study of the toxicity of MTX monotherapy in RA patients. The meta-analysis was stratified by whether genetic variants associated with MTX toxicity. Results: A total of 42 publications that included 28 genes with 88 gene SNPs associated with the transporters, enzymes, and metabolites of MTX or the progression of RA were included in the SR, and 31 studies were included in 7 meta-analyses. The meta-analysis showed a significant association between the toxicity of MTX and the RFC-1 80G > A (rs1051266) polymorphism in the European RA patients. Conclusion: RFC-1 80G > A (rs1051266) polymorphism was associated with MTX toxicity, and larger and more stringent study designs may provide more accurate results for the effect of these SNPs on the MTX toxicity. PMID:28296761

  19. Combined versus monotherapy or concurrent therapy for treatment of thalassaemia.

    PubMed

    Song, Ta-Shu; Hsieh, Yow-Wen; Peng, Ching-Tien; Chen, Tai-Lin; Lee, Hong-Zin; Chung, Jing-Gung; Hour, Mann-Jen

    2014-01-01

    A combined deferasirox (DFX) and deferiprone (DFP) treatment protocol for relieving thalassemia patients' iron-overload was designed and the pharmacokinetic study was performed by LC-MS/MS. For this open-label, randomized trial, eight patients were recruited and randomly allocated to different treatment regimens: (A) monotherapy with single oral dose of DFX 30 mg/kg, (B) monotherapy with DFP 80 mg/kg/day, twice daily, (C) combined therapy with DFX and DFP (DFX 30 mg/kg for first dose, DFP 40 mg/kg 7 hours later, and DFP 40 mg/kg after another 7 h) and (D) concurrent therapy with DFX 30 mg/kg and DFP 80 mg/kg. Descriptive statistics evaluated pharmacokinetic parameters, AUC0-t, AUC0-inf, Cmax, Tmax, T1/2 and MRT. A positive pharmacokinetic drug interaction was observed in combined therapy. In case of DFX, combined therapy tallied about 2-fold larger than monotherapy in AUC, 1.5-fold larger in Cmax, 1 h longer in Tmax, but 1 h shorter in T1/2. Regarding DFP, most such parameters of combined therapy concurred with monotherapy. Conversely, negative drug interaction was observed in concurrent therapy. With DFX, concurrent therapy attained 1.2- to 2.2-fold lower than monotherapy in AUC0-t and Cmax, 0.6-h shorter in Tmax, and 3-fold longer in T1/2. With DFP, concurrent therapy proved approximately 2-fold larger than monotherapy in AUC and Cmax, 2.5-fold longer in T1/2, and 1.4-fold longer in MRT. Follow-up of subjects' clinical examinations and subjective symptoms showed no adverse events. Our findings showed the combined therapy had advantages, safe, convenient and painless for patients, over the existing concurrent therapy with deferoxamine (DFO) and DFX. Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  20. Local Methotrexate Injection as the First-line Treatment for Cesarean Scar Pregnancy: Review of the Literature.

    PubMed

    Cheung, Vincent Y T

    2015-01-01

    The objective of this study was to determine the outcome of using ultrasound-guided local methotrexate injection as the first-line treatment of cesarean scar pregnancy (CSP). A literature review was performed on all eligible reports using this modality as the first-line treatment of CSP. Relevant publications were obtained from the PubMed electronic database from inception to December 2014. Ninety-six cases from 95 women reported in 17 articles were reviewed. The success rate was 73.9% after a single local methotrexate injection. An accumulated success rate of 88.5% could be achieved after additional local or intramuscular methotrexate administration. Eleven cases (11.5%) failed methotrexate treatment and required surgical interventions. Except for women with serum human chorionic gonadotropin levels higher than 100 000 IU/L, ultrasound-guided local methotrexate injection could be considered as a first-line treatment modality for CSP.

  1. Update on taxanes in the first-line treatment of advanced non-small-cell lung cancer.

    PubMed

    Socinski, M A

    2014-10-01

    Based on demonstrated favourable risk-benefit profiles, taxanes remain a key component in the first-line standard of care for advanced non-small-cell lung cancer (nsclc) and nsclc subtypes. In 2012, a novel taxane, nab-paclitaxel (Abraxane: Celgene Corporation, Summit, NJ, U.S.A.), was approved, in combination with carboplatin, for the first-line treatment of locally advanced or meta-static nsclc. The approval was granted because of demonstrated improved antitumour activity and tolerability compared with solvent-based paclitaxel-carboplatin in a phase iii trial. This review focuses on the evolution of first-line taxane therapy for advanced nsclc and the new options and advances in taxane therapy that might address unmet needs in advanced nsclc.

  2. Comparison of acarbose and gliclazide as first-line agents in patients with type 2 diabetes.

    PubMed

    Salman, S; Salman, F; Satman, I; Yilmaz, Y; Ozer, E; Sengül, A; Demirel, H O; Karşidağ, K; Dinççağ, N; Yilmaz, M T

    2001-01-01

    insufficiently controlled with diet alone, and both treatments were well tolerated. Because of its effects on weight reduction and PP hyperinsulinaemia, acarbose may be preferred as a first-line drug, particularly in the treatment of overweight type 2 diabetic patients.

  3. Bismuth, lansoprazole, amoxicillin and metronidazole or clarithromycin as first-line Helicobacter pylori therapy.

    PubMed

    Zhang, Wei; Chen, Qi; Liang, Xiao; Liu, Wenzhong; Xiao, Shudong; Graham, David Y; Lu, Hong

    2015-11-01

    To evaluate the efficacy and tolerability of replacing tetracycline with amoxicillin in bismuth quadruple therapy. Subjects who were infected with Helicobacter pylori and naïve to treatment were randomly (1:1) assigned to receive a 14-day modified bismuth quadruple therapy: lansoprazole 30 mg, amoxicillin 1 g, bismuth potassium citrate 220 mg (elemental bismuth), twice a day with metronidazole 400 mg four times a day (metronidazole group) or clarithromycin 500 mg twice a day (clarithromycin group). Six weeks after treatment, H. pylori eradication was assessed by 13C-urea breath test. Antimicrobial susceptibility was assessed by the twofold agar dilution method. This was a non-inferiority trial. Two hundred and fifteen subjects were randomised. Metronidazole and clarithromycin containing regimens achieved high cure rates: 94 of 97 (96.9%, 95% CI 93.5% to 100%) and 93 of 98 (94.9%, 95% CI 90.5% to 99.3%) by per-protocol and 88.9% (95% CI 83.0% to 94.8%) and 88.8% (95% CI 82.8% to 94.8%) by intention-to-treat, respectively. Amoxicillin, metronidazole and clarithromycin resistance rates were 1.5%, 45.5% and 26.5%, respectively. Only clarithromycin resistance reduced treatment success (e.g., susceptible 98.6%, resistant 76.9%, p=0.001). Adverse events were more common in the metronidazole group. These results suggest that amoxicillin can substitute for tetracycline in modified 14 day bismuth quadruple therapy as first-line treatment and still overcome metronidazole resistance in areas with high prevalence of metronidazole and clarithromycin resistance. Using clarithromycin instead of metronidazole was only effective in the presence of susceptible strains. NCT02175901. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  4. Lopinavir/r no longer recommended as a first-line regimen: a comparative effectiveness analysis

    PubMed Central

    Potard, Valérie; Rey, David; Poizot-Martin, Isabelle; Mokhtari, Saadia; Pradier, Christian; Rozenbaum, Willy; Brun-Vezinet, Françoise; Costagliola, Dominique

    2014-01-01

    Introduction We compared the effectiveness of tenofovir/emtricitabine (TDF/FTC) combined with either lopinavir/r (LPV/r) or another recommended third drug in the 2010 French guidelines in antiretroviral-naïve patients starting combination antiretroviral therapy in 2004–2008 in the French Hospital Database on HIV. Methods The outcomes were stop or switch of the third component, viral load (VL) <500 copies/ml, an increase of at least 100 CD4 cells/mm3, AIDS-defining event and non-AIDS-defining hospitalization or death. Propensity scores were estimated by logistic regression based on the clinical centre and other confounders. In each clinical centre, each patient initiating LPV/r was matched with a patient initiating another third drug (efavirenz or atazanavir/r) and having a close propensity score. Cox's proportional hazards models were then used, with treatment as covariate. Time was right-censored at four years. Results 1269 patients started LPV/r plus TDF/FTC, and 890 could be matched to 890 patients receiving another third drug. Baseline characteristics were well balanced between these two groups. LPV/r was associated with a higher risk of third drug stop (hazard ratio (HR): 1.69; 95% confidence interval (CI), 1.42–2.00) and with less rapid viral suppression (HR: 0.83; 95% CI, 0.72–0.95). There was no difference in the time required for a CD4 cell increment of at least 100/mm3, or to the occurrence of an AIDS-defining event. Non-AIDS-defining hospitalizations or deaths were more frequent with LPV/r (HR: 1.79; 95% CI, 1.33–2.39). Conclusions For first-line therapy, in this observational setting, TDF/FTC plus LPV/r were less durable than TDF/FTC plus another recommended third drug, led to a less rapid viral suppression and were associated with a higher risk of non-AIDS morbidity. PMID:25261780

  5. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.

    PubMed

    Carbone, David P; Reck, Martin; Paz-Ares, Luis; Creelan, Benjamin; Horn, Leora; Steins, Martin; Felip, Enriqueta; van den Heuvel, Michel M; Ciuleanu, Tudor-Eliade; Badin, Firas; Ready, Neal; Hiltermann, T Jeroen N; Nair, Suresh; Juergens, Rosalyn; Peters, Solange; Minenza, Elisa; Wrangle, John M; Rodriguez-Abreu, Delvys; Borghaei, Hossein; Blumenschein, George R; Villaruz, Liza C; Havel, Libor; Krejci, Jana; Corral Jaime, Jesus; Chang, Han; Geese, William J; Bhagavatheeswaran, Prabhu; Chen, Allen C; Socinski, Mark A

    2017-06-22

    Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC. We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more. Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy. Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a

  6. Survival outcomes for first-line antiretroviral therapy in India's ART program.

    PubMed

    Dandona, Rakhi; Rewari, Bharat B; Kumar, G Anil; Tanwar, Sukarma; Kumar, S G Prem; Vishnumolakala, Venkata S; Duber, Herbert C; Gakidou, Emmanuela; Dandona, Lalit

    2016-10-11

    Little is known about survival outcomes of HIV patients on first-line antiretroviral therapy (ART) on a large-scale in India, or facility level factors that influence patient survival to guide further improvements in the ART program in India. We examined factors at the facility level in addition to patient factors that influence survival of adult HIV patients on ART in the publicly-funded ART program in a high- and a low-HIV prevalence state. Retrospective chart review in public sector ART facilities in the combined states of Andhra Pradesh and Telangana (APT) before these were split in 2014 and in Rajasthan (RAJ), the high- and a low-HIV prevalence states, respectively. Records of adults initiating ART between 2007-12 and 2008-13 in APT and RAJ, respectively, were reviewed and facility-level information collected at all ART centres and a sample of link ART centres. Survival probability was estimated using Kaplan-Meier method, and determinants of mortality explored with facility and patient-level factors using Cox proportional hazard model. Based on data from 6581 patients, the survival probability of ART at 60 months was 76.3 % (95 % CI 73.0-79.2) in APT and 78.3 % (74.4-81.7) in RAJ. The facilities with cumulative ART patient load above the state average had lower mortality in APT (Hazard ratio [HR] 0.74, 0.57-0.95) but higher in RAJ (HR 1.37, 1.01-1.87). Facilities with higher proportion of lost to follow-up patients in APT had higher mortality (HR 1.47, 1.06-2.05), as did those with higher ART to pre-ART patient ratio in RAJ (HR 1.62, 1.14-2.29). In both states, there was higher hazard for mortality in patients with CD4 count 100 cells/mm(3) or less at ART initiation, males, and in patients with TB co-infection. These data from the majority of facilities in a high- and a low-HIV burden state of India over 5 years reveal reasonable and similar survival outcomes in the two states. The facilities with higher ART load in the longer established ART program in

  7. Nanoscaled hydrated antimony (V) oxide as a new approach to first-line antileishmanial drugs

    PubMed Central

    Franco, Antonia MR; Grafova, Iryna; Soares, Fabiane V; Gentile, Gennaro; Wyrepkowski, Claudia DC; Bolson, Marcos A; Sargentini, Ézio; Carfagna, Cosimo; Leskelä, Markku; Grafov, Andriy

    2016-01-01

    Background Coordination compounds of pentavalent antimony have been, and remain, the first-line drugs in leishmaniasis treatment for >70 years. Molecular forms of Sb (V) complexes are commercialized as sodium stibogluconate (Pentostam®) and meglumine antimoniate (MA) (Glucantime®). Ever-increasing drug resistance in the parasites limits the use of antimonials, due to the low drug concentrations being administered against high parasitic counts. Sb5+ toxicity provokes severe side effects during treatment. To enhance therapeutic potency and to increase Sb (V) concentration within the target cells, we decided to try a new active substance form, a hydrosol of Sb2O5·nH2O nanoparticles (NPs), instead of molecular drugs. Methodology/principal findings Sb2O5·nH2O NPs were synthesized by controlled SbCl5 hydrolysis in a great excess of water. Sb2O5·nH2O phase formation was confirmed by X-ray diffraction. The surface of Sb (V) NPs was treated with ligands with a high affinity for target cell membrane receptors. The mean particle size determined by dynamic light scattering and transmission electron microscopy was ~35–45 nm. In vitro tests demonstrated a 2.5–3 times higher antiparasitic activity of Sb (V) nanohybrid hydrosols, when compared to MA solution. A similar comparison for in vivo treatment of experimental cutaneous leishmaniasis with Sb5+ nanohybrids showed a 1.75–1.85 times more effective decrease in the lesions. Microimages of tissue fragments confirmed the presence of NPs inside the cytoplasm of infected macrophages. Conclusion/significance Sb2O5·nH2O hydrosols are proposed as a new form of treatment for cutaneous leishmaniasis caused by Leishmania amazonensis. The NPs penetrate directly into the affected cells, creating a high local concentration of the drug, a precondition to overcoming the parasite resistance to molecular forms of pentavalent antimonials. The nanohybrids are more effective at a lower dose, when compared to MA, the molecular drug. Our

  8. Follicular lymphoma: first-line treatment without chemotherapy for follicular lymphoma.

    PubMed

    Reagan, Patrick M; Friedberg, Jonathan W

    2015-07-01

    Opinion statement: The optimal initial treatment of follicular lymphoma (FL) is not known, and initial management of patients varies considerably between providers and institutions. The assertion that patients with low tumor burden can be observed for a period of time is being challenged owing to the safety and tolerability of novel therapeutics and the movement of the field away from traditional chemotherapy agents. Single agent rituximab has become increasingly popular as initial management of patients with low tumor burden disease, and there is evidence that prolonged treatment with rituximab can improve progression-free survival (PFS) when compared to induction with rituximab or observation. Radioimmunotherapy (RIT) has similarly shown efficacy in low tumor burden disease. Novel agents such as lenalidomide, idelalisib, and ibrutinib are being studied in the first-line setting. Importantly, none of these strategies have demonstrated an improved overall survival in a randomized study versus observation. It is the opinion of the authors that endpoints such as PFS alone, while important, should not drive changes in management with limited resources. Composite endpoints including quality of life are more informative on the true impact of treatments on patients with follicular lymphoma. Providers should encourage all patients to be treated in the context of an appropriate clinical trial when possible. If a patient is not a clinical trial candidate, we typically treat patients with advanced stage and high tumor burden with chemoimmunotherapy. The decision to give maintenance rituximab is individualized to the patient, as there is no overall survival benefit. In patients with early stage disease, we favor consideration of radiation therapy if the patient is a candidate. Our initial recommendation to patients with advanced stage, low tumor burden disease, is close observation or "watch and wait." We have observed that most patients become comfortable over time with an

  9. Selecting first-line bevacizumab-containing therapy for advanced breast cancer: TURANDOT risk factor analyses

    PubMed Central

    Brodowicz, T; Lang, I; Kahan, Z; Greil, R; Beslija, S; Stemmer, S M; Kaufman, B; Petruzelka, L; Eniu, A; Anghel, R; Koynov, K; Vrbanec, D; Pienkowski, T; Melichar, B; Spanik, S; Ahlers, S; Messinger, D; Inbar, M J; Zielinski, C

    2014-01-01

    Background: The randomised phase III TURANDOT trial compared first-line bevacizumab–paclitaxel (BEV–PAC) vs bevacizumab–capecitabine (BEV–CAP) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV–PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen. Methods: Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV–PAC (bevacizumab 10 mg kg−1 days 1 and 15 plus paclitaxel 90 mg m−2 days 1, 8 and 15 q4w) or BEV–CAP (bevacizumab 15 mg kg−1 day 1 plus capecitabine 1000 mg m−2 bid days 1–14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having ⩾2 vs ⩽1 of the following four risk factors: disease-free interval ⩽24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in ⩾3 organs. Results: The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV–PAC in the TNBC cohort and BEV–CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV–PAC. Grade ⩾3 adverse events were consistently less common with BEV–CAP. Conclusions: A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov NCT00600340). PMID:25268370

  10. Nanoscaled hydrated antimony (V) oxide as a new approach to first-line antileishmanial drugs.

    PubMed

    Franco, Antonia Mr; Grafova, Iryna; Soares, Fabiane V; Gentile, Gennaro; Wyrepkowski, Claudia Dc; Bolson, Marcos A; Sargentini, Ézio; Carfagna, Cosimo; Leskelä, Markku; Grafov, Andriy

    Coordination compounds of pentavalent antimony have been, and remain, the first-line drugs in leishmaniasis treatment for >70 years. Molecular forms of Sb (V) complexes are commercialized as sodium stibogluconate (Pentostam(®)) and meglumine antimoniate (MA) (Glucantime(®)). Ever-increasing drug resistance in the parasites limits the use of antimonials, due to the low drug concentrations being administered against high parasitic counts. Sb(5+) toxicity provokes severe side effects during treatment. To enhance therapeutic potency and to increase Sb (V) concentration within the target cells, we decided to try a new active substance form, a hydrosol of Sb2O5·nH2O nanoparticles (NPs), instead of molecular drugs. Sb2O5·nH2O NPs were synthesized by controlled SbCl5 hydrolysis in a great excess of water. Sb2O5·nH2O phase formation was confirmed by X-ray diffraction. The surface of Sb (V) NPs was treated with ligands with a high affinity for target cell membrane receptors. The mean particle size determined by dynamic light scattering and transmission electron microscopy was ~35-45 nm. In vitro tests demonstrated a 2.5-3 times higher antiparasitic activity of Sb (V) nanohybrid hydrosols, when compared to MA solution. A similar comparison for in vivo treatment of experimental cutaneous leishmaniasis with Sb(5+) nanohybrids showed a 1.75-1.85 times more effective decrease in the lesions. Microimages of tissue fragments confirmed the presence of NPs inside the cytoplasm of infected macrophages. Sb2O5·nH2O hydrosols are proposed as a new form of treatment for cutaneous leishmaniasis caused by Leishmania amazonensis. The NPs penetrate directly into the affected cells, creating a high local concentration of the drug, a precondition to overcoming the parasite resistance to molecular forms of pentavalent antimonials. The nanohybrids are more effective at a lower dose, when compared to MA, the molecular drug. Our data suggest that the new form of treatment has the potential to

  11. HIV Drug Resistance Among Children Initiating First-Line Antiretroviral Treatment in Uganda

    PubMed Central

    Sigaloff, Kim Catherina Eve; Boender, Tamara Sonia; Kaudha, Elizabeth; Kayiwa, Joshua; Musiime, Victor; Mukuye, Andrew; Kiconco, Mary; Nankya, Immaculate; Nakatudde-Katumba, Llilian; Calis, Job C.J.; Rinke de Wit, Tobias F.; Mugyenyi, Peter N.

    2016-01-01

    Abstract Background: There are limited data on primary human immunodeficiency virus drug resistance (HIVDR) in pediatric populations. This study aimed to assess the prevalence of primary HIVDR and associated risk factors among children initiating first-line antiretroviral therapy (ART) in Uganda. Methods: At three Ugandan clinics, children (age <12 years) requiring ART were recruited between January 2010 and August 2011. Before starting ART, blood was collected for viral load and pol gene sequencing. Drug resistance mutations were determined using the 2010 International AIDS Society–USA mutation list. Risk factors for HIVDR were assessed with multivariate regression analysis. Results: Three hundred nineteen HIV-infected children with a median age of 4.9 years were enrolled. Sequencing was successful in 279 children (87.5%). HIVDR was present in 10% of all children and 15.2% of children <3 years. Nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTI (NNRTI), and dual-class resistance was present in 5.7%, 7.5%, and 3.2%, respectively. HIVDR occurred in 35.7% of prevention of mother-to-child transmission (PMTCT)–exposed children, 15.6% in children with unknown PMTCT history, and 7.7% among antiretroviral-naive children. History of PMTCT exposure [adjusted odds ratio (AOR): 2.6, 95% CI: 1.3–5.1] or unknown PMTCT status (AOR: 3.8, 95% CI: 1.1–13.5), low CD4 (AOR: 2.2, 95% CI: 1.3–3.6), current breastfeeding (AOR: 7.4, 95% CI: 2.6–21), and current maternal ART use (AOR: 6.4, 95% CI: 3.4–11.9) emerged as risk factors for primary HIVDR in multivariate analysis. Conclusion: Pretreatment HIVDR is high, especially in children with PMTCT exposure. Protease inhibitor (PI)–based regimens are advocated by the World Health Organization, but availability in children is limited. Children with (unknown) PMTCT exposure, low CD4 count, current breastfeeding, or maternal ART need to be prioritized to receive PI-based regimens. PMID:26723018

  12. Bevacizumab plus XELOX as first-line treatment of metastatic colorectal cancer: The OBELIX study

    PubMed Central

    Antonuzzo, Lorenzo; Giommoni, Elisa; Pastorelli, Davide; Latiano, Tiziana; Pavese, Ida; Azzarello, Domenico; Aieta, Michele; Pastina, Ilaria; Di Fabio, Francesca; Bertolini, Alessandro; Corsi, Domenico Cristiano; Mogavero, Selene; Angelini, Valentina; Pazzagli, Mario; Di Costanzo, Francesco

    2015-01-01

    AIM: To confirm the efficacy and safety of bevacizumab/XELOX combination for the treatment of locally advanced or metastatic colorectal cancer (CRC) in Italy. METHODS: This multicentric, prospective, open-label study included patients with CRC previously untreated with chemotherapy. Patients were administered bevacizumab in combination with XELOX. The primary efficacy end-point was progression-free survival (PFS). Secondary end-points included time to overall response (TOR), duration of response (DOR), time to treatment failure (TTF) and overall survival (OS). The incidence and type of adverse events AEs and severe AEs were evaluated. Also, the mutational status of BRAF and KRAS was assessed by high resolution melting and direct sequencing, and quality of life (QoL) was measured by the EuroQoL EQ-5D questionnaire at baseline and at the last visit. RESULTS: The intention-to-treat population included 197 patients (mean age: 62.3 ± 9.9 years, 56.4% males). At baseline, 16/34 evaluable subjects (47.1%) harbored a KRAS and/or a BRAF mutation; the mean QoL index was 80.2 ± 14.3. First-line therapy was given for 223.7 ± 175.9 d, and after a mean follow-up of 387.7 ± 238.8 d all patients discontinued from the study mainly for disease progression (PD, 45.4%) and AEs (25.4%). Median PFS was 9.7 mo (95%CI: 8.4-10.5) and the median values for secondary end-points were: TOR = 3.9 mo (95%CI: 2.6-4.7), DOR = 8.5 mo (95%CI: 7.3-10.3), TTF = 6.7 mo (95%CI: 6.0-7.7) and OS = 23.2 mo (95%CI: 20.1-27.2). Patients carrying at least one lesion had a lower overall response rate (66.7% vs 88.9%) and a lower probability of achieving complete or partial response than those without mutations, but the difference in relative risk was not statistically significant (P = 0.2). Mean EQ-5D-3L raw index score significantly decreased to 74.9 ± 19.1 at the last visit (signed-rank test, P = 0.0076), but in general the evaluation on QoL perceived by patients was good. CONCLUSION: The efficacy of

  13. Efficacy of Bevacizumab-Capecitabine in Combination for the First-Line Treatment of Metastatic Breast Cancer

    PubMed Central

    Dyar, Stephen; Moreno-Aspitia, Alvaro

    2011-01-01

    There is an ongoing need for development of new chemotherapeutic regimens for metastatic breast cancer [mBC], especially when tumors lack therapeutic targets such as the estrogen or progesterone receptor [ER/PR], or the human epidermal growth factor receptor-2 [HER2]. Capecitabine is an orally bioavailable fluoropyrimidine approved for monotherapy in mBC, and bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor which has shown to be active in mBC and tolerable in combination with other chemotherapeutics. The combination of these two agents has been explored in multiple phase II and III clinical studies, with improvements in progression-free survival and overall response rates noted as compared to capecitabine monotherapy. However, the use of bevacizumab in combination with capecitabine and other chemotherapy agents for mBC remains beset with controversy due to safety concerns, cost issues, and pending regulatory decisions. PMID:22174585

  14. Conceptualizing Prevention as the First Line of Offense against Homelessness: Implications for the Federal Continuum of Care Model.

    ERIC Educational Resources Information Center

    Poole, Dennis L.; Zugazaga, Carole B.

    2003-01-01

    The Community Prevention Model, which reinforces competencies and strengths, promotes independent living and social mainstreaming, and utilizes emergency shelters as a last resort, is offered for discussion. It is argued that the federal continuum of care model does not adequately address prevention as the first line of offense against…

  15. Noninvasive molecular analysis of Helicobacter pylori: Is it time for tailored first-line therapy?

    PubMed Central

    Ierardi, Enzo; Giorgio, Floriana; Iannone, Andrea; Losurdo, Giuseppe; Principi, Mariabeatrice; Barone, Michele; Pisani, Antonio; Di Leo, Alfredo

    2017-01-01

    The main problem of Helicobacter pylori (H. pylori) infection management is linked to antibiotic resistances. This phenomenon has grown in the last decade, inducing a dramatic decline in conventional regimen effectiveness. The causes of resistance are point mutations in bacterial DNA, which interfere with antibiotic mechanism of action, especially clarithromycin and levofloxacin. Therefore, international guidelines have recently discouraged their use in areas with a relevant resistance percentage, suggesting first-line schedules with expected high eradication rates, i.e., bismuth containing or non-bismuth quadruple therapies. These regimens require the daily assumption of a large number of tablets. Consequently, a complete adherence is expected only in subjects who may be motivated by the presence of major disorders. However, an incomplete adherence to antibiotic therapies may lead to resistance onset, since sub-inhibitory concentrations could stimulate the selection of resistant mutants. Of note, a recent meta-analysis suggests that susceptibility tests may be more useful for the choice of first than second-line or rescue treatment. Additionally, susceptibility guided therapy has been demonstrated to be highly effective and superior to empiric treatments by both meta-analyses and recent clinical studies. Conventional susceptibility test is represented by culture and antibiogram. However, the method is not available everywhere mainly for methodology-related factors and fails to detect hetero-resistances. Polymerase chain reaction (PCR)-based, culture-free techniques on gastric biopsy samples are accurate in finding even minimal traces of genotypic resistant strains and hetero-resistant status by the identification of specific point mutations. The need for an invasive endoscopic procedure has been the most important limit to their spread. A further step has, moreover, been the detection of point mutations in bacterial DNA fecal samples. Few studies on clarithromycin

  16. Noninvasive molecular analysis of Helicobacter pylori: Is it time for tailored first-line therapy?

    PubMed

    Ierardi, Enzo; Giorgio, Floriana; Iannone, Andrea; Losurdo, Giuseppe; Principi, Mariabeatrice; Barone, Michele; Pisani, Antonio; Di Leo, Alfredo

    2017-04-14

    The main problem of Helicobacter pylori (H. pylori) infection management is linked to antibiotic resistances. This phenomenon has grown in the last decade, inducing a dramatic decline in conventional regimen effectiveness. The causes of resistance are point mutations in bacterial DNA, which interfere with antibiotic mechanism of action, especially clarithromycin and levofloxacin. Therefore, international guidelines have recently discouraged their use in areas with a relevant resistance percentage, suggesting first-line schedules with expected high eradication rates, i.e., bismuth containing or non-bismuth quadruple therapies. These regimens require the daily assumption of a large number of tablets. Consequently, a complete adherence is expected only in subjects who may be motivated by the presence of major disorders. However, an incomplete adherence to antibiotic therapies may lead to resistance onset, since sub-inhibitory concentrations could stimulate the selection of resistant mutants. Of note, a recent meta-analysis suggests that susceptibility tests may be more useful for the choice of first than second-line or rescue treatment. Additionally, susceptibility guided therapy has been demonstrated to be highly effective and superior to empiric treatments by both meta-analyses and recent clinical studies. Conventional susceptibility test is represented by culture and antibiogram. However, the method is not available everywhere mainly for methodology-related factors and fails to detect hetero-resistances. Polymerase chain reaction (PCR)-based, culture-free techniques on gastric biopsy samples are accurate in finding even minimal traces of genotypic resistant strains and hetero-resistant status by the identification of specific point mutations. The need for an invasive endoscopic procedure has been the most important limit to their spread. A further step has, moreover, been the detection of point mutations in bacterial DNA fecal samples. Few studies on clarithromycin

  17. Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer.

    PubMed

    Rizvi, Naiyer A; Hellmann, Matthew D; Brahmer, Julie R; Juergens, Rosalyn A; Borghaei, Hossein; Gettinger, Scott; Chow, Laura Q; Gerber, David E; Laurie, Scott A; Goldman, Jonathan W; Shepherd, Frances A; Chen, Allen C; Shen, Yun; Nathan, Faith E; Harbison, Christopher T; Antonia, Scott

    2016-09-01

    Nivolumab, a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody, has demonstrated improved survival in previously treated patients with advanced non-small-cell lung cancer (NSCLC). CheckMate 012, a phase I, multicohort study, was conducted to explore the safety and efficacy of nivolumab as monotherapy or combined with current standard therapies in first-line advanced NSCLC. Here, we report results for nivolumab plus platinum-based doublet chemotherapy (PT-DC). Patients (N = 56) received nivolumab (intravenously) plus PT-DC concurrently every 3 weeks for four cycles followed by nivolumab alone until progression or unacceptable toxicity. Regimens were nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies). The primary objective was to assess safety and tolerability. Secondary objectives included objective response rate and 24-week progression-free survival rate (per Response Evaluation Criteria in Solid Tumors version 1.1); exploratory objectives included overall survival (OS) and response by tumor programmed death ligand-1 expression. No dose-limiting toxicities occurred during the first 6 weeks of treatment. Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4 treatment-related adverse events (AEs); 7% of patients (n = 4) had pneumonitis. Twenty-one percent of patients (n = 12) discontinued all study therapy as a result of treatment-related AEs. Objective response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week progression-free survival rates were 51%, 71%, 38%, and 51%, respectively; 2-year OS rates were 25%, 33%, 27%, and 62%, respectively. Responses were achieved regardless of tumor programmed

  18. Sequential versus standard triple first-line therapy for Helicobacter pylori eradication.

    PubMed

    Nyssen, Olga P; McNicholl, Adrian G; Megraud, Francis; Savarino, Vincenzo; Oderda, Giuseppina; Fallone, Carlo A; Fischbach, Lori; Bazzoli, Franco; Gisbert, Javier P

    2016-06-28

    Non-bismuth quadruple sequential therapy (SEQ) comprising a first induction phase with a dual regimen of amoxicillin and a proton pump inhibitor (PPI) for five days followed by a triple regimen phase with a PPI, clarithromycin and metronidazole for another five days, has been suggested as a new first-line treatment option to replace the standard triple therapy (STT) comprising a proton pump inhibitor (PPI), clarithromycin and amoxicillin, in which eradication proportions have declined to disappointing levels. To conduct a meta-analysis of randomised controlled trials (RCTs) comparing the efficacy of a SEQ regimen with STT for the eradication of H. pylori infection, and to compare the incidence of adverse effects associated with both STT and SEQ H. pylori eradication therapies. We conducted bibliographical searches in electronic databases, and handsearched abstracts from Congresses up to April 2015. We sought randomised controlled trials (RCTs) comparing 10-day SEQ and STT (of at least seven days) for the eradication of H. pylori. Participants were adults and children diagnosed as positive for H. pylori infection and naïve to H. pylori treatment. We used a pre-piloted, tabular summary to collect demographic and medical information of included study participants as well as therapeutic data and information related to the diagnosis and confirmatory tests.We evaluated the difference in intention-to-treat eradication between SEQ and STT regimens across studies, and assessed sources of the heterogeneity of this risk difference (RD) using subgroup analyses.We evaluated the quality of the evidence following Cochrane standards, and summarised it using GRADE methodology. We included 44 RCTs with a total of 12,284 participants (6042 in SEQ and 6242 in STT). The overall analysis showed that SEQ was significantly more effective than STT (82% vs 75% in the intention-to-treat analysis; RD 0.09, 95% confidence interval (CI) 0.06 to 0.11; P < 0.001, moderate-quality evidence

  19. Necitumumab plus Gemcitabine and Cisplatin as First-Line Therapy in Patients with Stage IV EGFR- Expressing Squamous Non-Small-Cell Lung Cancer: German Subgroup Data from an Open-Label, Randomized Controlled Phase 3 Study (SQUIRE).

    PubMed

    Reck, Martin; Thomas, Michael; Kropf-Sanchen, Cornelia; Mezger, Jörg; Socinski, Mark A; Depenbrock, Henrik; Soldatenkova, Victoria; Brown, Jacqueline; Krause, Thomas; Thatcher, Nick

    2016-01-01

    In the SQUIRE study, adding the anti-epidermal growth factor receptor (EGFR) IgG1 antibody necitumumab to first-line gemcitabine and cisplatin (GC + N) in advanced squamous non-small-cell lung cancer (sqNSCLC) significantly improved overall survival (OS); the safety profile was acceptable. We explored data for the German subpopulation (N = 96) of SQUIRE patients with EGFR-expressing tumors. Patients with stage IV sqNSCLC were randomized 1:1 to up to 6 cycles of open-label GC + N or GC alone. GC + N patients with no progression continued on necitumumab monotherapy until disease progression or intolerable toxicity. The primary endpoint was OS; the secondary endpoints included progression-free survival (PFS), safety and health-related quality of life (EQ-5D, Lung Cancer Symptom Scale (LCSS)). The 96 German SQUIRE patients with EGFR-expressing tumors (GC + N 42, GC 54) received a median of 4 GC cycles; the GC + N patients received 5 cycles of necitumumab. Adding necitumumab was associated with 41% risk reduction of death (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.37-0.94, p = 0.026) and 44% risk reduction of progression (HR 0.56, 95% CI 0.33-0.95, p = 0.029). Adverse events typically associated with EGFR antibody treatment (including rash, hypomagnesemia) were more common with GC + N. The time to deterioration of the EQ-5D and LCSS scores showed no notable differences between the treatment arms, except for appetite loss (delayed for GC + N). The survival benefit from adding necitumumab to first-line GC was more pronounced in the German SQUIRE subpopulation with EGFR-expressing tumors than in the overall (intention-to-treat) population; toxicity was manageable and consistent with the overall population. © 2016 S. Karger GmbH, Freiburg.

  20. Comparative efficacy of first-line natalizumab vs IFN-β or glatiramer acetate in relapsing MS

    PubMed Central

    Kalincik, Tomas; Jokubaitis, Vilija; Zhang, Annie; Pellegrini, Fabio; Wiendl, Heinz; Belachew, Shibeshih; Hyde, Robert; Verheul, Freek; Lugaresi, Alessandra; Havrdová, Eva; Horáková, Dana; Grammond, Pierre; Duquette, Pierre; Prat, Alexandre; Iuliano, Gerardo; Terzi, Murat; Izquierdo, Guillermo; Hupperts, Raymond M.M.; Boz, Cavit; Pucci, Eugenio; Giuliani, Giorgio; Sola, Patrizia; Spitaleri, Daniele L.A.; Lechner-Scott, Jeannette; Bergamaschi, Roberto; Grand'Maison, François; Granella, Franco; Kappos, Ludwig; Trojano, Maria; Butzkueven, Helmut

    2016-01-01

    Abstract Background: We compared efficacy and treatment persistence in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS) initiating natalizumab compared with interferon-β (IFN-β)/glatiramer acetate (GA) therapies, using propensity score–matched cohorts from observational multiple sclerosis registries. Methods: The study population initiated IFN-β/GA in the MSBase Registry or natalizumab in the Tysabri Observational Program, had ≥3 months of on-treatment follow-up, and had active RRMS, defined as ≥1 gadolinium-enhancing lesion on cerebral MRI at baseline or ≥1 relapse within the 12 months prior to baseline. Baseline demographics and disease characteristics were balanced between propensity-matched groups. Annualized relapse rate (ARR), time to first relapse, treatment persistence, and disability outcomes were compared between matched treatment arms in the total population (n = 366/group) and subgroups with higher baseline disease activity. Results: First-line natalizumab was associated with a 68% relative reduction in ARR from a mean (SD) of 0.63 (0.92) on IFN-β/GA to 0.20 (0.63) (p [signed-rank] < 0.0001), a 64% reduction in the rate of first relapse (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.28–0.47; p < 0.001), and a 27% reduction in the rate of discontinuation (HR 0.73, 95% CI 0.58–0.93; p = 0.01), compared with first-line IFN-β/GA therapy. Confirmed disability progression and area under the Expanded Disability Status Scale–time curve analyses were not significant. Similar relapse and treatment persistence results were observed in each of the higher disease activity subgroups. Conclusions: This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse and treatment persistence outcomes compared to first-line IFN-β/GA. This needs to be balanced against the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients. Classification of evidence: This study

  1. Meta-analysis of first-line therapies with maintenance regimens for advanced non-small-cell lung cancer (NSCLC) in molecularly and clinically selected populations.

    PubMed

    Tan, Pui San; Bilger, Marcel; de Lima Lopes, Gilberto; Acharyya, Sanchalika; Haaland, Benjamin

    2017-08-01

    Evidence has suggested survival benefits of maintenance for advanced NSCLC patients not progressing after first-line chemotherapy. Additionally, particular first-line targeted therapies have shown survival improvements in selected populations. Optimal first-line and maintenance therapies remain unclear. Here, currently available evidence was synthesized to elucidate optimal first-line and maintenance therapy within patient groups. Literature was searched for randomized trials evaluating first-line and maintenance regimens in advanced NSCLC patients. Bayesian network meta-analysis was performed within molecularly and clinically selected groups. The primary outcome was combined clinically meaningful OS and PFS benefits. A total of 87 records on 56 trials evaluating first-line treatments with maintenance were included. Results showed combined clinically meaningful OS and PFS benefits with particular first-line with maintenance treatments, (1) first-line intercalated chemotherapy+erlotinib, maintenance erlotinib in patients with EGFR mutations, (2) first-line afatinib, maintenance afatinib in patients with EGFR deletion 19, (3) first-line chemotherapy + bevacizumab, maintenance bevacizumab in EGFR wild-type patients, (4) chemotherapy+conatumumab, maintenance conatumumab in patients with squamous histology, (5) chemotherapy+cetuximab, maintenance cetuximab or chemotherapy + necitumumab, maintenance necitumumab in EGFR FISH-positive patients with squamous histology, and (6) first-line chemotherapy+bevacizumab, maintenance bevacizumab or first-line sequential chemotherapy+gefitinib, maintenance gefitinib in patients clinically enriched for EGFR mutations with nonsquamous histology. No treatment showed combined clinically meaningful OS and PFS benefits in patients with EGFR L858R or nonsquamous histology. Particular first-line with maintenance treatments show meaningful OS and PFS benefits in patients selected by EGFR mutation or histology. Further research is needed

  2. Computed tomography or rhinoscopy as the first-line procedure for suspected nasal tumor: a pilot study.

    PubMed

    Finck, Marlène; Ponce, Frédérique; Guilbaud, Laurent; Chervier, Cindy; Floch, Franck; Cadoré, Jean-Luc; Chuzel, Thomas; Hugonnard, Marine

    2015-02-01

    There are no evidence-based guidelines as to whether computed tomography (CT) or endoscopy should be selected as the first-line procedure when a nasal tumor is suspected in a dog or a cat and only one examination can be performed. Computed tomography and rhinoscopic features of 17 dogs and 5 cats with a histopathologically or cytologically confirmed nasal tumor were retrospectively reviewed. The level of suspicion for nasal neoplasia after CT and/or rhinoscopy was compared to the definitive diagnosis. Twelve animals underwent CT, 14 underwent rhinoscopy, and 4 both examinations. Of the 12 CT examinations performed, 11 (92%) resulted in the conclusion that a nasal tumor was the most likely diagnosis compared with 9/14 (64%) for rhinoscopies. Computed tomography appeared to be more reliable than rhinoscopy for detecting nasal tumors and should therefore be considered as the first-line procedure.

  3. Comparison of three different regimens against Helicobacter pylori as a first-line treatment: A randomized clinical trial

    PubMed Central

    Kefeli, Ayse; Basyigit, Sebahat; Yeniova, Abdullah Ozgur; Kefeli, Tarık Tayfur; Aslan, Muzaffer; Tanas, Ozlem

    2016-01-01

    Treatments with bismuth-containing quadruple therapy (QT), sequential therapy (ST), or concomitant therapy (CT) have been proposed as empirical first-line regimens for Helicobacter pylori. We compared the efficacy and tolerability of 10 days bismuth-containing quadruple QT, 10 days ST, and 10 days CT with as first-line treatments for H. pylori in a randomized crossover study. The subjects were randomly divided into three groups. The first 130 patients were treated with rabeprazole, bismuth potassium citrate, metronidazole, and tetracycline for 10 days. The second 130 patients in the sequential group were treated with rabeprazole and amoxicillin for 5 days, and then rabeprazole, clarithromycin, and metronidazole for an additional 5 days. The last 130 patients in the concomitant group were treated with rabeprazole, amoxicillin, clarithromycin, and metronidazole for 10 days. H. pylori eradication was confirmed by urea breath test at 6 weeks. The primary outcome was eradication rates of first-line treatment by intention to treat and per protocol (PP) analyzes. There was no difference between the average ages and the male/female ratio of the groups. The PP analysis was performed on 121, 119, and 118 patients in the QT, ST, and CT groups, respectively. In the PP analysis, the successful eradication 94.2% (114/121), 95.0% (113/119), and 95.8% (113/118) the QT, ST, and CT groups, respectively. There was no significant difference among the three groups (p = 0.86). 10 days QT, ST, and CT are highly effective as empirical first-line therapies for H. pylori in the region with high clarithromycin resistance. PMID:26773183

  4. Clinical outcome of patients who reduced sunitinib or pazopanib during first-line treatment for advanced kidney cancer.

    PubMed

    Iacovelli, Roberto; Cossu Rocca, Maria; Galli, Luca; De Giorgi, Ugo; Sabbatini, Roberto; Santoni, Matteo; Mosca, Alessandra; Fornarini, Giuseppe; Massari, Francesco; Masini, Cristina; Bersanelli, Melissa; Biasco, Elisa; Lolli, Cristian; Guida, Annalisa; Berardi, Rossana; Terrone, Carlo; Pastorino, Alessandro; Ardizzoni, Andrea; Pinto, Carmine; Buti, Sebastiano; Nolè, Franco; Tortora, Giampaolo

    2017-09-01

    To investigate the different outcomes in patients with metastatic renal cell carcinoma (mRCC) who receive a reduced first-line dose of sunitinib or pazopanib compared to those who continue at the standard dose. All the patients treated in 11 oncological centers in Italy for mRCC who started first-line treatment with sunitinib or pazopanib at the standard dose. Descriptive statistical tests were used to highlight differences among groups. Survival was estimated by the Kaplan-Meier method and compared across the groups using log-rank tests, the Cox proportional hazards model adjusted for statistically significant variables was also done. A total of 591 patients were included in the study. Of these, 45.7% received a reduced dose of sunitinib or pazopanib after a median treatment time of 3.6 months at the standard dose. The median overall survival in the patients who continued to receive the standard dose was 24.0 months compared to 49.4 months for those who received a reduced dose (hazard ratio = 1.80; 95% CI: 1.42-2.29; P<0.001). Only 45% of the patients received second-line therapy: 42.5% had an mTOR and 54.1% a tyrosine kinase inhibitor. Second-line overall survival was 19.8 and 11.8 months, respectively, in the patients who received, or did not, a reduced dose during first-line therapy (P = 0.007). Toxicity-related dose reduction is a common event in mRCC patients who have started first-line therapy with either sunitinib or pazopanib. This is positively related to the outcomes of both first- and second-line therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Virologic Failure among Children Taking Lopinavir/Ritonavir-Containing First-Line Antiretroviral Therapy in South Africa

    PubMed Central

    Meyers, Tammy; Sawry, Shobna; Wong, Jessica Y.; Moultrie, Harry; Pinillos, Francoise; Fairlie, Lee; van Zyl, Gert

    2014-01-01

    Objective To report the outcomes, clinical management decisions and results of resistance testing among a group of children who developed virologic failure on first line lopinavir/ritonavir (LPV/r)-based therapy from a large cohort of ART-treated children in Soweto. Design Historical cohort study Methods Children with virologic failure were identified from a group of 1692 children <3 years who had initiated first-line LPV/r-containing therapy since 2000 up to end November 2011. Genotyping was conducted in some children and outcomes, management decisions and resistance results were described. Results 152 children with virologic failure on first-line LPV/r-containing ART were included. Resistance testing was performed in 75/152 (49%) and apart from a younger age (11.1 vs 15.1 months, p=0.04), the children with vs those without resistance testing were similar for baseline characteristics (weight, CD4, VL and time to failure). Genotyping revealed that 8/75 (10.7%) had significant LPV/r-associated resistance mutations, including 2 with intermediate DRV resistance. Among 63/75 (84%) children remaining on LPV/r-based therapy, 32/63 (51%) achieved virologic suppression, 2 of these children with significant LPV mutations. 12/152 (8%) children were switched to NNRTI-based therapy in accordance with local guidelines at the time. Of these, 4/12 (33%) resuppressed, and the rest did not achieve virologic suppression including the 2 with LPV mutations. Conclusions Virologic failure of LPV/r-containing first line regimens is associated with accumulation of LPV/r mutations in children. The implications are unclear and surveillance at selected sites is warranted for long-term virologic outcomes and development of resistance. PMID:25741970

  6. Clarithromycin Versus Metronidazole as First-line Helicobacter pylori Eradication: A Multicenter, Prospective, Randomized Controlled Study in Japan.

    PubMed

    Nishizawa, Toshihiro; Maekawa, Takama; Watanabe, Noriko; Harada, Naohiko; Hosoda, Yasuo; Yoshinaga, Masahiro; Yoshio, Toshiyuki; Ohta, Hajime; Inoue, Syuuji; Toyokawa, Tatsuya; Yamashita, Haruhiro; Saito, Hiroki; Kuwai, Toshio; Katayama, Shunsuke; Masuda, Eiji; Miyabayashi, Hideharu; Kimura, Toshio; Nishizawa, Yuko; Takahashi, Masahiko; Suzuki, Hidekazu

    2015-07-01

    Helicobacter pylori eradication rates achieved with a first-line regimen of clarithromycin (CLR) combined with amoxicillin (AMX) and a proton pump inhibitor have recently fallen to ≤80% because of the increasing incidence of CLR resistance in Japan. This randomized multicenter trial aimed to compare the eradication success of 2 first-line triple therapy regimens: rabeprazole, amoxicillin, and clarithromycin (RAC) versus rabeprazole, amoxicillin, and metronidazole (RAM). A total of 124 consecutive patients infected with H. pylori were randomized into one of two 7-day therapeutic regimens: RAC (n=60) or RAM (n=64). Eradication was confirmed by the C-urea breath test. Adverse effects were also assessed. Intention-to-treat and per protocol H. pylori eradication rates were 73.3%/77.2% in the RAC group and 90.6%/93.5% in the RAM group. The eradication rate of RAM therapy was significantly higher than that of RAC therapy. CLR, metronidazole, and AMX resistance was found in 36.2%, 2.1%, and 0% of patients, respectively. In addition, no relevant differences in adverse effects were observed. Metronidazole-based therapy (RAM) was superior to standard CLR-based therapy (RAC) for first-line H. pylori eradication. This reflects the progressive increase in CLR resistance observed in Japan.

  7. Surrogate end points and postprogression survival in renal cell carcinoma: an analysis of first-line trials with targeted therapies.

    PubMed

    Petrelli, Fausto; Barni, Sandro

    2013-12-01

    Our end point was to determine the correlations between progression-free survival (PFS), postprogression survival (PPS), response rate (RR), and disease control rate (DCR) (RR + stable disease) and overall survival (OS) in first-line trials of renal cell carcinoma (RCC) treated with targeted therapies and to identify a potential surrogate for OS. Data were collected from first-line phase III randomized trials in RCC. Linear regression was undertaken to evaluate the correlations between end points and a potential surrogate end point for OS. Six randomized trials were identified containing a total of 7 treatment arms. The nonparametric Spearman rank correlation coefficients (r(s)) between PFS, PPS, and RR/DCR and OS are 0.869, and 1, 0.96/1 (all P < .0001), respectively. There is a strong relationship between differences (Δ) in DCR and ΔOS (r(s) = 1). The slope of the regression line is 0.3963 ± 0.0019, indicating that a novel drug producing a 10% increase for DCR will yield an estimated absolute 3.9% increase in OS. In first-line trials including novel targeted agents for RCC, PFS is a relatively flawed surrogate end point because of PPS influence. Improvement in DCR is strongly associated with improvement in median OS. In this population, DCR may be an appropriate surrogate for OS.

  8. Safety profiles of first-line therapies for metastatic non-squamous non-small-cell lung cancer.

    PubMed

    Losanno, Tania; Gridelli, Cesare

    2016-06-01

    Lung cancer still represents the leading cause of death for cancer. About the 70% of diagnosis are in advanced-stage. Non-small-cell lung cancer (NSCLC) represents the 85% of all diagnosed lung cancers and non-squamous histology represents the 40% of all NSCLC. First-line therapies increase survival, control symptoms and improve quality of life, compared with best supportive care. It is crucial to choose a treatment with a low impact on patient's life considering the related toxicities. Adverse events (AEs) of first-line therapies for non-squamous NSCLC are here reviewed and discussed, from evidences in clinical trials conducting to drugs approval. For advanced disease, palliation and preserving patients QoL are still the primary goal of treatment. Therefore, differing toxicity profiles are often a deciding factor in first-line and also maintenance setting for non-squamous NSCLC. Special attention is necessary to renal function and drugs' nephrotoxicity. Moreover, it is to consider the specific AEs of drugs classes: hypertension, bleeding, and proteinuria, for anti-VEGF therapy; skin toxicity, diarrhea, interstitial lung disease for TKIs; vision disorders, and hepatotoxicity for ALK-inhibitor. It is important to select patients for a treatment on the basis of their comorbidities and the presence of risk factors.

  9. Percutaneous Cholecystostomy as a First-Line Therapy in Chronic Hemodialysis Patients with Acute Cholecystitis with Midterm Follow-up

    SciTech Connect

    Gumus, Burcak

    2011-04-15

    Purpose: The purpose of this article was to share midterm results of percutaneous cholecystostomy (PC) as a first-line therapy in chronic hemodialysis patients with acute cholecystitis. Methods: Fourteen chronic hemodialysis patients with acute cholecystitis underwent PC between March 2007 and May 2009 at our institute. On preoperative assessment, the patients were classified into the ASA score by the anesthesiology team. All patients were class IV because of severe underlying comorbidities. The patients were referred to interventional radiology unit for PC by consensus of the multidisciplinary team. Results: The PC was technically successful in all the patients without minor or major complications related to the procedure. Clinical symptoms in three patients who presented with sepsis and multiorgan failure did not resolve after PC, and these patients died following urgent surgery, including open cholecystectomy and common bile duct exploration. A new cholecystitis attack was detected in one patient in the acalculous group at the sixth month of the follow-up period. The mean catheterization time was 31.7 (range, 28-41) days. The mean follow-up time was 13.3 (range 4-21) months. Conclusions: The PC may come into consideration as a first-line treatment modality in the management of acute cholecystitis in poor surgical candidate chronic hemodialysis patients. This is the first report focusing on the midterm results of PC as a first-line therapy in hemodialysis patients with acute cholecystitis who could be operated on.

  10. First-line trastuzumab plus taxane-based chemotherapy for metastatic breast cancer: cost-minimization analysis.

    PubMed

    Nerich, Virginie; Chelly, Jennifer; Montcuquet, Philippe; Chaigneau, Loïc; Villanueva, Cristian; Fiteni, Frédéric; Meneveau, Nathalie; Perrin, Sophie; Voidey, Aline; Monnot, Tess; Pivot, Xavier; Limat, Samuel

    2014-10-01

    To carry out a cost-minimization analysis including a comparison of the costs arising from first-line treatment by trastuzumab plus docetaxel versus trastuzumab plus paclitaxel in patients with metastatic breast cancer. All consecutive patients with human epidermal growth receptor 2-postive metastatic breast cancer who were treated at Besançon University Hospital and Saint Vincent private hospital between 2001 and 2010 by first-line therapy containing trastuzumab plus taxane were retrospectively studied. Economic analysis took into account costs related to drugs, hospitalization, and healthcare travel. Progression-free survival difference between the two treatments was not significant (p = 0.65). First-line treatment by trastuzumab plus taxane was estimated at approximately €68,000 (p = 0.74). The drug costs represented around 70-75% of the total cost, mainly related to the use of trastuzumab. Our economic analysis shows that although the costs of the two trastuzumab plus taxane regimens are similar, they may contribute to the on-going debate about the availability and use of innovative chemotherapy drugs, in particular in human epidermal growth factor receptor 2-positive metastatic breast cancer with new therapies such as trastuzumab-DM1 and pertuzumab. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  11. [Bicalutamide monotherapy of patients with disseminated forms of prostatic cancer].

    PubMed

    Loran, O B; Pushkar', D Iu; Kosko, D; Bernikov, A N

    2001-01-01

    Combined antiandrogen therapy (complete androgen blocking) implies surgical or chemical castration in combination with antiandrogen therapy. Both sources of androgens are thus blocked in patients with locally disseminated prostatic cancer. The purpose of this study was to evaluate the efficiency of bikalutamide (150 mg) monotherapy. The study was carried out in 58 patients with prostatic cancer (stages T3-T4) divided into 2 groups: 1) bikalutamide monotherapy (150 mg daily) and 2) bikalutamide (50 mg daily) + bilateral orchidectomy. All patients were examined before and 3, 6, 12, 18, and 24 months after the beginning of therapy. The efficiency of non-steroid antiandrogen was higher in group 1. The mean level of prostate-specific antigen in this group decreased to 10.6 ng/ml by 24 months, while in group 2 to 25.3 ng/ml. Hence, bicalutamide was effective, safe, and well tolerated in our study, and is therefore recommended as monotherapy for patients with disseminated forms of prostatic cancer.

  12. Topical antibiotic monotherapy prescribing practices in acne vulgaris.

    PubMed

    Hoover, William D; Davis, Scott A; Fleischer, Alan B; Feldman, Steven R

    2014-04-01

    The aim of this study is to evaluate the frequency of dosing topical antibiotics as monotherapy in the treatment of acne vulgaris, and physician specialty prescribing these medications. This study is a retrospective review of all visits with a sole diagnosis of acne vulgaris (ICD-9-CM code 706.1) found on the National Ambulatory Medical Care Survey (NAMCS) in 1993-2010. We recorded the number of visits surveyed where acne vulgaris was the sole diagnosis, number of visits where topical antibiotics were the only treatment prescribed, and the specialty of physician in each encounter. Topical erythromycin or clindamycin were the sole medication prescribed in 0.81% of the visits recorded, with 60% of these prescriptions arising from dermatologists and 40% from non-dermatologists. The trend of prescribing topical antibiotic monotherapy is declining (p < 0.001) over the 18-year study period. The development of resistance of Propionibacterium acnes to topical antibiotic regimens has led to the need to re-evaluate the use of topical antibiotics in the treatment of acne vulgaris. While the rate of topical antibiotic monotherapy is declining, their use should be reserved for situations where the direct need for antibiotics arises. If a clinician feels that antibiotics are a necessary component to acne therapy, they should be used as part of a combination regimen.

  13. First-line cetuximab-based chemotherapies for patients with advanced or metastatic KRAS wild-type colorectal cancer

    PubMed Central

    Uemura, Mamoru; Kim, Ho Min; Hata, Tsuyoshi; Sakata, Kazuya; Okuyama, Masaki; Takemoto, Hiroyoshi; Fujii, Hitoshi; Fukuzaki, Takayuki; Morita, Tetsushi; Hata, Taishi; Takemasa, Ichiro; Satoh, Taroh; Mizushima, Tsunekazu; Doki, Yuichiro; Mori, Maski

    2016-01-01

    Colorectal cancer (CRC) is one of the most commonly occurring cancers worldwide. A burgeoning number of studies have demonstrated that the addition of cetuximab to another standard first-line regimen markedly improves the outcome of CRC treatment. However, at present, the efficacy and safety of cetuximab-based combination chemotherapy has not been well described in Japan. The aim of the present study was to evaluate the efficacy and safety of first-line chemotherapies that included cetuximab for patients with advanced or metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type CRC in Japan. This prospective multicenter observational study was conducted at 13 affiliated medical institutions. A total of 64 patients were enrolled between 2010 and 2013. The patients met the following criteria for eligibility: i) histologically confirmed, advanced or metastatic KRAS wild-type CRC; and ii) cetuximab-based chemotherapies administered as a first-line treatment. First-line cetuximab-based treatments were administered as follows: 29 patients (45.3%) received a combination of infusional fluorouracil, leucovorin and oxaliplatin; 14 patients (21.9%) received a combination of capecitabine and oxaliplatin; and 10 patients (15.6%) received a combination of infusional fluorouracil, leucovorin and irinotecan. The overall response rate (including complete plus partial responses) was 50% (32/64 patients). Initially, 48 lesions were diagnosed as unresectable. Among those, 13 lesions (27.1%) were converted to a resectable status following cetuximab-based combination chemotherapy treatments. The median overall survival time and the progression-free survival time were 1,189 and 359 days, respectively. The most frequent grade 3/4 adverse event was neutropenia, which occurred in 20.3% of the patients. The incidence of grade 3/4 skin toxicity was 17.2% (11/64 patients). Cetuximab-based therapies may represent a promising first-line regimen for patients with advanced or

  14. Bosutinib in combination with the aromatase inhibitor letrozole: a phase II trial in postmenopausal women evaluating first-line endocrine therapy in locally advanced or metastatic hormone receptor-positive/HER2-negative breast cancer.

    PubMed

    Moy, Beverly; Neven, Patrick; Lebrun, Fabienne; Bellet, Meritxell; Xu, Binghe; Sarosiek, Tomasz; Chow, Louis; Goss, Paul; Zacharchuk, Charles; Leip, Eric; Turnbull, Kathleen; Bardy-Bouxin, Nathalie; Duvillié, Ladan; Láng, István

    2014-04-01

    Endocrine therapy resistance in hormone receptor-positive (HR+) breast cancer (BC) may involve crosstalk between HRs and growth factor signaling pathways. We evaluated bosutinib, a dual Src/Abl tyrosine kinase inhibitor that has previously demonstrated some antitumor activity in BC, plus letrozole as first-line endocrine therapy in locally advanced or metastatic HR+/HER2- BC. METHODS; Sixteen postmenopausal women were enrolled in a phase II study evaluating the safety/efficacy of bosutinib plus letrozole. In the single-arm safety/dose-confirming lead-in (part 1), patients received oral bosutinib at 400 mg/day plus letrozole at 2.5 mg/day; adverse events (AEs) and dose-limiting toxicities (DLTs) were monitored, and initial efficacy was assessed. A randomized efficacy/safety phase (part 2) was planned to evaluate the combination versus letrozole monotherapy. Fifteen of 16 subjects experienced treatment-related AEs, most commonly diarrhea (69%). Treatment-related hepatotoxicity AEs (primarily alanine aminotransferase [ALT] or aspartate aminotransferase [AST] elevations) occurred in 6 of 16 patients (38%). Four of 15 evaluable patients (27%) experienced a DLT (grade 3/4 ALT/AST elevations, n = 2; grade 3 rash, n = 1; grade 3 diarrhea or vomiting, n = 1), including 1 Hy's law hepatotoxicity case. All DLTs resolved following treatment discontinuation. One patient achieved confirmed partial response; one had stable disease for >24 weeks. Study termination occurred before part 2. The unfavorable risk-benefit ratio did not warrant further investigation of bosutinib plus letrozole.

  15. Palbociclib as a first-line treatment in oestrogen receptor-positive, HER2-negative, advanced breast cancer not cost-effective with current pricing: a health economic analysis of the Swiss Group for Clinical Cancer Research (SAKK).

    PubMed

    Matter-Walstra, K; Ruhstaller, T; Klingbiel, D; Schwenkglenks, M; Dedes, K J

    2016-07-01

    Endocrine therapy continues to be the optimal systemic treatment for metastatic ER(+)HER2(-) breast cancer. The CDK4/6 inhibitor palbociclib combined with letrozole has recently been shown to significantly improve progression-free survival. Here we examined the cost-effectiveness of this regimen for the Swiss healthcare system. A Markov cohort simulation based on the PALOMA-1 trial (Finn et al. in Lancet Oncol 16:25-35, 2015) was used as the clinical course. Input parameters were based on summary trial data. Costs were assessed from the Swiss healthcare system perspective. Adding palbociclib to letrozole (PALLET) compared to letrozole monotherapy was estimated to cost an additional CHF342,440 and gain 1.14 quality-adjusted life years, resulting in an incremental cost-effectiveness ratio (ICER) of CHF301,227/QALY gained. In univariate sensitivity analyses, no tested variation in key parameters resulted in an ICER below a willingness-to-pay threshold of CHF100,000/QALY. PALLET had a 0 % probability of being cost-effective in probabilistic sensitivity analyses. Lowering PALLET's price by 75 % resulted in an ICER of CHF73,995/QALY and a 73 % probability of being cost-effective. At current prices, PALLET would cost the Swiss healthcare system an additional CHF155 million/year. Palbociclib plus letrozole cannot be considered cost-effective for the first-line treatment of patients with metastatic breast cancer in the Swiss healthcare system.

  16. Linagliptin monotherapy compared with voglibose monotherapy in patients with type 2 diabetes undergoing hemodialysis: a 12-week randomized trial

    PubMed Central

    Mori, Katsuhito; Emoto, Masanori; Shoji, Tetsuo; Inaba, Masaaki

    2016-01-01

    Objective Focusing on efficacy and tolerability, we compared linagliptin monotherapy with voglibose monotherapy in patients with type 2 diabetes undergoing hemodialysis (HD). Research design and methods In this multicenter, randomized, open-label, parallel-group, active-controlled study, 78 patients were randomized (1:1) to receive a 12-week treatment with 5 mg linagliptin once daily or 0.2 mg voglibose three times a day. To assess whether linagliptin was superior to voglibose, the primary efficacy end point was the change in glycated hemoglobin (HbA1c) level between baseline and week 12. Secondary efficacy end points included changes between baseline and week 12 in glycated albumin (GA) and casual plasma glucose (PG) levels. Results At week 12, the adjusted mean HbA1c levels had decreased by −0.60% after treatment with linagliptin and by −0.20% after treatment with voglibose (treatment difference: −0.40%, 95% CI −0.74% to −0.06%, p=0.022). A significant reduction in casual PG level was also observed after treatment with linagliptin compared with treatment with voglibose. Relative to voglibose, linagliptin tended to elicit reductions in GA, although without statistical significance. No hypoglycemic symptoms or severe hypoglycemia occurred during the study. Conclusions In patients with type 2 diabetes undergoing HD, linagliptin monotherapy provided significantly better glycemic control without severe hypoglycemia than voglibose monotherapy. Linagliptin represents a promising agent for glycemic management in patients with type 2 diabetes undergoing HD. Trial registration number UMIN000007635; results. PMID:27547421

  17. Effect of metformin monotherapy on cardiovascular diseases and mortality: a retrospective cohort study on Chinese type 2 diabetes mellitus patients.

    PubMed

    Fung, Colman Siu Cheung; Wan, Eric Yuk Fai; Wong, Carlos King Ho; Jiao, Fangfang; Chan, Anca Ka Chun

    2015-10-09

    Many factors influence whether the first-line oral anti-diabetic drug, metformin, should be initiated to a patient with type 2 diabetes mellitus (T2DM) early in the course of management in addition to lifestyle modifications. This study aims to evaluate the net effects of metformin monotherapy (MM) on the all-cause mortality and cardiovascular disease (CVD) events. A retrospective 5-year follow-up cohort study was conducted on Chinese adult patients with T2DM and without any CVD history under public primary care. Cox proportional hazard regressions were performed to compare the risk of all-cause mortality and CVD events (CHD, stroke, heart failure) between patients receiving lifestyle modifications plus MM (MM groups) and those with lifestyle modifications alone (control groups). 3400 pairs of matched patients were compared. MM group had an incidence rate of 7.5 deaths and 11.3 CVD events per 1000 person-years during a median follow-up period of 62.5 months whereas control group had 11.1 deaths and 16.3 per 1000 person-years during a median follow-up period of 43.5-44.5 months. MM group showed a 29.5 and 30-35% risk reduction of all-cause mortality and CVD events (except heart failure) than control group (P < 0.001). MM group was more prone to progress to chronic kidney disease but this was not statistically significant. Type 2 diabetic patients who were started on metformin monotherapy showed improvement in many of the clinical parameters and a reduction in all-cause mortality and CVD events than lifestyle modifications alone. If there is no contraindication and if tolerated, diabetic patients should be prescribed with metformin early in the course of the diabetic management to minimize their risk of having the cardiovascular events and mortality in the long run.

  18. Helicobacter pylori eradication with moxifloxacin-containing therapy following failed first-line therapies in South Korea

    PubMed Central

    Kang, Kyu Keun; Lee, Dong Ho; Oh, Dong Hyun; Yoon, Hyuk; Shin, Cheol Min; Park, Young Soo; Kim, Nayoung; Jung, Hyun Chae

    2014-01-01

    AIM: To investigate moxifloxacin-containing triple therapy as second-line treatment for Helicobacter pylori (H. pylori) infection following failed first-line treatment. METHODS: The sample included 312 patients for whom first-line treatment failed between January 2008 and May 2013; 27 patients were excluded, and a total of 285 patients received 7- or 14-d moxifloxacin-containing triple therapy as second-line treatment for H. pylori infection. First line regimens included 7-d standard triple (n = 172), 10-d bismuth-containing quadruple (n = 28), 14-d concomitant (n = 37), or 14-d sequential (n = 48) therapy. H. pylori status was evaluated using 13C-urea breath testing 4 wk later, after completion of the treatment. The primary outcome was the H. pylori eradication rate analyzed using intention-to-treat (ITT) and per protocol (PP) analyses. The secondary outcome was the occurrence of serious adverse events. Demographic and clinical factors were analyzed using Student’s t-tests and Pearson’s χ2 tests according to first- and second-line regimens. A P value of less than 0.05 was considered statistically significant. RESULTS: The eradication rate of moxifloxacin-containing triple therapy was 68.4% (ITT; 95%CI: 62.8-73.5) and 73.9% (PP; 95%CI: 68.3-78.8). The eradication rate was significantly higher with 14 d compared to 7 d of treatment (77.5% vs 62.5%, P = 0.017). Peptic ulcer patients had a higher eradication rate than the patients without ulcers (82.9% vs 70.6%, P = 0.046). The demographic and clinical characteristics were not significantly different between the groups according to first-line therapies. ITT and PP analyses of the moxifloxacin-containing triple therapy indicated the following eradication rates: 70.9% (95%CI: 63.8-77.2) and 77.2% (95%CI: 70.1-83.1) for standard triple; 67.9% (95%CI: 51.5-84.2) and 67.9% (95%CI: 51.5-84.2) for bismuth-containing quadruple; 60.4% (95%CI: 46.3-73.0) and 70.7% (95%CI: 54.0-80.9) for sequential; and 67.6% (95%CI: 51

  19. Resin-based Yttrium-90 microspheres for unresectable and failed first-line chemotherapy intrahepatic cholangiocarcinoma: preliminary results.

    PubMed

    Jia, Zhongzhi; Paz-Fumagalli, Ricardo; Frey, Gregory; Sella, David M; McKinney, J Mark; Wang, Weiping

    2017-03-01

    To evaluate the value of resin-based yttrium-90 ((90)Y) radioembolization for unresectable and failed first-line chemotherapy (cisplatin plus gemcitabine) intrahepatic cholangiocarcinoma (ICC). From February 2006 to September 2015, a retrospective study was conducted of all patients who underwent resin-based (90)Y therapy for unresectable and failed first-line chemotherapy ICC. Tumor response was assessed using modified RECIST criteria; side effects were assessed using Common Terminology Criteria for Adverse Events version 4.03; survivals were calculated from the date of diagnosis of ICC, beginning of first-line chemotherapy and first (90)Y procedure, respectively; effects of factors on survival were analyzed by Cox regression model. Twenty-four patients (eight male and 16 female) were included in this study. Mean 5.6 ± 1.6 cycles of first-line chemotherapy were performed prior to (90)Y treatment. The mean delivered activity of (90)Y was 1.6 ± 0.4 GBq with a total of 27 treatments. Disease control rate was 81.8% at 3 months after (90)Y therapy, with partial response (n = 8, 36.4%), stable disease (n = 10, 45.5%) and progressive disease (n = 6, 18.2%). CA199 changes pre- and 1 month post-treatment were complete (n = 2), partial (n = 2), none (n = 5) and progression (n = 2), respectively. Side effects included fatigue (n = 21, 87.5%), anorexia (n = 19, 79.2%), nausea (n = 15, 62.5%), abdominal pain (n = 10, 58.3%), vomiting (n = 4, 16.7%) and fever (n = 3, 12.5%). Radiation-induced gastrointestinal ulcer was identified in one patient. The mean follow-up was 11.3 ± 6.6 months, and the median survivals from the time of diagnosis of ICC, beginning of first-line chemotherapy and first (90)Y procedure were 24.0, 16.0 and 9.0 months, respectively, and the 6-, 12-, 18-, 24- and 30-month survival after (90)Y therapy were 69.9, 32.6, 27.2, 20.4 and 20.4%, respectively. ECOG performance status (P = 0.002) and lymph node metastases (P

  20. Targeted erlotinib for first-line treatment of advanced non-small cell lung cancer: a budget impact analysis.

    PubMed

    Bajaj, Preeti S; Veenstra, David L; Goertz, Hans-Peter; Carlson, Josh J

    2014-08-01

    A recent phase III trial showed that patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor specific EGFR mutations significantly benefit from first-line treatment with erlotinib compared to chemotherapy. This study sought to estimate the budget impact if coverage for EGFR testing and erlotinib as first-line therapy were provided in a hypothetical 500,000-member managed care plan. The budget impact model was developed from a US health plan perspective to evaluate administration of the EGFR test and treatment with erlotinib for EGFR-positive patients, compared to non-targeted treatment with chemotherapy. The eligible patient population was estimated from age-stratified SEER incidence data. Clinical data were derived from key randomized controlled trials. Costs related to drug, administration, and adverse events were included. Sensitivity analyses were conducted to assess uncertainty. In a plan of 500,000 members, it was estimated there would be 91 newly diagnosed advanced NSCLC patients annually; 11 are expected to be EGFR-positive. Based on the testing and treatment assumptions, it was estimated that 3 patients in Scenario 1 and 6 patients in Scenario 2 receive erlotinib. Overall health plan expenditures would increase by $0.013 per member per month (PMPM). This increase is largely attributable to erlotinib drug costs, in part due to lengthened progression-free survival and treatment periods experienced in erlotinib-treated patients. EGFR testing contributes slightly, whereas adverse event costs mitigate the budget impact. The budget impact did not exceed $0.019 PMPM in sensitivity analyses. Coverage for targeted first-line erlotinib therapy in NSCLC likely results in a small budget impact for US health plans. The estimated impact may vary by plan, or if second-line or maintenance therapy, dose changes/interruptions, or impact on patients' quality-of-life were included.

  1. Glass Microspheres 90Y Selective Internal Radiation Therapy and Chemotherapy as First-Line Treatment of Intrahepatic Cholangiocarcinoma.

    PubMed

    Edeline, Julien; Du, Fanny Le; Rayar, Michel; Rolland, Yan; Beuzit, Luc; Boudjema, Karim; Rohou, Tanguy; Latournerie, Marianne; Campillo-Gimenez, Boris; Garin, Etienne; Boucher, Eveline

    2015-11-01

    Intrahepatic cholangiocarcinoma's incidence is increasing. We studied the efficacy of Y selective internal radiation therapy (SIRT) as first-line treatment, with chemotherapy, and compared with the results of chemotherapy alone. We retrospectively studied data from patients treated at our institution with glass microspheres SIRT for intrahepatic cholangiocarcinoma as part of first-line treatment in combination with chemotherapy. We compared results with those of similar patients treated in the ABC-02 study (a study in advanced biliary tract cancer that defined the current standard chemotherapy), assessed as not progressing after the first evaluation. We assessed progression-free survival (PFS) and overall survival (OS). Twenty-four patients were treated with SIRT. Chemotherapy was given concomitantly in 10 (42%), as induction before SIRT in 13 (54%) or after SIRT in 1 (4%). Grade 3 adverse events were reported in 1 (4%). Median PFS after SIRT was 10.3 months. Longer PFS was observed when chemotherapy was given concomitantly than when chemotherapy was given before SIRT, with respective median of 20.0 versus 8.8 months (P = 0.001). Median OS after SIRT was not reached. Eleven patients went to surgery (46%). Thirty-three patients in ABC-02 had locally advanced nonextrahepatic cholangiocarcinoma, not progressing after first evaluation. From the start of any treatment, the median PFS was 16.0 months in our cohort versus 11.3 months in ABC-02 (P = 0.25), whereas the median OS was significantly higher in our cohort, not reached versus 17.9 months, respectively (P = 0.026). Selective internal radiation therapy combined with concomitant chemotherapy seems a promising strategy as first-line treatment for unresectable intrahepatic cholangiocarcinoma.

  2. Aspirin is first-line treatment for migraine and episodic tension-type headache regardless of headache intensity.

    PubMed

    Lampl, Christian; Voelker, Michael; Steiner, Timothy J

    2012-01-01

    (1) To establish whether pre-treatment headache intensity in migraine or episodic tension-type headache (ETTH) predicts success or failure of treatment with aspirin; and (2) to reflect, accordingly, on the place of aspirin in the management of these disorders. Stepped care in migraine management uses symptomatic treatments as first-line, reserving triptans for those in whom this proves ineffective. Stratified care chooses between symptomatic therapy and triptans as first-line on an individual basis according to perceived illness severity. We questioned the 2 assumptions underpinning stratified care in migraine that greater illness severity: (1) reflects greater need; and (2) is a risk factor for failure of symptomatic treatment but not of triptans. With regard to the first assumption, we developed a rhetorical argument that need for treatment is underpinned by expectation of benefit, not by illness severity. To address the second, we reviewed individual patient data from 6 clinical trials of aspirin 1000 mg in migraine (N = 2079; 1165 moderate headache, 914 severe) and one of aspirin 500 and 1000 mg in ETTH (N = 325; 180 moderate, 145 severe), relating outcome to pre-treatment headache intensity. In migraine, for headache relief at 2 hours, a small (4.7%) and non-significant risk difference (RD) in therapeutic gain favored moderate pain; for pain freedom at 2 hours, therapeutic gains were almost identical (RD: -0.2%). In ETTH, for headache relief at 2 hours, RDs for both aspirin 500 mg (-4.2%) and aspirin 1000 mg (-9.7%) favored severe pain, although neither significantly; for pain freedom at 2 hours, RDs (-14.2 and -3.6) again favored severe pain. In neither migraine nor ETTH does pre-treatment headache intensity predict success or failure of aspirin. This is not an arguable basis for stratified care in migraine. In both disorders, aspirin is first-line treatment regardless of headache intensity. © 2011 American Headache Society.

  3. Chemotherapy plus bevacizumab versus chemotherapy plus cetuximab as first-line treatment for patients with metastatic colorectal cancer

    PubMed Central

    Bai, Long; Wang, Feng; Li, Zhe-zhen; Ren, Chao; Zhang, Dong-sheng; Zhao, Qi; Lu, Yun-xin; Wang, De-shen; Ju, Huai-qiang; Qiu, Miao-zhen; Wang, Zhi-qiang; Wang, Feng-hua; Xu, Rui-hua

    2016-01-01

    Abstract The present observational cohort study was designed to elucidate the efficacy and safety profile of bevacizumab or cetuximab with chemotherapy as the first-line treatment in Chinese patients with metastatic colorectal cancer (mCRC). Clinical data were collected from a single-center registry study where mCRC patients received first-line fluoropyrimidine-based chemotherapy combined with either bevacizumab (188 patients with KRAS wild-type or mutated tumors) or cetuximab (101 patients with KRAS wild-type tumors) between January 2009 and December 2013. The Kaplan–Meier method was used for survival analysis. Cox proportional hazards model was used for estimating the prognostic and predictive values of clinicopathological characteristics. No statistically significant difference was observed between the bevacizumab and cetuximab groups in terms of median progression-free survival (PFS) (10.6 vs 8.7 months, P = 0.317), median overall survival (OS) (27.7 vs 28.3 months, P = 0.525), or overall response rate (43.1% vs 53.5%, P = 0.108). For the subset of patients with peritoneal dissemination, bevacizumab-based triplet appears to be superior to cetuximab-based triplet as measured by PFS (9.6 vs 6.1 months) and OS (26.3 vs 12.7 months), but not for patients without peritoneal dissemination (PFS, 10.6 vs 9.1 months; OS, 27.9 vs 30.7 months) (all unadjusted and adjusted interaction P < 0.05). Our study suggests that bevacizumab- or cetuximab-based regimens have similar effectiveness as first-line treatment of mCRC in Chinese population. Patients with peritoneal dissemination were likely to gain more benefit from bevacizumab than cetuximab treatment. Future prospective studies are required to further confirm these results. PMID:28002313

  4. Virological efficacy with first-line antiretroviral treatment in India: predictors of viral failure and evidence of viral resuppression.

    PubMed

    Shet, Anita; Neogi, Ujjwal; Kumarasamy, N; DeCosta, Ayesha; Shastri, Suresh; Rewari, Bharat Bhushan

    2015-11-01

    Combination antiretroviral therapy (ART) has improved in efficacy, durability and tolerability. Virological efficacy studies in India are limited. We determined incidence and predictors of virological failure among patients initiating first-line ART and described virological resuppression after confirmed failure, with the goal of informing national policy. Therapy-naïve patients initiated on first-line ART as per national guidelines were monitored every 3 months for adherence and virological response over 2 years. Genotyping on baseline samples was performed to assess primary drug resistance. Multivariate Cox regression analysis was used to assess predictors of virological failure. Virological failure rate among 599 eligible patients was 10.7 failures per 100 person-years. Cumulative failure incidence was 13.2% in the first year and 16.5% over 2 years. Patients initiated on tenofovir had a significantly lower rate of virological failure than those on stavudine or zidovudine (6.7 vs. 11.9 failures per 100 person-years, P = 0.013). Virological failure was independently associated with age <40 years, mean adherence <95%, non-tenofovir-containing regimens and presence of primary drug resistance. In a subset of 311 patients who were reassessed after treatment failure, 19% (11/58) patients resuppressed their viral load to <400 copies/ml after confirmed virological failure. Our results support the inclusion of tenofovir as first-line ART in resource-limited settings and a role for regular adherence counselling and virological monitoring for enhanced treatment success. Detection of early virological failure should provide an opportunity to augment adherence counselling and repeat viral load testing before therapy switch is considered. © 2015 John Wiley & Sons Ltd.

  5. The correlation between LDH serum levels and clinical outcome in advanced biliary tract cancer patients treated with first line chemotherapy.

    PubMed

    Faloppi, Luca; Del Prete, Michela; Casadei Gardini, Andrea; Santini, Daniele; Silvestris, Nicola; Bianconi, Maristella; Giampieri, Riccardo; Valgiusti, Martina; Brunetti, Oronzo; Bittoni, Alessandro; Andrikou, Kalliopi; Lai, Eleonora; Dessì, Alessandra; Cascinu, Stefano; Scartozzi, Mario

    2016-04-11

    LDH may represent an indirect marker of neo-angiogenesis and worse prognosis in many tumour types. We assessed the correlation between LDH and clinical outcome for biliary tract cancer (BTC) patients treated with first-line chemotherapy. Overall, 114 advanced BTC patients treated with first-line gemcitabine and cisplatin were included. Patients were divided into two groups (low vs. high LDH), according to pre-treatment LDH values. Patients were also classified according to pre- and post-treatment variation in LDH serum levels (increased vs. decreased). Median progression free survival (PFS) was 5.0 and 2.6 months respectively in patients with low and high pre-treatment LDH levels (p = 0.0042, HR = 0.56, 95% CI: 0.37-0.87). Median overall survival (OS) was 7.7 and 5.6 months (low vs. high LDH) (p = 0.324, HR = 0.81, 95% CI: 0.54-1.24). DCR was 71% vs. 43% (low vs. high LDH) (p = 0.002). In 38 patients with decreased LDH values after treatment, PFS and OS were respectively 6.2 and 12.1 months, whereas in 76 patients with post-treatment increased LDH levels, PFS and OS were respectively 3.0 and 5.1 months (PFS: p = 0.0009; HR = 0.49; 95% IC: 0.33-0.74; OS: p < 0.0001; HR = 0.42; 95% IC: 0.27-0.63). Our data seem to suggest that LDH serum level may predict clinical outcome in BTC patients receiving first-line chemotherapy.

  6. Disentangling the complexity of infectious diseases: Time is ripe to improve the first-line statistical toolbox for epidemiologists.

    PubMed

    Hanf, Matthieu; Guégan, Jean-François; Ahmed, Ismail; Nacher, Mathieu

    2014-01-01

    Because many biological processes related to the dynamics of infectious diseases are caused by complex interactions between the environment, the host(s) and the agent(s), the necessity to address the methodological implications of this inherent complexity has recently emerged in epidemiology. Most epidemiologists now acknowledge that most human infectious diseases are likely to have complex dynamics. However, this knowledge still percolates with difficulty in their statistical "modus operandi". Indeed, for the study of complex systems, the traditional first-line statistical toolbox of epidemiologists (mainly built around the Generalized Linear Model family), despite its undeniable practicality and robustness, has structural limitations deprecating its usefulness. Three major sources of complexity neglected or not taken into account by this first-line statistical toolbox and having deep statistical implications are the multi-level organization of data, the non-linear relationships between variables and the complex interactions between variables. Three promising candidates to incorporate along with traditional tools for a new first-line statistical toolbox more suitable to apprehend these sources of complexity are the generalized linear mixed models, the generalized additive models, and the structural equation models. The aforementioned methodologies have the advantage to be generalizations of GLM models and are relatively easy to implement. Their assimilation and implementation would thus be greatly facilitated for epidemiologists. More globally, this text underlines that an improved use of other methods as such described here compared to traditional ones has to be performed to better understand the complexity challenging epidemiologists every day. This is particularly true in the field of infectious diseases for which major public health challenges will have to be addressed in the coming decades.

  7. Risk Factors for Incident Diabetes in a Cohort Taking First-Line Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy.

    PubMed

    Karamchand, Sumanth; Leisegang, Rory; Schomaker, Michael; Maartens, Gary; Walters, Lourens; Hislop, Michael; Dave, Joel A; Levitt, Naomi S; Cohen, Karen

    2016-03-01

    Efavirenz is the preferred nonnucleoside reverse transcriptase inhibitor (NNRTI) in first-line antiretroviral therapy (ART) regimens in low- and middle-income countries, where the prevalence of diabetes is increasing. Randomized control trials have shown mild increases in plasma glucose in participants in the efavirenz arms, but no association has been reported with overt diabetes. We explored the association between efavirenz exposure and incident diabetes in a large Southern African cohort commencing NNRTI-based first-line ART. Our cohort included HIV-infected adults starting NNRTI-based ART in a private sector HIV disease management program from January 2002 to December 2011. Incident diabetes was identified by the initiation of diabetes treatment. Patients with prevalent diabetes were excluded. We included 56,298 patients with 113,297 patient-years of follow-up (PYFU) on first-line ART. The crude incidence of diabetes was 13.24 per 1000 PYFU. Treatment with efavirenz rather than nevirapine was associated with increased risk of developing diabetes (hazard ratio 1.27 (95% confidence interval (CI): 1.10-1.46)) in a multivariate analysis adjusting for age, sex, body mass index, baseline CD4 count, viral load, NRTI backbone, and exposure to other diabetogenic medicines. Zidovudine and stavudine exposure were also associated with an increased risk of developing diabetes. We found that treatment with efavirenz, as well as stavudine and zidovudine, increased the risk of incident diabetes. Interventions to detect and prevent diabetes should be implemented in ART programs, and use of antiretrovirals with lower risk of metabolic complications should be encouraged.

  8. Lithium for older adults with bipolar disorder: Should it still be considered a first-line agent?

    PubMed

    Shulman, Kenneth I

    2010-08-01

    The use of lithium carbonate for the treatment of bipolar disorder in older adults is decreasing at a significant rate. This change in prescription pattern is occurring at a time when all evidence-based treatment guidelines and systematic reviews still recommend lithium as a first-line treatment for bipolar disorder. Despite having the strongest evidence base for effectiveness, lithium does pose significant concerns in the older population, including the risk of drug interactions that cause toxicity associated with decreased creatinine clearance. The evidence for lithium's impact on chronic renal disease is still controversial and is reviewed in this article. Mixed evidence exists regarding the impact of lithium on suicide risk, although there is a consensus that it does have protective properties through its mood-stabilizing effect. Because of the very limited research base regarding the use of lithium in old age, guidelines for dosing and maintenance of serum concentrations are not well established, and this may be leading to increased episodes of lithium toxicity. At the same time that these legitimate concerns about lithium are being highlighted, evidence has accumulated that suggests that lithium may have neuroprotective properties. Its action of inhibiting the enzyme glycogen synthase kinase-3 may be responsible in part for a decrease in the induction of amyloid beta peptide and hyperphosphorylated tau protein, which have been implicated in the development of Alzheimer's disease. Very little evidence supports use of alternatives to lithium such as other mood-stabilizing agents, including atypical antipsychotics, in older adults. Thus, before we abandon lithium as a first-line agent, we should ensure that the guidelines for lithium treatment are safe, practical and effective. Newer agents must be appropriately tested in older adults before replacing this longstanding first-line treatment for bipolar disorder.

  9. Mean CD4 cell count changes in patients failing a first-line antiretroviral therapy in resource-limited settings

    PubMed Central

    2012-01-01

    Background Changes in CD4 cell counts are poorly documented in individuals with low or moderate-level viremia while on antiretroviral treatment (ART) in resource-limited settings. We assessed the impact of on-going HIV-RNA replication on CD4 cell count slopes in patients treated with a first-line combination ART. Method Naïve patients on a first-line ART regimen with at least two measures of HIV-RNA available after ART initiation were included in the study. The relationships between mean CD4 cell count change and HIV-RNA at 6 and 12 months after ART initiation (M6 and M12) were assessed by linear mixed models adjusted for gender, age, clinical stage and year of starting ART. Results 3,338 patients were included (14 cohorts, 64% female) and the group had the following characteristics: a median follow-up time of 1.6 years, a median age of 34 years, and a median CD4 cell count at ART initiation of 107 cells/μL. All patients with suppressed HIV-RNA at M12 had a continuous increase in CD4 cell count up to 18 months after treatment initiation. By contrast, any degree of HIV-RNA replication both at M6 and M12 was associated with a flat or a decreasing CD4 cell count slope. Multivariable analysis using HIV-RNA thresholds of 10,000 and 5,000 copies confirmed the significant effect of HIV-RNA on CD4 cell counts both at M6 and M12. Conclusion In routinely monitored patients on an NNRTI-based first-line ART, on-going low-level HIV-RNA replication was associated with a poor immune outcome in patients who had detectable levels of the virus after one year of ART. PMID:22742573

  10. High-dose esomeprazole and amoxicillin dual therapy for first-line Helicobacter pylori eradication: a proof of concept study

    PubMed Central

    Zullo, Angelo; Ridola, Lorenzo; Francesco, Vincenzo De; Gatta, Luigi; Hassan, Cesare; Alvaro, Domenico; Bellesia, Annamaria; de Nucci, Germana; Manes, Gianpiero

    2015-01-01

    Background The prevalence of resistance to clarithromycin and metronidazole has considerably increased, with a corresponding decrease in the eradication rate for Helicobacter pylori (H. pylori) infection. Primary resistance to amoxicillin is extremely low, and esomeprazole was found to exert a noteworthy antimicrobial activity in vitro against H. pylori. A dual therapy with high-dose of esomeprazole coupled with high-dose amoxicillin might be therefore an ideal first-line treatment for H. pylori eradication. We aimed to assess the efficacy of a first-line 10-day, high-dose dual therapy consisting of amoxicillin and esomeprazole to eradicate H. pylori infection. Methods Consecutive naïve H. pylori-infected patients, who underwent an upper endoscopy in 4 Italian hospitals due to dyspeptic symptoms and found to be infected at routine histological assessment, were invited to participate. Patients enrolled received a 10-day, high-dose dual therapy comprising esomeprazole (40 mg t.i.d) and amoxicillin (1 g t.i.d.). At least 4 weeks after the end of the treatment a 13C-urea breath test was performed to evaluate the eradication. Results A total of 56 patients agreed to participate in the study and were all followed-up. The overall eradication was 87.5% (95% CI=78.8•96.2), without a statistically significant difference among centres. Overall, 5 (8.9%; 1.5•16.4%) patients complained of side-effects. Conclusions The 10-day, high-dose dual therapy with esomeprazole and amoxicillin might be an effective and safe first-line regimen. The efficacy of a longer 14-day regimen should be tested. PMID:26423014

  11. Ultrasound as a first-line test in the diagnosis of carpal tunnel syndrome: a cost-effectiveness analysis.

    PubMed

    Fowler, John R; Maltenfort, Mitchell G; Ilyas, Asif M

    2013-03-01

    The American Academy of Orthopaedic Surgeons (AAOS) recommends that surgeons obtain a confirmatory test in patients for whom carpal tunnel surgery is being considered. The AAOS, however, does not specify a preferred test. Ultrasound reportedly causes less patient discomfort and takes less time to perform, while maintaining comparable sensitivity and specificity to electrodiagnostic testing (EDX). We determined whether ultrasound as a first-line diagnostic test is more cost-effective than using EDX alone or using ultrasound alone: (1) when used by a general practitioner; and (2) when used by a specialist. A fictional population of patients was created and each patient was randomly assigned a probability of having true-positive, false-positive, true-negative, and true-positive ultrasound and EDX tests over an expected range of sensitivity and specificity values using Monte Carlo methods. Charges were assigned based on Medicare charges for diagnostic tests and estimates of missed time from work. The average charge for the use of ultrasound as a first-line diagnostic test followed by EDX for confirmation of a negative ultrasound test was $562.90 per patient in the general practitioner scenario and $369.50 per patient in the specialist scenario, compared with $400.30 and $428.30 for EDX alone, respectively. The use of diagnostic ultrasound as a first-line test for confirmation of a clinical diagnosis of carpal tunnel syndrome is a more cost-effective strategy in the specialist population and results in improved false-negative rates in the generalist population despite increased cost. Level III, economic and decision analyses. See the Guidelines for Authors for a complete description of levels of evidence.

  12. Long-Term Efficacy of First Line Antiretroviral Therapy in Indian HIV-1 Infected Patients: A Longitudinal Cohort Study

    PubMed Central

    Neogi, Ujjwal; Heylen, Elsa; Shet, Anita; Chandy, Sara; Shamsunder, Ranjani; Sönnerborg, Anders; Ekstrand, Maria L.

    2013-01-01

    Background Short term efficacy of combination antiretroviral therapy (cART) in resource-constrained settings is comparable to that found in western studies. However, long term data are limited. India has the third largest HIV infected population in the world but the long-term outcome of first line therapy according to the national guidelines has not been evaluated yet. Therefore, we conducted a long-term longitudinal analysis of the efficacy of the national first-line therapy in India from an observational cohort of Indian patients in two different clinical settings. Methodology/Principal Findings A total 323 patients who had been on ART for a median of 23 months and achieved virological suppression <100 copies/ml by their study baseline visit, were included and followed for two years. Blood samples were collected every six months for viral load and CD4 count. Drug resistance genotyping was performed when the viral load was >2000 copies/mL. Adherence and treatment interruptions (>48 h) were assessed via self-report. In the studied patients, the median duration of viral suppression was 44 months; 15.8% of patients showed viral rebound, and 2.8% viral failure. Viral rebound or failure was significantly negatively related to perfect adherence (100% adherence and no treatment interruption >48 hrs). Virological re-suppression in the subsequent visit was observed in three patients without any change in therapy despite the presence of key mutations. Conclusion/Significance Our study reports for the first time, a good long-term response to the first line therapy for a median of nearly four years although a less than perfect adherence increases the risk for treatment failure and subsequent drug resistance development. The empirical findings in this study also indicate the overall success of the Indian ART program in two different settings which likely are representative of other clinics that operate under the national guidelines. PMID:23383185

  13. [Bevacizumab as first-line therapy in metastatic renal cell carcinoma: Progression-free survival for 3 years].

    PubMed

    Pichler, R; Horninger, W; Aigner, F; Heidegger, I

    2016-03-01

    We report the case of a 72-year-old woman who was diagnosed in 2006 with renal cell cancer (RCC) and had undergone consecutive tumor nephrectomy (clear-cell RCC, Fuhrmann grade II, stage pT3a, R0). Over the years, the patient underwent several surgical and radiological interventions due to various metastatic lesions. This case report describes the 3-year progression-free survival in a patient who underwent first-line therapy with the monoclonal antibody bevacizumab. Except for hypertension, the patient does not suffer currently from any other side effects of bevacizumab therapy.

  14. Appropriate use of bendamustine in first-line therapy of chronic lymphocytic leukemia. Recommendations from SIE, SIES, GITMO Group.

    PubMed

    Cuneo, Antonio; Marchetti, Monia; Barosi, Giovanni; Billio, Atto; Brugiatelli, Maura; Ciolli, Stefania; Laurenti, Luca; Mauro, Francesca Romana; Molica, Stefano; Montillo, Marco; Zinzani, Pierluigi; Tura, Sante

    2014-11-01

    By using the GRADE system we produced the following recommendations for the use of bendamustine in the first-line treatment of CLL: (1) bendamustine with rituximab is recommended in elderly fit patients potentially eligible to FCR; (2) Bendamustine alone is recommended in patients who are candidate to chlorambucil alone; (3) Rituximab-bendamustine is recommended in patients not eligible to FCR, but suitable to receive rituximab. Consensus-based recommendations addressed evidence-orphan issues concerning the use of bendamustine in genetically-defined high-risk patients and the appropriate dose of bendamustine as single agent or in association with rituximab. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. [A negative first-line work-up of Raynaud's phenomenon: And what if it were cancer?].

    PubMed

    Auboire, L; Landy, S; Perrot, J-Y; Maïza, D; Le Hello, C

    2010-02-01

    Raynaud's phenomenon is a transient paroxysmal vasomotor phenomenon affecting the extremities including manifestations of ischemia. It is a common phenomenon in the general population. In a routine clinical situation, the first step is to differentiate Raynaud's disease from a secondary Raynaud's phenomenon, the latter requiring complementary investigations. We report here the case of an 80-year-old woman who presented a secondary Raynaud's phenomenon. First-line investigations remained negative. A mammography was performed and revealed breast cancer. Raynaud's phenomenon disappeared after treatment of the breast carcinoma and did not recur during the 2-year follow-up.

  16. Chlorhexidine Monotherapy with Adjunctive Topical Corticosteroids for Acanthamoeba Keratitis

    PubMed Central

    Rahimi, Firoozeh; Hashemian, Seyed Mohammad Nasser; Tafti, Mohammadreza Falah; Mehjerdi, Mohammadali Zare; Safizadeh, Mona Seyed; Pour, Elias Khalili; Sefidan, Bahram Bohrani

    2015-01-01

    Purpose: To assess the efficacy of chlorhexidine monotherapy for Acanthamoeba keratitis, and to determine the therapeutic outcomes of concomitant topical corticosteroids. Methods: In this prospective interventional case series, 31 eyes of 31 patients with Acanthamoeba keratitis (AK) were treated with chlorhexidine 0.02% as monotherapy, from April 2010 to April 2011. The diagnosis of AK was made based on clinical manifestations and positive confocal microscopic (confoscan 3.4, Nidek Co. Ltd., Gamagori, Japan) results. We report the percentage of a favorable clinical response within two weeks of initiating treatment, worsening of the infection while receiving chlorhexidine, recovery of visual acuity (VA), duration of treatment with chlorhexidine and corticosteroids, necessity for addition of other anti-Acanthamoeba agents, presence of corneal scar at the end of the treatment, and need for penetrating keratoplasty (PK). Results: Two weeks after initiation of chlorhexidine, improvement in signs and symptoms was observed in 26 (83.9%) patients but 3 eyes required the addition of propamidine. After initial improvement in one patient, the infection worsened, necessitating the addition of Polyhexamethylene Biguanide (PHMB) and propamidine. A total of 26 (83.9%) patients received topical corticosteroids with mean duration of 65.8 ± 45.1 days. In 22 (71%) eyes, final visual acuity was ≥0.80. Improved VA occurred in 29 eyes (93.5%). Optical PK was considered in 3 (9.7%) eyes and a corneal scar developed in 8 (25.8%) eyes. Conclusion: Chlorhexidine is effective for monotherapy in AK and could be a good choice for initiating treatment. After the initial response to anti-Acanthamoeba agents, corticosteroids can be used as adjunctive therapy depending on the clinical condition. PMID:26425310

  17. Dolutegravir as maintenance monotherapy: first experiences in HIV-1 patients.

    PubMed

    Rokx, Casper; Schurink, Carolina A M; Boucher, Charles A B; Rijnders, Bart J A

    2016-06-01

    Dolutegravir is recommended as part of combination ART (cART) for HIV-1-infected patients. Toxicities, drug interactions and costs related to cART still warrant the search for improved treatment options. Dolutegravir's high resistance barrier might make it suitable as antiretroviral maintenance monotherapy. The feasibility of this strategy is currently unknown. This is a prospective case series on five consecutive HIV-1-infected patients on cART without previous virological failure who switched to dolutegravir monotherapy. All were HIV-RNA suppressed <50 copies/mL and had contraindications to current and alternative combinations of antiretroviral drugs. HIV-RNA was measured at baseline, week 4, week 8, week 12 and every 6 weeks thereafter. Patients would be switched back to their original cART upon confirmed HIV-RNA >50 copies/mL. The five patients had been HIV-RNA suppressed <50 copies/mL for ≥1.5 years prior to the initiation of dolutegravir monotherapy. All were on NNRTI-containing regimens at the switch. HIV-RNA remained <50 copies/mL at all timepoints in four patients. One patient, with end-stage renal disease and on calcium supplements, had a pre-cART HIV-RNA of 625 000 copies/mL with a CD4 nadir of 120 cells/mm(3) and had HIV-RNA of 8150 copies/mL at week 30. The dolutegravir Ctrough was 0.18 mg/L. This patient did not have acquired resistance or evidence of adherence problems and HIV-RNA was resuppressed after switching to his former cART. This case series indicates that dolutegravir monotherapy might be a valuable maintenance option in selected HIV-infected patients who are well suppressed on cART, if confirmed by future randomized clinical trials. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  18. Case Reports of Idiopathic Thrombocytopenia Unresponsive to First-Line Therapies Treated With Traditional Herbal Medicines Based on Syndrome Differentiation.

    PubMed

    Yang, Juno; Lee, Beom-Joon; Lee, Jun-Hwan

    The objective of our study is to present two cases showing the effects of traditional Korean herbal medicines based on traditional Korean medicine (TKM) for the treatment of immune thrombocytopenic purpura (ITP). One patient showed no response to treatment with steroids and an immunosuppressive agent. Moreover, liver toxicity and side effects of steroids were evident. However, after he ceased conventional treatment and started to take an herbal medicine, his liver function normalized and the steroid side effects resolved. Ultimately, he achieved complete remission. Another patient with ITP had sustained remission after steroid therapy in childhood, but extensive uterine bleeding and thrombocytopenia recurred when she was 16 years old. She was managed with steroids again for 2 years, but severe side effects occurred, and eventually she ceased taking steroids. She refused a splenectomy, and was then treated with a herbal medicine for 7 months, ultimately leading to sustained remission again. Many patients with resistance to first-line treatments tend to be reluctant to undergo a splenectomy, considered a standard second-line treatment. In conclusion, herbal medicines, based on TKM, may offer alternative treatments for persistent or chronic ITP that is resistant to existing first-line treatments.

  19. Metabolic syndrome in patients on first-line antiretroviral therapy containing zidovudine or tenofovir in rural Lesotho, Southern Africa.

    PubMed

    Labhardt, Niklaus Daniel; Müller, Urs Franz; Ringera, Isaac; Ehmer, Jochen; Motlatsi, Mokete M; Pfeiffer, Karolin; Hobbins, Michael A; Muhairwe, Josephine A; Muser, Juergen; Hatz, Christoph

    2017-06-01

    To assess the prevalence of metabolic syndrome (MetS) among patients in rural Lesotho who are taking first-line antiretroviral therapy (ART) containing either zidovudine or tenofovir disoproxil. Cross-sectional survey in 10 facilities in Lesotho among adult (≥16 years) patients on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line ART for ≥6 months. MetS was defined according to the International Diabetes Federation criteria. Among 1166 patients (65.8% female), 22.2% (95% CI: 19.3-25.3) of women and 6.3% (4.1-9.1) of men met the IDF definition of MetS (P < 0.001). In both sexes, there was no significant difference in MetS prevalence between NNRTIs. However, in women taking zidovudine as nucleoside reverse transcriptase inhibitor (NRTI), MetS prevalence was 27.9%, vs. 18.8% in those taking tenofovir. In the multivariate logistic regression allowing for socio-demographic and clinical covariates, ART containing zidovudine was associated with MetS in women (aOR 2.17 (1.46-3.22), P < 0.001) but not in men. In this study, taking ART containing zidovudine instead of tenofovir disoproxil was an independent predictor of MetS in women but not in men. This finding endorses WHO's recommendation of tenofovir as preferred NRTI. © 2017 John Wiley & Sons Ltd.

  20. Primary Tumor Location as a Predictive Factor for First-line Bevacizumab Effectiveness in Metastatic Colorectal Cancer Patients

    PubMed Central

    He, Wen-Zhuo; Liao, Fang-Xin; Jiang, Chang; Kong, Peng-Fei; Yin, Chen-Xi; Yang, Qiong; Qiu, Hui-Juan; Zhang, Bei; Xia, Liang-Ping

    2017-01-01

    Background: Published papers reported contradictory results about the correlation between bevacizumab effectiveness and primary tumor location of metastatic colorectal cancer (mCRC). Methods: 740 mCRC patients treated with chemotherapy (CT group) and 244 patients treated with bevacizumab plus chemotherapy as first-line setting (CT + B group) were included. Propensity score analyses were used for patients' stratification and matching. Kaplan-Meier curves with log-rank tests were used to detect different overall survival (OS). Results: Patients in CT + B group had similar OS comparing with CT group only when the primary tumor located at right-side colon (20.2 for CT + B versus 19.7 months for CT group, p = 0.269). For left-side colon and rectal cancer patients, significantly longer OS were observed in CT + B than CT group. Conclusion: Our data suggested only patients with left-side colon or rectal cancer could get survival benefit from the addition of bevacizumab to first-line chemotherapy. PMID:28261339

  1. Efficacy of rabbit antithymocyte globulin as first-line treatment of severe aplastic anemia: an Asian multicenter retrospective study.

    PubMed

    Chuncharunee, Suporn; Wong, Raymond; Rojnuckarin, Ponlapat; Chang, Cheng-Shyong; Chang, Kian Meng; Lu, Meng-Yao; Hwang, Wen-Li; Koh, Liang Piu; Chen, Tsai-Yun; Leung, Anskar Yh; Norasetthada, Lalita; Wang, Shih-Chung; Chang, Ming-Chih; Wu, Kang-Hsi; Issaragrisil, Surapol

    2016-10-01

    Due to the unavailability of horse antithymocyte globulin (ATG) in many markets worldwide, patients with severe aplastic anemia (SAA) are limited to the use of rabbit ATG. We aimed to analyze hematologic response and overall survival (OS) of Asian patients treated with rabbit ATG as first-line therapy of SAA. We retrospectively reviewed the medical records of 97 consecutive patients who received rabbit ATG as first-line treatment of SAA from 2006 to 2012 at centers in four Asian countries. The primary endpoint was 6- and 12-month overall response rates (ORR) for patients receiving rabbit ATG within the recommended dose range (2.5-3.75 mg/kg/day). Secondary endpoints included ORR in patients receiving any dose of rabbit ATG and 2-year OS. For patients who received rabbit ATG within the recommended dose range, 6- and 12-month ORRs were 17.4 and 63.6 %, respectively. For patients who received any dose of rabbit ATG, 6- and 12-month ORRs were 24.3 and 68.6 %, respectively. The 2-year OS rate was 86.3 %. Rabbit ATG is effective for treatment of SAA in Asian patients. The 12-month ORR and 2-year OS with rabbit ATG were comparable to historical results obtained with horse ATG.

  2. Combination of rituximab with chlorambucil as first line treatment in patients with mantle cell lymphoma: a highly effective regimen.

    PubMed

    Sachanas, Sotirios; Pangalis, Gerassimos A; Vassilakopoulos, Theodoros P; Korkolopoulou, Penelope; Kontopidou, Flora N; Athanasoulia, Maria; Yiakoumis, Xanthi; Kalpadakis, Christina; Georgiou, Georgios; Masouridis, Stavroula; Moschogiannis, Maria; Tsirkinidis, Pantelis; Pappis, Vassiliki; Kokoris, Styliani I; Siakantaris, Marina P; Panayiotidis, Panayiotis; Angelopoulou, Maria K

    2011-03-01

    The optimal treatment approach for patients with mantle cell lymphoma (MCL) is not well defined. Intensive therapeutic regimens result in high response rates and prolonged progression-free survival but at the expense of significant toxicity. We report here our results of the administration of rituximab plus chlorambucil (R-Chl) as first line treatment in patients with MCL. Twenty consecutively diagnosed patients were treated with this combination in which an induction and a maintenance arm were included. During induction, rituximab was administered at a dose of 375 mg/m(2) on day 1, while chlorambucil was given afterward at a dose of 10 mg/day for 10 consecutive days for eight cycles and then as a single agent for an additional four cycles. Maintenance consisted of rituximab administration every 2 months for 1 year. Most patients had indolent disease features such as a low mantle-cell international prognostic index (MIPI) score. The overall response rate was 95% (90% CR, 5% PR). Among patients in CR, 78% presented a molecular remission. The 3-year progression-free survival was 89%. There were no serious side effects. These results show that the R-Chl combination could be an effective therapeutic option as first line treatment in MCL, especially for patients with indolent disease characteristics.

  3. Antireflux Metal Stent as a First-Line Metal Stent for Distal Malignant Biliary Obstruction: A Pilot Study

    PubMed Central

    Hamada, Tsuyoshi; Isayama, Hiroyuki; Nakai, Yousuke; Togawa, Osamu; Takahara, Naminatsu; Uchino, Rie; Mizuno, Suguru; Mohri, Dai; Yagioka, Hiroshi; Kogure, Hirofumi; Matsubara, Saburo; Yamamoto, Natsuyo; Ito, Yukiko; Tada, Minoru; Koike, Kazuhiko

    2017-01-01

    Background/Aims In distal malignant biliary obstruction, an antireflux metal stent (ARMS) with a funnel-shaped valve is effective as a reintervention for metal stent occlusion caused by reflux. This study sought to evaluate the feasibility of this ARMS as a first-line metal stent. Methods Patients with nonresectable distal malignant biliary obstruction were identified between April and December 2014 at three Japanese tertiary centers. We retrospectively evaluated recurrent biliary obstruction and adverse events after ARMS placement. Results In total, 20 consecutive patients were included. The most common cause of biliary obstruction was pancreatic cancer (75%). Overall, recurrent biliary obstruction was observed in seven patients (35%), with a median time to recurrent biliary obstruction of 246 days (range, 11 to 246 days). Stent occlusion occurred in five patients (25%), the causes of which were sludge and food impaction in three and two patients, respectively. Stent migration occurred in two patients (10%). The rate of adverse events associated with ARMS was 25%: pancreatitis occurred in three patients, cholecystitis in one and liver abscess in one. No patients experienced non-occlusion cholangitis. Conclusions The ARMS as a first-line biliary drainage procedure was feasible. Because the ARMS did not fully prevent stent dysfunction due to reflux, further investigation is warranted. PMID:27282268

  4. Evaluation of Outcome and Tolerability of Combination Chemotherapy with Capecitabine and Oxaliplatin as First Line Therapy in Advanced Gastric Cancer

    PubMed Central

    Mashhadi, Mohammad Ali; Sepehri, Zahra; Bakhshipour, Ali Reza; Zivari, Ali; Danesh, Hossein Ali; Metanat, Hasan Ali; Karimkoshteh, Azra; Hashemi, Seyed Mehdi; Rahimi, Hossein; Kiani, Zohre

    2016-01-01

    Background: Combination chemotherapy is accepted as a high efficacy treatment for gastric cancer, whereas choice of standard treatment is unclear. Multiple chemotherapeutic regimens have been used to achieve higher efficacy and lower toxicity. This study was designed to evaluate the treatment results of advanced gastric cancer with Capecitabine and Oxaliplatin regimen. Subjects and Methods : All cases with documented gastric adenocarcinoma and advanced disease were candidates for receiving Xelox regimen (Capecitabine – 750 mg/m2/twice daily/ 1-14 days and Oxaliplatin 125 mg/m2 in 1st day). Results: Twenty five cases with advanced gastric cancer entered in study while 24 cases continued treatment protocol and were evaluated. Mean age was 59.5 ± 12.1 years (range: 20-75), male and female cases were 66.7% and 33.3%, respectively. All cases received at least four cycles of Xelox regimen. Overall response rate was 74.99% with 29.16% complete response. Overall survival rate was 13 ± 0.53 months and DFS (disease-free survival) was 6 ± 1.09 months. Extremities neuropathy (62.5%), headache (45.8%) and muscle cramps (29.2%) were the most common complains. Haematological changes were rare and 16.7% of cases had mild cytopenia. Treatment related death was not observed. Conclusion: Xelox regimen is a safe and highly effective first line treatment for gastric cancer; however, considering it as first line therapy needs larger studies. PMID:27928475

  5. First-line Bevacizumab and Paclitaxel for HER2-negative Metastatic Breast Cancer: A French Retrospective Observational Study.

    PubMed

    Dieras, Veronique; Pop, Simona; Berger, Frederique; Dujaric, Marie-Eglantine; Beuzeboc, Philippe; Escalup, Laurence; Bidard, François Clement; Cottu, Paul Henri; LE Tourneau, Christophe; Piperno-Neumann, Sophie; Laurence, Valerie; Robain, Mathieu; Asselain, Bernard; Pierga, Jean-Yves

    2017-03-01

    To assess outcomes in patients treated with first-line bevacizumab-containing therapy for human epidermal growth factor receptor (HER)2-negative metastatic breast cancer (mBC) at a single centre with a homogenous standard-of-care. Information on patient and disease characteristics, efficacy, and safety was extracted from computer-based records of all patients receiving first-line bevacizumab-paclitaxel at the Curie Institute, Paris, France, between 2008 and 2011. Median progression-free survival in the 116 treated patients was 13.2 months; median overall survival was 38.4 months. Corresponding values were 9.0 and 18.8 months, respectively, in patients with triple-negative mBC, and 19.4 and 58.8 months, respectively, in patients receiving maintenance endocrine therapy. No new safety signals were seen. Outcomes in patients treated with bevacizumab-paclitaxel at our center were consistent with efficacy in prospective clinical trials, with notable activity in poor-prognosis disease. Maintenance endocrine or oral therapy with bevacizumab after paclitaxel discontinuation was associated with long-term disease control. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  6. Evaluation of Outcome and Tolerability of Combination Chemotherapy with Capecitabine and Oxaliplatin as First Line Therapy in Advanced Gastric Cancer.

    PubMed

    Mashhadi, Mohammad Ali; Sepehri, Zahra; Bakhshipour, Ali Reza; Zivari, Ali; Danesh, Hossein Ali; Metanat, Hasan Ali; Karimkoshteh, Azra; Hashemi, Seyed Mehdi; Rahimi, Hossein; Kiani, Zohre

    2016-10-01

    Background: Combination chemotherapy is accepted as a high efficacy treatment for gastric cancer, whereas choice of standard treatment is unclear. Multiple chemotherapeutic regimens have been used to achieve higher efficacy and lower toxicity. This study was designed to evaluate the treatment results of advanced gastric cancer with Capecitabine and Oxaliplatin regimen. Subjects and Methods: All cases with documented gastric adenocarcinoma and advanced disease were candidates for receiving Xelox regimen (Capecitabine - 750 mg/m(2)/twice daily/ 1-14 days and Oxaliplatin 125 mg/m(2) in 1st day). Results: Twenty five cases with advanced gastric cancer entered in study while 24 cases continued treatment protocol and were evaluated. Mean age was 59.5 ± 12.1 years (range: 20-75), male and female cases were 66.7% and 33.3%, respectively. All cases received at least four cycles of Xelox regimen. Overall response rate was 74.99% with 29.16% complete response. Overall survival rate was 13 ± 0.53 months and DFS (disease-free survival) was 6 ± 1.09 months. Extremities neuropathy (62.5%), headache (45.8%) and muscle cramps (29.2%) were the most common complains. Haematological changes were rare and 16.7% of cases had mild cytopenia. Treatment related death was not observed. Conclusion: Xelox regimen is a safe and highly effective first line treatment for gastric cancer; however, considering it as first line therapy needs larger studies.

  7. KRAS mutations affect prognosis of non-small-cell lung cancer patients treated with first-line platinum containing chemotherapy

    PubMed Central

    Garassino, Marina C.; Shepherd, Frances A.; Piva, Sheila; Caiola, Elisa; Macerelli, Marianna; Bettini, Anna; Lauricella, Calogero; Floriani, Irene; Farina, Gabriella; Longo, Flavia; Bonomi, Lucia; Fabbri, M. Agnese; Veronese, Silvio; Marsoni, Silvia; Broggini, Massimo; Rulli, Eliana

    2015-01-01

    KRAS mutations seem to indicate a poor outcome in Non-Small-Cell Lung Cancer (NSCLC) but such evidence is still debated. The aim of this planned ancillary study within the TAILOR trial was to assess the prognostic value of KRAS mutations in advanced NSCLC patients treated with platinum-based first-line chemotherapy. Patients (N = 540), enrolled in the study in 52 Italian hospitals, were centrally genotyped twice in two independent laboratories for EGFR and KRAS mutational status. Of these, 247 patients were eligible and included in the present study. The primary endpoint was overall survival (OS) according to KRAS mutational status in patients harboring EGFR wild-type. Sixty (24.3%) out of 247 patients harbored KRAS mutations. Median OS was 14.3 months and 10.6 months in wild-type and mutated KRAS patients, respectively (unadjusted Hazard Ratio [HR]=1.41, 95%Confidence Interval [CI]: 1.03-1.94 P = 0.032; adjusted HR=1.39, 95%CI: 1.00-1.94 P = 0.050). This study, with all consecutive patients genotyped, indicates that the presence of KRAS mutations has a mild negative impact on OS in advanced NSCLC patient treated with a first-line platinum-containing regimen. Trial Registration: clinicaltrials.gov identifier NCT00637910 PMID:26416458

  8. Signet Ring Cells and Efficacy of First-line Chemotherapy in Advanced Gastric or Oesogastric Junction Adenocarcinoma.

    PubMed

    Lemoine, Nathalie; Adenis, Antoine; Bouche, Olivier; Duhamel, Alain; Heurgue, Alexandra; Leteurtre, Emmanuelle; Amela, Eric; Salleron, Julia; Hebbar, Mohamed

    2016-10-01

    To evaluate the efficacy of first-line palliative chemotherapy, regarding the presence of signet ring cells (SRC). Retrospective analysis of consecutive patients with locally advanced or metastatic gastric or oesogastric junction adenocarcinoma who received first-line chemotherapy. Response to chemotherapy, progression-free survival (PFS) and overall survival (OS) were compared between SRC and non-SRC (NSRC) groups. Two hundred and three patients were treated, with 57 (28%) having SRC adenocarcinoma. Objective response rate was significantly lower in SRC patients (5.3% vs. 28.1%, p=0.0004). PFS was not significantly different between SRC and NSRC patients (median=3.8 vs. 4.9 months, p=0.07). OS was significantly shorter in SRC patients (median=5.6 vs. 9.4 months, p<0.008). In multivariate analysis SRC was not an independent prognostic factor for OS (hazard ratio (HR)=1.28, p=0.15). Patients with advanced SRC adenocarcinomas seemed to benefit less from chemotherapy, whereas the presence of SRC was not an independent survival prognostic factor. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  9. Monitoring for treatment failure in patients on first-line antiretroviral treatment in resource-constrained settings.

    PubMed

    Lynen, Lutgarde; Van Griensven, Johan; Elliott, Julian

    2010-01-01

    The number of people living with HIV in low-income and middle-income countries (LMICs), who will fail first-line treatment and benefit from regimen switching, will steadily increase in the coming years. The diagnosis of treatment failure in many settings is challenging because of limited access to plasma HIV RNA testing. This article summarizes recent studies in LMICs, investigating the diagnosis of treatment failure. WHO recommended clinico-immunological criteria to identify first-line treatment failure, which have a low sensitivity and positive predictive value. The addition of adherence criteria or alternative clinical and laboratory markers improves performance, but overall the results are suboptimal. This situation leads to both delayed and inappropriately premature switching to more expensive second-line agents. The cost-effectiveness of alternative monitoring strategies is debated, but there is increasing interest in the use of viral load testing to confirm virological failure before switching to second-line therapy. However, access to viral load testing in LMICs remains limited and a simple point-of-care assay is not yet available. Monitoring the efficacy of antiretroviral therapy in LMICs remains a critical challenge. Current research priorities include the development of simpler, cheaper assays and optimizing monitoring strategies based on currently available technologies.

  10. First-line treatment of EGFR-mutated nonsmall cell lung cancer: critical review on study methodology.

    PubMed

    Sebastian, Martin; Schmittel, Alexander; Reck, Martin

    2014-03-01

    Recent advances in understanding the mechanisms of nonsmall cell lung cancer (NSCLC) has led to the development of targeted treatments, including the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib, and the irreversible ErbB family blocker afatinib. Several important activating EGFR mutations have now been identified, which correlate strongly with response to treatment with these agents. Multiple randomised controlled trials have confirmed the association between the presence of activating EGFR mutations and objective response to gefitinib, erlotinib and afatinib, thus demonstrating their superiority over platinum-based chemotherapy as first-line treatment for NSCLC patients with EGFR mutation-positive tumours, and resulting in approval of these agents for use in this setting. It can be tempting to compare outcome data across multiple clinical trials and agents; however, substantial differences in methodology between studies, including investigator versus independent assessment and differences in patient eligibility, makes such comparisons fraught with difficulty. This critical review provides an overview of the evolution of the methodology used in eight phase III trials investigating first-line targeted treatment of NSCLC, identifies key differences in methodology and reporting, and critically assesses how these differences should be taken into account when interpreting the findings from such trials.

  11. Intratympanic steroid injection as a first-line therapy in uremia patients with sudden sensorineural hearing loss.

    PubMed

    Tsai, Hsun-Tien; Hsueh, Naiwei; Huang, Chih-Ming; Lin, Hung-Ching

    2015-08-01

    ITSI as a first-line therapy in uremia patients with SSNHL offers a valid and safe treatment compared with intravenous systemic steroid treatment. A specific pathophysiology caused by possible sodium pump paralysis may be explained for uremia patients with SSNHL. To compare the efficacy of intratympanic steroid injection (ITSI) with that of systemic intravenous steroids as a first-line therapy in uremia patients with sudden sensorineural hearing loss (SSNHL). A total of 23 consecutive uremia patients with SSNHL were enrolled in this study. Patients were divided into two groups: the ITSI group (n = 15) and the non-ITSI group (n = 8), in which patients received intravenous systemic steroid treatment. The two groups were homogeneous in all respects. The hearing improvement and relative gain were statistically significant between the two groups. The value of hearing gain (ΔPTA = PTA pre - PTA post) in the ITSI group and the non-ITSI group was 24.6 ± 16.4dB and 8.4 ± 19.3dB. The value of relative gain (ΔPTA/PTApre) in the ITIS group and the non-ITSI group was 31.1 ± 22% and 9.4 ± 20.5%. In the ITSI group, 11 patients (73.3%) exhibited hearing recovery (ΔPTA > 10 dB).

  12. Ovarian cancer: advances in first-line treatment strategies with a particular focus on anti-angiogenic agents.

    PubMed

    Collinson, Fiona J; Seligmann, Jenny; Perren, Timothy J

    2012-12-01

    Ovarian cancer is an important health concern worldwide. The majority of patients present with advanced disease, and despite initial chemosensitivity, most relapse and die from their disease. Better therapeutic options are urgently required. Maximal surgical debulking in combination with platinum/taxane chemotherapy has been the standard of care in advanced ovarian cancer since the mid-1990s. Trials investigating the addition of a third chemotherapeutic agent have disappointingly failed to demonstrate benefit. Intra-peritoneal therapy demonstrated improvements in outcomes in some trials, but at the cost of increased toxicity and inconvenience. Encouragingly, prospective data has now demonstrated benefits with bevacizumab in both the first-line and relapsed settings; however, interpretation is complex, particularly considering recent data demonstrating non-inferiority of neo-adjuvant chemotherapy with delayed primary surgery, and other data demonstrating a substantial improvement in outcome as a result of first-line paclitaxel dose fractionation. This article reviews the recent advances in ovarian cancer treatment and discusses current management and key areas for future research.

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

    PubMed Central

    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) <400 copies/ml at 12 months from switch to second-line. Logistic regression was used to analyze (1) factors associated with multi-NRTI RAMs at first-line failure and (2) factors associated with virological suppression after 12 months on second-line. Results 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], 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

  14. Protease inhibitor monotherapy is not associated with increased viral replication in lymph nodes.

    PubMed

    Vinuesa, David; Parra-Ruiz, Jorge; Chueca, Natalia; Alvarez, Marta; Muñoz-Medina, Leopoldo; Garcia, Federico; Hernandez-Quero, Jose

    2014-07-31

    There are concerns about residual viremia in sanctuary sites among patients on protease inhibitor monotherapy, so we aimed to study viro-immunological parameters in tonsil's lymphoid tissue of patients on highly active antiretroviral therapy (HAART) and on protease inhibitor monotherapy. Despite fully suppressed serum HIV viral load, we found viral replication in both groups; in addition, more patients had detectable proviral DNA among those on HAART, compared to those on protease inhibitor monotherapy (P = 0.08), supporting the absence of a deleterious effect of protease inhibitor monotherapy.

  15. Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study.

    PubMed

    Robert, Caroline; Dummer, Reinhard; Gutzmer, Ralf; Lorigan, Paul; Kim, Kevin B; Nyakas, Marta; Arance, Ana; Liszkay, Gabriella; Schadendorf, Dirk; Cantarini, Mireille; Spencer, Stuart; Middleton, Mark R

    2013-07-01

    Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients with BRAF-mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of selumetinib and dacarbazine with dacarbazine alone. This double-blind, randomised, placebo-controlled phase 2 study investigated selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment in patients older than 18 years with histologically or cytologically confirmed advanced BRAF-mutant cutaneous or unknown primary melanoma. Patients were randomly assigned by central interactive voice response system (1:1 ratio, block size four) to take either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo; all patients received intravenous dacarbazine (1000 mg/m(2) on day 1 of a 21-day cycle). Patients, investigators, and the study team were masked to the treatment assigned. The primary endpoint was overall survival analysed by intention to treat. This study is registered at ClinicalTrials.gov, NCT00936221. Between July 20, 2009, and April 8, 2010, 91 patients were randomly assigned to receive dacarbazine in combination with selumetinib (n=45) or placebo (n=46). Overall survival did not differ significantly between groups (median 13·9 months, 80% CI 10·2-15·6, in the selumetinib plus dacarbazine group and 10·5 months, 9·6-14·7, in the placebo plus dacarbazine group; hazard ratio [HR] 0·93, 80% CI 0·67-1·28, one-sided p=0·39). However, progression-free survival was significantly improved in the selumetinib plus dacarbazine group versus the placebo plus dacarbazine group (HR 0·63, 80% CI 0·47-0·84, one-sided p=0·021), with a median of 5·6 months (80% CI 4·9-5·9) versus 3·0 months (2·8-4·6), respectively. The most frequent adverse events included nausea (28 [64

  16. First-Line Tests

    MedlinePlus

    ... always require further testing. Cutaneous porphyrias . Measuring total plasma porphyrins is effective for screening patients with skin ... any patient with skin manifestations due to Porphyria. Plasma porphyrins are seldom increased in other medical conditions. ...

  17. Levetiracetam monotherapy for late poststroke seizures in the elderly.

    PubMed

    Kutlu, Gulnihal; Gomceli, Yasemin B; Unal, Yasemin; Inan, Levent E

    2008-10-01

    Stroke is the most common cause of seizures in the elderly. Antiepileptic drugs are used to treat most patients with late poststroke seizures. The aim of this study was to evaluate the efficacy and tolerability of levetiracetam (LEV) in patients aged 60 or older with late-onset poststroke seizures. This prospective study evaluated patients 60 years of age or older, who had at least two late-onset poststroke seizures and were given LEV monotherapy. Demographic data and seizure and stroke characteristics were recorded. Outpatient visits were made after 2, 4, 6, 9, and 12 months and every 3 months thereafter, and the effectiveness and tolerability of LEV were investigated. Thirty-four patients with a mean age of 69.76+/-6.41 were included in this study. Average seizure frequency before treatment was 3.61+/-3.02/month. Mean follow-up time was 17.68+/-3.24 months. At daily doses of 1000-2000 mg, 82.4% of the patients were seizure free, and 7 patients (20.6%) had side effects. LEV was discontinued in one patient because of severe somnolence. Two patients were switched to another antiepileptic drug because of uncontrolled seizures despite an increase in dose up to 3000 mg/day. LEV monotherapy can be effective and well tolerated in elderly patients with late-onset poststroke seizures.

  18. Methotrexate: an effective monotherapy for refractory generalized morphea.

    PubMed

    Platsidaki, Eftychia; Tzanetakou, Vassiliki; Kouris, Anargyros; Stavropoulos, Panagiotis G

    2017-01-01

    Morphea is an inflammatory skin disorder characterized by excessive collagen deposition. Although treatment algorithms for morphea subtypes have been suggested, no consistent recommendations are available. This study attempts to evaluate the clinical efficacy of methotrexate (MTX) as monotherapy in refractory generalized morphea. It is a retrospective study, including 20 patients who had already been treated with various topical and systemic therapies with minimal clinical improvement. Patients received orally MTX at a of dosage 15 mg once weekly. Duration of the use, dosage of MTX, and adverse events were recorded. Clinical assessment of skin lesions was performed and documented. The mean disease duration was 27 months before the initiation of MTX treatment. After 12 months of therapy, very good response was achieved in 6 patients (30%), good response in 10 patients (50%), and fair response in 2 patients (10%), while 2 patients (10%) had failed treatment. Patients were followed up for a mean time interval of 21 months. No serious adverse event was recorded. MTX has been already proved to be an effective and well-tolerated treatment in pediatric patients with morphea. The majority of the group of adult patients showed very good and good improvement when treated with MTX. Although this is an uncontrolled study, MTX monotherapy was considered a safe and effective treatment for the management of this specific clinical subset of morphea in adults.

  19. Trends in First-Line Antiretroviral Therapy in Asia: Results from the TREAT Asia HIV Observational Database

    PubMed Central

    Boettiger, David Charles; Kerr, Stephen; Ditangco, Rossana; Merati, Tuti Parwati; Pham, Thuy Thi Thanh; Chaiwarith, Romanee; Kiertiburanakul, Sasisopin; Li, Chung Ki Patrick; Kumarasamy, Nagalingeswaran; Vonthanak, Saphonn; Lee, Christopher; Van Kinh, Nguyen; Pujari, Sanjay; Wong, Wing Wai; Kamarulzaman, Adeeba; Zhang, Fujie; Yunihastuti, Evy; Choi, Jun Yong; Oka, Shinichi; Ng, Oon Tek; Kantipong, Pacharee; Mustafa, Mahiran; Ratanasuwan, Winai; Sohn, Annette; Law, Matthew

    2014-01-01

    Background Antiretroviral therapy (ART) has evolved rapidly since its beginnings. This analysis describes trends in first-line ART use in Asia and their impact on treatment outcomes. Methods Patients in the TREAT Asia HIV Observational Database receiving first-line ART for ≥6 months were included. Predictors of treatment failure and treatment modification were assessed. Results Data from 4662 eligible patients was analysed. Patients started ART in 2003–2006 (n = 1419), 2007–2010 (n = 2690) and 2011–2013 (n = 553). During the observation period, tenofovir, zidovudine and abacavir use largely replaced stavudine. Stavudine was prescribed to 5.8% of ART starters in 2012/13. Efavirenz use increased at the expense of nevirapine, although both continue to be used extensively (47.5% and 34.5% of patients in 2012/13, respectively). Protease inhibitor use dropped after 2004. The rate of treatment failure or modification declined over time (22.1 [95%CI 20.7–23.5] events per 100 patient/years in 2003–2006, 15.8 [14.9–16.8] in 2007–2010, and 11.6 [9.4–14.2] in 2011–2013). Adjustment for ART regimen had little impact on the temporal decline in treatment failure rates but substantially attenuated the temporal decline in rates of modification due to adverse event. In the final multivariate model, treatment modification due to adverse event was significantly predicted by earlier period of ART initiation (hazard ratio 0.52 [95%CI 0.33–0.81], p = 0.004 for 2011–2013 versus 2003–2006), older age (1.56 [1.19–2.04], p = 0.001 for ≥50 years versus <30years), female sex (1.29 [1.11–1.50], p = 0.001 versus male), positive hepatitis C status (1.33 [1.06–1.66], p = 0.013 versus negative), and ART regimen (11.36 [6.28–20.54], p<0.001 for stavudine-based regimens versus tenofovir-based). Conclusions The observed trends in first-line ART use in Asia reflect changes in drug availability, global treatment recommendations and

  20. Algorithms in the First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma--Analysis Using Diagnostic Nodes.

    PubMed

    Rothermundt, Christian; Bailey, Alexandra; Cerbone, Linda; Eisen, Tim; Escudier, Bernard; Gillessen, Silke; Grünwald, Viktor; Larkin, James; McDermott, David; Oldenburg, Jan; Porta, Camillo; Rini, Brian; Schmidinger, Manuela; Sternberg, Cora; Putora, Paul M

    2015-09-01

    With the advent of targeted therapies, many treatment options in the first-line setting of metastatic clear cell renal cell carcinoma (mccRCC) have emerged. Guidelines and randomized trial reports usually do not elucidate the decision criteria for the different treatment options. In order to extract the decision criteria for the optimal therapy for patients, we performed an analysis of treatment algorithms from experts in the field. Treatment algorithms for the treatment of mccRCC from experts of 11 institutions were obtained, and decision trees were deduced. Treatment options were identified and a list of unified decision criteria determined. The final decision trees were analyzed with a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees. The most common treatment recommendations were determined, and areas of discordance were identified. The analysis revealed heterogeneity in most clinical scenarios. The recommendations selected for first-line treatment of mccRCC included sunitinib, pazopanib, temsirolimus, interferon-α combined with bevacizumab, high-dose interleukin-2, sorafenib, axitinib, everolimus, and best supportive care. The criteria relevant for treatment decisions were performance status, Memorial Sloan Kettering Cancer Center risk group, only or mainly lung metastases, cardiac insufficiency, hepatic insufficiency, age, and "zugzwang" (composite of multiple, related criteria). In the present study, we used diagnostic nodes to compare treatment algorithms in the first-line treatment of mccRCC. The results illustrate the heterogeneity of the decision criteria and treatment strategies for mccRCC and how available data are interpreted and implemented differently among experts. The data provided in the present report should not be considered to serve as treatment recommendations for the management of treatment-naïve patients with multiple metastases from metastatic clear cell renal cell carcinoma outside

  1. Ten-year survival of hepatocellular carcinoma patients undergoing radiofrequency ablation as a first-line treatment

    PubMed Central

    Yang, Wei; Yan, Kun; Goldberg, S Nahum; Ahmed, Muneeb; Lee, Jung-Chieh; Wu, Wei; Zhang, Zhong-Yi; Wang, Song; Chen, Min-Hua

    2016-01-01

    AIM: To investigate the long-term survival and prognostic factors in hepatocellular carcinoma (HCC) patients undergoing radiofrequency ablation (RFA) as a first-line treatment. METHODS: From 2000 to 2013, 316 consecutive patients with 404 HCC (1.0-5.0 cm; mean: 3.2 ± 1.1 cm) underwent ultrasonography-guided percutaneous RFA as a first-line treatment. There were 250 males and 66 females with an average age of 60.1 ± 10.8 years (24-87 years). Patients were followed for 1 year to > 10 years after RFA (234, 181, 136, and 71 for 3, 5, 7, and 10 years, respectively). Overall local response rates and long-term survival rates were assessed. Survival results were generated using Kaplan-Meier estimates, and multivariate analysis was performed using the Cox regression model. RESULTS: In total, 548 RFA sessions were performed and major complications occurred in 10 sessions (1.8%). Local tumor progression and/or new tumor development were observed in 43.3% (132/305) of the patients during the follow-up period. Overall 5- and 10-year survival rates were 49.7% and 28.4%, respectively. Based on multivariate analysis, three factors were identified as independent prognostic factors for overall survival: Child-Pugh classification (HR = 4.054, P < 0.001), portal vein hypertension (HR = 2.743, P = 0.002), and tumor number (HR = 2.693, P = 0.003). The local progression-free 5- and 10-year survival rates were 42.7% and 19.5%. In addition to the Child-Pugh classification and the number of tumors, the number of RFA sessions (HR = 1.550, P = 0.002) was associated with local progression-free survival. CONCLUSION: RFA can achieve acceptable outcomes for HCC patients as a first-line treatment, especially for patients with Child-Pugh class A, patients with a single tumor and patients without portal vein hypertension. PMID:26973395

  2. Rituximab for the first-line maintenance treatment of follicular non-Hodgkin's lymphoma : a NICE single technology appraisal.

    PubMed

    Greenhalgh, Janette; Bagust, Adrian; Boland, Angela; Blundell, Michaela; Oyee, James; Beale, Sophie; Dundar, Yenal; Hockenhull, Juliet; Proudlove, Chris; Chu, Patrick

    2013-05-01

    The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of rituximab (RTX) [Roche] to submit evidence for the clinical and cost effectiveness of RTX as first-line maintenance treatment for patients with follicular non-Hodgkin's lymphoma (fNHL) whose disease has responded to induction therapy with RTX plus cytotoxic chemotherapy (R-CTX) in accordance with the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarizes the ERG's review of the evidence submitted by the manufacturer and provides a summary of the Appraisal Committee's (AC) decision. The clinical evidence was derived from a multi-centred, open-label, randomized phase III study (PRIMA) comparing first-line maintenance treatment with RTX with observation only in 1,018 patients with previously untreated advanced fNHL. Median time to event (MTE) for the primary endpoint of progression-free survival (PFS) in the RTX arm was not estimable due to data immaturity; median PFS in the observation arm was 48.36 months. A statistically significant benefit of RTX maintenance therapy for PFS was reported (hazard ratio [HR] 0.55, 95 % CI 0.44-0.68; p < 0.0001). Statistically significant differences in favour of RTX were also reported for a range of secondary endpoints. Assessment of overall survival benefit could be not made due to insufficient events. The ERG's main concern with the clinical-effectiveness data presented was their lack of maturity. The submitted incremental cost-effectiveness ratio was within the NICE threshold. The ERG questioned the model on a number of grounds, particularly the use of Markov methodology rather than patient simulations, the impact of patient age on the outcome and the projective PFS modelling. The ERG considered it impossible to draw firm conclusions regarding the clinical or cost

  3. Trends in first-line antiretroviral therapy in Asia: results from the TREAT Asia HIV observational database.

    PubMed

    Boettiger, David Charles; Kerr, Stephen; Ditangco, Rossana; Merati, Tuti Parwati; Pham, Thuy Thi Thanh; Chaiwarith, Romanee; Kiertiburanakul, Sasisopin; Li, Chung Ki Patrick; Kumarasamy, Nagalingeswaran; Vonthanak, Saphonn; Lee, Christopher; Van Kinh, Nguyen; Pujari, Sanjay; Wong, Wing Wai; Kamarulzaman, Adeeba; Zhang, Fujie; Yunihastuti, Evy; Choi, Jun Yong; Oka, Shinichi; Ng, Oon Tek; Kantipong, Pacharee; Mustafa, Mahiran; Ratanasuwan, Winai; Sohn, Annette; Law, Matthew

    2014-01-01

    Antiretroviral therapy (ART) has evolved rapidly since its beginnings. This analysis describes trends in first-line ART use in Asia and their impact on treatment outcomes. Patients in the TREAT Asia HIV Observational Database receiving first-line ART for ≥ 6 months were included. Predictors of treatment failure and treatment modification were assessed. Data from 4662 eligible patients was analysed. Patients started ART in 2003-2006 (n = 1419), 2007-2010 (n = 2690) and 2011-2013 (n = 553). During the observation period, tenofovir, zidovudine and abacavir use largely replaced stavudine. Stavudine was prescribed to 5.8% of ART starters in 2012/13. Efavirenz use increased at the expense of nevirapine, although both continue to be used extensively (47.5% and 34.5% of patients in 2012/13, respectively). Protease inhibitor use dropped after 2004. The rate of treatment failure or modification declined over time (22.1 [95%CI 20.7-23.5] events per 100 patient/years in 2003-2006, 15.8 [14.9-16.8] in 2007-2010, and 11.6 [9.4-14.2] in 2011-2013). Adjustment for ART regimen had little impact on the temporal decline in treatment failure rates but substantially attenuated the temporal decline in rates of modification due to adverse event. In the final multivariate model, treatment modification due to adverse event was significantly predicted by earlier period of ART initiation (hazard ratio 0.52 [95%CI 0.33-0.81], p = 0.004 for 2011-2013 versus 2003-2006), older age (1.56 [1.19-2.04], p = 0.001 for ≥ 50 years versus <30 years), female sex (1.29 [1.11-1.50], p = 0.001 versus male), positive hepatitis C status (1.33 [1.06-1.66], p = 0.013 versus negative), and ART regimen (11.36 [6.28-20.54], p<0.001 for stavudine-based regimens versus tenofovir-based). The observed trends in first-line ART use in Asia reflect changes in drug availability, global treatment recommendations and prescriber preferences over the past decade. These changes have contributed to a declining rate of

  4. Neurocognitive Impairment in Patients Treated with Protease Inhibitor Monotherapy or Triple Drug Antiretroviral Therapy

    PubMed Central

    Pérez-Valero, Ignacio; González-Baeza, Alicia; Estébanez, Miriam; Montes-Ramírez, María L.; Bayón, Carmen; Pulido, Federico; Bernardino, José I.; Zamora, Francisco X.; Monge, Susana; Gaya, Francisco; Lagarde, María; Rubio, Rafael; Hernando, Asunción; Arnalich, Francisco; Arribas, José R.

    2013-01-01

    Background In patients who remain virologically suppressed in plasma with triple-drug ART a switch to protease inhibitor monotherapy maintains high rates of suppression; however it is unknown if protease inhibitor monotherapy is associated to a higher rate of neurocognitive impairment. Methods In this observational, cross-sectional study we included patients with plasma virological suppression (≥1 year) without concomitant major neurocognitive confounders, currently receiving for ≥1 year boosted lopinavir or darunavir as monotherapy or as triple ART. Neurocognitive impairment was defined as per the 2007 consensus of the American Association of Neurology. The association between neurocognitive impairment and protease inhibitor monotherapy, adjusted by significant confounders, was analysed. Results Of the 191 included patients - triple therapy: 96, 1–2 years of monotherapy: 40 and >2 years of monotherapy: 55 - proportions (95% CI) with neurocognitive impairment were: overall, 27.2% (20.9–33.6); triple therapy, 31.6% (22.1–41.0); short-term monotherapy, 25.0% (11.3–38.7); long-term monotherapy: 21.4% (10.5–32.3); p = 0.38. In all groups, neurocognitive impairment was mildly symptomatic or asymptomatic by self-report. There were not significant differences in Global Deficit Score by group. In the regression model confounding variables for neurocognitive impairment were years on ART, ethnicity, years of education, transmission category and the HOMA index. Adjusted by these variables the Odds Ratio (95% CI) for neurocognitive impairment of patients receiving short-term monotherapy was 0.85 (0.29–2.50) and for long-term monotherapy 0.40 (0.14–1.15). Conclusions Compared to triple drug antiretroviral therapy, monotherapy with lopinavir/ritonavir or darunavir/ritonavir in patients with adequate plasma suppression was not associated with a higher rate of asymptomatic neurocognitive impairment than triple drug ART. PMID:23936029

  5. Is Atherectomy the Best First-Line Therapy for Limb Salvage in Patients With Critical Limb Ischemia?

    PubMed Central

    Loor, Gabriel; Skelly, Christopher L.; Wahlgren, Carl-Magnus; Bassiouny, Hisham S.; Piano, Giancarlo; Shaalan, Wael

    2010-01-01

    Objective To determine the efficacy of atherectomy for limb salvage compared with open bypass in patients with critical limb ischemia. Methods Ninety-nine consecutive bypass and atherectomy procedures performed for critical limb ischemia between January 2003 and October 2006 were reviewed. Results A total of 99 cases involving TASC C (n = 43, 44%) and D (n = 56, 56%) lesions were treated with surgical bypass in 59 patients and atherectomy in 33 patients. Bypass and atherectomy achieved similar 1-year primary patency (64% vs 63%; P = .2). However, the 1-year limb salvage rate was greater in the bypass group (87% vs 69%; P = .004). In the tissue loss subgroup, there was a greater limb salvage rate for bypass patients versus atherectomy (79% vs 60%; P = .04). Conclusions Patients with critical limb ischemia may do better with open bypass compared with atherectomy as first-line therapy for limb salvage. PMID:19640919

  6. Topical application of LEVORAG® as first-line treatment for chronic anal fissures: a preliminary multicentric study.

    PubMed

    Giordano, P; Mistrangelo, M; Cracco, N; D'Elia, A; Creperio, G; Digito, F; Paduano, R; Tapparo, A; Quinto, S; Villa, E; Pagano, C

    2015-10-01

    The aim of the present study was to assess the safety and efficacy of this new topical agent as a first line treatment in patients with chronic anal fissures. Nine centres were involved in the study. Patients with chronic anal fissures were recruited and received Levorag® for 40 days. Follow-up visits were conducted at 10, 20 and 40 days from the recruitment. Primary outcome was the healing rate, secondary outcome the reduction of pain at the end of the treatment measured with a VAS scale. Fifty patients completed the treatment. No adverse events were recorded. 60% of patients healed completely at the end of the treatment. In those that did not heal the reduction of mean VAS values was 60%. The use of Levorag® on patients affected by chronic anal fissures achieved in the short term results similar to those experienced by more classic local treatments without any side effect.

  7. Amlodipine in hypertension: a first-line agent with efficacy for improving blood pressure and patient outcomes

    PubMed Central

    Fares, Hassan; DiNicolantonio, James J; O'Keefe, James H; Lavie, Carl J

    2016-01-01

    Objectives Hypertension is well established as a major risk factor for cardiovascular disease. Although there is undeniable evidence to support the beneficial effects of antihypertensive therapy on morbidity and mortality, adequate blood pressure management still remains suboptimal. Research into the treatment of hypertension has produced a multitude of drug classes with different efficacy profiles. These agents include β-blockers, diuretics, ACE inhibitors, angiotensin receptor blockers and calcium channel blockers. One of the oldest groups of antihypertensives, the calcium channel blockers are a heterogeneous group of medications. Methods This review paper will focus on amlodipine, a dihydropyridine calcium channel blockers, which has been widely used for 2 decades. Results Amlodipine has good efficacy and safety, in addition to strong evidence from large randomised controlled trials for cardiovascular event reduction. Conclusions Amlodipine should be considered a first-line antihypertensive agent. PMID:27752334

  8. Brief Report: Virologic Monitoring Can Be a Cost-Effective Strategy to Diagnose Treatment Failure on First-Line ART.

    PubMed

    Vandormael, Alain M; Boulware, David R; Tanser, Frank C; Bärnighausen, Till W; Stott, Katharine E; de Oliveira, Tulio

    2016-04-01

    CD4 count testing is perceived to be an affordable strategy to diagnose treatment failure on first-line antiretroviral therapy. We hypothesize that the superior accuracy of viral load (VL) testing will result in less patients being incorrectly switched to more expensive and toxic second-line regimens. Using data from a drug resistance cohort, we show that CD4 testing is approximately double the cost to make 1 correct regimen switch under certain diagnostic thresholds (CD4 = US $499 vs. VL = US $186 or CD4 = US $3031 vs. VL = US $1828). In line with World Health Organization guidelines, our findings show that VL testing can be both an accurate and cost-effective treatment monitoring strategy.

  9. Clinical and radiological control of highly active relapsing-remitting multiple sclerosis with first-line natalizumab.

    PubMed

    Meca-Lallana, José Eustasio; Carreón-Guarnizo, Ester; Hernández-Clares, Rocío; García-Molina, Estefanía; Díaz-Pérez, José; Leon-Hernández, Adelaida; Zamarro-Parra, Joaquín; Martín-Fernández, José Javier

    2017-06-01

    A 33-year-old man with gait instability, weakness of the left lower extremity, decreased visual acuity in the left eye, and urgency and urine incontinence was diagnosed of relapsing-remitting multiple sclerosis. He was treated with natalizumab (300 mg intravenously every 4 weeks) as first-line therapy, which reached at 6 months a favorable clinical evolution and dramatic radiological improvement (T2-weighted lesion load decreased by 50% and no gadolinium-enhancing T1 lesions) sustained over the course of 8 years. This clinical case shows the efficacy of natalizumab in a real-world setting and, particularly, the sustained effect of this drug in the long term as demonstrated by persistent radiological improvement. Natalizumab can be considered as the treatment of choice in relapsing-remitting multiple sclerosis forms presenting with two relapses and gadolinium-enhancing (Gd+) lesions.

  10. Antihyperglycemic Medications: A Claims-Based Estimate of First-Line Therapy Use Before Initialization of Second-Line Medications.

    PubMed

    Tseng, Yi-Ju; Steinberg, Gregory; Fox, Kathe P; Armstrong, Joanne; Mandl, Kenneth D

    2017-09-13

    The American Diabetes Association recommends metformin as first-line therapy for type 2 diabetes. However, nonadherence to antihyperglycemic medication is common, and a clinician could confuse nonadherence with pharmacologic failure, potentially leading to premature prescribing of second-line therapies. We measured metformin use before second-line therapy initialization. This retrospective cross-sectional study used unidentifiable member claims data from individuals covered from 2010 to 2015 by Aetna, a U.S. health benefits company. Beneficiaries with two physician claims or one hospitalization with a type 2 diabetes diagnosis were included. Recommended use of metformin was measured by the proportion of days covered over 60 days. Through sensitivity analysis, we varied estimates of the percentage of beneficiaries who used low-cost generic prescription medication programs. A total of 52,544 individuals with type 2 diabetes were eligible. Of 22,956 patients given second-line treatment, only 1,875 (8.2%) had evidence of recommended use of metformin in the prior 60 days, and 6,441 (28.0%) had no prior claims evidence of having taken metformin. At the top range of sensitivity, only 49.5% patients could have had recommended use. Patients were more likely to be given an additional second-line antihyperglycemic medication or insulin if they were given their initial second-line medication without evidence of recommended use of metformin (P < 0.001). Despite published guidelines, second-line therapy often is initiated without evidence of recommended use of first-line therapy. Apparent treatment failures, which may in fact be attributable to nonadherence to guidelines, are common. Point-of-care and population-level processes are needed to monitor and improve guideline adherence. © 2017 by the American Diabetes Association.

  11. Is open decortication superior to fibrinolytic therapy as a first line treatment in the management of pleural empyema?

    PubMed Central

    Ahmed, Sultan; Azam, Hammad; Basheer, Imran

    2016-01-01

    Objective: To confirm that either Fibrinolytic therapy or open decortication which of the two is an effective First line treatment of pleural empyema. Methods: This prospective comparative study was conducted in the department of surgery Sheikh Zayed Medical College and Hospital, Rahim Yaar Khan. Seventy eight (78) patients were included in this study. There were two groups of patients; Group I (n=35) patients treated with fibrinolytic therapy, Group II (n=43) patients treated with open decortication. Data was entered and analyzed in SPSS v16. Student’s t-test was used for comparison of quantitative variables. Chi-square and Fisher’s Exact test were used for comparison of qualitative variables. P-value ≤ 0.05 was taken as significant difference. Results: There was no significant difference in base baseline characteristics of patients of Group I and II. Incidence of comorbidities was also same between the groups. Most of the patients in Group I and II were in empyema stage III. Fluid cultures was positive in 33 (94.3%) patients in group I and 39 (90.7%) patients in group II. 30 (85.7%) was successfully treated using fibrinolytic therapy but this therapy failed in five (14.3%) patients, two of these patients expired within the hospital. There was only one (2.3%) treatment failure in open decortication Group that patient expired within the hospital (p-value 0.04). Overall duration of hospitalization was significantly high in fibrinolytic group, this was 17.6± 1.95 days versus 12.09± 2.18 days in open decortication group (p-value<0.0001). There was no significant difference regarding operative mortality within the two groups. Conclusion: Open Drainage is associated with better outcomes as compared to fibrinolytic therapy when used as a First line treatment of empyema. PMID:27182233

  12. First line antiretroviral treatment outcomes and durability in HIV-infectedchildren treatedthrough theuniversal coverage health program in Thailand.

    PubMed

    Teeraananchai, Sirinya; Bunupuradah, Torsak; Puthanakit, Thanyawee; Kerr, Stephen J; Ruxrungtham, Kiat; Chaivooth, Suchada; Bhakeecheep, Sorakij; Law, Matthew G; Chokephaibulkit, Kulkanya

    2017-03-10

    We assessed the treatment outcomes on first-line antiretroviral therapy (ART), and factors associated with switching regimen in HIV-infected children treated through the universal coverage health program (UC) in Thailand. Children aged <15 years at ART initiation who had been receiving ART for at least 6 months between 2008 and 2014 through UC were included in the analysis. The Kaplan-Meier method was used to estimate immunological recovery (IMR), immunologic failure (IMF) and virologic failure (VF). Cox models were used to assess predictors of IMR and VF. Competing risk models were used to assess factors associated with switching to a second-line regimen, with death considered as a competing risk. A total of 4,120 children initiated ART at a median (IQR) age of 9.3 (5.8-12.0) years. The median duration of ART was 3.7 years with 17,950 person-years of follow up. 2,805 children achieved IMR and the probability of IMR increased to76% by 3 years after ART initiation. Among 1,054 children switched to second-line regimens; 84% had VF and 19% had IMF. The cumulative rate of switching regimen increased from 4% to 20% from 1 to 3 years after treatment. Children aged ≥ 12 years at ART initiation, starting with NNRTIs, and baseline CD4% < 10% had an increased risk of switching to second-line regimens. Children receiving ART through UC had good treatment outcomes, although a fifth required switching regimen by 3 years. Earlier treatment initiation and avoiding NNRTI first-line regimens in high risk children may prevent treatment failure.

  13. Low muscle attenuation is a prognostic factor for survival in metastatic breast cancer patients treated with first line palliative chemotherapy.

    PubMed

    Rier, Hánah N; Jager, Agnes; Sleijfer, Stefan; van Rosmalen, Joost; Kock, Marc C J M; Levin, Mark-David

    2017-02-01

    Low muscle mass (LMM) and low muscle attenuation (LMA) reflect low muscle quantity and low muscle quality, respectively. Both are associated with a poor outcome in several types of solid malignancies. This study determined the association of skeletal muscle measures with overall survival (OS) and time to next treatment (TNT). A skeletal muscle index (SMI) in cm(2)/m(2) and muscle attenuation (MA) in Hounsfield units (HU) were measured using abdominal CT-images of 166 patients before start of first-line chemotherapy for metastatic breast cancer. Low muscle mass (SMI <41 cm(2)/m(2)), sarcopenic obesity (LMM and BMI ≥30 kg/m(2)) and low muscle attenuation (MA <41 HU and BMI <25 kg/m2 or MA <33 HU and BMI ≥25 kg/m2) were related to OS and TNT. The prevalence of LMM, sarcopenic obesity and LMA were 66.9%, 7.2% and 59.6% respectively. LMM and sarcopenic obesity showed no significant association with OS and TNT, whereas LMA was associated with both lower OS (HR 2.04, 95% CI 1.34-3.12, p = 0.001) and shorter TNT (HR 1.72, 95% CI 1.14-2.62, p = 0.010). Patients with LMA had a median OS and TNT of 15 and 8 months respectively, compared to 23 and 10 months in patients with normal MA. LMA is a prognostic factor for OS and TNT in metastatic breast cancer patients receiving first-line palliative chemotherapy, whereas LMM and sarcopenic obesity are not. Further research is needed to establish what impact LMA should have in daily clinical practice. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Success rates of first-line antibiotics for culture-negative sub-acute and chronic septic arthritis.

    PubMed

    Chuckpaiwong, Bavornrit; Phoompoung, Saravut

    2014-09-01

    A combination of surgical and medical treatment is normally required for patients with septic arthritis. Antibiotics selected for use on these patients are normally based on tissue culture results. However, in sub-acute and chronic septic arthritis cases, the results of the culture are usually negative as a result of prior treatment. The present study will investigate the incidence of culture-negative septic arthritis and the outcomes based on the use of first-line drug antibiotics for the treatment of sub-acute and chronic septic arthritis. For the present study, the authors retrospectively reviewed medical records of surgically treated septic arthritis cases over the past 10 years at Siriraj Hospital. The patient culture results, the antibiotics used, and the results of treatment were all recorded and analyzed. One hundredfifty-three septic arthritis patients were reviewed. Sixty-two patients were classified as having been diagnosed with either sub-acute or chronic septic arthritis. Thirty-six of 62 patients (58.1%) had a negative culture result. In the culture-positive patients, 42.3% had Streptococcus, 26.9% had Staphylococcus aureus, 11.5% had other gram positive bacteria, 15.4% had gram-negative bacteria, and 3.8% had tuberculus infection. In the culture-negative sub-acute and chronic group (36 of 62), 23 patients received Cefazolin, nine patients received Cloxacillin, and four patients received Clindamycin. Successful results were 69.9%, 66.7% and 75%, respectively. The present study reflects that the incidence ofculture-negative, sub-acute and chronic septic arthritis is approximately 58.1%. The first-line class of antibiotics remains the appropriate antibiotic choice for these patients because they are still effective for treatment of septic arthritis in up to 70% of all cases.

  15. Fluoropyrimidine-Based Chemotherapy as First-Line Treatment for Advanced Gastric Cancer: a Bayesian Network Meta-Analysis.

    PubMed

    Zhu, Lucheng; Liu, Jihong; Ma, Shenglin

    2016-10-01

    Fluoropyrimidine-based regimens are the most common treatments in advanced gastric cancer. We used a Bayesian network meta-analysis to identify the optimal fluoropyrimidine-based chemotherapy by comparing their relative efficacy and safety. We systematically searched databases and extracted data from randomized controlled trials, which compared fluoropyrimidine-based regimens as first-line treatment in AGC. The main outcomes were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3 or 4 adverse events (AEs). A total of 12 RCTs of 4026 patients were included in our network meta-analysis. Pooled analysis showed S-1 and capecitabine had a significant OS benefit over 5-Fu, with hazard ratios of 0.90 (95%CI = 0.81-0.99) and 0.88 (95%CI = 0.80-0.96), respectively. The result also exhibited a trend that S-1 and capecitabine prolonged PFS in contrast to 5-Fu, with hazard ratios of 0.84 (95%CI = 0.66-1.02) and 0.84 (95%CI = 0.65-1.03), respectively. Additionally, all the three fluoropyrimidine-based regimens were similar in terms of ORR and grade 3 or 4 AEs. Compared with regimens based on 5-Fu, regimens based on S-1 or capecitabine demonstrated a significant OS improvement without compromise of AEs as first-line treatment in AGC in Asian population. S-1 and capecitabine can be interchangeable according their different emphasis on AEs.

  16. Leg massage therapy promotes psychological relaxation and reinforces the first-line host defense in cancer patients.

    PubMed

    Noto, Yuka; Kitajima, Maiko; Kudo, Mihoko; Okudera, Koichi; Hirota, Kazuyoshi

    2010-12-01

    Patients with cancer suffer a wide range of physical symptoms coupled with psychological stress. Moreover, cancer chemotherapy induces immunosuppression and consequently causes respiratory infections. Massage therapy has been reported to reduce symptoms in cancer patients via an increase in psychosocial relaxation and to enhance and/or improve immune function. In the present study, we determined whether leg massage could induce psychosocial relaxation and activate the first line of the host defense system. To assess effects of rest and leg massage, 15 healthy volunteers rested on a bed for 20 min on the first day, and 3 days later the subjects received a standardized massage of the legs for 20 min with nonaromatic oil. Twenty-nine cancer patients also received the same standardized massage of the legs. Anxiety/stress was assessed before and just after the rest or the massage using the State-Trait Anxiety Inventory (STAI-s) and visual analogue scale (VAS). To evaluate oral immune function, salivary chromogranin A (CgA) and secretory immunoglobulin A (sIgA) levels were measured. In healthy volunteers, rest significantly reduced VAS by 34% and increased sIgA by 61%. In contrast, leg massage significantly reduced both STAI-s and VAS by 24% and 63%, and increased both sIgA and CgA by 104% and 90%, respectively. In cancer patients, leg massage significantly decreased both STAI-s and VAS by 16% and 38%, and increased both salivary CgA and sIgA by 33% and 35%, respectively. Leg massage may promote psychosocial relaxation and reinforce a first-line host defense with an increase in secretion of antimicrobial peptides.

  17. Impact of a shortage of first-line antituberculosis medication on tuberculosis control - United States, 2012-2013.

    PubMed

    2013-05-24

    Tuberculosis (TB) disease is treated in most cases with a regimen of several drugs taken for 6-9 months. Currently, 10 drugs are approved by the Food and Drug Administration (FDA) for treatment of TB. Of these, the four drugs that form the core for first-line treatment regimens are isoniazid (INH), rifampin, ethambutol, and pyrazinamide. In November 2012, the United States began to experience a severe interruption in the supply of INH. To assess the extent of the problem and its impact on TB control programs, a nationwide survey of programs was conducted in January 2013 by the National Tuberculosis Controllers Association (NTCA). The results indicated that the INH shortage was interfering with patient care and could contribute to TB transmission in the United States. This report summarizes the findings of that survey, which showed that 79% of the responding health departments reported difficulties with procuring INH within the last month, with 15% reporting that they no longer had INH and 41% reporting that they would no longer have a supply within 1 month of the survey. Because of local interruptions in INH supply, responding TB programs were changing INH suppliers (69%), prioritizing patients for treatment of latent TB infection (LTBI) (72%), delaying LTBI treatment (68%), and changing to alternative LTBI treatment regimens (88%). Potential solutions for alleviating the INH shortage and averting future shortages include maintaining a national supply of first-line drugs, sharing INH among jurisdictions, working with the World Health Organization's Global Drug Facility to obtain INH from foreign manufacturers, and strengthening reporting of shortages and impending shortages by drug suppliers to FDA.

  18. Biweekly cetuximab and first-line chemotherapy in chinese patients with k-ras wild-type colorectal cancers.

    PubMed

    Chan, Wing-Lok; Lee, Victor Ho Fun; Siu, Wai Kwan Steven; Ho, Pui Ying Patty; Liu, Rico King Yin; Leung, To Wai

    2014-07-01

    The efficacy and safety of using combination chemotherapy with cetuximab as first-line treatment in patients with K-ras wild-type colorectal cancers has been well established. In general, weekly cetuximab was given with biweekly chemotherapy FOLFOX-4 or FOLFIRI, synchronizing them would be appealed to both patients and health care professionals. This Phase II, prospective study investigated the efficacy and safety of using biweekly cetuximab 500 mg/m(2) with chemotherapy FOLFOX-4 or FOLFIRI as first-line treatment for Chinese patients with K-ras wild-type metastatic colorectal cancer. The study endpoints included overall objective response (OR), progression-free survival (PFS), overall survival (OS) and safety. Total 15 Chinese patients (male: 10 [67%]; median age: 60 [range 41-80]) were enrolled. Patients received median 12 cycles (range 2-12) of chemotherapy + cetuximab (FOLFOX-4 + cetuximab: 9 [60%]; FOLFIRI + cetuximab: 6 [40%]). Six patients (40%) with non-progressive disease after 12 cycles of chemotherapy + cetuximab carried on maintenance cetuximab. Median duration of follow-up (FU) was 23.7 months. The OR was 40% (complete response: 0%; partial response: 40%) for a disease control rate of 87%. Median PFS and OS were 7.8 months and 17.9 months respectively. For maintenance cetuximab phase, median PFS since the start of maintenance cetuximab was 6.8 months and median OS was 17.0 months. The only grade 3-4 toxicities were neutropenia (26.7%) in chemotherapy phase and acneiform rashes (16.7%) in maintenance phase. Biweekly cetuximab with combination chemotherapy was effective and safe as weekly dose. Further studies are warranted for the role of maintenance cetuximab.

  19. A Systematic Review and Network Meta-Analysis of Biologic Agents in the First Line Setting for Advanced Colorectal Cancer

    PubMed Central

    Kumachev, Alexander; Yan, Marie; Berry, Scott; Ko, Yoo-Joung; Martinez, Maria C. R.; Shah, Keya; Chan, Kelvin K. W.

    2015-01-01

    Background Epithelial growth factor receptor inhibitors (EGFRis) and bevacizumab (BEV) are used in combination with chemotherapy for the treatment of metastatic colorectal cancer (mCRC). However, few randomized controlled trials (RCTs) have directly compared their relative efficacy on progression-free survival (PFS) and overall survival (OS). Methods We conducted a systematic review of first-line RCTs comparing (1) EGFRis vs. BEV, with chemotherapy in both arms (2) EGFRis + chemotherapy vs. chemotherapy alone, or (3) BEV + chemotherapy vs. chemotherapy alone, using Cochrane methodology. Data on and PFS and OS were extracted using the Parmar method. Pairwise meta-analyses and Bayesian network meta-analyses (NMA) were conducted to estimate the direct, indirect and combined PFS and OS hazard ratios (HRs) comparing EGFRis to BEV. Results Seventeen RCTs contained extractable data for quantitative analysis. Combining direct and indirect data using an NMA did not show a statistical difference between EGFRis versus BEV (PFS HR = 1.11 (95% CR: 0.92–1.36) and OS HR = 0.91 (95% CR: 0.75–1.09)). Direct meta-analysis (3 RCTs), indirect (14 RCTs) and combined (17 RCTs) NMA of PFS HRs were concordant and did not show a difference between EGFRis and BEV. Meta-analysis of OS using direct evidence, largely influenced by one trial, showed an improvement with EGFRis therapy (HR = 0.79 (95% CR: 0.65–0.98)), while indirect and combined NMA of OS did not show a difference between EGFRis and BEV Successive inclusions of trials over time in the combined NMA did not show superiority of EGFRis over BEV. Conclusions Our findings did not support OS or PFS benefits of EGFRis over BEV in first-line mCRC. PMID:26474403

  20. [Cuadruple concomitant non-bismuth therapy vs. classical triple therapy as first line therapy for Helicobacter pylori infection].

    PubMed

    Campillo, Ana; Ostiz, Miriam; Amorena, Edurne; Kutz, Marcos; La Iglesia, Matilde

    2016-09-02

    In a previous study we found that the classical triple therapy for Helicobacter pylori (H. pylori) had low efficacy (under 70%) in our area. After this finding, in mid 2012 quadruple concomitant therapy started to be prescribed in our hospital. The aim of the present study is to compare the efficacy of classical triple therapy and quadruple concomitant therapy without bismuth. Observational retrospective study of prescribed treatments between 1st January 2012 and 5th May 2014 and their efficacy. During the study period 510 patients were prescribed a first line therapy; in 179 cases (35,1%) the combination amoxiciline+clarithromicine+PPI was prescribed during 7-14 days, and 298 patients (58,4%) were treated with amoxicillin+clarithromycin+metronidazole+PPI for 10 days. The quadruple concomitant therapy had a higher efficacy than the classical triple therapy, both in an "intention to treat" (84.8% vs. 65.7%, P=.001) and "per protocol" (86.9% vs. 67.2%, P=.001) analysis. Triple therapy had a higher efficacy when it was prescribed for 10 days compared to 7 days (77.9% vs. 56.5%, P=.005 per "intention to treat" and 77.9% vs. 58.5%, P=.011 "per protocol"). When quadruple concomitant therapy was compared with classical triple therapy prescribed over 10 days no significant differences were found. In our setting, cuadruple concomitant therapy without bismuth has a high efficacy as first line therapy for H. pylori eradication, with much better results than classical triple therapy in the way that it is most widely prescribed (short courses of 7-day with a single dose of omeprazole). Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  1. First-Line Use of Core Needle Biopsy for High-Yield Preliminary Diagnosis of Thyroid Nodules.

    PubMed

    Kim, H C; Kim, Y J; Han, H Y; Yi, J M; Baek, J H; Park, S Y; Seo, J Y; Kim, K W

    2017-02-01

    Although core needle biopsy was introduced as a diagnostic alternative to fine-needle aspiration, the utility and safety of core needle biopsy for thyroid nodules in a large population has yet to be studied comprehensively. We evaluate core needle biopsy yields on a large-scale basis to investigate its potential in the preliminary diagnosis of thyroid nodules. Between March 2005 and December 2013, 2448 initially detected thyroid nodules from 2120 consecutive patients who underwent core needle biopsy were retrospectively evaluated. Of these, 72 thyroid nodules from 63 patients were excluded due to prior fine-needle aspiration attempts. The inconclusive and conclusive result rates, diagnostic accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and unnecessary surgery rate of core needle biopsy were evaluated. With core needle biopsy as the first-line method, the inconclusive result rate was 11.9% (283/2376) and the conclusive result rate was 88.1% (2093/2376). The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of core needle biopsy for the diagnosis of malignancy were 96.7% (1160/1200), 89.7% (347/387), 100% (813/813), 100% (347/347), and 95.3% (813/853), respectively. There were no major complications and 12 minor complications. We have demonstrated that first-line use of core needle biopsy may well improve diagnostic accuracy in thyroid nodules, reducing inconclusive or false-negative results and unnecessary operations. Such benefits underscore the promising role of core needle biopsy in managing thyroid nodules and optimizing related surgical decision-making. © 2017 by American Journal of Neuroradiology.

  2. Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding after cardiac surgery.

    PubMed

    Cappabianca, Giangiuseppe; Mariscalco, Giovanni; Biancari, Fausto; Maselli, Daniele; Papesso, Francesca; Cottini, Marzia; Crosta, Sandro; Banescu, Simona; Ahmed, Aamer B; Beghi, Cesare

    2016-01-06

    Bleeding after cardiac surgery requiring surgical reexploration and blood component transfusion is associated with increased morbidity and mortality. Although prothrombin complex concentrate (PCC) has been used satisfactorily in bleeding disorders, studies on its efficacy and safety after cardiopulmonary bypass are limited. Between January 2005 and December 2013, 3454 consecutive cardiac surgery patients were included in an observational study aimed at investigating the efficacy and safety of PCC as first-line coagulopathy treatment as a replacement for fresh frozen plasma (FFP). Starting in January 2012, PCC was introduced as solely first-line treatment for bleeding following cardiac surgery. After one-to-one propensity score-matched analysis, 225 pairs of patients receiving PCC (median dose 1500 IU) and FFP (median dose 2 U) were included. The use of PCC was associated with significantly decreased 24-h post-operative blood loss (836 ± 1226 vs. 935 ± 583 ml, p < 0.0001). Propensity score-adjusted multivariate analysis showed that PCC was associated with significantly lower risk of red blood cell (RBC) transfusions (odds ratio [OR] 0.50; 95% confidence interval [CI] 0.31-0.80), decreased amount of RBC units (β unstandardised coefficient -1.42, 95% CI -2.06 to -0.77) and decreased risk of transfusion of more than 2 RBC units (OR 0.53, 95% CI 0.38-0.73). Patients receiving PCC had an increased risk of post-operative acute kidney injury (AKI) (OR 1.44, 95% CI 1.02-2.05) and renal replacement therapy (OR 3.35, 95% CI 1.13-9.90). Hospital mortality was unaffected by PCC (OR 1.51, 95% CI 0.84-2.72). In the cardiac surgery setting, the use of PCC compared with FFP was associated with decreased post-operative blood loss and RBC transfusion requirements. However, PCC administration may be associated with a higher risk of post-operative AKI.

  3. Cigarette smoking habit does not reduce the benefit from first line trastuzumab-based treatment in advanced breast cancer patients.

    PubMed

    Santini, Daniele; Vincenzi, Bruno; Adamo, Vincenzo; Addeo, Raffaele; Fusco, Vittorio; Russo, Antonio; Montemurro, Filippo; Roato, Ilaria; Redana, Stefania; Lanzetta, Gaetano; Satolli, Maria Antonietta; Berruti, Alfredo; Leoni, Valentina; Galluzzo, Sara; Antimi, Mauro; Ferraro, Giuseppa; Rossi, Maura; Del Prete, Salvatore; Valerio, Maria Rosaria; Marra, Monica; Caraglia, Michele; Tonini, Giuseppe

    2011-06-01

    Many ErbB2-positive cancers may show intrinsic resistance, and the frequent development of acquired resistance to ErbB-targeted agents represents a substantial clinical problem. The constitutive NF-κB activation in some HER-2/neu positive breast cancer may represent a potential cause of resistance to trastuzumab therapy. Preclinical data revealed that 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the tobacco-specific nitrosamine is able to enhance NF-κB DNA binding activity and theoretically to increase the resistance to trastuzumab. Two hundred and forty-eight women with pathologically confirmed, uni- or bidimensionally measurable, HER-2-positive metastatic breast cancer (MBC) treated with trastuzumab-based therapy as first line combination for metastatic disease were considered eligible. For all included patients data on smoking habit were detectable from medical records. We retrospectively analysed the smoking habits of 248 MBC patients and correlated these habits with activity and efficacy of trastuzumab-based therapy. No statistically significant difference in terms of response rate (RR), time to progression (TTP) and overall survival (OS) was identified between smokers (former plus active smokers) and never smokers. Moreover, no statistically significant difference in terms of RR, TTP and OS was identified either comparing active smokers and former smokers. Moreover, we did not observed any significant statistical difference in terms of TTP and OS between smokers ≥10 cigarettes/day and <10 cigarettes/day. This study clearly showed lack of any correlation between cigarette smoking habit and both activity and efficacy of trastuzumab-based first line therapy in metastatic HER2/neu positive breast cancer patients.

  4. First line treatment of advanced non-small-cell lung cancer – specific focus on albumin bound paclitaxel

    PubMed Central

    Gupta, Neha; Hatoum, Hassan; Dy, Grace K

    2014-01-01

    Lung cancer is the leading cause of cancer mortality worldwide in both men and women. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for more than 80% of cases. Paclitaxel has a broad spectrum of activity against various malignancies, including NSCLC. Paclitaxel is poorly soluble in water and thus, until recently, its commercially available preparations contained a non-ionic solvent Cremophor EL®. Cremophor EL® improves the solubility of paclitaxel and allows its intravenous administration. However, certain side-effects associated with paclitaxel, such as hypersensitivity reactions, myelosuppression, and peripheral neuropathy, are known to be worsened by Cremophor®. Nanoparticle albumin-bound paclitaxel ([nab-paclitaxel] ABRAXANE® ABI-007) is a new generation formulation of paclitaxel that obviates the need for Cremophor®, resulting in a safer and faster infusion without requiring the use of premedications to avoid hypersensitivity. Albumin-binding receptor-mediated delivery and lack of sequestering Cremophor® micelles allow higher intratumoral concentration of pharmacologically active paclitaxel. Multiple clinical trials have demonstrated a superior tolerability profile of nab-paclitaxel in comparison to solvent-bound paclitaxel (sb-paclitaxel). A recent Phase III trial compared the effects of weekly nab-paclitaxel in combination with carboplatin versus sb-paclitaxel in combination with carboplatin given every 3 weeks for first line treatment of NSCLC. This trial highlights the weekly nab-paclitaxel combination as an alternate treatment option for NSCLC, with higher response rate in squamous cell NSCLC and longer survival in elderly patients. This review will focus on the properties of nab-paclitaxel and its use in the first line treatment of NSCLC. PMID:24399877

  5. First line treatment of advanced non-small-cell lung cancer - specific focus on albumin bound paclitaxel.

    PubMed

    Gupta, Neha; Hatoum, Hassan; Dy, Grace K

    2014-01-01

    Lung cancer is the leading cause of cancer mortality worldwide in both men and women. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for more than 80% of cases. Paclitaxel has a broad spectrum of activity against various malignancies, including NSCLC. Paclitaxel is poorly soluble in water and thus, until recently, its commercially available preparations contained a non-ionic solvent Cremophor EL®. Cremophor EL® improves the solubility of paclitaxel and allows its intravenous administration. However, certain side-effects associated with paclitaxel, such as hypersensitivity reactions, myelosuppression, and peripheral neuropathy, are known to be worsened by Cremophor®. Nanoparticle albumin-bound paclitaxel ([nab-paclitaxel] ABRAXANE® ABI-007) is a new generation formulation of paclitaxel that obviates the need for Cremophor®, resulting in a safer and faster infusion without requiring the use of premedications to avoid hypersensitivity. Albumin-binding receptor-mediated delivery and lack of sequestering Cremophor® micelles allow higher intratumoral concentration of pharmacologically active paclitaxel. Multiple clinical trials have demonstrated a superior tolerability profile of nab-paclitaxel in comparison to solvent-bound paclitaxel (sb-paclitaxel). A recent Phase III trial compared the effects of weekly nab-paclitaxel in combination with carboplatin versus sb-paclitaxel in combination with carboplatin given every 3 weeks for first line treatment of NSCLC. This trial highlights the weekly nab-paclitaxel combination as an alternate treatment option for NSCLC, with higher response rate in squamous cell NSCLC and longer survival in elderly patients. This review will focus on the properties of nab-paclitaxel and its use in the first line treatment of NSCLC.

  6. Incidence of adipose tissue alterations in first-line antiretroviral therapy: the LipoICoNa Study.

    PubMed

    Galli, Massimo; Cozzi-Lepri, Alessandro; Ridolfo, Aana Lisa; Gervasoni, Cristina; Ravasio, Laura; Corsico, Laura; Gianelli, Erika; Vaccarezza, Mauro; Vullo, Vincenzo; Cargnel, Antonietta; Minoli, Lorenzo; Coronado, Olga; Giacometti, Andrea; Antinori, Andrea; Antonucci, Giorgio; D'Arminio Monforte, Antonella; Moroni, Mauro

    Adipose tissue alterations (ATAs) are a frequent untoward effect of antiretroviral therapy, the causes of which remain incompletely explained. To assess the incidence of ATAs and to identify the associated risk factors in patients infected with human immunodeficiency virus type 1 starting their first-line antiretroviral treatment. In a multicenter investigation designed to study issues related to the treatment of patients starting antiretroviral therapy, physicians were requested to assess the presence of ATAs at enrollment and every 6 months thereafter. The ATAs were considered altogether and grouped as fat loss (lipoatrophy), adipose tissue accumulation (lipohypertrophy), and combined forms. A total of 655 patients were followed up for a median of 86 weeks; 128 patients (19.6%) were diagnosed as having at least 1 morphologic alteration during the study. Female gender and positivity for hepatitis C virus were independently linked to an increased risk of developing morphologic alterations. Age was another independent correlate of risk of developing ATAs. To have been infected through drug injection was a correlate of reduced risk of ATAs. Stavudine exposure was predictive at borderline statistical significance of lipoatrophy (but not of the other forms), and indinavir exposure was associated with a significantly higher risk of developing combined forms. Patients who started therapy with 2 nucleoside reverse transcriptase inhibitors and subsequently added a protease inhibitor during the follow-up had a significantly higher risk of having ATAs compared with patients who continued taking 2 nucleoside reverse transcriptase inhibitors up to the end of follow-up. Different types of ATAs might derive from distinct pathways and multifactorial causes. Adipose tissue alterations are a frequent and relatively early finding during first-line antiretroviral therapy.

  7. Global Urine Metabolomics in Patients Treated with First-Line Tuberculosis Drugs and Identification of a Novel Metabolite of Ethambutol

    PubMed Central

    Arya, Rakesh; Debnath, Sanjita; Debnath, Rahul; Lodh, Anindita; Bishwal, Subasa Chandra

    2016-01-01

    Population level variation of drug metabolism phenotype (DMP) has great implications in treatment outcome, drug-related side effects, and resistance development. In this study, we used a gas chromatography-time of flight-mass spectrometry (GC-TOF-MS)-based untargeted urine metabolomics approach to understand the DMP of a tuberculosis (TB) patient cohort (n = 20) from Tripura, a state in the northeastern part of India. Urine samples collected at different postdose time points (2 h, 6 h, 12 h, 24 h, 36 h, and 48 h) from these newly diagnosed TB patients receiving first-line anti-TB drugs were analyzed, and we have successfully detected three of the four first-line drugs, viz., isoniazid (INH), ethambutol (ETB), and pyrazinamide (PZA). The majority of their known metabolites, acetyl-isoniazid (AcINH), isonicotinic acid (INA), isonicotinuric acid (INTA), 2,2′-(ethylenediimino)-dibutyric acid (EDBA), 5-hydroxypyrazinamide (5OH-PZA), pyrazinoic acid (POA), and 5-hydroxypyrazinoic acid (5OH-POA), were also detected. Analyzing the variation in abundances of drugs and their known metabolites and calculating the metabolic ratios in these samples, we offer comprehensive DMP information on this small patient cohort that represents Tripura, India. The majority (75%) of these patients are found to be slow acetylators of INH. The average metabolic ratios of POA/PZA and 5OH-POA/POA are 3.16 ± 3.03 and 6.09 ± 6.15, respectively. Employing correlation analysis of the metabolomics metadata and a manual prediction of drug catabolism, we have proposed 2-aminobutyric acid (AABA) as a novel metabolite of ETB. These observations indicate the usefulness of GC-MS-based metabolomics to characterize the DMP at a population level and also to identify novel drug metabolites. PMID:26833163

  8. Unresectable huge sternal and mediastinal metastasis of follicular thyroid carcinoma; radiotherapy as first-line and palliative therapy.

    PubMed

    Nar Demirer, A; Ayturk, S; Tutuncu, N B; Gursoy, A; Pak, Y; Demirag, N G

    2009-04-01

    Distant metastases as initial manifestation of follicular thyroid carcinoma is rare. We report a case of an unusual initial presentation of follicular thyroid carcinoma on follow-up. A 52- year-old woman presented with a 12-month history of progressively enlarging mass in the anterior chest wall. The mass was fixed to the chest wall, measuring 12 x 10 cm in diameter. Computed tomography demonstrated a lobulated soft-tissue mass (17 x 11 x 6 cm) destructing sternum and extending into the anterior mediastinum. There was no lung metastasis. Invasion of tumor to the ascending aorta, superior vena cava, and right atrium could not be excluded. Multiple lymph nodes were observed in the supraclavicular regions. Ultrasonography of the thyroid gland showed 46 x 37 mm nodule in the left lobe with milimetric gross calcifications and cystic-necrotic areas. Hyperthyroidism was detected. Biopsy from this nodule and the sternal mass revealed typical histology of follicular carcinoma. She was considered inoperable. Since there was huge tumor burden and iodinated contrast exposure for several times during evaluation, we decided to treat the patient with external beam radiotherapy (EBRT) rather than radioiodine as first-line therapy. After a course of conventional radiation with 50 Gy in 25 fractions over 4 weeks, encompassing the thyroid bed and the gross disease, tumor regressed remarkably in 6 months. In conclusion, when surgical resection is not possible, EBRT may be used for palliative purpose to obtain local control for extensive disease as first-line therapy. The indications of EBRT for differentiated thyroid cancer still remain poorly defined.

  9. Do Veterans With Posttraumatic Stress Disorder Receive First-Line Pharmacotherapy? Results From the Longitudinal Veterans Health Survey

    PubMed Central

    Greenbaum, Mark A.; Rosen, Craig S.

    2012-01-01

    Objective: Guidelines addressing the treatment of veterans with posttraumatic stress disorder (PTSD) strongly recommend a therapeutic trial of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). This study examined veteran characteristics associated with receiving such first-line pharmacotherapy, as well as how being a veteran of the recent conflicts in Afghanistan and Iraq impact receipt of pharmacotherapy for PTSD. Method: This was a national study of 482 Veterans Affairs (VA) outpatients between the ages of 18 and 69 years who had been newly diagnosed with PTSD (DSM-IV criteria: 309.81) during a VA outpatient visit between May 31, 2006, and December 7, 2007. Participants completed a mailed survey between August 11, 2006, and April 6, 2008. Veterans from the Afghanistan and Iraq conflicts and female veterans were intentionally oversampled. Logistic regression models were developed to predict 2 dependent variables: odds of initiating an SSRI/SNRI and, among veterans who initiated an SSRI/SNRI, odds of receiving an adequate therapeutic trial. Each dependent variable was regressed on a variety of sociodemographic and survey characteristics. Results: Of the 377 veterans prescribed a psychotropic medication, 73% (n = 276) received an SSRI/SNRI, of whom 61% (n = 168) received a therapeutic trial. Afghanistan and Iraq veterans were less likely to receive a therapeutic trial (odds ratio [OR] = 0.45; 95% CI, 0.27–0.75; P < .01), with presence of a comorbid depression diagnosis in the year after the index episode moderating this relationship, which further decreased the odds of completing a therapeutic trial (OR = 0.29; 95% CI, 0.09–0.95; P < .05). Conclusions: Reduced levels of receipt of first-line pharmacotherapy among recent veteran returnees parallel previous findings of less mental health treatment utilization in this population and warrant investigation. PMID:22943028

  10. First-Line Treatment of Metastatic Colorectal Cancer: Interpreting FIRE-3, PEAK, and CALGB/SWOG 80405.

    PubMed

    Elez, Elena; Argilés, Guillem; Tabernero, Josep

    2015-11-01

    The advances made in the therapeutic management of colorectal cancer (CRC) over recent years with the addition of therapies targeting angiogenesis or cell proliferation have positioned bevacizumab, cetuximab, and panitumumab as accepted first-line treatments when combined with FOLFOX or FOLFIRI for RAS wild-type (WT) metastatic CRC. The question has been raised as to the choice of targeted therapy to maximize chances of an optimal outcome. Three studies, the phase III FIRE-3 (AIO KRK-0306), the phase II PEAK, and the recently presented phase III CALGB/SWOG 80405 trial, have addressed this issue face-on, directly comparing the addition of bevacizumab versus cetuximab or panitumumab to FOLFOX/FOLFIRI in terms of efficacy outcomes. None of these studies met their primary endpoint (response rate, progression-free survival or overall survival respectively), meaning we are no closer to being able to categorically define an optimal targeted treatment in the first-line setting for patients with advanced CRC. This led to reflection over study design and further analyses, raising a number of important issues. High-sensitivity analysis of the mutational status of exons identified a population with a "pure" non-RAS-mutated profile showing benefit with anti-epidermal growth factor receptor (anti-EGFR) combinations, particularly in the context of early and greater depth of response. Coherent with a personalized therapeutic approach, the importance of performing individual high-sensitivity extended RAS testing is unequivocal and is currently a requirement in many countries to identify this all-RAS WT population, thus limiting unnecessary exposure and expense in patients unlikely to respond. These three studies, particularly the CALGB/SWOG 80405 trial, mark an important milestone in the roadmap of metastatic CRC treatment, highlighting the need for close analysis to fully exploit the available data.

  11. AZT Impairs Immunological Recovery on First-line ART: Collaborative analysis of cohort studies in Southern Africa

    PubMed Central

    WANDELER, Gilles; GSPONER, Thomas; MULENGA, Lloyd; GARONE, Daniela; WOOD, Robin; MASKEW, Mhairi; PROZESKY, Hans; HOFFMANN, Christopher; EHMER, Jochen; DICKINSON, Diana; DAVIES, Mary-Ann; EGGER, Matthias; KEISER, Olivia

    2013-01-01

    Objectives Zidovudine (AZT) is recommended for first-line antiretroviral therapy (ART) in resource limited settings. AZT may, however, lead to anemia and impaired immunological response. We compared CD4 counts over 5 years between patients starting ART with and without AZT in Southern Africa. Design Cohort study Methods Patients aged ≥16 years who started first-line ART in South Africa, Botswana, Zambia or Lesotho were included. We used linear mixed-effect models to compare CD4 cell count trajectories between patients on AZT-containing regimens and patients on other regimens, censoring follow-up at first treatment change. Impaired immunological recovery, defined as a CD4 count below 100 cells/μl at 1 year, was assessed in logistic regression. Analyses were adjusted for baseline CD4 count and haemoglobin level, age, gender, type of regimen, viral load monitoring and calendar year. Results 72,597 patients starting ART, including 19,758 (27.2%) on AZT, were analysed. Patients on AZT had higher CD4 cell counts (150 vs.128 cells/μl) and haemoglobin level (12.0 vs. 11.0 g/dl) at baseline, and were less likely to be female than those on other regimens. Adjusted differences in CD4 counts between regimens containing and not containing AZT were −16 cells/μl (95% CI −18 to −14) at 1 year and −56 cells/μl (95% CI −59 to −52) at 5 years. Impaired immunological recovery was more likely with AZT compared to other regimens (odds ratio 1.40, 95% CI 1.22–1.61). Conclusions In Southern Africa AZT is associated with inferior immunological recovery compared to other backbones. Replacing AZT with another NRTI could avoid unnecessary switches to second-line ART. PMID:23660577

  12. Rituximab as first-line treatment for the management of adult patients with non-severe hemophilia A and inhibitors.

    PubMed

    Lim, M Y; Nielsen, B; Lee, K; Kasthuri, R S; Key, N S; Ma, A D

    2014-06-01

    The role of immunosuppression in the management of patients with congenital hemophilia and inhibitors is uncertain. The use of rituximab has been limited to case reports and case series. In most reports, rituximab was used as second-line or third-line treatment following failure of conventional immune tolerance induction therapy, and more commonly in pediatric patients. The objective of this study was to describe our experience with rituximab for the eradication of factor VIII inhibitors in adult patients with non-severe hemophilia A. We retrospectively reviewed the medical records of adult patients with non-severe hemophilia A and a diagnosis of FVIII inhibitor treated with rituximab (four weekly doses of 375 mg m(-2) ) as first-line treatment at our hemophilia center. We identified nine consecutive adult patients with hemophilia A (moderate, n = 5; mild, n = 4) at our institution between 2000 and 2013, with a median age of 54 years (range, 24-77 years) at the time of inhibitor diagnosis. No patient received concomitant immune tolerance induction therapy. All nine patients had successful eradication of FVIII inhibitors. The median time from the first dose of rituximab to a clinical response was 95 days (range, 12-278 days). The median follow-up was 56 months (range, 13-139 months). Following inhibitor eradication, eight patients were rechallenged with FVIII concentrates. Two patients developed inhibitor recurrence associated with surgery. This case series demonstrates that rituximab is a useful first-line treatment to achieve sustained inhibitor eradication in adult patients with non-severe hemophilia A. © 2014 International Society on Thrombosis and Haemostasis.

  13. Cost effectiveness of personalized therapy for first-line treatment of stage IV and recurrent incurable adenocarcinoma of the lung.

    PubMed

    Handorf, Elizabeth A; McElligott, Sean; Vachani, Anil; Langer, Corey J; Bristol Demeter, Mirar; Armstrong, Katrina; Asch, David A

    2012-09-01

    Patients with epidermal growth factor receptor (EGFR) mutation-positive stage IV adenocarcinoma have improved survival with tyrosine kinase inhibitor (TKI) treatments, but the cost effectiveness of personalized first-line therapy using EGFR mutation testing is unknown. We created a decision analytic model comparing the costs and effects of platinum combination chemotherapy with personalized therapy in which patients with EGFR mutation-positive tumors were treated with erlotinib. We used two testing strategies: testing only those with tissue available and performing a repeat biopsy if tissue was not available versus three nontargeted chemotherapy regimens (ie, carboplatin and paclitaxel; carboplatin and pemetrexed; and carboplatin, pemetrexed, and bevacizumab). Compared with a carboplatin plus paclitaxel regimen, targeted therapy based on testing available tissue yielded an incremental cost-effectiveness ratio (ICER) of $110,644 per quality-adjusted life year (QALY), and the rebiopsy strategy yielded an ICER of $122,219 per QALY. Probabilistic sensitivity analysis revealed substantial uncertainty around these point estimates. With a willingness to pay of $100,000 per QALY, the testing strategy was cost effective 58% of the time, and the rebiopsy strategy was cost effective 54% of the time. Personalized therapy with an EGFR TKI was more favorable when the nontargeted chemotherapy regimen was more expensive. Compared with carboplatin, pemetrexed, and bevacizumab, ICERs were $25,547 per QALY for the testing strategy and $44,036 per QALY for the rebiopsy strategy. Although specific clinical circumstances should guide therapy, our cost-effectiveness analysis supports the strategy of testing for EGFR mutations in patients with stage IV or recurrent adenocarcinoma of the lung, rebiopsying patients if insufficient tissue is available for testing, and treating patients with EGFR mutations with erlotinib as first-line therapy.

  14. Update on the first-line treatment for Helicobacter pylori infection - a continuing challenge from an old enemy.

    PubMed

    Huang, Chih-Chieh; Tsai, Kuo-Wang; Tsai, Tzung-Jiun; Hsu, Ping-I

    2017-01-01

    Because the prevalence of antibiotic resistance markedly increases with time worldwide, anti-H. pylori treatment is continuing to be a great challenge forsphysicians in clinical practice. The Real-world Practice & Expectation of Asia-Pacific Physicians and Patients in Helicobacter Pylori Eradication (REAP-HP) Survey demonstrated that the accepted minimal eradication rate of anti-H. pylori regimen in H. pylori-infected patients was 91%. The Kyoto Consensus Report on Helicobacter Pylori Gastritis also recommended that, within any region, only regimens which reliably produce eradication rates of ≥90% in that population should be used for empirical treatment. This article is aimed to review current first-line eradication regimens with a per-protocol eradication rate exceeding 90% in most geographic areas. In regions with low (≦15%) clarithromycin resistance, 14-day hybrid (or reverse hybrid), 10 ~ 14-day sequential, 7 ~ 14-day concomitant, 10 ~ 14-day bismuth quadruple or 14-day triple therapy can achieve a high eradication rate in the first-line treatment of H. pylori infection. However, in areas with high (>15%) clarithromycin resistance, standard triple therapy should be abandoned because of low eradication efficacy, and 14-day hybrid (or reverse hybrid), 10 ~ 14-day concomitant or 10 ~ 14-day bismuth quadruple therapy are the recommended regimens. If no recent data of local antibiotic resistances of H. pylori strains are available, universal high efficacy regimens such as 14-day hybrid (or reverse hybrid), concomitant or bismuth quadruple therapy can be adopted to meet the recommendation of consensus report and patients' expectation.

  15. Point-Counterpoint: Large Multiplex PCR Panels Should Be First-Line Tests for Detection of Respiratory and Intestinal Pathogens.

    PubMed

    Schreckenberger, Paul C; McAdam, Alexander J

    2015-10-01

    The first FDA-approved multiplex PCR panel for a large number of respiratory pathogens was introduced in 2008. Since then, other PCR panels for detection of several respiratory and gastrointestinal pathogens have been approved by the FDA and are commercially available, and more such panels are likely to become available. These assays detect 12 to 20 pathogens, and some include pathogens that typically cause different manifestations of infection, although they infect the same organ system. Some of these tests are labor-intensive, while others require little labor, and all of them are expensive, both for the laboratory and for the patient or insurer. They include a bundle of tests with limited or no options for selecting which tests will be performed. Laboratories and hospitals have adopted different strategies for offering these assays. Some have implemented strategies to limit the use of the tests, such as limiting the frequency with which patients can be tested, restricting testing to specific groups of patients (e.g., immunocompromised patients), or providing education to encourage the use of less expensive tests before using large multiplex panels. Others have offered these assays without limiting their use, either relying on the ordering provider to exercise good judgment or because such assays are thought to be appropriate for first-line diagnostic testing. In this Point-Counterpoint, Paul Schreckenberger of Loyola University Medical Center explains why his laboratory offers these assays without restriction. Alex McAdam of Boston's Children Hospital explains the concerns about the use of these assays as first-line tests and why some limitations on their use might be appropriate. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  16. Point-Counterpoint: Large Multiplex PCR Panels Should Be First-Line Tests for Detection of Respiratory and Intestinal Pathogens

    PubMed Central

    2015-01-01

    The first FDA-approved multiplex PCR panel for a large number of respiratory pathogens was introduced in 2008. Since then, other PCR panels for detection of several respiratory and gastrointestinal pathogens have been approved by the FDA and are commercially available, and more such panels are likely to become available. These assays detect 12 to 20 pathogens, and some include pathogens that typically cause different manifestations of infection, although they infect the same organ system. Some of these tests are labor-intensive, while others require little labor, and all of them are expensive, both for the laboratory and for the patient or insurer. They include a bundle of tests with limited or no options for selecting which tests will be performed. Laboratories and hospitals have adopted different strategies for offering these assays. Some have implemented strategies to limit the use of the tests, such as limiting the frequency with which patients can be tested, restricting testing to specific groups of patients (e.g., immunocompromised patients), or providing education to encourage the use of less expensive tests before using large multiplex panels. Others have offered these assays without limiting their use, either relying on the ordering provider to exercise good judgment or because such assays are thought to be appropriate for first-line diagnostic testing. In this Point-Counterpoint, Paul Schreckenberger of Loyola University Medical Center explains why his laboratory offers these assays without restriction. Alex McAdam of Boston's Children Hospital explains the concerns about the use of these assays as first-line tests and why some limitations on their use might be appropriate. PMID:25762770

  17. Global Urine Metabolomics in Patients Treated with First-Line Tuberculosis Drugs and Identification of a Novel Metabolite of Ethambutol.

    PubMed

    Das, Mrinal Kumar; Arya, Rakesh; Debnath, Sanjita; Debnath, Rahul; Lodh, Anindita; Bishwal, Subasa Chandra; Das, Anjan; Nanda, Ranjan Kumar

    2016-04-01

    Population level variation of drug metabolism phenotype (DMP) has great implications in treatment outcome, drug-related side effects, and resistance development. In this study, we used a gas chromatography-time of flight-mass spectrometry (GC-TOF-MS)-based untargeted urine metabolomics approach to understand the DMP of a tuberculosis (TB) patient cohort (n= 20) from Tripura, a state in the northeastern part of India. Urine samples collected at different postdose time points (2 h, 6 h, 12 h, 24 h, 36 h, and 48 h) from these newly diagnosed TB patients receiving first-line anti-TB drugs were analyzed, and we have successfully detected three of the four first-line drugs,viz, isoniazid (INH), ethambutol (ETB), and pyrazinamide (PZA). The majority of their known metabolites, acetyl-isoniazid (AcINH), isonicotinic acid (INA), isonicotinuric acid (INTA), 2,2'-(ethylenediimino)-dibutyric acid (EDBA), 5-hydroxypyrazinamide (5OH-PZA), pyrazinoic acid (POA), and 5-hydroxypyrazinoic acid (5OH-POA), were also detected. Analyzing the variation in abundances of drugs and their known metabolites and calculating the metabolic ratios in these samples, we offer comprehensive DMP information on this small patient cohort that represents Tripura, India. The majority (75%) of these patients are found to be slow acetylators of INH. The average metabolic ratios of POA/PZA and 5OH-POA/POA are 3.16 ± 3.03 and 6.09 ± 6.15, respectively. Employing correlation analysis of the metabolomics metadata and a manual prediction of drug catabolism, we have proposed 2-aminobutyric acid (AABA) as a novel metabolite of ETB. These observations indicate the usefulness of GC-MS-based metabolomics to characterize the DMP at a population level and also to identify novel drug metabolites.

  18. Comparative Long-Term Effectiveness of a Monotherapy with Five Antiepileptic Drugs for Focal Epilepsy in Adult Patients: A Prospective Cohort Study

    PubMed Central

    Zhu, Pan; He, Ru-Qian; Bao, Yi-Xin; Zheng, Rong-Yuan; Xu, Hui-Qin

    2015-01-01

    Objective To evaluate and compare long-term effectiveness of five antiepileptic drugs (AEDs) for monotherapy of adult patients with focal epilepsy in routine clinical practice. Methods Adult patients with focal epilepsy, who were prescribed with carbamazepine (CBZ), valproate (VPA), lamotrigine (LTG), topiramate (TPM), or oxcarbazepine (OXC) as monotherapy, during the period from January 2004 to June 2012 registered in Wenzhou Epilepsy Follow Up Registry Database (WEFURD), were included in the study. Prospective long-term follow-up was conducted until June 2013. The endpoints were time to treatment failure, time to seizure remission, and time to first seizure. Results This study included 654 patients: CBZ (n=125), VPA (n=151), LTG (n=135), TPM (n=76), and OXC (n=167). The retention rates of CBZ, VPA, LTG, TPM, and OXC at the third year were 36.1%, 32.4%, 57.6%, 37.9%, and 41.8%, respectively. For time to treatment failure, LTG was significantly better than CBZ and VPA (LTG vs. CBZ, hazard ratio, [HR] 0.80 [95% confidence interval: 0.67-0.96], LTG vs. VPA, 0.53 [0.37-0.74]); TPM was worse than LTG (TPM vs. LTG, 1.77 [1.15-2.74]), and OXC was better than VPA (0.86 [0.78-0.96]). After initial target doses, the seizure remission rates of CBZ, VPA, LTG, TPM, and OXC were 63.0%, 77.0%, 83.6%, 67.9%, and 75.3%, respectively. LTG was significantly better than CBZ (1.44 [1.15-1.82]) and OXC (LTG vs. OXC, 0.76 [0.63-0.93]); OXC was less effective than LTG in preventing the first seizure (1.20 [1.02-1.40]). Conclusion LTG was the best, OXC was better than VPA only, while VPA was the worst. The others were equivalent for comparisons between five AEDs regarding the long-term treatment outcomes of monotherapy for adult patients with focal epilepsy in a clinical practice. For selecting AEDs for these patients among the first-line drugs, LTG is an appropriate first choice; others are reservation in the first-line but VPA is not. PMID:26147937

  19. Comparative Long-Term Effectiveness of a Monotherapy with Five Antiepileptic Drugs for Focal Epilepsy in Adult Patients: A Prospective Cohort Study.

    PubMed

    Zeng, Qing-Yi; Fan, Tian-Tian; Zhu, Pan; He, Ru-Qian; Bao, Yi-Xin; Zheng, Rong-Yuan; Xu, Hui-Qin

    2015-01-01

    To evaluate and compare long-term effectiveness of five antiepileptic drugs (AEDs) for monotherapy of adult patients with focal epilepsy in routine clinical practice. Adult patients with focal epilepsy, who were prescribed with carbamazepine (CBZ), valproate (VPA), lamotrigine (LTG), topiramate (TPM), or oxcarbazepine (OXC) as monotherapy, during the period from January 2004 to June 2012 registered in Wenzhou Epilepsy Follow Up Registry Database (WEFURD), were included in the study. Prospective long-term follow-up was conducted until June 2013. The endpoints were time to treatment failure, time to seizure remission, and time to first seizure. This study included 654 patients: CBZ (n=125), VPA (n=151), LTG (n=135), TPM (n=76), and OXC (n=167). The retention rates of CBZ, VPA, LTG, TPM, and OXC at the third year were 36.1%, 32.4%, 57.6%, 37.9%, and 41.8%, respectively. For time to treatment failure, LTG was significantly better than CBZ and VPA (LTG vs. CBZ, hazard ratio, [HR] 0.80 [95% confidence interval: 0.67-0.96], LTG vs. VPA, 0.53 [0.37-0.74]); TPM was worse than LTG (TPM vs. LTG, 1.77 [1.15-2.74]), and OXC was better than VPA (0.86 [0.78-0.96]). After initial target doses, the seizure remission rates of CBZ, VPA, LTG, TPM, and OXC were 63.0%, 77.0%, 83.6%, 67.9%, and 75.3%, respectively. LTG was significantly better than CBZ (1.44 [1.15-1.82]) and OXC (LTG vs. OXC, 0.76 [0.63-0.93]); OXC was less effective than LTG in preventing the first seizure (1.20 [1.02-1.40]). LTG was the best, OXC was better than VPA only, while VPA was the worst. The others were equivalent for comparisons between five AEDs regarding the long-term treatment outcomes of monotherapy for adult patients with focal epilepsy in a clinical practice. For selecting AEDs for these patients among the first-line drugs, LTG is an appropriate first choice; others are reservation in the first-line but VPA is not.

  20. Virological efficacy of PI monotherapy for HIV-1 in clinical practice

    PubMed Central

    El Bouzidi, Kate; Collier, Dami; Nastouli, Eleni; Copas, Andrew J.; Miller, Robert F.; Gupta, Ravindra K.

    2016-01-01

    Background Clinical trials of PI monotherapy indicate that most participants maintain viral suppression and emergent protease resistance is rare. However, outcomes among patients receiving PI monotherapy for clinical reasons, such as toxicity or adherence issues, are less well studied. Methods An observational study of patients attending an HIV treatment centre in London, UK, who had received PI monotherapy between 2004 and 2013, was conducted using prospectively collected clinical data and genotypic resistance reports. Survival analysis techniques were used to examine the times to virological failure and treatment discontinuation. Results Ninety-five patients had PI monotherapy treatment for a median duration of 126 weeks. Virological failure occurred during 64% of episodes and 8% of patients developed emergent protease mutations. We estimate failure occurs in half of episodes within 2 years following initiation. Where PI monotherapy was continued following virological failure, 68% of patients achieved viral re-suppression. Despite a high incidence of virological failure, many patients continued PI monotherapy and 79% of episodes were ongoing at the end of the study. The type of PI used, the presence of baseline protease mutations and the plasma HIV RNA at initiation did not have a significant impact on treatment outcomes. Conclusions There was a higher incidence of virological failure and emerging resistance in our UK clinical setting than described in PI monotherapy clinical trials and other European observational studies. Despite this, many patients continued PI monotherapy and regained viral suppression, indicating this strategy remains a viable option in certain individuals following careful clinical evaluation. PMID:27402006

  1. Effectiveness of First-Line Management Strategies for Stage I Follicular Lymphoma: Analysis of the National LymphoCare Study

    PubMed Central

    Friedberg, Jonathan W.; Byrtek, Michelle; Link, Brian K.; Flowers, Christopher; Taylor, Michael; Hainsworth, John; Cerhan, James R.; Zelenetz, Andrew D.; Hirata, Jamie; Miller, Thomas P.

    2012-01-01

    Purpose The optimal management of stage I follicular lymphoma, according to consensus guidelines, is based on uncontrolled experiences of select institutions. Diverse treatment approaches are used despite guidelines that recommend radiation therapy (XRT). Patients and Methods We analyzed outcomes of patients with stage I follicular lymphoma enrolled onto the National LymphoCare database. Results Of 471 patients with stage I follicular lymphoma, 206 patients underwent rigorous staging as defined by both a bone marrow aspirate and biopsy and an imaging study (a computed tomography [CT] scan of the whole body, a positron emission tomography [PET]/CT scan, or both). Rigorously staged patients had superior progression-free survival (PFS) compared with nonrigorously staged patients (hazard ratio [HR], 0.63). Treatments given to rigorously staged patients were rituximab/chemotherapy (R-chemo; 28%), XRT (27%), observation (17%), systemic therapy + XRT (13%), rituximab monotherapy (12%), and other (3%). With a median follow-up of 57 months for PFS, there were 44 progression events (in 21% of patients) for rigorously staged patients. For these patients, PFS was significantly improved with either R-chemo or systemic therapy + XRT compared with patients receiving XRT alone after adjustment for histology, LDH, and the presence of B symptoms. There were no differences in overall survival. Conclusion In this largest, prospectively enrolled group of patients with stage I follicular lymphoma, variable treatment approaches resulted in similar excellent outcomes, which challenges the paradigm that XRT should be standard for this presentation. PMID:22915662

  2. Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study.

    PubMed

    Friedberg, Jonathan W; Byrtek, Michelle; Link, Brian K; Flowers, Christopher; Taylor, Michael; Hainsworth, John; Cerhan, James R; Zelenetz, Andrew D; Hirata, Jamie; Miller, Thomas P

    2012-09-20

    The optimal management of stage I follicular lymphoma, according to consensus guidelines, is based on uncontrolled experiences of select institutions. Diverse treatment approaches are used despite guidelines that recommend radiation therapy (XRT). We analyzed outcomes of patients with stage I follicular lymphoma enrolled onto the National LymphoCare database. Of 471 patients with stage I follicular lymphoma, 206 patients underwent rigorous staging as defined by both a bone marrow aspirate and biopsy and an imaging study (a computed tomography [CT] scan of the whole body, a positron emission tomography [PET]/CT scan, or both). Rigorously staged patients had superior progression-free survival (PFS) compared with nonrigorously staged patients (hazard ratio [HR], 0.63). Treatments given to rigorously staged patients were rituximab/chemotherapy (R-chemo; 28%), XRT (27%), observation (17%), systemic therapy + XRT (13%), rituximab monotherapy (12%), and other (3%). With a median follow-up of 57 months for PFS, there were 44 progression events (in 21% of patients) for rigorously staged patients. For these patients, PFS was significantly improved with either R-chemo or systemic therapy + XRT compared with patients receiving XRT alone after adjustment for histology, LDH, and the presence of B symptoms. There were no differences in overall survival. In this largest, prospectively enrolled group of patients with stage I follicular lymphoma, variable treatment approaches resulted in similar excellent outcomes, which challenges the paradigm that XRT should be standard for this presentation.

  3. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial.

    PubMed

    Rini, Brian I; Stenzl, Arnulf; Zdrojowy, Romauld; Kogan, Mikhail; Shkolnik, Mikhail; Oudard, Stephane; Weikert, Steffen; Bracarda, Sergio; Crabb, Simon J; Bedke, Jens; Ludwig, Joerg; Maurer, Dominik; Mendrzyk, Regina; Wagner, Claudia; Mahr, Andrea; Fritsche, Jens; Weinschenk, Toni; Walter, Steffen; Kirner, Alexandra; Singh-Jasuja, Harpreet; Reinhardt, Carsten; Eisen, Tim

    2016-11-01

    In a phase 2 study in patients with metastatic renal cell carcinoma, overall survival was associated with T-cell responses against IMA901, a vaccine consisting of ten tumour-associated peptides. In this phase 3 trial, we aimed to determine the clinical effect of adding IMA901 to sunitinib, the standard first-line treatment in metastatic renal cell carcinoma with postulated favourable immunomodulatory effects. The IMPRINT study is an open-label, randomised, controlled, phase 3 trial done at 124 clinical sites in 11 countries. HLA-A*02-positive patients (aged ≥18 years) with treatment-naive, histologically confirmed metastatic or locally advanced (or both) clear-cell renal cell carcinoma were randomly assigned (3:2) to receive sunitinib plus up to ten intradermal vaccinations of IMA901 (4·13 mg) and granulocyte macrophage colony-stimulating factor (75 μg), with one dose of cyclophosphamide (300 mg/m(2)) 3 days before the first vaccination, or to receive sunitinib alone. Sunitinib (50 mg) was given orally once daily, with each cycle defined as 4 weeks on treatment followed by 2 weeks off treatment, until progression of disease as determined by the investigator, death, or withdrawal of consent. Block randomisation (block size five) was done centrally using an interactive web response system, stratified by prognostic risk, geographical region, and previous nephrectomy. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival from randomisation until death of any cause as determined by the investigator, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01265901. Between Dec 22, 2010, and Dec 15, 2012, we screened 1171 patients, of whom 339 were randomly assigned to receive sunitinib plus IMA901 (n=204) or sunitinib monotherapy (n=135). Patients had a median follow-up of 33·27 months (IQR 29·92-35·64). Median overall survival did not differ significantly between the

  4. Cost-Effectiveness of Tenofovir Instead of Zidovudine for Use in First-Line Antiretroviral Therapy in Settings without Virological Monitoring

    PubMed Central

    von Wyl, Viktor; Cambiano, Valentina; Jordan, Michael R.; Bertagnolio, Silvia; Miners, Alec; Pillay, Deenan; Lundgren, Jens; Phillips, Andrew N.

    2012-01-01

    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), which

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

    PubMed

    von Wyl, Viktor; Cambiano, Valentina; Jordan, Michael R; Bertagnolio, Silvia; Miners, Alec; Pillay, Deenan; Lundgren, Jens; Phillips, Andrew N

    2012-01-01

    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. 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. 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), which was below the WHO threshold

  6. Clinical psychometry and P3 in patients on phenytoin monotherapy.

    PubMed

    Misra, U K; Kalita, J; Babu, G N; Dwivedi, K D

    1997-03-01

    To study the cognitive effects of diphenylhydantoin (PTH), 17 patients of simple partial or generalised tonic clonic seizure, who were on PTH monotherapy for at least 6 months were included. None of them had a seizure in last one month and their CT scans were normal. Serum PTH levels of these patients were in the therapeutic range (10.2-17.7 micrograms/ml). The clinical signs of PTH toxicity in the form of gingival hyperplasia and cerebellar ataxia were present in 1 patient only. In 3 patients memory quotient (MQ) and Benton visual retention test (BVRT) scores were marginally abnormal but the group difference in the clinical psychometric tests were not significant. P3 latency was also normal in all the patients. In the therapeutic range, PTH does not seem to produce significant cognitive dysfunction.

  7. Lymphocutaneous Sporotrichosis during Treatment with Anti-TNF-Alpha Monotherapy

    PubMed Central

    Ursini, Francesco; Calabria, Marilena; Bruno, Caterina; Tripolino, Cesare; Naty, Saverio; Grembiale, Rosa Daniela

    2015-01-01

    Sporotrichosis is an infectious disease caused by Sporothrix schenckii, a dimorphic fungus isolated for the first time in 1896 by Benjamin Schenck from a 36-year-old male patient presenting lesions on the right hand and arm. The infection generally occurs by traumatic inoculation of soil, plants, and organic matter contaminated with the fungus. Different clinical syndromes are described as a direct consequence of S. schenckii infection, including lymphocutaneous and disseminated forms, although extracutaneous presentations are reported most frequently in AIDS patients. Here we describe the case of a 57-year-old Caucasian male diagnosed in 2004 with ankylosing spondylitis under stable treatment with adalimumab monotherapy (40 mg every other week). During a routine follow-up visit in March 2013, he presented with multiple nodular lesions arranged in a linear fashion along the left hand and forearm. After diagnostic aspiration of the lesions, lymphocutaneous sporotrichosis was diagnosed and appropriate therapy started. PMID:25755904

  8. Chemotherapy versus endocrine therapy as first-line treatment in patients with luminal-like HER2-negative metastatic breast cancer: A propensity score analysis.

    PubMed

    Bonotto, Marta; Gerratana, Lorenzo; Di Maio, Massimo; De Angelis, Carmine; Cinausero, Marika; Moroso, Stefano; Milano, Monica; Stanzione, Brigida; Gargiulo, Piera; Iacono, Donatella; Minisini, Alessandro Marco; Mansutti, Mauro; Fasola, Gianpiero; De Placido, Sabino; Arpino, Grazia; Puglisi, Fabio

    2017-02-01

    According to current guidelines, endocrine therapy (ET) is recommended as first-line treatment of luminal-like metastatic breast cancer (MBC), whereas chemotherapy (CT) should be considered in presence of life-threatening disease. In daily practice, CT is often used outside of this clinical circumstance. Factors influencing first-line choice and the relative impact on outcome are unknown. A consecutive series of luminal-like HER2-negative MBC patients treated from 2004 to 2014 was analyzed to test the association of disease- and patient-related factors with the choice of first-line treatment (ET vs. CT). A propensity score method was used to estimate impact of first-line strategy on outcome. Of 604 consecutive luminal-like MBC patients identified, 158 cases were excluded due to unknown or positive HER2-status. Among 446 HER2-negative cases, 171 (38%) received first-line CT. On multivariate analysis, the only factors significantly associated with lower CT use were old age (OR 0.25, 95%C.I. 0.13-0.49) or presence of bone metastases only (OR 0.26, 95%C.I. 0.13-0.53). In propensity score matched population, no differences were observed between CT and ET as first-line treatment either in terms of overall survival (37.5 months and 33.4 months respectively, log-rank test, P = 0.62) or progression-free survival (13.3 months and 9.9 months respectively, log-rank test, P = 0.92). High percentage of patients with luminal-like MBC received CT as first-line therapy in real-life. The choice was mainly driven by age and site of metastases. With the limitations of a non-randomized comparison, no differences on patients' outcome were observed depending on the first-line strategy. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Thioridazine Pharmacokinetic-Pharmacodynamic Parameters “Wobble” during Treatment of Tuberculosis: a Theoretical Basis for Shorter-Duration Curative Monotherapy with Congeners

    PubMed Central

    Musuka, Sandirai; Srivastava, Shashikant; Siyambalapitiyage Dona, Chandima Wasana; Meek, Claudia; Leff, Richard; Pasipanodya, Jotam

    2013-01-01

    Phenothiazines are being repurposed for treatment of tuberculosis. We examined time-kill curves of thioridazine and first-line drugs against log-growth-phase and semidormant bacilli under acidic conditions and nonreplicating persistent Mycobacterium tuberculosis. While both the potency and the efficacy of first-line drugs declined dramatically as M. tuberculosis replication rates decreased, those of thioridazine improved. The mutation prevalence to 3 times the thioridazine MIC was <1 × 10−11, better than for ≥2 first-line drugs combined. Hollow fiber system studies revealed that the relationship between sterilizing effect and pharmacodynamic indices (PDI) was characterized by an r2 of 0.88 for peak/MIC, an r2 of 0.47 for the area under the concentration-time curve (AUC) to MIC, and an r2 of 0.14 for the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%TMIC) at the end of the first week. However, the PDI linked to effect “wobbled” as the duration of therapy increased, so that by the fourth week the r2 was 0.88 for AUC/MIC, 0.78 for %TMIC, and 0.72 for peak/MIC. This “wobble” has implications on general pharmacokinetic/pharmacodynamic theory, whereby efficacy is linked to only one of the three PDIs in deterministic models. The potency changed 8.9-fold from the first to the fourth weeks. The non-protein-bound AUC/MIC associated with maximal kill at the end of therapy was 50.53 (protein binding = 99.5%). This thioridazine exposure was calculated to extinguish all three M. tuberculosis metabolic populations in human lungs in only 42.9 days of monotherapy. However, this concentration exceeds the 2- to 8-mg/liter thioridazine concentration in serum known to be lethal to humans. Therefore, the way forward for phenothiazine monotherapy that also reduces therapy duration is via synthesis of less toxic congeners. PMID:24041886

  10. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children☆

    PubMed Central

    Holmes, Gregory L.; Frank, L. Matthew; Sheth, Raj D.; Philbrook, Bryan; Wooten, John D.; Vuong, Alain; Kerls, Susan; Hammer, Anne E.; Messenheimer, John

    2008-01-01

    Summary Purpose To evaluate the efficacy, tolerability, and effects on behavior and psychosocial functioning of lamotrigine monotherapy in children with newly diagnosed typical absence seizures. Patients and methods Children meeting enrollment criteria (n = 54) received a confirmatory 24-h ambulatory electroencephalogram (EEG) and then entered a Escalation Phase of up to 20-weeks during which lamotrigine was titrated until seizures were controlled or maximum dose (10.2 mg/kg) was reached. Seizure freedom was assessed by diary review and clinic hyperventilation (clinic HV) and then confirmed by EEG with hyperventilation (HV/EEG). Patients who maintained seizure freedom for two consecutive weekly visits were entered into the Maintenance Phase (n = 30). Diary, clinic HV, and HV/EEG data were supplemented with 24-h ambulatory EEG at baseline and the ends of the Escalation and Maintenance Phases. Health outcome assessments were completed at screening and at the end of the Maintenance Phase. Results By the end of the Escalation Phase, seizure-free rates (responders) were 59% by seizure diary (n = 51), 56% by HV/EEG (n = 54) (primary endpoint), and 49% by 24-h ambulatory EEG (n = 49). During the Maintenance Phase, 89% (week 24) and 86% (week 32) remained seizure free by diary (n = 28), 78% by clinic HV (n = 27), and 81% by 24-h ambulatory EEG (n = 26). Seizure freedom was first observed beginning at the fifth week of the Escalation Phase. The most frequent adverse events were headache and cough. Health outcome scores were either improved or unchanged at the end of the Maintenance Phase. Conclusions Lamotrigine monotherapy results in complete seizure freedom in a substantial number of children with typical absence seizures. Lamotrigine was well tolerated in this study. PMID:18778916

  11. Bosutinib in Combination With the Aromatase Inhibitor Letrozole: A Phase II Trial in Postmenopausal Women Evaluating First-Line Endocrine Therapy in Locally Advanced or Metastatic Hormone Receptor-Positive/HER2-Negative Breast Cancer

    PubMed Central

    Neven, Patrick; Lebrun, Fabienne; Bellet, Meritxell; Xu, Binghe; Sarosiek, Tomasz; Chow, Louis; Goss, Paul; Zacharchuk, Charles; Leip, Eric; Turnbull, Kathleen; Bardy-Bouxin, Nathalie; Duvillié, Ladan; Láng, István

    2014-01-01

    Abstract Background. Endocrine therapy resistance in hormone receptor-positive (HR+) breast cancer (BC) may involve crosstalk between HRs and growth factor signaling pathways. We evaluated bosutinib, a dual Src/Abl tyrosine kinase inhibitor that has previously demonstrated some antitumor activity in BC, plus letrozole as first-line endocrine therapy in locally advanced or metastatic HR+/HER2− BC. Methods. Sixteen postmenopausal women were enrolled in a phase II study evaluating the safety/efficacy of bosutinib plus letrozole. In the single-arm safety/dose-confirming lead-in (part 1), patients received oral bosutinib at 400 mg/day plus letrozole at 2.5 mg/day; adverse events (AEs) and dose-limiting toxicities (DLTs) were monitored, and initial efficacy was assessed. A randomized efficacy/safety phase (part 2) was planned to evaluate the combination versus letrozole monotherapy. Results. Fifteen of 16 subjects experienced treatment-related AEs, most commonly diarrhea (69%). Treatment-related hepatotoxicity AEs (primarily alanine aminotransferase [ALT] or aspartate aminotransferase [AST] elevations) occurred in 6 of 16 patients (38%). Four of 15 evaluable patients (27%) experienced a DLT (grade 3/4 ALT/AST elevations, n = 2; grade 3 rash, n = 1; grade 3 diarrhea or vomiting, n = 1), including 1 Hy’s law hepatotoxicity case. All DLTs resolved following treatment discontinuation. One patient achieved confirmed partial response; one had stable disease for >24 weeks. Study termination occurred before part 2. Conclusion. The unfavorable risk-benefit ratio did not warrant further investigation of bosutinib plus letrozole. PMID:24674874

  12. Similar survival rates with first-line gefitinib, gemcitabine, or docetaxel in a randomized phase II trial in elderly patients with advanced non-small cell lung cancer and a poor performance status (IFCT-0301).

    PubMed

    Des Guetz, Gaetan; Landre, Thierry; Westeel, Virginie; Milleron, Bernard; Vaylet, Fabien; Urban, Thierry; Barlesi, Fabrice; Souquet, Pierre-Jean; Debieuvre, Didier; Braun, Denis; Fraboulet, Gislaine; Monnet, Isabelle; Uzzan, Bernard; Molinier, Olivier; Morin, Franck; Moro-Sibilot, Denis; Morère, Jean Francois

    2015-05-01

    We evaluated the impact of age in a randomized phase II trial that compared three first-line drugs in elderly patients with advanced non-small cell lung cancer (NSCLC) and a poor performance status (PS). Patients with advanced NSCLC with a PS of 2 or 3 were enrolled into a multicenter randomized trial: arm A, gefitinib; arm B, gemcitabine; and arm C, docetaxel. We performed subgroup analyses according to age. Between December 2004 and June 2007, 127 patients were enrolled. Analyses were performed between the two subgroups aged <70years (younger, n=56) and ≥70years (older, n=71). Patients mainly had adenocarcinoma (46% young vs. 51%: elderly), of which 62% vs. 75% had a PS of 2, respectively. Significantly more elderly patients were women and non-smokers, and there was a non-significant trend towards more PS-2 among the elderly. Progression-free survival (PFS) was 1.4months (95% CI: 1.1-1.9) for younger compared to 2.3months (95% CI: 2.1-2.9) for elderly patients. Overall survival (OS) was 2.0months (95% CI: 1.5-2.4) and 3.7months (95% CI: 2.4-4.8), respectively. Toxicity did not differ between younger and older patients. NSCLC was better controlled in elderly patients after three cycles of monotherapy compared to younger patients (p=0.034). When adjusted for stratification criteria, age was the main prognostic factor for PFS. Adjusted HRs for PFS was 0.57 (95% CI: 0.38-0.85) for the elderly compared to patients aged <70years (p=0.004). Older patients had a decreased risk of progression/death compared to younger patients. Single-agent chemotherapy can be considered for patients aged ≥70years with a PS of 2. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor-positive breast cancer which over-expresses human epidermal growth factor 2 (HER2): a systematic review and economic analysis.

    PubMed

    Fleeman, N; Bagust, A; Boland, A; Dickson, R; Dundar, Y; Moonan, M; Oyee, J; Blundell, M; Davis, H; Armstrong, A; Thorp, N

    2011-01-01

    Breast cancer is the uncontrolled, abnormal growth of malignant breast tissue affecting predominantly women. Metastatic breast cancer (mBC) is an advanced stage of the disease when the disease has spread beyond the original organ. Hormone receptor status and human epidermal growth factor 2 (HER2) status are two predictive factors that are taken into consideration when estimating the prognosis of patients with breast cancer. To review the clinical effectiveness and cost-effectiveness evidence base for lapatinib (LAP) in combination with an aromatase inhibitor (AI) and trastuzumab (TRA) in combination with an AI for the first-line treatment of patients who have hormone receptor-positive (HR+)/human epidermal growth factor 2-positive (HER2+) mBC. Relevant electronic databases and websites, including MEDLINE, EMBASE and the Cochrane Library, were searched until May 2010. Further data were derived from the manufacturers' submissions for LAP + AI and TRA + AI. A systematic review of the clinical effectiveness and cost-effectiveness of LAP + AI and TRA + AI was undertaken. As it was deemed inappropriate to compare LAP + AI with TRA + AI, two separate assessments of cost-effectiveness versus AIs alone were undertaken. Three trials were included in the systematic review [the patient populations of the efficacy and safety of lapatinib combined with letrozole (EGF30008) trial, the efficacy and safety of trastuzumab combined with anastrozole (TAnDEM) trial and the efficacy and safety of letrozole combined with trastuzumab (eLEcTRA) trial]. As a result of differences in the exclusion criteria and because one trial was halted prematurely, comparisons across trials were believed to be inappropriate and meta-analysis was not possible. Individually, however, the findings from the trials all suggest that LAP + AI or TRA + AI results in improved progression-free survival and/or time to progression when compared with AIs alone. The trials do not show a statistically significant

  14. Cost-utility of First-line Disease-modifying Treatments for Relapsing-Remitting Multiple Sclerosis.

    PubMed

    Soini, Erkki; Joutseno, Jaana; Sumelahti, Marja-Liisa

    2017-03-01

    This study evaluated the cost-effectiveness of first-line treatments of relapsing-remitting multiple sclerosis (RRMS) (dimethyl fumarate [DMF] 240 mg PO BID, teriflunomide 14 mg once daily, glatiramer acetate 20 mg SC once daily, interferon [IFN]-β1a 44 µg TIW, IFN-β1b 250 µg EOD, and IFN-β1a 30 µg IM QW) and best supportive care (BSC) in the health care payer setting in Finland. The primary outcome was the modeled incremental cost-effectiveness ratio (ICER; €/quality-adjusted life-year [QALY] gained, 3%/y discounting). Markov cohort modeling with a 15-year time horizon was employed. During each 1-year modeling cycle, patients either maintained the Expanded Disability Status Scale (EDSS) score or experienced progression, developed secondary progressive MS (SPMS) or showed EDSS progression in SPMS, experienced relapse with/without hospitalization, experienced an adverse event (AE), or died. Patients׳ characteristics, RRMS progression probabilities, and standardized mortality ratios were derived from a registry of patients with MS in Finland. A mixed-treatment comparison (MTC) informed the treatment effects. Finnish EuroQol Five-Dimensional Questionnaire, Three-Level Version quality-of-life and direct-cost estimates associated with EDSS scores, relapses, and AEs were applied. Four approaches were used to assess the outcomes: cost-effectiveness plane and efficiency frontiers (relative value of efficient treatments); cost-effectiveness acceptability frontier, which demonstrated optimal treatment to maximize net benefit; Bayesian treatment ranking (BTR); and an impact investment assessment (IIA; a cost-benefit assessment), which increased the clinical interpretation and appeal of modeled outcomes in terms of absolute benefit gained with fixed drug-related budget. Robustness of results was tested extensively with sensitivity analyses. Based on the modeled results, teriflunomide was less costly, with greater QALYs, versus glatiramer acetate and the IFNs

  15. Methadone as first-line opioid treatment for cancer pain in a developing country palliative care unit.

    PubMed

    Peirano, Gabriela P; Mammana, Guillermo P; Bertolino, Mariela S; Pastrana, Tania; Vega, Gloria F; Russo, Jorgelina; Varela, Gabriela; Vignaroli, Ernesto; Ruggiero, Raúl; Armesto, Arnaldo; Camerano, Gabriela; Dran, Graciela

    2016-08-01

    The use of methadone for cancer pain is limited by the need of expertise and close titration due to variable half-life. Yet, it is a helpful palliative strategy in low-resources countries given its long-acting effect at low cost and worth additional study. Our aim was to describe the prescription and outcomes of methadone as a first-line treatment for cancer pain in a tertiary palliative care unit (PCU) in Argentina. Retrospective review of medical records of patients with moderate to severe cancer pain seen at the PCU in 1-year period, who initiated strong opioids at the first consultation. Data collected during the first month of treatment included disease and pain characteristics, initial and final opioid type and dose and need for opioid rotation. Methadone was the most frequent opioid both at the initial and last assessment (71 and 66 % of the prescriptions). In all, treatment with strong opioids provided considerable decrease in pain intensity (p < 0.001) with low and stable opioid dose. Median and interquartile range (IR) of oral morphine equivalent daily dose (OMEDD) was 26 (16-32) and 39 (32-55) mg for initial and final assessments, respectively (p = 0.3). In patients initiated with methadone, the median (IR) daily methadone dose was 5 (4-6) mg at first and 7.5 (6-10) mg at final assessment, and the median (IR) index of opioid escalation was 0 (0-4) mg; (p < 0.05). Patients on methadone underwent less percentage of opioid rotation (15 versus 50 %; p < 0.001) and longer time to rotation (20.6 ± 4.4 versus 9.0 ± 2.7 days; p < 0.001) than patients on other opioids. Results indicate the preference of methadone as first-line strong opioid treatment in a PCU, providing good pain relief at low doses with low need for rotation. Several considerations about the costs of strong opioids in the region are given.

  16. High prevalence of HIV-1 drug resistance among patients on first-line antiretroviral treatment in Lomé, Togo

    PubMed Central

    2011-01-01

    Background With widespread use of antiretroviral (ARV) drugs in Africa, one of the major potential challenges is the risk of emergence of ARV drug-resistant HIV strains. Our objective is to evaluate the virological failure and genotypic drug-resistance mutations in patients receiving first-line highly active antiretroviral therapy (HAART) in routine clinics that use the World Health Organization public health approach to monitor antiretroviral treatment (ART) in Togo. Methods Patients on HAART for one year (10-14 months) were enrolled between April and October 2008 at three sites in Lomé, the capital city of Togo. Plasma viral load was measured with the NucliSENS EasyQ HIV-1 assay (Biomérieux, Lyon, France) and/or a Generic viral load assay (Biocentric, Bandol, France). Genotypic drug-resistance testing was performed with an inhouse assay on plasma samples from patients with viral loads of more than 1000 copies/ml. CD4 cell counts and demographic data were also obtained from medical records. Results A total of 188 patients receiving first-line antiretroviral treatment were enrolled, and 58 (30.8%) of them experienced virologic failure. Drug-resistance mutations were present in 46 patients, corresponding to 24.5% of all patients enrolled in the study. All 46 patients were resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTIs): of these, 12 were resistant only to NNRTIs, 25 to NNRTIs and lamivudine/emtricitabine, and eight to all three drugs of their ARV regimes. Importantly, eight patients were already predicted to be resistant to etravirine, the new NNRTI, and three patients harboured the K65R mutation, inducing major resistance to tenofovir. Conclusions In Togo, efforts to provide access to ARV therapy for infected persons have increased since 2003, and scaling up of ART started in 2007. The high number of resistant strains observed in Togo shows clearly that the emergence of HIV drug resistance is of increasing concern in countries where ART is

  17. Hybrid Therapy as First-Line Regimen for Helicobacter pylori Eradication in Populations with High Antibiotic Resistance Rates.

    PubMed

    Song, Zhiqiang; Zhou, Liya; Zhang, Jianzhong; He, Lihua; Bai, Peng; Xue, Yan

    2016-10-01

    Hybrid therapy has recently attracted widespread attention. However, many issues require further exploration. For example, research in regions with high antibiotic resistance rates is limited, and the correlation between eradication efficacy and antibiotic resistance remains unclear. The aim of this study was to determine the efficacy, compliance, safety, and risk factors of hybrid therapy as first-line regimen in a region with high antibiotic resistance rates. This prospective study was conducted in a tertiary hospital between January 2014 and June 2015. A total of 196 patients with dyspepsia but without prior eradication therapy received hybrid regimen (esomeprazole 20 mg and amoxicillin 1000 mg twice daily for 14 days with the addition of clarithromycin 500 mg and tinidazole 500 mg twice daily for the final 7 days). All patients underwent Helicobacter pylori culture, antibiotic susceptibility testing and cytochrome P450 isoenzyme 2C19 polymorphism testing. Hybrid therapy achieved eradication rates of 77.0% (95% confidence interval (CI), 70.9-83.7%) in intention-to-treat (ITT), 83.9% (78.9-88.9%) in modified ITT and 86.0% (80.2-91.3%) in per-protocol analyses in a setting with high antibiotic resistance rates (amoxicillin 2.0%, clarithromycin 44.9%, metronidazole 67.3% and dual clarithromycin and metronidazole 33.3%). Adverse reactions occurred in 31.9% patients and 2.7% discontinued medications due to adverse reactions. Good compliance was achieved by 92.0%. Multivariate analyses identified clarithromycin resistance (odds ratio, 3.494; 95% CI, 1.237-9.869), metronidazole resistance (3.012; 1.013-12.054) and poor compliance (5.840; 1.126-30.296) as independent predictors of treatment failure. The eradication rate with dual clarithromycin and metronidazole resistance (70.2%) was markedly decreased compared to isolated clarithromycin resistance (87.5%), isolated metronidazole resistance (88.6%), or dual susceptibility (96.4%) (p = .014). Despite good compliance and

  18. The influence of patient beliefs and treatment satisfaction on the discontinuation of current first-line antiretroviral regimens.

    PubMed

    Casado, J L; Marín, A; Romero, V; Bañón, S; Moreno, A; Perez-Elías, M J; Moreno, S; Rodriguez-Sagrado, M A

    2016-01-01

    Large cohort studies have shown a high rate of first-line combination antiretroviral therapy (cART) regimen discontinuation in HIV-infected patients, attributed to characteristics of the cART regimen or toxicity. A cohort study of 274 patients receiving a first-line regimen was carried out. Patients' perceptions and beliefs prior to initiation were assessed using an attitude towards medication scale (0-15 points), and their satisfaction during therapy was assessed using an HIV treatment satisfaction questionnaire (HIVTSQ). Treatment discontinuation was defined as any switch in the cART regimen. During 474.8 person-years of follow-up, 63 (23%) patients changed their cART regimen, mainly because of toxicity/intolerance (42; 67%). The overall rate of change was 13.2 per 100 patient-years [95% confidence interval (CI) 11.1-16.4 per 100 patient-years]. An efavirenz (EFV)-based single tablet regimen showed the highest rate of adverse events (27%), but the lowest rate of change (16%; 7.44 per 100 patient-years). Cox regression revealed a decreased hazard of first regimen termination with better initial attitude towards drugs [hazard ratio (HR) 0.76; 95% CI 0.62-0.93; P < 0.01] and higher satisfaction (HR 0.94; 95% CI 0.89-0.99; P = 0.01), and an increased hazard of termination with the presence of adverse events (HR 7.7; 95% CI 2.4-11.6; P < 0.01). One-third of patients (18 of 59; 31%) with mild/moderate adverse events (which were mainly central nervous system symptoms) continued the regimen; these patients, compared with those discontinuing therapy, showed better perception of therapy (mean score 14.4 versus 12.1, respectively; P = 0.05) and greater satisfaction during therapy (mean score 50.6 versus 44.6, respectively; P = 0.04). Patients' beliefs and satisfaction with therapy influence the durability of the first antiretroviral regimen. These patient-related factors modulate the impact of mild adverse events, and could explain differences in the

  19. Biologic Disease-modifying antirheumatic drug attributes in the first lines of treatment of rheumatoid arthritis. 2015 ACORDAR project.

    PubMed

    Muñoz-Fernández, Santiago; Bustabad Reyes, María Sagrario; Calvo Alén, Jaime; Castaño Sánchez, Manuel; Chamizo Carmona, Eugenio; Corominas, Héctor; Fernández-Llanio Comella, Nagore; Hidalgo Calleja, María Cristina; Pérez Venegas, José Javier; Rodríguez Heredia, José Manuel; Romero Yuste, Susana María; Ruiz-Esquide Torino, Virginia

    2017-01-03

    To date, between 17% and 35% of patients with rheumatoid arthritis (RA) do not respond as expected to the initial biological therapy. The objective of this project is to recognize and weigh the attributes of biologic DMARD (bDMARD) to identify the most appropriate for each case, in the first lines of treatment of RA (after inadequate response to at least one synthetic DMARD or previous bDMARD). To recognize the possible attributes that could define the bDMARD, we performed a systematic search of the literature that recognized the possible attributes involving general aspects, pharmacology, efficacy, safety, management, and cost. Then a Delphi process was conducted with two rounds among a group of selected expert rheumatologists in the management of RA indicating the degree of agreement with the attributes identified in the literature. The project was completed between February and September 2015, indicating the degree of importance that was ascribed to each attribute. Two criteria were applied to determine the consistency of results: 1) based on the median and interquartile range; and 2) on the simultaneous compliance with mean, median, standard deviation, interquartile range and coefficient of variation. The agreement and final ratification of the expert panel were also determined. Eighty-three Spanish rheumatologists participated and completed both rounds of the Delphi process. In no case was the importance of the 77 attributes identified considered to be low; 75 of 77 (97.4%) were considered highly important and 76 of 77 (98.7%) were ratified. Fifteen attributes had the support of 100% of the working group. There was a high degree of agreement concerning the selected attributes. Fifteen of them had the support of 100% of the working group and could be considered the definition of the ideal bDMARD in the first lines of RA treatment. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights

  20. Prognostic value of pretreatment inflammatory biomarkers in advanced lung adenocarcinoma patients receiving first-line pemetrexed/platinum doublet.

    PubMed

    Xiong, Yanjuan; Zhao, Ning; Zheng, Yu; Wang, Jian; Wei, Feng; Ren, Xiubao

    2017-06-01

    Inflammation is a new hallmark feature of cancer initiation and progression. We aimed to investigate the association between inflammatory response biomarkers and progression-free survival and overall survival in advanced lung adenocarcinoma patients treated with first-line pemetrexed and platinum doublet chemotherapy. Patients hospitalized between April 2012 and March 2015 were enrolled and eliminated according to the inclusion and exclusion criteria. The pretreatment neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, derived neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were calculated. Besides the well-established clinical prognostic factors, the prognostic values of the four markers were evaluated by the Kaplan-Meier method and Cox's proportional hazards regression model. A total of 78 patients were enrolled in this study. Elevated neutrophil-to-lymphocyte ratio and derived neutrophil-to-lymphocyte ratio were correlated with poor treatment response ( p = 0.014, 0.012, respectively). A high pretreatment neutrophil-to-lymphocyte ratio, derived neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio, as well as low lymphocyte-to-monocyte ratio, were associated with worse progression-free survival and overall survival. Multivariate analysis revealed that high neutrophil-to-lymphocyte ratio (hazard ratio = 2.056; 95% confidence interval, 1.281-3.299; p = 0.003) and ≥3 metastasis organs (hazard ratio = 1.989; 95% confidence interval, 1.069-3.702; p = 0.030) were independent prognostic factors for progression-free survival. Meanwhile, high neutrophil-to-lymphocyte ratio (hazard ratio = 5.540; 95% confidence interval, 2.974-10.321; p < 0.001) and habitual smoking (hazard ratio = 2.806; 95% confidence interval, 1.509-5.221; p = 0.001) were independent prognostic factors for overall survival. In conclusion, Pretreatment neutrophil-to-lymphocyte ratio was an independent prognostic factor for advanced lung adenocarcinoma patients

  1. Modeling and simulation of maintenance treatment in first-line non-small cell lung cancer with external validation.

    PubMed

    Han, Kelong; Claret, Laurent; Sandler, Alan; Das, Asha; Jin, Jin; Bruno, Rene

    2016-07-13

    Maintenance treatment (MTx) in responders following first-line treatment has been investigated and practiced for many cancers. Modeling and simulation may support interpretation of interim data and development decisions. We aimed to develop a modeling framework to simulate overall survival (OS) for MTx in NSCLC using tumor growth inhibition (TGI) data. TGI metrics were estimated using longitudinal tumor size data from two Phase III first-line NSCLC studies evaluating bevacizumab and erlotinib as MTx in 1632 patients. Baseline prognostic factors and TGI metric estimates were assessed in multivariate parametric models to predict OS. The OS model was externally validated by simulating a third independent NSCLC study (n = 253) based on interim TGI data (up to progression-free survival database lock). The third study evaluated pemetrexed + bevacizumab vs. bevacizumab alone as MTx. Time-to-tumor-growth (TTG) was the best TGI metric to predict OS. TTG, baseline tumor size, ECOG score, Asian ethnicity, age, and gender were significant covariates in the final OS model. The OS model was qualified by simulating OS distributions and hazard ratios (HR) in the two studies used for model-building. Simulations of the third independent study based on interim TGI data showed that pemetrexed + bevacizumab MTx was unlikely to significantly prolong OS vs. bevacizumab alone given the current sample size (predicted HR: 0.81; 95 % prediction interval: 0.59-1.09). Predicted median OS was 17.3 months and 14.7 months in both arms, respectively. These simulations are consistent with the results of the final OS analysis published 2 years later (observed HR: 0.87; 95 % confidence interval: 0.63-1.21). Final observed median OS was 17.1 months and 13.2 months in both arms, respectively, consistent with our predictions. A robust TGI-OS model was developed for MTx in NSCLC. TTG captures treatment effect. The model successfully predicted the OS outcomes of an independent study

  2. Budget impact analysis of first-line treatment with pazopanib for advanced renal cell carcinoma in Spain

    PubMed Central

    2013-01-01

    Background Due to economic constraints, cancer therapies are under close scrutiny by clinicians, pharmacists and payers alike. There is no published pharmacoeconomic evidence guiding the choice of first-line therapy for advanced renal cell carcinoma (RCC) in the Spanish setting. We aimed to develop a model describing the natural history of RCC that can be used in healthcare decision-making. We particularly analyzed the budget impact associated with the introduction of pazopanib compared to sunitinib under the Spanish National Healthcare System (NHS) perspective. Methods We developed a Markov model to estimate the future number of cases of advanced RCC (patients with favorable or intermediate risk) resulting either from initial diagnosis or disease progression after surgery. The model parameters were obtained from the literature. We assumed that patients would receive either pazopanib or sunitinib as first-line therapy until disease progression. Pharmacological costs and costs associated with the management of adverse events (AE) were considered. A univariate sensitivity analysis was undertaken in order to test the robustness of the results. Results The model predicted an adult RCC prevalence of 7.5/100,000 (1-year), 20.7/100,000 (3-year) and 32.5/100,000 (5-year). These figures are very close to GLOBOCAN reported RCC prevalence estimates of 7.6/100,000, 20.2/100,000 and 31.1/100,000, respectively. The model predicts 1,591 advanced RCC patients with favorable or intermediate risk in Spain in 2013. Annual per patient pharmacological costs were €32,365 and €39,232 with pazopanib and sunitinib, respectively. Annual costs associated with the management of AE were €662 and €974, respectively. Overall annual per patient costs were €7,179 (18%) lower with pazopanib compared to sunitinib. For every point increase in the percentage of patients treated with pazopanib, the NHS would save €67,236. If all the 1,591 patients predicted were treated with pazopanib, the

  3. Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors.

    PubMed

    Canale, Matteo; Petracci, Elisabetta; Delmonte, Angelo; Chiadini, Elisa; Dazzi, Claudio; Papi, Maximilian; Capelli, Laura; Casanova, Claudia; De Luigi, Nicoletta; Mariotti, Marita; Gamboni, Alessandro; Chiari, Rita; Bennati, Chiara; Calistri, Daniele; Ludovini, Vienna; Crinò, Lucio; Amadori, Dino; Ulivi, Paola

    2016-10-25

    Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC).Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).Results:TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53-mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21-8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71-36.63), P < 0.001]. Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P < 0.001, and 7.6 vs. not reached, P = 0.006, respectively), HR 6.99 (95% CI, 2.34-20.87, P < 0.001) and HR 4.75 (95% CI, 1.38-16.29, P = 0.013), respectively.Conclusions:TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions. Clin Cancer Res; 1-8. ©2016 AACR.

  4. Antimicrobial susceptibility testing before first-line treatment for Helicobacter pylori infection in patients with dual or triple antibiotic resistance

    PubMed Central

    Cosme, Angel; Montes, Milagrosa; Ibarra, Begoña; Tamayo, Esther; Alonso, Horacio; Mendarte, Usua; Lizasoan, Jacobo; Herreros-Villanueva, Marta; Bujanda, Luis

    2017-01-01

    AIM To evaluate the efficacy of antimicrobial susceptibility-guided therapy before first-line treatment for infection in patients with dual or triple antibiotic resistance. METHODS A total of 1034 patients infected by Helicobacter pylori (H. pylori) during 2013-2014 were tested for antimicrobial susceptibility. 157 of 1034 (15%) patients showed resistance to two (127/1034; 12%) and to three (30/1034; 3%) antibiotics. Sixty-eight patients with dual H. pylori-resistance (clarithromycin, metronidazole or levofloxacin) were treated for 10 d with triple therapies: OAL (omeprazole 20 mg b.i.d., amoxicillin 1 g b.i.d., and levofloxacin 500 mg b.i.d.) 43 cases, OAM (omeprazole 20 mg b.i.d., amoxicillin 1 g b.i.d., and metronidazole 500 mg b.i.d.) 12 cases and OAC (omeprazole 20 mg b.id., amoxicillin 1 g b.i.d., and clarithromycin 500 mg b.i.d.) 13 cases based on the antimicrobial susceptibility testing. Twelve patients showed triple H. pylori-resistance (clarithromycin, metronidazole and levofloxacin) and received for 10 d triple therapy with OAR (omeprazole 20 mg b.id., amoxicillin 1 g b.i.d., and rifabutin 150 mg b.i.d.). Eradication was confirmed by 13C-urea breath test. Adverse effects and compliance were assessed by a questionnaire. RESULTS Intention-to-treat eradication rates were: OAL (97.6%), OAM (91.6%), OAC (92.3%) and OAR (58.3%). Cure rate was significantly higher in naïve patients treated with OAR-10 compared to patients who had two or three previous treatment failures (83% vs 33%). Adverse events rates for OAL, OAM, OAC and OAR were 22%, 25%, 23% and 17%, respectively, all of them mild-moderate. CONCLUSION Antimicrobial susceptibility-guided triple therapies during 10 d for first-line treatment leads to an eradication rate superior to 90% in patients with dual antibiotic H. pylori resistance. PMID:28566898

  5. Early Warning Indicators for First-Line Virologic Failure Independent of Adherence Measures in a South African Urban Clinic

    PubMed Central

    Wu, Baohua; Hampton, Jane; Ordóñez, Claudia E.; Johnson, Brent A.; Singh, Dinesh; John, Sally; Gordon, Michelle; Hare, Anna; Murphy, Richard; Nachega, Jean; Kuritzkes, Daniel R.; del Rio, Carlos; Sunpath, Henry

    2013-01-01

    Abstract We sought to develop individual-level Early Warning Indicators (EWI) of virologic failure (VF) for clinicians to use during routine care complementing WHO population-level EWI. A case-control study was conducted at a Durban clinic. Patients after≥5 months of first-line antiretroviral therapy (ART) were defined as cases if they had VF [HIV-1 viral load (VL)>1000 copies/mL] and controls (2:1) if they had VL≤1000 copies/mL. Pharmacy refills and pill counts were used as adherence measures. Participants responded to a questionnaire including validated psychosocial and symptom scales. Data were also collected from the medical record. Multivariable logistic regression models of VF included factors associated with VF (p<0.05) in univariable analyses. We enrolled 158 cases and 300 controls. In the final multivariable model, male gender, not having an active religious faith, practicing unsafe sex, having a family member with HIV, not being pleased with the clinic experience, symptoms of depression, fatigue, or rash, low CD4 counts, family recommending HIV care, and using a TV/radio as ART reminders (compared to mobile phones) were associated with VF independent of adherence measures. In this setting, we identified several key individual-level EWI associated with VF including novel psychosocial factors independent of adherence measures. PMID:24320011

  6. First-line chemotherapy of advanced breast cancer with a combination of mitoxantrone, methotrexate, and vincristine (MIMO).

    PubMed

    Samonis, G; Bafaloukos, D; Margioris, A N; Katsarma, G; Toloudis, P; Bacoyannis, C; Karvounis, N; Georgoulias, V; Kosmidis, P

    1997-01-01

    Fifty-one patients with advanced breast cancer entered a prospective study of combination chemotherapy, consisting of mitoxantrone (10 mg/m2), methotrexate (30 mg/m2), and vincristine (1 mg/m2, MIMO) given intravenously every 21 days. None of the patients had received prior chemotherapy for metastatic disease, although 24 had been previously given adjuvant chemotherapy. Forty-seven patients were analyzed for response and toxicity. Objective response was observed in 20 of them (42%) with 3 complete responses (6%) stable disease in 7 (15%), and progression in 19 (40%). Best responses were achieved in lung metastases. Liver metastases did not respond. The median duration of response was 9 months and the median time to disease progression 11 months. Toxicity was mild. Nausea and myelotoxicity were the main side effects. MIMO was found to be an effective and well tolerated first-line treatment for advanced breast cancer. The regimen was compared historically with MIMO plus carboplatin. The two types of treatment were found equipotent, with MIMO being less toxic.

  7. Cost analysis of biologic drugs in rheumatoid arthritis first line treatment after methotrexate failure according to patients' body weight.

    PubMed

    Román Ivorra, José Andrés; Ivorra, José; Monte-Boquet, Emilio; Canal, Cristina; Oyagüez, Itziar; Gómez-Barrera, Manuel

    2016-01-01

    The objective was to assess the influence of patients' weight in the cost of rheumatoid arthritis treatment with biologic drugs used in first line after non-adequate response to methotrexate. Pharmaceutical and administration costs were calculated in two scenarios: non-optimization and optimization of intravenous (IV) vials. The retrospective analysis of 66 patients from a Spanish 1,000 beds-hospital Rheumatology Clinic Service was used to obtain posology and weight data. The study time horizon was two years. Costs were expressed in 2013 euros. For an average 69kg-weighted patient the lowest cost corresponded to abatacept subcutaneous (SC ABA) (€21,028.09) in the scenario without IV vials optimization and infliximab (IFX) (€20,779.29) with optimization. Considering patients' weight in the scenario without IV vials optimization infliximab (IFX) was the least expensive drug in patients ranged 45-49kg, IV ABA in 50-59kg and SC ABA in patients over 60kg. With IV vials optimization IFX was the least expensive drug in patients under 69kg and SC ABA over 70kg. Assuming comparable effectiveness of biological drugs, patient's weight is a variable to consider, potentials savings could reach €20,000 in two years. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  8. Selection of first-line i.v. antibiotics for acute pyelonephritis in patients requiring emergency hospital admission.

    PubMed

    Yasufuku, Tomihiko; Shigemura, Katsumi; Yamashita, Masuo; Arakawa, Soichi; Fujisawa, Masato

    2011-04-01

    Febrile urinary tract infections (UTIs) often require the intravenous infusion of antibiotics and/or hospitalization. Acute pyelonephritis (AP) is one of the most severe forms of UTI, and the antibiotics we should use as the first line and the risk factors for treatment failure remain controversial. The objective of this study was to investigate the efficacy of i.v. antibiotics selected for the treatment of febrile AP and to examine the risk factors for antibiotic resistance. We set risk factors for antibiotic treatment failure such as age, sex, and the presence of underlying urinary tract disease. We classified all cases into 49 cases of complicated AP and 24 cases of uncomplicated AP according to the presence of underlying urinary tract diseases, and examined the characteristics of the patients and the efficacy of the antibiotics used in this study. We investigated risk factors which relate to initial treatment failure and the duration of antibiotic treatment. Initial antibiotic treatment failure was significantly correlated to C-reactive protein in complicated AP and to positive blood culture in uncomplicated AP. We revealed a significant correlation between the duration of the given antibiotics and diabetes mellitus or positive blood culture in uncomplicated AP, and tazobactam/piperacillin was significantly related to prolongation of antibiotic treatment in complicated AP. In conclusion, in this study, a positive blood culture was the representative risk factor that related to both initial treatment failure and longer duration of the given antibiotics in uncomplicated AP.

  9. Cetuximab therapy in first-line metastatic colorectal cancer and intermittent palliative chemotherapy: review of the COIN trial.

    PubMed

    Adams, Richard; Meade, Angela; Wasan, Harpreet; Griffiths, Gareth; Maughan, Tim

    2008-08-01

    The aim of palliative chemotherapy is to increase survival whilst maintaining maximum quality of life for the individual concerned. It is evident that the survival advantage offered by palliative chemotherapy for metastatic colorectal cancer has increased incrementally with the addition of each newly licensed therapeutic agent. More recently, advances in the field have led to the introduction of targeted monoclonal antibodies, whose benefits are documented in clinical trials and are acknowledged in their approval and licensing. Whilst we are continuing to explore the optimum use of the more traditional chemotherapy agents, with respect to both quantity and quality of life, these novel agents are battling to find their optimum place in the armamentarium. It is evident that a continuing add-one-in policy is likely to be detrimental to both patient and budget. Defining the positioning and duration of these combination therapies has become the subject of much debate and numerous current clinical trials. The Medical Research Council COIN trial is one of these trials, with a remit to explore further the optimum use of both standard agents and novel agents in the first-line setting for metastatic colorectal cancer.

  10. Rate and predictors of non-response to first-line antipsychotic treatment in first-episode schizophrenia.

    PubMed

    Chiliza, Bonginkosi; Asmal, Laila; Kilian, Sanja; Phahladira, Lebogang; Emsley, Robin

    2015-05-01

    The goals of this study were to (i) estimate the rate of non-response to first-line treatment in first-episode schizophrenia, (ii) evaluate other outcomes associated with symptom non-response and (iii) identify demographic, baseline clinical and early treatment response predictors of non-response. This was a single-site, longitudinal cohort study assessing the effects of treatment with flupenthixol decanoate according to a standardised protocol over 12 months in patients with schizophrenia, schizophreniform and schizo-affective disorders. Of 126 patients who received at least one dose of study medication, 84 (67%) completed the study. Fifteen (12%) met our predefined criteria for non-response. Non-responders were younger and at baseline had more prominent disorganised symptoms, poorer social and occupational functioning, poorer quality of life for psychological, social and environmental domains, more prominent neurological soft signs (NSS) and lower body mass index. At endpoint, the non-responders were characterised by higher levels of symptomatology in all domains, poorer functional outcome, poorer quality of life and greater cognitive impairments. They also had more prominent NSS and lower body mass index. The strongest predictors of non-response were more prominent baseline NSS and poor early (7 weeks) treatment response. Results are consistent with a lower rate of refractoriness to treatment in first-episode schizophrenia compared with multi-episode samples. Copyright © 2015 John Wiley & Sons, Ltd.

  11. Albumin-bound paclitaxel: a review of its use for the first-line combination treatment of metastatic pancreatic cancer.

    PubMed

    Hoy, Sheridan M

    2014-10-01

    Nanoparticle albumin-bound paclitaxel (Abraxane(®)) [hereafter referred to as nab-paclitaxel] is an intravenously administered microtubule inhibitor. It was developed to avoid the toxicities associated with the polyoxyethylated castor oil solvent (Cremophor) and ethanol vehicles used to overcome paclitaxel's poor aqueous solubility. Nab-paclitaxel is indicated in the EU and the USA as first-line combination therapy with gemcitabine in adults with metastatic adenocarcinoma of the pancreas. Compared with gemcitabine alone, nab-paclitaxel plus gemcitabine significantly prolonged median overall survival, reflecting a 28 % reduction in the risk of death, in adults with metastatic pancreatic cancer participating in a multinational phase III study. In addition, median progression-free survival was significantly prolonged and the objective response rate was significantly higher with nab-paclitaxel plus gemcitabine than with gemcitabine therapy. Nab-paclitaxel plus gemcitabine had a manageable tolerability profile; in general, adverse events in the phase III study were grade 3 or lower and resolved without specific therapy. Neutropenia and peripheral neuropathy were the most frequently reported adverse reactions leading to nab-paclitaxel dose reductions, or to delays in or the withholding of nab-paclitaxel dosing. Peripheral neuropathy was rapidly reversible in the majority of patients following interruptions in nab-paclitaxel administration and a subsequent reduction in the nab-paclitaxel dose. Current evidence indicates that nab-paclitaxel plus gemcitabine is a valuable option for the treatment of metastatic pancreatic cancer.

  12. Adding Bismuth to Rabeprazole-Based First-Line Triple Therapy Does Not Improve the Eradication of Helicobacter pylori

    PubMed Central

    Wu, Meng-Chieh; Yu, Fang-Jung; Kuo, Fu-Chen; Liu, Min-Li

    2017-01-01

    This randomized controlled study aimed to evaluate whether adding bismuth to the standard first-line triple therapy could improve the eradication rate of Helicobacter pylori. A total of 162 patients with Helicobacter pylori infection were randomly assigned to either the 7-day triple therapy group (RAK regimen: rabeprazole 20 mg, amoxicillin 1 g, and clarithromycin 500 mg bid; n = 81) or the bismuth plus triple therapy group (n = 81). In the RBAK group, bismuth subcitrate 360 mg twice daily was added to the RAK regimen. A follow-up endoscopy or urea breath test was performed at least 4 weeks after eradication to confirm the treatment efficacy. Comparable compliance and Helicobacter pylori eradication rates were observed in both groups in either intention-to-treat [RAK 72.8% (59/81) versus RBAK 77.8% (63/81); p = 0.47] or per protocol analysis [RAK 74.7% (59/79) versus RBAK 81.8% (63/77); p = 0.26]. Adverse effects were commonly reported (50.6% for both groups) although most of these did not cause cessation of treatment. The resistance rate was 27.2% for metronidazole and 12.3% for clarithromycin. Adding bismuth to the standard 7-day triple therapy did not substantially increase the eradication rate. Further study is needed clarifying whether extending the duration of RBAK regimen to 10–14 days can lead to a better result. PMID:28791044

  13. Pertuzumab: a review of its use for first-line combination treatment of HER2-positive metastatic breast cancer.

    PubMed

    McCormack, Paul L

    2013-09-01

    Pertuzumab (Perjeta®) is a humanized anti-HER2 monoclonal antibody that binds to the extracellular dimerization subdomain of the HER2 receptor and reduces HER2 intracellular signalling by preventing HER2 from forming heterodimers with other HER receptors. Inhibition of HER2 signalling results in a reduction of tumour cell proliferation, invasiveness and survival. Pertuzumab and trastuzumab bind to different sites on the HER2 receptor and have complementary antitumour activities; they act synergistically in inhibiting the growth of HER2-overexpressing breast cancer cell lines in vitro. The efficacy of intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) in combination with trastuzumab plus docetaxel in the first-line treatment of HER2-positive metastatic breast cancer was demonstrated in the randomized, double-blind, placebo-controlled, multinational, phase III CLEOPATRA trial. Pertuzumab in combination with trastuzumab and docetaxel significantly increased independently assessed median progression-free survival (primary endpoint), objective response rate and overall survival compared with placebo in combination with trastuzumab and docetaxel. Pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel in the pivotal CLEOPATRA trial. Thus, pertuzumab is a valuable addition to the growing list of anti-HER2 targeted therapies for breast cancer.

  14. Rational deployment of antimalarial drugs in Africa: should first-line combination drugs be reserved for paediatric malaria cases?

    PubMed

    Sutherland, Colin J; Babiker, Hamza; Mackinnon, Margaret J; Ranford-Cartwright, Lisa; El Sayed, Badria Babiker

    2011-10-01

    Artemisinin-based combination therapy is exerting novel selective pressure upon populations of Plasmodium falciparum across Africa. Levels of resistance to non-artemisinin partner drugs differ among parasite populations, and so the artemisinins are not uniformly protected from developing resistance, already present in South East Asia. Here, we consider strategies for prolonging the period of high level efficacy of combination therapy for two particular endemicities common in Africa. Under high intensity transmission, two alternating first-line combinations, ideally with antagonistic selective effects on the parasite genome, are advocated for paediatric malaria cases. This leaves second-line and other therapies for adult cases, and for intermittent preventive therapy. The drug portfolio would be selected to protect the 'premier' combination regimen from selection for resistance, while maximising impact on severe disease and mortality in children. In endemic areas subject to low, seasonal transmission of Plasmodium falciparum, such a strategy may deliver little benefit, as children represent a minority of cases. Nevertheless, the deployment of other drug-based interventions in low transmission and highly seasonal areas, such as mass drug administration aimed to interrupt malaria transmission, or intermittent preventive therapy, does provide an opportunity to diversify drug pressure. We thus propose an integrated approach to drug deployment, which minimises direct selective pressure on parasite populations from any one drug component. This approach is suitable for qualitatively and quantitatively different burdens of malaria, and should be supported by a programme of routine surveillance for emerging resistance.

  15. Lapatinib plus Letrozole as First-Line Therapy for HER-2+ Hormone Receptor–Positive Metastatic Breast Cancer

    PubMed Central

    Schwartzberg, Lee S.; Franco, Sandra X.; Florance, Allison; O'Rourke, Lisa; Maltzman, Julie

    2010-01-01

    Objective. To evaluate the efficacy and tolerability of letrozole plus lapatinib versus letrozole plus placebo in women with hormone receptor (HR)+ human epidermal growth factor receptor (HER)-2+ tumors receiving first-line therapy for metastatic breast cancer (MBC). Patients and Methods. Postmenopausal women (n = 1,286) with HR+ MBC were randomized to daily oral treatment with letrozole (2.5 mg) plus lapatinib (1,500 mg) versus letrozole (2.5 mg) plus placebo. Of the 1,286 patients enrolled in the phase III study, 219 had HER-2+ tumors. The primary endpoint was progression-free survival (PFS) in HER-2+ patients. Results. Results in the HR+ HER-2+ population (n = 219) are presented. The addition of lapatinib to letrozole resulted in a significantly lower risk for disease progression than with letrozole alone (hazard ratio, 0.71; 95% confidence interval, 0.53–0.96). The PFS time was 8.2 months, versus 3.0 months. The objective response rate (ORR) (28% versus 15%) and clinical benefit rate (CBR) (48% versus 29%) were also significantly greater in lapatinib-treated women. The most common adverse events in the lapatinib group were diarrhea (68%) and rash (46%), primarily grade 1 and 2. Conclusions. The addition of lapatinib to letrozole is well tolerated and leads to a significantly greater PFS time, ORR, and CBR than with letrozole alone in women with MBC who coexpress HR and HER-2. PMID:20156908

  16. Long-term survival in advanced non-squamous NSCLC patients treated with first-line bevacizumab-based therapy.

    PubMed

    De Castro, J; González-Larriba, J L; Vázquez, S; Massutí, B; Sanchez-Torres, J M; Dómine, M; Garrido, P; Calles, A; Artal, A; Collado, R; García, R; Sereno, M; Majem, M; Macías, J A; Juan, O; Gómez-Codina, J; Hernández, B; Lázaro, M; Ortega, A L; Cobo, M; Trigo, J M; Carcereny, E; Rolfo, C; Macia, S; Muñoz, J; Diz, P; Méndez, M; Rosillo, F; Paz-Ares, L; Cardona, J V; Isla, D

    2017-02-01

    First-line bevacizumab-based therapies have been shown to improve clinical outcomes in patients with non-squamous non-small-cell lung cancer (NSCLC). We aimed to descriptively analyse patients with non-squamous NSCLC who received a long-term period of maintenance bevacizumab. This retrospective study included 104 patients who had already reached a progression-free survival (PFS) of at least 9 months. Median overall survival and PFS were 30.7 and 15.1 months, respectively. The overall response rate was 83 %. Weight loss ≤5 %, ECOG PS = 0, or low number of metastatic sites seem to be predictive factors of good evolution. The incidence of bevacizumab-related adverse events appeared to be similar as the previous studies. Our findings show that there is a long-term survivor group whom the administration of bevacizumab resulted in a relevant prolongation of response without new safety signals. Due to the population heterogeneity, it was not possible to identify the standardised predictive factors.

  17. Neurotoxicity as a prognostic factor in patients with metastatic breast cancer treated with ixabepilone as a first-line therapy.

    PubMed

    Durando, Xavier; Dalenc, Florence; Abrial, Catherine; Mouret-Reynier, Marie-Ange; Herviou, Pauline; Kwiatkowski, Fabrice; Chollet, Philippe; Roche, Henri; Thivat, Emilie

    2015-01-01

    This study is a longitudinal follow-up of metastatic breast cancer patients treated with ixabepilone as first-line chemotherapy, with the aim to evaluate the association between a mechanism-based neurotoxicity and the efficacy of ixabepilone. At the 2 main investigational sites of a phase II clinical trial, 50 patients previously treated with anthracycline received ixabepilone. A chart review was performed to evaluate overall survival (OS) and time to progression (TTP) and to describe the subsequent treatments. The severe neurotoxicity induced by ixabepilone (38%) is correlated with a higher overall response rate to ixabepilone (79 vs. 48%; p = 0.042), a longer TTP (11.4 vs. 6.8 months; p = 0.023) and a longer OS (36.6 vs. 19.9 months; p = 0.05). After ixabepilone discontinuation, patients received a median of 4 subsequent chemotherapy lines (range 1-12). Among the 31 patients who received taxanes, neither the neurotoxicity incidence under treatment with taxanes nor the response was affected by a previous occurrence under ixabepilone treatment. These findings suggest that neurotoxicity development under ixabepilone treatment is a predictor of treatment outcomes as well as a favorable prognostic factor. It highlights the risk-to-benefit ratio issue of ixabepilone. We noticed the possibility to treat patients with taxanes after ixabepilone without systematic recurrent neurotoxicity. © 2014 S. Karger AG, Basel.

  18. Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: a phase II study.

    PubMed

    Brandes, Alba A; Ermani, Mario; Basso, Umberto; Paris, Myriam K; Lumachi, Franco; Berti, Franco; Amistà, Pietro; Gardiman, Marina; Iuzzolino, Paolo; Turazzi, Sergio; Monfardini, Silvio

    2002-01-01

    To investigate the efficacy of temozolomide (TMZ) in relationship to progression free survival at 6 months (PFS-6), median time to progression (TTP), response rate and toxicity, a phase II study was conducted in patients with recurrent glioblastoma multiforme (GBM) following surgery plus radiotherapy and a first-line regimen based on nitrosourea, procarbazine and vincristine. Forty-two patients with GBM were administered TMZ at the dose of 150 mg/m(2)/daily for 5 days every 4 weeks. The PFS-6 and at 12 months (PFS-12) was 24% (95% Confidence Interval [CI] = 14-42%) and 8% (CI = 2-27%), respectively, with a median TTP of 11.7 weeks (CI = 9-22 weeks). The response was assessed in all 42 patients; we observed 2 complete responses (CR) (4.7%), 6 partial responses (PR) (14.3%), and 9 stable disease (SD) (21.4%), with CR+PR = 19% (CI = 7-31%). TMZ as a second line regimen is a valid option in patients with heavily pretreated GBM. Copyright 2002 S. Karger AG, Basel

  19. Docetaxel and cisplatin as first-line treatment for patients with metastatic esophageal cancer: a pilot study.

    PubMed

    Laack, Eckart; Andritzky, Birte; Dürk, Heinz; Burkholder, Iris; Edler, Lutz; Schuch, Gunter; Boeters, Ina; Görn, Michael; Lipp, Rainer; Horst, Hartmut; Popp, Johann; Hossfeld, Dieter K

    2005-12-01

    We investigated the combination of docetaxel and cisplatin as first-line chemotherapy in patients with metastatic esophageal cancer. 16 chemotherapy-naïve patients with distant metastases were included in the study (15 male, 1 female; median age: 58.5 years (range 37-69); median ECOG performance status: 1). 11 patients (69%) had esophageal cancer, and 5 patients (31%) had cancer of the gastroesophageal junction. Patients received docetaxel 75 mg/m2 and cisplatin 80 mg/m2 on day 1 every 3 weeks. A total of 55 chemotherapy cycles was administered. The median number of cycles was 3 (range 1-6). The overall response rate was 31.3%. 4 out of 10 patients (40%) with squamous cell carcinoma and 1 out of 5 patients (20%) with adenocarcinoma responded to chemotherapy. The median overall survival was 29.6 weeks, and the median progression-free survival was 18.6 weeks. Hematological and non-hematological toxicities were moderate (neutropenia WHO grade III/IV: 42.9%, alopecia grade II/III: 64.3%, nausea/vomiting grade II/III: 57.2%, neurotoxicity grade II: 14.3%). The combination of docetaxel and cisplatin is an active regimen with moderate toxicity in the treatment of patients with metastatic esophageal cancer. This pilot study demonstrates the feasibility of a combination treatment containing a taxane and cisplatin in metastatic esophageal cancer.

  20. Development and application of a SYBR green RT-PCR for first line screening and quantification of porcine sapovirus infection

    PubMed Central

    2012-01-01

    Background Sapoviruses are single stranded positive sense RNA viruses belonging to the family Caliciviridae. The virus is detected in different species including the human and the porcine species as an enteric pathogen causing asymptomatic to symptomatic enteritis. In this study, we report the development of a rapid real time qRT-PCR based on SYBR Green chemistry for the diagnosis of porcine sapovirus infection in swine. Results The method allows the detection of porcine sapoviruses and the quantification of the genomic copies present in stool samples. During its development, the diagnostic tool showed good correlation compared with the gold standard conventional RT-PCR and was ten-fold more sensitive. When the method was applied to field samples, porcine noroviruses from genogroup 2 genotype 11b were also detected. The method was also applied to swine samples from the Netherlands that were positive for PoSaV infection. Phylogenetic results obtained from the samples showed that PoSaV sequences were genetically related to the currently described genogroup III, to the proposed genogroup VII and also to the MI-QW19 sequence (close to the human SaV sequences). Conclusions A rapid, sensitive, and reliable diagnosis method was developed for porcine sapovirus diagnosis. It correlated with the gold standard conventional RT-PCR. Specificity was good apart for genogroup 2 genotype 11b porcine noroviruses. As a first line screening diagnosis method, it allows a quicker and easier decision on doubtful samples. PMID:23072668

  1. Factors associated with virological rebound in HIV-infected patients receiving protease inhibitor monotherapy.

    PubMed

    Stöhr, Wolfgang; Dunn, David T; Arenas-Pinto, Alejandro; Orkin, Chloe; Clarke, Amanda; Williams, Ian; Johnson, Margaret; Beeching, Nicholas J; Wilkins, Edmund; Sanders, Karen; Paton, Nicholas I

    2016-11-13

    The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial found that protease inhibitor monotherapy as a simplification strategy is well tolerated in terms of drug resistance but less effective than combination therapy in suppressing HIV viral load. We sought to identify factors associated with the risk of viral load rebound in this trial. PIVOT was a randomized controlled trial in HIV-positive adults with suppressed viral load for at least 24 weeks on combination therapy comparing a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy versus ongoing triple therapy. In participants receiving monotherapy, we analysed time to confirmed viral load rebound and its predictors using flexible parametric survival models. Of 290 participants initiating protease inhibitor monotherapy (80% darunavir, 14% lopinavir, and 6% other), 93 developed viral load rebound on monotherapy. The risk of viral load rebound peaked at 9 months after starting monotherapy and then declined to approximately 5 per 100 person-years from 18 months onwards. Independent predictors of viral load rebound were duration of viral load suppression before starting monotherapy (hazard ratio 0.81 per additional year <50 copies/ml; P < 0.001), CD4 cell count (hazard ratio 0.73 per additional 100 cells/μl for CD4 nadir; P = 0.008); ethnicity (hazard ratio 1.87 for nonwhite versus white, P = 0.025) but not the protease inhibitor agent used (P = 0.27). Patients whose viral load was analysed with the Roche TaqMan-2 assay had a 1.87-fold risk for viral load rebound compared with Abbott RealTime assay (P = 0.012). A number of factors can identify patients at low risk of rebound with protease inhibitor monotherapy, and this may help to better target those who may benefit from this management strategy.

  2. Cost-effectiveness of first-line antiretroviral therapy for HIV-infected African children less than 3 years of age

    PubMed Central

    Ciaranello, Andrea L.; Doherty, Kathleen; Penazzato, Martina; Lindsey, Jane C.; Harrison, Linda; Kelly, Kathleen; Walensky, Rochelle P.; Essajee, Shaffiq; Losina, Elena; Muhe, Lulu; Wools-Kaloustian, Kara; Ayaya, Samuel; Weinstein, Milton C.; Palumbo, Paul; Freedberg, Kenneth A.

    2015-01-01

    Background: The International Maternal, Pediatric, and Adolescent Clinical Trials P1060 trial demonstrated superior outcomes for HIV-infected children less than 3 years old initiating antiretroviral therapy (ART) with lopinavir/ritonavir compared to nevirapine, but lopinavir/ritonavir is four-fold costlier. Design/methods: We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-Pediatric model, with published and P1060 data, to project outcomes under three strategies: no ART; first-line nevirapine (with second-line lopinavir/ritonavir); and first-line lopinavir/ritonavir (second-line nevirapine). The base-case examined South African children initiating ART at age 12 months; sensitivity analyses varied all key model parameters. Outcomes included life expectancy, lifetime costs, and incremental cost-effectiveness ratios [ICERs; dollars/year of life saved ($/YLS)]. We considered interventions with ICERs less than 1× per-capita gross domestic product (South Africa: $7500)/YLS as ‘very cost-effective,’ interventions with ICERs below 3× gross domestic product/YLS as ‘cost-effective,’ and interventions leading to longer life expectancy and lower lifetime costs as ‘cost-saving’. Results: Projected life expectancy was 2.8 years with no ART. Both ART regimens markedly improved life expectancy and were very cost-effective, compared to no ART. First-line lopinavir/ritonavir led to longer life expectancy (28.8 years) and lower lifetime costs ($41 350/person, from lower second-line costs) than first-line nevirapine (27.6 years, $44 030). First-line lopinavir/ritonavir remained cost-saving or very cost-effective compared to first-line nevirapine unless: liquid lopinavir/ritonavir led to two-fold higher virologic failure rates or 15-fold greater costs than in the base-case, or second-line ART following first-line lopinavir/ritonavir was very ineffective. Conclusions: On the basis of P1060 data, first-line lopinavir/ritonavir leads to longer life

  3. Trends in selection and timing of first-line pharmacotherapy in older patients with type 2 diabetes diagnosed between 1994 and 2006.

    PubMed

    Foster, P D; Mamdani, M M; Juurlink, D N; Shah, B R; Paterson, J M; Gomes, T

    2013-10-01

    To characterize temporal trends in the selection and timing of first-line pharmacotherapy among older patients with Type 2 diabetes. We studied five population-based cohorts every 3 years, from 1994 to 2006. In each of those years, we identified all subjects aged 66 years or older newly diagnosed with diabetes and determined the initial glucose-lowering drug and the time between diagnosis and drug initiation. We calculated the proportion of patients prescribed each agent and estimated time from diagnosis to initiation using Kaplan-Meier survival analysis. We identified a total of 64 368 eligible people who initiated drug therapy during the study period. From 1994 to 2006, first-line metformin use increased from 20.1 to 79.0%. Glyburide (glibenclamide) decreased from 71.1% of all first-line therapies in 1994 to 9.8% in 2006, while first-line use of insulin or combination therapy have changed little at approximately 5% each. No other medication exceeded 2% of first-line therapies. The median time from diagnosis to initiation of pharmacotherapy increased dramatically during the study period, from 1.8 years in 1994 to 4.6 years in 2006. Metformin has become the most commonly used initial medication for the treatment of diabetes. Although guidelines have evolved to recommend more aggressive initiation and intensification of pharmacotherapy, our results suggest that the time from diagnosis to initiation has increased substantially. © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.

  4. Should First-Line Empiric Treatment Strategies For Neonates Cover Coagulase-Negative Staphylococcal Infections In Kenya?

    PubMed

    Seale, Anna C; Obiero, Christina W; Jones, Kelsey; Barsosio, Hellen C; Thitiri, Johnstone; Ngari, Moses; Morpeth, Susan; Mohammed, Shebe; Fegan, Greg; Mturi, Neema; Berkley, James A

    2017-07-18

    Neonatal mortality remains high in sub-Saharan Africa, and a third of deaths are estimated to result from infection. Whilst coagulase negative staphylococci (CoNS) are leading neonatal pathogens in resource-rich settings, their role, and the need for early anti-staphylococcal treatment in empiric antibiotic guidelines, is unknown in sub-Saharan Africa. We examined systematic clinical and microbiologic surveillance data from all neonatal admissions to Kilifi County Hospital (1998-2013) to determine associated case fatality and/or prolonged duration of admission associated with CoNS in neonates treated according to standard WHO guidelines. CoNS was isolated from blood culture in 995/9552 (10%) neonates. Case fatality amongst neonates with CoNS isolated from blood did not differ from other neonatal admissions (p=0.2), and duration of admission was not prolonged (OR=0.9(0.7-1.0), p=0.040). Neonates with CoNS were more likely to have convulsions (OR=1.4(1.0-1.8), p = 0.031), but less likely to have impaired consciousness or severe indrawing (OR 0.8(0.7-0.9), p=0.025; OR=0.9(0.7-1.0), p=0.065). CoNS isolation in blood cultures at admission was not associated with adverse clinical outcomes in neonates treated according to standard WHO guidelines for hospital care in this setting. There is no evidence that first-line antimicrobial treatment guidelines should be altered to increase cover for coagulase- negative staphylococcal infections in neonates in this setting.

  5. Quadruple-first line drug resistance in Mycobacterium tuberculosis in Vietnam: What can we learn from genes?

    PubMed

    Nguyen, Huy Quang; Nguyen, Nhung Viet; Contamin, Lucie; Tran, Thanh Hoa Thi; Vu, Thuong Thi; Nguyen, Hung Van; Nguyen, Ngoc Lan Thi; Nguyen, Son Thai; Dang, Anh Duc; Bañuls, Anne-Laure; Nguyen, Van Anh Thi

    2017-06-01

    In Vietnam, a country with high tuberculosis (137/100.000 population) and multidrug-resistant (MDR)-TB burdens (7.8/100.000 population), little is known about the molecular signatures of drug resistance in general and more particularly of second line drug (SLD) resistance. This study is specifically focused on Mycobacterium tuberculosis isolates resistant to four first-line drugs (FLDs) that make TB much more difficult to treat. The aim is to determine the proportion of SLD resistance in these quadruple drug resistant isolates and the genetic determinants linked to drug resistance to better understand the genetic processes leading to quadruple and extremely drug resistance (XDR). 91 quadruple (rifampicin, isoniazid, ethambutol and streptomycin) FLD resistant and 55 susceptible isolates were included. Spoligotyping and 24-locus MIRU-VNTR techniques were performed and 9 genes and promoters linked to FLD and SLD resistance were sequenced. SLD susceptibility testing was carried out on a subsample of isolates. High proportion of quadruple-FLD resistant isolates was resistant to fluoroquinolones (27%) and second-line injectable drugs (30.2%) by drug susceptibility testing. The sequencing revealed high mutation diversity with prevailing mutations at positions katG315, inhA-15, rpoB531, embB306, rrs1401, rpsL43 and gyrA94. The sensitivity and specificity were high for most drug resistances (>86%), but the sensitivity was lower for injectable drug resistances (<69%). The mutation patterns revealed 23.1% of pre-XDR and 7.7% of XDR isolates, mostly belonging to Beijing family. The genotypic diversity and the variety of mutations reflect the existence of various evolutionary paths leading to FLD and SLD resistance. Nevertheless, particular mutation patterns linked to high-level resistance and low fitness costs seem to be favored. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. HLA genotyping as first-line screening tool for coeliac disease in children with juvenile idiopathic arthritis.

    PubMed

    Skrabl-Baumgartner, Andrea; Christine Hauer, Almuthe; Erwa, Wolfgang; Jahnel, Jörg

    2017-07-01

    Coeliac disease (CD) and juvenile idiopathic arthritis (JIA) often coexist. This association warrants assessment for CD in patients with JIA. We evaluated the clinical relevance and cost-effectiveness of human leucocyte antigen (HLA) genotyping in first-line screening for development of CD in children with JIA. 95 patients with JIA were screened for CD using CD-specific antibodies. In case of positivity, a small intestinal biopsy was performed to confirm diagnosis. In addition, HLA genotyping was performed. 110 age-matched and sex-matched Caucasian children from the same geographical area served as controls. CD was diagnosed in 4 of 95 patients with JIA (4.2%), a rate significantly higher compared with controls (p<0.02) and 14 times higher than in the general population. Twenty-six patients (27.4%) had one of the variants of the risk genotypes. All four patients diagnosed with CD had a HLA-DQ2.5 genotype: one was homozygote, the remainder heterozygote. Twenty-two patients are, judging by their HLA genotypes, at risk of developing CD and require repeated serological screening. None of the 69 patients without HLA-DQ2/DQ8 genotypes had CD-specific antibodies. Screening with HLA genotyping becomes cheaper than screening without after the second determination. In our cohort of patients with JIA, lack of HLA-DQ2/DQ8 genotypes identified a majority not at risk of CD in whom repeated serological testing is unnecessary. Genotyping is nowadays the most efficient and cost-effective way to screen for CD risk in JIA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  7. FOLFIRI® and bevacizumab in first-line treatment for colorectal cancer patients: safety, efficacy and genetic polymorphisms.

    PubMed

    Bécouarn, Yves; Cany, Laurent; Pulido, Marina; Beyssac, Richard; Texereau, Patrick; Le Morvan, Valérie; Béchade, Dominique; Brunet, René; Aitouferoukh, Sofiane; Lalet, Caroline; Mathoulin-Pélissier, Simone; Fonck, Marianne; Robert, Jacques

    2014-04-23

    Over 50% of colorectal cancer (CRC) patients develop metastases. The aim of this study was to evaluate efficacy and tolerance of first-line FOLFIRI® + bevacizumab (B) treatment for metastatic CRC, and to assess genetic polymorphisms as potential markers. Adult patients with histologically-proven, non-resectable metastatic CRC and ECOG ≤ 2 were included. 14-day cycles consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m2), bolus FU (400 mg/m2) and leucovorin (400 mg/m2), followed by 46-hour FU infusions (2400 mg/m2). Primary endpoint was response rate according to RECIST criteria. Secondary endpoints were overall (OS) and progression-free (PFS) survivals, response duration, and toxicity. Associations between clinical data, UGT1A1, thymidylate synthase, VEGFA polymorphisms and PFS, OS and toxicity were analyzed. Sixty-two patients were enrolled (median age 68y). 59/62 patients were eligible and evaluable for response at 6 months: 28 showed partial response (47.5%; 95% CI; 34.3-60.9), 20 stable disease (33.9%) and 11 progression (18.6%). Grade 3/4 toxicities were as follows: neutropenia 16.1%; diarrhea 11.3%; nausea-vomiting 1.6%. Median response duration was 9.5 months (range 2.7-20); median PFS 10.3 months (range 8.8-11.7); and median OS 25.7 months (range 20.2-29.7). 11/59 initially unresectable patients were resectable after treatment. VEGFA polymorphism (rs25648) was associated with better OS (HR: 3.61; 95% CI: 1.57-8.30). FOLFIRI® + bevacizumab is active with good response rate, long median OS, and a good safety profile. A VEGFA polymorphism might have a prognostic value in this malignancy. Clinicaltrials.gov: NCT00467142 (registration date: April 25, 2007).

  8. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients.

    PubMed

    Foà, Robin; Del Giudice, Ilaria; Cuneo, Antonio; Del Poeta, Giovanni; Ciolli, Stefania; Di Raimondo, Francesco; Lauria, Francesco; Cencini, Emanuele; Rigolin, Gian Matteo; Cortelezzi, Agostino; Nobile, Francesco; Callea, Vincenzo; Brugiatelli, Maura; Massaia, Massimo; Molica, Stefano; Trentin, Livio; Rizzi, Rita; Specchia, Giorgina; Di Serio, Francesca; Orsucci, Lorella; Ambrosetti, Achille; Montillo, Marco; Zinzani, Pier Luigi; Ferrara, Felicetto; Morabito, Fortunato; Mura, Maria Angela; Soriani, Silvia; Peragine, Nadia; Tavolaro, Simona; Bonina, Silvia; Marinelli, Marilisa; De Propris, Maria Stefania; Starza, Irene Della; Piciocchi, Alfonso; Alietti, Alessandra; Runggaldier, Eva Josephine; Gamba, Enrica; Mauro, Francesca Romana; Chiaretti, Sabina; Guarini, Anna

    2014-05-01

    In a phase II trial, we evaluated chlorambucil and rituximab (CLB-R) as first-line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28-day cycles of CLB (8 mg/m(2) /day, days 1-7) and R (day 1 of cycle 3, 375 mg/m(2) ; cycles 4-8, 500 mg/m(2) ). Responders were randomized to 12 8-week doses of R (375 mg/m(2) ) or observation. As per intention-to-treat analysis, 82.4% (95% CI, 74.25-90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60-64 years, 92.3%; 65-69, 85.2%; 70-74, 75.0%; ≥75, 81.0%). CLB-R was well tolerated. After a median follow-up of 34.2 months, the median progression-free survival (PFS) was 34.7 months (95% CI, 33.1-39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB-R represents a promising option for elderly CLL patients. Copyright © 2014 Wiley Periodicals, Inc.

  9. Semi-quantitative analysis of salivary gland scintigraphy in Sjögren's syndrome diagnosis: a first-line tool.

    PubMed

    Angusti, Tiziana; Pilati, Emanuela; Parente, Antonella; Carignola, Renato; Manfredi, Matteo; Cauda, Simona; Pizzigati, Elena; Dubreuil, Julien; Giammarile, Francesco; Podio, Valerio; Skanjeti, Andrea

    2017-01-03

    The aim of this study was the assessment of semi-quantified salivary gland dynamic scintigraphy (SGdS) parameters independently and in an integrated way in order to predict primary Sjögren's syndrome (pSS). Forty-six consecutive patients (41 females; age 61 ± 11 years) with sicca syndrome were studied by SGdS after injection of 200 MBq of pertechnetate. In sixteen patients, pSS was diagnosed, according to American-European Consensus Group criteria (AECGc). Semi-quantitative parameters (uptake (UP) and excretion fraction (EF)) were obtained for each gland. ROC curves were used to determine the best cut-off value. The area under the curve (AUC) was used to estimate the accuracy of each semi-quantitative analysis. To assess the correlation between scintigraphic results and disease severity, semi-quantitative parameters were plotted versus Sjögren's syndrome disease activity index (ESSDAI). A nomogram was built to perform an integrated evaluation of all the scintigraphic semi-quantitative data. Both UP and EF of salivary glands were significantly lower in pSS patients compared to those in non-pSS (p < 0.001). ROC curve showed significantly large AUC for both the parameters (p < 0.05). Parotid UP and submandibular EF, assessed by univariated and multivariate logistic regression, showed a significant and independent correlation with pSS diagnosis (p value <0.05). No correlation was found between SGdS semi-quantitative parameters and ESSDAI. The proposed nomogram accuracy was 87%. SGdS is an accurate and reproducible tool for the diagnosis of pSS. ESSDAI was not shown to be correlated with SGdS data. SGdS should be the first-line imaging technique in patients with suspected pSS.

  10. Timing of first-line cancer treatments - early versus late - a systematic review of phase III randomized trials.

    PubMed

    Mhaskar, A R; Quinn, G; Vadaparampil, S; Djulbegovic, B; Gwede, C K; Kumar, A

    2010-12-01

    To conduct a systematic review and meta-analysis of all phase III randomized controlled trials comparing efficacy of early versus late first-line or initial treatments for cancer. A comprehensive literature search of MEDLINE and Cochrane library databases was performed (1966-2008). Data was extracted and pooled as per the methods recommended by the Cochrane Collaboration. Of the 570 identified studies, 10 (3811 patients) met inclusion criteria: three each in prostate cancer and multiple myeloma (MM), two in chronic lymphocytic leukemia (CLL), and one each in lung cancer, and follicular lymphoma. The analyses showed no survival benefit with early treatment except in prostate cancer (hazard ratio [HR]=1.23, 95% CI 1.11-1.37 p<0.001). There was no survival difference in MM (HR=0.92, 95% CI 0.56-1.52 p=0.74), CLL (HR=0.76, 95% CI 0.56-1.04 p=0.09), lung cancer (HR=0.95, 95% CI 0.72-1.24 p=0.71), or follicular lymphoma (HR=1, 95% CI 0.55-1.83 p=0.99). No statistically significant difference in response rate between early and late treatment was detected in any cancer type. Data shows that delaying cancer treatments does not necessarily compromise therapeutic outcomes except possibly in locally advanced prostate cancer. These findings provide a unique window to oncologists and patients to address time-sensitive issues if desired by patients. Copyright © 2010 Elsevier Ltd. All rights reserved.

  11. Genotypic HIV type-1 drug resistance among patients with immunological failure to first-line antiretroviral therapy in south India.

    PubMed

    Vidya, Madhavan; Saravanan, Shanmugam; Uma, Shanmugasundaram; Kumarasamy, Nagalingeswaran; Sunil, Solomon S; Kantor, Rami; Katzenstein, David; Ramratnam, Bharat; Mayer, Kenneth H; Suniti, Solomon; Balakrishnan, Pachamuthu

    2009-01-01

    HIV type-1 (HIV-1) monitoring in resource-limited settings relies on clinical and immunological assessment. The objective of this study was to study the frequency and pattern of reverse transcriptase (RT) drug resistance among patients with immunological failure (IF) to first-line therapy. A cross-sectional study of 228 patients with IF was done, of which 126 were drug-naive (group A) when starting highly active antiretroviral therapy (HAART) and 102 were exposed to mono/dual therapy prior to HAART initiation (group B). A validated in-house genotyping method and Stanford interpretation was used. Means, sd, median and frequencies (as percentages) were used to indicate the patient characteristics in each group. The chi(2) test and Fisher's exact test were used to compare categorical variables as appropriate. All analyses were performed using SPSS software, version 13.0. P-values <0.05 were considered to be statistically significant. RT drug resistance mutations were found in 92% and 96% of patients in groups A and B, respectively. Median (interquartile range) CD4(+) T-cell count at failure was 181 cells/microl (18-999) and time to failure was 40 months (2-100). M184V (80% versus 75%), thymidine analogue mutations (63% versus 74%), Y181C (39% versus 39%) and K103N (29% versus 39%) were predominant RT mutations in both groups. Extensive nucleoside reverse transcriptase inhibitor cross-resistance mutations were observed in 51% and 26% of patients in group B and A, respectively. Alternative strategies for initial therapy and affordable viral load monitoring could reduce resistance accumulations and preserve available drugs for future options in resource-limited settings.

  12. Genotypic HIV type-1 drug resistance among patients with immunological failure to first-line antiretroviral therapy in south India

    PubMed Central

    Vidya, Madhavan; Saravanan, Shanmugam; Uma, Shanmugasundaram; Kumarasamy, Nagalingeswaran; Sunil, Solomon S; Kantor, Rami; Katzenstein, David; Ramratnam, Bharat; Mayer, Kenneth H; Suniti, Solomon; Balakrishnan, Pachamuthu

    2013-01-01

    Background HIV type-1 (HIV-1) monitoring in resource limited settings relies on clinical and immunological assessment. The objective of this study was to study the frequency and pattern of reverse transcriptase (RT) drug resistance among patients with immunological failure (IF) to first-line therapy. Methods A cross-sectional study of 228 patients with IF was done, of which 126 were drug-naive (group A) when starting highly active antiretroviral therapy (HAART) and 102 were exposed to mono/dual therapy prior to HAART initiation (group B). A validated in-house genotyping method and Stanford interpretaion was used. Means, sd, median and frequencies (as percentages) were used to indicate the patient characteristics in each group. The χ2 test and Fisher's exact test were used to compare categorical variables as appropriate. All analyses were performed using SPSS software, version 13.0. P-values <0.05 were considered to be statistically significant. Results RT drug resistance mutations were found in 92% and 96% of patients in groups A and B, respectively. Median (interquartile range) CD4+ T–cell count at failure was 181cells/ml (18–999) and time to failure was 40 months (2–100). M184V (80% versus 75%), thymidine analogue mutations (63% versus 74%), Y181C (39% versus 39%) and K103N (29% versus 39%) were predominant RT mutations in both groups. Extensive nucleoside reverse transcriptase inhibitor cross-resistance mutations were observed in 51% and 26%of patients in group B and A, respectively. Conclusions Alternative strategies for initial therapy and affordable viral load monitoring could reduce resistance accumulations and preserve available drugs for future options in resource-limited settings. PMID:19918105

  13. Cost-effectiveness of capecitabine and bevacizumab maintenance treatment after first-line induction treatment in metastatic colorectal cancer.

    PubMed

    Franken, M D; van Rooijen, E M; May, A M; Koffijberg, H; van Tinteren, H; Mol, L; Ten Tije, A J; Creemers, G J; van der Velden, A M T; Tanis, B C; Uyl-de Groot, C A; Punt, C J A; Koopman, M; van Oijen, M G H

    2017-04-01

    Capecitabine and bevacizumab (CAP-B) maintenance therapy has shown to be more effective compared with observation in metastatic colorectal cancer patients achieving stable disease or better after six cycles of first-line capecitabine, oxaliplatin, bevacizumab treatment in terms of progression-free survival. We evaluated the cost-effectiveness of CAP-B maintenance treatment. Decision analysis with Markov modelling to evaluate the cost-effectiveness of CAP-B maintenance compared with observation was performed based on CAIRO3 study results (n = 558). An additional analysis was performed in patients with complete or partial response. The primary outcomes were the incremental cost-effectiveness ratio (ICER) defined as the additional cost per life year (LY) and quality-adjusted life years (QALY) gained, calculated from EQ-5D questionnaires and literature and LYs gained. Univariable sensitivity analysis was performed to assess the influence of input parameters on the ICER, and a probabilistic sensitivity analysis represents uncertainty in model parameters. CAP-B maintenance compared with observation resulted in 0.21 QALYs (0.18LYs) gained at a mean cost increase of €36,845, yielding an ICER of €175,452 per QALY (€204,694 per LY). Varying the difference in health-related quality of life between CAP-B maintenance and observation influenced the ICER most. For patients achieving complete or partial response on capecitabine, oxaliplatin, bevacizumab induction treatment, an ICER of €149,300 per QALY was calculated. CAP-B maintenance results in improved health outcomes measured in QALYs and LYs compared with observation, but also in a relevant increase in costs. Despite the fact that there is no consensus on cost-effectiveness thresholds in cancer treatment, CAP-B maintenance may not be considered cost-effective. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Monitoring and Switching of First-line Antiretroviral Therapy in sub-Saharan Africa: Collaborative Analysis of Adult Treatment Cohorts

    PubMed Central

    Haas, Andreas D.; Keiser, Olivia; Balestre, Eric; Brown, Steve; Bissagnene, Emmanuel; Chimbetete, Cleophas; Dabis, François; Davies, Mary-Ann; Hoffmann, Christopher J.; Oyaro, Patrick; Parkes-Ratanshi, Rosalind; Reynolds, Steven J.; Sikazwe, Izukanji; Wools-Kaloustian, Kara; Zannou, Djimon Marcel; Wandeler, Gilles; Egger, Matthias

    2015-01-01

    Background HIV-1 viral load (VL) testing is recommended to monitor antiretroviral therapy (ART) but not universally available. We examined monitoring of first-line and switching to second-line ART in sub-Saharan Africa, 2004–2013. Methods Adult HIV-1 infected patients starting combination ART in 16 countries were included. Switching was defined as a change from a non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen to a protease inhibitor (PI)-based regimen, with a change of ≥1 NRTI. Virological and immunological failures were defined per World Health Organization criteria. We calculated cumulative probabilities of switching and hazard ratios with 95% confidence intervals (CI) comparing routine VL monitoring, targeted VL monitoring, CD4 cell monitoring and clinical monitoring, adjusted for programme and individual characteristics. Findings Of 297,825 eligible patients, 10,352 patients (3·5%) switched during 782,412 person-years of follow-up. Compared to CD4 monitoring hazard ratios for switching were 3·15 (95% CI 2·92–3·40) for routine VL, 1·21 (1·13–1·30) for targeted VL and 0·49 (0·43–0·56) for clinical monitoring. Overall 58.0% of patients with confirmed virological and 19·3% of patients with confirmed immunological failure switched within 2 years. Among patients who switched the percentage with evidence of treatment failure based on a single CD4 or VL measurement ranged from 32·1% with clinical to 84.3% with targeted VL monitoring. Median CD4 counts at switching were 215 cells/µl under routine VL monitoring but lower with other monitoring (114–133 cells/µl). Interpretation Overall few patients switched to second-line ART and switching occurred late in the absence of routine viral load monitoring. Switching was more common and occurred earlier with targeted or routine viral load testing. PMID:26423252

  15. Phase I/II Trial of Sorafenib in Combination with Vinorelbine as First-Line Chemotherapy for Metastatic Breast Cancer

    PubMed Central

    Ferrario, Cristiano; Strepponi, Ivan; Charamis, Helen; Langleben, Adrian; Scarpi, Emanuela; Nanni, Oriana; Miller, Wilson H.; Panasci, Lawrence C.

    2016-01-01

    Background Preclinical models have reported a synergistic interaction between sorafenib and vinorelbine. We investigated the toxicity, efficacy, and pharmacokinetics interaction of this combination as first-line treatment for patients with metastatic breast cancer. Methods Patients were HER2-negative and treated with vinorelbine 30 mg/m2 IV days 1,8 every 21 plus daily oral sorafenib. In the phase I portion (3+3 design) patients received sorafenib 200 mg BID (cohort 1) or 400 mg BID (cohort 2). In the phase II expansion, 21 more evaluable patients were planned to receive the maximum tolerated dose (MTD). Pharmacokinetic analysis was performed in 6 patients: blood concentrations were compared for each drug in the presence or absence of the other drug. Results In cohort 1, one patient experienced a dose-limiting toxicity (DLT) (grade 3 pancreatitis), requiring the expansion of this cohort to 6 patients, without further documented DLTs. In cohort 2, one patient of six experienced a grade 4 DLT (asymptomatic rise in amylase not requiring drug discontinuation), establishing this dose level as the MTD (sorafenib 400 mg BID). After expansion at the MTD, a total of 27 patients (median age 57) were treated for a median of 8 cycles. One grade 5 febrile neutropenia occurred. With repeated cycles, 52% of patients required at least 1 dose reduction of either drug. One patient experienced a sustained grade 3 fatigue resulting in treatment discontinuation. The response rate was 30%. Median PFS was 5.7 months (95% CI 4.4–7.6), and clinical benefit (absence of disease progression at 6 months) was 48%. PK analysis showed a significant interaction between the two drugs, resulting in a higher Cmax of vinorelbine in the presence of sorafenib. Conclusion The combination of sorafenib and vinorelbine at full doses is feasible but not devoid of toxicity, likely also due to a significant PK interaction. Trial Registration ClinicalTrials.gov NCT00764972 PMID:27992451

  16. “Stepped Care”: A Health Technology Solution for Delivering Cognitive Behavioral Therapy as a First Line Insomnia Treatment

    PubMed Central

    Espie, Colin A.

    2009-01-01

    There is a large body of evidence that Cognitive Behavioral Therapy for insomnia (CBT) is an effective treatment for persistent insomnia. However, despite two decades of research it is still not readily available, and there are no immediate signs that this situation is about to change. This paper proposes that a service delivery model, based on “stepped care” principles, would enable this relatively scarce healthcare expertise to be applied in a cost-effective way to achieve optimal development of CBT services and best clinical care. The research evidence on methods of delivering CBT, and the associated clinical leadership roles, is reviewed. On this basis, self-administered CBT is posited as the “entry level” treatment for stepped care, with manualized, small group, CBT delivered by nurses, at the next level. Overall, a hierarchy comprising five levels of CBT stepped care is suggested. Allocation to a particular level should reflect assessed need, which in turn represents increased resource requirement in terms of time, cost and expertise. Stepped care models must also be capable of “referring” people upstream where there is an incomplete therapeutic response to a lower level intervention. Ultimately, the challenge is for CBT to be delivered competently and effectively in diversified formats on a whole population basis. That is, it needs to become “scalable”. This will require a robust approach to clinical governance. Citation: Espie CA. “Stepped care”: A health technology solution for delivering Cognitive Behavioral Therapy as a first line insomnia treatment. SLEEP 2009;32(12):1549-1558. PMID:20041590

  17. [Retrospective Study of Efficacy in BIM Gene Polymorphism on First-line EGFR-TKIs Treatment for Advanced Lung Adenocarcinoma].

    PubMed

    Qian, Kun; Zhang, Yi; Zhi, Xiuyi

    2017-08-20

    The aim of this study is to detect the BIM polymorphism in 85 formalin-fixed and parrffin-embedded (FFPE) and some blood samples of advanced lung adenocarcinoma patients and study the relativity betweenthe BIM polymorphism and tyrosine kinase inhibitor (TKI). The correlation between BIM detection of different types of specimens was discussed. There were 85 patients who were diagnosed as advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) 19 or 21 exon mutation in thoracic surgery of Xuanwu Hospital from February 2013 to November 2014, all of who were received EGFR-TKI as first-line treatment in the study. FFPE and some blood were used to detect the BIM polymorphism. The objective response rate (ORR) and progression-free survival (PFS) of two groups were compared. According to smoking, sex, EGFR mutation and other factors, the single factor analysis was performed, and the correlation between paraffin samples and blood test BIM was compared. The ORR in BIM polymorphism and non-polymorphism groups was no significant differences (P>0.05). The median PFS in BIM polymorphism and non-polymorphism group was 7.1 months and 12.8 months, respectively (P=0.013). Univariate analysis the median PFS, women were longer than men (12.1 months vs 10.7 months, P=0.835); Non-smokers were longer than smokers (12.1 months vs 9.7 months, P=0.974). Group in EGFR exon 21 is longer than group in EGFR exon 19 (12.2 months vs 8.7 months, P=0.303). Detection of BIM gene polymorphism in lung cancer patients with EGFR-TKIs treatment might be helpful for predicting prognosis. But a large sample study is needed.

  18. In vitro pharmacological interaction of caffeine and first-line antibiotics is antagonistic against clinically important bacterial pathogens.

    PubMed

    Olajuyigbe, Olufunmiso O; Adeoye-Isijola, Morenike O; Okon, Victoria; Adedayo, Otunola; Coopoosamy, Roger M

    2017-01-01

    The in vitro antibacterial activity of pure caffeine powder and its interaction with first line antibiotic against bacterial isolates were investigated with the macrobroth dilution and the checkerboard assay methods. This study showed that caffeine and the antibiotics exhibited various degrees of antibacterial activities. While caffeine had MICs ranging between 67.19 and 268.75 µg/ml, chloramphenicol was characterized by MICs between 0.98 and 31.25 µg/ml, kanamycin - 15.63-62.5 µg/ml, nalidixic acid - 0.49-250 µg/ml, erythromycin - 0.49-62.5 µg/ml, tetracycline - 1.99-62.5 µg/ml and metronidazole - 15.63-31.25 µg/ml. Combining ½ MICs and MICs of caffeine with the antibiotics as well as direct combination of caffeine and the antibiotics resulted in significant reduction of antibiotics' effectiveness. The fractional inhibitory concentration index (FICI) for the combination of ½ MICs of caffeine with different antibiotics showed antagonistic interactions with the antibiotics except kanamycin which had additive and indifferent interactions with caffeine. The FICI of the MICs of caffeine combined with antibiotics showed a reduction in the number of antagonistic interactions as chloramphenicol, nalidixic acid and erythromycin showed some indifferent interactions while kanamycin was the only antibiotic that showed indifferent interaction against all the bacterial isolates. The direct combination of caffeine and the antibiotics resulted in significant antagonistic interactions higher than in the case when caffeine, at the ½ MICs and MICs, was combined with the antibiotics. Although caffeine demonstrated significant antibacterial activity against the selected bacterial isolates, its combination with the selected antibiotics resulted in significant antagonistic interactions. Caffeine should not be combined with antibiotics as this could result in serious therapeutic failure and, possibly, drug toxicity in vivo.

  19. Duocarmycin-based prodrugs for cancer prodrug monotherapy.

    PubMed

    Tietze, Lutz F; Schuster, Heiko J; Schmuck, Kianga; Schuberth, Ingrid; Alves, Frauke

    2008-06-15

    The synthesis and biological evaluation of novel prodrugs based on the cytotoxic antibiotic duocarmycin SA (1) for a selective treatment of cancer using a prodrug monotherapy (PMT) are described. Transformation of the phenol 8 with the glucuronic acid benzyl ester trichloroacetimidate 9b followed by reaction with DMAI x HCl (10) gives the glucuronide 11b, which is deprotected to afford the desired prodrug 4a containing a glucuronic acid moiety. In addition, the prodrug 4b with a glucuronic methyl ester unit is prepared. The cytotoxicity of the glucuronides is determined using a HTCFA-assay with IC(50) values of 610 nM for 4a and 3300 nM for 4b. In the presence of beta-glucuronidase, 4a expresses an IC(50) value of 0.9 nM and 4b of 2.1 nM resulting in QIC(50) values of about 700 for 4a and 1600 for 4b.

  20. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial.

    PubMed

    Praga, M; Barrio, V; Juárez, G Fernández; Luño, J

    2007-05-01

    Membranous nephropathy is a common cause of nephrotic syndrome in adults. Although some patients with membranous nephropathy achieve a spontaneous remission, renal function continues to deteriorate in others. We conducted a prospective randomized trial evaluating monotherapy with tacrolimus to achieve complete or partial remission in patients with biopsy-proven membranous nephropathy. Twenty-five patients received tacrolimus (0.05 mg/kg/day) over 12 months with a 6-month taper, whereas 23 patients were in the control group. The probability of remission in the treatment group was 58, 82, and 94% after 6, 12, and 18 months but only 10, 24, and 35%, respectively in the control group. The decrease in proteinuria was significantly greater in the treatment group. Notably, six patients in the control group and only one in the treatment group reached the secondary end point of a 50% increase in their serum creatinine. No patient in the tacrolimus group showed a relapse during the taper period. Nephrotic syndrome reappeared in almost half of the patients who were in remission by the 18th month after tacrolimus withdrawal. We conclude that tacrolimus is a very useful therapeutic option for patients with membranous nephropathy and preserved renal function. The majority of patients experienced remission with a significant reduction in the risk for deteriorating renal function.

  1. P11: 18FDG-PET/CT for early prediction of response to first line platinum chemotherapy in advanced thymic epithelial tumors

    PubMed Central

    Palmieri, Giovannella; Ottaviano, Margaret; Del Vecchio, Silvana; Segreto, Sabrina; Tucci, Irene; Damiano, Vincenzo

    2015-01-01

    Background To investigate the value of the metabolic tumor response assessed with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), compared with clinicobiological markers, to predict the response disease to first line platinum based chemotherapy in advanced thymic epithelial tumors (TETs). Methods Twenty patients with diagnosis of TET and stage of disease III and IV sec, Masaoka-Koga, were retrospectively included in this monocentric study. Different pre-treatment clinical, biological and pathological parameters, including histotype sec, WHO 2004 and stage of disease sec, Masaoka-Koga were assessed. Tumor glucose metabolism at baseline and its change after the first line platinum based chemotherapy (from 4 to 6 cycles) were assessed using FDG-PET, moreover the response disease was assessed using total body CT scan for the evaluation of RECIST criteria 1.1. Results Twelve patients had an objective response to the first line platinum based chemotherapy according RECIST criteria 1.1 and all of them started with a SUVmax at baseline major than 5, indeed the other eight patients, non-responders to chemotherapy, had a SUVmax at baseline minor than 5. Conclusions It is important to define the chemosensitivity of advanced TETs early. Combining bio-pathological parameters with the metabolism at baseline assessed with FDG-PET can help the physician to early predict the probability of obtaining a disease response to first line platinum based chemotherapy. The SUVmax cut off of 5 at 18FDG-PET/CT performed at baseline treatment might be a new parameter for choosing the most powerful first line of chemotherapy. Given these results, further prospective studies are needed to establish a new first line therapy in advanced TETs with a low SUVmax at baseline, non-responders to conventional chemotherapy.

  2. Cost-effectiveness of epidermal growth factor receptor mutation testing and first-line treatment with gefitinib for patients with advanced adenocarcinoma of the lung.

    PubMed

    de Lima Lopes, Gilberto; Segel, Joel E; Tan, Daniel S W; Do, Young K; Mok, Tony; Finkelstein, Eric A

    2012-02-15

    Epidermal growth factor receptor (EGFR) testing and first-line therapy with gefitinib for patients with activating mutations is quickly becoming the standard option for the treatment of advanced lung adenocarcinoma. Yet, to date, little is known about the cost-effectiveness of this approach. A decision-analytic model was developed to determine the cost-effectiveness of EGFR testing and first-line treatment with gefitinib for those patients who harbor activating mutations versus standard care, which includes first-line treatment with chemotherapy followed by gefitinib as second-line treatment. The model uses clinical and outcomes data from randomized clinical trials and societal costs from Singapore cancer centers. Health effects were expressed as quality-adjusted life-years. All costs and cost-effectiveness ratios were expressed in 2010 Singapore dollars. Sensitivity and different scenarios analyses were conducted. EGFR testing and first-line treatment with gefitinib is a dominant strategy (with lower costs and greater effectiveness) compared with standard care. Because the primary savings result from not providing gefitinib to those who are not likely to benefit, this finding holds regardless of the prevalence of activating mutations. In a secondary analysis, first-line treatment with gefitinib was also dominant when compared with first-line chemotherapy in patients with activating EGFR mutations. This strategy can be considered a new standard of care and should be of great interest for health care payers and decision makers in an era in which our greatest challenge is to balance hard-won and incremental, yet small, improvements in patient outcomes with exponentially rising costs. Copyright © 2011 American Cancer Society.

  3. The Clinical and Economic Impact of Genotype Testing at First-line Antiretroviral Therapy Failure for HIV-Infected Patients in South Africa

    PubMed Central

    Levison, Julie H.; Wood, Robin; Scott, Callie A.; Ciaranello, Andrea L.; Martinson, Neil A.; Rusu, Corina; Losina, Elena; Freedberg, Kenneth A.; Walensky, Rochelle P.

    2013-01-01

    Background. In resource-limited settings, genotype testing at virologic failure on first-line antiretroviral therapy (ART) may identify patients with wild-type (WT) virus. After adherence counseling, these patients may safely and effectively continue first-line ART, thereby delaying more expensive second-line ART. Methods. We used the Cost-Effectiveness of Preventing AIDS Complications International model of human immunodeficiency virus (HIV) disease to simulate a South African cohort of HIV-infected adults at first-line ART failure. Two strategies were examined: no genotype vs genotype, assuming availability of protease inhibitor–based second-line ART. Model inputs at first-line ART failure were mean age 38 years, mean CD4 173/µL, and WT virus prevalence 20%; genotype cost was $300 per test and delay to results, 3 months. Outcomes included life expectancy, per-person costs (2010 US dollars), and incremental cost-effectiveness ratios (dollars per years of life saved [YLS]). Results. No genotype had a projected life expectancy of 106.1 months, which with genotype increased to 108.3 months. Per-person discounted lifetime costs were $16 360 and $16 540, respectively. Compared to no genotype, genotype was very cost-effective, by international guidance, at $900/YLS. The cost-effectiveness of genotype was sensitive to prevalence of WT virus (very cost-effective when prevalence ≥12%), CD4 at first-line ART failure, and ART efficacy. Genotype-associated delays in care ≥5 months decreased survival and made no genotype the preferred strategy. When the test cost was <$100, genotype became cost-saving. Conclusions. Genotype resistance testing at first-line ART failure is very cost-effective in South Africa. The cost-effectiveness of this strategy will depend on prevalence of WT virus and timely response to genotype results. PMID:23087386

  4. Efficacy and Safety of Metronidazole Monotherapy versus Vancomycin Monotherapy or Combination Therapy in Patients with Clostridium difficile Infection: A Systematic Review and Meta-Analysis.

    PubMed

    Li, Rui; Lu, Laichun; Lin, Yu; Wang, Mingxia; Liu, Xin

    2015-01-01

    Clostridium difficile infection (CDI) has become a global epidemiological problem for both hospitalized patients and outpatients. The most commonly used drugs to treat CDI are metronidazole and vancomycin. The aim of this study was to compare the efficacy and safety of metronidazole monotherapy with vancomycin monotherapy and combination therapy in CDI patients. A comprehensive search without publication status or other restrictions was conducted. Studies comparing metronidazole monotherapy with vancomycin monotherapy or combination therapy in patients with CDI were considered eligible. Meta-analysis was performed using the Mantel-Haenszel fixed-effects model, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated and reported. Of the 1910 records identified, seventeen studies from thirteen articles (n = 2501 patients) were included. No statistically significant difference in the rate of clinical cure was found between metronidazole and vancomycin for mild CDI (OR = 0.67, 95% CI (0.45, 1.00), p = 0.05) or between either monotherapy and combination therapy for CDI (OR = 1.07, 95% CI (0.58, 1.96), p = 0.83); however, the rate of clinical cure was lower for metronidazole than for vancomycin for severe CDI (OR = 0.46, 95% CI (0.26, 0.80), p = 0.006). No statistically significant difference in the rate of CDI recurrence was found between metronidazole and vancomycin for mild CDI (OR = 0.99, 95% CI (0.40, 2.45), p = 0.98) or severe CDI (OR = 0.98, 95% CI (0.63, 1.53), p = 0.94) or between either monotherapy and combination therapy for CDI (OR = 0.91, 95% CI (0.66, 1.26), p = 0.56). In addition, there was no significant difference in the rate of adverse events (AEs) between metronidazole and vancomycin (OR = 1.18, 95% CI (0.80, 1.74), p = 0.41). In contrast, the rate of AEs was significantly lower for either monotherapy than for combination therapy (OR = 0.30, 95% CI (0.17, 0.51), p < 0.0001). Metronidazole and vancomycin are equally effective for

  5. Efficacy and Safety of Metronidazole Monotherapy versus Vancomycin Monotherapy or Combination Therapy in Patients with Clostridium difficile Infection: A Systematic Review and Meta-Analysis

    PubMed Central

    Li, Rui; Lu, Laichun; Lin, Yu; Wang, Mingxia; Liu, Xin

    2015-01-01

    Background Clostridium difficile infection (CDI) has become a global epidemiological problem for both hospitalized patients and outpatients. The most commonly used drugs to treat CDI are metronidazole and vancomycin. The aim of this study was to compare the efficacy and safety of metronidazole monotherapy with vancomycin monotherapy and combination therapy in CDI patients. Methods A comprehensive search without publication status or other restrictions was conducted. Studies comparing metronidazole monotherapy with vancomycin monotherapy or combination therapy in patients with CDI were considered eligible. Meta-analysis was performed using the Mantel-Haenszel fixed-effects model, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated and reported. Results Of the 1910 records identified, seventeen studies from thirteen articles (n = 2501 patients) were included. No statistically significant difference in the rate of clinical cure was found between metronidazole and vancomycin for mild CDI (OR = 0.67, 95% CI (0.45, 1.00), p = 0.05) or between either monotherapy and combination therapy for CDI (OR = 1.07, 95% CI (0.58, 1.96), p = 0.83); however, the rate of clinical cure was lower for metronidazole than for vancomycin for severe CDI (OR = 0.46, 95% CI (0.26, 0.80), p = 0.006). No statistically significant difference in the rate of CDI recurrence was found between metronidazole and vancomycin for mild CDI (OR = 0.99, 95% CI (0.40, 2.45), p = 0.98) or severe CDI (OR = 0.98, 95% CI (0.63, 1.53), p = 0.94) or between either monotherapy and combination therapy for CDI (OR = 0.91, 95% CI (0.66, 1.26), p = 0.56). In addition, there was no significant difference in the rate of adverse events (AEs) between metronidazole and vancomycin (OR = 1.18, 95% CI (0.80, 1.74), p = 0.41). In contrast, the rate of AEs was significantly lower for either monotherapy than for combination therapy (OR = 0.30, 95% CI (0.17, 0.51), p<0.0001). Conclusions Metronidazole and

  6. The effectiveness of the McKenzie method in addition to first-line care for acute low back pain: a randomized controlled trial

    PubMed Central

    2010-01-01

    Background Low back pain is a highly prevalent and disabling condition worldwide. Clinical guidelines for the management of patients with acute low back pain recommend first-line treatment consisting of advice, reassurance and simple analgesics. Exercise is also commonly prescribed to these patients. The primary aim of this study was to evaluate the short-term effect of adding the McKenzie method to the first-line care of patients with acute low back pain. Methods A multi-centre randomized controlled trial with a 3-month follow-up was conducted between September 2005 and June 2008. Patients seeking care for acute non-specific low back pain from primary care medical practices were screened. Eligible participants were assigned to receive a treatment programme based on the McKenzie method and first-line care (advice, reassurance and time-contingent acetaminophen) or first-line care alone, for 3 weeks. Primary outcome measures included pain (0-10 Numeric Rating Scale) over the first seven days, pain at 1 week, pain at 3 weeks and global perceived effect (-5 to 5 scale) at 3 weeks. Treatment effects were estimated using linear mixed models. Results One hundred and forty-eight participants were randomized into study groups, of whom 138 (93%) completed the last follow-up. The addition of the McKenzie method to first-line care produced statistically significant but small reductions in pain when compared to first-line care alone: mean of -0.4 points (95% confidence interval, -0.8 to -0.1) at 1 week, -0.7 points (95% confidence interval, -1.2 to -0.1) at 3 weeks, and -0.3 points (95% confidence interval, -0.5 to -0.0) over the first 7 days. Patients receiving the McKenzie method did not show additional effects on global perceived effect, disability, function or on the risk of persistent symptoms. These patients sought less additional health care than those receiving only first-line care (P = 0.002). Conclusions When added to the currently recommended first-line care of acute

  7. Efficacy of PI monotherapy versus triple therapy for 1964 patients in 10 randomised trials.

    PubMed

    Arribas, Jose; Girard, Pierre-Marie; Paton, Nicholas; Winston, Alan; Marcelin, Anne-Genevieve; Elbirt, Daniel; Hill, Andrew; Hadacek, Maria Blanca

    2014-01-01

    The efficacy of protease inhibitor monotherapy has been analyzed with different endpoints: initial HIV-1 RNA rebound, long-term HIV-1 RNA suppression after re-intensification, treatment-emergent drug resistance, neurocognitive testing and HIV-1 RNA in the cerebrospinal fluid (CSF). A PUBMED search identified nine randomised trials of PI monotherapy versus triple therapy in patients with HIV RNA<50 copies/mL at baseline. RESULTS from the recently completed PROTEA trial were also included. The percentage of patients with HIV RNA suppression <50 copies/mL was analyzed using switch equals failure and intensification included endpoints (ITT). The number of patients with new drug resistance mutations, HIV RNA in the CSF or change in neurocognitive function was analyzed by treatment arm. Four trials evaluated darunavir/r monotherapy (n=785: MONET, MONOI, MONARCH, PROTEA), five evaluated lopinavir/r monotherapy (n=592: OK-04, KalMo, KALESOLO, KRETA, MOST) and one evaluated both (MRC PIVOT, n=587). HIV-1 RNA suppression rates tended to be lower on PI monotherapy than triple therapy in "switch equals failure" analysis (76% vs 82%), but not when the outcome of intensification was included (87% vs 85%). There were small numbers of patients taking PI monotherapy with detectable HIV-1 RNA in the CSF, in three trials: PROTEA (n=2), MONOI (n=2) and MOST (n=5), but only two cases of CSF viral escape (MONOI). In two trials, there was no difference in neurocognitive test results between PI monotherapy and triple therapy, based on z-scores from five domains (in PROTEA, mean change in NPZ-5 score=0.0 for DRV/r monotherapy vs -0.10 for triple therapy); similar results were observed in the MRC PIVOT trial. The risk of treatment emergent NRTI or PI resistance (Table 1) was 11/973 (1.1%) for patients on PI monotherapy, versus 7/991 (0.7%) for patients on triple therapy. In 10 randomised trials of 1964 patients with HIV-1 RNA suppression at baseline, PI monotherapy showed a higher risk of

  8. [One year persistence of metformin monotherapy versus metformin/sitagliptin fixed dose combination].

    PubMed

    Simonyi, Gábor; Ferenci, Tamás

    2016-04-17

    In treatment of type 2 diabetes mellitus it is important to reach glycaemic targets. The elements of this are the adequate diet and the patient's adherence to medication. The aim of the authors was to investigate the one year persistence of the metformin monotherapy and sitagliptin/metformin fixed dose combination in type 2 diabetic patients. National Health Insurance Found prescriptions database of Hungary on pharmacy-claims between October 1, 2012 and September 30, 2013 was analyzed. The authors identified patients who filled prescriptions for metformin monotherapy and fixed dose combinations of sitagliptin/metformin prescribed for the first time. Patients have not received similar drugs one year previous to study. To model the persistence, the apparatus of survival analysis was used, where "survival" was the time to abandon the medication. As it was available to month precision, discrete time survival analysis was applied: a generalized linear model was estimated with complementary log-log link function with the kind of drug being the only explanatory variable. During the trial period, metformin monotherapy or sitagliptin/metformin fixed dose combination was started in 63,386 and 10,039 patients, respectively. One year persistence rate in patients with metformin monotherapy was 30%, and 58% in patients with sitagliptin/metformin fixed dose combination. Considering only the 360-day study period, the mean duration of persistence was 173.4 days in patients on metformin monotherapy and 261.9 days on sitagliptin/metformin fixed dose combination. The hazard of discontinuation was more than twofold higher during treatment with metformin monotherapy compared with the use of the sitagliptin/metformin fixed dose combination (hazard ratio = 2.267, p<0.001). There is a significant difference between the one year persistence of metformin monotherapy and sitagliptin/metformin fixed dose combination in type 2 diabetic patients. The result demonstrated sitagliptin

  9. Successful Ziprasidone Monotherapy in a Case of Delusional Parasitosis: A One-Year Followup

    PubMed Central

    Serroni, Nicola; Marini, Stefano; Rapini, Gabriella; Valchera, Alessandro; Fornaro, Michele; Mazza, Monica; Martinotti, Giovanni; Di Giannantonio, Massimo

    2013-01-01

    Delusional parasitosis is characterized by the false idea that own body is infested by invisible mites, insects, or other parasites. This case report describes a 24-year-old woman with delusional parasitosis who was treated with ziprasidone monotherapy (120 mg/day) with a complete remission of delusion and followed for one year without symptom recurrences. These findings, although preliminary, indicate that further investigation of ziprasidone monotherapy for the treatment of delusional parasitosis is warranted in further trials. PMID:23762722

  10. High survival and treatment success sustained after two and three years of first-line ART for children in Cambodia

    PubMed Central

    2010-01-01

    Background Long-term outcomes of antiretroviral therapy (ART) in children remain poorly documented in resource-limited settings. The objective of this study was to assess two-and three-year survival, CD4 evolution and virological response among children on ART in a programmatic setting in Cambodia. Methods Children treated with first-line ART for at least 24 months were assessed with viral load testing and genotyping. We used Kaplan-Meier analysis for survival and Cox regression to identify risk factors associated with treatment failure. Results Of 1168 registered HIV-positive children, 670 (57%) started ART between January 2003 and December 2007. Survival probability was 0.93 (95% CI: 0.91-0.95) and 0.91 (95% CI: 0.88-0.93) at 24 and 36 months after ART initiation, respectively. Median CD4 gain for children aged over five years was 704 cells/mm3 at 24 months and 737 at 36 months. Median CD4 percentage gain for children under five years old was 15.2% at 24 months and 15% at 36 months. One hundred and thirty children completed at least 24 months of ART, and 138 completed 36 months: 128 out of 268 (48%) were female. Median age at ART initiation was six years. Overall, 22 children had viral loads of >1000 copies/ml (success ratio = 86% on intention-to-treat-analysis) and 21 of 21 presented mutations conferring resistance mostly to lamivudine and non-nucleoside reverse transcriptase inhibitors. Risk factors for failure after 24 and 36 months were CD4 counts below the threshold for severe immunosupression at those months respectively. Only two out of 22 children with viral loads of >1000 copies/ml met the World Health Organization immunological criteria for failure (sensitivity = 0.1). Conclusions Good survival, immunological restoration and viral suppression can be sustained after two to three years of ART among children in resource-constrained settings. Increased access to routine virological measurements is needed for timely diagnosis of treatment failure. PMID

  11. Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line.

    PubMed

    Sullivan, Ivana; Planchard, David

    2016-01-01

    Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advanced EGFR mutant non-small-cell lung cancer (NSCLC). First-generation EGFR TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating EGFR mutations (L858R and Del19). However, after a median duration of response of ~12 months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the EGFR T790M resistance mutation. The second-generation EGFR/HER TKIs were developed to treat resistant disease, targeting not only T790M but EGFR-activating mutations and wild-type EGFR. Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR. The third-generation EGFR TKIs selectively and irreversibly target EGFR T790M and activating EGFR mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type EGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating EGFR mutations. Among the third-generation EGFR TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic EGFR T790M NSCLC patients who have progressed on or after EGFR TKI therapy. In this review, we summarize the available post-progression therapies including third-generation EGFR inhibitors and combination treatment strategies for treating patients with NSCLC harboring EGFR mutations and address the

  12. Treating moderate acute malnutrition in first-line health services: an effectiveness cluster-randomized trial in Burkina Faso.

    PubMed

    Nikièma, Laetitia; Huybregts, Lieven; Kolsteren, Patrick; Lanou, Hermann; Tiendrebeogo, Simon; Bouckaert, Kimberley; Kouanda, Séni; Sondo, Blaise; Roberfroid, Dominique

    2014-07-01

    Management of moderate acute malnutrition (MAM) is, currently, focused on food supplementation approaches. However, the sustainability of these strategies remains weak in low- and middle-income countries. In food-secure settings, an educational/behavioral intervention could be an alternative for improving MAM management. This study compared the effectiveness of weekly context-appropriate child-centered counseling (CCC), with an improved corn-soy blend [corn-soy blend with added micronutrients (CSB++)] or a locally produced ready-to-use supplementary food (RUSF), in treating MAM through first-line rural health services. We used a cluster randomized controlled trial design with 3 arms, involving 18 rural health centers (6 by arm) and children aged 6-24 mo with uncomplicated MAM. In the first arm (CCC), trained health workers provided weekly personalized counseling to caretakers. In the 2 other arms, children received weekly either 455 g CSB++ or 350 g locally produced soy-based RUSF. Both food supplements provided ∼250 kcal/d. The recovery rate after 3 mo of treatment was significantly lower with CCC (57.8%) than with CSB++ (74.5%) and RUSF (74.2%) (P < 0001). Mothers' attendance at health facilities was also substantially lower in the CCC arm (P < 0001); this arm had a high defaulter rate (P < 0.003). When the analysis was adjusted for attendance, we did not find a significant difference between the 3 arms, with incidence rate ratios of 1.14 (95% CI: 0.99, 1.31) and 1.13 (95% CI: 0.98, 1.30) for the CSB++ and RUSF arms, respectively, compared with the CCC arm. Whereas supplement-based treatment of MAM was found to be more effective than the provision of CCC, we hypothesize that appropriate and specific nutrition counseling centered on children's needs, through primary health facilities, might be an alternative strategy for MAM treatment in rural food-secure areas, provided that attendance at counseling sessions by the caregiver is ensured. This trial was

  13. Survival of patients with cirrhosis and acute peptic ulcer bleeding compared with variceal bleeding using current first-line therapies.

    PubMed

    Ardevol, Alba; Ibañez-Sanz, Gemma; Profitos, Joaquim; Aracil, Carles; Castellvi, Josep M; Alvarado, Edilmar; Cachero, Alba; Horta, Diana; Miñana, Josep; Gomez-Pastrana, Bárbara; Pavel, Oana; Dueñas, Eva; Casas, Meritxell; Planella, Montserrat; Castellote J, Jose; Villanueva, Candid

    2017-07-17

    The presence of cirrhosis increases the mortality of patients with peptic ulcer bleeding (PUB). Both acute variceal bleeding (AVB) and PUB are associated with substantial mortality in cirrhosis. This multicenter cohort study was performed to assess whether the mortality of cirrhotic patients with PUB is different from that of those with AVB. Patients with cirrhosis and acute gastrointestinal bleeding were consecutively included and treated with somatostatin and PPI infusion from admission and with antibiotic prophylaxis. Emergency endoscopy with endoscopic therapy was performed within the first 6-hours. 646 patients with AVB and 144 with PUB were included. There were baseline differences between groups, such as use of gastro-erosive drugs or β-blockers. Child-Pugh and MELD scores were similar. Further bleeding was more frequent in AVB-group than in those PUB-group (18% vs 10%; OR= 0.50, 95%CI= 0.29-0.88). However, mortality risk at 45-day was similar in both groups (19% in AVB-group vs 17% in PUB-group; OR= 0.85, 95% CI= 0.55-1.33, P= 0.48). Different parameters, such as Child-Pugh score, AKI, ACLF or presence of shock or bacterial infection, but not the cause of bleeding, were related to the risk of death. Only 2% of PUB-group vs 3% of AVB-group died with uncontrolled bleeding (P= 0.39), while the majority of patients in either group died from liver failure or due to other comorbidities. Using current first-line-therapy, patients with cirrhosis and acute peptic ulcer bleeding have a similar survival than those with variceal bleeding. The risk of further bleeding is higher in patients with variceal hemorrhage. However, few patients in both groups died from uncontrolled bleeding, while the cause of death was usually related to liver failure or co-morbidities. This article is protected by copyright. All rights reserved. © 2017 by the American Association for the Study of Liver Diseases.

  14. [Epilepsy in Lao Popular Democratic Republic: difficult procurement of a first-line antiepileptic contributes to widening the treatment gap].

    PubMed

    Chivorakoun, P; Harimanana, A; Clavel, S; Jousseaume, S; Barennes, H

    2012-03-01

    In Laos, over 95% of people with epilepsy (PWE) do not receive a proper treatment. Traditional beliefs and practices have long explained this wide treatment gap. From 2008 to 2010 we evaluated the procurement process for phenobarbital, the leading first-line antiepileptic drug (AED) in Laos, and its availability at a national scale as a potential additional major cause of this treatment gap in Laos. Data were drawn from several surveys conducted from 2008 to 2010: (i) semi structured interviews of key persons from the Ministry of Health and from pharmaceutical factories, wholesalers, pharmacists, neurologists, psychiatrists, and non-governmental organisations; (ii) retrospective survey of AED prescriptions in three main hospitals of Vientiane the capital city during two randomised weeks from June to August 2009; (iii) self-administered questionnaires of pediatricians regarding their knowledge about phenobarbital; (iv) a national survey of the AED availability in pharmacies and drug shops in 16/17 provinces, 16 districts and 96 villages (multistage randomised survey) in 2010 and a survey among the population in 2009. Phenobarbital is imported in Laos via a carefully controlled importation process either as raw material to be processed by factory N(o) 2 or in the form of tablets. The International Narcotics Control Board (Vienne) delivers a yearly quota of 25kg of raw phenobarbital to the Food and Drug department (FDA). This allows the production of 245000 tablets per year (around 671 annual adult treatments). The overall importation process for phenobarbital lasts 6months. Grade 1 pharmacists (mostly located in urban areas) and regional and district hospitals are authorized to deliver phenobarbital. The cost of phenobarbital ranged from 0.11 to 0.2US dollars/tablet per day (39 to 67US dollars per year). High cost of transportation and increased cost of phenobarbital (5- to 10-fold greater than the international market) contribute to reduce access to treatment. Needs

  15. Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line

    PubMed Central

    Sullivan, Ivana; Planchard, David

    2017-01-01

    Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advanced EGFR mutant non-small-cell lung cancer (NSCLC). First-generation EGFR TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating EGFR mutations (L858R and Del19). However, after a median duration of response of ~12 months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the EGFR T790M resistance mutation. The second-generation EGFR/HER TKIs were developed to treat resistant disease, targeting not only T790M but EGFR-activating mutations and wild-type EGFR. Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR. The third-generation EGFR TKIs selectively and irreversibly target EGFR T790M and activating EGFR mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type EGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating EGFR mutations. Among the third-generation EGFR TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic EGFR T790M NSCLC patients who have progressed on or after EGFR TKI therapy. In this review, we summarize the available post-progression therapies including third-generation EGFR inhibitors and combination treatment strategies for treating patients with NSCLC harboring EGFR mutations and address the

  16. Cost-effectiveness of adalimumab, etanercept, and tocilizumab as first-line treatments for moderate-to-severe rheumatoid arthritis.

    PubMed

    Soini, E J; Hallinen, T A; Puolakka, K; Vihervaara, V; Kauppi, M J

    2012-01-01

    The aim of this study was to assess the cost-utility and value of reducing the uncertainty associated with the decision to use first-line biologic treatment (bDMARD) after the failure of one or more traditional drugs (tDMARD) in moderate-to-severe rheumatoid arthritis (msRA) in Finland. The treatment sequences were compared among 3000 hypothetical Finnish msRA patients using a probabilistic microsimulation model in a lifetime scenario. Adalimumab + methotrexate, etanercept + methotrexate, or tocilizumab + methotrexate were used as first biologics followed by rituximab + methotrexate and infliximab + methotrexate. Best supportive care (BSC), including tDMARDs, was assumed to be used after the exhaustion of the biologics. Methotrexate alone was added as a further comparator. Efficacy was based on ACR responses that were obtained from a mixed treatment comparison. The resources were valued with Finnish unit costs (year 2010) from the healthcare payer perspective. Additional analyses were carried out, including productivity losses. The Health Assessment Questionnaire (HAQ) values were mapped to the EQ-5D values using the tocilizumab trials; 3% annual discounting for costs and quality-adjusted life years (QALY) and extensive sensitivity analyses were completed. Incremental cost per QALY gained and multinomial expected value of perfect information (mEVPI). bDMARDs significantly increase the QALYs gained when compared to methotrexate alone. Tocilizumab + methotrexate was more cost-effective than adalimumab + methotrexate or etanercept + methotrexate in comparison with methotrexate alone, and adalimumab + methotrexate was dominated by etanercept + methotraxate. A QALY gained with retail-priced (wholesale-priced) tocilizumab + methotrexate costs €18,957 (€17,057) compared to methotrexate alone. According to the cost-effectiveness efficiency frontier and cost-effectiveness acceptability frontier (CEAF), tocilizumab

  17. Ponatinib as first-line treatment for patients with chronic myeloid leukaemia in chronic phase: a phase 2 study

    PubMed Central

    Jain, Preetesh; Kantarjian, Hagop; Jabbour, Elias; Gonzalez, Graciela Nogueras; Borthakur, Gautam; Pemmaraju, Naveen; Daver, Naval; Gachimova, Evguenia; Ferrajoli, Alessandra; Kornblau, Steven; Ravandi, Farhad; O’Brien, Susan; Cortes, Jorge

    2015-01-01

    Summary Background Ponatinib has shown efficacy in patients with refractory chronic myeloid leukaemia (CML) and in those with CML with a Thr315Ile mutation. We aimed to investigate the activity and safety of ponatinib as first-line treatment for patients with chronic-phase CML. Methods We did a single-arm, phase 2 trial at MD Anderson Cancer Center in Houston, TX, USA. Between May 3, 2012, and Sept 24, 2013, we enrolled patients with early (<6 months) chronic-phase CML and treated them with oral ponatinib once a day. Patients enrolled before July 25, 2013, were given a starting dose of 45 mg per day; we lowered this due to tolerability issues and patients enrolled after this date were given a starting dose of 30 mg per day. After a warning by the US Food and Drug Administration (FDA) in Oct 6, 2013, for vascular complications with ponatinib, we started all patients on aspirin 81 mg daily and reduced the dose of ponatinib to 30 mg or 15 mg per day for all patients. The primary endpoint was the proportion of patients who achieved complete cytogenetic response by 6 months in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01570868. Findings We enrolled 51 patients. Median follow-up was 20.9 months (IQR 14.9–25.2). 43 patients were started on 45 mg ponatinib every day; eight patients were started on 30 mg per day. 43 (94%) of 46 evaluable patients achieved complete cytogenetic response at 6 months. Most frequent toxicities included skin-related effects (n=35; 69%) and elevated lipase (n=32; 63%). Cardiovascular events (mainly hypertension) occurred in 25 (49%) patients. Grade 3–4 myelosuppression occurred in 15 (29%) patients. Five (10%) patients developed cerebrovascular or vaso-occlusive disease. 43 (85%) patients needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated June 18, 2014, at the recommendation of the FDA due to concern about the increased risk of thromboembolism

  18. Conditional Survival of Patients With Metastatic Testicular Germ Cell Tumors Treated With First-Line Curative Therapy.

    PubMed

    Ko, Jenny J; Bernard, Brandon; Tran, Ben; Li, Haocheng; Asif, Tehmina; Stukalin, Igor; Lee, Margaret; Day, Daphne; Alimohamed, Nimira; Sweeney, Christopher J; Bedard, Philippe L; Heng, Daniel Y C

    2016-03-01

    The International Germ Cell Cancer Collaborative Group (IGCCCG) criteria prognosticate survival outcomes in metastatic testicular germ cell tumor (MT-GCT), but how the initial risk changes over time for those who survived since curative treatment is unknown. We assessed patients eligible for first-line therapy for MT-GCT at five tertiary cancer centers from 1990 to 2012 for 2-year conditional overall survival (COS) and conditional disease-free survival (CDFS), defined as the probability of surviving, or surviving and being disease free, respectively, for an additional 2 years at a given time point since the initial diagnosis. For all patients (N = 942), 2-year COS increased from 92% (95% CI, 91% to 94%) at 0 months to 98% (95% CI, 97% to 99%), and 2-year CDFS increased from 83% (95% CI, 81% to 86%) at baseline to 98% (95% CI, 97% to 99%) at 24 months after diagnosis. Two-year COS improved by 2% (97% at 0 months, 99% at 24 months) in the IGCCCG favorable-risk group, by 5% (94% at 0 months, 99% at 24 months) in the intermediate-risk group, and by 22% (71% at 0 months to 93% at 24 months) in the poor-risk group. Two-year CDFS improved significantly at 12 months for each risk group (favorable, 91% baseline v 95% at 12 months; intermediate, 84% v 95%; poor, 55% v 85%). Baseline IGCCCG risk stratification was not associated with long-term COS or CDFS for patients who survived to greater than 2 years post therapy. No significant differences in COS and CDFS were noted between seminoma and nonseminoma; patients ≥ 40 years old had inferior 2-year COS from 0 to 12 months, but no differences were noted at 18 months. Our data suggest that the concept of conditional survival applies to patients with MT-GCT treated with curative therapy. Patients with MT-GCT who survived and remained disease free more than 2 years after the diagnosis had an excellent chance of staying alive and disease free in additional subsequent years, regardless of the initial IGCCCG risk stratification.

  19. Treatment and outcomes of UK and German patients with relapsed intracranial germ cell tumors following uniform first-line therapy.

    PubMed

    Murray, Matthew J; Bailey, Shivani; Heinemann, Katja; Mann, Jillian; Göbel, Ulrich K; Saran, Frank; Hale, Juliet P; Calaminus, Gabriele; Nicholson, James C

    2017-08-01

    We aimed to retrospectively assess treatments/outcomes, including the value of high-dose-chemotherapy and autologous-stem-cell-rescue (HDC + AuSCR) and re-irradiation, in a large, European patient-cohort with relapsed intracranial germ-cell-tumors (GCTs) receiving uniform first-line therapy, including radiotherapy as standard-of-care. Fifty-eight UK/German patients (48 male/10 female) with relapsed intracranial-GCTs [13 germinoma/45 non-germinomatous GCT (NGGCT)] treated 1996-2010 as per the SIOP-CNS-GCT-96 protocol were evaluated. For germinoma, six patients relapsed with germinoma and five with NGGCT (one palliative, one teratoma patient excluded). Five-year overall-survival (OS) for the whole-group (n = 11) was 55%. Four of six germinoma relapses and two of five relapsing with NGGCT were salvaged; patients were salvaged with either standard-dose-chemotherapy (SDC) and re-irradiation or HDC + AuSCR with/without re-irradiation. Of 45 relapsed NGGCT patients, 13 were excluded (three non-protocol adherence, five teratoma, five palliation). Five-year OS for the remaining 32 relapsed malignant NGGCT patients treated with curative intent was 9% (95%CI: 2-26%). By treatment received, 5-year OS for the 10 patients receiving SDC and 22 patients treated with intention for HDC + AuSCR was 0% (0-0%) and 14% (3-36%), respectively. The three relapsed NGGCT survivors had raised HCG markers alone; two received additional irradiation. Patients with relapsed germinoma had better 5-year OS than those with relapsed NGGCT (55 vs. 9%; p = 0.007). Patients with relapsed germinoma were salvaged both with SDC and re-irradiation or HDC + AuSCR with/without re-irradiation; both represent valid treatment options. Outcomes for malignant relapse following initial diagnosis of NGGCT were exceptionally poor; the few survivors received thiotepa-based HDC + AuSCR, which is a treatment option at first malignant relapse for such patients, with further surgery