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Sample records for first-line antiglaucomatous monotherapy

  1. Monotherapy or Polytherapy for First-Line Treatment of SE?

    PubMed

    Alvarez, Vincent; Rossetti, Andrea O

    2016-02-01

    Status epilepticus (SE) is one of the most frequent neurologic emergencies, and a rapid and effective treatment is warranted. Current guidelines recommend a stepwise approach using a sequence of different antiepileptic drugs with benzodiazepines (BZD) being the first treatment proposed. To provide the more effective treatment as soon as possible, some authors have suggested using a combined polytherapy as first-line treatment. Strong evidence supports the use of benzodiazepines, mostly lorazepam and midazolam as initial monotherapy treatment for SE. Insufficient data are available to support the use of nonsedating antiepileptic drugs as phenytoin, valproic acid, or levetiracetam without a previous benzodiazepine administration. Studies assessing the role of a combined initial therapy are rare, if not missing. Moreover, owing the wide range of SE etiologies, a "one fits all" initial polytherapy seems difficult to achieve. After reviewing the available evidence, guidelines, and current practices regarding monotherapy and polytherapy as first-line treatment in SE in adults, the authors propose a rational algorithm for early antiseizure treatment in SE. PMID:26840871

  2. 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

  3. 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. PMID:27324802

  4. 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.

  5. 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

  6. Ocular Surface Alterations and Topical Antiglaucomatous Therapy: A Review

    PubMed Central

    Actis, Alessandro G; Rolle, Teresa

    2014-01-01

    Ocular Surface Disease (OSD) is prevalent among medically treated patients with glaucoma. This is basically related to three key-points: OSD and glaucoma are both prevalent in elderly and are common comorbidities in the same patient; the role of the active ingredient of the medical antiglaucomatous therapy; the role of the preservative agent of this medical therapy. Considering the actual state of literature we can state that the active glaucoma agent have a role in OSD, but the main cause seems to be the preservative agent, in particular referring to benzalkonium chloride, BAK. In the clinical evaluation of dry eye patients there is no actually established gold standard. Since the ocular surface injury not only causes dry eye, red eye, eye itching, photophobia and other discomforts, but also increases the risk of failure of glaucoma surgery in patients, it becomes fundamental a complete and good clinical evaluation of OSD (considering Schirmer’s test, tear breakup time, corneal and conjunctival staining) together with a good evaluation of patients’ quality of life (with validated questionnaires). Development of complex preparations, preservative-free and/or novel preservative preparations for glaucoma therapy could provide a promising approach in the prevention of ocular surface injuries. PMID:25317218

  7. Clinical Outcomes with First-line Endocrine Therapy or Chemotherapy in Postmenopausal HR+/HER2− Metastatic Breast Cancer

    PubMed Central

    Song, Yan; Hao, Yanni; Macalalad, Alexander R.; Lin, Peggy L.; Signorovitch, James E.; Wu, Eric Q.

    2015-01-01

    OBJECTIVE To describe patient profiles and clinical outcomes associated with first-line endocrine monotherapy (ET) and chemotherapy (CT) for postmenopausal HR+/HER2− metastatic breast cancer (mBC) patients. METHODS This is a retrospective chart review of 139 postmenopausal HR+/HER2− mBC patients initiating first-line ET monotherapy or CT. Overall survival (OS) was described using Kaplan–Meier curves. Exploratory comparative proportional hazards regression was conducted. RESULTS Patients on first-line CT had significantly more frequent liver metastases than patients on first-line ET monotherapy at baseline. The median OS was 35.5 months [95% confidence interval (CI), 22.7–41.2 months] for patients on first-line ET monotherapy and 22.2 months (95% CI, 13.6–25.9 months) for those on first-line CT (P = 0.021). Adjusting for baseline characteristics, the OS between first-line ET monotherapy and CT was not significantly different. CONCLUSIONS Patients who were prescribed CT as first-line treatment had evidence of more advanced disease at baseline and shorter OS than those who received ET monotherapy as first-line treatment, suggesting a need for additional safe and effective treatment options for these patients. PMID:26380551

  8. 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.

  9. Human factors of first-line security

    NASA Astrophysics Data System (ADS)

    van Renesse, Rudolf L.

    1998-04-01

    Human inspection of security features is based on a cycle of actions: the development and execution of a strategy, and the observation and evaluation of results. These actions aim at establishing the state of the object: genuine or fake. These actions require knowledge, which is either in the head (memorized) or in the world (provided by the object). It is argued that knowledge in the world is most suitable for adequate inspection of first line security features. In contrast, knowledge in the head cannot be relied on, unless standardization is consistently implemented. From the action cycle five pertinent questions ensue. How easily can the user: (1) determine and understand the function of the device? (2) tell what actions are possible? (3) execute the actions? (4) observe the results? (5) compare the observed results with the expected results? A set of generic design rules is derived, involving the function of the device, the execution of a strategy, and the evaluation of the result. A number of first line security features is evaluated from this human factors point of view. These comprise substrate embedded features (watermark, windowed thread), features added to the ink (iridescent pigment), printed features (intaglio, small lettering, see-throughs, latent images), and post-printed features (iridescent foils). It is concluded that many current security features do not meet basic ergonomic design rules. However, iridescent optically variable devices tend to have a potential to meet these requirements.

  10. Monotherapy versus combination therapy.

    PubMed

    Patel, Shilpa M; Saravolatz, Louis D

    2006-11-01

    The science of antibiotic therapy for infectious diseases continues to evolve. In many instances where empiric coverage is necessary, treatment with more than one agent is considered prudent. If an etiology is identified, antibiotics are modified based on culture and susceptibility data. Even when the organism is known, more than one antibiotic may be needed. Decisions about antibiotics should be made after assessments of pertinent clinical information, laboratory and microbiology information, ease of administration, patient compliance, potential adverse effects, cost, and available evidence supporting various treatment options. Clinicians also need to consider synergy and local resistance patterns in selecting therapeutic options. In this article, the authors outline monotherapy and combination therapy options for several common infectious diseases. PMID:17116443

  11. Perindopril: first-line treatment for hypertension.

    PubMed

    Zanchetti, A; Desche, P

    1989-01-01

    The antihypertensive efficacy and acceptability of perindopril (P) were compared to those of captopril (C), atenolol (A) and a diuretic, hydrochlorothiazide + amiloride (D), in 3 double-blind parallel multicenter studies involving 165, 173, and 165 patients, respectively. Patients with essential hypertension and a supine DBP between 95 and 125 mmHg (mean 103.9, 106.2, and 105.2 mmHg, respectively) after a 1-month placebo period were randomized to P 4 mg once daily (o.d.) and either C 25 mg twice daily, or A 50 mg o.d. or D (hydrochlorothiazide 50 mg + amiloride 5 mg o.d.) and treated for 3 months, with visits at monthly intervals. If necessary, treatment was adjusted at each visit to control BP (supine DBP less than or equal to 90 mm Hg): firstly by doubling the dose and secondly, one month later, by the addition of a second drug, a diuretic in the studies versus C or A, a beta-blocker in the study versus D. At 3 months, BP control on monotherapy in the three studies was achieved in the following proportion of patients: 49% with P vs 49% with C; 55% with P vs 48% with A; 72% with P vs 72% with D. Most of the patients controlled by P received 4 mg, about 15% were controlled with 8 mg. A further percentage of patients was controlled with combination therapy, the combination with a diuretic being more effective with P than with C (26 vs 8%) or A (23 vs 10%) and the combination with a beta-blocker being less effective with P than with D (5 vs 13%). The total percentage of patients controlled was greater with P than with C (75 vs 57%, p = 0.016) or A (78 vs 58%, p = 0.006) and there was no significant difference between P and D (78 vs 84%). The drop-out rate due to side-effects was up to 6% with P, similar to that observed with C (4%), A (5%) and D (5%). Most of the complaints reported with P were minor and non-specific, their incidence being similar to that observed with the other drugs. Cough was reported with both P (1%) and C (2%) as well as with A (1%) and D (1

  12. Ceftaroline fosamil as first-line versus second-line treatment for acute bacterial skin and skin structure infections (ABSSSI) or community-acquired bacterial pneumonia (CABP).

    PubMed

    Guervil, David J; Kaye, Keith S; Hassoun, Ali; Cole, Phillip; Huang, Xing-Yue; Friedland, H David

    2016-06-01

    The Clinical Assessment Program and Teflaro(®) Utilization Registry (CAPTURE) is a multicenter registry study of acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP) patients treated with ceftaroline fosamil in the US. Data for this analysis were collected between August 2011 and February 2013 at US study centres by randomly ordered chart review. Clinical success rates among ABSSSI patients were >81% when ceftaroline fosamil was used as first- or second-line therapy, including monotherapy and concurrent therapy. Among CABP patients, clinical success rates were >77% among first-line and second-line patients and patients who received first-line concurrent therapy or second line monotherapy or concurrent therapy. For CABP patients treated with ceftaroline fosamil as first-line monotherapy, the clinical success rate was 70%. Ceftaroline fosamil is an effective treatment option for patients with ABSSSI or CABP with similar clinical success rates when used as first-line or second-line treatment. PMID:25817579

  13. Perindopril/indapamide combination in the first-line treatment of hypertension and end-organ protection.

    PubMed

    Gosse, Philippe

    2006-05-01

    This article examines evidence-based findings in the literature on the efficacy of perindopril 2 mg/indapamide 0.625 mg, a first-line, low-dose antihypertensive drug combination. In regulatory Phase II and III trials, perindopril/indapamide significantly lowered blood pressure compared with other first-line therapies (atenolol, losartan and irbesartan). This was also the case in STRAtegies of Treatment in Hypertension: Evaluation, a postregistration study versus current monotherapies and stepped-care therapy with different classes of antihypertensive agents. The efficacy/safety ratio (both clinical and with regard to laboratory parameters) of perindopril/indapamide was good. Perindopril/indapamide provides additional antihypertensive efficacy compared with each component used alone and with current monotherapies, with major efficacy on systolic blood pressure, an important predictor of cardiovascular risk. It also reduces pulse pressure, an independent cardiovascular risk factor, large-vessel arterial stiffness and microcirculatory alterations. The fixed dosage of a once-daily tablet, ensures optimal ease of use and enhances patient compliance. Perindopril/indapamide also reduces target organ damage in patients at high cardiovascular risk, such as patients with cardiac hypertrophy and Type 2 diabetics with albuminuria. These benefits, together with the good efficacy/tolerability ratio, fulfill the requirements of the European Society of Hypertension and of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines for low-dose, first-line combination therapy in hypertension. PMID:16716093

  14. [Monotherapy in treatment-naïve patients].

    PubMed

    Arranz Caso, José Alberto

    2008-12-01

    The development of antiretroviral therapy (ART) with current triple drug combinations has dramatically reduced morbidity and mortality in HIV-infected patients. However, there is a need for less toxic treatments without sacrificing efficacy, as well as for less expensive drugs to facilitate universal access to this therapy. The protease inhibitors (PI) administered with ritonavir have a favorable pharmacokinetic profile and high genetic barrier and consequently are ideal candidates for use in monotherapy, thus avoiding the toxicity and cost associated with nucleoside analogs, as well as preserving drugs for future options. The promising results of studies performed with lopinavir/ritonavir (LPV/r) in induction-maintenance regimens in patients without prior failure to PIs encourage research into the cost-effectiveness of LPV/r in monotherapy from the beginning of ART. The few studies performed in this context seem to indicate the following: a) LPV/r monotherapy achieves undetectable viral loads in a large proportion of treatment-naïve patients, b) future treatment options are not compromised in patients not achieving undetectable viral loads since the likelihood of resistance mutations is low and treatment intensification achieves suppression of viral replication, and c) strategies for early detection can probably be considered in patients who will not achieve complete suppression with LPV/r monotherapy. Nevertheless, before LPV/r monotherapy can be considered a first-line option, new studies with larger samples and longer follow-up are required. These studies should pay particular attention to viral replication in areas where PI show less penetration. PMID:19572437

  15. 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

  16. 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

  17. 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,…

  18. 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

  19. Pemetrexed/cisplatin as first-line chemotherapy for advanced lung cancer with brain metastases

    PubMed Central

    He, Guangzhao; Xiao, Xiaoguang; Zou, Man; Zhang, Chengliang; Xia, Shu

    2016-01-01

    Abstract Background: Brain metastases (BMs) are a common and serious complication of non-small cell lung cancer (NSCLC). Whole-brain radiotherapy (WBRT), surgery, and molecular targeted therapy are usually used to treat NSCLC with BM. Chemotherapeutic options for BM are limited by tumor resistance, ineffective agents, and the blood–brain barrier. Pemetrexed/cisplatin is the preferred chemotherapy in nonsquamous NSCLC, but the efficacy of this treatment for nonsquamous NSCLC with BM is uncertain. Methods: We present a case of nonsquamous NSCLC with asymptomatic BM presenting with irritating cough and right shoulder back pain (unknown sensitizing epidermal growth factor receptor mutations or anaplastic lymphoma kinase). Results: He benefited from administration of first-line chemotherapy of pemetrexed/cisplatin. Partial remission was achieved in the primary lesion of the lungs and BM lesion. He was further given 3 cycles of pemetrexed monotherapy and WBRT. Complete remission was further achieved in BM lesion. Conclusion: The findings of clinical trials and theoretical studies about the current pemetrexed/cisplatin in the treatment of nonsquamous NSCLC with BM are also summarized to provide a reference for the application of pemetrexed/cisplatin in nonsquamous NSCLC with BM. Whether or not pemetrexed/cisplatin is definitely effective in nonsquamous NSCLC with BM must be proven by subsequent phase III clinical trials. PMID:27512852

  20. First line nurse managers: optimizing the span of control.

    PubMed

    Alidina, S; Funke-Furber, J

    1988-05-01

    Span of control, the number of people reporting to a manager, is an important management concept. It determines the structure of an organization and has financial, human resource, and quality of care implications. In nursing, the first line manager fills one of the most critical roles in the administration of nursing services. For this manager to perform her responsibilities effectively, an optimal span of control is necessary. Span of control is influenced by a number of factors. By understanding these factors, we can influence them to optimize the span of control of the nurse manager. PMID:3367230

  1. Efficacy of first-line tocilizumab therapy in early polymyalgia rheumatica: a prospective longitudinal study

    PubMed Central

    Devauchelle-Pensec, Valérie; Berthelot, Jean Marie; Cornec, Divi; Marhadour, Thierry; Jousse-Joulin, Sandrine; Querellou, Solène; Garrigues, Florent; De Bandt, Michel; Gouillou, Maelenn; Saraux, Alain

    2016-01-01

    Background Glucocorticoids are the cornerstone treatment of polymyalgia rheumatica (PMR) but induce adverse events. Objectives To evaluate the efficacy and safety of first-line tocilizumab in PMR. Methods In a prospective open-label study (ClinicalTrials.gov: NCT01713842), 20 glucocorticoid-free patients fulfilling Chuang's PMR criteria, with symptom onset within the last 12 months and a PMR activity score (PMR-AS) >10, each received three tocilizumab infusions at 4-week intervals, without glucocorticoids, followed by oral prednisone from weeks 12 to 24 (0.15 mg/kg if PMR-AS ≤10 and 0.30 mg/kg otherwise). The primary end point was the proportion of patients with PMR-AS≤10 at week 12. Results Baseline median PMR-AS was 36.6 (IQR 30.4–43.8). At week 12, all patients had PMR-AS≤10 and received the low prednisone dosage. Median PMR-AS at weeks 12 and 24 was 4.5 (3.2–6.8) and 0.95 (IQR 0.4–2), respectively (p<0.001 vs baseline for both time points). No patient required rescue treatment. Positron emission tomography-CT showed significant improvements. The most common adverse events were transient neutropenia (n=3) and leucopenia (n=5); in one patient, the second tocilizumab infusion was omitted due to leucopenia. Conclusions Tocilizumab monotherapy is effective in recent-onset PMR. Randomised controlled trials are warranted. Trial registration number NCT01713842. PMID:26929219

  2. Very-low-dose combination: a first-line choice for the treatment of hypertension?

    PubMed

    Waeber, Bernard

    2003-06-01

    Essential hypertension is a very heterogeneous disease and different pressor mechanisms might interact to increase blood pressure. It is therefore not surprising that antihypertensive drugs given as monotherapies normalize blood pressure in only a proportion of hypertensive patients. This is, for instance, the case for diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor antagonists administered as single agents. The rationale for combining antihypertensive agents relates in part to the concept that the blood pressure-decreasing effect may be enhanced when two classes are coadministered. Also, combination treatment serves to counteract the counter-regulatory mechanisms that are triggered whenever pharmacologic intervention is initiated and act to limit the efficacy of the antihypertensive medication. For example, the compensatory increase in renin secretion induced by sodium depletion may become the predominant factor sustaining high blood pressure. Simultaneous blockade of the renin-angiotensin system, with either an ACE inhibitor or an AT1 receptor blocker, makes this compensatory hyper-reninaemia ineffective and allows maximum benefit from sodium depletion. The increased effectiveness obtained by combining a blocker of the renin-angiotensin system with a low dose of a diuretic is not obtained at the expense of reduced tolerability compared with the individual components administered alone. Fixed very-low-dose combinations containing an ACE inhibitor or an AT1 receptor blocker and a diuretic are therefore likely to become increasingly used, not only as second-line therapy, but also as first-line treatment. This is the case, for instance, for the fixed very-low-dose combination of the ACE inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), as this preparation is very effective in decreasing blood pressure while maintaining a tolerability that is similar to that of placebo. PMID:12929469

  3. Efficacy and safety of icotinib as first-line therapy in patients with advanced non-small-cell lung cancer

    PubMed Central

    Shen, Yan-Wei; Zhang, Xiao-Man; Li, Shu-Ting; Lv, Meng; Yang, Jiao; Wang, Fan; Chen, Zhe-Ling; Wang, Bi-Yuan; Li, Pan; Chen, Ling; Yang, Jin

    2016-01-01

    Background and objective Several clinical trials have proven that icotinib hydrochloride, a novel epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor, exhibits encouraging efficacy and tolerability in patients with advanced non-small-cell lung cancer (NSCLC) who failed previous chemotherapy. This study was performed to assess the efficacy and toxicity of icotinib as first-line therapy for patients with advanced pulmonary adenocarcinoma with EGFR-sensitive mutation. Patients and methods Thirty-five patients with advanced NSCLC with EGFR-sensitive mutation who were sequentially admitted to the First Affiliated Hospital of Xi’an Jiaotong University from March 2012 to March 2014 were enrolled into our retrospective research. All patients were administered icotinib as first-line treatment. The tumor responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Results Among the 35 patients, the tumor objective response rate (ORR) and disease control rate were 62.9% (22/35) and 88.6% (31/35), respectively. The median progression-free survival was 11.0 months (95% confidence interval [CI]: 10.2–11.8 months), and median overall survival was 21.0 months (95% CI: 20.1–21.9 months). The most common drug-related toxicities were rashes (eleven patients) and diarrhea (nine patients), but these were generally manageable and reversible. Conclusion Icotinib monotherapy is effective and tolerable as first-line treatment for patients with advanced lung adenocarcinoma with EGFR-sensitive mutation. PMID:26966381

  4. Oseltamivir: a first line defense against swine flu.

    PubMed

    Agrawal, Ritesh; Rewatkar, Prarthana V; Kokil, Ganesh R; Verma, Arunima; Kalra, Atin

    2010-07-01

    Oseltamivir (has known by its brand name 'Tamiflu') is a prodrug, requiring ester hydrolysis for conversion to the active form, Oseltamivir carboxylate. Oseltamivir was the first orally active neuraminidase inhibitor commercially developed by US based Gilead Sciences and is currently marketed by F. Hoffmann-La Roche (Roche). Oseltamivir is an antiviral drug which works by blocking the function of the viral neuraminidase protein. US FDA approved Oseltamivir for prophylaxis of uncomplicated influenza A and B. Currently, Oseltamivir is the only first line defense drug available for the treatment of Swine Flu. Orally Oseltamivir is well tolerated and effective in treatment of influenza in adolescents and adults, including the elderly and patients with chronic cardiac and/or respiratory disease. Many of the pharmaceutical companies targeted Oseltamivir as a block buster molecule. In present review, we have tried to cover chemistry, mode of binding, total synthesis, current patent status, adverse effect and clinical status of Oseltamivir giving emphasis on medicinal chemistry aspect. PMID:20843284

  5. 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. PMID:26643920

  6. Amrubicin Monotherapy for Patients with Platinum-Refractory Gastroenteropancreatic Neuroendocrine Carcinoma.

    PubMed

    Ando, Takayuki; Hosokawa, Ayumu; Yoshita, Hiroki; Ueda, Akira; Kajiura, Shinya; Mihara, Hiroshi; Nanjo, Sohachi; Fujinami, Haruka; Nishikawa, Jun; Ogawa, Kohei; Nakajima, Takahiko; Imura, Johji; Sugiyama, Toshiro

    2015-01-01

    Objective. Patients with gastroenteropancreatic neuroendocrine carcinoma (NEC) have a poor prognosis. Platinum-based combination chemotherapy is commonly used as first-line treatment; however, the role of salvage chemotherapy remains unknown. This study aimed to analyze the efficacy and safety of amrubicin monotherapy in patients with platinum-refractory gastroenteropancreatic NEC. Methods. Among 22 patients with advanced gastroenteropancreatic NEC, 10 received amrubicin monotherapy between September 2007 and May 2014 after failure of platinum-based chemotherapy. The efficacy and toxicity of the treatment were analyzed retrospectively. Results. Eight males and two females (median age, 67 years (range, 52-78)) received platinum-based chemotherapy, including cisplatin plus irinotecan (n = 7, 70%), cisplatin plus etoposide (n = 2, 20%), and carboplatin plus etoposide (n = 1, 10%) before amrubicin therapy. Median progression-free survival and overall survival after amrubicin therapy were 2.6 and 5.0 months, respectively. Two patients had partial response (20% response rate), and their PFS were 6.2 months and 6.3 months, respectively. Furthermore, NEC with response for amrubicin had characteristics with a high Ki-67 index and receipt of prior chemotherapy with cisplatin and irinotecan. Grade 3-4 neutropenia and anemia were observed in four and five patients, respectively. Conclusion. Amrubicin monotherapy appears to be potentially active and well-tolerated for platinum-refractory gastroenteropancreatic NEC. PMID:26199623

  7. 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

  8. First-line therapy for treatment-naive patients with advanced/metastatic renal cell carcinoma: a systematic review of published randomized controlled trials.

    PubMed

    Takyar, Shweta; Diaz, Jose; Sehgal, Manu; Sapunar, Francisco; Pandha, Hardev

    2016-06-01

    In the recent years, a number of targeted therapies have been approved for first-line treatment of patients with metastatic renal cell carcinoma. A systematic review was conducted to assess the clinical efficacy, safety and effect of all first-line treatments evaluated to date on health-related quality of life (HRQoL). A systematic search of Embase, Cochrane and MEDLINE databases was performed to identify randomized controlled trials (1980-2015) evaluating any targeted therapy/immunotherapy against placebo or any other targeted intervention/immunotherapy in treatment-naive patients with metastatic renal cell carcinoma. Conference proceedings from major cancer congresses (2007-2015) were handsearched. Sixteen randomized controlled trials were identified, mostly phase III. Overall, targeted therapies were associated with either improved [sunitinib, bevacizumab+interferon α (IFNα) and temsirolimus] or comparable (sorafenib) progression-free survival (PFS) versus IFNα monotherapy. Sunitinib demonstrated comparable PFS and overall survival to pazopanib, comparable PFS to sorafenib and shorter PFS compared with bevacizumab+IFNα (although no conclusions were made with regard to superiority/inferiority). Compared with sorafenib, tivozanib demonstrated a significantly longer PFS, and both tivozanib and axitinib demonstrated higher response rates. Nintedanib demonstrated comparable PFS and overall survival to sunitinib in a phase II trial. Temsirolimus, sunitinib and sorafenib treatment led to better HRQoL versus IFNα; pazopanib was associated with better HRQoL versus sunitinib. No direct meta-analyses or indirect treatment comparison analysis were undertaken because of noncomparability of the trials. In general, targeted therapies demonstrated favourable clinical efficacy and improved HRQoL compared with IFNα monotherapy. The newer therapies, tivozanib and axitinib (but not nintedanib), appeared to exhibit greater clinical benefit (response rate) than older tyrosine

  9. [A case of non-small cell lung cancer with hemodialysis which responded to docetaxel monotherapy].

    PubMed

    Abe, Yumiko; Tanaka, Kentaro; Matsumoto, Koichiro; Takayama, Koichi; Inoue, Hiroyuki; Izumi, Miiru; Inoue, Hiromasa; Nakanishi, Yoichi

    2010-10-01

    A 56-year-old man receiving hemodialysis treatment was hospitalized for examination of a mass in the right middle lobe. Chest computed tomography showed a right hilar mass shadow accompanied by pleural effusion. Non-small cell lung cancer (NSCLC) was diagnosed by cytological examination of the pleural effusion. No epidermal growth factor receptor (EGFR) mutation was found. He was treated with 6 courses of docetaxel as first-line chemotherapy. Docetaxel was administered on the same day as hemodialysis. Adverse events, including hematotoxicity, were managed safely and no delay in administration occurred. This chemotherapy resulted in a partial response. Because docetaxel is metabolized in the liver and does not affect renal function, it can be administered as a standard regimen. This suggests that docetaxel monotherapy is an efficient therapy for non-small cell lung cancer patients receiving hemodialysis. PMID:21066867

  10. Efficacy and safety of capecitabine-based first-line chemotherapy in advanced or metastatic breast cancer: a meta-analysis of randomised controlled trials

    PubMed Central

    Liu, Gang; Huang, Li; Gao, Shegan; Feng, Xiaoshan

    2015-01-01

    We sought to evaluate the efficacy and safety of capecitabine-based therapy as first-line chemotherapy in advanced breast cancer. Randomised controlled trials of capecitabine monotherapy or combined treatment were included in the meta-analysis. PubMed, EMBASE, the Cochrane Library database and important meeting summaries were searched systematically. Outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and grades 3–4 drug-related adverse events. Nine trials with 1798 patients were included. The results indicated a significant improvement with capecitabine-based chemotherapy compared with capecitabine-free chemotherapy in ORR (relative risk [RR] 1.14, 95% confidence interval [CI] 1.03 to 1.26, P = 0.013) and PFS (hazard ratio [HR] 0.77, 95% CI 0.69 to 0.87, P < 0.0001). Overall survival favoured capecitabine-based chemotherapy, but this was not significant. There were more incidences of neutropenia and neutropenic fever in the capecitabine-free chemotherapy group and more vomiting, diarrhoea and hand–foot syndrome in the capecitabine-based chemotherapy group. There were no significant differences in nausea, fatigue, cardiotoxicity or mucositis/stomatitis between the two treatment regimens. Capecitabine-based chemotherapy significantly improves ORR and PFS in patients with advanced breast cancer, but has no demonstrable impact on OS. Capecitabine-based regimens are suitable as first-line treatment for patients with advanced breast cancer. PMID:26420815

  11. Efficacy and safety of capecitabine-based first-line chemotherapy in advanced or metastatic breast cancer: a meta-analysis of randomised controlled trials.

    PubMed

    Yin, Weijiao; Pei, Guangsheng; Liu, Gang; Huang, Li; Gao, Shegan; Feng, Xiaoshan

    2015-11-17

    We sought to evaluate the efficacy and safety of capecitabine-based therapy as first-line chemotherapy in advanced breast cancer. Randomised controlled trials of capecitabine monotherapy or combined treatment were included in the meta-analysis. PubMed, EMBASE, the Cochrane Library database and important meeting summaries were searched systematically. Outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and grades 3-4 drug-related adverse events.Nine trials with 1798 patients were included. The results indicated a significant improvement with capecitabine-based chemotherapy compared with capecitabine-free chemotherapy in ORR (relative risk [RR] 1.14, 95% confidence interval [CI] 1.03 to 1.26, P = 0.013) and PFS (hazard ratio [HR] 0.77, 95% CI 0.69 to 0.87, P < 0.0001). Overall survival favoured capecitabine-based chemotherapy, but this was not significant. There were more incidences of neutropenia and neutropenic fever in the capecitabine-free chemotherapy group and more vomiting, diarrhoea and hand-foot syndrome in the capecitabine-based chemotherapy group. There were no significant differences in nausea, fatigue, cardiotoxicity or mucositis/stomatitis between the two treatment regimens.Capecitabine-based chemotherapy significantly improves ORR and PFS in patients with advanced breast cancer, but has no demonstrable impact on OS. Capecitabine-based regimens are suitable as first-line treatment for patients with advanced breast cancer. PMID:26420815

  12. First-Line Treatment for Tuberculosis (TB), Drug Resistant TB -- A Visual Tour

    MedlinePlus

    ... Skip Content Marketing Share this: Main Content Area Tuberculosis Drugs First-Line Treatment of TB for Drug- ... ago. See how these drugs work . Multidrug-Resistant Tuberculosis (MDR TB) and Second-Line Treatments MDR TB ...

  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. PMID:25628769

  15. 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

  16. 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. PMID:27572869

  17. 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. PMID:26332019

  18. 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

  19. 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…

  20. 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…

  1. Eslicarbazepine Acetate Monotherapy: A Review in Partial-Onset Seizures.

    PubMed

    Shirley, Matt; Dhillon, Sohita

    2016-04-01

    Eslicarbazepine acetate (Aptiom(®)) is a once-daily, orally administered antiepileptic drug (AED) approved previously in the EU, USA and several other countries for use as adjunctive therapy for the treatment of partial-onset seizures. Based on the findings of two randomized, dose-blinded, conversion-to-monotherapy phase III trials in patients with uncontrolled partial epilepsy, the US license for eslicarbazepine acetate has recently been expanded to include use as monotherapy for partial-onset seizures. The pivotal trials demonstrated that seizure control following conversion from other AEDs was superior for eslicarbazepine acetate monotherapy (1200 or 1600 mg once daily) compared with a pseudo-placebo historical control. Other efficacy outcomes appeared to support the benefit of treatment, with up to 10 % of patients remaining seizure free and up to 46 % of patients experiencing a ≥50 % reduction from baseline in standardized seizure frequency during the monotherapy periods of the trials. Eslicarbazepine acetate monotherapy was generally well tolerated, with most treatment-emergent adverse events being mild to moderate in severity. Its tolerability profile was generally consistent with the established profile of the drug based on its use as adjunctive therapy. Thus, once-daily eslicarbazepine acetate, either as monotherapy or adjunctive therapy, represents a useful option for the treatment of patients with partial-onset seizures. The recent licensing of the drug in the USA as monotherapy expands the range of treatment options for patients with partial-onset seizures and increases the opportunity to tailor therapy to the individual patient. PMID:27055527

  2. Type 2 diabetes and metformin. First choice for monotherapy: weak evidence of efficacy but well-known and acceptable adverse effects.

    PubMed

    2014-11-01

    Many guidelines recommend metformin as first-line therapy for patients with type 2 diabetes. This recommendation is primarily based on the results of the Ukpds trial published in 1998. However, the methodology of this trial has been criticised. In 2014, does the harm-benefit balance of metformin still justify its first-line use in type 2 diabetes? To answer this question, we conducted a review of the literature using the standard Prescrire methodology. In the Ukpds trial, involving about 1700 overweight diabetic patients, metformin monotherapy for about 10 years was more effective in reducing mortality than glycaemic control based mainly on dietary measures, and also more effective than treatment with a sulphonylurea such as chlorpropamide or glibenclamide, or with insulin. However, these results are undermined by several methodological flaws. In the Adopt trial, in which about 4400 patients were followed for 4 years, metformin, glibenclamide and rosiglitazone did not have significantly different effects on the risk of death or cardiovascular events. A meta-analysis of ten randomised trials versus placebo or other hypoglycaemic drugs did not show that metformin monotherapy had a statistically significant effect on mortality. In the Cosmic trial, including more than 5000 patients, metformin monotherapy for one year was not more effective in reducing mortality than another oral hypoglycaemic drug. In the Spread-Dimcad trial in 304 diabetic patients with coronary artery disease, metformin monotherapy appeared to be more effective in preventing cardiovascular complications than glipizide after 5 years of follow-up. The adverse effects of metformin mainly consist of dose-dependent gastrointestinal disorders and rare cases or life-threatening lactic aciaosis. Kidney failure reduces metformin elimination. Metformin rarely causes hypoglycaemia and has no effect on body weight. It does not increase cancer-related mortality. It sometimes causes vitamin B12 deficiency leading

  3. 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

  4. 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

  5. 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. PMID:20082945

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

    PubMed

    Elsayed, H; Mostafa, A M; Soliman, S; Shoukry, T; El-Nori, A A; El-Bawab, H Y

    2016-07-01

    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

  7. Has the time come to abandon efavirenz for first-line antiretroviral therapy?

    PubMed

    Raffi, Francois; Pozniak, Anton L; Wainberg, Mark A

    2014-07-01

    Efavirenz has been recommended as a preferred third agent together with two nucleos(t)ides for first-line combination antiretroviral therapy (ART) for >15 years. The availability of efavirenz in a fixed-dose combination makes it very attractive. However, because of (i) adverse events associated with efavirenz, (ii) a poorer overall efficacy of efavirenz compared with newer antiretrovirals, (iii) the ranking of efavirenz as FDA Pregnancy Category D and (iv) the relatively high prevalence of transmitted drug-resistance mutations, there is a need to reconsider the role of efavirenz in first-line ART. We review the available evidence that challenges efavirenz's current position in first-line HIV treatment guidelines. Apart from its animal teratogenic potential, and moderate neuropsychiatric adverse events associated with its use, efavirenz has recently been associated with an increased risk of suicidality when compared with other antiretroviral drugs. Most importantly, efavirenz has demonstrated overall inferior efficacy to various comparator drugs, which include rilpivirine, raltegravir and dolutegravir, in antiretroviral-naive patients. Furthermore, epidemiological data indicate that the prevalence of non-nucleoside reverse transcriptase inhibitor resistance has reached 5%-8% in various parts of the world, and minority transmitted non-nucleoside reverse transcriptase inhibitor resistance-associated mutations can have a negative impact on the outcome of first-line efavirenz-based ART. Based on considerations of efficacy, toxicity and resistance, it is time to reconsider the routine use of efavirenz in ART. This, of course, presupposes that other antiretrovirals will be available in place of efavirenz, and may not be applicable in certain developing country settings where this is not the case. PMID:24603962

  8. First-line therapy for chronic myeloid leukemia: Past, present, and future.

    PubMed

    Pavlovsky, Carolina; Kantarjian, Hagop; Cortes, Jorge E

    2009-05-01

    The development of Bcr-Abl tyrosine kinase inhibitors has dramatically changed the prognosis of patients with newly diagnosed chronic myeloid leukemia (CML). Standard-dose imatinib (400 mg/day in chronic phase, 600 mg/day in advanced CML) now dominates the management of this disease, producing considerably higher hematologic, cytogenetic, and molecular response rates than seen with previous drug therapies. However, although many patients respond well to standard-dose imatinib initially, some patients do not achieve adequate levels of response or discontinue therapy because of resistance. One approach to improving treatment response with first-line imatinib may be to increase the imatinib dose (800 mg/day), although recent trial data indicate that overall increases in response rates may be modest. Newer Bcr-Abl tyrosine kinase inhibitors can induce responses in patients with all phases of imatinib-resistant CML, even those with imatinib-resistant mutations in the BCR-ABL gene. Furthermore, in initial studies, first-line dasatinib or nilotinib treatment has produced response rates that compare favorably with historical controls treated with imatinib, although confirmation is required from head-to-head clinical trials. Future clinical approaches may include drug combinations, which may allow quiescent leukemia stem cells to be eradicated. Further improvements in drug treatment for first-line CML are expected during the next few years. PMID:19306355

  9. Cetuximab for the first-line treatment of metastatic colorectal cancer.

    PubMed

    Meads, C; Round, J; Tubeuf, S; Moore, D; Pennant, M; Bayliss, S

    2010-05-01

    This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of cetuximab for the first-line treatment of metastatic colorectal cancer (mCRC), in accordance with the licensed indication, based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The ERG project ran between 22 January 2008 and 4 November 2008. The clinical evidence came from two unpublished randomised controlled trials (RCTs) of cetuximab plus chemotherapy versus chemotherapy alone in the first-line treatment of mCRC. A third RCT submitted later compared cetuximab with irinotecan in combination with 5-fluorouracil (5-FU) and folinic acid (FA) and cetuximab with oxaliplatin in combination with 5-FU and FA in patients with mCRC with liver metastases only. No published economic evaluations of cetuximab for first-line chemotherapy in mCRC were identified in the submission. A de novo model examined the cost-effectiveness of cetuximab in patients with mCRC that was epidermal growth factor receptor positive, k-ras wild type and with liver metastases. The main source of clinical effectiveness evidence came from the first two RCTs which provided follow up information for 1-2 years. Secondary information was used to estimate survival for a further 22 years. The model focused on the patients for whom the treatment had been licensed. This limited the applicability of the model to the NHS setting in which patients would be a mixture of k-ras wild type and mutations and also a mixture of patients with liver metastases and other metastases. The difference in progression-free survival for the two trials was between 0.5 to 1.2 months over a 7-10 month period. Eight months' treatment with cetuximab, given as an initial loading dose and then weekly until progression, would cost around 22,932 pounds for an average man and 18,427 pounds for an average

  10. Antiretroviral Therapy and Efficacy After Virologic Failure on First-line Boosted Protease Inhibitor Regimens

    PubMed Central

    Zheng, Yu; Hughes, Michael D.; Lockman, Shahin; Benson, Constance A.; Hosseinipour, Mina C.; Campbell, Thomas B.; Gulick, Roy M.; Daar, Eric S.; Sax, Paul E.; Riddler, Sharon A.; Haubrich, Richard; Salata, Robert A.; Currier, Judith S.

    2014-01-01

    Background. Virologic failure (VF) on a first-line ritonavir-boosted protease inhibitor (PI/r) regimen is associated with low rates of resistance, but optimal management after failure is unknown. Methods. The analysis included participants in randomized trials who experienced VF on a first-line regimen of PI/r plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) and had at least 24 weeks of follow-up after VF. Antiretroviral management and virologic suppression (human immunodeficiency virus type 1 [HIV-1] RNA <400 copies/mL) after VF were assessed. Results. Of 209 participants, only 1 participant had major PI-associated treatment-emergent mutations at first-line VF. The most common treatment approach after VF (66%) was to continue the same regimen. The virologic suppression rate 24 weeks after VF was 64% for these participants, compared with 72% for those who changed regimens (P = .19). Participants remaining on the same regimen had lower NRTI resistance rates (11% vs 30%; P = .003) and higher CD4+ cell counts (median, 275 vs 213 cells/µL; P = .005) at VF than those who changed. Among participants remaining on their first-line regimen, factors at or before VF significantly associated with subsequent virologic suppression were achieving HIV-1 RNA <400 copies/mL before VF (odds ratio [OR], 3.39 [95% confidence interval {CI}, 1.32–8.73]) and lower HIV-1 RNA at VF (OR for <10 000 vs ≥10 000 copies/mL, 3.35 [95% CI, 1.40–8.01]). Better adherence after VF was also associated with subsequent suppression (OR for <100% vs 100%, 0.38 [95% CI, .15–.97]). For participants who changed regimens, achieving HIV-1 RNA <400 copies/mL before VF also predicted subsequent suppression. Conclusions. For participants failing first-line PI/r with no or limited drug resistance, remaining on the same regimen is a reasonable approach. Improving adherence is important to subsequent treatment success. PMID:24842909

  11. Paclitaxel combined with capecitabine as first-line chemotherapy for advanced or recurrent gastric cancer.

    PubMed

    Yuan, Meiqin; Yang, Yunshan; Lv, Wangxia; Song, Zhengbo; Zhong, Haijun

    2014-07-01

    Chemotherapy is of crucial importance in advanced gastric cancer (AGC) patients, in order to obtain palliation of symptoms and improve survival. To date, no standard chemotherapy regimen has been established for AGC. The purpose of the present study was to evaluate the efficacy and toxicity of the combination regimen of paclitaxel and capecitabine (PX) as first-line chemotherapy in patients with advanced or recurrent gastric cancer. Patients with advanced or recurrent gastric cancer who were treated with PX as first-line chemotherapy between January 2001 and December 2012 at the Zhejiang Cancer Hospital (Hangzhou, China) were retrospectively investigated. Survival was evaluated using the Kaplan-Meier method. In total, 36 patients were enrolled, with a median age of 53.5 years and a Karnofsky performance status (KPS) score of ≥80. A median of 4 PX cycles were administered (range, 2-8 cycles). The median progression-free survival time was 3.7 months [95% confidence interval (CI), 2.9-4.5 months) and the median overall survival time was 12.0 months (95% CI, 9.8-14.1 months). From the 36 patients evaluated, one (2.8%) achieved a complete response, seven (19.4%) achieved a partial response, 24 (66.7%) exhibited stable disease and four (11.1%) exhibited progressive disease. The objective response rate was 22.2% (8/36), and the disease control rate was 88.9% (32/36). All 36 patients were assessed for treatment toxicity. Grade 3 or 4 adverse events included neutropenia (2.8% of patients), hand-foot syndrome (2.8%) and vomiting (2.8%). No neutropenic fever or treatment-related mortalities were observed. PX combination chemotherapy may be a valuable first-line therapy for advanced or recurrent gastric cancer. PMID:24959275

  12. 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

  13. 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

  14. Is resistance to dolutegravir possible when this drug is used in first-line therapy?

    PubMed

    Mesplède, Thibault; Wainberg, Mark A

    2014-09-01

    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

  15. [MEDICAL THERAPY FOR THE MANAGEMENT OF PRETERM LABOR: IS THERE A FIRST LINE AGENT?].

    PubMed

    Garmi, Gali; Salim, Raed

    2015-10-01

    Preterm birth is defined as delivery before 37 weeks. It is the leading cause of perinatal morbidity and mortality. Spontaneous preterm birth accounts for approximately 70% of all preterm births. Postponing delivery for 48 hours in order to allow administration of corticosteroids, magnesium for neuroprotection and in order to transfer women to a center with neonatal intensive care unit are the goals of tocolytic therapy. The benefits of tocolytic therapy between 24.0 and 34.0 weeks of gestation outweigh the risk of maternal and fetal complications and it should be initiated provided no contraindications exist. Tocolytic agents that have been used are: prostaglandin synthetase inhibitors, calcium channel antagonists, B-adrenergic agonists, magnesium and oxytocin receptor antagonists. All drugs have demonstrated limited benefit that consists mainly of prolonging the gestational age for 48 hours, without a reduction in the incidence of perinatal mortality and morbidity. Additionally, most available tocolytic agents carry inherent risks of adverse effects. According to the American College of Obstetricians and Gynecologists recommendations, there is no clear first line tocolytic drug to manage preterm labor. Other subjects of debate related to the use of tocolytic therapy include: The effectiveness of combination therapy, the use of tocolytic therapy in multiple pregnancies and the use of progesterone as an adjuvant therapy. We will address the efficacy and tolerability of the tocolytic agents available, the issue of maintenance therapy and debates mentioned above, and try to suggest a first line tocolytic agent based on a study performed at our institution. PMID:26742230

  16. Role of cetuximab in first-line treatment of metastatic colorectal cancer

    PubMed Central

    Sotelo, Miguel Jhonatan; García-Paredes, Beatriz; Aguado, Carlos; Sastre, Javier; Díaz-Rubio, Eduardo

    2014-01-01

    The treatment of metastatic colorectal cancer (mCRC) has evolved considerably in the last decade, currently allowing most mCRC patients to live more than two years. Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor play an important role in the current treatment of these patients. However, only antibodies directed against EGFR have a predictive marker of response, which is the mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC. The CRYSTAL study showed that adding cetuximab to FOLFIRI (regimen of irinotecan, infusional fluorouracil and leucovorin) significantly improved results in the first-line treatment of KRAS wild-type mCRC. However, results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory. On the other hand, recent advances in the management of colorectal liver metastases have improved survival in these patients. Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients. In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC. PMID:24764659

  17. How to select the optimal treatment for first line metastatic colorectal cancer

    PubMed Central

    Stein, Alexander; Bokemeyer, Carsten

    2014-01-01

    Choice of first line treatment for patients with metastatic colorectal cancer (mCRC) is based on tumour and patient related factors and molecular information for determination of individual treatment aim and thus treatment intensity. Recent advances (e.g., extended RAS testing) enable tailored patient assignment to the most beneficial treatment approach. Besides fluoropyrimidines, irinotecan and oxaliplatin, a broad variety of molecular targeting agents are currently available, e.g., anti-angiogenic agents (bevacizumab) and epidermal growth factor receptor (EGFR) antibodies (cetuximab, panitumumab) for first line treatment of mCRC. Although some combinations should be avoided (e.g., oral or bolus fluoropyrimidines, oxaliplatin and EGFR antibodies), treatment options range from single agent to highly effective four-drug regimen. Preliminary data comparing EGFR antibodies and bevacizumab, both with chemotherapy, seem to favour EGFR antibodies in RAS wildtype disease. However, choosing the most appropriate treatment approach for mCRC patients remains a complex issue, with numerous open questions. PMID:24574764

  18. The first-line use of electroconvulsive therapy in major affective disorders.

    PubMed

    Maletzky, Barry M

    2004-06-01

    Although electroconvulsive therapy (ECT) has generally been reserved for patients refractory to other forms of treatment, its use as a first-line treatment, prior to the use of other biologic approaches, has occasionally been mentioned in the literature on the treatment of affective disorders and, when indicated, can prove rapidly effective and even life saving. The present study retrospectively reviewed 27 cases treated over the span of a decade in which ECT was chosen as the first treatment of an affective episode. In none of these cases was antidepressant medication or other biologic approaches used for the current episode. A clinical global rating scale was employed to measure improvement. Although the majority of such patients were treated with ECT first based upon the severity of their depressive illness, 13 received ECT because of their obtunded condition and these patients, initially diagnosed as catatonic on admission, were suspected of having a bipolar condition, as revealed on their discharge diagnosis. In addition, ECT was recommended preferentially in 4 patients because they were pregnant and in another 4 because it had worked well in the past; an additional patient received ECT first because of his fragile medical condition. Almost all patients recovered and none suffered serious adverse effects. Sample case histories are provided along with tentative guidelines for the consideration of first-line use of ECT in clinically difficult cases. PMID:15167428

  19. 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

  20. 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. PMID:26629769

  1. 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

  2. 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. PMID:26612773

  3. [First-line screening guidelines for renal stone disease patients: a CLAFU update].

    PubMed

    Haymann, J-P; Daudon, M; Normand, M; Hoznek, A; Meria, P; Traxer, O

    2014-01-01

    This text summarizes the CLAFU first-line screening guidelines for renal stone disease patients. We have focused on the useful information provided by renal stone analysis and also the identification of relevant stone risk factors detected in a 24-hour urine collection. Indeed, evaluation of water, sodium and protein intake may be easily achieved in a current clinical setting and allows a useful pedagogic tool for patients' advices and follow-up: daily diuresis above 2000 mL, calcium intake between 800 mg and 1 g/day, a moderate daily sodium and proteins restricted diet (<9 g and <1.2 g/kg per day respectively). General therapeutical principles are reviewed, including circumstances requiring specialized management. PMID:24365623

  4. Second-generation tyrosine kinase inhibitors in first-line treatment of chronic myeloid leukaemia (CML).

    PubMed

    Abruzzese, Elisabetta; Breccia, Massimo; Latagliata, Roberto

    2014-02-01

    Tyrosine kinase inhibitors (TKIs) have contributed to marked improvements in survival in patients with chronic myeloid leukaemia (CML). This article discusses the place of the second-generation TKIs dasatinib and nilotinib in the first-line treatment of CML and is based on published literature. The new agents are more potent and effective than imatinib. Data from pivotal clinical trials indicate that response to dasatinib and nilotinib is greater and more rapid than that to imatinib, resulting in a higher probability of patients achieving an optimal response to treatment. Differences between the newer agents with respect to patient groups for whom caution is advised, drug interaction potential, haematological toxicity, pulmonary toxicity, changes in the immune system and effects on laboratory parameters are discussed. With similar levels of efficacy, the choice of second-generation agents should be guided by the characteristics of the individual patient and the most suitable dosing regimen. PMID:24043361

  5. 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. PMID:25780283

  6. Rationale of first-line endoscopy-based fertility exploration using transvaginal hydrolaparoscopy and minihysteroscopy.

    PubMed

    De Wilde, R L; Brosens, I

    2012-08-01

    The transvaginal access for exploration of tubo-ovarian function in women with unexplained infertility has been revived since transvaginal hydrolaparoscopy (THL) was introduced in 1998. One prospective double-blind trial and several reviews have validated the diagnostic value of THL in comparison with laparoscopy for the exploration of women with unexplained infertility. A review of the recent literature confirms the efficacy and safety of the technique for first-line endoscopy-based exploration of fertility. The standard policy of 1-year delay for laparoscopic investigation in unexplained infertility is challenged. In older women and particularly in women experienced in fertility awareness methods, THL and minihysteroscopy can be performed after a waiting period of 6-12 months. PMID:22674201

  7. Catheter Ablation as First-Line Therapy for Atrial Fibrillation: Ready for Prime-Time?

    PubMed

    Carrizo, Aldo G; Morillo, Carlos A

    2016-07-01

    Current guidelines include atrial fibrillation (AF) catheter ablation as part of the management strategy in patients that have failed at least one oral antiarrhythmic drug treatment course. However, growing evidence derived from both randomized and non-randomized studies demonstrate lower rates of AF recurrence and AF burden in patients with paroxysmal AF that are naïve to antiarrhythmic drug treatment. Furthermore, progression from paroxysmal AF to persistent AF appears to be delayed by early catheter ablation of AF. The current review addresses the question of the best timing for ablation in patients with paroxysmal AF and provides the rationale for offering AF ablation as first-line therapy based on the most updated evidence available. PMID:27300744

  8. Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy.

    PubMed

    Jurinovic, Vindi; Kridel, Robert; Staiger, Annette M; Szczepanowski, Monika; Horn, Heike; Dreyling, Martin H; Rosenwald, Andreas; Ott, German; Klapper, Wolfram; Zelenetz, Andrew D; Barr, Paul M; Friedberg, Jonathan W; Ansell, Stephen; Sehn, Laurie H; Connors, Joseph M; Gascoyne, Randy D; Hiddemann, Wolfgang; Unterhalt, Michael; Weinstock, David M; Weigert, Oliver

    2016-08-25

    Follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. Posttreatment surrogate end points, such as progression of disease within 24 months (POD24) are promising predictors for overall survival (OS) but are of limited clinical value, primarily because they cannot guide up-front treatment decisions. We used the clinical and molecular data from 2 independent cohorts of symptomatic patients in need of first-line immunochemotherapy (151 patients from a German Low-Grade Lymphoma Study Group [GLSG] trial and 107 patients from a population-based registry of the British Columbia Cancer Agency [BCCA]) to validate the predictive utility of POD24, and to evaluate the ability of pretreatment risk models to predict early treatment failure. POD24 occurred in 17% and 23% of evaluable GLSG and BCCA patients, with 5-year OS rates of 41% (vs 91% for those without POD24, P < .0001) and 26% (vs 86%, P < .0001), respectively. The m7-FL International Prognostic Index (m7-FLIPI), a prospective clinicogenetic risk model for failure-free survival, had the highest accuracy to predict POD24 (76% and 77%, respectively) with an odds ratio of 5.82 in GLSG (P = .00031) and 4.76 in BCCA patients (P = .0052). A clinicogenetic risk model specifically designed to predict POD24, the POD24-PI, had the highest sensitivity to predict POD24, but at the expense of a lower specificity. In conclusion, the m7-FLIPI prospectively identifies the smallest subgroup of patients (28% and 22%, respectively) at highest risk of early failure of first-line immunochemotherapy and death, including patients not fulfilling the POD24 criteria, and should be evaluated in prospective trials of precision medicine approaches in FL. PMID:27418643

  9. 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

  10. [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. PMID:27426243

  11. EUS-guided FNA for biliary disease as first-line modality to obtain histological evidence

    PubMed Central

    Onda, Saori; Ogura, Takeshi; Kurisu, Yoshitaka; Masuda, Daisuke; Sano, Tatsushi; Takagi, Wataru; Fukunishi, Shinya; Higuchi, Kazuhide

    2016-01-01

    Background: Few reports have described endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) for biliary lesions. In addition, adverse events were not completely examined in previous reports, due to the inclusion of cases in which biliary stents had already been placed. The present study aimed to investigate the diagnostic yield and adverse events of EUS-FNA for biliary lesions as the first-line diagnostic modality for consecutive prospectively registered patients. Methods: Inclusion criteria were as follows: (1) patients with suspected cholangiocarcinoma (CCA) based on computed tomography or other imaging modalities; (2) patients who had not previously undergone endoscopic retrograde cholangiopancreatography or EUS-FNA; (3) absence of surgically altered anatomy, such as Roux-en-Y anastomosis or duodenal obstruction caused by tumor invasion, through which an endoscope could not pass; and (4) provision of written informed consent to all procedures associated with the study. Results: A total of 47 consecutive patients with suspected CCA were registered to this study. Sensitivity and accuracy were 89% and 87%, respectively. On multivariate analysis, puncture site was the only factor associated with reduced diagnostic yield (hazard ration, 6.879; 95% confidence interval, 1.172–40.374; P = 0.033). Remarkably, no adverse events such as bleeding or bile leakage were associated with EUS-FNA in any of the 47 patients. Conclusions: Our results suggest that EUS-FNA can be safely performed for biliary disease without biliary stenting. Furthermore, this procedure may warrant use as the first-line diagnostic method, although our results need to be validated in future prospective studies. PMID:27134660

  12. Systematic review: What is the best first-line approach for cesarean section ectopic pregnancy?

    PubMed

    Kanat-Pektas, Mine; Bodur, Serkan; Dundar, Ozgur; Bakır, Vuslat Lale

    2016-04-01

    This systematic review aims to analyze the case reports, case series, or clinical studies describing the women with cesarean scar ectopic pregnancy (CSEP), and thus, to determine the efficacy and safety of different primary treatment modalities in the management of CSEP. A thorough search of electronic databases showed that 274 articles on CSEP were published between January 1978 and April 2014. Systemic methotrexate, uterine artery embolization, dilatation and curettage (D&C), hysterotomy, and hysteroscopy were the most frequently adopted first-line approaches. The success rates of systemic methotrexate, uterine artery embolization, hysteroscopy, D&C, and hysterotomy were 8.7%, 18.3%, 39.1%, 61.6%, and 92.1%, respectively. The hysterectomy rates were 3.6%, 1.1%, 0.0%, 7.3%, and 1.7% in CSEP cases that were treated by systemic methotrexate, uterine artery embolization, hysteroscopy, D&C, and hysterotomy, respectively. The ability to achieve a subsequent term pregnancy is related to successful systemic methotrexate treatment (p = 0.001) or hysterotomy (p = 0.009). Future term pregnancy was significantly more frequent in the hysterotomy group (p = 0.001). Hysteroscopy and laparoscopic hysterotomy are safe and efficient surgical procedures that can be adopted as primary treatment modalities for CSEP. Uterine artery embolization should be reserved for cases with significant bleeding and/or a high suspicion index for arteriovenous malformation. Systemic methotrexate and D&C are not recommended as first-line approaches for CSEP, as these procedures are associated with high complication and hysterectomy rates. PMID:27125412

  13. [Biologics as first line therapy in the treatment of rheumatoid arthritis. A posture a favor].

    PubMed

    Hernández Cruz, Blanca

    2009-04-01

    Changes in diagnosis and treatment of rheumatoid arthritis oblige us to question clinical practice. Evidence demonstrates that the combination of biologics and methotrexate in rapid increments leads to larger remission rates than methotrexate alone. The combination has a faster clinical response in activity, physical function, quality of life, fatigue and sleep. But the most significant effect of biologics is on radiographic progression. The reduction in radiological damage has a spectrum that goes from anti-TNF+methotrexate to anti-TNF monotherapy, being less with methotrexate, and independent from improvement in activity; it occurs with all of the anti-TNF drugs and with other targets with different mechanisms of action (anti-CD20, T cell costimulation inhibitors and anti IL-6). The clinical significance of this finding will be seen in the future, when more is known of its impact on the poor outcomes of RA patients. Because methotrexate is an excellent drug, it seems madness to say that all patients should receive biologics+methotrexate, but it is reasonable to consider that a subgroup must receive them from the start. The American College of Rheumatology recommends their use in patients with RA of less than 6 months since onset, with no previous exposure to methotrexate, persistent and elevated activity (<3 months) and poor prognostic factors or those with persistent and elevated activity (3-6 months) independent of poor prognostic factors, and if the patient "has insurance". A final thought would be: Is there a new treatment pyramid which has cost at its base now? PMID:21794638

  14. 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

  15. Economic Evaluation of First-Line Adjuvant Chemotherapies for Resectable Gastric Cancer Patients in China

    PubMed Central

    Tan, Chongqing; Peng, Liubao; Zeng, Xiaohui; Li, Jianhe; Wan, Xiaomin; Chen, Gannong; Yi, Lidan; Luo, Xia; Zhao, Ziying

    2013-01-01

    Background First-line postoperative adjuvant chemotherapies with S-1 and capecitabine and oxaliplatin (XELOX) were first recommended for resectable gastric cancer patients in the 2010 and 2011 Chinese NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer; however, their economic impact in China is unknown. Objective The aim of this study was to compare the cost-effectiveness of adjuvant chemotherapy with XELOX, with S-1 and no treatment after a gastrectomy with extended (D2) lymph-node dissection among patients with stage II-IIIB gastric cancer. Methods A Markov model, based on data from two clinical phase III trials, was developed to analyse the cost-effectiveness of patients in the XELOX group, S-1 group and surgery only (SO) group. The costs were estimated from the perspective of Chinese healthcare system. The utilities were assumed on the basis of previously published reports. Costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICER) were calculated with a lifetime horizon. One-way and probabilistic sensitivity analyses were performed. Results For the base case, XELOX had the lowest total cost ($44,568) and cost-effectiveness ratio ($7,360/QALY). The relative scenario analyses showed that SO was dominated by XELOX and the ICERs of S-1 was $58,843/QALY compared with XELOX. The one-way sensitivity analysis showed that the most influential parameter was the utility of disease-free survival. The probabilistic sensitivity analysis predicted a 75.8% likelihood that the ICER for XELOX would be less than $13,527 compared with S-1. When ICER was more than $38,000, the likelihood of cost-effectiveness achieved by S-1 group was greater than 50%. Conclusions Our results suggest that for patients in China with resectable disease, first-line adjuvant chemotherapy with XELOX after a D2 gastrectomy is a best option comparing with S-1 and SO in view of our current study. In addition, S-1 might be a better choice, especially with a

  16. 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

  17. 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

  18. [Evidence on afatinib in patients progressing on a first-line treatment].

    PubMed

    Artal Cortés, Ángel; Gimeno Pelegrín, Joaquín; Alejandro, María Álvarez

    2016-04-01

    After description of the importance of EGFR mutations in non-small cell lung cancer and confirmation that tyrosine-kinase inhibitors are more beneficial than chemotherapy in patients with EGFR+ tumours, treatment with one of these drugs has become the standard recommendation. Despite this advance, patients continue to progress and consequently there is a need to search for alternative treatments. Some studies have analysed afatinib activity after first-generation TKI therapy, as well as its administration in combination with conventional chemotherapy. Afatinib produces significant response rates and progression-free survival times after the development of clinical resistance, which are independent of the presence of the T790M resistance mutation and can be attributed to continued pan-HER inhibition. In addition to the initial clinical trial, LUX-LUNG-1, data are available from the use of afatinib in routine clinical practice, within extended use programs. Overall, response rates of between 7 and 15% can be expected with a duration of approximately 24 months and a median progression-free time of about 4 months. A study combining afatinib with cetuximab has obtained a high response rate. Afatinib toxicity in second-line treatment is similar to that appears when the drug is used as first-line therapy (mainly mucocutaneous and diarrhoea) and can be managed with routine measures. In conclusion, afatinib should be considered as a treatment option in patients with EGFR mutations who show disease progression after a first tyrosine-kinase inhibitor. PMID:27426244

  19. First-line autologous stem cell transplantation in primary CNS lymphoma.

    PubMed

    Brevet, M; Garidi, R; Gruson, B; Royer, B; Vaida, I; Damaj, G

    2005-10-01

    The treatment of primary central nervous system lymphoma (PCNSL) has been considerably improved over recent years. In this article, we report six cases of PCNSL treated by first-line induction chemotherapy followed by intensive chemotherapy and autologous stem cell transplantation (ASCT). Six immunocompetent patients presenting with a PCNSL, confirmed by thoraco-abdomino-pelvic computer tomography scan and bone marrow biopsy, were treated with induction chemotherapy followed by BEAM intensive chemotherapy and ASCT and radiotherapy. At the end of the treatment, all the patients were in complete remission. After a median follow-up of 41.5 months (17-70 months), four patients were alive without signs of relapse (median survival: 35.5 months). Two patients died from relapse at 19 and 23 months. The neurotoxicity was low with epilepsy in one patient and persistent left side dysesthesia in another one. These results are fairly encouraging. Other studies with greater numbers of patients and longer follow-up are needed to confirm this study. PMID:16146534

  20. 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. PMID:22316351

  1. Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia.

    PubMed

    Gugliotta, Gabriele; Castagnetti, Fausto; Breccia, Massimo; Gozzini, Antonella; Usala, Emilio; Carella, Angelo M; Rege-Cambrin, Giovanna; Martino, Bruno; Abruzzese, Elisabetta; Albano, Francesco; Stagno, Fabio; Luciano, Luigia; D'Adda, Mariella; Bocchia, Monica; Cavazzini, Francesco; Tiribelli, Mario; Lunghi, Monia; Pia Falcone, Antonietta; Musolino, Caterina; Levato, Luciano; Venturi, Claudia; Soverini, Simona; Cavo, Michele; Alimena, Giuliana; Pane, Fabrizio; Martinelli, Giovanni; Saglio, Giuseppe; Rosti, Gianantonio; Baccarani, Michele

    2016-06-01

    The introduction of second-generation tyrosine-kinase inhibitors (TKIs) has generated a lively debate on the choice of first-line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR-ABL1 positive, chronic phase, CML patients. One hundred twenty-three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93%, 87%, and 61%, respectively. The 5-year overall survival and progression-free survival were 89%. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5%). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their use. Am. J. Hematol. 91:617-622, 2016. © 2016 Wiley Periodicals, Inc. PMID:26971721

  2. An online survey of specialists' opinion on first line management options for unexplained subfertility.

    PubMed

    Nandi, Anupa; Gudi, Anil; Shah, Amit; Homburg, Roy

    2015-03-01

    The recent National Institute for Health and Care Excellence (NICE) guideline on Fertility (2012) suggests that IVF should be offered to couples with unexplained subfertility after 2 years of expectant management. The evidence on which these recommendations are based is not robust and there is a lack of agreement among specialists regarding the management of unexplained subfertility. We conducted an online survey among fertility specialists to find out the general consensus regarding the management of these couples. An e-mail questionnaire was sent to 420 reproductive medicine clinicians and 136 (32.38%) replied. Only 16% said they would always recommend IVF as the first line management for these couples, irrespective of age and duration of infertility. Of those surveyed, 39% agreed to the new NICE proposal, 33% agreed partly and 25% did not agree at all. A total of 27% of the respondents said they would definitely change their practice according to the NICE proposal but 30% said they would not; 29% said they might change their policy while the rest were unsure. This survey confirms the ongoing clinical uncertainty among fertility specialists in managing couples with unexplained subfertility. PMID:25162601

  3. Thrombolysis: A Critical First-Line Therapy with an Unfulfilled Potential.

    PubMed

    Gurewich, Victor

    2016-06-01

    A blood clot or thrombus triggers the onset of most vascular diseases, like stroke or heart attack. Thrombolysis is the only treatment that can restore blood flow rapidly and easily. Unfortunately, the standard thrombolytic, tissue plasminogen activator (tPA), has proven inadequate and is being replaced by invasive endovascular procedures, which are time consuming and limited in their availability in relation to the scope of the problem. Historically, when tPA clinical trials began, it was not recognized sufficiently that without the other natural plasminogen activator, prourokinase (proUK), thrombolysis by tPA was seriously compromised. The reason is that the 2 activators have complementary mechanisms of action in fibrinolysis, making their combination a requirement for optimal efficacy and synergy. Biological fibrinolysis also uses both activators, explaining why such low endogenous concentrations are sufficient. A low-dose sequential combination of tPA and proUK was tested in acute myocardial infarction, where it was exceptionally effective and safe. Because native proUK at pharmacological doses was vulnerable to spontaneous conversion to urokinase, jeopardizing safety, a site-directed mutant was developed that improved proUK's plasma stability fivefold without interfering with its mode of action. Mini-bolus tPA followed by low-dose proUK infusion is a simple, safe, effective, and promising first-line treatment of acute thrombotic disorders. PMID:26714208

  4. Comparison of Automated Treponemal and Nontreponemal Test Algorithms as First-Line Syphilis Screening Assays

    PubMed Central

    Chung, Jae-Woo; Park, Seong Yeon; Chae, Seok Lae

    2016-01-01

    Background 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. Methods 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). Results 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. Conclusions 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. PMID:26522755

  5. Expert opinion on first-line therapy in the treatment of castration-resistant prostate cancer.

    PubMed

    Maroto, Pablo; Solsona, Eduardo; Gallardo, Enrique; Mellado, Begoña; Morote, Juan; Arranz, José Ángel; Gómez-Veiga, Francisco; Unda, Miguel; Climent, Miguel Ángel; Alcaraz, Antonio

    2016-04-01

    Treatment of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized in recent years. It is well known that androgen receptor is still active in most patients with disease progression and serum testosterone levels <50 ng/dL. Moreover, further hormonal maneuvers, either through decreasing androgen levels (abiraterone) or by targeting the androgen receptor (AR) pathway (enzalutamide), prolong survival. In addition, a new cytostatic able to overcome docetaxel resistance, cabazitaxel, and the radioisotope radium 223 have been incorporated to the armamentarium of mCRPC. mCRPC is not only a heterogeneous tumor, it changes over time developing neuroendocrine features or selection of clones resistant to hormonal maneuvers. In addition, the multiplicity of current treatments, make it necessary to design algorithms that help the specialist to choose the most appropriate treatment for a particular patient. The lack of randomized trials comparing face to face the different available options limit the scope of this review. In this article, the authors describe the prognostic factors for first line therapy in patients with mCRPC, and propose a treatment algorithm for mCRPC based on the levels of scientific evidence available and, if not available, on the consensus between medical professionals. Finally, the panel discuss how to define progressive disease in the setting of mCRPC and treatment with targeted therapies. PMID:26363809

  6. 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

  7. 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. PMID:27076499

  8. 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

  9. First-line eradication of Helicobacter pylori: are the standard triple therapies obsolete? A different perspective.

    PubMed

    Buzás, György-Miklós

    2010-08-21

    Studies concerning the eradication of Helicobacter pylori have resulted in a proliferation of meta-analyses. To date, there are 303 meta-analyses cited in PubMed, 113 dealing with the therapy of the infection. A chronological analysis of the results of meta-analyses performed between 1998 and 2010 shows that first-line standard triple therapies achieved eradication rates on an intention-to-treat basis of around 80%; prolonging treatment to 14, but not 10 d should improve the results. The proton pump inhibitors have a similar efficiency, and giving a double dose is more efficient than the standard doses of these drugs. Triple and quadruple therapies proved to be equivalent. Based on meta-analytical data, the decrease in efficiency over time cannot be substantiated: eradication rates < 80% followed from the introduction of triple therapies. As alternatives, ranitidine bismuth citrate-, levofloxacin- or furazolidone-based therapies were shown to obtain the same eradication rates as standard triple regimens. Sequential therapies and quadruple non-bismuth-based therapies were superior to standard triple therapies but their use is limited to certain countries. In the author's opinion, and from a meta-analytical viewpoint, standard triple therapies cannot yet be considered obsolete. Furthermore, non-inferiority trials are proposed for the future, including assessment of local contemporary antimicrobial resistance profiles and the CagA and CYP2C19 status of the enrolled patients. PMID:20712046

  10. Colorectal stenting as first-line treatment in acute colonic obstruction

    PubMed Central

    García-Cano, Jesús

    2013-01-01

    Tumoral obstructions in almost the entire gastrointestinal tract can be resolved with interventional digestive endoscopy techniques. Self-expanding metal stent (SEMS) insertion in the obstructed colon is a minimally invasive and relatively simple procedure providing an effective first-line treatment for relief of acute malignant obstruction symptoms and serving either as a preoperative or “bridge to surgery” procedure or as palliative definitive care. This technique was introduced in the early 1990s. Although there is still debate about its real value, a lot of reports have been published since then and the procedure is advocated by many surgical groups as the method of choice for the initial treatment of left-sided tumoral colonic obstruction. Before the procedure, colonic obstruction has to be diagnosed by abdominal radiographs, water contrast enema and/or a computed tomography scan. The greatest information is provided by the latter and it is perhaps the method of choice prior to stenting. Skills and training are mandatory, as in all interventional procedures. The key step for success is to cross the malignant stricture with a guidewire. Care must be taken not to over insufflate an obstructed colon during the procedure. SEMS slide over the guidewire through the endoscope working channel or in parallel, outside the endoscope. An average 7% perforation rate has been reported during the procedure and other minor complications can appear in the follow up. However, as a whole, this technique seems to compare favorably with surgery. PMID:24147193

  11. 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

  12. Receipt of Glucocorticoid Monotherapy Among Medicare Beneficiaries With Rheumatoid Arthritis

    PubMed Central

    YAZDANY, JINOOS; TONNER, CHRIS; SCHMAJUK, GABRIELA; LIN, GRACE A.; TRIVEDI, AMAL N.

    2015-01-01

    Objective Using disease-modifying antirheumatic drugs (DMARDs) improves outcomes in rheumatoid arthritis (RA) and is a nationally endorsed quality measure. We investigated the prevalence and predictors of receiving glucocorticoids alone for the treatment of RA in a nationwide sample of Medicare beneficiaries. Methods Among individuals ages ≥65 years with RA enrolled in the Part D prescription drug benefit in 2009, we compared those with ≥1 DMARD claim to those receiving glucocorticoid monotherapy, defined as no DMARD claim and an annual glucocorticoid supply of ≥180 days or an annual dose of ≥900 mg of prednisone or equivalent. We fit multivariable models to determine the sociodemographic and clinical factors associated with glucocorticoid monotherapy. Results Of 8,125 beneficiaries treated for RA, 10.2% (n = 825) received glucocorticoids alone. Beneficiaries with low incomes were more likely to receive glucocorticoids alone (12.3%; 95% confidence interval [95% CI] 10.9–13.8% versus 9.4%; 95% CI 8.6–10.1%), as were those living in certain US regions. More physician office visits and hospitalizations were associated with glucocorticoid monotherapy. Individuals who had no contact with a rheumatologist were significantly more likely to receive glucocorticoids alone (17.5%; 95% CI 16.0–19.0% versus 8.5%; 95% CI 7.4–9.5% for those with no rheumatology visits versus 1–4 visits). Conclusion Approximately 1 in 10 Medicare beneficiaries treated for RA received glucocorticoids without DMARDs in 2009. Compared to DMARD users, glucocorticoid users were older, had lower incomes, were more likely to live in certain US regions, and were less likely to have seen a rheumatologist, suggesting persistent gaps in quality of care despite expanded drug coverage under Part D. PMID:25244314

  13. Zinc monotherapy is effective in Wilson’s disease patients with mild liver disease diagnosed in childhood: a retrospective study

    PubMed Central

    2014-01-01

    Background Wilson’s disease (WD) evolves rapidly and is fatal if untreated. The treatment of WD patients with mild liver disease is not clearly defined. To address this issue, we evaluated long-term outcomes of three treatment regimens (D-penicillamine, zinc or both) in patients diagnosed in childhood. Methods We retrospectively evaluated efficacy, compliance and reasons for treatment discontinuation in 42 WD patients (median age at diagnosis: 6 years; median follow-up: 12 years) with mild liver disease. Treatment duration for each treatment block until a medication change or completion of follow-up was analyzed. Events of change of treatment were evaluated using Kaplan-Meier analysis. Results Total discontinuations due to treatment failure or adverse events were more frequent in patients receiving D-penicillamine (45%) or combination (36%) therapy than in patients receiving zinc (12%) (P = .001 and P = .02, respectively). Treatment failure was more frequent on D-penicillamine (28%) and combination therapy (36%) than on zinc (12%); the difference was statistically significant only between zinc and combination therapy (P = .03). First-line zinc monotherapy controlled WD-related liver disease in 13/15 patients (87%); the two subjects that failed on zinc were poor adherent. Zinc was effective in 3/5 (60%) patients that failed on D-penicillamine and combination regimens. All 15 D-penicillamine responders that switched to zinc had good control of liver disease at a median follow-up of 13.1 years. Among 6 D-penicillamine non-responders that switched to zinc, 4 (67%) responded. At follow-up completion, only 5/42 (12%) patients failed. Adverse event-induced discontinuation was significantly more frequent in patients on D-penicillamine than in patients receiving zinc (P = .03). Conclusions Zinc monotherapy is effective in controlling WD-related liver disease both as first-line and as maintenance treatment in patients with mild liver disease diagnosed in

  14. Extensive Darier Disease Successfully Treated with Doxycycline Monotherapy

    PubMed Central

    Sfecci, Alicia; Orion, Camille; Darrieux, Laure; Tisseau, Laurent; Safa, Gilles

    2015-01-01

    Darier disease (DD) is a rare dominantly inherited genodermatosis characterized by loss of intercellular adhesion (acantholysis) and abnormal keratinization. DD is often difficult to manage. Numerous treatments have reportedly been used for the treatment of DD, with limited success. Systemic retinoids are considered the drug of choice for treating DD. However, their use is limited by potential deleterious side effects. Considering the recently reported efficacy of doxycycline for Hailey-Hailey disease, an inherited acantholytic skin disorder pathogenetically similar to DD, we report the case of a patient with extensive DD who showed a dramatic response to oral doxycycline monotherapy. PMID:26594170

  15. Extensive Darier Disease Successfully Treated with Doxycycline Monotherapy.

    PubMed

    Sfecci, Alicia; Orion, Camille; Darrieux, Laure; Tisseau, Laurent; Safa, Gilles

    2015-01-01

    Darier disease (DD) is a rare dominantly inherited genodermatosis characterized by loss of intercellular adhesion (acantholysis) and abnormal keratinization. DD is often difficult to manage. Numerous treatments have reportedly been used for the treatment of DD, with limited success. Systemic retinoids are considered the drug of choice for treating DD. However, their use is limited by potential deleterious side effects. Considering the recently reported efficacy of doxycycline for Hailey-Hailey disease, an inherited acantholytic skin disorder pathogenetically similar to DD, we report the case of a patient with extensive DD who showed a dramatic response to oral doxycycline monotherapy. PMID:26594170

  16. Effective treatment of bipolar depression: monotherapy and combination strategies.

    PubMed

    Manning, J Sloan

    2015-11-01

    Managing patients with bipolar disorder remains a challenge due to its chronic nature. In addition, bipolar depression remains understudied even though patients spend more time in depressive episodes than in manic ones. Effective treatment requires an accurate and timely diagnosis, psychoeducation, psychotherapy, pharmacotherapy, and implementation of elements of the chronic care model. Pharmacologic strategies for treating bipolar depression differ from those for bipolar mania as well as those for unipolar depression and require knowledge of the efficacy and safety of agents including mood stabilizers, atypical antipsychotics, and antidepressants both as monotherapy and in combination. PMID:26646048

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

    PubMed

    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

  18. 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

  19. Drug-drug interaction studies on first-line anti-tuberculosis drugs.

    PubMed

    Bhutani, Hemant; Singh, Saranjit; Jindal, K C

    2005-01-01

    The purpose of this study was to carry out drug-drug compatibility studies on pure first line anti-tuberculosis drugs, viz., rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol hydrochloride (E). Various possible binary, ternary, and quaternary combinations of the four drugs were subjected to accelerated stability test conditions of 40 degrees C and 75% relative humidity (RH) for 3 months. For comparison, parallel studies were also conducted on single drugs. Changes were looked for in the samples drawn after 15, 30, 60, and 90 days of storage. Analyses for R, H, and Z were carried out using a validated HPLC method. The E was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as it does not absorb in ultraviolet (UV). All single pure drugs were relatively stable and showed only 3%-5% degradation under accelerated conditions for 3 months. However, significant interactions were observed in case of the drug mixtures. In particular, ternary and quaternary drug combinations containing R and H along with Z and/or E were very unstable, showing 90%-95% and 70%-75% loss of R and H, respectively. In all these cases, isonicotinyl hydrazone (HYD) of 3-formylrifamycin and H was found to be the major degradation product. In case of RE and RZE mixtures, where H was absent, 3-formylrifamycin was instead the key degradation product. Another unidentified peak was observed in the mixture containing RZE. Apart from these chemical changes, considerable physical changes were also observed in pure E and the mixtures containing E, viz., RE, ZE, RHE, RZE, and RHZE. In addition, significant physical changes associated with noteworthy loss of H and E were also observed in mixtures containing HE and HZE. The present study thus amply shows that the four primary anti-tuberculosis drugs, when present together, interact with each other in a multiple and complex manner. PMID:16370181

  20. Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma.

    PubMed

    Hadoux, J; Malka, D; Planchard, D; Scoazec, J Y; Caramella, C; Guigay, J; Boige, V; Leboulleux, S; Burtin, P; Berdelou, A; Loriot, Y; Duvillard, P; Chougnet, C N; Déandréis, D; Schlumberger, M; Borget, I; Ducreux, M; Baudin, E

    2015-06-01

    There is no standard for second-line chemotherapy in poorly differentiated grade 3 neuroendocrine carcinoma (G3-NEC) patients. We analyzed the antitumor efficacy of 5-fluorouracil and oxaliplatin (FOLFOX) chemotherapy in this population. A single-center retrospective analysis of consecutive G3-NEC patients treated with FOLFOX chemotherapy after failure of a cisplatinum-based regimen between December 2003 and June 2012 was performed. Progression-free survival (PFS), overall survival (OS), response rate, and safety were assessed according to RECIST 1.1 and NCI.CTC v4 criteria. Twenty consecutive patients were included (seven males and 13 females; median age 55; range 23-87 years) with a performance status of 0-1 in 75% of them. Primary location was gastroenteropancreatic in 12, thoracic in four, other in two, and unknown in two patients. There were 12 (65%) large-cell and 7 (30%) small-cell G3-NEC tumors, and 1 (5%) unknown. All patients had distant metastases. Twelve (60%) patients received FOLFOX as second-line treatment and 8 (40%) as third-line treatment or later and the median number of administered cycles was 6 (range 3-14). The median follow-up was 19 months. Median PFS was 4.5 months. Among the 17 evaluable patients, five partial responses (29%), six stable diseases (35%), and six progressive diseases (35%) were observed. Median OS was 9.9 months. Main Grade 3-4 toxicities were neutropenia (35%), thrombopenia (20%), nausea/vomiting (10%), anemia (10%), and elevated liver transaminases (10%). Our results indicate that the FOLFOX regimen could be considered as a second-line option in poorly differentiated G3-NEC patients after cisplatinum-based first-line treatment but warrant further confirmation in future larger prospective studies. PMID:25770151

  1. Tuberculosis treatment and risk of stavudine substitution in first line antiretroviral therapy

    PubMed Central

    Westreich, Daniel J.; Sanne, Ian; Maskew, Mhairi; Malope-Kgokong, Babatyi; Conradie, Francesca; Majuba, Pappie; Funk, Michele Jonsson; Kaufman, Jay S.; Van Rie, Annelies; MacPhail, Patrick

    2009-01-01

    Background Treatment for tuberculosis (TB) is common among individuals receiving stavudine-containing highly active antiretroviral therapy (HAART), but the effect of TB treatment on stavudine toxicity has received little attention. We estimated the effect of TB treatment on risk of stavudine substitution among individuals receiving first-line HAART. Methods We evaluated a cohort of 7,066 patients who initiated HAART between April 2004 and March 2007 in Johannesburg, South Africa. Three exposure categories were considered: ongoing TB treatment at HAART initiation; concurrent initiation of TB treatment and HAART; incident TB treatment after HAART initiation. The outcome was single-drug stavudine substitution. Adjusted hazard ratios (aHRs) were estimated using marginal structural models to control for confounding, loss to follow-up, and competing risks. Results Individuals with ongoing and concurrent TB treatment were at increased risk of stavudine substitution, irrespective of stavudine dose. For ongoing TB treatment, aHR was 3.18 (95% confidence interval [CI] 1.82-5.56) in the first two months of HAART, 2.51 (95% CI 1.77-3.54) in months 3-6, and 1.19 (95% CI 0.94-1.52) thereafter. For concurrent TB treatment, aHR was 6.60 (95% CI 3.03-14.37) in the first two months,1.88 (95% CI 0.87-4.09) in months 3-6, and 1.07 (95% CI 0.65-1.76) thereafter. There was no effect of incident TB on stavudine substitution risk. Conclusions Risk of stavudine substitution was increased among patients receiving TB treatment, especially soon after HAART initiation. In settings where alternative antiretroviral drugs are available, initiation of stavudine in patients receiving TB treatment may need to be reconsidered. PMID:19385733

  2. 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

  3. 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

  4. Two cases of verified clinical failures using internationally recommended first-line cefixime for gonorrhoea treatment, Norway, 2010.

    PubMed

    Unemo, M; Golparian, D; Syversen, G; Vestrheim, D F; Moi, H

    2010-11-25

    Neisseria gonorrhoeae has developed resistance to most of the available therapeutic antimicrobials. The susceptibility to extended-spectrum cephalosporins, the last remaining first-line treatment option, is decreasing globally. This report describes the first two cases outside Japan of verified gonorrhoea clinical failures using internationally recommended first-line cefixime treatment. Enhanced awareness and more frequent follow-up examination, test-of-cure and appropriate verification/falsification of presumed clinical treatment failures, involving several clinical and laboratory parameters should be strongly emphasised worldwide. PMID:21144442

  5. 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

  6. 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

  7. 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

  8. 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

  9. Failure of First-Line Antibiotics in Nonoperative Management of Appendiceal Mass, toward a Second-Line Instead of Surgery?

    PubMed

    Parmentier, Benoît; Berrebi, Dominique; Peycelon, Matthieu; Doit, Catherine; Ghoneimi, Alaa El; Bonnard, Arnaud

    2016-06-01

    Background Conservative approach for complicated appendicitis has been gradually adopted in children to decrease postoperative morbidity. The first aim of this study was to assess the efficacy of a second-line antibiotics enlarged on Pseudomonas aeruginosa and Enterococcus in case of poor clinical outcome after initial conservative approach for appendiceal mass and abscess. The second aim of this study was to identify predictive factors of failure of first-line antibiotics. Methods We performed a prospective review of all the cases of appendiceal mass or abscess managed at our institution between November 2007 and September 2011 after implementation of a conservative protocol including a second-line antibiotics in case of poor initial clinical outcome. Results A total of 64 consecutive patients were included. We observed a success in 46 patients after the first-line antibiotics and in 14 of the remaining patients after the second-line. The only predictive factor of failure of the first-line antibiotics was a shorter duration of symptoms before admission (p = 0.02). Laparoscopic appendectomy was performed in all the cases (emergency or interval procedure) with six postoperative complications and two conversions to open surgery. Conclusions A gradual adapted antibiotherapy in nonoperative management of appendiceal abscess and mass is effective. We found no relevant predictive factor of failure of the first-line antibiotics. PMID:25988749

  10. Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag–protease genes

    PubMed Central

    Sutherland, Katherine A.; Mbisa, Jean L.; Ghosn, Jade; Chaix, Marie-Laure; Cohen-Codar, Isabelle; Hue, Stephane; Delfraissy, Jean-Francois; Delaugerre, Constance; Gupta, Ravindra K.

    2014-01-01

    Objectives Major protease mutations are rarely observed following first-line failure with PIs and interpretation of genotyping results in this context may be difficult. We performed extensive phenotyping of viruses from five patients failing lopinavir/ritonavir monotherapy in the MONARK study without major PI mutations by standard genotyping. Methods Phenotypic susceptibility testing and viral infectivity assessments were performed using a single-cycle assay and fold changes (FC) relative to a lopinavir-susceptible reference strain were calculated. Results >10-fold reduced baseline susceptibility to lopinavir occurred in two of five patients and >5-fold in another two. Four of five patients exhibited phylogenetic evidence of a limited viral evolution between baseline and failure, with amino acid changes at drug resistance-associated positions in one: T81A emerged in Gag with M36I in the protease gene, correlating with a reduction in lopinavir susceptibility from FC 7 (95% CI 6–8.35) to FC 13 (95% CI 8.11–17.8). Reductions in darunavir susceptibility (>5 FC) occurred in three individuals. Discussion This study suggests both baseline reduced susceptibility and evolution of resistance could be contributing factors to PI failure, despite the absence of classical PI resistance mutations by standard testing methods. Use of phenotyping also reveals lower darunavir susceptibility, warranting further study as this agent is commonly used following lopinavir failure. PMID:25096075

  11. First-line treatment patterns and lipid target levels attainment in very high cardiovascular risk outpatients

    PubMed Central

    2013-01-01

    Objectives Previous studies have demonstrated gaps in achievement of low-density lipoprotein-cholesterol (LDL-C) goals among patients at very high cardiovascular risk. We aimed to investigate lipid treatment patterns, rates and predictors of lipid targets attainment, in such outpatients in an urban area of Greece. Methods This was a prospective observational study, conducted in 19 outpatient clinics of Western Greece. We recruited patients with established cardiovascular disease (CVD) and/or diabetes mellitus (DM), previously (at least 3 months before baseline assessment) untreated with any lipid lowering medication. Lipid profile assessment was performed at baseline (prior to lipid-lowering treatment initiation) and at follow-up. Lipid lowering treatment choice was at physicians’ discretion and was kept constant until follow-up. Results We recruited 712 patients with a mean age 61.4 ± 10.4 years, 68.0% males, 43.0% with DM, 64.7% with prior coronary artery disease-CAD. In total, 237/712 (33.3%) of prescribed regimens were of high or very high LDL-C lowering efficacy and out of them 113/237 (47.7%) comprised a combination of statin and ezetimibe. At follow-up the primary target of LDL-C < 70 mg/dL (1.8 mmol/L) was achieved in 71(10.0%) patients. The secondary target of non-HDL-C < 100 mg/dL (2.6 mmol/L) in the subgroup of patients with DM or increased triglycerides levels (>150 mg/dl or 1.7 mmol/L) was achieved in 45(11.6%) of patients. In multivariate logistic regression analysis (AUC = 0.71, 95% CIs 0.65-0.77, p < 0.001) male gender, smoking, baseline LDL-C and very high potency LDL-C lowering regimen emerged as independent predictors of LDL-C goal attainment (OR = 1.88, 95% CIs 1.03-3.44, p = 0.04, OR = 0.57, 95% CIs 0.33-0.96, p = 0.04, OR = 0.98, 95% CIs 0.98-0.99, p < 0.001 and OR = 2.21, 95% CIs 1.15-4.24, p = 0.02 respectively). Conclusions First-line management of dyslipidemia among very

  12. Survival and Lifetime Costs Associated With First-Line Bevacizumab Use in Older Patients With Metastatic Colorectal Cancer

    PubMed Central

    Mummy, David; Koepl, Lisel; Bansal, Aasthaa; Mirick, Dana K.; Yu, Elaine; Morlock, Rob; Ogale, Sarika; Ramsey, Scott D.

    2014-01-01

    Introduction. The objective of this study was to investigate clinical effectiveness and incremental lifetime costs associated with first-line bevacizumab in older patients with metastatic colorectal cancer (mCRC). Methods. Patients diagnosed with mCRC in 2004–2007 were identified from the Surveillance, Epidemiology, and End Results-Medicare database and stratified by first-line treatment (no chemotherapy [CTx], CTx alone, CTx plus bevacizumab). The impact of first-line bevacizumab on survival was investigated using a propensity score adjusted multivariate Cox proportional hazards model. Mean lifetime costs for each cohort were calculated using Medicare claims for all services rendered between diagnosis and end of follow-up, adjusting for death and censoring. Results. A total of 4,414 patients (mean age: 77.3 years) were identified, of whom 15% received first-line bevacizumab. Among first-line-treated patients, bevacizumab receipt was associated with improved overall survival (hazard ratio: 0.85 [95% confidence interval: 0.75–0.97]; p = .013), and this benefit was limited to patients who received >1 month of bevacizumab therapy. Median and mean survival were greatest in patients treated with CTx plus bevacizumab relative to CTx alone (CTx plus bevacizumab median 19.4 months [mean 28.0 months] vs. CTx alone median 15.1 months [mean 22.9 months]; p < .001), as were mean lifetime costs (mean per patient cost $143,284 vs. $111,280). Compared with CTx alone, CTx plus bevacizumab was associated with a 5.1-month increase in mean survival and a $32,004 increase in mean lifetime treatment costs, with an incremental cost of $75,303 per life-year gained. Conclusion. Bevacizumab use is associated with longer survival than CTx alone in older patients treated in real-world clinical settings, at an incremental cost of $75,303 per life-year gained. PMID:25085899

  13. Oxaliplatin-based first-line chemotherapy is associated with improved overall survival compared to first-line treatment with irinotecan-based chemotherapy in patients with metastatic colorectal cancer – Results from a prospective cohort study

    PubMed Central

    Marschner, Norbert; Arnold, Dirk; Engel, Erik; Hutzschenreuter, Ulrich; Rauh, Jacqueline; Freier, Werner; Hartmann, Holger; Frank, Melanie; Jänicke, Martina

    2015-01-01

    Purpose Several randomized trials investigating the preferable first-line combination chemotherapy regimen for metastatic colorectal cancer have shown inconsistent findings. Because a substantial number of patients are still being treated with “chemo-only” first-line therapies without targeted agents, we compared overall survival (OS) of patients treated in routine practice with oxaliplatin–fluoropyrimidine and irinotecan–fluoropyrimidine. Patients and methods Using the database of the Tumor Registry Colorectal Cancer, we identified 605 patients with metastatic colorectal cancer who received first-line fluoropyrimidine combination chemotherapy with either oxaliplatin (n=430) or irinotecan (n=175). The Tumor Registry Colorectal Cancer is a cohort study that prospectively documents treatment of colorectal cancer by office-based medical oncologists in Germany and has recruited over 5,000 patients. OS was estimated using the Kaplan–Meier method, and a multivariate Cox proportional hazard model was used to adjust for potentially confounding variables. Results Median OS was 26.8 (95% confidence interval [CI] 22.4–31.9) months with an oxaliplatin–fluoropyrimidine combination and 18.3 (95% CI 15.1–23.2) months with irinotecan–fluoropyrimidine first-line “chemo-only” therapy. Median progression-free survival was 9.0 (8.1–10.2) and 7.9 (7.2–10.2) months, respectively. The difference in OS was confirmed if analysis was restricted to patients with synchronous metastases (no prior treatment). Among other variables, proportion of patients receiving any second-line therapy did not differ between groups. Oxaliplatin-based first-line therapy was associated with improved OS in multivariate analysis adjusted for potentially confounding variables (hazard ratio 0.678, 95% CI 0.510–0.901, P=0.007). Conclusion In clinical routine practice, first-line treatment with oxaliplatin–fluoropyrimidine combination chemotherapy compared to irinotecan

  14. JC virus Reactivation During Prolonged Natalizumab Monotherapy for Multiple Sclerosis

    PubMed Central

    Chalkias, Spyridon; Dang, Xin; Bord, Evelyn; Stein, Marion C.; Kinkel, R. Philip; Sloane, Jacob A.; Donnelly, Maureen; Ionete, Carolina; Houtchens, Maria K.; Buckle, Guy J.; Batson, Stephanie; Koralnik, Igor J.

    2015-01-01

    Objective To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS). Methods We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy>18 months, 6 on interferon β-1a monotherapy>36 months and 5 untreated controls. We performed QPCR in cerebrospinal fluid (CSF), blood and urine for JCV DNA and we determined JCV-specific T cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides. Results JCV DNA was detected in the CSF of 2/27 (7.4%) natalizumab-treated MS patients who had no symptoms or MRI lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12/43 (27.9%) and in urine of 11/43 (25.6%) subjects without difference between natalizumab-treated patients and controls. JC viral load was higher in CD34+ cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot, and JCV-specific T cell responses, mediated by both CD4+ and CD8+ T-lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4+ T-cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34+ (p=0.05) and B cells (p=0.03). Interpretation Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34+ cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4+ T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment. PMID:24687904

  15. [A case of nephrotic syndrome achieving remission with cyclosporine monotherapy].

    PubMed

    Nagatoya, Katsuyuki

    2010-01-01

    The case was a female in her early 80's. Due to abdominal bloating and lower limb edema, she visited a nearby doctor, was diagnosed to have nephrotic syndrome, and then was referred to our department. Upon initial consultation, TP of 4.1 g/dl, Alb of 1.7 g/dl, UN of 73 mg/dl, and Cr of 1.43 mg/dl, along with pleural effusion were observed by chest X-ray. A renal biopsy was not performed because permission could not be obtained. Despite the fact that management of the edema was performed using diuretic agents and albumin preparations, a reduced renal function and deterioration of the fluid retention were gradually observed. She originally displayed lower back pain and digestive symptoms and, therefore, cyclosporine monotherapy was initiated in order to address concerns of side effects such as osteoporosis and peptic ulcer due to adrenocortical steroid drugs (hereinafter abbreviated as steroid). Subsequently, hemodialysis was temporarily required but reduced urine protein and an improved renal function were gradually observed and she eventually achieved a complete remission. The possibility of a spontaneous remission of membranous nephropathy, etc. was considered, but a relapse occurred when the amount of cyclosporine was reduced. Thereafter, a complete remission was obtained with an increased dosage. As a result, the effectiveness of cyclosporine was thus confirmed. In treating nephrotic syndrome, steroid therapy is commonly performed and it is common for cyclosporine to be limited to steroid-resistant cases and/or steroid-dependent cases. However, it is believed that monotherapy could also be an option in cases in which the use of steroids is difficult, such as in cases of elderly patients. PMID:21116092

  16. 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

  17. 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. PMID:27277747

  18. Efficacy of Adding Bevacizumab in the First-Line Chemotherapy of Metastatic Colorectal Cancer: Evidence from Seven Randomized Clinical Trials

    PubMed Central

    Chen, Yan-xian; Yang, Qiong; Kuang, Jun-jie; Chen, Shi-yu; Wei, Ying; Jiang, Zhi-min; Xie, De-rong

    2014-01-01

    Background. Efficacy of adding bevacizumab in first-line chemotherapy of metastatic colorectal cancer (mCRC) has been controversial. The aim of this study is to gather current data to analyze efficacy of adding bevacizumab to the most used combination first-line chemotherapy in mCRC, based on the 2012 meta-analysis reported by Macedo et al.  Methods. Medline, EMBASE and Cochrane library, meeting presentations and abstracts were searched. Eligible studies were randomized controlled trials (RCTs) which evaluated first-line chemotherapy with or without bevacizumab in mCRC. The extracting data were included and examined in the meta-analysis according to the type of chemotherapy regimen. Results. Seven trials, totaling 3436 patients, were analyzed. Compared with first-line chemothery alone, the adding of bevacizumab did not show clinical benefit for OS both in first-line therapy and the most used combination chemotherapy (HR = 0.89; 95% CI = 0.78–1.02; P = 0.08; HR = 0.93; 95% CI = 0.83–1.05; P = 0.24). In contrast with OS, the addition of bevacizumab resulted in significant improvement for PFS (HR = 0.68; 95% CI = 0.59–0.78; P < 0.00001). Moreover, it also demonstrated statistical benefit for PFS in the most used combination first-line chemotherapy (HR = 0.84; 95% CI = 0.75–0.94; P = 0.002). And the subgroup analysis indicated only capacitabine-based regimens were beneficial. Conclusions. This meta-analysis shows that the addition of bevacizumab to FOLFOX/FOLFIRI/XELOX regimens might not be beneficial in terms of OS. Benefit has been seen when PFS has been taken into account. In subgroup analysis, benefit adding bevacizumab has been seen when capecitabine-based regimens are used. Further studies are warranted to explore the combination with bevacizumab. PMID:24971091

  19. 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

  20. Partial Response to First-Line Crizotinib in an Elderly Male Patient with ROS1 Translocation-Positive Lung Cancer

    PubMed Central

    Overbeck, Tobias R.; Schmitz, Katja; Engelke, Christoph; Sahlmann, Carsten-Oliver; Hugo, Sara; Kellner, Laura; Trümper, Lorenz; Schildhaus, Hans-Ulrich

    2016-01-01

    We report on a 90-year-old male patient with a ROS1-translocated adenocarcinoma of the lung who was treated with crizotinib as first-line therapy. After 11 months of treatment, we noticed complete metabolic response as measured by 18F-FDG-PET/CT scan and a partial response according to RECIST criteria. This patient indicates that ROS1 translocations are not restricted to young age, female gender and low stage. Furthermore, this case illustrates exemplarily that crizotinib therapy is effective and manageable even as first-line treatment in elderly patients with comorbidities. Based on our findings, we recommend to include elderly patients with advanced pulmonary adenocarcinomas in molecular screening approaches for ROS1 translocations. PMID:27065847

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

    PubMed Central

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

    2015-01-01

    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. PMID:25694669

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

    PubMed

    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

  3. Percutaneous CT-guided microwave ablation as maintenance after first-line treatment for patients with advanced NSCLC

    PubMed Central

    Ni, Xiang; Han, Jun-Qing; Ye, Xin; Wei, Zhi-Gang

    2015-01-01

    Background Systemic therapy is recommended for advanced non-small-cell lung cancer (NSCLC). However, conventional first-line treatment has generated a plateau in response rate of 25% to 35%. Few studies have shown patients benefit from microwave ablation (MWA) in combination with radiotherapy and chemotherapy. This study aims to evaluate safety and efficacy of percutaneous computed tomography-guided MWA as maintenance after first-line treatment for patients with advanced NSCLC. Methods Patients with histologically verified NSCLC stage IIIB or IV between January 2010 and March 2014 were involved. After completion of first-line treatment with partial response or stable disease, 35 patients with 39 tumors underwent 39 MWA procedures. Complications, progression-free survival (PFS), overall survival (OS), and correlated predictors were analyzed. Results During a median follow-up of 17.7 months and 10.8 months after initial MWA, local efficacy was 87.2%, median MWA-related local control time was 10.6 months, and tumor size was the only predictor (P=0.002). Median MWA-related PFS, MWA-related OS, PFS, and OS were 5.4, 10.6, 11.8 and 17.7 months, respectively. Local efficacy was significantly correlated with MWA-related PFS (P=0.003), MWA-related OS (P=0.000), and OS (P=0.001). There were no procedure-specific deaths. Total incidence of major complications was 12.8%, including pneumothorax resolved by closed pleural drainage and pneumonia controlled by antibiotics in a short time. Conclusion This study concluded two points, including: 1) patients benefited from MWA as maintenance both in local control and survival; 2) as maintenance MWA was superior to conventional maintenance therapy with improved survival and well-tolerated complications. Therefore, MWA was a safe and effective maintenance after first-line treatment in patients with advanced NSCLC. PMID:26604789

  4. 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

  5. Global Comparison of Drug Resistance Mutations After First-Line Antiretroviral Therapy Across Human Immunodeficiency Virus-1 Subtypes

    PubMed Central

    Huang, Austin; Hogan, Joseph W.; Luo, Xi; DeLong, Allison; Saravanan, Shanmugam; Wu, Yasong; Sirivichayakul, Sunee; Kumarasamy, Nagalingeswaran; Zhang, Fujie; Phanuphak, Praphan; Diero, Lameck; Buziba, Nathan; Istrail, Sorin; Katzenstein, David A.; Kantor, Rami

    2016-01-01

    Background. Human immunodeficiency virus (HIV)-1 drug resistance mutations (DRMs) often accompany treatment failure. Although subtype differences are widely studied, DRM comparisons between subtypes either focus on specific geographic regions or include populations with heterogeneous treatments. Methods. We characterized DRM patterns following first-line failure and their impact on future treatment in a global, multi-subtype reverse-transcriptase sequence dataset. We developed a hierarchical modeling approach to address the high-dimensional challenge of modeling and comparing frequencies of multiple DRMs in varying first-line regimens, durations, and subtypes. Drug resistance mutation co-occurrence was characterized using a novel application of a statistical network model. Results. In 1425 sequences, 202 subtype B, 696 C, 44 G, 351 circulating recombinant forms (CRF)01_AE, 58 CRF02_AG, and 74 from other subtypes mutation frequencies were higher in subtypes C and CRF01_AE compared with B overall. Mutation frequency increased by 9%–20% at reverse transcriptase positions 41, 67, 70, 184, 215, and 219 in subtype C and CRF01_AE vs B. Subtype C and CRF01_AE exhibited higher predicted cross-resistance (+12%–18%) to future therapy options compared with subtype B. Topologies of subtype mutation networks were mostly similar. Conclusions. We find clear differences in DRM outcomes following first-line failure, suggesting subtype-specific ecological or biological factors that determine DRM patterns. PMID:27419147

  6. 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.

  7. 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

  8. Intravitreal bevacizumab monotherapy for choroidal neovascularisation secondary to choroidal osteoma.

    PubMed

    Papastefanou, V P; Pefkianaki, M; Al Harby, L; Arora, A K; Cohen, V M L; Andrews, R M; Sagoo, M S

    2016-06-01

    PurposeThe purpose of this study is to present the outcomes of a series of patients with choroidal neovascular membrane (choroidal neovascularisation (CNV)) secondary to a choroidal osteoma undergoing anti-VEGF monotherapy.Patients and methodsRetrospective series of patients with choroidal neovascularization secondary to choroidal osteoma. All patients underwent clinical and imaging assessment (fundus photo, B-scan ultrasonography, fluorescein angiography, and optical coherence tomography-where available), and were managed with intravitreal anti-VEGF injections (Bevacizumab). Visual acuity and central retinal thickness were recorded pre treatment and at the end of the follow-up period.ResultsEight patients were included in this study. Of this, 6/8 had predominantly classic or classic and 2/8 patients had minimally classic or occult CNV. Each patient received 3-10 injections of bevacizumab. Median follow-up was 9 months (3-15 months). Visual acuity improved in 5 patients, by 2-6 Snellen lines. CNV completely regressed in 5 cases and partially regressed in 3 cases. Mean CRT reduction was 122 μm (6 to -230 μm).ConclusionIntravitreal bevacizumab can be an effective treatment modality in the management of vision threatening CNV secondary to choroidal osteoma. PMID:27034203

  9. 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

  10. 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

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

    PubMed Central

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

    2016-01-01

    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. PMID:27063994

  12. 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. PMID:26945366

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

    PubMed Central

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

    2016-01-01

    Abstract 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. PMID:26945366

  14. 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. PMID:24035791

  15. Radiofrequency ablation following first-line transarterial chemoembolization for patients with unresectable hepatocellular carcinoma beyond the Milan criteria

    PubMed Central

    2014-01-01

    Background Recent studies suggest that a combination of radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) may have theoretical advantages over TACE alone for treatment of hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the effectiveness and safety of radiofrequency ablation following first-line TACE treatment in the management of HCC beyond the Milan Criteria. Methods Forty-five patients who consecutively underwent RFA following first-line TACE treatment for HCC beyond the Milan criteria were enrolled in this study. RFA was performed within 1–2 months after TACE treatment in patients who had incomplete necrotic tumor nodules. Primary effectiveness, complications, survival rates, and prognostic factors were evaluated retrospectively. Results Complete ablation was achieved in 76.2% of the lesions according to 1-month follow-up computed tomography/magnetic resonance imaging evaluation. The mean follow-up period was 30.9 months (range 3–94 months). There were no major complications after RFA therapy. The median overall survival was 29 months (range 20–38 months), with 1-, 2-, and 3-year survival of 89%, 61%, and 43%, respectively. Multivariate analysis revealed that tumor diameter (P = 0.045, hazard ratio [HR] = 0.228, 95% confidence interval [CI]: 0.054-0.968) and pretreatment serum alpha-fetoprotein level (P = 0.024, HR = 2.239, 95% CI: 1.114-4.500) were independent predictors for long-term survival. Conclusions HCC beyond the Milan criteria can be completely and safely ablated by radiofrequency ablation following first-line TACE treatment with a low rate of complications and favorable survival outcome. Further assessment of the survival benefits of combination treatment for HCCs beyond the Milan Criteria is warranted. PMID:24410841

  16. 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

  17. Improving first-line mental health services in Canada: addressing two challenges caused by the deinstitutionalization movement.

    PubMed

    Spagnolo, Jessica

    2014-01-01

    The deinstitutionalization movement in Canada began in the 1960s. It is defined as the process of discharging chronic mental health patients into the community in order for them to receive care from community mental health services. The deinstitutionalization movement is failing in Canada at this time for two main reasons: (1) the provinces' community mental health programs lack integration; and (2) the negative stigma attached to mental illness is still present in the community. This article will discuss ways to ensure the integration of first-line mental health services and the elimination of stigma through organizational and systemic changes in Canada. PMID:25906464

  18. [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. PMID:26471795

  19. Disability may influence patient willingness to participate in decision making on first-line therapy in multiple sclerosis.

    PubMed

    D'Amico, E; Leone, C; Patti, F

    2016-01-01

    Patient autonomy is a concept that implies variable degrees of patient participation in different aspects of health and healthcare, including the choice of therapy. This study, conducted in patients with multiple sclerosis (MS), examined several factors in relation to the patient's role in the therapeutic decision-making process. One hundred newly diagnosed patients with MS attending their first ever specialist consultation at the MS center of Catania, Italy, were consecutively enrolled in a single-center, open, observational study. Clinical and demographic data were collected as part of this routine first consultation. Through administration of the Control Preferences Scale, we ascertained the patients' willingness to participate in the decision-making process on their first-line treatment, classifying them, on the basis of their attitude, as passive, collaborative or active. Of 100 patients with MS, 40 had a passive attitude, while 35 were willing to collaborate and 25 wanted to play an active role in the decision-making process. The patients showing an active attitude had a significantly higher Expanded Disability Status Scale score and a significantly higher number of relapses (p<0.5 for both) than those who showed other attitudes. Persons with MS prefer to know the benefits and risks related to the first-line treatment. Those with higher disability prefer to be active in the decision-making process. PMID:27027890

  20. Sequential Therapy versus Triple Therapy for the First Line Treatment of Helicobacter pylori in Korea: A Nationwide Randomized Trial

    PubMed Central

    Kim, Joon Sung; Kim, Byung-Wook; Hong, Su Jin; Kim, Jin Il; Shim, Ki-Nam; Kim, Jie-Hyun; Baik, Gwang Ho; Kim, Sang Wook; Song, Hyun Joo; Kim, Ji Hyun

    2016-01-01

    Background/Aims Eradication of Helicobacter pylori infection with standard triple therapy (TT) has declined primarily because of increased antibiotic resistance. Sequential therapy (ST) has been suggested as an alternative to TT for the first-line treatment of H. pylori. The purpose of this study was to compare the efficacy of ST with TT. Methods This was a multicenter, randomized open-label trial performed at nine centers in Korea. Patients with H. pylori infection were randomly assigned to receive either 7 day TT or 10 day ST. Eradication rates, drug compliance, and adverse events were compared among the two regimens. Results A total of 601 patients were enrolled between March 2011 and September 2014. The intention-to-treat eradication rates were 70.8% for TT and 82.4% for ST (p=0.001). The corresponding per protocol eradication rates were 76.9% and 88.8% for TT and ST, respectively (p=0.000). There were no statistically significant differences between the two regimens with respect to drug compliance and adverse events. Conclusions ST achieved better eradication rates than TT as a first-line therapy for H. pylori eradication in Korea. PMID:27114421

  1. Disability may influence patient willingness to participate in decision making on first-line therapy in multiple sclerosis

    PubMed Central

    D’Amico, Emanuele; Leone, Carmela; Patti, Francesco

    2016-01-01

    Summary Patient autonomy is a concept that implies variable degrees of patient participation in different aspects of health and healthcare, including the choice of therapy. This study, conducted in patients with multiple sclerosis (MS), examined several factors in relation to the patient’s role in the therapeutic decision-making process. One hundred newly diagnosed patients with MS attending their first ever specialist consultation at the MS center of Catania, Italy, were consecutively enrolled in a single-center, open, observational study. Clinical and demographic data were collected as part of this routine first consultation. Through administration of the Control Preferences Scale, we ascertained the patients’ willingness to participate in the decision-making process on their first-line treatment, classifying them, on the basis of their attitude, as passive, collaborative or active. Of 100 patients with MS, 40 had a passive attitude, while 35 were willing to collaborate and 25 wanted to play an active role in the decision-making process. The patients showing an active attitude had a significantly higher Expanded Disability Status Scale score and a significantly higher number of relapses (p<0.5 for both) than those who showed other attitudes. Persons with MS prefer to know the benefits and risks related to the first-line treatment. Those with higher disability prefer to be active in the decision-making process. PMID:27027890

  2. Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial

    PubMed Central

    Windbichler, G H; Hausmaninger, H; Stummvoll, W; Graf, A H; Kainz, C; Lahodny, J; Denison, U; Müller-Holzner, E; Marth, C

    2000-01-01

    Intraperitoneal treatment with interferon-γ (IFN-γ) has been shown to achieve surgically documented responses in the second-line therapy of ovarian cancer. To assess its efficacy in the first-line therapy, we conducted a randomized controlled trial with 148 patients who had undergone primary surgery for FIGO stage Ic–IIIc ovarian cancer. In the control arm women received 100 mg m−2cisplatin and 600 mg m−2cyclophosphamide, the experimental arm included the above regimen with IFN-γ 0.1 mg subcutaneously on days 1, 3, 5, 15, 17 and 19 of each 28-day cycle. Progression-free survival at 3 years was improved from 38% in controls to 51% in the treatment group corresponding to median times to progression of 17 and 48 months (P = 0.031, relative risk of progression 0.48, confidence interval 0.28–0.82). Three-year overall survival was 58% and 74% accordingly (n.s., median not yet reached). Complete clinical responses were observed in 68% with IFN-γ versus 56% in controls (n.s.). Toxicity was comparable in both groups except for a mild flu-like syndrome, experienced by most patients after administration of IFN-γ. Thus, with acceptable toxicity, the inclusion of IFN-γ in the first-line chemotherapy of ovarian cancer yielded a benefit in prolonging progression-free survival. © 2000 Cancer Research Campaign PMID:10735496

  3. Docetaxel/S-1 Versus Docetaxel/Capecitabine as First-Line Treatment for Advanced Breast Cancer: A Retrospective Study.

    PubMed

    Li, Jinyu; You, Junhao; Si, Wen; Zhu, Yanyun; Chen, Yi; Yang, Bo; Han, Chun; Linghu, Ruixia; Zhang, Xingyang; Jiao, Shunchang; Yang, Junlan

    2015-10-01

    The treatment efficacy of advanced breast cancer is still not promising. This study aimed to compare the efficacy and safety of docetaxel/S-1 (DS1) versus docetaxel/capecitabine (DX) as the first-line treatment for advanced breast cancer.From June 2008 to June 2013, 22 patients with advanced breast cancer were treated with the DS1 regimen. Another 26 age- and disease status-matched patients treated with the DX regimen served as controls. The 2 groups were compared in terms of time to progression (TTP), objective response rate, disease control rate, clinical benefit rate, and safety profiles.Median TTP did not differ significantly between the DS1 group and the DX group (9.04 vs 10.94 months, P = 0.473). There were no significant differences in objective response rate, disease control rate, and clinical benefit rate between the 2 groups. Both the DS1 and the DX regimens showed good tolerability. The 2 regimens showed no significant difference in adverse events except degree III hand-foot syndrome (DS1 0 vs DX 23.1%, P = 0.025).For the first-line treatment of advanced breast cancer, the DS1 and the DX regimens showed similar efficacy and safety. The DS1 regimen had less severe hand-foot syndrome than the DX regimen. PMID:26469889

  4. 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

  5. The neurological assessment in young children treated with artesunate monotherapy or artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria

    PubMed Central

    Ambler, Michael T; Dubowitz, Lilly M; Arunjerdja, Ratree; Hla, Eh Paw; Thwai, Kyaw Lay; Viladpainguen, Jacher; Singhasivanon, Pratap; Luxemburger, Christine; Nosten, François; McGready, Rose

    2009-01-01

    Background Mefloquine and artesunate combination therapy is the recommended first-line treatment for uncomplicated malaria throughout much of south-east Asia. Concerns have been raised about the potential central nervous system (CNS) effects of both drug components and there are no detailed reports in very young children. Methods Children, aged between three months and five years, with acute uncomplicated Plasmodium falciparum malaria were randomized to either 7 days of artesunate monotherapy or the same schedule of artesunate plus mefloquine on day 7 and 8. Neurological testing targeting coordination and behaviour was carried out at day 0, 7, 9, 10, 14 and 28. Non-febrile healthy control children from the same population were tested on days 0, 7, 14 and 28. Results From December 1994 to July 1997, 91 children with uncomplicated P. falciparum, 45 treated with artesunate monotherapy, 46 treated with mefloquine and artesunate combination therapy and 36 non-febrile controls, underwent neurological testing. Malaria and fever had a significant negative impact on testing performance. By contrast, the anti-malarial treatments were not associated with worsening performances in the various components of the test. Artesunate and mefloquine do not appear to have a significant influence on coordination and behaviour. Children treated with mefloquine were significantly less likely to suffer recurrent malaria infection during follow-up compared to those treated with artesunate alone (P = 0.033). Conclusion In keeping with the results of randomized controlled trials in adults, mefloquine was not associated with a decrease in specific items of neurological performance. Likewise, children treated with artesunate did not perform significantly differently to control children. This study does not exclude subtle or rare treatment CNS effects of artesunate or mefloquine. Treatment of acute uncomplicated malaria results in a significant improvement on items of neurological performance

  6. 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. ...

  7. 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

  8. Economic evaluation of first-line and maintenance treatments for advanced non-small cell lung cancer: a systematic review

    PubMed Central

    Chouaïd, Christos; Crequit, Perinne; Borget, Isabelle; Vergnenegre, Alain

    2015-01-01

    During these last years, there have been an increased number of new drugs for non-small cell lung cancer (NSCLC), with a growing financial effect on patients and society. The purpose of this article was to review the economics of first-line and maintenance NSCLC treatments. We reviewed economic analyses of NSCLC therapies published between 2004 and 2014. In first-line settings, in unselected patients with advanced NSCLC, the cisplatin gemcitabine doublet appears to be cost-saving compared with other platinum doublets. In patients with nonsquamous NSCLC, the incremental cost-effectiveness ratios (ICERs) per life-year gained (LYG) were $83,537, $178,613, and more than $300,000 for cisplatin-pemetrexed compared with, respectively, cisplatin-gemcitabine, cisplatin-carboplatin-paclitaxel, and carboplatin-paclitaxel-bevacizumab. For all primary chemotherapy agents, use of carboplatin is associated with slightly higher costs than cisplatin. In all the analysis, bevacizumab had an ICER greater than $150,000 per quality-adjusted life-year (QALY). In epidermal growth factor receptor mutated advanced NSCLC, compared with carboplatin-paclitaxel doublet, targeted therapy based on testing available tissue yielded an ICER of $110,644 per QALY, and the rebiopsy strategy yielded an ICER of $122,219 per QALY. Compared with the triplet carboplatin-paclitaxel-bevacizumab, testing and rebiopsy strategies had ICERs of $25,547 and $44,036 per QALY, respectively. In an indirect comparison, ICERs per LYG and QALY of erlotinib versus gefitinib were $39,431 and $62,419, respectively. In anaplastic lymphoma kinase-positive nonsquamous advanced NSCLC, the ICER of first-line crizotinib compared with that of chemotherapy was $255,970 per QALY. For maintenance therapy, gefitinib had an ICER of $19,214 per QALY, erlotinib had an ICER of $127,343 per LYG, and pemetrexed had an ICER varying between $183,589 and $205,597 per LYG. Most recent NSCLC strategies are based on apparently no cost

  9. 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

  10. Brief Report: Virologic Monitoring Can Be a Cost-Effective Strategy to Diagnose Treatment Failure on First-Line ART

    PubMed Central

    Boulware, David R.; Tanser, Frank C.; Bärnighausen, Till W.; Stott, Katharine E.; de Oliveira, Tulio

    2016-01-01

    Abstract: 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. PMID:26484740

  11. Antiretroviral Resistance After First-Line Antiretroviral Therapy Failure in Diverse HIV-1 Subtypes in the SECOND-LINE Study.

    PubMed

    Lam, Edward P; Moore, Cecilia L; Gotuzzo, Eduardo; Nwizu, Chidi; Kamarulzaman, Adeeba; Chetchotisakd, Ploenchan; van Wyk, Jean; Teppler, Hedy; Kumarasamy, Nagalingeswaran; Molina, Jean-Michel; Emery, Sean; Cooper, David A; Boyd, Mark A

    2016-09-01

    We investigate mutations and correlates according to HIV-1 subtype after virological failure (VF) of standard first-line antiretroviral therapy (ART) (non-nucleoside/nucleotide reverse transcriptase inhibitor [NNRTI] +2 nucleoside/nucleotide reverse transcriptase inhibitor [N(t)RTI]). SECOND-LINE study participants were assessed at baseline for HIV-1 subtype, demographics, HIV-1 history, ART exposure, viral load (VL), CD4(+) count, and genotypic ART resistance. We used backward stepwise multivariate regression (MVR) to assess associations between baseline variables and presence of ≥3 N(t)RTI mutations, ≥1 NNRTI mutation, ≥3 thymidine analog-N(t)RTI [ta-N(t)RTI] mutations (TAMs), the K65/K70 mutation, and predicted etravirine (ETV)/rilpivirine (RPV) activity. The inclusion p-value for MVR was p < .2. The exclusion p-value from stepwise elimination was p > .05. Of 541 participants, 491 (91%) had successfully characterized baseline viral isolates. Subtype distribution: B (n = 123, 25%), C (n = 202, 41%), CRF01_AE (n = 109, 22%), G (n = 25, 5%), and CRF02_AG (n = 27, 5%). Baseline CD4(+) 200-394 cells/mm(3) were associated with <3 N(t)RTI mutations (OR = 0.47; 95% CI 0.29-0.77; p = .003), absence of the K65/K70 mutation (OR = 0.43; 95% CI 0.26-0.73; p = .002), and higher ETV sensitivity (OR = 0.52; 95% CI 0.35-0.78; p = .002). Recent tenofovir (TDF) use was associated with K65/K70 mutations (OR = 8.91; 95% CI 5.00-15.85; p < .001). Subtype CRF01_AE was associated with ≥3 N(t)RTI mutations (OR = 2.34; 95% CI 1.31-4.17; p = .004) and higher RPV resistance (OR = 2.13; 95% CI 1.30-3.49; p = .003), and subtype C was associated with <3 TAMs (OR = 0.45; 95% CI 0.21-0.99; p = .015). Subtypes CRF01_AE (OR = 2.46; 95% CI 1.26-4.78; p = .008) and G (OR = 4.77; 95% CI 1.44-15.76; p = .01) were associated with K65/K70 mutations. Higher VL at confirmed first-line VF was

  12. Moving molecularly directed therapies to the first-line in ALK-positive lung cancer: crizotinib is just the beginning.

    PubMed

    Klempner, Samuel J; Raufi, Alexander; Ou, Sai-Hong Ignatius

    2015-10-01

    The increasing appreciation of oncogenic driver alterations in non-small cell lung cancer (NSCLC) has resulted in a rapid expansion of therapeutic compounds. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) alterations are the prototypical examples and have driven the paradigm shift in NSCLC management. Early phase studies in previously treated ALK+ patients demonstrated activity and recently Solomon et al. confirmed the superiority of crizotinib over chemotherapy in first line treatment. The phase III PROFILE 1014 represents the culmination of the rapid development of crizotinib and provides lessons for future generation ALK inhibitors and other molecularly directed therapies in NSCLC. Important considerations for second and third generation inhibitors include the ability to overcome known resistance mechanisms, CNS activity, improvement in side effect profile, and safety in possible combination strategies. PMID:26629439

  13. A marvel of mucosal T cells and secretory antibodies for the creation of first lines of defense.

    PubMed

    Kunisawa, J; Kiyono, H

    2005-06-01

    The mucosal immune system acts as a first line of defense against bacterial and viral infections while also playing a crucial role in the establishment and maintenance of mucosal homeostasis between the host and the outside environment. In addition to epithelial cells and antigen-presenting cells (dendritic cells and macrophages), B and T lymphocytes form a dynamic mucosal network for the induction and regulation of secretory IgA (S-IgA) and cytotoxic T lymphocyte (CTL) responses. This review seeks to shed light on the pathways of induction and regulation of these responses and to elucidate the role they simultaneously play in fending off pathogen invasion and maintaining mucosal homeostasis. PMID:15971106

  14. 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

  15. Risk factors for and outcomes of patients with POEMS syndrome who experience progression after first-line treatment.

    PubMed

    Kourelis, T V; Buadi, F K; Gertz, M A; Lacy, M Q; Kumar, S K; Kapoor, P; Go, R S; Lust, J A; Hayman, S R; Rajkumar, V; Zeldenrust, S R; Russell, S J; Dingli, D; Lin, Y; Leung, N; Hwa, Y L; Gonsalves, W; Kyle, R A; Dispenzieri, A

    2016-05-01

    Although clinical improvement is almost universal with therapy in patients with POEMS (an acronym for polyneuropathy, organomegaly, endocrinopathies, monoclonal protein and a variety of skin changes) syndrome, outcomes and management of patients who relapse or progress (R/P) after first-line treatment have not been described. We retrospectively identified 262 patients with POEMS syndrome treated at the Mayo Clinic from 1974 to 2014 and who had follow-up information. The 5-year progression-free survival (PFS) and overall survival (OS) was 58% and 78%, respectively. Median time to R/P was 42 months. Seventy-nine patients (30%) had an R/P, with 52 (19%) experiencing a symptomatic R/P. Eighteen patients relapsed with symptoms or signs that were not documented at diagnosis. Median times to vascular endothelial growth factor, hematologic, radiographic and clinical R/P were 35 months (range, 4-327 months), 72 months (range, 4-327 months), 51 months (range, 4-327 months) and 48 months (range, 6-311 months), respectively. On multivariate analyses, low albumin at diagnosis and failure to achieve a complete hematologic response to first-line therapy were independent risk factors for PFS. Thirty patients had documentation of a second R/P at a median of 26 months from diagnosis of the first R/P. An early R/P was a risk factor for death, but most patients with an R/P had salvageable disease. A majority of patients are still without R/P at 5 years from diagnosis. PMID:26669974

  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. 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. PMID:25762770

  18. Tailored Selection of First-Line Cisplatin-Based Chemotherapy in Patients with Metastatic Urothelial Carcinoma of Bladder

    PubMed Central

    Hsieh, Meng-Che; Huang, Cheng-Hua; Chiang, Po-Hui; Chen, Yen-Yang; Tang, Yeh; Su, Yu-Li

    2016-01-01

    Purpose: Methotrexate, vinblastine, doxorubicin plus cisplatin (MVAC) and gemcitabine plus cisplatin (GC) are both effective first-line chemotherapy. We explore the responsive variables of MVAC and GC for patients with metastatic urothelial carcinoma of bladder (mUCB). Materials and Methods: Patients who were initially diagnosed to have mUCB and received MVAC or GC as metastatic first-line chemotherapy between 2000 and 2014 at Kaohsiung Chang Gung Memorial Hospital were reviewed. Totally, 130 patients were enrolled into our study. Univariable Cox proportional hazard models were constructed for OS. Hazard ratio (HR) and 95% confidence intervals (CIs) was also presented. Results: There were 50 patients (38%) in the MVAC group and 80 patients (62%) in the GC group. The median OS was insignificantly different between MVAC and GC groups, accounting for 17.0 and 14.4 months (P = 0.214), respectively. OS of MVAC group was significantly longer with regard to age ≦ 60 years (HR: 0.38, 95% CI: 0.12-0.97, P = 0.036), pure urothelial carcinoma (HR: 0.56, 95% CI: 0.34-0.90, P = 0.015), > 1 metastatic sites (HR: 0.19, 95% CI: 0.08-0.44, P = < 0.001), and neutrophil to lymphocyte ratio > 3(HR: 0.45, 95% CI: 0.25-0.81, P = 0.006), while OS with GC group was significantly longer with regard to variant urothelial carcinoma (HR: 0.56, 95% CI: 0.34-0.90, P = 0.015). Conclusions: Our study disclosed the predictive factors of different regimen for mUCB. These results have clinical implication for physicians who treat patients with mUCB. PMID:27390610

  19. 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. PMID:26833163

  20. Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy.

    PubMed

    Paré, L; Marcuello, E; Altés, A; del Río, E; Sedano, L; Salazar, J; Cortés, A; Barnadas, A; Baiget, M

    2008-10-01

    To determine whether molecular parameters could be partly responsible for resistance or sensitivity to oxaliplatin (OX)-based chemotherapy used as first-line treatment in advanced colorectal cancer (CRC). We studied the usefulness of the excision repair cross-complementing 1 (ERCC1), xeroderma pigmentosum group D (XPD), XRCC1 and GSTP1 polymorphisms as predictors of clinical outcome in these patients. We treated 126 CRC patients with a first-line OX/5-fluorouracil chemotherapeutic regimen. Genetic polymorphisms were determined by real-time PCR on an ABI PRISM 7000, using DNA from peripheral blood. Clinical response (CR), progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. In the univariate analysis for CR, ERCC1-118 and XPD 751 polymorphisms were significant (P=0.02 and P=0.05, respectively). After adjustment for the most relevant clinical variables, only ERCC1-118 retained significance (P=0.008). In the univariate analysis for PFS, ERCC1-118 and XPD 751 were significant (P=0.003 and P=0.009, respectively). In the multivariant analysis, only the XPD 751 was significant for PFS (P=0.02). Finally, ERCC1-118 and XPD 751 polymorphisms were significant in the univariate analysis for OS (P=0.006 and P=0.015, respectively). Both genetic variables remained significant in the multivariate Cox survival analysis (P=0.022 and P=0.03). Our data support the hypothesis that enhanced DNA repair diminishes the benefit of platinum-based treatments. PMID:18797464

  1. Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy

    PubMed Central

    Paré, L; Marcuello, E; Altés, A; Río, E del; Sedano, L; Salazar, J; Cortés, A; Barnadas, A; Baiget, M

    2008-01-01

    To determine whether molecular parameters could be partly responsible for resistance or sensitivity to oxaliplatin (OX)-based chemotherapy used as first-line treatment in advanced colorectal cancer (CRC). We studied the usefulness of the excision repair cross-complementing 1 (ERCC1), xeroderma pigmentosum group D (XPD), XRCC1 and GSTP1 polymorphisms as predictors of clinical outcome in these patients. We treated 126 CRC patients with a first-line OX/5-fluorouracil chemotherapeutic regimen. Genetic polymorphisms were determined by real-time PCR on an ABI PRISM 7000, using DNA from peripheral blood. Clinical response (CR), progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. In the univariate analysis for CR, ERCC1-118 and XPD 751 polymorphisms were significant (P=0.02 and P=0.05, respectively). After adjustment for the most relevant clinical variables, only ERCC1-118 retained significance (P=0.008). In the univariate analysis for PFS, ERCC1-118 and XPD 751 were significant (P=0.003 and P=0.009, respectively). In the multivariant analysis, only the XPD 751 was significant for PFS (P=0.02). Finally, ERCC1-118 and XPD 751 polymorphisms were significant in the univariate analysis for OS (P=0.006 and P=0.015, respectively). Both genetic variables remained significant in the multivariate Cox survival analysis (P=0.022 and P=0.03). Our data support the hypothesis that enhanced DNA repair diminishes the benefit of platinum-based treatments. PMID:18797464

  2. Microwave ablation of hepatocellular carcinoma as first-line treatment: long term outcomes and prognostic factors in 221 patients.

    PubMed

    Wang, Tao; Lu, Xiao-Jie; Chi, Jia-Chang; Ding, Min; Zhang, Yuan; Tang, Xiao-Yin; Li, Ping; Zhang, Li; Zhang, Xiao-Yu; Zhai, Bo

    2016-01-01

    This retrospective study aimed at evaluating the long-term outcomes and prognostic factors of microwave ablation (MWA) as a first-line treatment for hepatocellular carcinoma (HCC). 221 consecutive patients receiving MWA in our center between October 11, 2010 and December 31, 2013 were enrolled. Technique effectiveness was evaluated one month post-ablation. Initial complete ablation (CA1(st)) was gained in 201 (90.95%) patients, secondary CA (CA2(nd)) in 8 (3.62%) patients and the remaining 12 (5.43%) patients suffered from incomplete ablation (IA2(nd)) after two sessions of MWA. Patients with tumor size >5 cm were less likely to gain CA1(st). Procedure-related complications were recorded and no procedure-related death occurred. 22 (10.4%) complications occurred with 8 (3.8%) being major ones. Tumor characteristics (size, number, location) do not significantly influence complication rates. After a median follow-up of 41.0 (ranging 25.0-63.5) months, the median RFS and OS was 14.0 months (95% CI: 9.254-18.746) and 41.0 months (95% CI: 33.741-48.259) respectively. Multivariate analysis identified two significant prognosticators (levels of alpha fetal protein [AFP] and gamma-glutamyl transpeptidase [GGT]) of RFS and five significant prognosticators (tumor number, tumor size, AFP, GGT and recurrence type) of OS. In conclusion, MWA provides high technique effectiveness rate and is well tolerated in patients with HCC as a first-line treatment. PMID:27620527

  3. Cytotoxic Chemotherapy as First-Line Therapy for Advanced Non-Small-Cell Lung Cancer in Taiwan: Daily Practice

    PubMed Central

    Liang, Yi-Hsin; Shao, Yu-Yun; Liao, Bin-Chi; Lee, Ho-Sheng; Yang, James Chih-Hsin; Chen, Ho-Min; Chiang, Chun-Ju; Cheng, Ann-Lii; Lai, Mei-Shu

    2016-01-01

    Aim: Cytotoxic chemotherapy is the standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) without specific gene alterations. This study examined the prescription pattern and the survival outcome of cytotoxic chemotherapy regimens in daily practice in Taiwan. Methods:We established a population-based cohort of patients diagnosed with advanced NSCLC between 2005 and 2009 using the databases of Taiwan Cancer Registry and National Health Insurance in Taiwan. We then analyzed chemotherapy prescriptions and the survival outcomes of patients. Results:A total of 25,008 patients with advanced NSCLC were identified, 17,443 (70.0%) of which received first-line chemotherapy and were therefore included in this study. Among them, 11,551 (66.2%) patients had adenocarcinoma and 3,292 (18.9%) patients had squamous cell carcinoma (SCC). Approximately 70% of the patients were diagnosed with NSCLC in medical centers. Platinum-based doublet chemotherapy was administered to 66.9% of the patients. Among all chemotherapy regimens, platinum with gemcitabine (33.8%) was the most common, irrespective of geographic region. The second and third most common regimens were vinorelbine alone (13.0%) and platinum with docetaxel (11.6%). The prevalence of platinum-based doublet chemotherapy regimens decreased from 71.4% in 2005 to 64.1% in 2009. Among patients with adenocarcinoma histology, those who received platinum with pemetrexed had longer OS than did patients who received other platinum-based regimens (p < 0.001). Conclusion: Our findings reaffirm that in real-world practice, treatment plans of advanced NSCLC should be drawn up according to histology type. PMID:27471567

  4. First-Line Matched Related Donor Hematopoietic Stem Cell Transplantation Compared to Immunosuppressive Therapy in Acquired Severe Aplastic Anemia

    PubMed Central

    Peinemann, Frank; Grouven, Ulrich; Kröger, Nicolaus; Bartel, Carmen; Pittler, Max H.; Lange, Stefan

    2011-01-01

    Introduction Acquired severe aplastic anemia (SAA) is a rare and progressive disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells is a first-line treatment option if HLA-matched related donors are available. First-line immunosuppressive therapy may be offered as alternative. The aim was to compare the outcome of these patients in controlled trials. Methods A systematic search was performed in the bibliographic databases MEDLINE, EMBASE, and The Cochrane Library. To show an overview of various outcomes by treatment group we conducted a meta-analysis on overall survival. We evaluated whether studies reported statistically significant factors for improved survival. Results 26 non-randomized controlled trials (7,955 patients enrolled from 1970 to 2001) were identified. We did not identify any RCTs. Risk of bias was high except in 4 studies. Young age and recent year of treatment were identified as factors for improved survival in the HSCT group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the IST group. In 19 studies (4,855 patients), summary statistics were sufficient to be included in meta-analysis. Considerable heterogeneity did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies. Conclusions Young age and recent year of treatment were identified as factors for improved survival in the transplant group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the immunosuppressive group. Considerable heterogeneity of non-randomized controlled studies did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies. PMID:21541024

  5. Cost Effectiveness of Personalized Therapy for First-Line Treatment of Stage IV and Recurrent Incurable Adenocarcinoma of the Lung

    PubMed Central

    Handorf, Elizabeth A.; McElligott, Sean; Vachani, Anil; Langer, Corey J.; Bristol Demeter, Mirar; Armstrong, Katrina; Asch, David A.

    2012-01-01

    Purpose: 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. Methods: 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). Results: 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. Conclusion: 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. PMID

  6. Rapid Response of Advanced Squamous Non-Small Cell Lung Cancer with Thrombocytopenia after First-Line Treatment with Pembrolizumab Plus Autologous Cytokine-Induced Killer Cells

    PubMed Central

    Hui, Zhenzhen; Zhang, Xinwei; Ren, Baozhu; Li, Runmei; Ren, Xiubao

    2015-01-01

    We present the first clinical evidence of advanced squamous non-small cell lung cancer with severe thrombocytopenia showing dramatic improvement after first-line treatment with pembrolizumab plus autologous cytokine-induced killer cells. PMID:26734004

  7. Fluvoxamine monotherapy for psychotic depression: the potential role of sigma-1 receptors

    PubMed Central

    2009-01-01

    Background Psychotic depression is a clinical subtype of major depressive disorder. A number of clinical studies have demonstrated the efficacy of the combination of an antidepressant (for example, a tricyclic antidepressant or selective serotonin reuptake inhibitor (SSRI)) and an atypical antipsychotic or electroconvulsive therapy in treating psychotic depression. In some cases, the clinician or patient may prefer to avoid antipsychotic drugs altogether because of the risk of extrapyramidal side effects (EPS) in patients with psychotic depression treated with these drugs. Methods We report five cases where fluvoxamine monotherapy was effective in the patients with psychotic depression. Results The scores on the Hamilton Depression (HAM-D) scale and the Brief Psychiatric Rating Scale (BPRS) in the five patients with psychotic depression were reduced after fluvoxamine monotherapy. Conclusion Doctors should consider fluvoxamine monotherapy as an alternative approach in treating psychotic depression because it avoids the risk of EPS from antipsychotic drugs. PMID:20025739

  8. Bevacizumab in combination with a taxane for the first-line treatment of HER2-negative metastatic breast cancer.

    PubMed

    Rodgers, M; Soares, M; Epstein, D; Yang, H; Fox, D; Eastwood, A

    2011-05-01

    versus docetaxel in terms of overall survival. The manufacturer developed a de novo economic model that considered patients with the same baseline characteristics as women in the E2100 trial. The model assessed BEV + PAC - bevacizumab 10 mg/kg every 2 weeks in combination with paclitaxel 90 mg/m2 weekly for 3 weeks followed by 1 week of rest; PAC q.w. - paclitaxel (monotherapy) 90 mg/m2 weekly for 3 weeks followed by 1 week of rest; DOC - docetaxel (monotherapy) 75 mg/m2 on day 1 every 21 days (considered current UK NHS clinical practice in the submission); and GEM + PAC - gemcitabine 1250 mg/m2 on days 1 and 8 plus paclitaxel 175 mg/m2 on day 1 every 21 days. Pairwise comparisons were made between BEV + PAC and PAC (using the E2100 trial), BEV + PAC and DOC, and BEV + PAC and GEM + PAC. Based on NHS list prices, the manufacturer's model estimated incremental cost-effectiveness ratios (ICERs) for BEV + PAC of £ 117,803, £ 115,059 and £ 105,777 per QALY gained, relative to PAC, DOC and GEM + PAC regimens, respectively. If the NHS Purchasing and Supply Agency prices for PAC with a 10-g cap on the cost per patient of BEV were used instead, the ICERs for BEV + PAC were estimated at £ 77,314, £ 57,753 and £ 60,101 per QALY, respectively. The submission suggested that the regimen of BEV + DOC is not cost-effective because it is considered less effective and more costly than BEV + PAC. Analysis by the ERG suggested that alternative assumptions can increase the ICERs further and, based on current prices, no plausible changes to the model assumptions will bring the ICERs for BEV + PAC lower. PMID:21609648

  9. First-line antiretroviral therapy with nevirapine versus lopinavir-ritonavir based regimens in a resource-limited setting

    PubMed Central

    Clumeck, Nathan; Mwamba, Claude; Kabeya, Kabamba; Matanda, Serge; Vaira, Dolorès; Necsoi, Coca; Kadiebwe, David; Delforge, Marc; Kasamba, Eric; Milolo, Chantal; Ilunga, Joe; Kapend, Liévin

    2014-01-01

    Objective: To compare WHO first-line antiretroviral therapy (ART) with nonnucleoside reverse transcriptase inhibitors (NNRTI)-based regimen with a boosted protease inhibitor (bPI) regimen in a resource-limited setting regarding treatment outcome and emergence of drug resistance mutations (DRMs). Methods: Treatment-naive adults were randomized to nevirapine (NVP) or ritonavir-boosted lopinavir (LPV/r) regimens each in combination with tenofovir (TDF)/emtricitabine (FTC) or zidovudine (ZDV)/lamivudine (3TC). Primary endpoint was the incidence of therapeutical (clinical and/or virologic) failure at week 48 with follow-up till week 96. Results: Four hundred and twenty-five patients (120 men; 305 women) received at least one dose of the study drug. mITT analysis showed no difference in proportion of therapeutical failure between treatment arms [67/209 (32%) in NVP vs. 63/216 (29%) LPV/r at week 48 (P = 0.53); 88/209 (42%) in NVP vs. 83/216 (38%) in LPV/r at week 96 (P = 0.49)]. Per-protocol analysis demonstrated significantly more virologic failure with NVP than with LPV/r regimens [at week 48: 19/167 (11%) vs. 7/166 (4%), P = 0.014; at week 96: 27/158 (17%) vs. 13/159 (8%), P =  0.019)]. Drug resistance mutations to NNRTI were detected in 19 out of 22 (86.3%) and dual-class resistance to nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI in 15 out of 27 (68.2%) of NVP failing patients. K65R mutation was present in seven out of 14 patients failing NVP-TDF/FTC regimen. No major protease inhibitor-DRM was detected among LPV/r failing patients. Discontinuation for adverse events was similar between treatment groups. Conclusion: In resource-limited settings, first-line NNRTI-NRTI regimen as compared with bPI-based regimen provides similar outcome but is associated with a significantly higher number of virologic failure and resistance mutations in both classes that jeopardize future options for second-line therapy. PMID:25028911

  10. 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

  11. Comparing the effects of first-line antiepileptic drugs on the gait of dogs with idiopathic epilepsy.

    PubMed

    Suiter, E J; Packer, R M A; Volk, H A

    2016-06-25

    Idiopathic epilepsy (IE) is a common chronic neurological disease of the dog. Previous studies of anti-epileptic drug (AED) treatment have indicated that acceptable AED adverse effects are as important to owners as reductions in seizure frequency. AEDs in both dogs and human beings are frequently associated with the adverse-effect ataxia. The aim of this study was to compare ataxia levels in dogs with IE treated chronically with phenobarbitone or imepitoin, the two currently available first-line AED treatments. The gait of 6 imepitoin-treated dogs, 8 phenobarbitone-treated dogs and 10 age-matched healthy control dogs were compared. Fifty strides from a walking gait were analysed for each dog, quantifying ataxia via the variability in six established gait parameters. Three variables differed significantly between groups: lateral distance between (i) pelvic paw placements, (ii) thoracic paw placements and (iii) stance time, which were significantly more variable in the phenobarbitone-treated dogs than imepitoin-treated or control dogs. These results indicate that dogs treated with phenobarbitone experience ataxia compared with controls and imepitoin-treated dogs. Conversely, there was no difference between imepitoin-treated dogs and controls. These results along with further research are needed to quantify AEDs adverse effects, to help vets and owners make more informed drug-choices. PMID:27302918

  12. 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. PMID:23982598

  13. Bendamustine and Rituximab, as First Line Treatment, in Intermediate, High Risk Splenic Marginal Zone Lymphomas of Elderly Patients

    PubMed Central

    Castelli, Roberto; Gidaro, Antonio; Deliliers, Giorgio Lambertenghi

    2016-01-01

    Background Splenic marginal zone lymphoma (SMZL) is a chronic B-cell lymphoproliferative disorder, comprising less than 2% of non-Hodgkin’s lymphomas, and affecting mainly middle-aged and elderly patients with a median survival of >10 years. The typical clinical features of SMZL include splenomegaly. Treatment should be patient-tailored and can range from a ‘watchful waiting’ approach for asymptomatic patients without cytopenias to surgery, localized radiation therapy or immuno/chemotherapies. Recently, the combination of rituximab and Bendamustine (R-Benda) has been defined as highly active in patients with follicular lymphomas, but little is known about the efficacy of R-Benda in SMZL. Aim of the study The purpose of this retrospective study was to report our experience on the efficacy of R-Benda as first line treatment in 23 consecutive elderly SMZL patients. Results All patients had a complete resolution of splenomegaly along with restoration of their blood counts. Nineteen patients (83%) achieved a complete response (CR) to therapy; three patients (13%) achieved a partial response (PR).Ten patients (43%) obtained molecular remission. Toxicities were mild and mainly haematological and result in dose reductions for fourteen patients. Conclusions Our data suggest a high activity and good tolerance of R-Benda, despite dose reduction due to potential toxicity. PMID:27413523

  14. Profile of panitumumab as first-line treatment in patients with wild-type KRAS metastatic colorectal cancer.

    PubMed

    Patel, Shiven B; Gill, David; Garrido-Laguna, Ignacio

    2016-01-01

    Targeted therapies against EGFR, vascular endothelial growth factor, and vascular endothelial growth factor receptor have expanded treatment options for patients with metastatic colorectal cancer (mCRC). Unfortunately, biomarkers to identify patients that are most likely to derive benefit from targeted therapies in this disease are still needed. Indeed, only RAS mutations have been identified as predictive of lack of benefit from monoclonal antibodies against EGFR in patients with mCRC. Panitumumab is a fully humanized monoclonal antibody against EGFR. In this study, we review data to support the use of panitumumab in combination with a chemotherapy backbone, in the first line setting in patients with RAS wild-type mCRC. Ongoing efforts are aimed at identifying smaller subsets of patients within the RAS wild-type group that will derive the largest benefit from anti-EGFR therapy. In the meantime, treatment with anti-EGFR therapy should be reserved for patients with RAS wild-type mCRC. PMID:26770060

  15. 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

  16. Profile of panitumumab as first-line treatment in patients with wild-type KRAS metastatic colorectal cancer

    PubMed Central

    Patel, Shiven B; Gill, David; Garrido-Laguna, Ignacio

    2016-01-01

    Targeted therapies against EGFR, vascular endothelial growth factor, and vascular endothelial growth factor receptor have expanded treatment options for patients with metastatic colorectal cancer (mCRC). Unfortunately, biomarkers to identify patients that are most likely to derive benefit from targeted therapies in this disease are still needed. Indeed, only RAS mutations have been identified as predictive of lack of benefit from monoclonal antibodies against EGFR in patients with mCRC. Panitumumab is a fully humanized monoclonal antibody against EGFR. In this study, we review data to support the use of panitumumab in combination with a chemotherapy backbone, in the first line setting in patients with RAS wild-type mCRC. Ongoing efforts are aimed at identifying smaller subsets of patients within the RAS wild-type group that will derive the largest benefit from anti-EGFR therapy. In the meantime, treatment with anti-EGFR therapy should be reserved for patients with RAS wild-type mCRC. PMID:26770060

  17. Risk factors for the development of non-response to first-line treatment for tuberculosis in southern Vietnam.

    PubMed

    Keane, V P; de Klerk, N; Krieng, T; Hammond, G; Musk, A W

    1997-10-01

    Since 1979, the International Organization for Migration has provided tuberculosis screening and treatment for those who intend to migrate from Viet Nam--a country with one of the highest tuberculosis incidence rates. The factors associated with non-response to first-line tuberculosis treatment were investigated in a comparative study of 130 non-responders (cases) and 673 responders (controls). Cases had worse radiologic signs and greater numbers of acid-fast bacilli on their sputum smears than controls. When these two factors were used as a diagnostic test to predict non-response, the model had a sensitivity of 70% and a specificity of 80%. Sensitivity increased to 80% when variables measured in the first 3 months of treatment were used. Failure to respond to treatment can be a result of infection with other mycobacteria, infection with a multi-drug resistant tuberculosis strain, or acquisition of resistance after the initiation of therapy. Further analysis of the same database is underway to determine the natural history and success of second-line treatment. PMID:9363535

  18. First-line nitrosourea-based chemotherapy in symptomatic non-resectable supratentorial pure low-grade astrocytomas.

    PubMed

    Frenay, M P; Fontaine, D; Vandenbos, F; Lebrun, C

    2005-09-01

    At the present time, there are no proven beneficial effects of chemotherapy (CT) for the treatment of pure low-grade astrocytomas. Brain radiotherapy (RT) still remains the standard treatment in order to reduce or delay tumor progression or symptoms, despite possible long-term neurologic complications. We report 10 patients, with histologically proven pure low-grade fibrillary astrocytomas, to which we administered a first-line nitrosourea-based CT. All patients were symptomatic with pharmaco-resistant epilepsy or neurologic symptoms, and had been rejected for neurosurgical resection. All patients with epilepsy had a clinical improvement with reduction in seizure frequency and 60% became seizure-free. CT was well tolerated; all patients developed myelosuppression with 40% of grade III/IV hematotoxicity. Seven were alive at the time of writing with a mean follow-up of 6.5 years (3.5-12) from first recorded symptoms. The three deceased patients died 7.5, 7.5, and 8.5 years from first symptoms. These results demonstrate that some patients with symptomatic non-resectable fibrillary low-grade astrocytomas can be treated with up-front CT to improve their neurologic status. This report suggests that benefits of CT on symptoms, survival, and quality of life should be prospectively compared with RT. PMID:16128869

  19. Cross-market cost-effectiveness analysis of erlotinib as first-line maintenance treatment for patients with stable non-small cell lung cancer

    PubMed Central

    Vergnenègre, Alain; Ray, Joshua A; Chouaid, Christos; Grossi, Francesco; Bischoff, Helge G; Heigener, David F; Walzer, Stefan

    2012-01-01

    Background Platinum-doublet, first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) is limited to 4–6 cycles. An alternative strategy used to prolong the duration of first-line treatment and extend survival in metastatic NSCLC is first-line maintenance therapy. Erlotinib was approved for first-line maintenance in a stable disease population following results from a randomized, controlled Phase III trial comparing erlotinib with best supportive care. We aimed to estimate the incremental cost-effectiveness of erlotinib 150 mg/day versus best supportive care when used as first-line maintenance therapy for patients with locally advanced or metastatic NSCLC and stable disease. Methods An economic decision model was developed using patient-level data for progression-free survival and overall survival from the SATURN (SequentiAl Tarceva in UnResectable NSCLC) study. An area under the curve model was developed; all patients entered the model in the progression-free survival health state and, after each month, moved to progression or death. A time horizon of 5 years was used. The model was conducted from the perspective of national health care payers in France, Germany, and Italy. Probabilistic sensitivity analyses were performed. Results Treatment with erlotinib in first-line maintenance resulted in a mean life expectancy of 1.39 years in all countries, compared with a mean 1.11 years with best supportive care, which represents 0.28 life-years (3.4 life-months) gained with erlotinib versus best supportive care. In the base-case analysis, the cost per life-year gained was €39,783, €46,931, and €27,885 in France, Germany, and Italy, respectively. Conclusion Erlotinib is a cost-effective treatment option when used as first-line maintenance therapy for locally advanced or metastatic NSCLC. PMID:22347803

  20. Non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer: a Cochrane systematic review.

    PubMed

    Kunath, Frank; Grobe, Henrik R; Rücker, Gerta; Motschall, Edith; Antes, Gerd; Dahm, Philipp; Wullich, Bernd; Meerpohl, Joerg J

    2015-07-01

    To assess the effects of non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for treating advanced hormone-sensitive stages of prostate cancer. We searched the Cochrane Prostatic Diseases and Urologic Cancers Group Specialized Register (PROSTATE), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science with Conference Proceedings, three trial registries and abstracts from three major conferences to 23 December 2013, together with reference lists, and contacted selected experts in the field and manufacturers. We included randomized controlled trials comparing non-steroidal antiandrogen monotherapy with medical or surgical castration monotherapy for men in advanced hormone-sensitive stages of prostate cancer. Two review authors independently examined full-text reports, identified relevant studies, assessed the eligibility of studies for inclusion, extracted data and assessed risk of bias as well as quality of evidence according to the GRADE working group guidelines. We used Review Manager 5.2 for data synthesis and the fixed-effect model as primary analysis (when heterogeneity was low with I(2) < 50%); we used a random-effects model when confronted with substantial or considerable heterogeneity (when I(2) ≥50%). A total of 11 studies involving 3060 randomly assigned participants were included in the present review. Use of non-steroidal antiandrogens resulted in lower overall survival times (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.05-1.48, six studies, 2712 participants) and greater clinical progression (1 year: risk ratio [RR] 1.25, 95% CI 1.08-1.45, five studies, 2067 participants; 70 weeks: RR 1.26, 95% CI 1.08-1.45, six studies, 2373 participants; 2 years: RR 1.14, 95% CI 1.04-1.25, three studies, 1336 participants), as well as treatment failure (1 year: RR 1.19, 95% CI 1.02-1.38, four studies, 1539 participants; 70 weeks: RR 1

  1. Pharmacotherapy of acute mania: monotherapy or combination therapy with mood stabilizers and antipsychotics?

    PubMed

    Grande, Iria; Vieta, Eduard

    2015-03-01

    The use of combination therapy with mood stabilizers and antipsychotics in acute mania in bipolar disorder (BD) is widespread, although most treatment guidelines recommend monotherapy as the first option, and reserve combination therapy, which is associated with more frequent and more severe side effects, for when patients do not respond to the former treatment option. Reasons to prescribe combination therapy include the lack of efficacy of the current treatment (either real or due to undisclosed poor adherence), psychiatric comorbidities, severe previous course of illness, slow cross-tapering during treatment switching, and potential benefits from particular combinations. The decision to start with monotherapy or combination therapy may depend on the patient characteristics, and is still under debate. Clinical trials designed to ascertain whether combination therapy or monotherapy is more advantageous for patients in acute mania and beyond, according to illness severity, are urgently needed. Adding a third monotherapy arm to the conventional two-arm, adjunctive-design trials or initiating combination therapy from the beginning may help to shed some light on the issue. PMID:25711483

  2. Efficacy of combined pharmacotherapy and psychotherapy versus monotherapy in the treatment of anxiety disorders.

    PubMed

    Black, Donald W

    2006-10-01

    Anxiety disorders in the United States are prevalent, widespread, and disabling. These illnesses may account for almost one third of the $148 billion total mental health bill each year. Pharmacologic options include tricyclic antidepressants, monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, and anxiolytics. Psychological treatments include cognitive-behavioral therapy (CBT), cognitive therapy, exposure, and ritual prevention therapies. Despite insufficient evidence, many experts recommend combined treatment, generally medication with CBT. A literature review was conducted to examine studies with random assignment, adequate methods and sample sizes, blind assessments, sufficient dosages and durations of treatment, and satisfactory reporting of data, to determine whether combined treatment was superior to monotherapy. Twenty-six randomized clinical trials were identified; nine met review criteria. A review of relevant studies could not confirm the superiority of combined treatment over monotherapy. In one of four studies of obsessive-compulsive disorder, combined treatment produced better results than monotherapy. There was no evidence of superiority for combined therapy over monotherapy for the treatment of social phobia or generalized anxiety disorder. There were no studies that met review criteria for either specific phobia or posttraumatic stress disorder (PTSD). With panic disorder, there was evidence that combined treatment might actually lead to worse outcome. Combined treatment is commonly recommended, but empirical support is limited. More research is needed. There are few well-designed studies, and little data regarding PTSD and specific phobias. PMID:17008828

  3. Effects of N-acetylcysteine on First-Line Sequential Therapy for Helicobacter pylori Infection: A Randomized Controlled Pilot Trial

    PubMed Central

    Yoon, Hyuk; Lee, Dong Ho; Jang, Eun Sun; Kim, Jaihwan; Shin, Cheol Min; Park, Young Soo; Hwang, Jin-Hyeok; Kim, Jin-Wook; Jeong, Sook-Hayng; Kim, Nayoung

    2016-01-01

    Background/Aims To evaluate the adjuvant effects of N-acetylcysteine (NAC) on first-line sequential therapy (SQT) for Helicobacter pylori infection. Methods Patients with H. pylori infections were randomly assigned to receive sequential therapy with (SQT+NAC group, n=49) or without (SQT-only group, n=50) NAC. Sequential therapy consisted of rabeprazole 20 mg and amoxicillin 1 g for the first 5 days, followed by rabeprazole 20 mg, clarithromycin 500 mg and metronidazole 500 mg for the remaining 5 days; all drugs were administered twice daily. For the SQT+NAC group, NAC 400 mg bid was added for the first 5 days of sequential therapy. H. pylori eradication was evaluated 4 weeks after the completion of therapy. Results The eradication rates by intention-to-treat analysis were 58.0% in the SQT-only group and 67.3% in the SQT+NAC group (p=0.336). The eradication rates by per-protocol analysis were 70.0% in the SQT-only group and 80.5% in the SQT+NAC group (p=0.274). Compliance was very good in both groups (SQT only/SQT+NAC groups: 95.2%/100%, p=0.494). There was no significant difference in the adverse event rates between groups (SQT-only/SQT+NAC groups: 26.2%/26.8%, p=0.947). Conclusions The H. pylori eradication rate was numerically higher in the SQT+NAC group than in the SQT-only group. As our data did not reach statistical significance, larger trials are warranted. PMID:26347514

  4. 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

  5. Incidence and predictors of severe anemia in Asian HIV-infected children using first-line antiretroviral therapy

    PubMed Central

    Bunupuradah, Torsak; Kariminia, Azar; Chan, Kwai-Cheng; Ramautarsing, Reshmie; Huy, Bui Vu; Han, Ning; Nallusamy, Revathy; Hansudewechakul, Rawiwan; Saphonn, Vonthanak; Sirisanthana, Virat; Chokephaibulkit, Kulkanya; Kurniati, Nia; Kumarasamy, Nagalingeswaran; Yusoff, Nik Khairulddin Nik; Razali, Kamarul; Fong, Siew Moy; Sohn, Annette H.; Lumbiganon, Pagakrong

    2014-01-01

    Objective There are limited data on treatment-related anemia in Asian HIV-infected children. Methods Data from Asian HIV-infected children aged <18 years on first-line highly active antiretroviral therapy (HAART) were used. Children who had preexisting severe anemia at baseline were excluded. Anemia was graded by using the DAIDS 2004 table. Potential risk factors of severe anemia were assessed by logistic regression. Results Data from 1,648 children (51.9% female, 62.8% WHO stage 3/4) were analyzed. Median (IQR) age was 6.8 (3.7–9.6) years, CD4% was 9 (3–16)% and plasma HIV-RNA was 5.2 (4.7–5.6) log10 copies/ml at HAART initiation in those with available testing. The most common regimens were stavudine/lamivudine/nevirapine (42%) and zidovudine/lamivudine/nevirapine (25%). Severe anemia was identified in 47 (2.9%) children after a median time of 6 months after HAART initiation with an incidence rate of 5.4 per 100 child-years. Mild anemia or moderate anemia at baseline (p=0.024 and p=0.005, respectively), previous or current use of zidovudine (p<0.0001 and p=0.013, respectively), and male sex (p=0.008) were associated with severe anemia. Higher weight-for-age z-score (p=0.004) was protective. Conclusions The incidence of severe anemia in Asian HIV-infected children after HAART initiation was low and mainly occurred during the first few months after HAART initiation. Mild to moderate anemia at baseline and using AZT were independent risk factors of developing severe anemia. PMID:23764352

  6. Should dopamine be the first line inotrope in the treatment of neonatal hypotension? Review of the evidence

    PubMed Central

    Bhayat, Sadaf I; Gowda, Harsha M S; Eisenhut, Michael

    2016-01-01

    AIM: To determine if dopamine is effective in treating neonatal hypotension and safe to use comparing to other inotropes. METHODS: This is a review of evidence on inotropic treatment of neonatal hypotension. Databases searched were MEDLINE and the Cochrane Library, a total of 134 studies were identified. Only studies with high quality evidence (level 1a and b and 2a) were included. After review, only eight studies were included in the final analysis. Pooled risk ratios derived for each outcome [Mantel-Haenzel (M-H) fixed effect] with CI, as reported in the Cochrane reviews were plotted in forest plot form. RESULTS: Eight articles met inclusion criteria, which all included treatment in preterm infants. Dopamine increased mean arterial blood pressure (BP) (n = 163; r = 0.88, 95%CI: 0.76 to 0.94) and systolic BP (n = 142; r = 0.81, 95%CI: 0.42 to 0.94) comparing to placebo. Dopamine has been shown overall to be statistically more effective in increasing BP than dobutamine (n = 251, r = 0.26, 95%CI: 0.20-0.32). However there were no differences in short term outcomes (periventricular leucomalacia, periventricular haemorrhage) and mortality between both drugs. There is no statistical evidence of dopamine being more effective than adrenaline or corticosteroids. There was no difference in morbidity and mortality outcomes when dopamine was compared to hydrocortisone (RR 1.81, 95%CI: 0.18 to 18.39) or adrenaline. CONCLUSION: In preterms, dopamine is the most studied drug, and we suggest it could be used as first line treatment in hypotension. PMID:27170932

  7. First-line treatment with FOLFOXIRI for advanced pancreatic cancer in clinical practice: Patients' outcome and analysis of prognostic factors.

    PubMed

    Vivaldi, Caterina; Caparello, Chiara; Musettini, Gianna; Pasquini, Giulia; Catanese, Silvia; Fornaro, Lorenzo; Lencioni, Monica; Falcone, Alfredo; Vasile, Enrico

    2016-08-15

    FOLFIRINOX is a standard first-line treatment for advanced pancreatic cancer (aPC). The Gruppo Oncologico Nord Ovest (GONO) FOLFOXIRI regimen demonstrated efficacy in metastatic colorectal cancer. We aimed to evaluate activity and tolerability of FOLFOXIRI regimen in patients with aPC and to explore putative prognostic factors. One hundred thirty-seven consecutive aPC patients were treated with FOLFOXIRI in our institution between 2008 and 2014. Clinical, laboratory and pathological data were collected and their association with activity, progression free survival (PFS) and overall survival (OS) was investigated. After a median follow up of 30 months, median PFS and OS were 8.0 months (95% CI 6.19-9.81) and 12 months (95% CI 9.75-14.25), respectively. Response rate was 38.6%, while disease-control rate 72.2%. At multivariate analysis liver metastases (p = 0.019; Hazard Ratio, HR, 0.59, 95% Confidence Interval, CI, 0.380.96), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (p = 0.001; HR 2.26, 95%CI 1.42-3.59) and neutrophil-lymphocyte ratio (NLR)> 4 (p= 0.002; HR: 2.42; 95% CI 1.38-4.25) were associated with poorer OS. We categorized 119 pts with complete available data as good-risk (0 factors, 38 pts), intermediate-risk (1 factor, 49 pts) and poor-risk (≥2 factors, 32 pts). Median OS for these three groups were 17.6, 11.1 and 7.4 months, respectively (p < 0.001). FOLFOXIRI is active and feasible in aPC. Prognosis of aPC pts treated with FOLFOXIRI is influenced by easily available factors: our analysis revealed ECOG PS, liver metastases and NLR as the most important predictors of survival. These factors could be helpful for treatment decision and clinical trial design. PMID:27038273

  8. Efficacy of continued cetuximab for unresectable metastatic colorectal cancer after disease progression during first-line cetuximab-based chemotherapy: a retrospective cohort study

    PubMed Central

    Yu, Yiyi; Ye, Qinghai; Ding, Jianyong; Chen, Jingwen; Chang, Wenju; Zhong, Yunshi; Zhu, Dexiang; Lin, Qi; Yang, Liangliang; Qin, Xinyu; Xu, Jianmin

    2016-01-01

    This study assessed second-line continued use of cetuximab for treatment of unresectable metastatic colorectal cancer (mCRC) after disease progression during first-line cetuximab-based therapy. Consecutive patients with wild-type KRAS exon 2 and unresectable mCRC were retrospectively enrolled after disease progression during first-line cetuximab-based chemotherapy. Second-line continued cetuximab plus changed chemotherapy (cetuximab continuation group, n = 102) was compared with changed chemotherapy only (chemotherapy only group, n = 96) with respect to treatment efficacy and safety endpoints. NRAS and other KRAS genotypes were also detected as a post hoc analysis. The cetuximab continuation group showed better progression-free survival (median, 6.3 vs. 4.5 months, P = 0.004), overall survival (median, 17.3 vs. 14.0 months, P < 0.001) and disease control rate (70.6% vs. 53.1%, P = 0.011), and a potentially better overall response rate (18.6% vs. 9.4%, P = 0.062) than the chemotherapy only group. These benefits were seen mainly in patients with all RAS wild-type and exhibiting first-line early tumor shrinkage (ETS). For patients with other RAS mutations or who did not achieve first-line ETS, there was no difference between the two groups. These findings suggest that for patients with all RAS wild-type and unresectable mCRC who had disease progression during first-line cetuximab-based treatment, second-line continued cetuximab is effective. Moreover, ETS during first-line cetuximab-based treatment may be predictive of the efficacy of second-line continued cetuximab. PMID:26863631

  9. 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.

  10. First-line nurse administrators in academe: how are they prepared, what do they do, and will they stay in their jobs?

    PubMed

    Princeton, J C; Gaspar, T M

    1991-01-01

    This article examines the role characteristics, responsibilities, and anticipated career patterns of first-line nurse administrators employed in university-based nursing education programs throughout the nation. First-line administration is the first level on the administrative ladder, and these administrators are most frequently entitled department chairpersons; division, program, and level directors; or coordinators. This was an exploratory and descriptive research project, and the questions addressed were (1) How are first-line nurse administrators in academe formally educated and informally prepared for their administrative role? (2) What are the administrative competencies important for this administrative role? (3) What strains, conflicts, and work overload are associated with the first-line administrative role, and what strategies are used to cope? (4) What do these administrators anticipate as a career pattern in administration based on their experiences as first-line administrators? Fifty-six first-line nurse administrators were interviewed from 42 schools of nursing that offer both bachelor's degree and graduate nursing programs. Data indicated that one third of the study participants completed graduate level courses in administration, and the majority had worked with administrative mentors. They ranked having character and integrity as their most important competency, which was defined as being trusted by faculty, other administrators, and students. Settling priorities for their administrative work caused them their greatest strain, and work overload was most predominant. Role conflict was present consistently as they attempted to meet the traditional triad of faculty responsibilities (research and scholarship, teaching, service) plus administrative duties. Numerous time-management strategies were used to cope, but nonetheless, one half will not continue in an administration career pathway. Implications for academic nurse administrators are cited. PMID

  11. Consolidation of first-line therapy with busulphan and melphalan, and autologous stem cell rescue in children with Ewing's sarcoma.

    PubMed

    Drabko, K; Raciborska, A; Bilska, K; Styczynski, J; Ussowicz, M; Choma, M; Wojcik, B; Zaucha-Prazmo, A; Gorczynska, E; Skoczen, S; Wozniak, W; Chybicka, A; Wysocki, M; Gozdzik, J; Kowalczyk, J

    2012-12-01

    According to the published report on current practice of hematopoietic SCT in Europe, high-dose therapy (HDT) with autologous stem cell support is a standard of care in paediatric patients with high risk (HR) or relapsed Ewing's sarcoma (ES). Randomized trials, however, have not confirmed the value of this procedure yet. In this retrospective analysis we intended to evaluate the role of HDT as a consolidation therapy in first remission of ES. A total of 102 patients were included in the analysis and divided according to the following risk factors: metastatic disease at presentation, feasibility of surgery and histological response after induction. Forty-one patients were classified as standard risk (SR) patients, while the remaining 61 children, with at least one risk factor, were classified as HR patients. HR group patients were non-randomized and qualified according to the decision of the local clinician to give a conventional consolidation (CC) or to perform high-dose chemotherapy and radiotherapy in selected patients. Twenty-six children were given CC while 35 patients were treated with HDT. The HDT consisted of oral BU 4 mg/kg p.o. in divided doses daily for 4 days (total dose 16 mg/kg) followed by melphalan 140 mg/m(2) i.v. on day -2. Probability of relapse-free survival (RFS) in median observation time was significantly worse in HR patients who were given CC therapy as compared with children with HR features receiving high-dose chemotherapy (0.27 vs 0.66 (P = 0.008); OS 0.31 vs 0.71 (P = 0.007), respectively). Patients from the SR group had a probability of RFS of 0.72 and OS of 0.75, and the difference between SR and HR patients after HDT was NS (P = 0.37). Our observation confirms that the consolidation of the first-line treatment with BU and melphalan improves the outcome in ES patients with HR features. PMID:22609883

  12. Experience with methotrexate, 5-fluorouracil, and leucovorin (MFL): a first line effective, minimally toxic regimen for metastatic breast cancer.

    PubMed

    Auerbach, Michael; Elias, E George; Orford, James

    2002-01-01

    Thirty-two women with untreated metastatic breast cancer were treated with 100 mg/M2 i.v. methotrexate (MTX), 600 mg/M2 5-fluorouracil (5FU) and leucovorin 15 mg orally every 6 hr, 24 hr after MTX (MFL) on days 1 and 8 every 28 days. Stratification was according to sites of metastases (mets), adjuvant (adj), chemotherapy (CTX), and/or hormonal therapy or no adj therapy (Tx). Treatment continued until documented radiographic or clinical disease was in progression. Toxicity was mild, consisting of only minimal elevations of transaminases and mild cytopenias. There was no pulmonary toxicity. There were no hospitalizations, treatment delays or cessations for toxicity. One patient with skeletal mets had a complete response and 7 had partial responses. The overall median progression free survival (PFS) was 13.8 months (mos). Eighteen patients with skeletal mets had PFS from 7-70 mos (median 15.9). Five patients with lung mets only had PFS from 6-20 mos (median 9.8 mos). Patients with liver alone or with other visceral mets showed progression within 2-5 mos. However, patients with bone and visceral mets without liver involvement had PFS from 8-50 mos (median 20.5). Of 21 adj Tx failures the median PFS was 8.8 mos (2-94). Six who received adj CTX had a median PFS of 7.6 mos (3-12) and 4 tamoxifen (tam) failures a median PFS of 11 mos (8-15). Eleven patients who received adj CTX+tam had a median PFS of 8.5 mos (2-94). Six patients received tam at adj failure and MFL at progression. These six had a median PFS of 19.8 mos (8-50). The patients (six, who received no prior adj Tx) had a median PFS of 24.3 (8-70). MFL is as effective in achieving clinical remissions in metastatic breast cancer, is inexpensive and is far less toxic than other CTX regimes. MFL should strongly be considered as first line Tx. PMID:11852998

  13. Memantine Monotherapy for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

    PubMed Central

    Matsunaga, Shinji; Kishi, Taro; Iwata, Nakao

    2015-01-01

    Background We performed an updated meta-analysis of randomized placebo-controlled trials testing memantine monotherapy for patients with Alzheimer’s disease (AD). Methods The meta-analysis included randomized controlled trials of memantine monotherapy for AD, omitting those in which patients were also administered a cholinesterase inhibitor. Cognitive function, activities of daily living, behavioral disturbances, global function, stage of dementia, drug discontinuation rate, and individual side effects were compared between memantine monotherapy and placebo groups. The primary outcomes were cognitive function and behavioral disturbances; the others were secondary outcomes. Results Nine studies including 2433 patients that met the study’s inclusion criteria were identified. Memantine monotherapy significantly improved cognitive function [standardized mean difference (SMD)=−0.27, 95% confidence interval (CI)=−0.39 to −0.14, p=0.0001], behavioral disturbances (SMD=−0.12, 95% CI=−0.22 to −0.01, p=0.03), activities of daily living (SMD=−0.09, 95% CI=−0.19 to −0.00, p=0.05), global function assessment (SMD=−0.18, 95% CI=−0.27 to −0.09, p=0.0001), and stage of dementia (SMD=−0.23, 95% CI=−0.33 to −0.12, p=0.0001) scores. Memantine was superior to placebo in terms of discontinuation because of inefficacy [risk ratio (RR)=0.36, 95% CI=0.17¬ to 0.74, p=0.006, number needed to harm (NNH)=non significant]. Moreover, memantine was associated with less agitation compared with placebo (RR=0.68, 95% CI=0.49 to 0.94, p=0.02, NNH=non significant). There were no significant differences in the rate of discontinuation because of all causes, all adverse events, and individual side effects other than agitation between the memantine monotherapy and placebo groups. Conclusions Memantine monotherapy improved cognition, behavior, activities of daily living, global function, and stage of dementia and was well-tolerated by AD patients. However, the effect

  14. First-line thalidomide-dexamethasone therapy in preparation for autologous stem cell transplantation in young patients (<61 years) with symptomatic multiple myeloma.

    PubMed

    Abdelkefi, A; Torjman, L; Ben Romdhane, N; Ladeb, S; El Omri, H; Ben Othman, T; Elloumi, M; Bellaj, H; Lakhal, A; Jeddi, R; Aissaouï, L; Saad, A; Hsaïri, M; Boukef, K; Dellagi, K; Ben Abdeladhim, A

    2005-08-01

    Thalidomide-dexamethasone therapy was given in patients (<61 years) with previously untreated symptomatic multiple myeloma. The aim of this study was to assess the efficacy and toxicity of this combination as first-line therapy, and to determine its effect on stem cell collection and engraftment. During first-line therapy, thalidomide and dexamethasone were administered for 75 days (200 mg/day) and 3 months, respectively. The monthly dose of dexamethasone was 20 mg/m2/day for 4 days, with cycles repeated on days 9 to 12 and 17 to 20 on the first and the third month of therapy. After first-line therapy, a collection of peripheral blood stem cells (PBSC) was performed. Between May 2003 and September 2004, 60 patients were included. On an intent-to-treat basis, the overall response (> or =partial response) rate was 74%, including 24% of patients who obtained a complete remission. Grade 3-4 toxicities consisted of infections (12%), deep-vein thrombosis (3%), constipation (5%), and neuropathy (5%). A total of 58 patients (96%) proceeded to PBSC mobilisation and yielded a median number of 8 x 10(6) CD34+ cells/kg. First-line thalidomide-dexamethasone therapy is effective and relatively well tolerated in young patients with symptomatic multiple myeloma. This combination does not affect PBSC mobilisation. PMID:15968290

  15. Pregnancy outcomes in patients with severe pulmonary hypertension and Eisenmenger syndrome treated with sildenafil monotherapy

    PubMed Central

    Alan, Pichy Ann; Benedicto, Jubert

    2014-01-01

    Pregnancy outcomes in patients with pulmonary arterial hypertension have not been documented in our local setting. In our institution, access to therapies like nitric oxide, inhaled prostacyclin and iloprost is limited. We describe two such women given sildenafil monotherapy between April and May 2011. Both had an atrial septal defect complicated by Eisenmenger syndrome. Both survived – one after elective Caesarean section for malpresentation (breech) under general anaesthesia, the other after an assisted vaginal delivery. In addition to oral sildenafil, both received oxygen supplementation. To date, there have been three reported cases of pulmonary arterial hypertension in pregnancy treated with sildenafil in combination with another drug. Our two cases demonstrate that treatment for pulmonary arterial hypertension using sildenafil as monotherapy may allow stabilization of the maternal condition and improve clinical outcomes for both mother and baby. However, pregnancy is still discouraged in women with pulmonary arterial hypertension.

  16. A case of esophageal adenocarcinoma on long-term rapamycin monotherapy.

    PubMed

    Canha, Catarina; Ferreira, Raquel; Rovira, Jordi; Moya-Rull, Daniel; Castells, Antoni; Diekmann, Fritz; Oppenheimer, Federico; Campistol, Josep Maria; Revuelta, Ignacio

    2015-10-01

    Cancer in transplant recipients represents a therapeutic challenge even when the patient is already under mTOR inhibitors. A 78-year-old man received a deceased donor kidney transplant in 1993. After 6 months, he developed a multifocal cutaneous and nonvisceral Kaposi's Sarcoma while on cyclosporine immunosuppressant therapy. The patient was converted to sirolimus monotherapy in 2001 with subsequent complete recovery within 2 years. In 2007, the patient was diagnosed with an esophageal adenocarcinoma stage IIA. An esophagectomy was performed without requirement of further treatment. He has continued on sirolimus monotherapy ever since, with no other incidents and no recurrences of either tumor. In this report, we describe an interesting case of a second cancer while on immunosuppressive therapy with anticancer activity. Moreover, the present knowledge of the matter is discussed. PMID:25939687

  17. [Complete response in a case of anastomotic recurrence of rectal cancer treated with S-1 monotherapy].

    PubMed

    Kabashima, Akira; Kitagawa, Dai; Nakamura, Toshihiko; Kondo, Naoko; Teramoto, Seiichi; Saito, Genkichi; Funahashi, Tomoru; Adachi, Eisuke; Ikeda, Yoichi

    2014-11-01

    A 63-year-old woman underwent a low anterior resection for rectal cancer in 2002.A n anastomotic recurrence was diagnosed in July 2011.S he rejected the possibility of colostomy as radical surgery.Chemotherapy consisting of capecitabine+ oxaliplatin (XELOX) or folinic acid, fluorouracil, and oxaliplatin (FOLFOX6) + bevacizumab were not possible because of high costs. In view of the lower costs and the potential for ambulation, S-1 monotherapy was started. After 3 months, a reduction in the recurrent lesion was observed.After 19 months, the recurrent lesion revealed a scar, which was judged by biopsy to be Group 1.We had achieved a pathological complete response (CR).The standard treatment for recurrent colon cancer is surgical resection or multidrug chemotherapy. However, in view of a patient's quality of life (QOL), S-1 monotherapy may be considered as a potential therapy. PMID:25731306

  18. [Gemcitabine Monotherapy for Advanced Mycosis Fungoides--Two Case Reports and a Literature Review].

    PubMed

    Masuzawa, Mamiko; Takasu, Hiroshi; Amoh, Yasuyuki

    2015-12-01

    Gemcitabine, a pyrimidine nucleoside analogue, is gaining recognition as a potential therapeutic agent for advanced-stage and refractory cutaneous T-cell lymphoma (CTCL). We report of 2 patients whose advanced-stage mycosis fungoides was not sufficiently controlled by prior CHOP therapy. Both patients showed great improvement in the skin lesions with weekly gemcitabine therapy (1,000-1,200 mg/m2). The patients received four and 8 cycles of gemcitabine monotherapy, respectively, and no grade 3-4 hematological or hepatic adverse events occurred. This is the first report of the efficacy of gemcitabine for CTCL in Japan. Gemcitabine is well tolerated and is an effective monotherapy for CTCL. PMID:26809303

  19. Parameters of metabolic syndrome in Indian children with epilepsy on valproate or phenytoin monotherapy

    PubMed Central

    Dhir, Aditi; Sharma, Suvasini; Jain, Puneet; Bhakhri, Bhanu K.; Aneja, Satinder

    2015-01-01

    Objectives: The prevalence of obesity is rapidly increasing among Indian children, who, in general, are more prone to develop metabolic complications at an early age. Valproate and phenytoin are commonly used antiepileptic drugs in children. This study aimed to assess the parameters of the metabolic syndrome in Indian children with epilepsy on valproate or phenytoin monotherapy. Methods: This cross-sectional study recruited children from the Pediatric Epilepsy Clinic, Department of Pediatrics, Kalawati Saran Children Hospital, New Delhi from March 2012 to September 2012. All consecutive children diagnosed with epilepsy as per International League Against Epilepsy definition aged 3–18 years on valproate or phenytoin monotherapy for at least 6 months were enrolled at a tertiary care children's hospital in Northern India. After clinical and anthropometric evaluation (including body mass index [BMI] and waist circumference), the blood samples were analyzed for fasting serum glucose, total cholesterol, high-density lipoprotein-cholesterol, and serum triglyceride. Results: Children with BMI >95th centile and waist circumference >90th centile were not significantly different among children on valproate and phenytoin monotherapy. Children on valproate had significantly higher mean serum triglyceride (96.9 mg/dL vs. 77.6 mg/dL; P < 0.001) and total cholesterol (148.3 mg/dL vs. 132.8 mg/dL; P = 0.002) levels as compared to children on phenytoin monotherapy. Conclusions: The lipid abnormalities may be observed in children on valproate or phenytoin therapy and may warrant periodic screening. PMID:26557161

  20. High-Dose-Rate Monotherapy: Safe and Effective Brachytherapy for Patients With Localized Prostate Cancer

    SciTech Connect

    Demanes, D. Jeffrey; Martinez, Alvaro A.; Ghilezan, Michel; Hill, Dennis R.; Schour, Lionel; Brandt, David; Gustafson, Gary

    2011-12-01

    Purpose: High-dose-rate (HDR) brachytherapy used as the only treatment (monotherapy) for early prostate cancer is consistent with current concepts in prostate radiobiology, and the dose is reliably delivered in a prospectively defined anatomic distribution that meets all the requirements for safe and effective therapy. We report the disease control and toxicity of HDR monotherapy from California Endocurietherapy (CET) and William Beaumont Hospital (WBH) in low- and intermediate-risk prostate cancer patients. Methods and Materials: There were 298 patients with localized prostate cancer treated with HDR monotherapy between 1996 and 2005. Two biologically equivalent hypofractionation protocols were used. At CET the dose was 42 Gy in six fractions (two implantations 1 week apart) delivered to a computed tomography-defined planning treatment volume. At WBH the dose was 38 Gy in four fractions (one implantation) based on intraoperative transrectal ultrasound real-time treatment planning. The bladder, urethral, and rectal dose constraints were similar. Toxicity was scored with the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3. Results: The median follow-up time was 5.2 years. The median age of the patients was 63 years, and the median value of the pretreatment prostate-specific antigen was 6.0 ng/mL. The 8-year results were 99% local control, 97% biochemical control (nadir +2), 99% distant metastasis-free survival, 99% cause-specific survival, and 95% overall survival. Toxicity was scored per event, meaning that an individual patient with more than one symptom was represented repeatedly in the morbidity data table. Genitourinary toxicity consisted of 10% transient Grade 2 urinary frequency or urgency and 3% Grade 3 episode of urinary retention. Gastrointestinal toxicity was <1%. Conclusions: High disease control rates and low morbidity demonstrate that HDR monotherapy is safe and effective for patients with localized prostate cancer.

  1. Combination therapy using maxacalcitol and corticosteroid lotions preliminary to monotherapy with maxacalcitol lotion for scalp psoriasis.

    PubMed

    Okubo, Yukari; Natsume, Shoko; Usui, Kae; Muro, Mayuko; Tsuboi, Ryoji

    2014-02-01

    Topical treatment with betamethasone butyrate propionate lotion on 37 patients with scalp psoriasis was replaced with a combination therapy using maxacalcitol lotion (on weekdays) and BBP (on the weekends). This combination therapy was later switched to MXA monotherapy. To identify the optimum duration of the combination therapy, the patients were divided into two groups: a 4-week group and an 8-week group, which were given combination therapy and monotherapy. In both groups, the total mean scores for the skin symptoms had significantly improved in comparison with that obtained at the outset of the study (p < 0.01). In terms of overall improvement, 20.0% of the 4-week group and 72.7% of the 8-week group yielded scores reflecting moderate or greater improvement. The treatment administered to the 8-week group was significantly more effective than that given to the 4-week group at the end of the trial (p < 0.01). This study also suggests that a 4-week combination therapy is an option before switching to monotherapy, but that an 8-week therapy is preferable in severe cases. PMID:22515652

  2. Effects of candesartan and propranolol combination therapy versus propranolol monotherapy in reducing portal hypertension

    PubMed Central

    Kim, Jae Hyun; Kim, Jung Min; Cho, Youn Zoo; Na, Ji Hoon; Kim, Hyun Sik; Kim, Hyoun A; Kang, Hye Won; Baik, Soon Koo; Kwon, Sang Ok; Cha, Seung Hwan; Kim, Young Ju

    2014-01-01

    Background/Aims Angiotensin receptor blockers (ARBs) inhibit activated hepatic stellate cell contraction and are thought to reduce the dynamic portion of intrahepatic resistance. This study compared the effects of combined treatment using the ARB candesartan and propranolol versus propranolol monotherapy on portal pressure in patients with cirrhosis in a prospective, randomized controlled trial. Methods Between January 2008 and July 2009, 53 cirrhotic patients with clinically significant portal hypertension were randomized to receive either candesartan and propranolol combination therapy (26 patients) or propranolol monotherapy (27 patients). Before and 3 months after the administration of the planned medication, the hepatic venous pressure gradient (HVPG) was assessed in both groups. The dose of propranolol was subsequently increased from 20 mg bid until the target heart rate was reached, and the candesartan dose was fixed at 8 mg qd. The primary endpoint was the HVPG response rate; patients with an HVPG reduction of >20% of the baseline value or to <12 mmHg were defined as responders. Results The mean portal pressure declined significantly in both groups, from 16 mmHg (range, 12-28 mmHg) to 13.5 mmHg (range, 6-20 mmHg) in the combination group (P<0.05), and from 17 mmHg (range, 12-27 mmHg) to 14 mmHg (range, 7-25 mmHg) in the propranolol monotherapy group (P<0.05). However, the medication-induced pressure reduction did not differ significantly between the two groups [3.5 mmHg (range, -3-11 mmHg) vs. 3 mmHg (range, -8-10 mmHg), P=0.674]. The response rate (55.6% vs. 61.5%, P=0.435) and the reductions in mean blood pressure or heart rate also did not differ significantly between the combination and monotherapy groups. Conclusions The addition of candesartan (an ARB) to propranolol confers no benefit relative to classical propranolol monotherapy for the treatment of portal hypertension, and is thus not recommended. PMID:25548744

  3. Treatment options after virological failure of first-line tenofovir-based regimens in South Africa: an analysis by deep sequencing.

    PubMed

    Casadellà, Maria; Noguera-Julian, Marc; Sunpath, Henry; Gordon, Michelle; Rodriguez, Cristina; Parera, Mariona; Kuritzkes, Daniel R; Marconi, Vincent C; Paredes, Roger

    2016-04-24

    In a South African cohort of participants living with HIV developing virological failure on first-line tenofovir disoproxyl fumarate (TDF)-based regimens, at least 70% of participants demonstrated TDF resistance according to combined Sanger and MiSeq genotyping. Sanger sequencing missed the K65R mutation in 30% of samples. Unless HIV genotyping is available to closely monitor epidemiological HIV resistance to TDF, its efficacy as second-line therapy will be greatly compromised. PMID:26807968

  4. Impact of Smoking and Brain Metastasis on Outcomes of Advanced EGFR Mutation Lung Adenocarcinoma Patients Treated with First Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

    PubMed Central

    Jain, Amit; Lim, Cindy; Gan, Eugene MingJin; Ng, David Zhihao; Ng, Quan Sing; Ang, Mei Kim; Takano, Angela; Chan, Kian Sing; Tan, Wu Meng; Kanesvaran, Ravindran; Toh, Chee Keong; Loo, Chian Min; Hsu, Anne Ann Ling; Devanand, Anantham; Lim, Chong Hee; Koong, Heng Nung; Koh, Tina; Fong, Kam Weng; Yap, Swee Peng; Kim, Su Woon; Chowbay, Balram; Oon, Lynette; Lim, Kiat Hon; Lim, Wan Teck; Tan, Eng Huat; Tan, Daniel Shao Weng

    2015-01-01

    Objectives This purpose of this study was to examine clinical-pathologic factors – particularly smoking and brain metastases – in EGFR mutation positive (M+) lung adenocarcinoma (ADC) to determine their impact on survival in patients treated with first line EGFR TKI. Methods A retrospective review of EGFR mutation reflex testing experience for all ADC diagnosed at a tertiary Asian cancer centre from January 2009 to April 2013. Amongst this cohort, patients with advanced EGFR M+ ADC treated with first line EGFR TKI were identified to determine factors that influence progression free and overall survival. Results 444/742 (59.8%) ADC reflex tested for EGFR mutations were EGFR M+. Amongst never-smokers (n=468), EGFR M+ were found in 74.5% of females and 76.3% of males, and amongst ever smokers (n=283), in 53.3% of females and 35.6% of males. Exon 20 mutations were found more commonly amongst heavy smokers (> 50 pack years and > 20 pack years, Pearson’s chi square p=0.044, and p=0.038 respectively). 211 patients treated with palliative first line TKI had a median PFS and OS of 9.2 and 19.6 months respectively. 26% of patients had brain metastasis at diagnosis. This was significantly detrimental to overall survival (HR 1.85, CI 1.09-3.16, p=0.024) on multivariate analysis. There was no evidence that smoking status had a significant impact on survival. Conclusions The high prevalence of EGFR M+ in our patient population warrants reflex testing regardless of gender and smoking status. Smoking status and dosage did not impact progression free or overall survival in patients treated with first line EGFR TKI. The presence of brain metastasis at diagnosis negatively impacts overall survival. PMID:25955322

  5. Post-study therapy as a source of confounding in survival analysis of first-line studies in patients with advanced non-small-cell lung cancer

    PubMed Central

    Zietemann, Vera D; Schuster, Tibor; Duell, Thomas HG

    2011-01-01

    Clinical trials exploring the long-term effects of first-line therapy in patients with advanced non-small-cell lung cancer generally disregard subsequent treatment although most patients receive second and third-line therapies. The choice of further therapy depends on critical intermediate events such as disease progression and it is usually left at the physician’s discretion. Time-dependent confounding may then arise with standard survival analyses producing biased effect estimates, even in randomized trials. Herein we describe the concept of time-dependent confounding in detail and discuss whether the response to first-line treatment may be a potential time-dependent confounding factor for survival in the context of subsequent therapy. A prospective observational study of 406 patients with advanced non-small-cell lung cancer served as an example base. There is evidence that time-dependent confounding may occur in multivariate survival analysis after first-line therapy when disregarding subsequent treatment. In the light of this important but underestimated aspect some of the large and meaningful recent clinical first-line lung cancer studies are discussed, focussing on subsequent treatment and its potential impact on the survival of the study patients. No recently performed lung cancer trial applied adequate statistical analyses despite the frequent use of subsequent therapies. In conclusion, effect estimates from standard survival analysis may be biased even in randomized controlled trials because of time-dependent confounding. To adequately assess treatment effects on long-term outcomes appropriate statistical analyses need to take subsequent treatment into account. PMID:22263071

  6. Effectiveness of Trastuzumab in First-Line HER2+ Metastatic Breast Cancer After Failure in Adjuvant Setting: A Controlled Cohort Study

    PubMed Central

    Negri, Eva; Zambelli, Alberto; Franchi, Matteo; Rossi, Marta; Bonifazi, Martina; Corrao, Giovanni; Moja, Lorenzo; Zocchetti, Carlo

    2014-01-01

    Background. The evidence supporting the use of trastuzumab (T) in a metastatic setting comes from studies that included (almost) only patients who never received prior T. We investigated the effectiveness of T as first-line therapy for metastatic breast cancer (mBC) in women previously treated with T in the adjuvant setting. Materials and Methods. By using record linkage of five administrative health care databases of Lombardy, Italy, we identified 2,046 women treated with T for early breast cancer (eBC) in 2006–2009, 96 of whom developed a metastasis and were retreated with T in first-line treatment for mBC (treatment group). We compared the overall survival (OS) of these women with that of 197 women treated with T in first-line treatment for mBC, who were treated with therapies other than T for early disease (control group). We computed Kaplan-Meier 2-year OS and used a proportional hazard model to estimate the multivariate hazard ratio (HR) of death in the intervention group compared with the control group, adjusted by age, use of endocrine therapy, and site of metastasis. Results. Two-year OS was 60.0% in the treatment group and 59.5% in the control group. The adjusted HR of death in the treatment group compared with the control group was 0.79 (95% confidence interval, 0.50–1.26). Conclusion. Our data provide convincing evidence that the outcome of women receiving first-line T treatment for mBC after T failure in the adjuvant setting is comparable to that of women not receiving T for eBC. These data are of specific interest, given the unavailability of data from randomized clinical trials. PMID:25355843

  7. Cumulative meta-analysis of epidermal growth factor receptor-tyrosine kinase inhibitors as first-line therapy in metastatic non-small-cell lung cancer.

    PubMed

    Normando, Sávia R C; Cruz, Felipe M; Del Giglio, Auro

    2015-10-01

    We carried out a meta-analysis to evaluate the benefit of epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKI) over the standard first-line platinum-based chemotherapy for metastatic non-small-cell lung cancer (NSCLC). Studies that were considered eligible included controlled prospective randomized phase III studies in patients with NSCLC stages IIIB or IV. These patients received standard first-line platinum-based chemotherapy or EGFR-TKI; overall survival and progression-free survival (PFS) with adequate data were available to calculate and estimate the hazard ratio (HR) with a confidence interval (CI) of 95%. Eight studies were identified that compared EGFR-TKI versus standard first-line platinum-based chemotherapy to treat NSCLC in 2962 patients. Patients receiving EGFR-TKI showed significantly longer PFS [HR=0.266 (95% CI=0.20-0.35), P<0.0001]. No significant difference in overall survival [HR=0.946 (95% CI=0.35-2.53), P=0.912] was observed between the groups. The cumulative meta-analysis of the studies showed that, since 2011 (OPTIMAL study), the PFS benefit in the EGFR-TKI arm was statistically significantly longer. Toxicity values greater than or equal to 3 in the most prevalent EGFR-TKI group included skin rash, diarrhea, and increased aminotransferase. EGFR-TKI treatment significantly extends PFS, with acceptable toxicities than platinum-based chemotherapy. Thus, they should be considered as the first choice in the first-line treatment for patients with NSCLC and with the EGFR mutation. PMID:26237501

  8. Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations Associated with First-Line Stavudine-Containing Antiretroviral Therapy: Programmatic Implications for Countries Phasing Out Stavudine

    PubMed Central

    Tang, Michele W.; Rhee, Soo-Yon; Bertagnolio, Silvia; Ford, Nathan; Holmes, Susan; Sigaloff, Kim C.; Hamers, Raph L.; de Wit, Tobias F. Rinke; Fleury, Herve J.; Kanki, Phyllis J.; Ruxrungtham, Kiat; Hawkins, Claudia A.; Wallis, Carole L.; Stevens, Wendy; van Zyl, Gert U.; Manosuthi, Weerawat; Hosseinipour, Mina C.; Ngo-Giang-Huong, Nicole; Belec, Laurent; Peeters, Martine; Aghokeng, Avelin; Bunupuradah, Torsak; Burda, Sherri; Cane, Patricia; Cappelli, Giulia; Charpentier, Charlotte; Dagnra, Anoumou Y.; Deshpande, Alaka K.; El-Katib, Ziad; Eshleman, Susan H.; Fokam, Joseph; Gody, Jean-Chrysostome; Katzenstein, David; Koyalta, Donato D.; Kumwenda, Johnstone J.; Lallemant, Marc; Lynen, Lutgarde; Marconi, Vincent C.; Margot, Nicolas A.; Moussa, Sandrine; Ndung'u, Thumbi; Nyambi, Phillipe N.; Orrell, Catherine; Schapiro, Jonathan M.; Schuurman, Rob; Sirivichayakul, Sunee; Smith, Davey; Zolfo, Maria; Jordan, Michael R.; Shafer, Robert W.

    2013-01-01

    Background The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. Methods We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. Results Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. Conclusions Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy. PMID:23687292

  9. Target hepatic artery regional chemotherapy and bevacizumab perfusion in liver metastatic colorectal cancer after failure of first-line or second-line systemic chemotherapy.

    PubMed

    Chen, Hui; Zhang, Ji; Cao, Guang; Liu, Peng; Xu, Haifeng; Wang, Xiaodong; Zhu, Xu; Gao, Song; Guo, Jianhai; Zhu, Linzhong; Zhang, Pengjun

    2016-02-01

    Colorectal cancer liver metastasis (CRLM) is a refractory disease after failure of first-line or second-line chemotherapy. Bevacizumab is recommended as first-line therapy for advanced colorectal cancer, but is unproven in CRLM through the hepatic artery. We report favorable outcomes with targeted vessel regional chemotherapy (TVRC) for liver metastatic gastric cancer. TVRC with FOLFOX and bevacizumab perfusion through the hepatic artery was attempted for CRLM for efficacy and safety evaluation. In a single-institution retrospective observational study, 246 patients with CRLM after at least first-line or second-line failure of systemic chemotherapy received TVRC with FOLFOX (i.e. oxaliplatin, leucovorin, and 5-fluorouracil). Of 246 patients, 63 were enrolled into two groups: group 1 (n=30) received bevacizumab and TVRC following tumor progression during previous TVRC treatments; group 2 (n=33) received TVRC plus bevacizumab for CRLM on initiating TVRC. There were no significant differences in the median survival time (14.7 vs. 13.2 months, P=0.367), although the median time to progression was significant (3.3 vs. 5.5 months, P=0.026) between groups. No severe adverse events related to TVRC plus bevacizumab perfusion occurred. Target vessel regional chemotherapy with FOLFOX plus bevacizumab perfusion through the hepatic artery was effective and safe in CRLM. The optimal combination of TVRC and bevacizumab needs further confirmation in future phase II-III clinical trials. PMID:26566233

  10. Intensified therapy followed by autologous stem-cell transplantation (ASCT) versus conventional therapy as first-line treatment of follicular lymphoma: a meta-analysis.

    PubMed

    Wang, Baohong; Ren, Cuiai; Zhang, Weide; Ma, Xiaoyan; Xia, Bingsen; Sheng, Zhixin

    2013-03-01

    There are two different international standards for the treatment of follicular lymphoma (FL): intensified therapy followed by autologous stem-cell transplantation (ASCT) and conventional therapy in the first-line setting. However, their role remains unclear. Our aim was to define the treatment effect of intensified therapy followed by ASCT compared with conventional therapy as first-line treatment of patients with FL in terms of overall survival (OS) and event-free survival (EFS). We searched for randomised controlled trials in Medline, Embase, the Cochrane controlled trials register and the Science Citation Index (1985 to June 2011). Effect measures used were hazard ratios (HR) for OS, EFS and secondary tumour rate. Two independent review authors extracted data and assessed quality of trials. Four trials were identified, covering a total of 941 subjects. The random-effects summary HR by comparing the treatment effect on OS between intensified and conventional therapy was 0.95 [0.70, 1.30] (p = 0.75), indicating that no additional survival benefit was derived from the intensified therapy followed by ASCT. A significant benefit of intensified therapy followed by ASCT as first-line treatment was detected in terms of EFS: the random-effects summary HR (intensified versus conventional therapy) was 0.59 [0.44, 0.79] (p < 0.001). This meta-analysis showed that despite its superior EFS, intensified therapy followed by ASCT does not improve the OS compared with conventional therapy. PMID:22488650

  11. Impact of ELN recommendations in the management of first-line treated chronic myeloid leukaemia patients: a French cross-sectional study.

    PubMed

    Etienne, Gabriel; Huguet, Francoise; Guerci-Bresler, Agnès; Nicolini, Franck E; Maloisel, Frédéric; Coiteux, Valérie; Dauriac, Charles; Carpentier, Nathalie; Bourdeix, Isabelle; Tulliez, Michel; Cony-Makhoul, Pascale

    2016-07-01

    The availability of tyrosine kinase inhibitors has extended therapeutic options for chronic myeloid leukaemia (CML) patients. Monitoring recommendations and clinical response goals have recently been updated. The objective of this study was to describe the profile of CML patients in chronic phase currently receiving first-line therapy, including treatment, monitoring and response kinetics. A multicentre, cross-sectional, epidemiological survey in unselected chronic phase CML patients in France attending consultations during a one-month period was performed. 438 of 697 (62·8%) reported patients were currently receiving first-line treatment and were analysed. Imatinib was the most frequently received treatment (72·4% of patients). Retrospective cytogenetic and molecular assessments at 3, 6, 12 or 18 months were available in 88·4% of patients. At the 12-month assessment, 32·2% were not in major molecular response (MMR). At last assessment, among 355 patients with duration of treatment ≥ 12 months, 91·5% had achieved MMR and 66·5% were in deep molecular response. This study, performed in everyday practice population of CML patients, suggests that monitoring of molecular responses in real-life practice is aligned with European LeukaemiaNet recommendations. The majority of patients still receiving first-line treatment are in optimal response, with a few being classified as in the warning area or responding to failure. PMID:27060881

  12. Nab-paclitaxel plus gemcitabine as first-line palliative chemotherapy in a patient with metastatic pancreatic cancer with Eastern Cooperative Oncology Group performance status of 2

    PubMed Central

    MARTÍN, ANDRÉS J. MUÑOZ; ALFONSO, PILAR GARCÍA; RUPÉREZ, ANA B.; JIMÉNEZ, MIGUEL MARTÍN

    2016-01-01

    Metastatic pancreatic cancer (PC) has been associated with a considerably poor prognosis. Due to its toxicity, first-line combination chemotherapy is limited to patients with a good performance status (PS). Previously nab-paclitaxel plus gemcitabine has been demonstrated to improve the overall survival rate in patients with advanced pancreatic cancer with a good PS. The present study reports a case of a patient with metastatic PC with a poor PS (Eastern Cooperative Oncology Group 2) and a complex set of comorbidities treated with nab-paclitaxel plus gemcitabine as a first-line palliative therapy. Adjusted doses of nab-paclitaxel plus gemcitabine reached a favourable clinical, radiological and biochemical response in the present patient, which increased the quality of life for the patient. Eventually, the patient succumbed to acute cholangitis. Based on the results of the present study, nab-paclitaxel plus gemcitabine appears to be a favourable treatment as first-line palliative chemotherapy for patients with metastatic PC, comorbidities and poor PS. PMID:27347207

  13. [Systematic review and Meta-analysis of Shenqi Fuzheng injection combined with first-line chemotherapy for non-small cell lung cancer].

    PubMed

    Hao, Teng-teng; Xie, Yan-ming; Liao, Xing; Wang, Jing

    2015-10-01

    The paper is to systematically evaluate the effect and safety of Shenqi Fuzheng injection (SFI) combined with first-line chemotherapy for non-small cell lung cancer (NSCLC). Randomized controlled trials (RCTs) on Shenqi Fuzheng injection (SFI) combined with first-line chemotherapy (experiment group) and chemotherapy alone group ( control group) were electronically retrieved from Medline, EMbase, Clinical Trials, Cochrane Library, CBM, CNKI, VIP, and Wanfang Data base. All trials were assessed for quality according to the Cochrane Reviewer's Handbook for Systematic Reviews of Intervention and then Meta-analysis was performed withRevMan5. 2 Software. A total of 43 RCTs (3433 patients) were included after screening and selecting. Results of Meta-analysis showed that: Objective remission rate (ORR): ORR of experimental group was about 20% higher than that of control group [RR = 1.23, 95% CI (1.11,1.35), P < 0.0001]. Disease control rate (DCR):DCR of SFI combined with first-line chemotherapy was 11% higher than that of first-line chemotherapy alone [RR = 1.11, 95% CI (1.07, 1.16), P < 0.000 01]. Life quality evaluated by Kosovan performance status (KPS) showed that: life quality improvement rate of experimental group was about twice of that in control group [RR = 2.02, 95% CI (1.81, 2.26), P < 0.000 01]. Toxic and side reaction analysis showed that: the incidence of side reactions in experimental group was about 50% lower than that in control group [RR = 0.59, 95% CI (0.53, 0.66), P < 0.000 01]. Immune function test showed that: the function of experimental group was 3.2 (standard deviations) times greater than that of control group [MD = 3.23, 95% CI (2.86, 3.60), P < 0.000 01]. We can see that SFI combined with first-line chemotherapy for NSCLC can increase objective efficacy, improve life quality, decrease toxic and side reactionsinduced by chemotherapy, and improve the immune functions. As most of the included studies in this systematic evaluation had poor quality

  14. Treatment of Metastatic Breast Cancer in a Real-World Scenario: Is Progression-Free Survival With First Line Predictive of Benefit From Second and Later Lines?

    PubMed Central

    Bonotto, Marta; Gerratana, Lorenzo; Iacono, Donatella; Minisini, Alessandro Marco; Rihawi, Karim; Fasola, Gianpiero

    2015-01-01

    Introduction. Despite the availability of several therapeutic options for metastatic breast cancer (MBC), no robust predictive factors are available to help clinical decision making. Nevertheless, a decreasing benefit from first line to subsequent lines of treatment is commonly observed. The aim of this study was to assess the impact of benefit from first-line therapy on outcome with subsequent lines. Methods. We analyzed a consecutive series of 472 MBC patients treated with chemotherapy (CT) and/or endocrine therapy (ET) between 2004 and 2012. We evaluated progression-free survival (PFS) at first (PFS1), second, third, and fourth therapeutic lines, according to treatment (ET and/or CT) and tumor subtypes. Results. In the whole cohort, median overall survival was 34 months, and median PFS1 was 9 months. A 6-month benefit was shown by 289 patients (63.5%) at first line, 128 (40.5%) at second line, 76 (33.8%) at third line, and 34 (23.3%) at fourth line. Not having a 6-month benefit at PFS1 was associated with less chance of benefit at second line (odds ratio [OR]: 0.48; 95% confidence interval [CI]: 0.29–0.77, p = .0026) and at any line beyond first (OR: 0.39; 95% CI: 0.24–0.62, p < .0001). In the total series, after stratification for tumor subtypes, a strong predictive effect was observed among HER2-positive tumors (OR: 0.2; 95% CI: 0.05–0.73, p = .0152). Conclusion. Our results suggest that the absence of at least a 6-month benefit in terms of PFS with first-line therapy predicts a reduced probability of benefit from subsequent therapeutic lines, especially in HER2-positive disease. Implications for Practice: This study supports evidence showing that the absence of a 6-month benefit in terms of progression-free survival with first-line therapy predicts a lack of benefit from subsequent therapeutic lines in metastatic breast cancer. The random distribution of benefit experienced by a subset of the cohort further spurs an interest in identifying predictive

  15. Treatment failure and drug resistance in HIV-positive patients on tenofovir-based first-line antiretroviral therapy in western Kenya

    PubMed Central

    Brooks, Katherine; Diero, Lameck; DeLong, Allison; Balamane, Maya; Reitsma, Marissa; Kemboi, Emmanuel; Orido, Millicent; Emonyi, Wilfred; Coetzer, Mia; Hogan, Joseph; Kantor, Rami

    2016-01-01

    Introduction Tenofovir-based first-line antiretroviral therapy (ART) is recommended globally. To evaluate the impact of its incorporation into the World Health Organization (WHO) guidelines, we examined treatment failure and drug resistance among a cohort of patients on tenofovir-based first-line ART at the Academic Model Providing Access to Healthcare, a large HIV treatment programme in western Kenya. Methods We determined viral load (VL), drug resistance and their correlates in patients on ≥six months of tenofovir-based first-line ART. Based on enrolled patients’ characteristics, we described these measures in those with (prior ART group) and without (tenofovir-only group) prior non-tenofovir-based first-line ART using Wilcoxon rank sum and Fisher's exact tests. Results Among 333 participants (55% female; median age 41 years; median CD4 336 cells/µL), detectable (>40 copies/mL) VL was found in 18%, and VL>1000 copies/mL (WHO threshold) in 10%. Virologic failure at both thresholds was significantly higher in 217 participants in the tenofovir-only group compared with 116 in the prior ART group using both cut-offs (24% vs. 7% with VL>40 copies/mL; 15% vs. 1% with VL>1000 copies/mL). Failure in the tenofovir-only group was associated with lower CD4 values and advanced WHO stage. In 35 available genotypes from 51 participants in the tenofovir-only group with VL>40 copies/mL (69% subtype A), any resistance was found in 89% and dual-class resistance in 83%. Tenofovir signature mutation K65R occurred in 71% (17/24) of the patients infected with subtype A. Patients with K65R had significantly lower CD4 values, higher WHO stage and more resistance mutations. Conclusions In this Kenyan cohort, tenofovir-based first-line ART resulted in good (90%) virologic suppression including high suppression (99%) after switch from non-tenofovir-based ART. Lower virologic suppression (85%) and high observed resistance levels (89%) in the tenofovir-only group impact future treatment

  16. “…still waiting for chloroquine”: the challenge of communicating changes in first-line treatment policy for uncomplicated malaria in a remote Kenyan district

    PubMed Central

    2014-01-01

    Background Widespread parasite resistance to first-line treatment for uncomplicated malaria leads to introduction of new drug interventions. Introducing such interventions is complex and sensitive because of stakeholder interests and public resistance. To enhance take up of such interventions, health policy communication strategies need to deliver accurate and accessible information to empower communities with necessary information and address problems of cultural acceptance of new interventions. Objectives To explore community understanding of policy changes in first-line treatment for uncomplicated malaria in Kenya; to evaluate the potential role of policy communication in influencing responses to changes in first-line treatment policy. Methods Data collection involved qualitative strategies in a remote district in the Kenyan Coast: in-depth interviews (n = 29), focus group discussions (n = 14), informal conversations (n = 11) and patient narratives (n = 8). Constant comparative method was used in the analysis. Being malaria-prone and remotely located, the district offered an ideal area to investigate whether or not and how policy communication about a matter as critical as change of treatment policy reaches vulnerable populations. Results Three years after initial implementation (2009), there was limited knowledge or understanding regarding change of first-line treatment from sulphadoxine-pyrimethamine (SP) to artemether-lumefantrine (AL) for treatment of uncomplicated malaria in the study district. The print and electronic media used to create awareness about the drug change appeared to have had little impact. Although respondents were aware of the existence of AL, the drug was known neither by name nor as the official first-line treatment. Depending on individuals or groups, AL was largely viewed negatively. The weaknesses in communication strategy surrounding the change to AL included poor choice of communication tools, confusing

  17. Outcomes after viral load rebound on first-line antiretroviral therapy in HIV-infected children in the UK/Ireland: an observational cohort study

    PubMed Central

    CHILDS, Tristan; SHINGADIA, Delane; GOODALL, Ruth; DOERHOLT, Katja; LYALL, Hermione; DUONG, Trinh; JUDD, Ali; GIBB, Di M; COLLINS, Intira Jeannie

    2015-01-01

    Background Approximately one-third of HIV-infected children experience virological failure within two years of initiating antiretroviral therapy (ART). We determined the probability of switch to second-line ART or viral load (VL) re-suppression without switch among children who experienced VL rebound on first-line ART in an observational cohort in the UK/Ireland. Methods Children with VL rebound (confirmed VL>400c/ml following suppression <400c/ml) on first-line ART were included. Competing risk analysis estimated the probability of: switch to second-line; confirmed re-suppression (two consecutive VL<400c/ml) without switch; and continued VL>400c/ml without switch. Predictors of time to switch were assessed. Findings Of 900 children starting first-line ART who had VL<400c/ml by one year, 170 (19%) experienced VL rebound by median [IQR] 20·6 months [9·7-40·5]. At rebound, median age was 10·6 years [5·6-13·4], VL 3·6 log10c/ml [3·1-4·2], and CD4% 24 [17-32]. Eighty-nine (52%) switched to second-line ART at median 4·9 months [1·7-13·4] after VL rebound, 53 (31%) re-suppressed without switch (61% of those on PI-based and 24% of those on NNRTI-based first-line regimens), while 28 (16%) neither re-suppressed nor switched. At 12 months after rebound, probabilities of switch or re-suppression without switch were 38% (95% CI 30-45) and 27% (95% CI 21-34), respectively. Faster time to switch was associated with higher VL (p<0·0001), later calendar year (p=0·02) at VL rebound, and NNRTI- or triple NRTI- versus PI-based first-line (p=0·001). Interpretation One-third of children with VL rebound re-suppressed without switch. The possibility of re-suppression with adherence support should be considered prior to switching. Funding NHS England PMID:26413561

  18. First-Line Treatment Patterns and Clinical Outcomes in Patients With HER2-Positive and Hormone Receptor-Positive Metastatic Breast Cancer From registHER

    PubMed Central

    Kaufman, Peter A.; Brufsky, Adam M.; Mayer, Musa; Yood, Marianne Ulcickas; Yoo, Bongin; Quah, Cheng; Yardley, Denise; Rugo, Hope S.

    2013-01-01

    Background. Limited data are available describing the natural history of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC). We examined first-line treatment patterns and clinical outcomes in patients with HER2-positive, HR-positive MBC in a real-world setting. Methods. registHER is a prospective, observational cohort of 1,023 patients with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up time: 27 months). Demographics, first-line treatment patterns, and clinical outcomes were examined for 530 HER2-positive, HR-positive patients. Progression-free survival (PFS) and overall survival (OS) times were examined. Multivariate analyses adjusted for baseline demographic and prognostic factors. Results. HER2-positive, HR-positive patients receiving first-line trastuzumab plus hormonal therapy had significantly longer PFS times than patients who received hormonal therapy only (13.8 vs. 4.8 months; adjusted hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.22–0.60); a nonsignificant reduction in OS time was observed (adjusted HR: 0.55, 95% CI: 0.27–1.14). Compared with patients who received first-line trastuzumab plus chemotherapy, patients who received first-line trastuzumab plus chemotherapy and hormonal therapy had longer median PFS times (20.4 months vs. 9.5 months; adjusted HR: 0.53, 95% CI: 0.42–0.68); a statistically significant reduction in risk of death was observed (adjusted HR: 0.50, 95% CI: 0.36–0.70). Sequential use of chemotherapy and hormonal therapy was associated with improved OS times when compared with concurrent use (adjusted PFS HR: 0.81, 95% CI: 0.54–1.21; adjusted OS HR: 0.48, 95% CI: 0.26–0.89). Conclusions. These real-world data in patients with HER2-positive/HR-positive MBC provide evidence that, with or without chemotherapy, dual targeting of HRs and HER2 receptors is associated with significantly prolonged

  19. Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis

    PubMed Central

    Fleischmann, Roy M; Huizinga, Tom W J; Kavanaugh, Arthur F; Wilkinson, Bethanie; Kwok, Kenneth; DeMasi, Ryan; van Vollenhoven, Ronald F

    2016-01-01

    Introduction Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib monotherapy was previously shown to inhibit structural damage, reduce clinical signs and symptoms of RA, and improve physical functioning over 24 months in methotrexate (MTX)-naive adult patients with RA. In this post hoc analysis, we compared efficacy and safety of tofacitinib in patients with early (disease duration <1 year) versus established (≥1 year) RA. Methods MTX-naive patients ≥18 years with active RA received tofacitinib monotherapy (5 or 10 mg two times a day, or MTX monotherapy, in a 24-month Phase 3 trial. Results Of 956 patients (tofacitinib 5 mg two times a day, n=373; tofacitinib 10 mg two times a day, n=397; MTX, n=186), 54% had early RA. Baseline disease activity and functional disability were similar in both groups; radiographic damage was greater in patients with established RA. At month 24, clinical response rates were significantly greater in patients with early versus established RA in the tofacitinib 5 mg two times a day group. Both tofacitinib doses had greater effects on clinical, functional and radiographic improvements at 1 and 2 years compared with MTX, independent of disease duration. No new safety signals were observed. Conclusions Treatment response was generally similar in early and established RA; significantly greater improvements were observed at month 24 with tofacitinib 5 mg two times a day in early versus established RA. Tofacitinib 5 and 10 mg two times a day demonstrated greater efficacy versus MTX irrespective of disease duration. No difference in safety profiles was observed between patients with early or established RA. Trial registration number NCT01039688; Results. PMID:27493790

  20. Risk Factors for Treatment Failure of Polymyxin B Monotherapy for Carbapenem-Resistant Klebsiella pneumoniae Infections

    PubMed Central

    Dubrovskaya, Yanina; Scipione, Marco R.; Esaian, Diana; Phillips, Michael S.; Papadopoulos, John; Mehta, Sapna A.

    2013-01-01

    Polymyxins are reserved for salvage therapy of infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). Though synergy has been demonstrated for the combination of polymyxins with carbapenems or tigecycline, in vitro synergy tests are nonstandardized, and the clinical effect of synergy remains unclear. This study describes outcomes for patients with CRKP infections who were treated with polymyxin B monotherapy. We retrospectively reviewed the medical records of patients with CRKP infections who received polymyxin B monotherapy from 2007 to 2011. Clinical, microbiology, and antimicrobial treatment data were collected. Risk factors for treatment failure were identified by logistic regression. Forty patients were included in the analysis. Twenty-nine of 40 (73%) patients achieved clinical cure as defined by clinician-documented improvement in signs and symptoms of infections, and 17/32 (53%) patients with follow-up culture data achieved microbiological cure. End-of-treatment mortality was 10%, and 30-day mortality was 28%. In a multivariate analysis, baseline renal insufficiency was associated with a 6.0-fold increase in clinical failure after adjusting for septic shock (odds ratio [OR] = 6.0; 95% confidence interval [CI] = 1.22 to 29.59). Breakthrough infections with organisms intrinsically resistant to polymyxins occurred in 3 patients during the treatment. Eighteen of 40 (45%) patients developed a new CRKP infection a median of 23 days after initial polymyxin B treatment, and 3 of these 18 infections were polymyxin resistant. The clinical cure rate achieved in this retrospective study was 73% of patients with CRKP infections treated with polymyxin B monotherapy. Baseline renal insufficiency was a risk factor for treatment failure after adjusting for septic shock. Breakthrough infections with organisms intrinsically resistant to polymyxin B and development of resistance to polymyxin B in subsequent CRKP isolates are of concern. PMID:23959321

  1. Prostate-Specific Antigen Bounce After High-Dose-Rate Monotherapy for Prostate Cancer

    SciTech Connect

    Mehta, Niraj H.; Kamrava, Mitchell; Wang, Pin-Chieh; Steinberg, Michael; Demanes, Jeffrey

    2013-07-15

    Purpose: To characterize the magnitude and kinetics of prostate-specific antigen (PSA) bounces after high-dose-rate (HDR) monotherapy and determine relationships between certain clinical factors and PSA bounce. Methods and Materials: Longitudinal PSA data and various clinical parameters were examined in 157 consecutive patients treated with HDR monotherapy between 1996 and 2005. We used the following definition for PSA bounce: rise in PSA ≥threshold, after which it returns to the prior level or lower. Prostate-specific antigen failure was defined per the Phoenix definition (nadir +2 ng/mL). Results: A PSA bounce was noted in 67 patients (43%). The number of bounces per patient was 1 in 45 cases (67%), 2 in 19 (28%), 3 in 2 (3%), 4 in 0, and 5 in 1 (1%). The median time to maximum PSA bounce was 1.3 years, its median magnitude was 0.7, and its median duration was 0.75 years. Three patients (2%) were noted to have PSA failure. None of the 3 patients who experienced biochemical failure exhibited PSA bounce. In the fully adjusted model for predicting each bounce, patients aged <55 years had a statistically significant higher likelihood of experiencing a bounce (odds ratio 2.22, 95% confidence interval 1.38-3.57, P=.001). There was also a statistically significant higher probability of experiencing a bounce for every unit decrease in Gleason score (odds ratio 1.52, 95% confidence interval 1.01-2.04, P=.045). Conclusions: A PSA bounce occurs in a significant percentage of patients treated with HDR monotherapy, with magnitudes varying from <1 in 28% of cases to ≥1 in 15%. The median duration of bounce is <1 year. More bounces were identified in patients with lower Gleason score and age <55 years. Further investigation using a model to correlate magnitude and frequency of bounces with clinical variables are under way.

  2. HIV-1 subtype influences susceptibility and response to monotherapy with the protease inhibitor lopinavir/ritonavir

    PubMed Central

    Sutherland, K. A.; Ghosn, J.; Gregson, J.; Mbisa, J. L.; Chaix, M. L.; Cohen Codar, I.; Delfraissy, J. F.; Delaugerre, C.; Gupta, R. K.

    2015-01-01

    Objective PI susceptibility results from a complex interplay between protease and Gag proteins, with Gag showing wide variation across HIV-1 subtypes. We explored the impact of pre-treatment susceptibility on the outcome of lopinavir/ritonavir monotherapy. Methods Treatment-naive individuals who experienced lopinavir/ritonavir monotherapy failure from the MONARK study were matched (by subtype, viral load and baseline CD4 count) with those who achieved virological response (‘successes’). Successes were defined by viral load <400 copies/mL after week 24 and <50 copies/mL from week 48 to week 96. Full-length Gag–protease was amplified from patient samples for in vitro phenotypic susceptibility testing, with susceptibility expressed as fold change (FC) relative to a subtype B reference strain. Results Baseline lopinavir susceptibility was lower in viral failures compared with viral successes, but the differences were not statistically significant (median lopinavir susceptibility: 4.4 versus 8.5, respectively, P = 0.17). Among CRF02_AG/G patients, there was a significant difference in lopinavir susceptibility between the two groups (7.1 versus 10.4, P = 0.047), while in subtype B the difference was not significant (2.7 versus 3.4, P = 0.13). Subtype CRF02_AG/G viruses had a median lopinavir FC of 8.7 compared with 3.1 for subtype B (P = 0.001). Conclusions We report an association between reduced PI susceptibility (using full-length Gag–protease sequences) at baseline and subsequent virological failure on lopinavir/ritonavir monotherapy in antiretroviral-naive patients harbouring subtype CRF02_AG/G viruses. We speculate that this may be important in the context of suboptimal adherence in determining viral failure. PMID:25228587

  3. Genotoxicity evaluation in patients on phenobarbital monotherapy by sister chromatid exchange.

    PubMed

    Schaumann, B A; Winge, V B; Pederson, M

    1989-01-01

    The potential of phenobarbital to interact with DNA has been studied using the sister chromatid exchange (SCE) assay in peripheral lymphocytes of nine adult male patients with epilepsy and of their matched controls. All patients were otherwise healthy individuals, treated chronically with phenobarbital in monotherapy. No statistically significant differences in SCE levels were found between the patient and control groups. Smoking was associated with increased SCE frequencies. The experiment was repeated with five available patients, using a slightly modified methodology. Although different SCE scores were obtained, the results of both tests were comparable. PMID:2585535

  4. Long-term assessment of prostaglandin analogs and timolol fixed combinations vs prostaglandin analogs monotherapy

    PubMed Central

    Liu, Ai-Wei; Gan, Lin-Yang; Yao, Xiang; Zhou, Jian

    2016-01-01

    AIM To draw a Meta-analysis over the comparison of the intraocular pressure (IOP)-lowering efficacy and safety between the commonly used fixed-combinations of prostaglandin analogs and 0.5% timolol with prostaglandin analogs (PGAs) monotherapy. METHODS After searching the published reports from MEDLINE, EMBASE, the Cochrane Library, all randomized controlled clinical trials (RCTs) comparing the fixed combination of PGAs/timolol therapy (FCs) and PGAs monotherapy with treatment duration at least 6mo were included. The efficacy outcomes were mean diurnal IOP, percentage of participants whose IOP were lower than 18 mm Hg, incidence of visual field change, while the safety outcomes included corneal side effects, hyperemia and eye irritation. The analysis was carried out in RevMan version 5.3 software. RESULTS After six-month medical intervention, the mean diurnal IOP of FCs was lower than PGAs (MD -1.14, 95% CI -1.82 to -0.46, P=0.001); the percentage of target IOP achieving between FCs and PGAs showed no significant difference (RR 1.18, 95% CI 0.97 to 1.43, P=0.10). No statistically significant differences of the incidence of hyperemia (RR 0.67, 95% CI 0.45 to 1.01, P=0.06) and eye irritation (RR 1.20, 95% CI 0.95 to 1.51, P=0.12) between the FCs and PGAs monotherapy were detected. Only one research involved in corneal events, result of this trial revealed no difference between two intervention groups regarding corneal effects (central endothelial cell density, MD -0.20, 95% CI -0.72 to 0.32, P=0.45; central corneal thickness, MD -0.01, 95% CI -0.02 to 0.00, P=0.23). The evaluation of visual field change was not performed due to the limited duration of the trials included in this Meta-analysis. CONCLUSION The long-term efficacy of the FCs overweighed the PGAs monotherapy in lowering IOP, but in the incidence of hyperemia and eye irritation syndromes, the differences are not statically significant. More RCTs with detailed and authentic data over the assessments of

  5. Hepatitis B Virus Reactivation Following Salazosulfapyridine Monotherapy in a Patient with Rheumatoid Arthritis.

    PubMed

    Akashi, Kengo; Saegusa, Jun; Nakamachi, Yuji; Nakazawa, Takashi; Kumagai, Shunichi; Morinobu, Akio

    2016-01-01

    A 72-year-old man was diagnosed with rheumatoid arthritis (RA) and prior hepatitis B virus (HBV) infection. He began treatment with salazosulfapyridine (SASP). Several months later, his blood tests reflected a slightly elevated liver function. Serum tests were positive for hepatitis B surface antigen and HBV-DNA, and the diagnosis of de novo HBV hepatitis was made. A genetic analysis showed that he had polymorphisms of ABCG2 and NAT2, which could lead to high plasma concentrations of SASP and sulfapyridine. To the best of our knowledge, this is the first report of de novo hepatitis developing during SASP monotherapy for RA. PMID:27181550

  6. Efficacy and Safety of Levetiracetam and Carbamazepine as Monotherapy in Partial Seizures.

    PubMed

    Suresh, Swaroop Hassan; Chakraborty, Ananya; Virupakshaiah, Akash; Kumar, Nithin

    2015-01-01

    Introduction. Levetiracetam (LEV) is a newer antiepileptic drug with better pharmacokinetic profile. Currently, it is frequently used for the treatment of partial seizures. The present study was undertaken to compare the efficacy and safety of LEV and Carbamazepine (CBZ) in partial epilepsy. Methods. This was a prospective, open labeled, randomized study. It was conducted in participants suffering from partial seizures after the approval of ethics committee and written informed consent. The first group received Tab LEV (500 to 3000 mg/day) and the second group received Tab CBZ (300 to 600 mg/day). The primary outcomes were efficacy and safety. The secondary outcome was the Quality of Life (QOL). Efficacy was assessed by comparing the seizure freedom rates at the end of 6 months. Safety profile was evaluated by comparing the adverse effects. QOL was assessed by QOLIE-10 scale. Results. The overall seizure freedom rate at the end of 6 months was 71.42% in CBZ group compared to 78.57% in LEV group (p = 0.2529). Both LEV and CBZ reported a similar incidence of adverse reactions. LEV group reported more behavioral changes like increased aggression and anxiety. Also, it showed better QOL compared to the CBZ group. Conclusion. LEV monotherapy and CBZ monotherapy demonstrated similar efficacy for treatment of partial epilepsy and were found to be well tolerated. PMID:26798511

  7. Oncologic Outcome of Radical Prostatectomy as Monotherapy for Men with High-risk Prostate Cancer

    PubMed Central

    Furukawa, Junya; Miyake, Hideaki; Inoue, Taka-aki; Ogawa, Takayoshi; Tanaka, Hirokazu; Fujisawa, Masato

    2016-01-01

    Background The objective of this study was to review our experience with radical prostatectomy (RP) as monotherapy for men with high-risk prostate cancer (PCa). Patients and Methods This study included 382 consecutive patients who were diagnosed with high-risk PCa according to the D'Amico definition and subsequently underwent RP without neoadjuvant therapy. Biochemical recurrence (BR) was defined as a serum prostate-specific antigen (PSA) level ≥ 0.2 ng/ml on two consecutive measurements, and none of the patients received any adjuvant therapies until their serum PSA levels reached ≥ 0.4 ng/ml. Results The median preoperative serum PSA level in these 382 patients was 15.9 ng/ml. Pathological stages ≥ pT2c and Gleason scores ≥ 8 were observed in 288 and 194 patients, respectively. During the observation period (median, 48.0 months), BR occurred in 134 patients, and the 5-year BR-free survival rate was 60.1%; however, no patient died of cancer progression. Multivariate analysis identified capsular invasion, seminal vesicle invasion, and surgical margin status as independent predictors of BR. Conclusions Comparatively favorable cancer control could be achieved using RP as monotherapy for men with high-risk PCa; however, RP alone may be insufficient for patients with capsular invasion, seminal vesicle invasion, and/or surgical margin positivity. PMID:27390578

  8. A Randomized Control Trial Comparing the Efficacy of Antiandrogen Monotherapy: Flutamide vs. Bicalutamide.

    PubMed

    Nakai, Yasushi; Tanaka, Nobumichi; Anai, Satoshi; Miyake, Makito; Tatsumi, Yoshihiro; Fujimoto, Kiyohide

    2015-08-01

    The study aims to compare serial changes in prostate-specific antigen (PSA), testosterone, dehydroepiandrosterone (DHEA), and androstenedione in patients treated with either of the antiandrogen agents, bicalutamide or flutamide, using a randomized controlled study. Patients had to meet the following inclusion criteria: (1) presence of histopathologically confirmed prostate cancer, (2) prostate cancer treatment naive, (3) no current treatment with luteinizing hormone-releasing hormone (LH-RH) agonist for sexual interest and physical capacity, (4) clinical stage T1-cT3N0M0, (5) Gleason score ≤ 7, and (6) Cooperative Oncology Group performance status 0-1. Patients were randomly allocated to two groups: flutamide and bicalutamide monotherapy group 1:1. PSA levels were significantly decreased in both groups at 4 weeks. PSA levels were significantly lower in the bicalutamide group compared with the flutamide group at 4 and 8 weeks. Testosterone levels in the bicalutamide group were significantly higher than the baseline levels between 4 and 24 weeks of treatment. Testosterone levels in the flutamide group were significantly increased at 4 and 12 weeks and returned to baseline levels at 16 and 24 weeks. DHEA levels in the bicalutamide group were unchanged from baseline at 4 and 24 weeks. However, DHEA levels in the flutamide group were decreased at 24 weeks. Androstenedione levels increased slightly in both groups, but the increase did not reach statistical significance. PSA, testosterone, and DHEA levels significantly differed between bicalutamide and flutamide monotherapy. PMID:26024831

  9. Duration of valproic acid monotherapy correlates with subclinical thyroid dysfunction in children with epilepsy.

    PubMed

    Ilić, Violeta; Bogićević, Dragana; Miljković, Branislava; Ješić, Maja; Kovačević, Marijana; Prostran, Milica; Kovačević, Sandra Vezmar

    2016-06-01

    To identify potential risk factors for the development of subclinical hypothyroidism following long-term valproic acid monotherapy in children with epilepsy. Serum levels of thyroid-stimulating hormone, free thyroxine, free triiodothyronine, thyreoglobulin antibodies, and thyroid peroxidase antibodies were determined in 41 patients and in 41 sex- and age-matched healthy children. Mean valproic acid treatment duration was 2.80±1.96 years. The valproic acid group had higher serum thyroid-stimulating hormone (p<0.001) and free triiodothyronine (p<0.05) levels compared to the control group. Serum thyroid-stimulating hormone and free triiodothyronine were above the upper limit for healthy controls in 34% and 32% of patients, respectively, and no clinical features of thyroid dysfunction were observed. Duration of valproic acid monotherapy for less than four years was a risk factor for elevated thyroid-stimulating hormone levels. One third of children with normal range serum valproic acid levels may have elevated serum thyroid-stimulating hormone and free triiodothyronine levels, especially in the first four years of treatment. PMID:27099936

  10. Hypertonic saline monotherapy in children with perennial allergic rhinitis: a pilot study.

    PubMed

    Barberi, S; D'Auria, E; Bernardo, L; Ferrara, F; Pietra, B; Pinto, F; Ferrero, F; Ciprandi, G

    2016-01-01

    Perennial allergic rhinitis (PAR) is very common in children and has a relevant impact on their families. House dust mites (HDM) are the most relevant cause of PAR. The present pilot study aimed to evaluate whether hypertonic saline (3%) nasal spray as monotherapy is able to improve: nasal symptom severity and parental perception of rhinitis control, sleep, and school performance in HDM-mono-sensitized children with PAR. Globally, 25 children (13 males and 12 females; mean age 9.5±3.1 years) were treated for 3 weeks. They were visited at baseline, at the end of treatment, and after a 2-week follow-up. Hypertonic saline significantly reduced total symptom score, and improved the perception, according to their parents, of rhinitis control, sleep, and school performance. In conclusion, the present pilot study provided the first evidence that 3% hypertonic saline monotherapy was able to relieve nasal symptoms and parental perception of PAR impact as well as being safe and well tolerated. PMID:27049102

  11. Rapid and Complete Remission of Metastatic Adrenocortical Carcinoma Persisting 10 Years After Treatment With Mitotane Monotherapy

    PubMed Central

    Ghorayeb, Nada El; Rondeau, Geneviève; Latour, Mathieu; Cohade, Christian; Olney, Harold; Lacroix, André; Perrotte, Paul; Sabourin, Alexis; Mazzuco, Tania L; Bourdeau, Isabelle

    2016-01-01

    Abstract Mitotane has been used for more than 5 decades as therapy for adrenocortical carcinoma (ACC). However its mechanism of action and the extent of tumor response remain incompletely understood. To date no cases of rapid and complete remission of metastatic ACC with mitotane monotherapy has been reported. A 52-year-old French Canadian man presented with metastatic disease 2 years following a right adrenalectomy for stage III nonsecreting ACC. He was started on mitotane which was well tolerated despite rapid escalation of the dose. The patient course was exceptional as he responded to mitotane monotherapy after only few months of treatment. Initiation of chemotherapy was not needed and he remained disease-free with good quality of life on low maintenance dose of mitotane during the following 10 years. A germline heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found. Immunohistochemical stainings for IGF-2 and cytoplasmic β-catenin were positive. Advanced ACC is an aggressive disease with poor prognosis and the current therapeutic options remain limited. These findings suggest that mitotane is a good option for the treatment of metastatic ACC and might result in rapid complete remission in selected patients. PMID:27043680

  12. Effectiveness and safety of topical tacrolimus monotherapy for repigmentation in vitiligo: a comprehensive literature review*

    PubMed Central

    Sisti, Andrea; Sisti, Giovanni; Oranges, Carlo Maria

    2016-01-01

    Thus far, several small studies and case reports on the use of topical immunomodulators in vitiligo have been published. We undertook a comprehensive literature review, searching for studies evaluating clinical response to tacrolimus topical therapy for vitiligo. A search was performed on PubMed/Medline using the term “vitiligo”, combined with “topical” and “ointment”. Our inclusion criteria were: use of tacrolimus ointment as monotherapy to treat vitiligo. We found 29 studies from 2002 to 2014. Overall, 709 patients were treated in 29 studies. Pooling the lesions, 50% repigmentation of vitiligo patches was never achieved before 2 months of treatment, with a peak after 6 months of therapy. The best results were obtained on lesions of the cephalic region, especially the face, with tacrolimus 0.1% ointment two times daily. The percentage of non-responsive patients ranged from 0% to 14%. Treatment was generally well-tolerated; only localized adverse effects were reported. Our objective was to verify the effectiveness and safety of tacrolimus ointment monotherapy. It has good efficacy and tolerability. At present, only small trials and case series are available in the literature. Further, standardized investigations on a larger number of patients are needed. PMID:27192518

  13. CRIM-negative infantile Pompe disease: Characterization of immune responses in patients treated with ERT monotherapy

    PubMed Central

    Berrier, Kathryn L.; Kazi, Zoheb B.; Prater, Sean N.; Bali, Deeksha S.; Goldstein, Jennifer; Stefanescu, Mihaela C.; Rehder, Catherine W.; Botha, Eleanor G.; Ellaway, Carolyn; Bhattacharya, Kaustuv; Tylki-Szymanska, Anna; Karabul, Nesrin; Rosenburg, Amy S.; Kishnani, Priya S.

    2015-01-01

    Purpose Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) prolongs survival in infantile Pompe disease (IPD). However, the majority of cross reactive immunologic material (CRIM)-negative (CN) patients have immune responses with significant clinical decline despite continued ERT. We aimed to characterize immune responses in CN IPD patients receiving ERT monotherapy. Methods A chart review identified 20 CN IPD patients treated with ERT monotherapy for ≥6 months. Patients were stratified by anti-rhGAA antibody titers: high sustained antibody titers (HSAT) ≥51,200 at least twice; low titers (LT) <6,400 throughout treatment; or sustained intermediate titers (SIT) 6,400–25,600. Results Despite early initiation of treatment, the majority (85%) of CN patients developed significant antibody titers, most with HSAT associated with invasive ventilation and death. Nearly all patients with HSAT had at least one nonsense GAA mutation, while the LT group exclusively carried splice site or frameshift mutations. Only one patient in the HSAT group is currently alive after successful immune modulation in the entrenched setting. Conclusion Immunological responses are a significant risk in CN IPD; thus, immune tolerance induction in the naïve setting should strongly be considered. Further exploration of factors influencing immune responses is required, particularly with the advent of newborn screening for Pompe disease. PMID:25741864

  14. Salmonella Bacterial Monotherapy Reduces Autochthonous Prostate Tumor Burden in the TRAMP Mouse Model

    PubMed Central

    Kazmierczak, Robert A.; Gentry, Bettina; Mumm, Tyler; Schatten, Heide; Eisenstark, Abraham

    2016-01-01

    Attenuated Salmonella typhimurium injected in the circulatory system of mammals selectively targets tumors. Using weekly intraperitoneal injections of attenuated Salmonella strain CRC2631, we tested for regression and/or inhibition of tumor development in the TRAMP prostate tumor mouse model, which utilizes SV40 early region expression for autochthonous formation of prostate tumors that progress into metastatic, poorly differentiated prostatic carcinomas in an immunocompetent murine model. Thirteen weekly intraperitoneal administrations of 105–107 CFU CRC2631 into 10 week old mice were well tolerated by the TRAMP model. Sacrifice and histological analysis of TRAMP prostates at 22 weeks indicated that Salmonella monotherapy at administrated levels decrease visible tumor size (>29%) but did not significantly inhibit previously described SV40 expression-driven TRAMP tumor progression to undifferentiated carcinomas when histologically examined. In conclusion, this work demonstrates baseline results for CRC2631 Salmonella monotherapy using the immunocompetent TRAMP prostate tumor model in preparation for study of combination therapies that resolve autochthonously generated TRAMP prostate tumors, further reduce tumor size, or inhibit prostate tumor progression. PMID:27504973

  15. Presumed Allergic Proctocolitis Resolves with Probiotic Monotherapy: A Report of 4 Cases.

    PubMed

    Martin, Victoria J; Shreffler, Wayne G; Yuan, Qian

    2016-01-01

    BACKGROUND The prevalence of allergic diseases has been dramatically rising in the United States and other developed nations over recent decades. Growing evidence suggests a partial role for the microbiome in the development of these allergic diseases. Food protein-induced allergic proctocolitis (AP) (also referred to as cow's milk protein intolerance or allergy) is among the earliest and most common food allergic diseases of infancy, yet its pathophysiology is not well understood. The currently accepted clinical practice is to restrict the diet until 12 months of age. CASE REPORT We present 4 cases of clinically diagnosed AP whose symptoms quickly and completely resolved with probiotic Lactobacillus rhamnosus GG (LGG) monotherapy. All 4 infants avoided any dietary restrictions. The range of time from probiotic initiation to symptom resolution was 7-28 days. CONCLUSIONS These cases suggest an important role for the infant intestinal microbiome in the development of gastrointestinal mucosal food allergies such as AP. Prospective investigation of the intestinal microbiome in infants with AP may further our understanding of this disease's pathogenesis. The potential use of probiotic monotherapy in the treatment of AP also warrants further investigation. PMID:27568925

  16. Presumed Allergic Proctocolitis Resolves with Probiotic Monotherapy: A Report of 4 Cases

    PubMed Central

    Martin, Victoria J.; Shreffler, Wayne G.; Yuan, Qian

    2016-01-01

    Case series Patients: — Final Diagnosis: Allergic proctocolitis Symptoms: Hematochezia • fussiness Medication: — Clinical Procedure: — Specialty: Pediatrics and Neonatology Objective: Unusual clinical course Background: The prevalence of allergic diseases has been dramatically rising in the United States and other developed nations over recent decades. Growing evidence suggests a partial role for the microbiome in the development of these allergic diseases. Food protein-induced allergic proctocolitis (AP) (also referred to as cow’s milk protein intolerance or allergy) is among the earliest and most common food allergic diseases of infancy, yet its patho physiology is not well understood. The currently accepted clinical practice is to restrict the diet until 12 months of age. Case Reports: We present 4 cases of clinically diagnosed AP whose symptoms quickly and completely resolved with probiotic Lactobacillus rhamnosus GG (LGG) monotherapy. All 4 infants avoided any dietary restrictions. The range of time from probiotic initiation to symptom resolution was 7–28 days. Conclusions: These cases suggest an important role for the infant intestinal microbiome in the development of gastrointestinal mucosal food allergies such as AP. Prospective investigation of the intestinal microbiome in infants with AP may further our understanding of this disease’s pathogenesis. The potential use of probiotic monotherapy in the treatment of AP also warrants further investigation. PMID:27568925

  17. [A case of recurrent breast cancer successfully treated with capecitabine monotherapy].

    PubMed

    Mitsuyama, Shoshu; Anan, Keisei; Ono, Minoru

    2005-08-01

    A 51-year-old woman underwent pectoralis-preserving mastectomy for right breast cancer (squamous cell cancer, f, T1c, ly0, v0, N2 (18/33), p53 (3+), HER2 (2+), ER (-), PgR (-), T1cN2M0 (Stage IIIA) in March 2001, and received systemic chemotherapy using doxorubicin combined with cyclophosphamide, followed by paclitaxel. After chemotherapy, radiotherapy was added to the chest wall, supraclavicular and parasternal regions. In March 2002 (disease-free interval of one year), liver metastasis was revealed. Systemic therapy using docetaxel, and hepatic artery infusion therapy with epirubicin following docetaxel, failed. Since June 2003, capecitabine monotherapy (2,400 mg/day) was initiated for the liver and lymph node metastases in the mediastinum and retroperitoneum. After 3 cycles, all metastases responded and a marked response has been maintained for 15 months. This therapy is being continued (18 cycles), and no serious side effects have been encountered. Capecitabine monotherapy is safe and very useful for recurrent breast cancer. PMID:16121919

  18. Salmonella Bacterial Monotherapy Reduces Autochthonous Prostate Tumor Burden in the TRAMP Mouse Model.

    PubMed

    Kazmierczak, Robert A; Gentry, Bettina; Mumm, Tyler; Schatten, Heide; Eisenstark, Abraham

    2016-01-01

    Attenuated Salmonella typhimurium injected in the circulatory system of mammals selectively targets tumors. Using weekly intraperitoneal injections of attenuated Salmonella strain CRC2631, we tested for regression and/or inhibition of tumor development in the TRAMP prostate tumor mouse model, which utilizes SV40 early region expression for autochthonous formation of prostate tumors that progress into metastatic, poorly differentiated prostatic carcinomas in an immunocompetent murine model. Thirteen weekly intraperitoneal administrations of 105-107 CFU CRC2631 into 10 week old mice were well tolerated by the TRAMP model. Sacrifice and histological analysis of TRAMP prostates at 22 weeks indicated that Salmonella monotherapy at administrated levels decrease visible tumor size (>29%) but did not significantly inhibit previously described SV40 expression-driven TRAMP tumor progression to undifferentiated carcinomas when histologically examined. In conclusion, this work demonstrates baseline results for CRC2631 Salmonella monotherapy using the immunocompetent TRAMP prostate tumor model in preparation for study of combination therapies that resolve autochthonously generated TRAMP prostate tumors, further reduce tumor size, or inhibit prostate tumor progression. PMID:27504973

  19. Cost-effectiveness of adalimumab, infliximab or vedolizumab as first-line biological therapy in moderate-to-severe ulcerative colitis

    PubMed Central

    Yokomizo, Lauren; Limketkai, Berkeley; Park, K T

    2016-01-01

    Background There are no head-to-head randomised controlled trials (RCTs) comparing the effectiveness of biologics in ulcerative colitis (UC). We aimed to assess the cost-effectiveness of adalimumab, infliximab and vedolizumab as first-line agents to induce clinical remission and mucosal healing (MH) in UC. Methods We constructed a decision tree based on a payer's perspective in the USA to estimate the first year costs of adalimumab, infliximab or vedolizumab to achieve clinical remission and MH in patients with moderate-to-severe UC. Transition probabilities were derived from ACT, ULTRA and GEMINI RCT data. Costs were derived from Medicare reimbursement rates and wholesale drug prices. Results Assuming a biological-naïve cohort, infliximab 5 mg/kg every 8 weeks was more cost-effective ($99 171 per MH achieved) than adalimumab 40 mg every other week ($316 378 per MH achieved) and vedolizumab every 8 weeks ($301 969 per MH achieved) at 1 year. Non-drug administration cost of infliximab exceeding $1974 per infusion would make adalimumab more cost-effective. First-line UC therapy with vedolizumab would be cost-effective if the drug acquisition price was <$2537 for each 300 mg administration during the 1-year time horizon. Conclusions If non-drug costs of infliximab administration are not excessive (<$2000), infliximab is the most cost-effective first-line biologic for moderate-to-severe UC. Exceeding this threshold infusion-related cost would make adalimumab the more cost-effective therapy. Considering its drug costs in the USA, vedolizumab appears to be appropriately used as a second-line biologic after antitumour necrosis factor failure. PMID:27195130

  20. Prognosis of metastatic renal cell carcinoma with first-line interferon-α therapy in the era of molecular-targeted therapy.

    PubMed

    Kawano, Yoshiaki; Takahashi, Wataru; Eto, Masatoshi; Kamba, Tomomi; Miyake, Hideaki; Fujisawa, Masato; Kamai, Takao; Uemura, Hirotsugu; Tsukamoto, Taiji; Azuma, Haruhito; Matsubara, Akio; Nishimura, Kazuo; Nakamura, Tsuyoshi; Ogawa, Osamu; Naito, Seiji

    2016-07-01

    The RCC-SELECT study showed the correlation between single nucleotide polymorphisms (SNP) in STAT3 gene and survival in metastatic renal cell carcinoma (mRCC) patients with first-line interferon-α (IFN-α). In that study, even patients with STAT3 SNP linked to shorter overall survival (OS) exhibited remarkably improved prognosis. All 180 patients evaluated in the above study were further analyzed for correlation between OS and demographics/clinicopathological parameters. OS was estimated using the Kaplan-Meier method. Associations between OS and potential prognostic factors were assessed using the log-rank test and the Cox proportional hazards model. The median OS was 42.8 months. Univariate analysis showed that worse Eastern Cooperative Oncology Group-performance status (ECOG-PS), high T stage, regional lymph node metastasis, distant metastasis, higher grade, infiltrative growth pattern, the presence of microscopic vascular invasion (MVI), hypercalcemia, anemia, thrombocytopenia and elevated C-reactive protein were significantly associated with OS. Multivariate analysis revealed that ECOG-PS (hazard ratio [HR] = 3.665, P = 0.0004), hypercalcemia (HR = 6.428, P = 0.0005) and the presence of MVI (HR = 2.668, P = 0.0109) were jointly significant poor prognostic factors. This is the first study analysing prognostic factors of mRCC patients with first-line IFN-α using large cohort of the prospective study. The present study suggests that first-line IFN-α is still a useful therapy for mRCC even in the era of molecular targeted therapy. PMID:27089226

  1. Magnitude and correlates of moderate to severe anemia among adult HIV patients receiving first line HAART in Northwestern Tanzania: a cross sectional clinic based study

    PubMed Central

    Gunda, Daniel Wilfred; Kilonzo, Semvua Bukheti; Mpondo, Bonaventura Cornel

    2016-01-01

    Introduction Moderate to severe anemia is an important clinical problem in HIV patients on Highly Active Antiretroviral Therapy. The rate of progression and mortality in this sub group of patients is high compared to non anemic patients. In sub Saharan Africa with scale up of Anti retroviral therapy, the magnitude of this problem is not known especially in Tanzania. This study aimed at determining the magnitude and correlates of moderate to severe anemia in HIV patients receiving first line ART in northwestern Tanzania. Methods This was a cross sectional clinic based study, involving adult HIV patients on first line Highly Active Antiretroviral Therapy at Bugando Medical Centre Care and Treatment Center. The patients’ data were analyzed using STATA version 11 to determine the prevalence of moderate to severe anemia and risk factors that could predict occurrence of anemia. Results In this study 346 patients on Highly Active Anti-Retroviral Therapy were enrolled, of whom 100(40.46%) had moderate to severe anemia. The odds of being anemic were strongly predicted by Zidovudine based regime, low baseline CD4 count (< 200 cells/μl) and HIV stage 3&4 at enrollment. Most of the anemic patients had mean corpuscular volume of >100fl. Conclusion The prevalence of moderate to severe anemia is significantly high in this cohort of HIV-infected patients on first line Anti Retroviral Therapy and it is strongly predicted by Zidovudine based regime, low baseline CD4 and HIV stage 3 and 4. On clinical grounds this suggests that patients who are initiated on Zidovudine based regimen and those in advanced HIV at enrollment should have regular haemoglobin follow up to identify anemia at its earliest stage to improve the clinical outcome of these patients. PMID:27200131

  2. Comparative efficacy and safety of first-line treatments in patients with metastatic renal cell cancer: a network meta-analysis based on phase 3 RCTs.

    PubMed

    Chang, Xiaofeng; Zhang, Fan; Liu, Tieshi; Yang, Rong; Ji, Changwei; Zhao, Xiaozhi; Xu, Linfeng; Liu, Guangxiang; Guo, Hongqian

    2016-03-29

    It is impossible to conduct head-to-head trials of all the therapies to determine optimal treatment in the rapidly advancing era of therapies for metastatic renal cell carcinoma (mRCC). In this network meta-analysis,we aimed to compare efficacy and safety of first-line treatments for mRCC. We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, and unpublished studies were also sought through "clinicaltrials.gov" from their inception through January 31, 2016. A database search identified 1253 articles, with 11 studies meeting the eligibility criteria. A total of 7597 patients in twelve different treatment arms were assessed. Network meta-analysis showed sunitinib had a significantly longer PFS than IFN-α (SMD=-5.68; 95%CI: -10.76,-0.86; P<0.001) and placebo (SMD=-6.71; 95%CI: -12.65,-0.79; P<0.001), meanwhile, pazopanib had a significantly longer PFS compared with placebo (SMD=5.13; 95%CI: 0.43, 10.09; P<0.001). The cumulative ranking probability curve indicated that sunitinib had the highest probability of being the best treatment modality in terms of PFS and it also had the highest probability of being the safest drugs as the first-line treatment when it came to SAE. Thus, sunitinib might be the best choice of first-line treatment for patients with mRCC because it has the most favorable balance between efficacy and safety. PMID:26908455

  3. The Impact and Cost-Effectiveness of a Four-Month Regimen for First-Line Treatment of Active Tuberculosis in South Africa

    PubMed Central

    Knight, Gwenan M.; Gomez, Gabriela B.; Dodd, Peter J.; Dowdy, David; Zwerling, Alice; Wells, William A.; Cobelens, Frank; Vassall, Anna; White, Richard G.

    2015-01-01

    Background A 4-month first-line treatment regimen for tuberculosis disease (TB) is expected to have a direct impact on patient outcomes and societal costs, as well as an indirect impact on Mycobacterium tuberculosis transmission. We aimed to estimate this combined impact in a high TB-burden country: South Africa. Method An individual based M. tb transmission model was fitted to the TB burden of South Africa using a standard TB natural history framework. We measured the impact on TB burden from 2015–2035 of introduction of a non-inferior 4-month regimen replacing the standard 6-month regimen as first-line therapy. Impact was measured with respect to three separate baselines (Guidelines, Policy and Current), reflecting differences in adherence to TB and HIV treatment guidelines. Further scenario analyses considered the variation in treatment-related parameters and resistance levels. Impact was measured in terms of differences in TB burden and Disability Adjusted Life Years (DALYs) averted. We also examined the highest cost at which the new regimen would be cost-effective for several willingness-to-pay thresholds. Results It was estimated that a 4-month regimen would avert less than 1% of the predicted 6 million person years with TB disease in South Africa between 2015 and 2035. A similarly small impact was seen on deaths and DALYs averted. Despite this small impact, with the health systems and patient cost savings from regimen shortening, the 4-month regimen could be cost-effective at $436 [NA, 5983] (mean [range]) per month at a willingness-to-pay threshold of one GDP per capita ($6,618). Conclusion The introduction of a non-inferior 4-month first-line TB regimen into South Africa would have little impact on the TB burden. However, under several scenarios, it is likely that the averted societal costs would make such a regimen cost-effective in South Africa. PMID:26717007

  4. Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia

    PubMed Central

    Gugliotta, Gabriele; Castagnetti, Fausto; Breccia, Massimo; Levato, Luciano; D’Adda, Mariella; Stagno, Fabio; Tiribelli, Mario; Salvucci, Marzia; Fava, Carmen; Martino, Bruno; Cedrone, Michele; Bocchia, Monica; Trabacchi, Elena; Cavazzini, Francesco; Usala, Emilio; Rossi, Antonella Russo; Bochicchio, Maria Teresa; Soverini, Simona; Alimena, Giuliana; Cavo, Michele; Pane, Fabrizio; Martinelli, Giovanni; Saglio, Giuseppe; Baccarani, Michele; Rosti, Gianantonio

    2015-01-01

    Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052). PMID:26113419

  5. Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia.

    PubMed

    Gugliotta, Gabriele; Castagnetti, Fausto; Breccia, Massimo; Levato, Luciano; D'Adda, Mariella; Stagno, Fabio; Tiribelli, Mario; Salvucci, Marzia; Fava, Carmen; Martino, Bruno; Cedrone, Michele; Bocchia, Monica; Trabacchi, Elena; Cavazzini, Francesco; Usala, Emilio; Russo Rossi, Antonella; Bochicchio, Maria Teresa; Soverini, Simona; Alimena, Giuliana; Cavo, Michele; Pane, Fabrizio; Martinelli, Giovanni; Saglio, Giuseppe; Baccarani, Michele; Rosti, Gianantonio

    2015-09-01

    Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥ 2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052). PMID:26113419

  6. The association of clinical outcome and peripheral T-cell subsets in metastatic colorectal cancer patients receiving first-line FOLFIRI plus bevacizumab therapy.

    PubMed

    Roselli, Mario; Formica, Vincenzo; Cereda, Vittore; Jochems, Caroline; Richards, Jacob; Grenga, Italia; Orlandi, Augusto; Ferroni, Patrizia; Guadagni, Fiorella; Schlom, Jeffrey

    2016-07-01

    The first-line standard of care for patients with metastatic colorectal cancer (mCRC) is FOLFIRI (irinotecan, levo-leucovorin, 5-fluorouracil (5-FU)) plus bevacizumab. With the renewed interest in cancer immunotherapy with agents such as vaccines, checkpoint inhibitors and immune modulators, the possibility exists for the use of one or more of these immunotherapeutics in the first-line setting and thus in combination with the FOLFIRI and bevacizumab regimen. Studies were undertaken to study the effects of FOLFIRI and bevacizumab therapy on peripheral T-cell subsets, and to determine if there are any associations between these subsets and response to therapy. Peripheral blood mononuclear cell subsets of patients with mCRC (n = 23) were analyzed prior to and during therapy. While there were differences among patients, the majority of patients showed either a minimal change or an increase in CD4(+) T cell to regulatory T cell (Treg) ratios during therapy, as well as either minimal change or a decrease in Treg suppressive activity during therapy. There was also an association (p = 0.036) between a decrease in Treg frequency during FOLFIRI therapy and overall survival, and an association (p = 0.037) between the frequency of Tregs prior to therapy and progression-free survival. Responders to the chemotherapy by RECIST criteria also had a greater decrease in Tregs during therapy vs. pre-therapy (p = 0.0064) as compared to non-responders. While the number of mCRC patients undergoing chemotherapy in this study is relatively small, it provides the rationale for the use of immunotherapeutics in this first-line metastatic setting. PMID:27622042

  7. Comparative efficacy and safety of first-line treatments in patients with metastatic renal cell cancer: a network meta-analysis based on phase 3 RCTs

    PubMed Central

    Chang, Xiaofeng; Zhang, Fan; Liu, Tieshi; Yang, Rong; Ji, Changwei; Zhao, Xiaozhi; Xu, Linfeng; Liu, Guangxiang; Guo, Hongqian

    2016-01-01

    It is impossible to conduct head-to-head trials of all the therapies to determine optimal treatment in the rapidly advancing era of therapies for metastatic renal cell carcinoma (mRCC). In this network meta-analysis,we aimed to compare efficacy and safety of first-line treatments for mRCC. We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, and unpublished studies were also sought through “clinicaltrials.gov” from their inception through January 31, 2016. A database search identified 1253 articles, with 11 studies meeting the eligibility criteria. A total of 7597 patients in twelve different treatment arms were assessed. Network meta-analysis showed sunitinib had a significantly longer PFS than IFN-α (SMD=−5.68; 95%CI: −10.76,−0.86; P<0.001) and placebo (SMD=−6.71; 95%CI: −12.65,−0.79; P<0.001), meanwhile, pazopanib had a significantly longer PFS compared with placebo (SMD=5.13; 95%CI: 0.43, 10.09; P<0.001). The cumulative ranking probability curve indicated that sunitinib had the highest probability of being the best treatment modality in terms of PFS and it also had the highest probability of being the safest drugs as the first-line treatment when it came to SAE. Thus, sunitinib might be the best choice of first-line treatment for patients with mRCC because it has the most favorable balance between efficacy and safety. PMID:26908455

  8. Changes in First-Line cART Regimens and Short-Term Clinical Outcome between 1996 and 2010 in The Netherlands

    PubMed Central

    Smit, Mikaela; Smit, Colette; Geerlings, Suzanne; Gras, Luuk; Brinkman, Kees; Hallett, Timothy B.; de Wolf, Frank

    2013-01-01

    Objectives Document progress in HIV-treatment in the Netherlands since 1996 by reviewing changing patterns of cART use and relating those to trends in patients' short-term clinical outcomes between 1996 and 2010. Design and Methods 1996–2010 data from 10,278 patients in the Dutch ATHENA national observational cohort were analysed. The annual number of patients starting a type of regimen was quantified. Trends in the following outcomes were described: i) recovery of 150 CD4 cells/mm3 within 12 months of starting cART; ii) achieving viral load (VL) suppression ≤1,000 copies/ml within 12 months of starting cART; iii) switching from first-line to second-line regimen within three years of starting treatment; and iv) all-cause mortality rate per 100 person-years within three years of starting treatment. Results Between 1996 and 2010, first-line regimens changed from lamivudine/zidovudine-based or lamivudine/stavudine-based regimens with unboosted-PIs to tenofovir with either emtricitabine or lamivudine with NNRTIs. Mortality rates did not change significantly over time. VL suppression and CD4 recovery improved over time, and the incidence of switching due to virological failure and toxicity more than halved between 1996 and 2010. These effects appear to be related to the use of new regimens rather than improvements in clinical care. Conclusion The use of first-line cART in the Netherlands closely follows changes in guidelines, to the benefit of patients. While there was no significant improvement in mortality, newer drugs with better tolerability and simpler dosing resulted in improved immunological and virological recovery and reduced incidences of switching due to toxicity and virological failure. PMID:24098764

  9. Efficacy of pemetrexed plus platinum doublet chemotherapy as first-line treatment for advanced nonsquamous non-small-cell-lung cancer: a systematic review and meta-analysis

    PubMed Central

    Xiao, Huai-Qing; Tian, Rong-Hua; Zhang, Zhi-Hao; Du, Kai-Qi; Ni, Yi-Ming

    2016-01-01

    Purpose To assess the efficacy of pemetrexed plus platinum doublet chemotherapy as first-line treatment for advanced nonsquamous non-small-cell lung cancer (NSCLC) through a trial-level meta-analysis. Methods Trials published between 1990 and 2015 were identified by an electronic search of public databases (Medline, Embase, and Cochrane Library). All clinical studies were independently identified by two authors. Demographic data, treatment regimens, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were extracted and analyzed using comprehensive meta-analysis software (version 2.0). Results A total of 2,551 patients with advanced nonsquamous NSCLC from ten trials were included for analysis: 1,565 patients were treated with pemetrexed plus platinum doublet chemotherapy and 986 with platinum plus other first-line chemotherapy. Pooled ORR for pemetrexed plus platinum chemotherapy was 37.8% (95% confidence interval [CI]: 31.7%–44.3%), with median PFS and OS of 5.7 and 16.05 months, respectively. When compared to other platinum-based doublet chemotherapies, the use of pemetrexed plus platinum chemotherapy significantly improved OS (hazard ratio [HR] =0.86, 95% CI: 0.77–0.97, P=0.01) but not PFS (HR =0.90, 95% CI: 0.80–1.01, P=0.084) in advanced nonsquamous NSCLC patients. Conclusion Pemetrexed plus platinum doublet regimen is an efficacious treatment for advanced nonsquamous NSCLC patients. Our findings support the use of pemetrexed plus platinum doublet regimen as first-line treatment in advanced nonsquamous NSCLC patients because of its potential survival benefits. PMID:27042115

  10. Study protocol: systematic review and meta-analysis of randomized controlled trials in first-line treatment of squamous non-small cell lung cancer

    PubMed Central

    2014-01-01

    Background There is a high unmet need for effective treatments for patients with squamous non-small cell lung cancer (NSCLC). Eli Lilly and Company is conducting a phase III, randomized, multicenter, open-label study of gemcitabine plus cisplatin plus necitumumab (GC + N) versus gemcitabine plus cisplatin (GC) for the first-line treatment of patients with stage IV squamous NSCLC. Given GC is not the only treatment commonly used for the treatment of squamous NSCLC, this study was designed to compare the survival, toxicity, and quality of life outcomes of current treatment strategies for squamous NSCLC in the first-line setting. Methods/Design A systematic review and meta-analysis (including indirect comparisons) of treatments used in squamous NSCLC will be conducted to assess the clinical efficacy (overall and progression-free survival), health-related quality of life (HRQoL), and safety (grade 3–4 toxicity) of GC + N compared to other treatments used in squamous NSCLC. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines will be followed for all aspects of this study. A systematic literature review will be conducted to identify randomized controlled trials evaluating chemotherapy treatment in first-line NSCLC. Eligible articles will be restricted to randomized controlled trials (RCTs) among chemotherapy-naïve advanced NSCLC cancer patients that report outcome data (survival, toxicity, or quality of life) for patients with squamous histology. Following data extraction and validation, data consistency and study heterogeneity will be assessed. A network meta-analysis will be conducted based on the available hazard ratios for overall and progression-free survival, odds ratios for published toxicity data, and mean difference of HRQoL scales. Sensitivity analyses will be conducted. Discussion This is a presentation of the study protocol only. Results and conclusions are pending completion of this study. Systematic review

  11. Is It Time for Integrase Inhibitors to be the Preferred Regimen for the First-Line Treatment of HIV-1-Infected Naive Patients?

    PubMed

    Yombi, Jean Cyr; Pozniak, Anton L

    2016-01-01

    Thanks to the emergence of combination antiretroviral therapy, HIV/AIDS has been transformed into a manageable, chronic condition in just 30 years and the life expectancy of patients living with HIV is now comparable to those without. Recent data (START) support the strategy of starting all HIV-positive patients regardless of CD4 count. However, patients and physicians want more than just viral control: they want better tolerability, convenience, and few drug-drug interactions. Are the guidelines right in recommending an integrase inhibitor-based regimen as the first-line treatment of choice? PMID:27196353

  12. Simulations using a drug-disease modeling framework and phase II data predict phase III survival outcome in first-line non-small-cell lung cancer.

    PubMed

    Claret, L; Lu, J-F; Bruno, R; Hsu, C-P; Hei, Y-J; Sun, Y-N

    2012-11-01

    Simulations were performed for carboplatin/paclitaxel (C/P) plus motesanib or bevacizumab vs. C/P as first-line treatment for advanced non-small-cell lung cancer (NSCLC) using a published drug-disease model. With 700 patients in each arm, simulated hazard ratios for motesanib (0.87; 95% confidence interval [CI], 0.71-1.1) and bevacizumab (0.89; 95% CI, 0.73-1.1) agreed with results from the respective phase III studies but did not discriminate between failed and successful studies. The current model may require further enhancement to improve its utility for predicting phase III outcomes. PMID:22910440

  13. The Effectiveness and Safety of Fluoroquinolone-Containing Regimen as a First-Line Treatment for Drug-Sensitive Pulmonary Tuberculosis: A Systematic Review and Meta-Analysis

    PubMed Central

    Lee, Hyun Woo; Lee, Jung Kyu; Kim, Eunyoung; Yim, Jae-Joon; Lee, Chang-Hoon

    2016-01-01

    Background Fluoroquinolone is recommended as a pivotal antituberculous agent for treating multi-drug-resistant pulmonary tuberculosis. However, its effectiveness as first-line treatment remains controversial. The present study was conducted to validate the fluoroquinolone-containing regimen for drug-sensitive pulmonary tuberculosis. Methods We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials until June 5, 2015. Randomized controlled trials (RCTs) that compared antituberculous regimens containing fluoroquinolone with the standard regimen were included. Results Eleven RCTs that included 6,334 patients were selected. Fluoroquinolone-containing regimens had a higher rate of sputum culture conversion at 2 months of treatment (M-H fixed odds ratio [OR], 1.36; 95% confidence interval [CI], 1.20–1.54). However, the outcomes were less favorable (M-H fixed OR, 0.69; 95% CI, 0.59–0.82) and the associated total adverse events were more frequent (M-H fixed OR, 1.84; 95% CI, 1.46–2.31) in the fluoroquinolone-containing regimen group, without a significant heterogeneity according to treatment duration. Treatment with the fluoroquinolone-containing regimen for 4 months showed a higher relapse rate. Conclusions Despite a higher culture conversion rate at 2 months of treatment, the fluoroquinolone-containing regimen had limitations, including less favorable outcomes and more adverse events, as the first-line therapy for drug-sensitive pulmonary tuberculosis. PMID:27455053

  14. Update on drug interactions with phosphodiesterase-5 inhibitors prescribed as first-line therapy for patients with erectile dysfunction or pulmonary hypertension.

    PubMed

    Gur, Serap; Kadowitz, Philip J; Gokce, Ahmet; Sikka, Suresh C; Lokman, Utku; Hellstrom, Wayne J G

    2013-02-01

    Phosphodiesterase-5 inhibitors (PDE5i, sildenafil, vardenafil, tadalafil and avanafil) are a first-line medical therapy for erectile dysfunction (ED). In all likelihood, PDE5i usage will increase because sildenafil (Viagra® and Revatio®) and tadalafil (Cialis® and Adcirca®) have recently been recommended as first-line therapy for patients with pulmonary hypertension (PH). PDE5i exhibit higher plasma concentrations when co-administered with cytochrome P (CYP) 3A inhibitors, which influences their side-effect profile. The higher PDE5i plasma concentrations, caused by CYP3A inhibitors, influence the severity and timing of PDE5i drug interactions and require dose adjustment. PDE5i are safe when used with most antihypertensive agents, but co-administration with nitrates or α-blockers can cause severe hypotension and syncope. Dose adjustment is also necessary when PDE5i are co-administered with CYP3A inducers. The combination of oral tadalafil and bosentan (endothelin receptor antagonist) reduces tadalafil levels and requires dose adjustment. Current literature reports a number of interactions between PDE5i and other agents and further studies are needed to expand our knowledge base of these interactions. This review discusses relevant PDE5i drug interactions, including those with CYP 450 inhibitors and inducers which are frequently used during the treatment of ED and PH. PMID:23140258

  15. L-asparaginase-based regimen as a first-line treatment for newly diagnosed nasal type extranodal natural killer cell/T-cell lymphoma

    PubMed Central

    BU, SHANSHAN; YUAN, FANGFANG; WEI, XUDONG; YIN, QINGSONG; LI, YUFU; MI, RUIHUA; YANG, HAIPING; LI, HONGYI; GE, SHOUBEI; LIU, YANYAN; SONG, YONGPING

    2016-01-01

    The aim of the present study was to compare the efficacy of an L-asparaginase-based regimen and a CHOP regimen followed by radiotherapy as first-line treatments for newly diagnosed nasal type extranodal natural killer cell/T-cell lymphoma (ENKTL). A total of 69 patients received the CHOP regimen as the first-line treatment and 112 patients received the L-asparaginase-based regimen. All patients received radical radiotherapy following two cycles of chemotherapy. The overall response rates of the L-asparaginase-based and CHOP treatment groups were 90.18 and 72.46%, respectively (P=0.002). The one, two, and five-year overall survival (OS) rates and progression-free survival (PFS) rates of the L-asparaginase group were 96.0, 88.3, 65.1, 94.2, 79.8 and 50.0%, respectively. The one, two, and five-year OS and PFS rates of the CHOP group were 82.6, 61.9, 25.8, 63.8, 44.0 and 21.0%, respectively (P<0.001). Compared with CHOP treatment, L-asparaginase-based chemotherapy combined with radiotherapy was a safe and highly effective treatment for newly diagnosed ENKTL. PMID:27313673

  16. Changes in expression levels of ERCC1, DPYD, and VEGFA mRNA after first-line chemotherapy of metastatic colorectal cancer: results of a multicenter study

    PubMed Central

    Uemoto, Shinji; Yoshida, Kazuhiro; Saiura, Akio; Watanabe, Masayuki; Maehara, Yoshihiko; Oki, Eiji; Ikeda, Yasuharu; Matsuda, Hiroyuki; Yamamoto, Masakazu; Shimada, Mitsuo; Taketomi, Akinobu; Unno, Michiaki; Sugihara, Kenichi; Ogata, Yutaka; Eguchi, Susumu; Kitano, Seigo; Shirouzu, Kazuo; Saiki, Yasumitsu; Takamori, Hiroshi; Mori, Masaki; Hirata, Toshihiko; Wakabayashi, Go; Kokudo, Norihiro

    2015-01-01

    Our previous study showed that administering oxaliplatin as first-line chemotherapy increased ERCC1 and DPD levels in liver colorectal cancers (CRCs) metastases. Second, whether the anti-VEGF monoclonal antibody bevacizumab alters tumoral VEGFA levels is unknown. We conducted this multicenter observational study to validate our previous findings on ERCC1 and DPD, and clarify the response of VEGFA expression to bavacizumab administration. 346 CRC patients with liver metastases were enrolled at 22 Japanese institutes. Resected liver metastases were available for 175 patients previously treated with oxaliplatin-based chemotherapy (chemotherapy group) and 171 receiving no previous chemotherapy (non-chemotherapy group). ERCC1, DPYD, and VEGFA mRNA levels were measured by real-time RT-PCR. ERCC1 mRNA expression was significantly higher in the chemotherapy group than in the non-chemotherapy group (P = 0.033), and were significantly correlated (Spearman's correlation coefficient = 0.42; P < 0.0001). VEGFA expression level was higher in patients receiving bevacizumab (n = 51) than in those who did not (n = 251) (P = 0.007). This study confirmed that first-line oxaliplatin-based chemotherapy increases ERCC1 and DPYD expression levels, potentially enhancing chemosensitivity to subsequent therapy. We also found that bevacizumab induces VEGFA expression in tumor cells, suggesting a biologic rationale for extending bevacizumab treatment beyond first progression. PMID:26372896

  17. Cost-effectiveness of rituximab in addition to fludarabine and cyclophosphamide (R-FC) for the first-line treatment of chronic lymphocytic leukemia.

    PubMed

    Müller, Dirk; Fischer, Kirsten; Kaiser, Peter; Eichhorst, Barbara; Walshe, Ronald; Reiser, Marcel; Kellermann, Lenka; Borsi, Lisa; Civello, Daniele; Mensch, Alexander; Bahlo, Jasmin; Hallek, Michael; Stock, Stephanie; Fingerle-Rowson, Günter

    2016-05-01

    The cost-effectiveness of rituximab in combination with fludarabine/cyclophosphamide (R-FC) for the first line treatment of chronic lymphocytic leukemia (CLL) was evaluated. Based on long-term clinical data (follow-up of 5.9 years) from the CLL8-trial, a Markov-model with three health states (Free from disease progression, Progressive disease, Death) was used to evaluate the cost per quality-adjusted life-year (QALY) and cost per life years gained (LYG) of R-FC from the perspective of the German statutory health insurance (SHI). The addition of rituximab to FC chemotherapy results in a gain of 1.1 quality-adjusted life-years. The incremental cost-effectiveness ratio (ICER) of R-FC compared with FC was €17 979 per QALY (€15 773 per LYG). Results were robust in deterministic and probabilistic sensitivity analyses. From the German SHI perspective, rituximab in combination with FC chemotherapy represents good value for first-line treatment of patients with CLL and compares favorably with chemotherapy alone. PMID:26584689

  18. Afatinib in the first-line treatment of epidermal-growth-factor-receptor mutation-positive non-small cell lung cancer: a review of the clinical evidence.

    PubMed

    Ke, E-E; Wu, Yi-Long

    2016-06-01

    First-line afatinib significantly improved progression-free survival, patient-reported outcomes, and quality of life compared with chemotherapy regimens in patients with advanced epidermal-growth-factor-receptor (EGFR) mutation-positive non-small cell lung cancer, based on results of the LUX-Lung 3 and LUX-Lung 6 trials. When the analysis of these trials was restricted to patients with common EGFR mutations only (exon 19 deletions and L858R), the advantage over chemotherapy was even more pronounced. A significant overall survival advantage was firstly demonstrated versus chemotherapy in patients with non-small cell lung cancer-harboring EGFR exon 19 deletion (del19) mutations. First-line afatinib was also effective in patients with certain uncommon EGFR mutation and patients with central nervous system metastasis. So far, these data are not sufficient to conclude that afatinib is better than first-generation EGFR inhibitors. In addition, the toxicity profile of afatinib was somewhat worse than that observed with either erlotinib or gefitinib. In the absence of direct comparisons, for each patient the choice among the available EGFR inhibitors should take into account all the clinically relevant endpoints, including disease control, survival prolongation, tolerability, and quality of life. PMID:26929305

  19. A multicentre Phase II study of non-pegylated liposomal doxorubicin in combination with trastuzumab and docetaxel as first-line therapy in metastatic breast cancer.

    PubMed

    Venturini, M; Bighin, C; Puglisi, F; Olmeo, N; Aitini, E; Colucci, G; Garrone, O; Paccagnella, A; Marini, G; Crinò, L; Mansutti, M; Baconnet, B; Barbato, A; Del Mastro, L

    2010-10-01

    To evaluate the cardiotoxicity, general toxicity, and activity of non-pegylated liposomal doxorubicin, in combination with docetaxel and trastuzumab, as first-line therapy in metastatic breast cancer. Thirty-one patients with metastatic human epidermal growth factor receptor 2-overexpressing breast cancer, who had not previously received chemotherapy for metastatic disease, received non-pegylated liposomal doxorubicin (50 mg/m(2)), docetaxel (75 mg/m(2)) and trastuzumab (2 mg/kg/week) for up to eight cycles, followed by trastuzumab alone for up to 52 weeks. Cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF) to below 45%, or a decrease in LVEF of at least 20% from baseline. Mean LVEF was maintained at baseline level also in the subset of patients who had received anthracycline previously. Cardiotoxicity developed in three patients during the treatment cycles, and in two further patients after the end of the study. The most common adverse events were haematological toxicity, alopecia, asthenia and fever. The best overall response rate was 65.5%. Median time to progression was 13.0 months. The combination of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab combines acceptable cardiac and general toxicity and promising activity as first-line therapy in metastatic breast cancer. PMID:20185313

  20. Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures

    PubMed Central

    Taylor, Stephen; Smith, Catrin Tudur; Williamson, Paula R; Marson, Anthony G

    2014-01-01

    Background This is an updated version of the original Cochrane review published in Issue 4, 2001. Worldwide, phenytoin and phenobarbitone are commonly used antiepileptic drugs. They are more likely to be used in the developing world than the developed world, primarily because they are inexpensive. The aim of this review is to summarize data from existing trials comparing phenytoin and phenobarbitone. Objectives To review the effects of phenobarbitone compared to phenytoin when used as monotherapy in patients with partial onset seizures or generalized tonic-clonic seizures with or without other generalized seizure types. Search methods We searched the Cochrane Epilepsy Group trials register (20 October 2009), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2009) and MEDLINE (1950 to October week 2, 2009). In addition, we handsearched relevant journals, and contacted pharmaceutical companies and researchers in the field to seek any ongoing or unpublished studies. Selection criteria Randomized controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. Trials must have included a comparison of phenobarbitone monotherapy with phenytoin monotherapy. Data collection and analysis This was an individual patient data review. Outcomes were time to (a) withdrawal of allocated treatment, (b) 12-month remission and (c) first seizure post randomization. Data were analyzed using a stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (95% CI), where a HR > 1 indicates an event is more likely to occur earlier on phenobarbitone than phenytoin. Main results To date, data have been obtained for four of ten studies meeting the inclusion criteria, amounting to 599 individuals, or approximately 65% of the potential data. The main overall results (HR) were (a) time to treatment withdrawal 1.62 (95% confidence interval 1.22 to 2.14); (b) time to 12-month

  1. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome

    PubMed Central

    Kargiotis, Konstantinos; Athyros, Vasilios G; Giouleme, Olga; Katsiki, Niki; Katsiki, Evangelia; Anagnostis, Panagiotis; Boutari, Chrysoula; Doumas, Michael; Karagiannis, Asterios; Mikhailidis, Dimitri P

    2015-01-01

    AIM: To investigate the effect of rosuvastatin monotherapy on non-alcoholic steatohepatitis (NASH). At present there is no effective treatment for non-alcoholic fatty liver disease or its advanced form NASH. METHODS: This prospective study included 20 biopsy proven patients with NASH, metabolic syndrome (MetS) and dyslipidaemia. Biochemical parameters of the blood of the patients and an ultrasonography of the liver were performed at baseline. Then patients received lifestyle advice and were treated for a 12 mo period with rosuvastatin (10 mg/d) monotherapy. Patients were re-evaluated during the study at 3 mo intervals, during which biochemical parameters of the blood were measured including liver enzymes. A repeat biopsy and ultrasonography of the liver were performed at the end of the study in all 20 patients. Changes in liver enzymes, fasting plasma glucose, serum creatinine, serum uric acid (SUA), high sensitivity C reactive protein (hsCRP) and lipid profile were assessed every 3 mo. The primary endpoint was the resolution of NASH and the secondary endpoints were the changes in liver enzyme and lipid values. RESULTS: The repeat liver biopsy and ultrasonography showed complete resolution of NASH in 19 patients, while the 20th, which had no improvement but no deterioration either, developed arterial hypertension and substantial rise in triglyceride levels during the study, probably due to changes in lifestyle including alcohol abuse. Serum alanine transaminase, aspartate transaminase, and γ-glutamyl transpeptidase were normalised by the 3rd treatment month (ANOVA P < 0.001), while alkaline phosphatase activities by the 6th treatment month (ANOVA, P = 0.01). Fasting plasma glucose and glycated haemoglobin were significantly reduced (P < 0.001). Lipid values were normalised by the 3rd treatment month. No patient had MetS by the 9th treatment month. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and

  2. First-Line Supervisory Training.

    ERIC Educational Resources Information Center

    West Virginia State Dept. of Education, Charleston. Bureau of Vocational, Technical, and Adult Education.

    This document contains ten information modules designed for use in an industrial supervisory training seminar. The first module focuses on the role of the supervisor. Topics include a definition of supervision and its four basic functions: planning, organizing, directing, and controlling. The second module deals with authority, power influence,…

  3. The First Line of Defense

    PubMed Central

    Hammer, Adam M.; Morris, Niya L.; Earley, Zachary M.; Choudhry, Mashkoor A.

    2015-01-01

    Alcohol (ethanol) is one of the most globally abused substances, and is one of the leading causes of premature death in the world. As a result of its complexity and direct contact with ingested alcohol, the intestine represents the primary source from which alcohol-associated pathologies stem. The gut is the largest reservoir of bacteria in the body, and under healthy conditions, it maintains a barrier preventing bacteria from translocating out of the intestinal lumen. The intestinal barrier is compromised following alcohol exposure, which can lead to life-threatening systemic complications including sepsis and multiple organ failure. Furthermore, alcohol is a major confounding factor in pathology associated with trauma. Experimental data from both human and animal studies suggest that alcohol perturbs the intestinal barrier and its function, which is exacerbated by a “second hit” from traumatic injury. This article highlights the role of alcohol-mediated alterations of the intestinal epithelia and its defense against bacteria within the gut, and the impact of alcohol on intestinal immunity, specifically on T cells and neutrophils. Finally, it discusses how the gut microbiome both contributes to and protects the intestines from dysbiosis after alcohol exposure and trauma. PMID:26695746

  4. Combination With Low-dose Dextromethorphan Improves the Effect of Amlodipine Monotherapy in Clinical Hypertension

    PubMed Central

    Yin, Wei-Hsian; Chen, Pei; Yeh, Hung-I; Wang, Kuo-Yang; Hung, Yi-Jen; Tseng, Wei-Kung; Wen, Ming-Shien; Wu, Tao-Cheng; Wu, Chau-Chung; Cheng, Shu-Meng; Chen, Jaw-Wen

    2016-01-01

    Abstract The combination of low rather than high dose of dextromethorphan (DXM) with amlodipine (AM) could improve blood pressure (BP) reduction in hypertensive animals. The study aimed to evaluate the feasibility of different doses of DXM combined with standard AM treatment in clinical hypertension. This was a prospective, 14-week, dose-escalation, multicenter study. After 2-week run-in period with AM 5 mg/day, hypertensive patients who got the BP goal of 140/90 mmHg kept receiving AM monotherapy for another 12 weeks. The nonresponders, while kept on AM 5 mg/day, received additional DXM treatment for 3 sequential dose-titrated periods with initially 2.5 mg/day, followed by 7.5 mg/day, and finally 30 mg/day. Each period was for 4 weeks. The patients at BP goal after each treatment period were defined as the responders and kept on the same combination till the end of the study. The responder rate of each treatment period was recorded. The changes of BP and serum antioxidant/endothelial markers between week 14 and week 2 were evaluated. Of the 103 patients initially enrolled, 89 entered the treatment period. In the 78 patients completing the study, 31 (40%) at BP goal after 2-week AM run-in kept on AM monotherapy (DXM0). The addition of 2.5 (DXM2.5) and 7.5 mg/day (DXM7.5) of DXM enabled BP goal achievement in 22 (47%) nonresponders to AM monotherapy including 16 (29%) with DXM2.5 and 6 (18%) with DXM7.5. Only 4 patients (16%) reached BP goal with the combination of DXM 30 mg/day (DXM30). Overall, 73% of the 78 patients reached BP goal at the end of the 14-week study. Mean systolic BP was reduced by 7.9% ± 7.0% with DXM2.5 (P < 0.001) and by 5.4% ± 2.4% with DXM7.5 (P = 0.003) respectively at week 14 from that at week 2, which was unchanged in either DXM0 or DXM30 group. Besides, the effects of combination treatment were particularly significant in the patients with impaired endothelial function suggested by reduced serum NOx level

  5. Total and free valproic acid: plasma level/dose ratio in monotherapy.

    PubMed

    Abadín, J A; Durán, J A; Sánchez, A; Serrano, J S

    1991-04-01

    Free plasma level/dose ratio of valproic acid (L/D-F) can be more effective than total plasma level/dose ratio (L/D-T) in adjusting dosage regimens. The influence of age, dose, and plasma concentration have been studied on L/D-T and L/D-F ratios. L/D-T and L/D-F ratios from 67 outpatients under long-term monotherapy were obtained. Analytical data was carried out by fluorescent polarized immunoassay. L/D-T and L/D-F ratios do not vary according to age. L/D-T and L/D-F ratios decreased while the dosage increased; both ratios increased with an increase in total plasma level of valproic acid. Significant differences were found between L/D-T and L/D-F ratios. Dose and interindividual variations are the factors which most influence L/D ratios of valproic acid. PMID:2051846

  6. Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody.

    PubMed

    Corti, Davide; Misasi, John; Mulangu, Sabue; Stanley, Daphne A; Kanekiyo, Masaru; Wollen, Suzanne; Ploquin, Aurélie; Doria-Rose, Nicole A; Staupe, Ryan P; Bailey, Michael; Shi, Wei; Choe, Misook; Marcus, Hadar; Thompson, Emily A; Cagigi, Alberto; Silacci, Chiara; Fernandez-Rodriguez, Blanca; Perez, Laurent; Sallusto, Federica; Vanzetta, Fabrizia; Agatic, Gloria; Cameroni, Elisabetta; Kisalu, Neville; Gordon, Ingelise; Ledgerwood, Julie E; Mascola, John R; Graham, Barney S; Muyembe-Tamfun, Jean-Jacques; Trefry, John C; Lanzavecchia, Antonio; Sullivan, Nancy J

    2016-03-18

    Ebola virus disease in humans is highly lethal, with case fatality rates ranging from 25 to 90%. There is no licensed treatment or vaccine against the virus, underscoring the need for efficacious countermeasures. We ascertained that a human survivor of the 1995 Kikwit Ebola virus disease outbreak maintained circulating antibodies against the Ebola virus surface glycoprotein for more than a decade after infection. From this survivor we isolated monoclonal antibodies (mAbs) that neutralize recent and previous outbreak variants of Ebola virus and mediate antibody-dependent cell-mediated cytotoxicity in vitro. Strikingly, monotherapy with mAb114 protected macaques when given as late as 5 days after challenge. Treatment with a single human mAb suggests that a simplified therapeutic strategy for human Ebola infection may be possible. PMID:26917593

  7. Fluoxetine Monotherapy in Attention-Deficit/Hyperactivity Disorder and Comorbid Non-Bipolar Mood Disorders in Children and Adolescents

    ERIC Educational Resources Information Center

    Quintana, Humberto; Butterbaugh, Grant J.; Purnell, William; Layman, Ann K.

    2007-01-01

    Children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for developing comorbid non-bipolar mood disorders. Fluoxetine monotherapy is an established treatment for pediatric mood disorders; however its efficacy in ADHD and comorbid mood disorder is unknown. Therefore, we evaluated 30 children who met DSM-IV criteria for…

  8. An Open-Label Study of Lamotrigine Adjunct or Monotherapy for the Treatment of Adolescents with Bipolar Depression

    ERIC Educational Resources Information Center

    Chang, Kiki; Saxena, Kirti; Howe, Meghan

    2006-01-01

    Objective: The treatment of pediatric bipolar depression has not been well studied. The authors wished to prospectively study the efficacy of lamotrigine as adjunctive or monotherapy in adolescents with bipolar disorder who were experiencing a depressive episode. Method: This was an 8-week open-label trial of lamotrigine with 20 adolescents ages…

  9. Boosted protease inhibitor monotherapy in HIV-infected adults: outputs from a pan-European expert panel meeting

    PubMed Central

    2013-01-01

    While the introduction of combination highly active antiretroviral therapy (HAART) regimens represents an important advance in the management of human immunodeficiency virus (HIV)-infected patients, tolerability can be an issue and the use of several different agents may produce problems. The switch of combination HAART to ritonavir-boosted protease inhibitor (PI) monotherapy may offer the opportunity to maintain antiviral efficacy while reducing treatment complexity and the risks of toxicity. Current European AIDS Clinical Society (EACS) guidelines recognise ritonavir-boosted PI monotherapy with twice-daily lopinavir/ritonavir or once-daily darunavir/ritonavir as a possible option in patients who have intolerance to nucleoside reverse transcriptase inhibitors, or for treatment simplification. Clinical trials data for PI boosted monotherapy are encouraging, showing substantial efficacy in the majority of patients; however, further data are required before this approach can be recommended as a routine treatment. Available data indicate that the most suitable candidates for the use of boosted PI monotherapy are long-term virologically suppressed patients who have demonstrated good adherence to antiretroviral therapy, who do not have chronic hepatitis B, have no history of treatment failure on PIs and are able to tolerate low-dose ritonavir. PMID:23347595

  10. Two cases of malignant lymphoma with reactivation of resolved hepatitis B virus infection after bendamustine hydrochloride monotherapy.

    PubMed

    Hiraki, Yoshiki; Kawano, Akira; Shigematsu, Hirohisa; Miki, Koichiro; Nomura, Hideyuki; Shimoda, Shinji

    2016-09-01

    A 63-year-old female and a 63-year-old male with resolved HBV infection suffered a relapse of malignant lymphoma. After bendamustine hydrochloride monotherapy, HBV reactivation occurred. Entecavir treatment was commenced immediately, with tests for HBV DNA negative without development of hepatitis. Regular monitoring of HBV DNA based on the guidelines from the Japan Society of Hepatology was useful. PMID:27593368

  11. A Meta-analysis of Sequential Intravenous/Oral Moxifloxacin Monotherapy for Treatment of Skin and Skin Structure Infections.

    PubMed

    Chu, Y; Qu, J; Qu, L-Y; Luo, Y-F; Jiang, M-Y

    2015-12-01

    Moxifloxacin is widely recognized for the treatment of bacterial infections of the respiratory tract such as community acquired pneumonia, acute bacterial sinusitis and acute exacerbations of chronic bronchitis. However, the use of moxifloxacin for skin infections is much valued in recent years. This study is to compare the clinical efficacy and safety of moxifloxacin monotherapy among adults with skin and skin structure infections. The meta-analysis of RCTs is conducted by searching Medline, Embase, Pubmed and the Cochrane Library. 6 RCTs, involving a total of 2608 patients, were included in the meta-analysis. English and Chinese language papers were reviewed. The results of the meta-analysis showed that the moxifloxacin monotherapy has similar clinical cure rate, bacteriological success rates and mortality compared with the control group. The drug-related adverse of moxifloxacin was significantly higher than that in the control group, although the overall incidence of adverse events, serious adverse events, and serious drug-related adverse events were similar between the compared treatment groups. Through this meta-analysis, we can draw a conclusion that moxifloxacin monotherapy has similar effectiveness and relative safety as other recommended antibiotics for the treatment of SSSIs. At the same time, it possesses the superior bacteria eradication rate. The once-daily dosing of moxifloxacin monotherapy may be a useful alternative for other recommended antibiotic therapy. PMID:26070015

  12. Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study

    PubMed Central

    2016-01-01

    Summary Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene. Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27–1·77 for CD4 cell count <100 cells per μL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1·48, 95% CI 1·20–1·82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma

  13. Nilotinib vs imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours: randomised phase 3 trial results and subgroup analysis of molecular subtypes

    PubMed Central

    Blay, Jean-Yves; Shen, Lin; Kang, Yoon-Koo; Rutkowski, Piotr; Qin, Shukui; Nosov, Dmitry; Wan, Desen; Trent, Jonathan; Srimuninnimit, Vichien; Pápai, Zsuzsanna; Le Cesne, Axel; Novick, Steven; Taningco, Lilia; Mo, Shuyuan; Green, Steven; Reichardt, Peter; Demetri, George D

    2015-01-01

    Background Nilotinib inhibits the tyrosine kinase activity of ABL1/BCR-ABL1, as well as KIT, platelet-derived growth factor receptors (PDGFRs), and the discoidin domain receptor. Gain-of-function mutations in KIT or PDGFRα are key drivers in most gastrointestinal stromal tumours (GISTs). This trial was designed to test the efficacy and safety of nilotinib vs imatinib as first-line therapy for patients with advanced GISTs. Methods This randomised, open-label, multicentre phase 3 trial included 647 adult patients with previously untreated, histologically confirmed, metastatic and/or unresectable GISTs. Patients were stratified by prior adjuvant therapy and randomised in a 1:1 ratio to receive oral imatinib 400 mg once daily or oral nilotinib 400 mg twice daily. Centrally reviewed progression-free survival (PFS) was the primary endpoint. Response rates, toxicity, and overall survival were also analysed for the overall population and for mutation-defined subsets. Efficacy endpoints used the intention to treat principle. Here, the final results are reported. This trial is registered with ClinicalTrials.gov, number NCT00785785. Findings Because the futility boundary was crossed at a preplanned interim analysis, trial accrual terminated in April 2011. At final analysis of the core study (data cutoff, October 2012), PFS was higher with imatinib overall (hazard ratio [HR] 1.47) and in the KIT exon 9 subgroup (HR 32.46) but roughly similar between arms in the KIT exon 11 subgroup (HR 1.12). Sensitivity analyses suggested that informative censoring may have contributed, because of the high proportion of premature nilotinib progressions declared by local investigators and the design changes implemented following the interim analysis, potentially biasing PFS data in favour of the nilotinib arm. The most common adverse events were nausea, diarrhoea, and peripheral oedema in the imatinib arm and rash, nausea, and abdominal pain in the nilotinib arm. The most common serious

  14. Trends of Mycobacterium bovis Isolation and First-Line Anti-tuberculosis Drug Susceptibility Profile: A Fifteen-Year Laboratory-Based Surveillance

    PubMed Central

    Bobadilla-del Valle, Miriam; Torres-González, Pedro; Cervera-Hernández, Miguel Enrique; Martínez-Gamboa, Areli; Crabtree-Ramirez, Brenda; Chávez-Mazari, Bárbara; Ortiz-Conchi, Narciso; Rodríguez-Cruz, Luis; Cervantes-Sánchez, Axel; Gudiño-Enríquez, Tomasa; Cinta-Severo, Carmen; Sifuentes-Osornio, José; Ponce de León, Alfredo

    2015-01-01

    Background Mycobacterium tuberculosis causes the majority of tuberculosis (TB) cases in humans; however, in developing countries, human TB caused by M. bovis may be frequent but undetected. Human TB caused by M. bovis is considered a zoonosis; transmission is mainly through consumption of unpasteurized dairy products, and it is less frequently attributed to animal-to-human or human-to-human contact. We describe the trends of M. bovis isolation from human samples and first-line drug susceptibility during a 15-year period in a referral laboratory located in a tertiary care hospital in Mexico City. Methodology/Principal Findings Data on mycobacterial isolates from human clinical samples were retrieved from the laboratory’s database for the 2000–2014 period. Susceptibility to first-line drugs: rifampin, isoniazid, streptomycin (STR) and ethambutol was determined. We identified 1,165 isolates, 73.7% were M. tuberculosis and 26.2%, M. bovis. Among pulmonary samples, 16.6% were M. bovis. The proportion of M. bovis isolates significantly increased from 7.8% in 2000 to 28.4% in 2014 (X2trend, p<0.001). Primary STR resistance was higher among M. bovis compared with M. tuberculosis isolates (10.9% vs.3.4%, p<0.001). Secondary multidrug resistance (MDR) rates were 38.5% and 34.4% for M. bovis and M. tuberculosis, respectively (p = 0.637). A rising trend of primary STR monoresistance was observed for both species (3.4% in 2000–2004 vs. 7.6% in 2010–2014; p = 0.02). Conclusions/Significance There is a high prevalence and a rising trend of M. bovis isolates in our region. The proportion of pulmonary M. bovis isolates is higher than in previous reports. Additionally, we report high rates of primary anti-tuberculosis resistance and secondary MDR in both M. tuberculosis and M. bovis. This is one of the largest reports on drug susceptibility of M. bovis from human samples and shows a significant proportion of first-line anti-tuberculosis drug resistance. PMID:26421930

  15. Efficacy and safety of trastuzumab combined with chemotherapy for first-line treatment and beyond progression of HER2-overexpressing advanced breast cancer

    PubMed Central

    Shao, Bin; Yan,, Yin; Song, Guohong; Liu, Xiaoran; Wang, Jing; Liang, Xu

    2016-01-01

    Objective To observe the efficacy and safety of trastuzumab combined with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing advanced breast cancer. Methods A total of 90 patients with HER2-overexpressing advanced breast cancer were enrolled in this study. All patients were diagnosed with ductal invasive breast cancer by pathological analysis, and were aged between 31–73 years with a median of 51 years. HER2-positivity was defined as 3(+) staining in immunochemistry or amplification of fluorescence in situ hybridization (FISH, ratio ≥2.0). Trastuzumab was administered in combination with chemotherapy as first-line treatment and beyond progression as a secondline, third-line, and above treatment in 90, 34, 14, and 6 patients, respectively. The chemotherapy regimen was given according to normal clinical practice. The response rate was evaluated every two cycles, and the primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival curves were estimated by using Kaplan-Meier graphs and were compared by using log-rank test statistics. Multivariate analysis was done using Cox’s proportional hazards regression model, and the level of significance was P<0.05. Results All 90 patients received at least one dose of trastuzumab, and efficacy could be evaluated in 85 patients. The median follow-up was 50 months. In total, 72 (80.00%) patients had visceral metastasis, and 43 (47.78%) patients had progressed after one or more extensive chemotherapy regimens for metastatic diseases. The median PFS for first-line trastuzumab was 10 months (range, 2–59 months), and the median OS after metastasis or initially local advanced disease was 22 months (range, 2–116 months). Conclusions Trastuzumab combined with chemotherapy was active and well-tolerated as a first-line treatment and even beyond progression in HER2-overexpressing advanced breast cancer as a second-line or third-line treatment. However, its

  16. Ranibizumab in monotherapy and combined with photodynamic therapy for retinal angiomatous proliferation

    PubMed Central

    Arias, Luis; Gómez-Ulla, Francisco; Ruiz-Moreno, José M

    2016-01-01

    Purpose To compare the effects of intravitreal ranibizumab in monotherapy (group A) and combined with photodynamic therapy (PDT) with verteporfin (group B) in retinal angiomatous proliferation (RAP) treatment. Methods This was a multicentric, prospective, randomized clinical study conducted with parallel groups. The study eye in both groups received ranibizumab on days 1, 30, and 60 (loading dose); group B received PDT additionally on day 1. Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) testing and optical coherence tomography were performed monthly, and fluorescein angiography and indocyanine green angiography were performed quarterly. Retreatment criteria were leakage in fluorescein angiography or indocyanine green angiography, mean foveal thickness increase ≥100 µm, or VA decrease ≥5 letters. Results Twenty patients were recruited (ten patients in each group). Six eyes had previous treatment (three eyes in group A and three eyes in group B), so only 14 eyes were naïve. At 12-month follow-up, mean VA improved +1.5 letters in group A and +5.6 letters in group B (analysis of variance test; P>0.05). Two patients (20%) in both groups gained ≥15 letters (chi-square test; P>0.05). Mean changes in greatest linear dimension and in foveal thickness were not statistically significant between groups of treatment (analysis of variance test; P>0.05). Mean retreatments per patient were 1.8 (group A) and 0.9 (group B) (Mann–Whitney U-test; P>0.05). One patient died due to underlying disease not related to study medication. Conclusion Intravitreal ranibizumab administered in monotherapy or combined with PDT was efficacious in terms of VA stabilization in patients with RAP. PMID:27274190

  17. Systemic corticosteroid monotherapy for clinically diagnosed acute rhinosinusitis: a randomized controlled trial

    PubMed Central

    Venekamp, Roderick P.; Bonten, Marc J.M.; Rovers, Maroeska M.; Verheij, Theo J.M.; Sachs, Alfred P.E.

    2012-01-01

    Background: Patients with acute rhinosinusitis are frequently encountered in primary care. Although corticosteroids are being increasingly used for symptom control, evidence supporting their use is inconclusive. We conducted a randomized controlled trial to examine the effectiveness of systemic corticosteroid monotherapy for clinically diagnosed, uncomplicated acute rhinosinusitis. Methods: We conducted a block-randomized, double-blind, placebo-controlled clinical trial at 54 primary care practices (68 family physicians) in the Netherlands between Dec. 30, 2008, and Apr. 28, 2011. Adult patients with clinically diagnosed acute rhinosinusitis were randomly assigned to receive either prednisolone 30 mg/d or placebo for 7 days and asked to complete a symptom diary for 14 days. The primary outcome measure was the proportion of patients with resolution of facial pain or pressure on day 7. Results: Of the 185 patients included in the trial (93 in the treatment group, 92 in the placebo group), 2 withdrew from the study and 9 were excluded from the primary analysis because of incomplete symptom reporting. The remaining 174 patients (88 in the treatment group, 86 in the placebo group) were included in the intention-to-treat analysis. The proportions of patients with resolution of facial pain or pressure on day 7 were 62.5% (55/88) in the prednisolone group and 55.8% (48/86) in the placebo group (absolute risk difference 6.7%, 95% confidence interval −7.9% to 21.2%). The groups were similar with regard to the decrease over time in the proportion of patients with total symptoms (combined symptoms of runny nose, postnasal discharge, nasal congestion, cough and facial pain) and health-related quality of life. Adverse events were mild and did not differ significantly between the groups. Interpretation: Systemic corticosteroid monotherapy had no clinically relevant beneficial effects among patients with clinically diagnosed acute rhinosinusitis. Netherlands Trial Register

  18. Fractional CO2 Laser Resurfacing as Monotherapy in the Treatment of Atrophic Facial Acne Scars

    PubMed Central

    Majid, Imran; Imran, Saher

    2014-01-01

    Background: While laser resurfacing remains the most effective treatment option for atrophic acne scars, the high incidence of post-treatment adverse effects limits its use. Fractional laser photothermolysis attempts to overcome these limitations of laser resurfacing by creating microscopic zones of injury to the dermis with skip areas in between. Aim: The aim of the present study is to assess the efficacy and safety of fractional CO2 laser resurfacing in atrophic facial acne scars. Materials and Methods: Sixty patients with moderate to severe atrophic facial acne scars were treated with 3-4 sessions of fractional CO2 laser resurfacing at 6-week intervals. The therapeutic response to treatment was assessed at each follow up visit and then finally 6 months after the last laser session using a quartile grading scale. Response to treatment was labelled as ‘excellent’ if there was >50% improvement in scar appearance and texture of skin on the grading scale while 25-50% response and <25% improvement were labelled as ‘good’ and ‘poor’ response, respectively. The overall satisfaction of the patients and any adverse reactions to the treatment were also noted. Results: Most of the patients showed a combination of different morphological types of acne scars. At the time of final assessment 6 months after the last laser session, an excellent response was observed in 26 patients (43.3%) while 15 (25%) and 19 patients (31.7%) demonstrated a good and poor response respectively. Rolling and superficial boxcar scars responded the best while pitted scars responded the least to fractional laser monotherapy. The commonest reported adverse effect was transient erythema and crusting lasting for an average of 3-4 and 4-6 days, respectively while three patients developed post-inflammatory pigmentation lasting for 8-12 weeks. Conclusions: Fractional laser resurfacing as monotherapy is effective in treating acne scars especially rolling and superficial boxcar scars with minimal

  19. LONG-TERM TREATMENT WITH PEGVISOMANT AS MONOTHERAPY IN PATIENTS WITH ACROMEGALY: EXPERIENCE FROM ACROSTUDY

    PubMed Central

    Freda, Pamela U.; Gordon, Murray B.; Kelepouris, Nicky; Jonsson, Peter; Koltowska-Haggstrom, Maria; van der Lely, A.J.

    2015-01-01

    Objective To evaluate use of pegvisomant, a GH receptor antagonist, as monotherapy in ACROSTUDY, a global safety surveillance study set in 14 countries (373 sites). Methods A descriptive analysis of safety, magnetic resonance imaging (MRI) reading and treatment outcomes in 710 subjects who received at least one pegvisomant dose as monotherapy during and up to 5 years follow-up in ACROSTUDY. Results Subjects received 5.4 yr. (mean) of pegvisomant and were followed in ACROSTUDY 3.8 yr. (mean). A total of 1255 adverse events were reported in 345 subjects (48.6%). Serious adverse events were reported in 133 (18.7%) subjects including 22 deaths, none of which were attributed to pegvisomant use. Of 670 (94%) subjects with at least one liver function test reported in ACROSTUDY, 8 (1.2%) had reported increases in transaminases > 3X ULN. No liver failure was reported. Based on central MRI reading, 12 of 542 subjects (2.2%) had a confirmed increase or increase/decrease in tumor size. Injection-site reactions were reported in 2.3%. At 5 years of therapy, IGF-1 level was reported normal in 67.5% (mean dose 17.2 mg/day) and elevated in 29.9% (mean dose 19.8 mg/day). Subjects on 20 mg per day or more rose from 36% at 3 years to 41% at 5 years of therapy. Conclusions ACROSTUDY data indicate that pegvisomant used as sole medical therapy is safe and effective medical treatment for acromegaly. The reported low incidence of pituitary tumor size increase and liver enzyme elevations are reassuring and support the positive benefit–risk of pegvisomant therapy. PMID:25370326

  20. Increased Beta Frequency (15-30 Hz) Oscillatory Responses in Euthymic Bipolar Patients Under Lithium Monotherapy.

    PubMed

    Tan, Devran; Özerdem, Ayşegül; Güntekin, Bahar; Atagün, M Ilhan; Tülay, Elif; Karadağ, Figen; Başar, Erol

    2016-04-01

    The effect of lithium on neurocognition is not still fully explored. Brain oscillatory activity is altered in bipolar disorder. We aimed to assess the oscillatory responses of euthymic bipolar patients and how they are affected by lithium monotherapy. Event-related oscillations in response to visual target stimulus during an oddball paradigm in 16 euthymic drug-free and 13 euthymic lithium-treated bipolar patients were compared with 16 healthy controls. The maximum peak-to-peak amplitudes were measured for each subject's averaged beta (15-30 Hz) responses in the 0- to 300-ms time window over frontal (F3, Fz, F4), central (C3, Cz, C4), temporal (T7, T8), temporo-parietal (TP7, TP8), parietal (P3, Pz, P4), and occipital (O1, Oz, O2) areas. Patients under lithium monotherapy had significantly higher beta responses to visual target stimuli than healthy controls (P=.017) and drug-free patients (P=.015). The increase in beta response was observed at all electrode locations, however, the difference was statistically significant for the left (T7; P=.016) and right (T8; P=.031) temporal beta responses. Increased beta responses in drug-free patients and further significant increase in lithium-treated patients may be indicative of a core pathophysiological process of bipolar disorder and how it is affected by lithium. Whether the finding corresponds to lithium's corrective effect on the underlying pathology or to its neurocognitive side effect remains to be further explored. In either case, the finding is a sign that the oscillatory activity may be useful in tracking medication effect in bipolar disorder. PMID:25465436

  1. Comparative effectiveness of biologic monotherapy versus combination therapy for patients with psoriatic arthritis: results from the Corrona registry

    PubMed Central

    Mease, Philip J; Collier, David H; Saunders, Katherine C; Li, Guo; Kremer, Joel M; Greenberg, Jeffrey D

    2015-01-01

    Objectives To characterise the comparative effectiveness of combination therapy (a tumour necrosis factor inhibitor (TNFi) and a conventional synthetic disease-modifying antirheumatic drug (csDMARD) such as methotrexate) and monotherapy (TNFi only) for psoriatic arthritis (PsA) from a large US registry. Methods The analysis included adult patients with PsA who were enrolled in the Corrona database (ClinicalTrials.gov, NCT01402661), had initiated a TNFi, were biologic naïve, and had a follow-up visit ≥90 days after drug initiation. The endpoints of the analysis were TNFi persistence (drug survival) and time to Clinical Disease Activity Index (CDAI) remission. All analyses were performed using propensity scoring, which were estimated using CDAI and patient sex, to control for channelling bias. Results Of 519 patients meeting the inclusion criteria (318 with combination therapy and 201 with monotherapy), the analysis population was 497 for TNFi persistence and 380 for time to remission. The difference between combination therapy (TNFi+methotrexate, 91% of patients; TNFi+other csDMARD, 9%) and monotherapy was not statistically significant for TNFi persistence (32 and 31 months, p=0.73) and time to remission (21 and 25 months, p=0.56). Predictors of TNFi persistence included Hispanic ethnicity (longer persistence), PsA duration (longer persistence), history of methotrexate use (shorter persistence), body mass index (shorter persistence) and disease activity (shorter persistence). Conclusions Patients with PsA from a large US registry experienced similar TNFi persistence on combination therapy and monotherapy. Prospective, randomised clinical trials evaluating the efficacy of combination therapy versus monotherapy would provide much-needed clarity on treatment options for patients with PsA. Trial registration number NCT01402661. PMID:26819748

  2. Comparison of tenofovir plus lamivudine versus tenofovir monotherapy in patients with lamivudine-resistant chronic hepatitis B

    PubMed Central

    Park, Chan Ho; Jung, Seok Won; Shin, Jung Woo; Bae, Mi Ae; Lee, Yoon Im; Park, Yong Tae; Chung, Hwa Sik; Park, Neung Hwa

    2016-01-01

    Background/Aims: Tenofovir disoproxil fumarate (TDF) exhibits similar antiviral efficacy against treatment-naïve and lamivudine (LAM)-resistant chronic hepatitis B (CHB). However, there are few clinical reports on the antiviral effects of TDF–LAM combination therapy compared to TDF monotherapy in patients with LAM-resistant CHB. Methods: We investigated the antiviral efficacy of TDF monotherapy vs. TDF–LAM combination therapy in 103 patients with LAM-resistant CHB. Results: The study subjects were treated with TDF alone (n=40) or TDF–LAM combination therapy (n=63) for ≥6 months. The patients had previously been treated with TDF-based rescue therapy for a median of 30.0 months (range, 8–36 months). A virologic response (VR) was achieved in 99 patients (96.1%): 95.0% (38/40) of patients in the TDF monotherapy group and 96.8% (61/63) of patients in the TDF–LAM combination therapy group. The VR rates were not significantly different between the TDF monotherapy and TDF–LAM combination therapy groups (88.9 vs. 87.3% at month 12, and 94.4 vs. 93.7% at month 24, log-rank p=0.652). Univariate and multivariate analyses revealed that none of the pretreatment factors were significantly associated with VR. Conclusions: TDF monotherapy was as effective as TDF–LAM combination therapy for maintaining viral suppression in the vast majority of patients with LAM-resistant CHB, which suggests that TDF add-on therapy with LAM is unnecessary. PMID:27044766

  3. 90Y-ibritumomab tiuxetan radiotherapy as first-line therapy for early stage low-grade B-cell lymphomas, including bulky disease.

    PubMed

    Samaniego, Felipe; Berkova, Zuzana; Romaguera, Jorge E; Fowler, Nathan; Fanale, Michelle A; Pro, Barbara; Shah, Jatin J; McLaughlin, Peter; Sehgal, Lalit; Selvaraj, Vijairam; Braun, Frank K; Mathur, Rohit; Feng, Lei; Neelapu, Sattva S; Kwak, Larry W

    2014-10-01

    (90) Y-ibritumomab-tiuxetan ((90) YIT) was used as a first-line therapy for patients with early-stage follicular lymphoma (FL) or marginal zone B-cell lymphoma (MZL). Thirty-one patients were treated, with an overall 3-month response rate of 100% (68% complete response, 29% unconfirmed complete response and 3% partial response). At a median follow-up of 56 months, ten patients (32%) had disease relapse or progression. The progression-free rates at 3 and 5 years were lower in males, patients with FL, stage II disease and non-bulky disease, although they did not reach statistical significance. Grade 3-4 neutropenia, thrombocytopenia and anaemia were 61%, 35%, and 3%, respectively. (90) YIT was well tolerated, including in those patients over 60 years old, and achieved high response rates in patients with early-stage low-grade B-cell lymphomas. Bulky disease did not adversely affect tumour response. PMID:25040450

  4. Is epirubicin effective in first-line chemotherapy of metastatic breast cancer (MBC) after an epirubicin-containing adjuvant treatment? A single centre phase III trial

    PubMed Central

    Pacilio, C; Morabito, A; Nuzzo, F; Gravina, A; Labonia, V; Landi, G; Rossi, E; De Maio, E; Di Maio, M; D'aiuto, G; Botti, G; Normanno, N; Chiodini, P; Gallo, C; Perrone, F; de Matteis, A

    2006-01-01

    The aim of the study was to demonstrate the superiority of docetaxel and epirubicin vs docetaxel alone as first-line therapy in metastatic breast cancer patients pretreated with adjuvant or neoadjuvant epirubicin. We compared single agent docetaxel 100 mg m−2 (D) with the combination of docetaxel 80 mg m−2 and epirubicin 75 mg m−2 (ED). The response rate (72 vs 79%), the progression-free survival (median 9 vs 11 months) and the overall survival (median 18 vs 21 months) were not significantly different between the ED (n=26) and D arms (n=25), respectively. Leucopaenia, nausea and stomatitis were significantly worse with ED. In conclusion, epirubicin should not be administered in combination with taxanes in metastatic breast cancer patients relapsed after an anthracycline-based adjuvant or neoadjuvant therapy. PMID:16622454

  5. Updates on first-line treatment of metastatic pancreatic adenocarcinoma. Highlights from the "2011 ASCO Annual Meeting". Chicago, IL, USA; June 3-7, 2011.

    PubMed

    Strimpakos, Alexios S; Syrigos, Kostas N; Saif, Muhammad Wasif

    2011-07-01

    Despite the extensive research, mounting knowledge in the cancer field and enormous investments, pancreatic cancer remains a rather incurable disease with aggressive natural course and high mortality rate. The very slow progress is a result of the complex pathogenesis of this disease, which prevents us from targeting the culprit and making a step forward. Therefore, the field is still unexplored and this is a real challenge and opportunity for new ideas and novel approaches. In this paper, we will present the most interesting studies in the first line pancreatic cancer setting, presented at the American Society of Clinical Oncology (ASCO) 2011 Annual Meeting. While there are few studies testing the role of combining the cytotoxic S-1 and gemcitabine, the majority of the studies are examining the safety and impact of adding to the classic gemcitabine treatment novel molecular agents which target key pathways or overexpressed proteins. PMID:21737891

  6. HIV-1 Infection and First Line ART Induced Differential Responses in Mitochondria from Blood Lymphocytes and Monocytes: The ANRS EP45 “Aging” Study

    PubMed Central

    Perrin, Sophie; Cremer, Jonathan; Roll, Patrice; Faucher, Olivia; Ménard, Amélie; Reynes, Jacques; Dellamonica, Pierre; Naqvi, Alissa; Micallef, Joëlle; Jouve, Elisabeth; Tamalet, Catherine; Solas, Caroline; Pissier, Christel; Arnoux, Isabelle; Nicolino-Brunet, Corine; Espinosa, Léon; Lévy, Nicolas; Kaspi, Elise; Robaglia-Schlupp, Andrée; Poizot-Martin, Isabelle; Cau, Pierre

    2012-01-01

    Background The ANRS EP45 “Aging” study investigates the cellular mechanisms involved in the accelerated aging of HIV-1 infected and treated patients. The data reported focus on mitochondria, organelles known to be involved in cell senescence. Methods 49 HIV-1 infected patients untreated with antiretroviral therapy, together with 49 seronegative age- and sex-matched control subjects and 81 HIV-1 infected and treated patients, were recruited by 3 AIDS centres (Marseille, Montpellier, Nice; France; http://clinicaltrials.gov/, NCT01038999). In more than 88% of treated patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm3. ROS (reactive oxygen species) production and ΔΨm (inner membrane potential) were measured by flow cytometry in blood lymphocytes and monocytes (functional parameters). Three mitochondrial network quantitative morphological parameters were computed using confocal microscopy and image analysis. Three PBMC mitochondrial proteins (porin and subunits 2 and 4 of cytochrome C oxidase encoded by mtDNA or nuclear DNA, respectively) were analysed by western blotting. Results Quantitative changes in PBMC mitochondrial proteins were not induced by either HIV-1 infection or ART. Discriminant analysis integrating functional (ROS production and ΔΨm) or morphological (network volume density, fragmentation and branching) parameters revealed HIV-1 infection and ART differential effects according to cell type. First line ART tended to rescue lymphocyte mitochondrial parameters altered by viral infection, but induced slight changes in monocytes. No statistical difference was found between the effects of three ART regimens on mitochondrial parameters. Correlations between functional parameters and viral load confirmed the damaging effects of HIV-1 in lymphocyte mitochondria. Conclusions In patients considered to be clinically stable, mitochondria exhibited functional and morphological modifications in PBMCs resulting from either direct or

  7. Fibrinogen concentrate as first-line therapy in aortic surgery reduces transfusion requirements in patients with platelet counts over or under 100×109/L

    PubMed Central

    Solomon, Cristina; Rahe-Meyer, Niels

    2015-01-01

    Background Administration of fibrinogen concentrate, targeting improved maximum clot firmness (MCF) of the thromboelastometric fibrin-based clot quality test (FIBTEM) is effective as first-line haemostatic therapy in aortic surgery. We performed a post-hoc analysis of data from a randomised, placebo-controlled trial of fibrinogen concentrate, to investigate whether fibrinogen concentrate reduced transfusion requirements for patients with platelet counts over or under 100×109/L. Material and methods Aortic surgery patients with coagulopathic bleeding after cardiopulmonary bypass were randomised to receive either fibrinogen concentrate (n=29) or placebo (n=32). Platelet count was measured upon removal of the aortic clamp, and coagulation and haematology parameters were measured peri-operatively. Transfusion of allogeneic blood components was recorded and compared between groups. Results After cardiopulmonary bypass, haemostatic and coagulation parameters worsened in all groups; plasma fibrinogen level (determined by the Clauss method) decreased by 43–58%, platelet count by 53–64%, FIBTEM maximum clot firmness (MCF) by 38–49%, FIBTEM maximum clot elasticity (MCE) by 43–54%, extrinsically activated test (EXTEM) MCF by 11–22%, EXTEM MCE by 25–41% and the platelet component of the clot by 23–39%. Treatment with fibrinogen concentrate (mean dose 7–9 g in the 4 groups) significantly reduced post-operative allogeneic blood component transfusion requirements when compared to placebo both for patients with a platelet count ≥100×109/L and for patients with a platelet count <100×109/L. Discussion FIBTEM-guided administration of fibrinogen concentrate reduced transfusion requirements when used as a first-line haemostatic therapy during aortic surgery in patients with platelet counts over or under 100×109/L. PMID:25369608

  8. Phase II study of necitumumab plus modified FOLFOX6 as first-line treatment in patients with locally advanced or metastatic colorectal cancer

    PubMed Central

    Elez, E; Hendlisz, A; Delaunoit, T; Sastre, J; Cervantes, A; Varea, R; Chao, G; Wallin, J; Tabernero, J

    2016-01-01

    Background: This single-arm phase II study investigated the EGFR monoclonal antibody necitumumab plus modified FOLFOX6 (mFOLFOX6) in first-line treatment of locally advanced or metastatic colorectal cancer (mCRC). Methods: Patients received 800-mg intravenous necitumumab (day 1; 2-week cycles), followed by oxaliplatin 85 mg m−2, folinic acid 400 mg m−2, and 5-fluorouracil (400 mg m−2 bolus then 2400 mg m−2 over 46 h). Radiographic evaluation was performed every 8 weeks until progression. Primary endpoint was objective response rate. Results: Forty-four patients were enrolled and treated. Objective response rate was 63.6% (95% confidence interval 47.8–77.6); complete response was observed in four patients; median duration of response was 10.0 months (7.0–16.0). Median overall survival (OS) and progression-free survival (PFS) were 22.5 (11.0–30.0) and 10.0 months (7.0–12.0), respectively. Clinical outcome was better in patients with KRAS exon 2 wild type (median OS 30.0 months (23.0–NA); median PFS 12.0 (8.0–20.0)), compared with KRAS exon 2 mutant tumours (median OS 7.0 months (5.0–37.0); median PFS 7.0 (4.0–18.0)). The most common grade ⩾3 adverse events were neutropenia (29.5%), asthenia (27.3%), and rash (20.5%). Conclusion: First-line necitumumab+mFOLFOX6 was active with manageable toxicity in locally advanced or mCRC; additional evaluation of the impact of tumour RAS mutation status is warranted. PMID:26766738

  9. Impact of dose intensity on outcome of fludarabine, cyclophosphamide, and rituximab regimen given in the first-line therapy for chronic lymphocytic leukemia

    PubMed Central

    Bouvet, Emmanuelle; Borel, Cécile; Obéric, Lucie; Compaci, Gisèle; Cazin, Bruno; Michallet, Anne-Sophie; Laurent, Guy; Ysebaert, Loic

    2013-01-01

    Fludarabine-cyclophosphamide-rituximab is the most efficient first-line treatment for chronic lymphocytic leukemia patients. Many dose adjustments of the original MD Anderson Cancer Center regimen have been proposed. However, whether fludarabine-cyclophosphamide-rituximab relative dose intensity may have an impact on outcome has not yet been investigated. We retrospectively assessed relative dose intensity in 106 community-based patients included in our regional healthcare network from 2004-11, all receiving fludarabine-cyclophosphamide-rituximab as first-line treatment outside clinical trials. Dose reductions were observed in 51.4% of patients, mainly decided by the individual physician and not based on recommendations (52.7%), while there were fewer reports of toxicity or dose reduction because of impaired renal function. Progression-free survival was significantly reduced in patients who had a reduction in dose intensity of more than 20% in fludarabine-cyclophosphamide and/or rituximab. Multivariate analysis showed dose of rituximab had a significant impact on minimal residual disease and progression-free survival. Although prophylactic granulocyte-colony stimulating factor significantly reduced the rate of grade 3-4 neutropenia and febrile neutropenia, it had no impact on relative dose intensity and outcome. This study shows that, in routine clinical practice, there is low adherence to the original MD Anderson Cancer Center fludarabine-cyclophosphamide-rituximab schedule, and that the decision to modify dosage was mostly taken by the individual physician and was based on anticipated toxicity. This study shows that reduction of fludarabine-cyclophosphamide and, more importantly, of rituximab doses seriously interferes with progression-free survival. PMID:23065520

  10. Gefitinib as first line therapy in Malaysian patients with EGFR mutation-positive non-small-cell lung cancer: A single-center retrospective study

    PubMed Central

    ABDULLAH, MATIN MELLOR; BHAT, AMIT; MOHAMED, AHMAD KAMAL; CHING, FOO YOKE; AHMED, NIDA; GANTOTTI, SANDEEP

    2016-01-01

    The present retrospective, single-center study evaluated the objective response rate (ORR) and progression-free survival (PFS) of epidermal growth factor receptor (EGFR) mutation-positive Malaysian patients with advanced lung adenocarcinoma treated with gefitinib. During May 2008 to July 2013, 33 patients with Stage IV, EGFR mutation-positive non-small-cell lung cancer (NSCLC) were identified and received gefitinib (250 mg) as first line treatment. The primary and secondary end points were ORR, PFS and safety, respectively. A total of 18 (54.5%) and 2 (6.1%) patients achieved partial response (PR) and complete response (CR) to gefitinib therapy, respectively, yielding an ORR of 60.6% (95% CI, 42.1–77.1%). Patients with exon 20 or 21 mutations (n=6, 66.7%) tended to have better ORR compared with exon 19 (n=22, 59.1%). The median PFS was 8.9 months in Malaysian patients with EGFR mutation-positive NSCLC, treated with gefitinib. The majority of treatment-related toxicity was mild in nature. The most frequently reported adverse events included dry skin (39.4%), skin rash (27.2%), and dermatitis acneiform (15.2%). In conclusion, Malaysian patients with locally advanced and metastatic EGFR mutation-positive NSCLC responded favorably to gefitinib therapy in terms of ORR, median PFS, and tolerability, the results of which were consistent with those of the IPASS study conducted in an Asian population. Considering the efficacy and safety profile of gefitinib, it is a favorable option for the first-line treatment of Malaysian patients with EGFR mutation-positive NSCLC. However, future long-term studies in a larger population of Malaysian patients are required to support whether the prolonged PFS conferred by gefitinib will translate into prolonged overall survival. PMID:27073548

  11. Prevalence of extended treatment in pulmonary tuberculosis patients receiving first-line therapy and its association with recurrent tuberculosis in Beijing, China

    PubMed Central

    Xia, YinYin; Goel, Sonu; Harries, Anthony D.; Zhang, ZhiGuo; Gao, TieJie; Wang, LiXia; Cheng, ShiMing; Lin, Yan; Du, Xin

    2014-01-01

    Background In China, it is known that extended treatment is given to patients with pulmonary TB after they have successfully completed 6 months of first-line treatment. This practice is not officially reported to the National Tuberculosis Control Programme, so there are no data on its prevalence, its possible benefits in terms of preventing recurrent disease or the costs. This study aimed to provide information, from a single TB dispensary in Beijing, China, on the prevalence of extended anti-TB treatment and its relationship with recurrent TB. Methods Retrospective cohort study using the electronic national TB information system and dispensary medical records. Results Of 935 patients with pulmonary TB who completed 6–7 months of first-line drug treatment, 399 (43%) were given extended treatment. This was more common in patients with smear-positive disease, and those with lung cavities and more extensive radiographic lobar involvement at the time of diagnosis. Over 3–4 years' follow-up, recurrent disease was not significantly different in patients who received extended treatment (2.8%, 11/399) as compared to those who received the standard 6-month treatment (3.7%, 20/534). The median length of extended treatment was 89 days at a median cost of US$111 for drugs and US$32 for laboratory examinations. Conclusions This study shows that extended treatment is common in one TB dispensary in Beijing. Further studies are needed to determine the countrywide prevalence of this practice and ascertain more conclusively the apparent lack of benefit. PMID:24864048

  12. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study

    PubMed Central

    Douillard, J-Y; Ostoros, G; Cobo, M; Ciuleanu, T; McCormack, R; Webster, A; Milenkova, T

    2014-01-01

    Background: Phase-IV, open-label, single-arm study (NCT01203917) to assess efficacy and safety/tolerability of first-line gefitinib in Caucasian patients with stage IIIA/B/IV, epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Methods: Treatment: gefitinib 250 mg day−1 until progression. Primary endpoint: objective response rate (ORR). Secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objective: EGFR mutation analysis in matched tumour and plasma samples. Results: Of 1060 screened patients with NSCLC (859 known mutation status; 118 positive, mutation frequency 14%), 106 with EGFR sensitising mutations were enrolled (female 70.8% adenocarcinoma 97.2% never-smoker 64.2%). At data cutoff: ORR 69.8% (95% confidence interval (CI) 60.5–77.7), DCR 90.6% (95% CI 83.5–94.8), median PFS 9.7 months (95% CI 8.5–11.0), median OS 19.2 months (95% CI 17.0–NC; 27% maturity). Most common adverse events (AEs; any grade): rash (44.9%), diarrhoea (30.8%); CTC (Common Toxicity Criteria) grade 3/4 AEs: 15% SAEs: 19%. Baseline plasma 1 samples were available in 803 patients (784 known mutation status; 82 positive; mutation frequency 10%). Plasma 1 EGFR mutation test sensitivity: 65.7% (95% CI 55.8–74.7). Conclusion: First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. Plasma samples could be considered for mutation analysis if tumour tissue is unavailable. PMID:24263064

  13. Prevalence and Evolution of Low Frequency HIV Drug Resistance Mutations Detected by Ultra Deep Sequencing in Patients Experiencing First Line Antiretroviral Therapy Failure

    PubMed Central

    Recordon-Pinson, Patricia; Reigadas, Sandrine; Bidet, Yannick; Bruyand, Mathias; Bonnet, Fabrice; Lazaro, Estibaliz; Neau, Didier; Fleury, Hervé; Dabis, François; Morlat, Philippe; Masquelier, Bernard

    2014-01-01

    Objectives Clinical relevance of low-frequency HIV-1 variants carrying drug resistance associated mutations (DRMs) is still unclear. We aimed to study the prevalence of low-frequency DRMs, detected by Ultra-Deep Sequencing (UDS) before antiretroviral therapy (ART) and at virological failure (VF), in HIV-1 infected patients experiencing VF on first-line ART. Methods Twenty-nine ART-naive patients followed up in the ANRS-CO3 Aquitaine Cohort, having initiated ART between 2000 and 2009 and experiencing VF (2 plasma viral loads (VL) >500 copies/ml or one VL >1000 copies/ml) were included. Reverse transcriptase and protease DRMs were identified using Sanger sequencing (SS) and UDS at baseline (before ART initiation) and VF. Results Additional low-frequency variants with PI-, NNRTI- and NRTI-DRMs were found by UDS at baseline and VF, significantly increasing the number of detected DRMs by 1.35 fold (p<0.0001) compared to SS. These low-frequency DRMs modified ARV susceptibility predictions to the prescribed treatment for 1 patient at baseline, in whom low-frequency DRM was found at high frequency at VF, and 6 patients at VF. DRMs found at VF were rarely detected as low-frequency DRMs prior to treatment. The rare low-frequency NNRTI- and NRTI-DRMs detected at baseline that correlated with the prescribed treatment were most often found at high-frequency at VF. Conclusion Low frequency DRMs detected before ART initiation and at VF in patients experiencing VF on first-line ART can increase the overall burden of resistance to PI, NRTI and NNRTI. PMID:24475178

  14. A phase II, multicenter, single-arm trial of eribulin as first-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer.

    PubMed

    Takashima, Tsutomu; Tokunaga, Shinya; Tei, Seika; Nishimura, Shigehiko; Kawajiri, Hidemi; Kashiwagi, Shinichiro; Yamagata, Shigehito; Noda, Satoru; Nishimori, Takeo; Mizuyama, Yoko; Sunami, Takeshi; Tezuka, Kenji; Ikeda, Katsumi; Ogawa, Yoshinari; Onoda, Naoyoshi; Ishikawa, Tetsuro; Kudoh, Shinzoh; Takada, Minoru; Hirakawa, Kosei

    2016-01-01

    The treatment goals for metastatic breast cancer (MBC) are prolonging survival and improving the quality of life. Eribulin, a non-taxane tubulin inhibitor, demonstrated improved survival in previous studies and also showed mild toxicity when used in late-line therapy for MBC. We conducted a phase II study to investigate the efficacy of eribulin mesylate as the first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative MBC. This was a phase II, open-label, single-arm, multicenter trial conducted in Japan. Patients with HER2-negative MBC received intravenous eribulin (1.4 mg/m(2) on days 1 and 8 of each 21-day cycle). The primary efficacy outcome was overall response rate (ORR). Secondary outcomes included time to treatment failure, progression-free survival (PFS), overall survival (OS), and safety. A total of 35 patients were enrolled and received a median of 8 (range 1-21) cycles of eribulin therapy. ORR and clinical benefit rate were 54.3 and 62.9 %, respectively. Median PFS was 5.8 months and median OS was 35.9 months. Grade 3 or 4 neutropenia was observed in 63 % of patients. The majority of non-hematological adverse events were mild in severity. The present trial demonstrated that eribulin has antitumor activity comparable with other key established cytotoxic agents with acceptable safety and tolerability. Thus, eribulin as first-line chemotherapy might be beneficial for patients with HER2-negative MBC. PMID:27026861

  15. Low rate of virological failure and maintenance of susceptibility to HIV-1 protease inhibitors with first-line lopinavir/ritonavir-based antiretroviral treatment in clinical practice.

    PubMed

    Prosperi, Mattia C F; Zazzi, Maurizio; Punzi, Grazia; Monno, Laura; Colao, Grazia; Corsi, Paola; Di Giambenedetto, Simona; Meini, Genny; Ghisetti, Valeria; Bonora, Stefano; Pecorari, Monica; Gismondo, Maria Rita; Bagnarelli, Patrizia; Carli, Tiziana; De Luca, Andrea

    2010-12-01

    Protease inhibitor (PI)-resistant HIV-1 has hardly ever been detected at failed boosted PI-based first-line antiretroviral regimens in clinical trials. However, this phenomenon has not been investigated in clinical practice. To address this gap, data from patients starting a first-line lopinavir/ritonavir (LPV/rtv)-based therapy with available baseline HIV-1 RNA load, a viral genotype and follow-up viral load after 3 and 6 months of treatment were extracted from the Italian Antiretroviral Resistance Cohort Analysis (ARCA) observational database. Based on survival analysis, 39 (7.1%) and 43 (7.8%) of the 548 examined patient cases had an HIV-1 RNA >500 and >50 copies/ml, respectively, after 6 months of treatment. Cox proportional hazard models detected baseline HIV-1 RNA (RH 1.79, 95%CI 1.10-2.92 per 1-log(10) increase, P=0.02) and resistance to the nucleoside backbone (RH 1.04, 95%CI 1.02-1.06 per 10-point increase using the Stanford HIVdb algorithm, P<0.001) as independent predictors of HIV-1 RNA at >500 copies/ml, but not at the >50 copies/ml cutoff criteria. Higher baseline viral load, older patient age, heterosexual route of infection and use of tenofovir/emtricitabine were predictors of failure at month 3 using the 50-copy and/or 500-copy threshold. Resistance to LPV/rtv did not occur or increase in any of the available 36 follow-up HIV-1 genotypes. Resistance to the nucleoside backbone (M184V) developed in four cases. Despite the likely differences in patient population and adherence, both the low rate of virological failure and the lack of development of LPV/rtv resistance documented in clinical trials are thus confirmed in clinical practice. PMID:20981785

  16. First-line antiretroviral treatment failure and associated factors in HIV patients at the University of Gondar Teaching Hospital, Gondar, Northwest Ethiopia

    PubMed Central

    Ayalew, Mohammed Biset; Kumilachew, Dawit; Belay, Assefa; Getu, Samson; Teju, Derso; Endale, Desalegn; Tsegaye, Yemisirach; Wale, Zebiba

    2016-01-01

    Background Antiretroviral therapy (ART) restores immune function and reduces HIV-related adverse outcomes. But treatment failure erodes this advantage and leads to an increased morbidity and compromised quality of life in HIV patients. The aim of this study was to determine the prevalence and factors associated with first-line ART failure in HIV patients at the University of Gondar Teaching Hospital. Patients and methods A retrospective study was conducted on 340 adults who had started ART during the period of September 2011 to May 2015. Data regarding patients’ sociodemographics, baseline characteristics, and treatment-related information were collected through review of their medical charts. Data were analyzed using SPSS version 21. Descriptive statistics, cross-tabs, and binary and multiple logistic regressions were utilized. P<0.05 was used to declare association. Results Among the 340 patients enrolled, 205 were females (60.3%). The mean age at ART initiation was 34.4 years. A total of 14 (4.1%) patients were found to have treatment failure. The median duration of treatment failure from initiation of treatment was 17.5 months (8–36 months). Poor adherence to treatment and low baseline CD4 cell count were found to be significant predictors of treatment failure. Conclusion The prevalence of first-line ART failure was 4.1%. Treatment failure was most likely to occur for the patients who had poor drug adherence and those who were delayed to start ART till their CD4 cell count became very low (<100 cells/mm3). PMID:27621669

  17. Mycobacterium tuberculosis Genotypes Determined by Spoligotyping to Be Circulating in Colombia between 1999 and 2012 and Their Possible Associations with Transmission and Susceptibility to First-Line Drugs

    PubMed Central

    Puerto, Gloria; Erazo, Lina; Wintaco, Maira; Castro, Claudia; Ribón, Wellman; Guerrero, Martha Inírida

    2015-01-01

    Introduction Tuberculosis (TB) remains a primary public health problem worldwide. The number of multidrug-resistant tuberculosis (MDR TB) cases has increased in recent years in Colombia. Knowledge of M. tuberculosis genotypes defined by spoligotyping can help determine the circulation of genotypes that must be controlled to prevent the spread of TB. Objective To describe the genotypes of M. tuberculosis using spoligotyping in resistant and drug-sensitive isolates and their possible associations with susceptibility to first-line drugs. Methods An analytical observational study was conducted that included 741 isolates of M. tuberculosis from patients. The isolates originated from 31 departments and were obtained by systematic surveillance between 1999 and 2012. Results In total 61.94% of the isolates were resistant to 1 or more drugs, and 147 isolates were MDR. In total, 170 genotypes were found in the population structure of Colombian M. tuberculosis isolates. The isolates were mainly represented by four families: LAM (39.9%), Haarlem (19%), Orphan (17%) and T (9%). The SIT42 (LAM 9) was the most common genotype and contained 24.7% of the isolates, followed by the genotypes SIT62 (Haarlem1), SIT53 (T1), and SIT50 (H3). A high clustering of isolates was evident with 79.8% of the isolates classified into 32 groups. The Beijing family was associated with resistant isolates, whereas the Haarlem and T families were associated with sensitive isolates. The Haarlem family was also associated with grouped isolates (p = 0.031). Conclusions A high proportion (approximately 80%) of isolates was found in clusters; these clusters were not associated with resistance to first-line drugs. The Beijing family was associated with drug resistance, whereas the T and Haarlem families were associated with susceptibility in the Colombian isolates studied. PMID:26066494

  18. MicroRNA Expression Profiling of Peripheral Blood Samples Predicts Resistance to First-line Sunitinib in Advanced Renal Cell Carcinoma Patients12

    PubMed Central

    Gámez-Pozo, Angelo; Antón-Aparicio, Luis M; Bayona, Cristina; Borrega, Pablo; Gallegos Sancho, María I; García-Domínguez, Rocío; de Portugal, Teresa; Ramos-Vázquez, Manuel; Pérez-Carrión, Ramón; Bolós, María V; Madero, Rosario; Sánchez-Navarro, Iker; Fresno Vara, Juan A; Arranz, Enrique Espinosa

    2012-01-01

    Anti-angiogenic therapy benefits many patients with advanced renal cell carcinoma (RCC), but there is still a need for predictive markers that help in selecting the best therapy for individual patients. MicroRNAs (miRNAs) regulate cancer cell behavior and may be attractive biomarkers for prognosis and prediction of response. Forty-four patients with RCC were recruited into this observational prospective study conducted in nine Spanish institutions. Peripheral blood samples were taken before initiation of therapy and 14 days later in patients receiving first-line therapy with sunitinib for advanced RCC. miRNA expression in peripheral blood was assessed using microarrays and L2 boosting was applied to filtered miRNA expression data. Several models predicting poor and prolonged response to sunitinib were constructed and evaluated by binary logistic regression. Blood samples from 38 patients and 287 miRNAs were evaluated. Twenty-eight miRNAs of the 287 were related to poor response and 23 of the 287 were related to prolonged response to sunitinib treatment. Predictive models identified populations with differences in the established end points. In the poor response group, median time to progression was 3.5 months and the overall survival was 8.5, whereas in the prolonged response group these values were 24 and 29.5 months, respectively. Ontology analyses pointed out to cancer-related pathways, such angiogenesis and apoptosis. miRNA expression signatures, measured in peripheral blood, may stratify patients with advanced RCC according to their response to first-line therapy with sunitinib, improving diagnostic accuracy. After proper validation, these signatures could be used to tailor therapy in this setting. PMID:23308047

  19. Randomized Phase III Placebo-Controlled Trial of Letrozole Plus Oral Temsirolimus As First-Line Endocrine Therapy in Postmenopausal Women With Locally Advanced or Metastatic Breast Cancer

    PubMed Central

    Wolff, Antonio C.; Lazar, Ann A.; Bondarenko, Igor; Garin, August M.; Brincat, Stephen; Chow, Louis; Sun, Yan; Neskovic-Konstantinovic, Zora; Guimaraes, Rodrigo C.; Fumoleau, Pierre; Chan, Arlene; Hachemi, Soulef; Strahs, Andrew; Cincotta, Maria; Berkenblit, Anna; Krygowski, Mizue; Kang, Lih Lisa; Moore, Laurence; Hayes, Daniel F.

    2013-01-01

    Purpose Recent data showed improvement in progression-free survival (PFS) when adding everolimus to exemestane in patients with advanced breast cancer experiencing recurrence/progression after nonsteroidal aromatase inhibitor (AI) therapy. Here, we report clinical outcomes of combining the mammalian target of rapamycin (mTOR) inhibitor temsirolimus with letrozole in AI-naive patients. Patients and Methods This phase III randomized placebo-controlled study tested efficacy/safety of first-line oral letrozole 2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks) versus letrozole/placebo in 1,112 patients with AI-naive, hormone receptor–positive advanced disease. An independent data monitoring committee recommended study termination for futility at the second preplanned interim analysis (382 PFS events). Results Patients were balanced (median age, 63 years; 10% stage III, 40% had received adjuvant endocrine therapy). Those on letrozole/temsirolimus experienced more grade 3 to 4 events (37% v 24%). There was no overall improvement in primary end point PFS (median, 9 months; hazard ratio [HR], 0.90; 95% CI, 0.76 to 1.07; P = .25) nor in the 40% patient subset with prior adjuvant endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus in patients ≤ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P = .009), which was separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment effect pattern plot methodology (P = .003). Conclusion Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive advanced breast cancer. Exploratory analyses of benefit in younger postmenopausal patients require external confirmation. PMID:23233719

  20. Final results of a phase II study of nab-paclitaxel, bevacizumab, and gemcitabine as first-line therapy for patients with HER2-negative metastatic breast cancer.

    PubMed

    Lobo, Christopher; Lopes, Gilberto; Baez, Odalys; Castrellon, Aurelio; Ferrell, Annapoorna; Higgins, Connie; Hurley, Erin; Hurley, Judith; Reis, Isildinha; Richman, Stephen; Seo, Pearl; Silva, Orlando; Slingerland, Joyce; Tukia, Keleni; Welsh, Catherine; Glück, Stefan

    2010-09-01

    In order to examine the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-P) in combination with bevacizumab (B) and gemcitabine (G) for the first-line treatment of patients with HER2-negative metastatic breast cancer (MBC). In this single-center, open-label phase II trial, patients with HER2-negative MBC received gemcitabine 1500 mg/m(2), nab-paclitaxel 150 mg/m(2), and bevacizumab 10 mg/kg (each administered intravenously) on days 1 and 15 of a 28-day cycle. The primary end point was progression free survival (PFS); secondary end points were overall response rate (ORR), complete (CR) and partial (PR) response rates, clinical benefit (ORR + stable disease), overall survival (OS), and safety. Thirty patients were enrolled. One patient was ineligible and was not included in analysis. Median PFS was 10.4 months (95% CI: 5.6-15.2 months). ORR was 75.9%, comprising eight (27.6%) CRs and 14 (48.3%) PRs; five patients had stable disease (SD) and two patients (6.9%) had progressive disease (PD) as their best response. The clinical benefit rate was 93.1% (27/29) in the overall group and 84.6% in the triple-negative cohort (11/13). The 18-month survival rate was 77.2% (95% CI: 51.1-90.5%). Eight (27.6%) patients experienced grade 3 or 4 toxicity: grade 4 neutropenic fever (n = 1) and grade 3 infection (n = 6), leukopenia, thrombocytopenia, peripheral neuropathy, seizure, shortness of breath, hematuria, and cardiac tamponade (one each). First-line therapy with nab-P, B, and G demonstrated a median PFS of 10.4 months and a 75.9% ORR with acceptable toxicity; this novel combination warrants investigation in a randomized study. PMID:20585851

  1. Does the type of first-line regimens influence the receipt of second-line chemotherapy treatment? An analysis of 3211 metastatic colon cancer patients.

    PubMed

    Zheng, Zhiyuan; Hanna, Nader; Onukwugha, Eberechukwu; Reese, Emily S; Seal, Brian; Mullins, C Daniel

    2014-02-01

    With new agents entering the market, the sequencing of first-line (Tx1), second-line (Tx2), and subsequent chemotherapy/biologics regimens are being examined. We examined how Tx1 regimens impacted the likelihood of receiving Tx2 among metastatic colon cancer (mCC) patients. Surveillance, Epidemiology and End Results (SEER)-Medicare data were used to identify elderly mCC patients between 2003 and 2007. The inverse probability weighting Cox regression method was utilized to study the relationship between receipt of Tx2 and Tx1 regimens, controlling for patient-level factors. Of the 7895 elderly patients identified, 3211 (41%) received Tx1 of which 1440 proceeded to Tx2. The impact of Tx1 on receipt of Tx2 varied by the specific regimens utilized. As compared to 5FU/LV users, IROX (Hazard Ratio [HR] = 0.03; P < 0.01) and IROX + Biologics (HR = 0.20; P < 0.01) users were less likely to receive Tx2; (oxaliplatin) OX + Biologics (HR = 1.26; P < 0.01) users were more likely to receive Tx2. Significant patient-level factors included: Hispanic ethnicity (HR = 0.67; P < 0.01); being married (HR = 0.87; P = 0.01); proxy for poor performance status (HR = 0.82; P = 0.05); each 10-year age increment (HR = 1.14; P < 0.01); and State buy-in status (HR = 1.21; P = 0.01). The specific first-line regimen does impact mCC patients' likelihood of receiving Tx2 in clinical practice. Elderly mCC patients, their health care providers, and policy makers will benefit from new evidence about the impact of sequencing of treatment lines. PMID:24403130

  2. Recombinant FSH Compared to Clomiphene Citrate as the First-Line in Ovulation Induction in Polycystic Ovary Syndrome Using Newly Designed Pens: A Randomized Controlled Trial

    PubMed Central

    Hossein-Rashidi, Batool; Khandzad, Bahareh; Shahrokh-Tehraninejad, Ensieh; Bagheri, Maryam; Gorginzadeh, Mansoureh

    2016-01-01

    Objective: Since there is still controversy regarding the best first-line choice for ovulation induction (OI) other than clomiphene citrate (CC) in infertile women diagnosed with polycystic ovary syndrome (PCOS), the aim of the present study was to compare recombinant human FSH with CC as the first course of OI in these women. Materials and methods: In this pilot randomized controlled trial, 104 infertile women diagnosed with PCOS were randomized in two groups to receive either CC with the dose of 100mg per day from day 3 of a spontaneous or progestin-induced menstruation for 5 days or rFSH with the starting dose of 50 IU daily {and weekly dose increment of as low as 12.5 IU}, on the day4 of the cycle. They were assessed during a single OI course. The pregnancy rate (PR) and live birth rate (LBR) were the primary outcomes. The follicular response, endometrial thickness, cancellation of the cycles and ovarian hyper stimulation (OHSS) rate were the secondary outcomes. Results: Analyzing data of 96 patients using Chi2 and Fischer’s Exact test (44 in rFSH group and 52 in CC group), both PR and LBR were comparable in the two groups {13.6% vs. 9.6% and 11.4% vs. 9.6% respectively}, with the difference not to be significant (p > 0.05). No cases of OHSS or multiple gestations happened during the treatment course. Conclusion: It seems that rFSH is as efficacious as CC while not with more complications for the first-line OI in infertile women with PCOS. However, due to the limitations of the present study including the small population and the single cycle of treatment, our results did not come out to prove this and more studies with larger study population are needed to compare the cumulative PR and LBR. PMID:27385973

  3. Comparative Efficacy and Safety of Antidiabetic Drug Regimens Added to Metformin Monotherapy in Patients with Type 2 Diabetes: A Network Meta-Analysis

    PubMed Central

    Sobieraj, Diana M.; White, C. Michael; Saulsberry, Whitney J.; Kohn, Christine G.; Doleh, Yunes; Zaccaro, Eric

    2015-01-01

    Introduction When first line therapy with metformin is insufficient for patients with type 2 diabetes (T2D), the optimal adjunctive therapy is unclear. We assessed the efficacy and safety of adjunctive antidiabetic agents in patients with inadequately controlled T2D on metformin alone. Materials and Methods A search of MEDLINE and CENTRAL, clinicaltrials.gov, regulatory websites was performed. We included randomized controlled trials of 3–12 months duration, evaluating Food and Drug Administration or European Union approved agents (noninsulin and long acting, once daily basal insulins) in patients experiencing inadequate glycemic control with metformin monotherapy (≥1500 mg daily or maximally tolerated dose for ≥4 weeks). Random-effects network meta-analyses were used to compare the weighted mean difference for changes from baseline in HbA1c, body weight (BW) and systolic blood pressure (SBP), and the risk of developing hypoglycemia, urinary (UTI) and genital tract infection (GTI). Results Sixty-two trials evaluating 25 agents were included. All agents significantly reduced HbA1c vs. placebo; albeit not to the same extent (range, 0.43% for miglitol to 1.29% for glibenclamide). Glargine, sulfonylureas (SUs) and nateglinide were associated with increased hypoglycemia risk vs. placebo (range, 4.00–11.67). Sodium glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 analogs, miglitol and empagliflozin/linagliptin significantly reduced BW (range, 1.15–2.26kg) whereas SUs, thiazolindinediones, glargine and alogliptin/pioglitazone caused weight gain (range, 1.19–2.44kg). SGLT2 inhibitors, empagliflozin/linagliptin, liraglutide and sitagliptin decreased SBP (range, 1.88–5.43mmHg). No therapy increased UTI risk vs. placebo; however, SGLT2 inhibitors were associated with an increased risk of GTI (range, 2.16–8.03). Conclusions Adding different AHAs to metformin was associated with varying effects on HbA1c, BW, SBP, hypoglycemia, UTI and GTI

  4. Impact of Young Age on Treatment Efficacy and Safety in Advanced Colorectal Cancer: A Pooled Analysis of Patients From Nine First-Line Phase III Chemotherapy Trials

    PubMed Central

    Blanke, Charles D.; Bot, Brian M.; Thomas, David M.; Bleyer, Archie; Kohne, Claus-Henning; Seymour, Matthew T.; de Gramont, Aimery; Goldberg, Richard M.; Sargent, Daniel J.

    2011-01-01

    Purpose Colorectal cancer predominantly occurs in the elderly, but approximately 5% of patients are 50 years old or younger. We sought to determine whether young age is prognostic, or whether it influences efficacy/toxicity of chemotherapy, in patients with advanced disease. Methods We analyzed individual data on 6,284 patients from nine phase III trials of advanced colorectal cancer (aCRC) that used fluorouracil-based single-agent and combination chemotherapy. End points included progression-free survival (PFS), overall survival (OS), response rate (RR), and grade 3 or worse adverse events. Stratified Cox and adjusted logistic-regression models were used to test for age effects and age-treatment interactions. Results A total of 793 patients (13%) were younger than 50 years old; 188 of these patients (3% of total patients) were younger than 40 years old. Grade 3 or worse nausea (10% v 7%; P = .01) was more common, and severe diarrhea (11% v 14%; P = .001) and neutropenia (23% v 26%; P < .001) were less common in young (younger than 50 years) than in older (older than 50 years) patients. Age was prognostic for PFS, with poorer outcomes occurring in those younger than 50 years (median, 6.0 v 7.5 months; hazard ratio, 1.10; P = .02), but it did not affect RR or OS. In the subset of monotherapy versus combination chemotherapy trials, the relative benefits of multiagent chemotherapy were similar for young and older patients. Results were comparable when utilizing an age cut point of 40 years. Conclusion Young age is modestly associated with poorer PFS but not OS or RR in treated patients with aCRC, and young patients have more nausea but less diarrhea and neutropenia with chemotherapy in general. Young versus older patients derive the same benefits from combination chemotherapy. Absent results of a clinical trial, standard combination chemotherapy approaches are appropriate for young patients with aCRC. PMID:21646604

  5. Chlorambucil-rituximab as first-line therapy in patients affected by follicular non-Hodgkin's lymphoma: a retrospective single-centre study.

    PubMed

    Martinelli, Giovanni; Montoro, Juan; Vanazzi, Anna; Andreola, Giovanna; Liptrott, Sarah; Radice, Davide; Negri, Mara; Preda, Lorenzo; Pruneri, Giancarlo; Laszlo, Daniele

    2015-12-01

    Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, has been shown to be active in newly diagnosed and relapsed patients with follicular lymphoma (FL), both as monotherapy and in combination with chemotherapy. Many studies suggest that the prognosis of patients with FL may improve when it is used in combination with chemotherapy. Despite these advances, the disease remains essentially incurable with standard therapy, and novel approaches to treatment are needed because optimal therapy is not defined. The combination of chlorambucil-rituximab is one of several standard treatment options for FL. Here, we considered data arising from 75 patients with newly diagnosed FL at the European Institute of Oncology treated with the combination of rituximab plus chlorambucil. The aim of this study was to evaluate the efficacy and safety of chlorambucil and rituximab, delivered 6 mg/m(2) /day orally for 6 weeks and 375 mg/m(2) in a standard 4-weekly schedule, respectively. Patients responding to the induction therapy received a prolonged therapy with four additional cycles of chlorambucil plus rituximab. Seventy-one patients (94.6%) completed the treatment; four patients discontinued treatment because of grade 3-4 hematological toxicity. The overall response rate was 97.3% including 74.7% of complete responses. Only two patients had a stable disease at revaluation after treatment. With a median follow-up of 57 months, 72 patients (96%) are alive. Median event-free survival (EFS) and median overall survival (OS) were not reached; 5-year OS rate was 98.4%. The 5-year EFS was 71.3%. By univariate and multivariate analyses, elevated beta-2 microglobulin levels and partial responses to therapy were correlated with worse EFS. These results suggest that the combination of chlorambucil and rituximab is an active and safe regimen in patients with newly diagnosed FL, principally in those with low tumour burden and favourable prognostic factors. PMID

  6. Monotherapy versus dual therapy for the initial treatment of hypertension (PATHWAY-1): a randomised double-blind controlled trial

    PubMed Central

    MacDonald, Thomas M; Williams, Bryan; Caulfield, Mark; Cruickshank, J Kennedy; McInnes, Gordon; Sever, Peter; Webb, David J; Mackenzie, Isla S; Salsbury, Jackie; Morant, Steve; Ford, Ian; Brown, Morris J

    2015-01-01

    Introduction Previous studies have suggested that more intensive initial therapy for hypertension results in better long-term blood pressure (BP) control. We test this hypothesis comparing initial monotherapy with dual therapy in the management of essential hypertension. Methods and analysis The study is a prospective, multicentre, double-blind, active-controlled trial in patients with essential hypertension. Around 50% of patients studied will be newly diagnosed and the others will be known hypertensives who previously received only monotherapy. The trial is divided into three phases as follows: Phase 1 (Week 0–Week 16): Randomised, parallel-group, masked assignation to either combination or monotherapy. Phase 2 (Week 17–Week 32): Open-label combination therapy. Phase 3 (Week 33–Week 52): Open-label combination therapy plus open-label add-on (if BP is above 140/90 mm Hg). Hierarchical primary end points are: a comparison of home BP (home systolic blood pressure (HSBP)) averaged over the duration of phase 1 and 2 in the combination versus monotherapy arms. If combination is superior in this analysis, then the averaged mean HSBP between initial monotherapy and initial combination therapy at the end of phase 2 will be compared. Secondary end points include: BP control at 1 year; the role of age, baseline renin, sodium status, plasma volume, haemodynamic compensation and peripheral resistance on BP control; validation of the National Institute for Clinical Excellence/British Hypertension Society joint guideline algorithm; safety and tolerability of combination therapy; and the impact of combination versus monotherapy on left ventricular mass and aortic pulse wave velocity. A sample size of 536 (268 in each group) will have 90% power to detect a difference in means of 4 mm Hg. Ethics and dissemination PATHWAY 1 was approved by UK ethics (REC Reference 09/H0308/132). Trial results will be published and all participating subjects will be informed of the

  7. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

    PubMed Central

    Maughan, Timothy S; Adams, Richard A; Smith, Christopher G; Meade, Angela M; Seymour, Matthew T; Wilson, Richard H; Idziaszczyk, Shelley; Harris, Rebecca; Fisher, David; Kenny, Sarah L; Kay, Edward; Mitchell, Jenna K; Madi, Ayman; Jasani, Bharat; James, Michelle D; Bridgewater, John; Kennedy, M John; Claes, Bart; Lambrechts, Diether; Kaplan, Richard; Cheadle, Jeremy P

    2011-01-01

    Summary Background In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival. Methods In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448. Findings 1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3–29·2] in the control group vs 17·0 months [9·4–30·1] in the cetuximab group; HR 1·04, 95% CI 0·87–1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0–12·5] in the control group vs 8·6 months [5·1–13·8] in the cetuximab group; HR 0·96, 0·82–1·12, p=0·60). Overall response rate increased from 57% (n=209

  8. Monotherapy with Levetiracetam Versus Older AEDs: A Randomized Comparative Trial of Effects on Bone Health.

    PubMed

    Hakami, Tahir; O'Brien, Terence J; Petty, Sandra J; Sakellarides, Mary; Christie, Jemma; Kantor, Susan; Todaro, Marian; Gorelik, Alexandra; Seibel, Markus J; Yerra, Raju; Wark, John D

    2016-06-01

    Long-term anti-epileptic drug (AED) therapy is associated with increased fracture risk. This study tested whether substituting the newer AED levetiracetam has less adverse effects on bone than older AEDs. An open-label randomized comparative trial. Participants had "failed" initial monotherapy for partial epilepsy and were randomized to substitution monotherapy with levetiracetam or an older AED (carbamazepine or valproate sodium). Bone health assessments, performed at 3 and 15 months, included areal bone mineral density (aBMD) and content at lumbar spine (LS), total hip (TH), forearm (FA), and femoral neck (FN), radial and tibial peripheral quantitative computed tomography and serum bone turnover markers. Main outcomes were changes by treatment group in aBMD at LS, TH, and FA, radial and tibial trabecular BMD and cortical thickness. 70/84 patients completed assessments (40 in levetiracetam- and 30 in older AED group). Within-group analyses showed decreases in both groups in LS (-9.0 %; p < 0.001 in levetiracetam vs. -9.8 %; p < 0.001 in older AED group), FA (-1.46 %; p < 0.001 vs. -0.96 %; p < 0.001, respectively) and radial trabecular BMD (-1.46 %; p = 0.048 and -2.31 %; p = 0.013, respectively). C-terminal telopeptides of type I collagen (βCTX; bone resorption marker) decreased in both groups (-16.1 %; p = 0.021 vs. -15.2 %; p = 0.028, respectively) whereas procollagen Ι N-terminal peptide (PΙNP; bone formation marker) decreased in older AED group (-27.3 %; p = 0.008). The treatment groups did not differ in any of these measures. In conclusion, use of both levetiracetam and older AEDs was associated with bone loss over 1 year at clinically relevant fracture sites and a reduction in bone turnover. PMID:26842957

  9. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma

    PubMed Central

    Weiss, Brendan M.; Plesner, Torben; Bahlis, Nizar J.; Belch, Andrew; Lonial, Sagar; Lokhorst, Henk M.; Voorhees, Peter M.; Richardson, Paul G.; Chari, Ajai; Sasser, A. Kate; Axel, Amy; Feng, Huaibao; Uhlar, Clarissa M.; Wang, Jianping; Khan, Imran; Ahmadi, Tahamtan; Nahi, Hareth

    2016-01-01

    The efficacy and favorable safety profile of daratumumab monotherapy in multiple myeloma (MM) was previously reported. Here, we present an updated pooled analysis of 148 patients treated with daratumumab 16 mg/kg. Data were combined from part 2 of a first-in-human phase 1/2 study of patients who relapsed after or were refractory to ≥2 prior therapies and a phase 2 study of patients previously treated with ≥3 prior lines of therapy (including a proteasome inhibitor [PI] and an immunomodulatory drug [IMiD]) or were double refractory. Among the pooled population, patients received a median of 5 prior lines of therapy (range, 2 to 14 prior lines of therapy), and 86.5% were double refractory to a PI and an IMiD. Overall response rate was 31.1%, including 13 very good partial responses, 4 complete responses, and 3 stringent complete responses. The median duration of response was 7.6 months (95% confidence interval [CI], 5.6 to not evaluable [NE]). The median progression-free survival (PFS) and overall survival (OS) were 4.0 months (95% CI, 2.8-5.6 months) and 20.1 months (95% CI, 16.6 months to NE), respectively. When stratified by responders vs stable disease/minimal response vs progressive disease/NE, median PFS was 15.0 months (95% CI, 7.4 months to NE) vs 3.0 months (95% CI, 2.8-3.7 months) vs 0.9 months (95% CI, 0.9-1.0 months), respectively, and median OS was NE (95% CI, NE to NE) vs 18.5 months (95% CI, 15.1-22.4 months) vs 3.7 months (95% CI, 1.7-7.6 months), respectively. No new safety signals were identified. In this pooled data set, daratumumab 16 mg/kg monotherapy demonstrated rapid, deep, and durable responses, with a clinical benefit that extended to patients with stable disease or better. PMID:27216216

  10. Pegylated interferon monotherapy for hepatitis C virus infection in patients on hemodialysis: A single center study.

    PubMed

    Agarwal, S K; Bhowmik, D; Mahajan, S; Bagchi, S

    2016-01-01

    There is no published study from India on hepatitis C virus (HCV) treatment in dialysis patients. Patients on dialysis with HCV infection treated with pegylated interferon (Peg-INF) monotherapy were studied. All patients were subjected to HCV-polymerase chain reaction, viral load, genotype, and liver biopsy. Quantitative HCV-RNA was performed monthly. Patients with genotype 1 and 4 were given 12 month therapy while those with genotypes 2 and 3 were given 6 months therapy. Response was classified as per standard criteria of rapid virological response (RVR), early virological response (EVR), end of treatment response (ETR), and sustained virological response (SVR). A total of 85 patients were treated. Mean age was 35.2 ± 10.5 (range 15-67) years, and 77.6% were males. HCV genotypes were 1 in 40.9%, 2 in 12%, 3 in 36.1%, 4 in 3.6%, and others in 7.2%. Mean viral load was 10(6) copies/mL. Mean liver biopsy grade was 4 ± 1.7 and stage 0.8 ± 0.8. Mean time from diagnosis of HCV infection and the treatment start was 10.7 ± 14.3 months. One patient died of unrelated illness, one was lost to follow-up, and three could not sustain treatment due to cost. Forty-three of the 80 (54%) patients had RVR while 49 (61%) patients had EVR and ETR. There was no difference in term of RVR related to genotype. Fifty -four percentage had SVR. Mild flu-like symptoms were seen in all patients. Sixty-four (80%) patients required increase in erythropoietin doses. Twenty-eight (35%) patients developed leukopenia (three treatment-limiting) and 16 (20%) developed thrombocytopenia (one treatment-limiting). Five patients developed tuberculosis, five bacterial pneumonia, and one bacterial knee monoarthritis. None of the patients developed depression. Our study concludes that Peg-INF monotherapy resulted in 54% RVR and SVR in dialysis patients with HCV infection. Therapy was well-tolerated with minimal side effects. There was no effect of viral genotype on response to therapy. PMID:27512295

  11. Efficacy and Safety of the Once-Daily GLP-1 Receptor Agonist Lixisenatide in Monotherapy

    PubMed Central

    Fonseca, Vivian A.; Alvarado-Ruiz, Ricardo; Raccah, Denis; Boka, Gabor; Miossec, Patrick; Gerich, John E.

    2012-01-01

    OBJECTIVE To assess efficacy and safety of lixisenatide monotherapy in type 2 diabetes. RESEARCH DESIGN AND METHODS Randomized, double-blind, 12-week study of 361 patients not on glucose-lowering therapy (HbA1c 7–10%) allocated to one of four once-daily subcutaneous dose increase regimens: lixisenatide 2-step (10 μg for 1 week, 15 μg for 1 week, and then 20 μg; n = 120), lixisenatide 1-step (10 μg for 2 weeks and then 20 μg; n = 119), placebo 2-step (n = 61), or placebo 1-step (n = 61) (placebo groups were combined for analyses). Primary end point was HbA1c change from baseline to week 12. RESULTS Once-daily lixisenatide significantly improved HbA1c (mean baseline 8.0%) in both groups (least squares mean change vs. placebo: −0.54% for 2-step, −0.66% for 1-step; P < 0.0001). Significantly more lixisenatide patients achieved HbA1c <7.0% (52.2% 2-step, 46.5% 1-step) and ≤6.5% (31.9% 2-step, 25.4% 1-step) versus placebo (26.8% and 12.5%, respectively; P < 0.01). Lixisenatide led to marked significant improvements of 2-h postprandial glucose levels and blood glucose excursions measured during a standardized breakfast test. A significant decrease in fasting plasma glucose was observed in both lixisenatide groups versus placebo. Mean decreases in body weight (∼2 kg) were observed in all groups. The most common adverse events were gastrointestinal—nausea was the most frequent (lixisenatide 23% overall, placebo 4.1%). Symptomatic hypoglycemia occurred in 1.7% of lixisenatide and 1.6% of placebo patients, with no severe episodes. Safety/tolerability was similar for the two dose regimens. CONCLUSIONS Once-daily lixisenatide monotherapy significantly improved glycemic control with a pronounced postprandial effect (75% reduction in glucose excursion) and was safe and well tolerated in type 2 diabetes. PMID:22432104

  12. Efficacy of fimasartan/hydrochlorothiazide combination in hypertensive patients inadequately controlled by fimasartan monotherapy

    PubMed Central

    Rhee, Moo-Yong; Baek, Sang Hong; Kim, Weon; Park, Chang Gyu; Park, Seung Woo; Oh, Byung-Hee; Kim, Sang-Hyun; Kim, Jae-Joong; Shin, Joon-Han; Yoo, Byung-Su; Rim, Se-Joong; Ha, Jong-Won; Doh, Joon Hyung; Ahn, Youngkeun; Chae, Jei Keon; Park, Jeong Bae; Kim, Soon-Kil; Kim, Cheol Ho

    2015-01-01

    Background The study reported here compared the blood pressure (BP)-lowering efficacy of fimasartan alone with that of fimasartan/hydrochlorothiazide (HCTZ) combination in patients whose BP goal was not achieved after 4 weeks of treatment with once-daily fimasartan 60 mg. Methods Patients with sitting diastolic blood pressure (siDBP) ≥90 mmHg with 4 weeks of once-daily fimasartan 60 mg were randomly assigned to receive either once-daily fimasartan 60 mg/HCTZ 12.5 mg or fimasartan 60 mg for 4 weeks. After 4 weeks, the dose was increased from fimasartan 60 mg/HCTZ 12.5 mg to fimasartan 120 mg/HCTZ 12.5 mg or from fimasartan 60 mg to fimasartan 120 mg if siDBP was ≥90 mmHg. Results Of the 263 randomized patients, 256 patients who had available efficacy data were analyzed. The fimasartan/HCTZ treatment group showed a greater reduction of siDBP compared to the fimasartan treatment group at Week 4 (6.88±8.10 mmHg vs 3.38±7.33, P=0.0008), and the effect persisted at Week 8 (8.67±9.39 mmHg vs 5.02±8.27 mmHg, P=0.0023). Reduction of sitting systolic BP in the fimasartan/HCTZ treatment group was also greater than that in the fimasartan treatment group (at Week 4, 10.50±13.76 mmHg vs 5.75±12.18 mmHg, P=0.0069 and, at Week 8, 13.45±15.15 mmHg vs 6.84±13.57 mmHg, P=0.0007). The proportion of patients who achieved a reduction of siDBP ≥10 mmHg from baseline and/or a mean siDBP <90 mmHg after 4 weeks of treatment was higher in the fimasartan/HCTZ treatment group than in the fimasartan treatment group (53.6% vs 39.8%, P=0.0359). The overall incidence of adverse drug reaction was 11.79% with no significant difference between the treatment groups. Conclusion The combination treatment of fimasartan and HCTZ achieved better BP control than fimasartan monotherapy, and had comparable safety and tolerance to fimasartan monotherapy. PMID:26082615

  13. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma.

    PubMed

    Usmani, Saad Z; Weiss, Brendan M; Plesner, Torben; Bahlis, Nizar J; Belch, Andrew; Lonial, Sagar; Lokhorst, Henk M; Voorhees, Peter M; Richardson, Paul G; Chari, Ajai; Sasser, A Kate; Axel, Amy; Feng, Huaibao; Uhlar, Clarissa M; Wang, Jianping; Khan, Imran; Ahmadi, Tahamtan; Nahi, Hareth

    2016-07-01

    The efficacy and favorable safety profile of daratumumab monotherapy in multiple myeloma (MM) was previously reported. Here, we present an updated pooled analysis of 148 patients treated with daratumumab 16 mg/kg. Data were combined from part 2 of a first-in-human phase 1/2 study of patients who relapsed after or were refractory to ≥2 prior therapies and a phase 2 study of patients previously treated with ≥3 prior lines of therapy (including a proteasome inhibitor [PI] and an immunomodulatory drug [IMiD]) or were double refractory. Among the pooled population, patients received a median of 5 prior lines of therapy (range, 2 to 14 prior lines of therapy), and 86.5% were double refractory to a PI and an IMiD. Overall response rate was 31.1%, including 13 very good partial responses, 4 complete responses, and 3 stringent complete responses. The median duration of response was 7.6 months (95% confidence interval [CI], 5.6 to not evaluable [NE]). The median progression-free survival (PFS) and overall survival (OS) were 4.0 months (95% CI, 2.8-5.6 months) and 20.1 months (95% CI, 16.6 months to NE), respectively. When stratified by responders vs stable disease/minimal response vs progressive disease/NE, median PFS was 15.0 months (95% CI, 7.4 months to NE) vs 3.0 months (95% CI, 2.8-3.7 months) vs 0.9 months (95% CI, 0.9-1.0 months), respectively, and median OS was NE (95% CI, NE to NE) vs 18.5 months (95% CI, 15.1-22.4 months) vs 3.7 months (95% CI, 1.7-7.6 months), respectively. No new safety signals were identified. In this pooled data set, daratumumab 16 mg/kg monotherapy demonstrated rapid, deep, and durable responses, with a clinical benefit that extended to patients with stable disease or better. PMID:27216216

  14. Pegylated interferon monotherapy for hepatitis C virus infection in patients on hemodialysis: A single center study

    PubMed Central

    Agarwal, S. K.; Bhowmik, D.; Mahajan, S.; Bagchi, S.

    2016-01-01

    There is no published study from India on hepatitis C virus (HCV) treatment in dialysis patients. Patients on dialysis with HCV infection treated with pegylated interferon (Peg-INF) monotherapy were studied. All patients were subjected to HCV-polymerase chain reaction, viral load, genotype, and liver biopsy. Quantitative HCV-RNA was performed monthly. Patients with genotype 1 and 4 were given 12 month therapy while those with genotypes 2 and 3 were given 6 months therapy. Response was classified as per standard criteria of rapid virological response (RVR), early virological response (EVR), end of treatment response (ETR), and sustained virological response (SVR). A total of 85 patients were treated. Mean age was 35.2 ± 10.5 (range 15–67) years, and 77.6% were males. HCV genotypes were 1 in 40.9%, 2 in 12%, 3 in 36.1%, 4 in 3.6%, and others in 7.2%. Mean viral load was 106 copies/mL. Mean liver biopsy grade was 4 ± 1.7 and stage 0.8 ± 0.8. Mean time from diagnosis of HCV infection and the treatment start was 10.7 ± 14.3 months. One patient died of unrelated illness, one was lost to follow-up, and three could not sustain treatment due to cost. Forty-three of the 80 (54%) patients had RVR while 49 (61%) patients had EVR and ETR. There was no difference in term of RVR related to genotype. Fifty -four percentage had SVR. Mild flu-like symptoms were seen in all patients. Sixty-four (80%) patients required increase in erythropoietin doses. Twenty-eight (35%) patients developed leukopenia (three treatment-limiting) and 16 (20%) developed thrombocytopenia (one treatment-limiting). Five patients developed tuberculosis, five bacterial pneumonia, and one bacterial knee monoarthritis. None of the patients developed depression. Our study concludes that Peg-INF monotherapy resulted in 54% RVR and SVR in dialysis patients with HCV infection. Therapy was well-tolerated with minimal side effects. There was no effect of viral genotype on response to therapy. PMID:27512295

  15. Sterilizing Activity of Pyrazinamide in Combination with First-Line Drugs in a C3HeB/FeJ Mouse Model of Tuberculosis

    PubMed Central

    Betoudji, Fabrice

    2015-01-01

    Pyrazinamide (PZA) is a key sterilizing drug in first-line tuberculosis (TB) regimens and exerts its activity entirely during the first 2 months in human infections. We recently described the reduced activity of PZA in C3HeB/FeJ mice with large caseous tubercles due to neutral pH. Here, we aimed to determine the contribution of PZA to the sterilizing activity of the first-line TB regimen in C3HeB/FeJ and BALB/c mice. Three regimens were compared (in combinations: R, rifampin; H, isoniazid; E, ethambutol; Z, pyrazinamide; with numbers indicating the treatment duration, in months): 2RHEZ/4RH, 2RHE/4RH, and 2RHEZ/4RHZ. Lung CFU counts were assessed after 0 and 2 months of treatment, and relapse rates were assessed 3 months after 3, 4.5, and 6 months of treatment. The relapse rates after 3 months of treatment were 53% and 95% in C3HeB/FeJ mice receiving 2RHEZ/1RH and 2RHE/1RH, respectively, and 67%, 100%, and 80% in BALB/c receiving 2RHEZ/1RH, 2RHE/1RH, and 2RHEZ/1RHZ, respectively. The relapse rates after 4.5 months of treatment were 32%, 20%, and 0% in C3HeB/FeJ mice receiving 2RHEZ/2.5RH, 2RHE/2.5RH, and 2RHEZ/2.5RHZ, respectively, and 0% and 67% in BALB/c receiving 2RHEZ/2.5RH and 2RHE/2.5RH, respectively. The month-6 relapse rates were 0%, 13%, and 0% in C3HeB/FeJ mice given 2RHEZ/4RH, 2RHE/4RH, and 2RHEZ/4RHZ, respectively, and 7% in BALB/c mice receiving 2RHE/4RH. The addition of PZA shortens the duration of treatment needed to prevent relapse in both mouse strains. However, while its contribution is limited to the first 2 months of treatment in BALB/c mice, continuing PZA beyond the first 2 months is beneficial in C3HeB/FeJ mice by preventing relapse among those with the highest disease burden. PMID:26643352

  16. Absence of Effect of Menopause Status at Initiation of First-Line Antiretroviral Therapy on Immunologic or Virologic Responses: A Cohort Study from Rio de Janeiro, Brazil

    PubMed Central

    Calvet, Guilherme Amaral; Velasque, Luciane; Luz, Paula Mendes; Cardoso, Sandra Wagner; Derrico, Monica; Moreira, Ronaldo Ismério; de Andrade, Angela Cristina Vasconcelos; Cytryn, Andrea; Pires, Elaine; Veloso, Valdiléa Gonçalves; Grinsztejn, Beatriz; Friedman, Ruth Khalili

    2014-01-01

    Objective To compare the effectiveness of first-line combination antiretroviral therapy (cART) between premenopausal and postmenopausal women. Methods ART-naïve women initiating cART between January 2000/June 2010 at the Instituto de Pesquisa Clínica Evandro Chagas Cohort were studied. Women were defined as postmenopausal after 12 consecutive months of amenorrhea. CD4 cell counts and HIV-1 RNA viral load (VL) measurements were compared between pre- and postmenopausal at 6, 12 and 24 months after cART initiation. Women who modified/discontinued a drug class or died due to an AIDS defining illness were classified as ART-failures. Variables were compared using Wilcoxon test, χ2 or Fisher’s exact test. The odds of cART effectiveness (VL<400 copies/mL and/or no need to change cART) were compared using logistic regression. Linear model was used to access relationship between CD4 change and menopause. Results Among 383 women, 328 (85%) were premenopausal and 55 (15%) postmenopausal. Median pre cART CD4 counts were 231 and 208 cells/mm3 (p = 0.14) in pre- and postmenopausal women, respectively. No difference in the median pre cART VL was found (both 4.8 copies/mL). Median CD4 changes were similar at 6 and 12 months. At 24 months after cART initiation, CD4 changes among postmenopausal women were significantly lower among premenopausal women (p = 0.01). When the analysis was restricted to women with VL<400 copies/mL, no statistical difference was observed. Overall, 63.7% achieved cART effectiveness at 24 months without differences between groups at 6, 12 and 24 months. Conclusion Menopause status at the time of first-line cART initiation does not impact CD4 cell changes at 24 months among women with a virologic response. No relationship between menopause status and virologic response was observed. PMID:24586673

  17. "Poker" association of weekly alternating 5-fluorouracil, irinotecan, bevacizumab and oxaliplatin (FIr-B/FOx) in first line treatment of metastatic colorectal cancer: a phase II study

    PubMed Central

    2010-01-01

    Background This phase II study investigated efficacy and safety of weekly alternating Bevacizumab (BEV)/Irinotecan (CPT-11) or Oxaliplatin (OHP) associated to weekly 5-Fluorouracil (5-FU) in first line treatment of metastatic colorectal carcinoma (MCRC). Methods Simon two-step design: delta 20% (p0 50%, p1 70%), power 80%, α 5%, β 20%. Projected objective responses (ORR): I step, 8/15 patients (pts); II step 26/43 pts. Schedule: weekly 12 h-timed-flat-infusion/5-FU 900 mg/m2, days 1-2, 8-9, 15-16, 22-23; CPT-11 160 mg/m2 plus BEV 5 mg/kg, days 1,15; OHP at three dose-levels, 60-70-80 mg/m2, days 8, 22; every 4 weeks. Results Fifty consecutive, unselected pts < 75 years were enrolled: median age 63; young-elderly (yE) 24 (48%); liver metastases (LM) 33 pts, 66% Achieved OHP recommended dose, 80 mg/m2. ORR 82% intent-to-treat and 84% as-treated analysis. Median progression-free survival 12 months. Equivalent efficacy was obtained in yE pts. Liver metastasectomies were performed in 26% of all pts and in 39% of pts with LM. After a median follow-up of 21 months, median overall survival was 28 months. Cumulative G3-4 toxicities per patient: diarrhea 28%, mucositis 6%, neutropenia 10%, hypertension 2%. They were equivalent in yE pts. Limiting toxicity syndromes (LTS), consisting of the dose-limiting toxicity, associated or not to G2 or limiting toxicities: 44% overall, 46% in yE. Multiple versus single site LTS, respectively: overall, 24% versus 20%; yE pts, 37.5% versus 8%. Conclusion Poker combination shows high activity and efficacy in first line treatment of MCRC. It increases liver metastasectomies rate and can be safely administered. Trial registration Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2007-004946-34 PMID:20958992

  18. Virological Outcomes and Drug Resistance in Chinese Patients after 12 Months of 3TC-Based First-Line Antiretroviral Treatment, 2011–2012

    PubMed Central

    Xu, Xiaoqin; Liu, Yong; He, Jianmei; Ling, Hua; Ding, Ping; Tong, Yi; Zou, Xiaobai; Zhou, Quanhua; Liao, Lingjie; Wang, Xia; Ruan, Yuhua; Shao, Yiming; Xing, Hui

    2014-01-01

    Objective To determine the prevalence of virological failure and HIV drug resistance among Chinese patients one year after initiating lamivudine-based first-line antiretroviral treatment. Methods A prospective cohort study with follow-up at 12 months was conducted in four urban sentinel sites in China. Antiretroviral naive patients ≥18 years old were recruited. Blood samples were collected for testing CD4 cell count, viral load, and (for samples with HIV-1 RNA ≥1000 copies/ml) genotyping of drug resistance. Results A total of 513 patients were enrolled in this cohort, of whom 448 (87.3%) were retained at 12 months. The median final CD4 cell count was 313 cells/mm3, which increased from 192 cells/mm3 at baseline (P<0.0001). Of the 448 remaining subjects, 394 (87.9%) had successful virological suppression (HIV RNA <1000 copies/ml). Among 54 samples with viral load ≥1000 copies/ml, 40 were successfully genotyped, and 11 were found with detectable HIV drug resistance mutations. Of these, the proportions of drug resistance to NNRTIs, NRTIs and PIs were 100%, 81.8% and 0%, respectively. Injecting drug use (AOR = 0.40, 95% CI: 0.19,0.84; P = 0.0154), CD4 count at baseline ≥350 cells/mm3 (AOR = 0.32, 95% CI: 0.14,0.72; P = 0.0056), and missed doses in the past month (AOR = 0.30, 95% CI: 0.15,0.60; P = 0.0006) were significantly negatively associated with HIV RNA <1000 copies/ml. Conclusions Our study demonstrates effective virological and immunological outcomes at 12 months among these who initiated first-line ART treatment. However, patients infected through drug injection, who missed doses, or with higher CD4 count at baseline are at increased risk for poor virological response. PMID:24516631

  19. HIV Protease Inhibitors Do Not Cause the Accumulation of Prelamin A in PBMCs from Patients Receiving First Line Therapy: The ANRS EP45 “Aging” Study

    PubMed Central

    Perrin, Sophie; Cremer, Jonathan; Faucher, Olivia; Reynes, Jacques; Dellamonica, Pierre; Micallef, Joëlle; Solas, Caroline; Lacarelle, Bruno; Stretti, Charlotte; Kaspi, Elise; Robaglia-Schlupp, Andrée; Tamalet, Corine Nicolino-Brunet Catherine; Lévy, Nicolas; Poizot-Martin, Isabelle; Cau, Pierre; Roll, Patrice

    2012-01-01

    Background The ANRS EP45 “Aging” study investigates the cellular mechanisms involved in the accelerated aging of HIV-1 infected and treated patients. The present report focuses on lamin A processing, a pathway known to be altered in systemic genetic progeroid syndromes. Methods 35 HIV-1 infected patients being treated with first line antiretroviral therapy (ART, mean duration at inclusion: 2.7±1.3 years) containing boosted protease inhibitors (PI/r) (comprising lopinavir/ritonavir in 65% of patients) were recruited together with 49 seronegative age- and sex-matched control subjects (http://clinicaltrials.gov/, NCT01038999). In more than 88% of patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm3. Prelamin A processing in peripheral blood mononuclear cells (PBMCs) from patients and controls was analysed by western blotting at inclusion. PBMCs from patients were also investigated at 12 and 24 months after enrolment in the study. PBMCs from healthy controls were also incubated with boosted lopinavir in culture medium containing various concentrations of proteins (4 to 80 g/L). Results Lamin A precursor was not observed in cohort patient PBMC regardless of the PI/r used, the dose and the plasma concentration. Prelamin A was detected in PBMC incubated in culture medium containing a low protein concentration (4 g/L) but not in plasma (60–80 g/L) or in medium supplemented with BSA (40 g/L), both of which contain a high protein concentration. Conclusions Prelamin A processing abnormalities were not observed in PBMCs from patients under the PI/r first line regimen. Therefore, PI/r do not appear to contribute to lamin A-related aging in PBMCs. In cultured PBMCs from healthy donors, prelamin A processing abnormalities were only observed when the protein concentration in the culture medium was low, thus increasing the amount of PI available to enter cells. ClinicalTrials.gov NCT01038999 http://clinicaltrials.gov/ct2/show/NCT01038999. PMID

  20. Fulvestrant 500 mg Versus Anastrozole 1 mg for the First-Line Treatment of Advanced Breast Cancer: Overall Survival Analysis From the Phase II FIRST Study

    PubMed Central

    Ellis, Matthew J.; Llombart-Cussac, Antonio; Feltl, David; Dewar, John A.; Jasiówka, Marek; Hewson, Nicola; Rukazenkov, Yuri; Robertson, John F.R.

    2015-01-01

    Purpose To compare overall survival (OS) for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for advanced breast cancer. Patients and Methods The Fulvestrant First-Line Study Comparing Endocrine Treatments (FIRST) was a phase II, randomized, open-label, multicenter trial. Postmenopausal women with estrogen receptor–positive, locally advanced/metastatic breast cancer who had no previous therapy for advanced disease received either fulvestrant 500 mg (days 0, 14, 28, and every 28 days thereafter) or anastrozole 1 mg (daily). The primary end point (clinical benefit rate [72.5% and 67.0%]) and a follow-up analysis (median time to progression [23.4 months and 13.1 months]) have been reported previously for fulvestrant 500 mg and anastrozole, respectively. Subsequently, the protocol was amended to assess OS by unadjusted log-rank test after approximately 65% of patients had died. Treatment effect on OS across several subgroups was examined. Tolerability was evaluated by adverse event monitoring. Results In total, 205 patients were randomly assigned (fulvestrant 500 mg, n = 102; anastrozole, n = 103). At data cutoff, 61.8% (fulvestrant 500 mg, n = 63) and 71.8% (anastrozole, n = 74) had died. The hazard ratio (95% CI) for OS with fulvestrant 500 mg versus anastrozole was 0.70 (0.50 to 0.98; P = .04; median OS, 54.1 months v 48.4 months). Treatment effects seemed generally consistent across the subgroups analyzed. No new safety issues were observed. Conclusion There are several limitations of this OS analysis, including that it was not planned in the original protocol but instead was added after time-to-progression results were analyzed, and that not all patients participated in additional OS follow-up. However, the present results suggest fulvestrant 500 mg extends OS versus anastrozole. This finding now awaits prospective confirmation in the larger phase III FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy Naïve Advanced Breast

  1. Pazopanib monotherapy in a patient with a malignant granular cell tumor originating from the right orbit: A case report

    PubMed Central

    MORITA, SACHI; HIRAMATSU, MARIKO; SUGISHITA, MIHOKO; GYAWALI, BISHAL; SHIBATA, TAKASHI; SHIMOKATA, TOMOYA; URAKAWA, HIROSHI; MITSUMA, AYAKO; MORITANI, SUZUKO; KUBOTA, TOSHINOBU; ICHIHARA, SHU; ANDO, YUICHI

    2015-01-01

    Granular cell tumors are uncommon, usually benign tumors of Schwann cell origin. The malignant variant is extremely rare, representing <2% of all granular cell tumors. Therefore, standard systemic chemotherapy for this disease does not exist. The present study reports the case of a 40-year-old female with a malignant granular cell tumor that originally arose in the right orbit and subsequently relapsed. The patient was started on pazopanib monotherapy following treatment with two investigational drugs, a smoothened inhibitor and then a phosphatidylinositol 3-kinase inhibitor, as part of a clinical trial. Although additional radiotherapy for local control was necessary, the lung metastases remained stable during the pazopanib monotherapy, which lasted for 7 months, following which a clinically stable disease state was determined. This case suggests that pazopanib can be a treatment option for the stabilization of disease progression in metastatic malignant granular cell tumor. PMID:26622607

  2. Susceptibility of Mycobacterium tuberculosis to first-line antimycobacterial agents in a Brazilian hospital: assessing the utility of the tetrazolium (MTT) microplate assay.

    PubMed

    Ferrari, Michela De Luca; Telles, Maria Alice da Silva; Ferrazoli, Lucilaine; Levy, Carlos Emílio; Villares, Maria Cecília Barison; Moretti, Maria Luiza; Resende, Mariângela Ribeiro

    2010-08-01

    We conducted a cross-sectional, hospital-based study between January 2006-March 2008 to estimate the resistance of Mycobacterium tuberculosis to first-line drugs in patients with tuberculosis at a Brazilian hospital. We evaluated the performance of the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] (MTT) microplate assay compared with the Bactec-MGIT 960 system for mycobacteria testing. The prevalence of resistance in M. tuberculosis was 6.7%. Multidrug-resistance [resistance to rifampicin (RMP) and isoniazid (INH)], INH-resistance and streptomycin (SM)-resistance accounted for 1%, 3.8% and 3.8% of all resistance, respectively, and all isolates were susceptible to ethambutol (EM). The resistance was primary in four cases and acquired in three cases and previous treatment was associated with resistance (p = 0.0129). Among the 119 M. tuberculosis isolates, complete concordance of the results for INH and EM was observed between the MTT microplate and Bactec-MGIT 960TM methods. The observed agreement for RMP was 99% (sensitivity: 90%) and 95.8% for SM (sensitivity 90.9%), lower than those for other drugs. The MTT colourimetric method is an accurate, simple and low-cost alternative in settings with limited resources. PMID:20835613

  3. Medical Decision-Making Incapacity among Newly Diagnosed Older Patients with Hematological Malignancy Receiving First Line Chemotherapy: A Cross-Sectional Study of Patients and Physicians

    PubMed Central

    Sugano, Koji; Okuyama, Toru; Iida, Shinsuke; Komatsu, Hirokazu; Ishida, Takashi; Kusumoto, Shigeru; Uchida, Megumi; Nakaguchi, Tomohiro; Kubota, Yosuke; Ito, Yoshinori; Takahashi, Kazuhisa; Akechi, Tatsuo

    2015-01-01

    Background Decision-making capacity to provide informed consent regarding treatment is essential among cancer patients. The purpose of this study was to identify the frequency of decision-making incapacity among newly diagnosed older patients with hematological malignancy receiving first-line chemotherapy, to examine factors associated with incapacity and assess physicians’ perceptions of patients’ decision-making incapacity. Methods Consecutive patients aged 65 years or over with a primary diagnosis of malignant lymphoma or multiple myeloma were recruited. Decision-making capacity was assessed using the Structured Interview for Competency and Incompetency Assessment Testing and Ranking Inventory-Revised (SICIATRI-R). Cognitive impairment, depressive condition and other possible associated factors were also evaluated. Results Among 139 eligible patients registered for this study, 114 completed the survey. Of these, 28 (25%, 95% confidence interval [CI]: 17%-32%) were judged as having some extent of decision-making incompetency according to SICIATRI-R. Higher levels of cognitive impairment and increasing age were significantly associated with decision-making incapacity. Physicians experienced difficulty performing competency assessment (Cohen’s kappa -0.54). Conclusions Decision-making incapacity was found to be a common and under-recognized problem in older patients with cancer. Age and assessment of cognitive impairment may provide the opportunity to find patients that are at a high risk of showing decision-making incapacity. PMID:26296202

  4. Simulations to Predict Clinical Trial Outcome of Bevacizumab Plus Chemotherapy vs. Chemotherapy Alone in Patients With First-Line Gastric Cancer and Elevated Plasma VEGF-A.

    PubMed

    Han, K; Claret, L; Piao, Y; Hegde, P; Joshi, A; Powell, J R; Jin, J; Bruno, R

    2016-07-01

    To simulate clinical trials to assess overall survival (OS) benefit of bevacizumab in combination with chemotherapy in selected patients with gastric cancer (GC), a modeling framework linking OS with tumor growth inhibition (TGI) metrics and baseline patient characteristics was developed. Various TGI metrics were estimated using TGI models and data from two phase III studies comparing bevacizumab plus chemotherapy vs. chemotherapy as first-line therapy in 976 GC patients. Time-to-tumor-growth (TTG) was the best TGI metric to predict OS. TTG, Eastern Cooperative Oncology Group (ECOG) score, albumin level, and Asian ethnicity were significant covariates in the final OS model. The model correctly predicted a decreased hazard ratio favorable to bevacizumab in patients with high baseline plasma VEGF-A above the median of 113.4 ng/L. Based on trial simulations, in trials enrolling patients with elevated baseline plasma VEGF-A (500 patients per arm), the expected hazard ratio was 0.82 (95% prediction interval: 0.70-0.95), independent of ethnicity. PMID:27404946

  5. Reduced medical costs and hospital days when using oral arsenic plus ATRA as the first-line treatment of acute promyelocytic leukemia.

    PubMed

    Jiang, Hao; Liang, Gong-Wen; Huang, Xiao-Jun; Jiang, Qian; Han, Sheng; Shi, Lu-Wen; Zhu, Hong-Hu

    2015-12-01

    We have demonstrated that oral arsenic (Realgar-Indigo naturalis formula, RIF) plus all-trans retinoic acid (ATRA) is not inferior to intravenous arsenic trioxide (ATO) plus ATRA as the first-line treatment of acute promyelocytic leukemia (APL). To compare the cost-effectiveness of oral and intravenous arsenic, we analyzed the results of 30 patients in each group involved in a randomized controlled trial at our center. The median total medical costs were $13,183.49 in the RIF group compared with $24136.98 in the ATO group (p<0.0001). This difference primarily resulted from the different costs of induction therapy (p=0.016) and maintenance treatment (p<0.0001). The length of hospitalization for the RIF group was significantly lower than that for the ATO group (24 vs. 31 days, p<0.0001) during induction therapy. During maintenance treatment, the estimated medical costs were $2047.14 for each patient in the RIF group treated at home compared with $11273.81 for each patient in the ATO group treated in an outpatient setting (p<0.0001). We conclude that oral RIF plus ATRA significantly reduced the medical costs and length of hospital stay during induction and remission therapy compared with ATO plus ATRA in APL patients. PMID:26403986

  6. First-line systemic treatment of advanced stage non-small-cell lung cancer in Asia: consensus statement from the Asian Oncology Summit 2009.

    PubMed

    Soo, Ross A; Anderson, Benjamin O; Cho, Byoung Chul; Yang, Chih-Hsin; Liao, Meilin; Lim, Wan-Teck; Goldstraw, Peter; Mok, Tony S

    2009-11-01

    Non-small-cell lung cancer (NSCLC) is an increasing global challenge, especially in low-income countries. Most guidelines for the management of advanced-stage NSCLC have limited effect in countries with resource constraints. Following a systematic literature search, we present an overview of the management of advanced-stage NSCLC in the first-line setting, discuss resources required for systemic therapy, and provide treatment recommendations stratified to four resources levels. Treatment guidelines appropriate for different resource levels offer a realistic approach to management of advanced-stage NSCLC, by recognising the limitations of a particular health-care system. Although there are many barriers to cancer control in low-resource countries, these can be overcome by using measures that are culturally appropriate, economically feasible, and evidence-based. Initiatives include strategic planning, tobacco control, training of health-care workers, access to therapeutic agents, acquisition of information, public education, and alliances with established institutions and international organisations. PMID:19880064

  7. Prognostic impact of KRAS mutant type and MET amplification in metastatic and recurrent gastric cancer patients treated with first-line S-1 plus cisplatin chemotherapy

    PubMed Central

    Matsusaka, Satoshi; Kobunai, Takashi; Yamamoto, Noriko; Chin, Keisho; Ogura, Mariko; Tanaka, Gotaro; Matsuoka, Kazuaki; Ishikawa, Yuichi; Mizunuma, Nobuyuki; Yamaguchi, Toshiharu

    2016-01-01

    Receptor tyrosine kinase (RTK)-related genes, including HER2, EGFR, MET, FGFR2 and KRAS, are target molecules that are clinically beneficial in gastric cancer (GC). We investigated the correlation between RTK-related genes and the curative effect of first-line S-1 plus cisplatin (SP) combination chemotherapy in metastatic and recurrent GC. We enrolled 150 patients with histopathologically confirmed metastatic and recurrent GC treated with SP. KRAS mutation was detected using direct sequencing. DNA copy number was measured by real-time PCR. Formalin-fixed paraffin-embedded specimens were examined immunohistochemically for HER2, EGFR, FGFR2 and MET. Among 144 patients, KRAS mutation was detected in five (3.5%) at codon 12 and one (0.7%) at codon 13. FGFR2, EGFR, HER2, MET and KRAS gene amplification was suggested in 4.4%, 5.9%, 9%, 3.7% and 10.3% of patients, respectively. KRAS mutation, but not KRAS amplification, was associated with significantly shorter overall and progression-free survival. MET membranous overexpression was associated with a significantly higher tumor response. MET amplification was associated with significantly shorter overall survival. We show for the first time that KRAS mutation and MET amplification are promising predictive markers in metastatic and recurrent GC patients treated with SP. KRAS status may be a useful prognostic marker in patients treated with SP. PMID:27014419

  8. A modified vaginal wall patch sling technique as a first-line surgical approach for genuine stress incontinence with urethral hypermobility: long-term follow up.

    PubMed

    Mikhail, Magdy S; Rosa, Hector; Packer, Paul; Palan, Prabhudas; Lazarou, George

    2004-01-01

    We describe our long-term outcome for patients with genuine stress incontinence (GSI) and urethral hypermobility using a modified vaginal wall patch sling technique. Fifty-three patients were studied. Preoperatively, all patients had a positive standing stress test and urethral hypermobility on Q-tip testing. On urodynamics, all patients had absence of detrusor contractions on subtracted cystometry. The mean age of the patients was 45+10.2 years. Forty-four patients demonstrated complete symptomatic and urodynamic improvement. Five patients had a noticeable failure observed within the first 12 months of follow up and four patients developed later recurrence despite initial success. The overall success rate after 5 years of follow up was 83% (n=44/53). The modified vaginal wall patch sling technique appears to have a good long-term success rate with low operative morbidity and minimal postoperative voiding dysfunction. The patch sling can be used as a first-line surgical approach for GSI with urethral hypermobility and be combined with other vaginal surgery. PMID:15014942

  9. Letrozole as the first-line treatment of infertile women with poly cystic ovarian syndrome (PCOS) compared with clomiphene citrate: A clinical trial

    PubMed Central

    Ghahiri, Ataollah; Mogharehabed, Neda; Mamourian, Mahboobeh

    2016-01-01

    Background: The purpose of this study was to determine the efficacy and safety of letrozole on ovulation induction and pregnancy in comparison with clomiphene citrate in PCOS patients. Materials and Methods: The study was based on prospective randomized clinical trial comparing the efficacy of letrozole as the first-line management of the PCOS patients in comparison to clomiphene citrate during 2009 to 2011 and was performed in one private infertility clinic. The study included 100 patients divided into 2 equal groups. Results: Pregnancy occurred in 29 of 50 patients in letrozole group (58%) and 24 of 51 patients in clomiphene group (47%). The difference was not statistically significant (P value = 0.23). Thirty patients in clomiphene group and 36 patients in letrozole group showed regular menses after or during the treatment course. No significant difference between the 2 groups was observed (P value = 0.21). Conclusion: Our findings suggest letrozole and clomiphene citrate are equally effective for induction of ovulation and achieving pregnancy in patients with PCOS. PMID:26962508

  10. A randomised phase 2 study combining LY2181308 sodium (survivin antisense oligonucleotide) with first-line docetaxel/prednisone in patients with castration-resistant prostate cancer.

    PubMed

    Wiechno, Paweł; Somer, Bradley G; Mellado, Begoña; Chłosta, Piotr L; Cervera Grau, José Manuel; Castellano, Daniel; Reuter, Christoph; Stöckle, Michael; Kamradt, Jörn; Pikiel, Joanna; Durán, Ignacio; Wedel, Steffen; Callies, Sophie; André, Valérie; Hurt, Karla; Brown, Jacqueline; Lahn, Michael; Heinrich, Bernhard

    2014-03-01

    Castration-resistant prostate cancer (CRPC) is partially characterised by overexpression of antiapoptotic proteins, such as survivin. In this phase 2 study, patients with metastatic CRPC (n=154) were randomly assigned (1:2 ratio) to receive standard first-line docetaxel/prednisone (control arm) or the combination of LY2181308 with docetaxel/prednisone (experimental arm). The primary objective was to estimate progression-free survival (PFS) for LY2181308 plus docetaxel. Secondary efficacy measures included overall survival (OS), several predefined prostate-specific antigen (PSA)-derived end points, and Brief Pain Inventory (BPI) and Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores. The median PFS of treated patients for the experimental arm (n=98) was 8.64 mo (90% confidence interval [CI], 7.39-10.45) versus 9.00 mo (90% CI, 7.00-10.09) in the control arm (n=51; p=0.755). The median OS for the experimental arm was 27.04 mo (90% CI, 19.94-33.41) compared with 29.04 mo (90% CI, 20.11-39.26; p=0.838). The PSA responses (≥ 50% PSA reduction), BPI, and FACT-P scores were similar in both arms. In the experimental arm, patients had a numerically higher incidence of grades 3-4 neutropenia, anaemia, thrombocytopenia, and sensory neuropathy. In conclusion, this study failed to detect a difference in efficacy between the two treatment groups. PMID:24246407

  11. The Effects of Topical Antiglaucoma Drugs as Monotherapy on the Ocular Surface: A Prospective Study

    PubMed Central

    Aydin Kurna, Sevda; Acikgoz, Semih; Ozbay, Nurver; Sengor, Tomris; Olcaysu, Osman Okan

    2014-01-01

    Purpose. The aim was to compare the effects of antiglaucoma eye drops on the tear functions and ocular surface. Method. Eighty-five eyes of 43 patients with glaucoma were included into this randomized prospective study. Timolol without preservative (1), timolol with benzododecinium bromide (2), latanoprost (3), bimatoprost (4), travoprost with benzalkonium chloride (5), and brimonidine with purite (6) were given to 6 groups. Schirmer I, tear film breakup time (TBUT), staining scores, and impression cytology samples were evaluated before and during 12-month-follow-up period. Results. At the end of 12 months, there was no detected change in Schirmer I and TBUT tests indicating dry eye. Corneal staining scores were higher in groups 1 and 2, while conjunctival staining scores were higher in group 6. Goblet cell count decreased in groups 1 and 5 in superior and inferior, group 2 in superior, and groups 3 and 6 in inferior conjunctiva. Squamous metaplasia grades showed a significant increase in groups 1 and 2 at 3rd, 6th, and 12th month controls (P < 0.05). Conclusion. We observed nonserious impact on tear functions and ocular surface with antiglaucoma monotherapy. Beta blockers induced more damage on the ocular surface suggesting the role of the dosing and active substances beside preservatives. PMID:25009742

  12. Aldosterone Antagonists in Monotherapy Are Protective against Streptozotocin-Induced Diabetic Nephropathy in Rats

    PubMed Central

    Banki, Nora F.; Ver, Agota; Wagner, Laszlo J.; Vannay, Adam; Degrell, Peter; Prokai, Agnes; Gellai, Renata; Lenart, Lilla; Szakal, Dorottya-Nagy; Kenesei, Eva; Rosta, Klara; Reusz, Gyorgy; Szabo, Attila J.; Tulassay, Tivadar; Baylis, Chris; Fekete, Andrea

    2012-01-01

    Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are the standard clinical therapy of diabetic nephropathy (DN), while aldosterone antagonists are only used as adjuncts. Previously in experimental DN we showed that Na/K ATPase (NKA) is mislocated and angiotensin II leads to superimposed renal progression. Here we investigated the monotherapeutic effect of aldosterone blockers on the progression of DN and renal NKA alteration in comparison to ACEi and ARBs. Streptozotocin-diabetic rats developing DN were treated with aldosterone antagonists; ACEi and ARB. Renal function, morphology, protein level and tubular localization of NKA were analyzed. To evaluate the effect of high glucose per se; HK-2 proximal tubular cells were cultured in normal or high concentration of glucose and treated with the same agents. Aldosterone antagonists were the most effective in ameliorating functional and structural kidney damage and they normalized diabetes induced bradycardia and weight loss. Aldosterone blockers also prevented hyperglycemia and diabetes induced increase in NKA protein level and enzyme mislocation. A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers. PMID:22761931

  13. Aldosterone antagonists in monotherapy are protective against streptozotocin-induced diabetic nephropathy in rats.

    PubMed

    Banki, Nora F; Ver, Agota; Wagner, Laszlo J; Vannay, Adam; Degrell, Peter; Prokai, Agnes; Gellai, Renata; Lenart, Lilla; Szakal, Dorottya-Nagy; Kenesei, Eva; Rosta, Klara; Reusz, Gyorgy; Szabo, Attila J; Tulassay, Tivadar; Baylis, Chris; Fekete, Andrea

    2012-01-01

    Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are the standard clinical therapy of diabetic nephropathy (DN), while aldosterone antagonists are only used as adjuncts. Previously in experimental DN we showed that Na/K ATPase (NKA) is mislocated and angiotensin II leads to superimposed renal progression. Here we investigated the monotherapeutic effect of aldosterone blockers on the progression of DN and renal NKA alteration in comparison to ACEi and ARBs. Streptozotocin-diabetic rats developing DN were treated with aldosterone antagonists; ACEi and ARB. Renal function, morphology, protein level and tubular localization of NKA were analyzed. To evaluate the effect of high glucose per se; HK-2 proximal tubular cells were cultured in normal or high concentration of glucose and treated with the same agents. Aldosterone antagonists were the most effective in ameliorating functional and structural kidney damage and they normalized diabetes induced bradycardia and weight loss. Aldosterone blockers also prevented hyperglycemia and diabetes induced increase in NKA protein level and enzyme mislocation. A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers. PMID:22761931

  14. Effects of combined MAO-B inhibitors and levodopa vs. monotherapy in Parkinson’s disease

    PubMed Central

    Krishna, Rakhee; Ali, Manal; Moustafa, Ahmed A.

    2014-01-01

    Background: Prior studies report that monoamine oxidases inhibitors (MAO-I) when used as an adjunct to levodopa ameliorate motor symptoms in Parkinson’s disease (PD), but this was not tested in relation to cognitive or psychiatric measures. Objective: Here, we tested the effects of MAO-I as an adjunct to levodopa, in comparison to levodopa or dopamine (DA) agonists alone, on various cognitive, affective and quality of life measures. Methods: We studied three groups of subjects: healthy controls, PD patients on combined levodopa and MAO-I, and PD patients on levodopa or DA agonists only. Results: We found that compared to monotherapy, combined MAO-I and levodopa seemed to improve cognition, including probabilistic learning, working memory and executive functions. There were no differences between the different medication regimes on deterministic learning, attention or memory recall. It was also found that MAO-I as an adjunct to levodopa improves affective measures such as depression, apathy, anxiety and quality of life. Interestingly, this enhancing effect of combined levodopa and MAO-I was more pronounced in PD patients with severe akinesia, compared to patients with severe tremor. Conclusion: Our data are in agreement with (a) the Continuous Dopaminergic Stimulation (CDS) theory which states that continuous stimulation of the basal ganglia enhances motor, psychiatric and cognitive functions in PD patients; and/or (b) findings that MAO-I increase the bioavailability of monoamines that have beneficial effects on motor and behavioral dysfunction in PD. PMID:25120478

  15. Efficacy and safety of prostaglandin E1 plus lipoic acid combination therapy versus monotherapy for patients with diabetic peripheral neuropathy.

    PubMed

    Jiang, De-Qi; Li, Ming-Xing; Ma, Yan-Jiao; Wang, Yan; Wang, Yong

    2016-05-01

    The aim of this report was to evaluate the efficacy and safety of prostaglandin E1 (PGE1) plus lipoic acid (LA) for the treatment of diabetic peripheral neuropathy (DPN) compared with that of PGE1 or LA monotherapy. Randomized controlled trials (RCT) published up to 3 August 2014 were reviewed. A random or fixed effect model was used to analyze outcomes expressed as risk ratios (RR) or mean difference (MD) with a 95% confidence interval (CI). I(2) statistic was used to assess heterogeneity. Subgroup and sensitivity analyses were performed. The outcomes measured were as follows: clinical efficacy, median motor nerve conduction velocity (MNCV), median sensory nerve conduction velocity (SNCV), peroneal MNCV, peroneal SNCV and adverse effects. Thirty-one RCT with 2676 participants were included. Clinical efficacy of PGE1+LA combination therapy was significantly better than monotherapy (p<0.00001, RR=1.32, 95% CI 1.26 to 1.38). Compared with monotherapy, PGE1+LA combination therapy led to significant improvements in median MNCV (p<0.00001, MD=4.69, 95% CI 3.16 to 6.23), median SNCV (p<0.00001, MD=5.46, 95% CI 4.04 to 6.88), peroneal MNCV (p<0.00001, MD=5.19, 95% CI 3.71 to 6.67) and peroneal SNCV (p<0.00001, MD=5.50, 95% CI 3.30 to 7.70). There were no serious adverse events associated with drug intervention. PGE1+LA combination therapy is superior to PGE1 or LA monotherapy for improvement of neuropathic symptoms and nerve conduction velocities in patients with DPN. These findings should be further validated by larger well-designed and high-quality RCT. PMID:26775115

  16. Aliskiren: a review of its use as monotherapy and as combination therapy in the management of hypertension.

    PubMed

    Duggan, Sean T; Chwieduk, Claudine M; Curran, Monique P

    2010-10-22

    Aliskiren is an orally administered, nonpeptide direct renin inhibitor indicated for the management of hypertension. Aliskiren was effective in controlling blood pressure (BP) as monotherapy and in combination with other antihypertensives, in large, randomized trials. Aliskiren 150-300 mg/day as monotherapy was effective in lowering BP across short- (≤12 weeks) and longer-term (up to 54 weeks) periods, providing sustained and consistent effects with 24-hour BP control. Compared with other antihypertensives, aliskiren was generally as effective as hydrochlorothiazide (HCTZ), valsartan, losartan, irbesartan and lisinopril in reducing BP. Furthermore, short-term aliskiren was noninferior to ramipril in reducing BP, but with a longer treatment duration, a greater efficacy of aliskiren-based therapy over ramipril-based therapy was demonstrated. Additional BP-lowering effects occurred when aliskiren was coadministered (as a fixed-dose combination or separate tablets) with other antihypertensives, including HCTZ, valsartan and amlodipine, according to large, randomized trials of short- (≤12 weeks) and longer-term (up to 54 weeks) duration. Combination therapy with aliskiren plus HCTZ was effective in hypertensive patients when administered as initial therapy or to patients previously treated with HCTZ or aliskiren monotherapy. Aliskiren-based therapy was also effective in lowering BP in obese patients, patients with type 1 or 2 diabetes mellitus, patients with metabolic syndrome and the elderly. Aliskiren efficacy was observed irrespective of patient age, sex or ethnicity. Aliskiren monotherapy or combination therapy was generally well tolerated over short- and longer-term study durations in large, randomized clinical trials. Clinical trials to evaluate the effects of aliskiren on clinical outcomes, including renoprotective and cardioprotective effects, are currently ongoing. Thus, aliskiren is a useful option for the treatment of patients with stage 1 to stage 2

  17. Efficacy of biological agents administered as monotherapy in rheumatoid arthritis: a Bayesian mixed-treatment comparison analysis

    PubMed Central

    Migliore, Alberto; Bizzi, Emanuele; Egan, Colin Gerard; Bernardi, Mauro; Petrella, Lea

    2015-01-01

    Background Biological agents provide an important therapeutic alternative for rheumatoid arthritis patients refractory to conventional disease-modifying antirheumatic drugs. Few head-to-head comparative trials are available. Purpose The aim of this meta-analysis was to compare the relative efficacy of different biologic agents indicated for use as monotherapy in rheumatoid arthritis. Methods A systemic literature search was performed on electronic databases to identify articles reporting double-blind randomized controlled trials investigating the efficacy of biologic agents indicated for monotherapy. Efficacy was assessed using American College of Rheumatology (ACR) 20, 50, and 70 criteria at 16–24 weeks. Relative efficacy was estimated using Bayesian mixed-treatment comparison models. Outcome measures were expressed as odds ratio and 95% credible intervals. Results Ten randomized controlled trials were selected for data extraction and analysis. Mixed-treatment comparison analysis revealed that tocilizumab offered 100% probability of being the best treatment for inducing an ACR20 response versus placebo, methotrexate, adalimumab, or etanercept. Likewise, for ACR50 and ACR70 outcome responses, tocilizumab had a 99.8% or 98.7% probability of being the best treatment, respectively, compared to other treatments or placebo. Tocilizumab increased the relative probability of being the best treatment (vs methotrexate) by 3.2-fold (odds ratio: 2.1–3.89) for all ACR outcomes. Conclusion Tocilizumab offered the greatest possibility of obtaining an ACR20, ACR50, and ACR70 outcome vs other monotherapies or placebo. PMID:26366085

  18. Use of Low-Level Laser Therapy as Monotherapy or Concomitant Therapy for Male and Female Androgenetic Alopecia

    PubMed Central

    Munck, Andréia; Gavazzoni, Maria Fernanda; Trüeb, Ralph M

    2014-01-01

    Background: Androgenetic alopecia (AGA) is the most common form of hair loss in men and in women. Currently, minoxidil and finasteride are the treatments with the highest levels of medical evidence, but patients who exhibit intolerance or poor response to these treatments are in need of additional treatment modalities. Objective: The aim was to evaluate the efficacy and safety of low-level laser therapy (LLLT) for AGA, either as monotherapy or as concomitant therapy with minoxidil or finasteride, in an office-based setting. Materials and Methods: Retrospective observational study of male and female patients with AGA, treated with the 655 nm-HairMax Laser Comb®, in an office-based setting. Efficacy was assessed with global photographic imaging. Results: Of 32 patients (21 female, 11 male), 8 showed significant, 20 moderate, and 4 no improvement. Improvement was seen both with monotherapy and with concomitant therapy. Improvement was observed as early as 3 months and was sustained up to a maximum observation time of 24 months. No adverse reactions were reported. Conclusions: LLLT represents a potentially effective treatment for both male and female AGA, either as monotherapy or concomitant therapy. Combination treatments with minoxidil, finasteride, and LLLT may act synergistic to enhance hair growth. PMID:25191036

  19. Pazopanib for the first-line treatment of patients with advanced and/or metastatic renal cell carcinoma : a NICE single technology appraisal.

    PubMed

    Kilonzo, Mary; Hislop, Jenni; Elders, Andrew; Fraser, Cynthia; Bissett, Donald; McClinton, Samuel; Mowatt, Graham; Vale, Luke

    2013-01-01

    The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of pazopanib hydrochloride (GlaxoSmithKline) to submit evidence of the clinical and cost effectiveness of the drug for the first-line treatment of advanced and/or metastatic renal cell carcinoma, as part of the Institute's single technology appraisal (STA) process. The Aberdeen Health Technology Assessment Group were commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. The objective of this paper is to summarize the independent review and critique of the evidence submitted for the consideration of the NICE Appraisal Committee and NICE's subsequently issued guidance. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer's submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. For progression-free survival (PFS), there was a statistically significant longer survival for pazopanib compared with placebo (as assessed by the ERG, based upon the original manufacturer submission with a clinical cut-off date of 23 May 2008) [median 11.1 vs. 2.8 months; hazard ratio (HR) 0.40; 95 % CI 0.27, 0.60]. Data from the indirect comparison suggested that pazopanib had a greater survival than interferon alpha (IFN-α) [HR 0.512; 95 % CI 0.326, 0.802] but provided no evidence of any difference compared with sunitinib (HR 0.949; 95 % CI 0.575, 1.568). With regard to overall survival, 64 % (n = 99) of patients in the pazopanib arm and 63 % (n = 49) of patients in the placebo arm had died and a total of 51 % (n = 40) of placebo patients had crossed over to receive pazopanib. Although data were provided on an intention-to-treat basis, crossover between therapies

  20. Research influence on antimalarial drug policy change in Tanzania: case study of replacing chloroquine with sulfadoxine-pyrimethamine as the first-line drug

    PubMed Central

    Mubyazi, Godfrey M; Gonzalez-Block, Miguel A

    2005-01-01

    Introduction Research is an essential tool in facing the challenges of scaling up interventions and improving access to services. As in many other countries, the translation of research evidence into drug policy action in Tanzania is often constrained by poor communication between researchers and policy decision-makers, individual perceptions or attitudes towards the drug and hesitation by some policy decision-makers to approve change when they anticipate possible undesirable repercussions should the policy change as proposed. Internationally, literature on the role of researchers on national antimalarial drug policy change is limited. Objectives To describe the (a) role of researchers in producing evidence that influenced the Tanzanian government replace chloroquine (CQ) with sulfadoxine-pyrimethamine (SP) as the first-line drug and the challenges faced in convincing policy-makers, general practitioners, pharmaceutical industry and the general public on the need for change (b) challenges ahead before a new drug combination treatment policy is introduced in Tanzania. Methods In-depth interviews were held with national-level policy-makers, malaria control programme managers, pharmaceutical officers, general medical practitioners, medical research library and publications officers, university academicians, heads of medical research institutions and district and regional medical officers. Additional data were obtained through a review of malaria drug policy documents and participant observations were also done. Results In year 2001, the Tanzanian Government officially changed its malaria treatment policy guidelines whereby CQ – the first-line drug for a long time was replaced with SP. This policy decision was supported by research evidence indicating parasite resistance to CQ and clinical CQ treatment failure rates to have reached intolerable levels as compared to SP and amodiaquine (AQ). Research also indicated that since SP was also facing rising resistance trend

  1. STAT3 polymorphisms may predict an unfavorable response to first-line platinum-based therapy for women with advanced serous epithelial ovarian cancer

    PubMed Central

    Permuth-Wey, Jennifer; Fulp, William J.; Reid, Brett M.; Chen, Zhihua; Georgeades, Christina; Cheng, Jin Q.; Magliocco, Anthony; Chen, Dung-Tsa; Lancaster, Johnathan M.

    2016-01-01

    Cancer stem cells (CSC) contribute to epithelial ovarian cancer (EOC) progression and therapeutic response. We hypothesized that germline single nucleotide polymorphisms (SNPs) in CSC-related genes may predict an initial therapeutic response for women newly diagnosed with EOC. A nested case–control design was used to study 361 women with advanced-stage serous EOC treated with surgery followed by first-line platinum-based combination therapy at Moffitt Cancer Center or as part of The Cancer Genome Atlas Study. “Cases” included 102 incomplete responders (IRs) and “controls” included 259 complete clinical responders (CRs) to therapy. Using Illumina genotyping arrays and imputation, DNA samples were evaluated for 5,509 SNPs in 24 ovarian CSC-related genes. We also evaluated the overall significance of each CSC gene using the admixture maximum likelihood (AML) test, and correlated genotype with EOC tumor tissue expression. The strongest SNP-level associations with an IR to therapy were identified for correlated (r2 > 0.80) SNPs within signal transducer and activator of transcription 3 (STAT3) [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.32–3.78; p = 0.0027], after adjustment for age, population stratification, grade and residual disease. At the gene level, STAT3 was significantly associated with an IR to therapy (pAML 5 0.006). rs1053004, a STAT3 SNP in a putative miRNA-binding site, was associated with STAT3 expression (p = 0.057). This is the first study to identify germline STAT3 variants as independent predictors of an unfavorable therapeutic response for EOC patients. Findings suggest that STAT3 genotype may identify high-risk women likely to respond more favorably to novel therapeutic combinations that include STAT3 inhibitors. PMID:26264211

  2. A retrospective observational study on the safety and efficacy of first-line treatment with bevacizumab combined with FOLFIRI in metastatic colorectal cancer

    PubMed Central

    López, R; Salgado, M; Reboredo, M; Grande, C; Méndez, J C; Jorge, M; Romero, C; Quintero, G; de la Cámara, J; Candamio, S

    2010-01-01

    Background: Combination of bevacizumab and FOLFIRI has currently become one of the standard therapeutic regimens. However, published information is still limited. The objective of the present retrospective observational study is to analyse the response and toxicity of first-line treatment with FOLFIRI+bevacizumab in patients with metastatic colorectal cancer (mCRC). Methods: Data were collected from patients from nine Spanish sites diagnosed with mCRC, ECOG⩽2, whose first treatment for advanced disease was at least three cycles of FOLFIRI+bevacizumab. Results: A total of 95 patients were enrolled into the study: 64.2% males, median age of 59 years (53.2–67.1 years), ECOG=0–1 in 96.9% of patients. The main site of primary tumour was the colon (69.7%), and most metastases occurred in the liver (71.6%). Clinical benefit was detected in 67.4% (57.0–76.6; 95% confidence interval (CI)), with 8.4% of CR and 42.1% of PR. Median TTP was 10.6 months (10.0–11.3; 95% CI), PFS was 10.6 months (9.8–11.3; 95% CI), and OS was 20.7 months (17.1–24.2; 95% CI). Main grade I–II toxicities included haematological toxicity (35.8%), diarrhea (27.3%), mucositis (25.3%), asthenia (19.0%), haemorrhages (11.6%), and emesis (10.6%). Toxicities reaching grades III–IV were haematological toxicity (9.5%), diarrhea (8.5%), mucositis (5.3%), hepatic toxicity (2.1%), asthenia (2.1%), proteinuria (1.1%), emesis (1.1%), pain (1.1%), and colics (1.1%). Conclusion: Results of this study support the beneficial effect of adding bevacizumab to FOLFIRI regimen in terms of efficacy and show a favourable tolerability profile. PMID:20940719

  3. Economic implications of using bendamustine, alemtuzumab, or chlorambucil as a first-line therapy for chronic lymphocytic leukemia in the US: a cost-effectiveness analysis

    PubMed Central

    Kongnakorn, Thitima; Sterchele, James A; Salvador, Christopher G; Getsios, Denis; Mwamburi, Mkaya

    2014-01-01

    Background The objective of this analysis was to evaluate the cost-effectiveness of using bendamustine versus alemtuzumab or bendamustine versus chlorambucil as a first-line therapy in patients with Binet stage B or C chronic lymphocytic leukemia (CLL) in the US. Methods A discrete event simulation of the disease course of CLL was developed to evaluate the economic implications of single-agent treatment with bendamustine, alemtuzumab, or chlorambucil, which are indicated for a treatment-naïve patient population with Binet stage B or C CLL. Data from clinical trials were used to create a simulated patient population, risk equations for progression-free survival and survival post disease progression, response rates, and rates of adverse events. Costs from a US health care payer perspective in 2012 US dollars, survival (life years), and quality-adjusted life years (QALYs) were estimated over a patient’s lifetime; all were discounted at 3% per year. Results Compared with alemtuzumab, bendamustine was considered to be a dominant treatment providing greater benefit (6.10 versus 5.37 life years and 4.02 versus 3.45 QALYs) at lower cost ($78,776 versus $121,441). Compared with chlorambucil, bendamustine was associated with higher costs ($78,776 versus $42,337) but with improved health outcomes (6.10 versus 5.21 life years and 4.02 versus 3.30 QALYs), resulting in incremental cost-effectiveness ratios of $40,971 per life year gained and $50,619 per QALY gained. Conclusion Bendamustine is expected to provide cost savings and greater health benefit than alemtuzumab in treatment-naïve patients with CLL. Furthermore, it can be considered as a cost-effective treatment providing health benefits at an acceptable cost versus chlorambucil in the US. PMID:24729719

  4. 5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study

    PubMed Central

    Hecht, J Randolph; Mitchell, Edith P; Yoshino, Takayuki; Welslau, Manfred; Lin, Xun; Chow Maneval, Edna; Paolini, Jolanda; Lechuga, Maria Jose; Kretzschmar, Albrecht

    2015-01-01

    Background Sunitinib is an oral inhibitor of tyrosine kinase receptors implicated in tumor proliferation, angiogenesis, and metastasis. In this randomized, multicenter, open-label Phase IIb study, sunitinib plus mFOLFOX6 (oxaliplatin plus leucovorin plus 5-fluorouracil) was compared with bevacizumab plus mFOLFOX6 as first-line therapy in patients with metastatic colorectal cancer. Methods Patients were stratified by performance status, baseline lactate dehydrogenase level, and prior adjuvant treatment, and randomized 1:1 to receive sunitinib 37.5 mg/day for 4 weeks on and 2 weeks off plus mFOLFOX6 every 2 weeks or bevacizumab 5 mg/kg every 2 weeks plus mFOLFOX6 every 2 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, overall survival, safety, and quality of life. Results Enrollment was closed early following accrual of 191 patients, based on an interim analysis showing an inferior trend in the primary progression-free survival efficacy endpoint for sunitinib. Ninety-six patients were randomized to sunitinib plus mFOLFOX6 and 95 to bevacizumab plus mFOLFOX6. Median progression-free survival was 9.3 months and 15.4 months, respectively, but the objective response rate was similar between the study arms. Median overall survival was 23.7 months and 34.1 months, respectively. Dose reductions and interruptions were more common with sunitinib. Hematologic toxicity was more common in the sunitinib arm. Conclusion While the results of the sunitinib arm are comparable with those of previously reported FOLFOX combinations, the sunitinib-based combination was associated with more toxicity than that observed with bevacizumab and mFOLFOX6. The bevacizumab arm had an unexpectedly good outcome, and was much better than that seen in the Phase III trials. Combination therapy with sunitinib plus mFOLFOX6 is not recommended for patients with metastatic colorectal cancer. PMID:26109878

  5. The preparation of core/shell structured microsphere of multi first-line anti-tuberculosis drugs and evaluation of biological safety

    PubMed Central

    Zeng, Hao; Pang, Xiaoyang; Wang, Shuo; Xu, Zhengquan; Peng, Wei; Zhang, Penghui; Zhang, Yupeng; Liu, Zheng; Luo, Chengke; Wang, Xiyang; Nie, Hemin

    2015-01-01

    To introduce a modified method, namely coaxial electrohydrodynamic atomization for the fabrication of distinct core/shell structured microspheres of four first-line ant-tuberculosis drugs with different characteristics in hydrophilic properties in one single step. In group B, we prepared microspheres in which the core and the shell contain hydrophobic and hydrophilic drugs, respectively. In contrast, in group C, the opposite is prepared. The detection of encapsulation efficiency and in vitro release test were performed to confirm the feasibility of the drug-loaded core/shell structured microspheres. Moreover, cell culture experiments and animal experiments have been carried out to evaluate the biological safety of different microspheres in cell growth, cell viability, osteogenesis and migration of BMSCs in vitro and the bone fusion in a bone deficits model in SD rat. Meanwhile, the distribution of drugs and liver and kidney toxicity were monitored. The release patterns of the two groups are significantly different. The release of drugs from Group B microspheres is rather sequential, whereas group C microspheres release drugs in a parallel (co-release) manner. And various concentrations of carrier materials produces core/shell structured microspheres with different appearance. Moreover, the biological safety of core/shell structured microspheres was testified to be satisfactory. These findings present the advantages and possible application of this kind of multi-drug release system in treating skeletal tuberculosis. Moreover, the characteristic sequential release of multi-drugs can be controlled and adjusted based on treatment need and used in treating other disorders. PMID:26309493

  6. Endovascular Treatment of Phlegmasia Cerulea Dolens with Impending Venous Gangrene: Manual Aspiration Thrombectomy as the First-Line Thrombus Removal Method

    SciTech Connect

    Oguzkurt, Levent Ozkan, Ugur; Demirturk, Orhan S.; Gur, Serkan

    2011-12-15

    Purpose: Our purpose was to report the outcome of endovascular treatment with manual aspiration thrombectomy as the first-line thromboablative method for phlegmasia cerulea dolens. Methods: Between October 2006 and May 2010, seven consecutive patients (5 women, 2 men; age range, 31-80 years) with the diagnosis of phlegmasia cerulea dolens secondary to acute iliofemoral deep venous thrombosis had endovascular treatment with manual aspiration thrombectomy. Catheter-directed thrombolysis and stent placement were used as adjunctive procedures. Phlegmasia was left-sided in five and right-sided in two patients. Results: All patients had associated great saphenous vein thrombosis in addition to iliofemoral deep vein thrombosis (DVT). Aspiration thrombectomy completely removed the thrombus from the popliteal vein to the inferior vena cava (IVC) in all cases. Three patients with May-Thurner syndrome had stent placement in the left common iliac vein. Two patients had early recurrences. Repeated aspiration thrombectomy was unsuccessful in one patient. There were no complications related to the procedure. One patient who had been successfully treated died of sepsis and another patient who had unsuccessful repeated interventions had below-the-knee amputation. Overall, the clinical success and survival rates of patients in this study were 86%. On follow-up, three patients with successful treatment were asymptomatic with no deep venous insufficiency. One of these patients died during the 4-month follow-up period. Two patients had mild ankle swelling with deep venous insufficiency. Conclusions: Manual aspiration thrombectomy with adjunctive use of catheter-directed thrombolysis and stent placement is an effective endovascular treatment method with high clinical success and survival rates for phlegmasia cerulean dolens.

  7. A prospective study to assess the efficacy and safety of oral propranolol as first-line treatment for infantile superficial hemangioma

    PubMed Central

    Yun, Yeong Ju; Gyon, Yun Hee; Yang, Sohyoung; Lee, Youn Kyung; Park, Joohyun

    2015-01-01

    Purpose To determine the efficacy and safety of oral propranolol as a first-line treatment for superficially located infantile hemangioma (IH) and propose an assessment tool to measure treatment response. Methods Patients with superficial IH under 1 year of age were prospectively recruited between May 2012 and December 2013 at the Department of Pediatrics of Chungbuk National University Hospital. Propranolol was administered to 12 infants (median age, 3.8 months) while monitoring cardiovascular and adverse metabolic effects. If a patient showed no adverse events, the dosage was gradually increased up to 3 mg/kg/day and maintained for 1 year. We used our own scoring system to assess treatment response using parameters like change in color, and longest diameter, and thickness of the IH. Results Eleven out of 12 patients completed the protocol with consistent improvement of hemangiomas during therapy. Patients on propranolol showed a more than 50% involution in the first 3 months, with additional steady involution until 1 year. Patients with the highest scores at 1 month maintained their score and showed better responses until treatment termination. The patient with the lowest score at 1 month did not show any further regression and stopped propranolol treatment 4 months after initiation. In two children with recurrences after successful therapeutic regression, propranolol was effective after being reintroduced. Propranolol treatment was not interrupted in any patient due to adverse events. Conclusion Oral propranolol at 3 mg/kg/day showed a consistent, rapid, and therapeutic effect on superficial IHs without significant adverse events. PMID:26770224

  8. Targeted therapies and complete responses in first line treatment of metastatic renal cell carcinoma. A meta-analysis of published trials.

    PubMed

    Iacovelli, Roberto; Alesini, Daniele; Palazzo, Antonella; Trenta, Patrizia; Santoni, Matteo; De Marchis, Laura; Cascinu, Stefano; Naso, Giuseppe; Cortesi, Enrico

    2014-03-01

    Antiangiogenic agents (AAs) have reported grater efficacy compared to interferon. Despite these advances, radiological complete response to therapy is rare. We meta-analyzed the incidence of complete response in patients treated with AAs and in controls in main randomized clinical trials for first-line therapy in metastatic renal cell carcinoma. PubMed was reviewed for phase II-III randomized clinical trials with AAs vs. non-AAs in patients with good or intermediate prognosis. We calculated the relative risk of events in patients assigned to AAs compared to control. Five RCTs were found; four were phase III and one was phase II. A total of 2747 patients was valuable for final analysis and randomized to receive AAs or control. Patients in the control-group had interferon (85%) or placebo (15%); patients in the AAs-group received bevacizumab (48%), sunitinib (26%), pazopanib (20%) or sorafenib (6%). The incidence of complete response in patients treated with AAs was 2.0% (95% CI, 1.2-2.8) compared to 1.4% (95% CI, 0.7-2.1) in the control arm. Comparing the different type of AAs, the incidence of complete response was 2.5% (95% CI, 1.2-3.8) in the bevacizumab group and 1.6% (95% CI, 0.1-2.5) in the TKIs group. The relative risk to have a complete response was 1.52 (95% CI, 0.85-2.73; p=0.16) in patients treated with AAs compared to controls; this was found higher in patients treated with TKIs compared to bevacizumab. The complete response is a rare event in metastatic kidney tumor, even if AAs reported greater efficacy in terms of progression-free survival and of overall response rate, they did not increase the curative rate of metastatic disease. Probably, some biologic factors other than angiogenesis may influence the complete response in this disease. PMID:24070900

  9. STAT3 polymorphisms may predict an unfavorable response to first-line platinum-based therapy for women with advanced serous epithelial ovarian cancer.

    PubMed

    Permuth-Wey, Jennifer; Fulp, William J; Reid, Brett M; Chen, Zhihua; Georgeades, Christina; Cheng, Jin Q; Magliocco, Anthony; Chen, Dung-Tsa; Lancaster, Johnathan M

    2016-02-01

    Cancer stem cells (CSC) contribute to epithelial ovarian cancer (EOC) progression and therapeutic response. We hypothesized that germline single nucleotide polymorphisms (SNPs) in CSC-related genes may predict an initial therapeutic response for women newly diagnosed with EOC. A nested case-control design was used to study 361 women with advanced-stage serous EOC treated with surgery followed by first-line platinum-based combination therapy at Moffitt Cancer Center or as part of The Cancer Genome Atlas Study. "Cases" included 102 incomplete responders (IRs) and "controls" included 259 complete clinical responders (CRs) to therapy. Using Illumina genotyping arrays and imputation, DNA samples were evaluated for 5,509 SNPs in 24 ovarian CSC-related genes. We also evaluated the overall significance of each CSC gene using the admixture maximum likelihood (AML) test, and correlated genotype with EOC tumor tissue expression. The strongest SNP-level associations with an IR to therapy were identified for correlated (r(2) > 0.80) SNPs within signal transducer and activator of transcription 3 (STAT3) [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.32-3.78; p = 0.0027], after adjustment for age, population stratification, grade and residual disease. At the gene level, STAT3 was significantly associated with an IR to therapy (pAML = 0.006). rs1053004, a STAT3 SNP in a putative miRNA-binding site, was associated with STAT3 expression (p = 0.057). This is the first study to identify germline STAT3 variants as independent predictors of an unfavorable therapeutic response for EOC patients. Findings suggest that STAT3 genotype may identify high-risk women likely to respond more favorably to novel therapeutic combinations that include STAT3 inhibitors. PMID:26264211

  10. Suboptimal adherence associated with virological failure and resistance mutations to first-line highly active antiretroviral therapy (HAART) in Bangalore, India

    PubMed Central

    Ekstrand, Maria L.; Shet, Anita; Chandy, Sara; Singh, Girija; Shamsundar, Ranjani; Madhavan, Vidya; Saravanan, Shanmugam; Heylen, Elsa; Kumarasamy, Nagalingeswaran

    2010-01-01

    This study was conducted to examine the relationship between adherence, viral load (VL) and resistance among outpatients receiving highly active antiretroviral therapy (HAART) in Bangalore, India. In total, 552 outpatients were recruited and VL testing was conducted for all study participants. HIV-1 genotypic resistance testing was performed for 92 participants with a VL ≥ 1000 copies/ml. Interpretation of resistance mutations was performed according to the Stanford database. Past-month adherence and treatment interruptions for >48 h were assessed via self-report. At baseline, 34 participants (6%) reported <95% past-month adherence and 110 (20%) reported a history of >48 h treatment interruptions. Combining the two adherence measures, 22% of participants were classified as ‘suboptimally adherent’. In total, 24% of study participants (n = 132) had a detectable VL. Among the 92 samples sent for resistance testing, 68% had at least one nucleoside reverse transcriptase inhibitor (NRTI) mutation, with M184V being the most common (62%) and with 48% having thymidine analogue mutations. Moreover, 72% had at least one non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation and 23% had three or more NNRTI mutations. Both adherence measures were significantly associated with VL (P < 0.001). Suboptimal adherence was significantly associated with resistance mutations (P < 0.02). The findings illustrate for the first time the strong association between suboptimal adherence, treatment failure and drug resistance to first-line HAART in India. The predictive value of standard adherence measures was improved by including treatment interruption data. The observed mutations can jeopardise future treatment options, especially in light of limited access to second-line treatments. To develop effective adherence interventions, research is needed to examine culturally-specific reasons for treatment interruptions. PMID:21516199

  11. Bendamustine plus rituximab versus R-CHOP as first-line treatment for patients with indolent non-Hodgkin's lymphoma: evidence from a multicenter, retrospective study.

    PubMed

    Mondello, Patrizia; Steiner, Normann; Willenbacher, Wolfgang; Wasle, Ines; Zaja, Francesco; Zambello, Renato; Visentin, Andrea; Mauro, Endri; Ferrero, Simone; Ghione, Paola; Pitini, Vincenzo; Cuzzocrea, Salvatore; Mian, Michael

    2016-06-01

    The optimal first-line treatment for advanced low-grade non-Hodgkin lymphomas (LG-NHL) is still highly debated. Recently, the StiL and the BRIGHT trials showed that the combination of rituximab and bendamustine (R-B) is non-inferior to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with a better toxicity profile. Utilizing a retrospective analysis, we compared the efficacy and safety of both regimens in clinical practice. From November 1995 to January 2014, 263 LG-NHL patients treated with either R-B or R-CHOP were retrospectively assessed in seven European cancer centers. Ninety patients were treated with R-B and 173 with R-CHOP. Overall response rate was 94 and 92 % for the R-B and the R-CHOP group, respectively. The percentage of complete response was similar for both groups (63 vs. 66 % with R-B and R-CHOP, respectively; p = 0.8). R-B was better tolerated and less toxic than R-CHOP. The median follow-up was 6.8 and 5.9 years for the R-CHOP and the R-B group, respectively. Overall, no difference in progression-free survival (PFS) (108 vs. 110 months; p = 0.1) was observed in the R-B group compared to the R-CHOP cohort. Nevertheless, R-B significantly prolonged PFS in FL patients (152 and 132 months in the R-B and R-CHOP group, respectively; p = 0.05). However, this result was not verified in multivariate analysis probably due to the limits of the present study. We confirm that the R-B regimen administered in patients with LG-NHL is an effective and less toxic therapeutic option than R-CHOP in clinical practice. PMID:27103007

  12. cis-platinum and ovarian carcinoma. In vitro chemosensitivity of cultured tumour cells from patients receiving high dose cis-platinum as first line treatment.

    PubMed Central

    Wilson, A. P.; Ford, C. H.; Newman, C. E.; Howell, A.

    1987-01-01

    A study on the in vitro sensitivity of tumour cells from patients with ovarian cancer has been carried out in parallel with a clinical study designed to evaluate the role of high-dose cis-platinum (CIS) as first-line chemotherapy. A total of 50 samples from 102 patients have been successfully cultured and screened for in vitro chemosensitivity to 7 drugs, including CIS. The malignant nature of cells growing in culture was confirmed using a combination of karyology, morphology and immunohistochemical staining with HMFG2. Tumours were graded as sensitive (less than 40% of control 3H-leucine incorporation), intermediate (41-60% of control) or resistant (greater than 61% of control) to CIS. Correlation of in vitro sensitivity to cis-platinum with clinical response to cis-platinum assessed using CT scan and second-look laparotomy, showed positive correlation in 9/11 (89%) patients (8 = S/S; 1 = R/R); positive correlation between in vitro sensitivity to phosphoramide mustard and clinical response was also found in 4/6 patients receiving cyclophosphamide (3 = S/S; 1 = R/R). All patients with sensitive tumours showed a clinical response to cis-platinum. Comparison of cis-platinum sensitivity with sensitivity to phosphoramide mustard and melphalan showed that some tumours were sensitive only to cis-platinum; resistance to cis-platinum and sensitivity to phosphoramide mustard/melphalan was an infrequent occurrence. Some tumours which were resistant to cis-platinum showed sensitivity to adriamycin and bleomycin, particularly those from untreated patients. Sensitivity to 5-fluorouracil and resistance to cis-platinum was found in approximately equal proportions of tumours in both the treated and untreated groups. PMID:3435704

  13. Cyclophosphamide and tucotuzumab (huKS-IL2) following first-line chemotherapy in responding patients with extensive-disease small-cell lung cancer.

    PubMed

    Gladkov, Oleg; Ramlau, Rodryg; Serwatowski, Piotr; Milanowski, Janusz; Tomeczko, Janusz; Komarnitsky, Philip B; Kramer, Daniel; Krzakowski, Maciej J

    2015-11-01

    The humanized KS-interleukin-2, tucotuzumab (huKS-IL2; EMD 273066), is an EpCAM-specific immunocytokine with reported immunologic activity in combination with cyclophosphamide. This Phase 2, randomized, open-label study compared tucotuzumab/cyclophosphamide, administered as maintenance, with best supportive care (BSC) in patients with extensive-disease small-cell lung cancer (ED-SCLC) who responded to first-line platinum-based chemotherapy with/without prophylactic cranial irradiation (PCI). Patients received cyclophosphamide (300 mg/m, Day 1 of every 3-week cycle), followed by tucotuzumab (1.5 mg/m, Days 2-4) until disease progression. The primary endpoint was 6-month progression-free survival (PFS); the secondary objectives included overall survival (OS), treatment response, and safety. The 6-month PFS rate was lower in the tucotuzumab/cyclophosphamide group (n=64) than in the BSC group (n=44): 6.4 versus 12.2% [hazard ratio (HR): 0.98; 80% confidence interval (CI): 0.74-1.31]. HRs for PFS, time to progression, and OS indicated a similar risk of disease progression and death in both groups and best overall responses were generally comparable. For patients with previous PCI (n=26), there was a nonsignificant trend toward prolonged median PFS (1.7 vs. 1.5 months; HR: 0.60; 80% CI: 0.33-1.11) and OS (21.5 vs. 14.3 months; HR: 0.58; 80% CI: 0.31-1.05) in the tucotuzumab/cyclophosphamide group. Adverse events were more frequent with tucotuzumab/cyclophosphamide (92.2%) than with BSC (47.7%). Tucotuzumab/cyclophosphamide was well tolerated in ED-SCLC patients, but did not show PFS or OS benefits compared with BSC. The observed trend toward prolonged PFS and OS in the subgroup of patients receiving previous PCI may support further confirmation in a larger population. PMID:26295868

  14. A Phase II Biomarker-Embedded Study of Lapatinib plus Capecitabine as First-line Therapy in Patients with Advanced or Metastatic Gastric Cancer.

    PubMed

    LaBonte, Melissa J; Yang, Dongyun; Zhang, Wu; Wilson, Peter M; Nagarwala, Yasir M; Koch, Kevin M; Briner, Colleen; Kaneko, Tomomi; Rha, Sun-Young; Gladkov, Oleg; Urba, Susan G; Sakaeva, Dina; Pishvaian, Michael J; Hsieh, Ruey-Kuen; Lee, Wei-Ping; Lenz, Heinz-Josef

    2016-09-01

    An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinib-induced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma independent of tumor HER2 status. Tumor biopsies obtained before and after 7-day lapatinib (1,250 mg) to analyze changes in gene expression, followed by a 14-day course of capecitabine (1,000 mg/m(2) twice daily, 14/21 days) plus lapatinib 1,250 mg daily. Blood samples were acquired for pharmacokinetic analysis. Primary clinical objectives were response rate (RR) and 5-month progression-free survival (PFS). Secondary objectives were overall survival (OS), PFS, time to response, duration of response, toxicity, and identification of associations between lapatinib pharmacokinetics and biomarker endpoints. Primary biomarker objectives were modulation of 5-FU-pathway genes by lapatinib, effects of germline SNPs on treatment outcome, and trough steady-state plasma lapatinib concentrations. Sixty-eight patients were enrolled; (75% gastric cancer, 25% gastroesophageal junction). Twelve patients (17.9%) had confirmed partial response, 31 (46.3%) had stable disease, and 16 (23.9%) had progressive disease. Median PFS and OS were 3.3 and 6.3 months, respectively. Frequent adverse events included diarrhea (45%), decreased appetite (39%), nausea (36%), and fatigue (36%). Lapatinib induced no changes in gene expression from baseline and no significant associations were found for SNPs analyzed. Elevated baseline HER3 mRNA expression was associated with a higher RR (33% vs. 0%; P = 0.008). Lapatinib plus capecitabine was well tolerated, demonstrating modest antitumor activity in patients with advanced gastric cancer. The association of elevated HER3 and RR warrants further investigation as an important player for HER-targeted regimens in combination with capecitabine. Mol Cancer Ther

  15. Preliminary evidence for gender effects of levetiracetam monotherapy duration on bone health of patients with epilepsy.

    PubMed

    Artemiadis, Artemios K; Lambrinoudaki, Irene; Voskou, Panagiota; Tsivgoulis, Georgios; Safouris, Apostolos; Bougea, Anastasia; Giannopoulos, Sotiris; Gatzonis, Stergios; Triantafyllou, Nikolaos

    2016-02-01

    Enzyme-inducing antiepileptic drugs AEDs have adverse effects on bone mineral density (BMD), whereas studies on levetiracetam (LEV), a nonenzyme-inducing agent, have showed conflicting results. The aim of this study was to further elucidate the role of LEV in bone health. A sample of forty-six patients with epilepsy (mean age: 35.7 years, range: 20.2-64.2 years, 39.1% males) on LEV monotherapy for at least one year (range: 1.5-14.5 years, median 5.5 years) underwent femoral neck (FN) and lumbar spine (LS) BMD measurements. The T- and Z-scores were calculated. Results showed that 15.2% of the patients were identified with osteopenia and none with osteoporosis. Pearson's correlations revealed a negative but not significant association of LEV duration with bone-related measurements (range of rhos: from -0.004 to -0.23), except for LS T-scores. In terms of FN BMD measurements, Z-scores, and T-scores, longer LEV therapy duration had adverse but not significant effects on bone health after adjusting for age and gender. With regard to LS BMD measurements, Z-scores, and T-scores, men taking LEV for at least 5.5 years had better, although not significant, bone health compared with men with shorter LEV exposure, after adjusting for age. The opposite was found in women, although differences did not reach significance. These preliminary results are indicative of a differential effect of LEV therapy duration in men and women, which could presumably account for the incongruity of the already published studies. Also, LS assessments were more sensitive to these gender differences. Future larger studies should validate these results. PMID:26773675

  16. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia

    PubMed Central

    Flynn, Joseph M.; Kipps, Thomas J.; Boxer, Michael; Kolibaba, Kathryn S.; Carlile, David J.; Fingerle-Rowson, Guenter; Tyson, Nicola; Hirata, Jamie; Sharman, Jeff P.

    2016-01-01

    Obinutuzumab is a glycoengineered, type 2 anti-CD20 humanized antibody with single-agent activity in relapsed chronic lymphocytic leukemia (CLL). With other CD20 antibodies, a dose-response relationship has been shown. We therefore performed a randomized phase 2 study in symptomatic, untreated CLL patients to evaluate if an obinutuzumab dose response exists. Obinutuzumab was given at a dose of 1000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 8 and day 15 of cycle 1; 1000 mg day 1 of cycles 2-8) or 2000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 3, 2000 mg day 8 and day 15 of cycle 1; 2000 mg day 1 of cycles 2-8). The primary end point was overall response rate (ORR). Eighty patients were enrolled with similar demographics: median age 67 years, 41% high-risk Rai disease, and 10% del(17p)(13.1). ORR (67% vs 49%, P = .08) and complete response (CR) or CR with incomplete cytopenia response (20% vs 5%) favored 2000 mg obinutuzumab. Overall, therapy was well tolerated, and infusion events were manageable. This study demonstrates significant efficacy of obinutuzumab monotherapy, for 1000 mg as well as for 2000 mg, in untreated CLL patients with acceptable toxicity. Although exploratory, a dose-response relationship may exist, but its relevance to improving progression-free survival is uncertain and will require further follow-up. This trial was registered at www.clinicaltrials.gov as #NCT01414205. PMID:26472752

  17. Frequency of neutropenia among Turkish and Syrian pediatric thalassemia patients under deferiprone monotherapy.

    PubMed

    Belen, Burcu Fatma; Polat, Meltem; Özsevik, Sevinç Nursev; Soylu, Esma

    2016-02-01

    Weekly monitoring of absolute neutrophil count (ANC) under deferiprone therapy in thalassemia patients is recommended to avoid agranulocytosis adverse event. Actually, this recommendation may not be applicable in clinical setting. Our study aimed to establish incidence of neutropenia under deferiprone (DFP) monotherapy when it was monitored bimonthly due to socioeconomic conditions effecting local and refugee thalassemic patients including Syrian origin (SYR; n = 26) and Turkish origin (TR; n = 26) groups. Patients on DFP were followed up for 12 months. Fifteen neutropenic episodes were seen in 5 patients. All 5 patients (4 from SYR group and 1 from TR group) had splenomegaly and hypersplenism, and neutropenia ceased in 4 patients after splenectomy despite continuation of deferiprone. In the TR group, the frequency of patients who have neutropenia (absolute neutrophil count [ANC] <1500/mm(3)) was 3.8% (n = 1) in the 1st month, no patients in TR group had neutropenia until 10th month when again there was 1 patient with mild neutropenia. In SYR group, the frequency of patients who have neutropenia was 3.8% (n = 1), 7.7% (n = 2), and 11.5% (n = 3) in the 1st, 2nd, and 3rd months, respectively, and was found to be 3.8% (n = 1) between 6 and 12 months. Whether or not DFP therapy should be interrupted in case of mild neutropenia and the frequency of monitoring ANC in real-life conditions should be documented with further studies. Other causes of neutropenia in DFP-treated patients should also be kept in mind. PMID:26918459

  18. Long-Term Quality of Life Outcome After Proton Beam Monotherapy for Localized Prostate Cancer

    SciTech Connect

    Coen, John J.; Paly, Jonathan J.; Niemierko, Andrzej; Weyman, Elizabeth; Rodrigues, Anita; Shipley, William U.; Zietman, Anthony L.; Talcott, James A.

    2012-02-01

    Objectives: High-dose external radiation for localized prostate cancer results in favorable clinical outcomes and low toxicity rates. Here, we report long-term quality of life (QOL) outcome for men treated with conformal protons. Methods: QOL questionnaires were sent at specified intervals to 95 men who received proton radiation. Of these, 87 men reported 3- and/or 12-month outcomes, whereas 73 also reported long-term outcomes (minimum 2 years). Symptom scores were calculated at baseline, 3 months, 12 months, and long-term follow-up. Generalized estimating equation models were constructed to assess longitudinal outcomes while accounting for correlation among repeated measures in an individual patient. Men were stratified into functional groups from their baseline questionnaires (normal, intermediate, or poor function) for each symptom domain. Long-term QOL changes were assessed overall and within functional groups using the Wilcoxon signed-rank test. Results: Statistically significant changes in all four symptom scores were observed in the longitudinal analysis. For the 73 men reporting long-term outcomes, there were significant change scores for incontinence (ID), bowel (BD) and sexual dysfunction (SD), but not obstructive/irritative voiding dysfunction (OID). When stratified by baseline functional category, only men with normal function had increased scores for ID and BD. For SD, there were significant changes in men with both normal and intermediate function, but not poor function. Conclusions: Patient reported outcomes are sensitive indicators of treatment-related morbidity. These results quantitate the long-term consequences of proton monotherapy for prostate cancer. Analysis by baseline functional category provides an individualized prediction of long-term QOL scores. High dose proton radiation was associated with small increases in bowel dysfunction and incontinence, with more pronounced changes in sexual dysfunction.

  19. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia.

    PubMed

    Byrd, John C; Flynn, Joseph M; Kipps, Thomas J; Boxer, Michael; Kolibaba, Kathryn S; Carlile, David J; Fingerle-Rowson, Guenter; Tyson, Nicola; Hirata, Jamie; Sharman, Jeff P

    2016-01-01

    Obinutuzumab is a glycoengineered, type 2 anti-CD20 humanized antibody with single-agent activity in relapsed chronic lymphocytic leukemia (CLL). With other CD20 antibodies, a dose-response relationship has been shown. We therefore performed a randomized phase 2 study in symptomatic, untreated CLL patients to evaluate if an obinutuzumab dose response exists. Obinutuzumab was given at a dose of 1000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 8 and day 15 of cycle 1; 1000 mg day 1 of cycles 2-8) or 2000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 3, 2000 mg day 8 and day 15 of cycle 1; 2000 mg day 1 of cycles 2-8). The primary end point was overall response rate (ORR). Eighty patients were enrolled with similar demographics: median age 67 years, 41% high-risk Rai disease, and 10% del(17p)(13.1). ORR (67% vs 49%, P = .08) and complete response (CR) or CR with incomplete cytopenia response (20% vs 5%) favored 2000 mg obinutuzumab. Overall, therapy was well tolerated, and infusion events were manageable. This study demonstrates significant efficacy of obinutuzumab monotherapy, for 1000 mg as well as for 2000 mg, in untreated CLL patients with acceptable toxicity. Although exploratory, a dose-response relationship may exist, but its relevance to improving progression-free survival is uncertain and will require further follow-up. This trial was registered at www.clinicaltrials.gov as #NCT01414205. PMID:26472752

  20. Severity of liver disease affects HCV kinetics in patients treated with intravenous silibinin monotherapy

    DOE PAGESBeta

    Canini, Laetitia; DebRoy, Swati; Mariño, Zoe; Conway, Jessica M.; Crespo, Gonzalo; Navasa, Miquel; D’Amato, Massimo; Ferenci, Peter; Cotler, Scott J.; Forns, Xavier; et al

    2014-06-10

    HCV kinetic analysis and modeling during antiviral therapy have not been performed in decompensated cirrhotic patients awaiting liver transplantation. Here, viral and host parameters were compared in patients treated with daily intravenous silibinin (SIL) monotherapy for 7 days according to the severity of their liver disease. Data were obtained from 25 patients, 12 non-cirrhotic, 8 with compensated cirrhosis and 5 with decompensated cirrhosis. The standard-biphasic model with time-varying SIL effectiveness (from 0 to εmax) was fit to viral kinetic data. Our results show that baseline viral load and age were significantly associated with the severity of liver disease (p<0.0001). Amore » biphasic viral decline was observed in most patients with a higher first phase decline patients with less severe liver disease. The maximal effectiveness, εmax, was significantly (p≤0.032) associated with increasing severity of liver disease (εmax[s.e.]=0.86[0.05], εmax=0.69[0.06] and εmax=0.59[0.1]). The 2nd phase decline slope was not significantly different among groups (mean 1.88±0.15 log10IU/ml/wk, p=0.75) as was the rate of change of SIL effectiveness (k=2.12/day[standard error, SE=0.18/day]). HCV-infected cell loss rate (δ[SE]=0.62/day[0.05/day]) was high and similar among groups. We conclude that the high loss rate of HCV-infected cells suggests that sufficient dose and duration of SIL might achieve viral suppression in advanced liver disease.« less

  1. Severity of liver disease affects HCV kinetics in patients treated with intravenous silibinin monotherapy

    SciTech Connect

    Canini, Laetitia; DebRoy, Swati; Mariño, Zoe; Conway, Jessica M.; Crespo, Gonzalo; Navasa, Miquel; D’Amato, Massimo; Ferenci, Peter; Cotler, Scott J.; Forns, Xavier; Perelson, Alan S.; Dahari, Harel

    2014-06-10

    HCV kinetic analysis and modeling during antiviral therapy have not been performed in decompensated cirrhotic patients awaiting liver transplantation. Here, viral and host parameters were compared in patients treated with daily intravenous silibinin (SIL) monotherapy for 7 days according to the severity of their liver disease. Data were obtained from 25 patients, 12 non-cirrhotic, 8 with compensated cirrhosis and 5 with decompensated cirrhosis. The standard-biphasic model with time-varying SIL effectiveness (from 0 to εmax) was fit to viral kinetic data. Our results show that baseline viral load and age were significantly associated with the severity of liver disease (p<0.0001). A biphasic viral decline was observed in most patients with a higher first phase decline patients with less severe liver disease. The maximal effectiveness, εmax, was significantly (p≤0.032) associated with increasing severity of liver disease (εmax[s.e.]=0.86[0.05], εmax=0.69[0.06] and εmax=0.59[0.1]). The 2nd phase decline slope was not significantly different among groups (mean 1.88±0.15 log10IU/ml/wk, p=0.75) as was the rate of change of SIL effectiveness (k=2.12/day[standard error, SE=0.18/day]). HCV-infected cell loss rate (δ[SE]=0.62/day[0.05/day]) was high and similar among groups. We conclude that the high loss rate of HCV-infected cells suggests that sufficient dose and duration of SIL might achieve viral suppression in advanced liver disease.

  2. Clinical importance of androgen receptor in breast cancer patients treated with adjuvant tamoxifen monotherapy.

    PubMed

    Honma, Naoko; Horii, Rie; Iwase, Takuji; Saji, Shigehira; Younes, Mamoun; Ito, Yoshinori; Akiyama, Futoshi

    2012-02-01

    BACKGROUND: Despite many studies, the clinicopathological importance of the androgen receptor (AR) in breast cancer is not well established, and its significance as an independent predictor of clinical outcome is controversial. A large and systematic study is needed to address these issues. The aim of the present study was to elucidate whether AR has independent clinical value, examining its importance in a large and well-predefined patient group with a long follow-up period and complete clinicopathological data. METHODS: Archival materials of 403 invasive breast cancers from women treated with adjuvant tamoxifen monotherapy (median follow-up period 11.0 years) were subjected to immunohistochemical study using anti-AR monoclonal antibody. AR expression was compared with established clinicopathological factors, estrogen receptor (ER)-β expression, and clinical outcome. RESULTS: AR positivity was correlated with ER-α positivity, progesterone receptor positivity, ER-β positivity, and a lower nuclear grade. Patients with AR-positive carcinomas exhibited a significantly better clinical outcome than those with AR-negative carcinomas (P = 0.0165 for disease-free survival, P = 0.0344 for overall survival). Multivariate analysis did not yield significant differences in clinical outcome according to the AR status, whereas the ER-β status showed significant differences in multivariate analysis. CONCLUSIONS: Although, and in agreement with previous reports, AR positivity correlated with some established favorable prognostic factors and with ER-β positivity, AR was not an independent predictor of clinical outcome. Controversy regarding the value of AR as an independent predictor of clinical outcome may at least partly reflect the relatively limited power of AR in breast cancer. PMID:22302643

  3. Atazanavir/ritonavir monotherapy as maintenance strategy in HIV-1 treated subjects with viral suppression: 96-week analysis results of the MODAT study

    PubMed Central

    Spagnuolo, Vincenzo; Galli, Laura; Bigoloni, Alba; Nozza, Silvia; d'Arminio Monforte, Antonella; Antinori, Andrea; Di Biagio, Antonio; Rusconi, Stefano; Guaraldi, Giovanni; Di Giambenedetto, Simona; Lazzarin, Adriano; Castagna, Antonella

    2014-01-01

    Introduction The 48-week interim analysis of the MODAT study showed that confirmed virologic failure (CVF) was more frequent in patients simplifying to ATV/r monotherapy compared to maintaining ATV/r-based triple therapy. The DSMB recommended stopping study enrollment but continuing follow-up of enrolled patients. We present the 96-week efficacy analysis. Material and Methods Multicentre, randomized, open-label, non-inferiority trial (non-inferiority margin −10%). Treatment failure (TF) was defined as CVF (two consecutive HIV-RNA >50 cp/mL) or discontinuation for any cause. In the monotherapy arm, patients with CVF re-introduced their previous NRTIs and remained in the study if HIV-RNA <50 copies/mL within 12 weeks of re-intensification. Results 101 patients evaluated (Figure 1): 85% males, 21% HCV-positive, median (IQR) age of 42 (36–48) years, baseline CD4+ 576 (447–743) cells/µL. In the 96-week analysis (ITT; TF=failure), efficacy was 64% (32/50) in the monotherapy arm and 63% (32/51) in the triple-therapy arm (difference +1.3%, 95% CI −17.5–20.1). Fourteen patients in monotherapy and two in triple-therapy arm had CVF; median HIV-RNA was 136 (72–376) copies/mL. In monotherapy arm, no PI or NRTI associated resistance mutations were observed at CVF. All patients who re-intensified re-suppressed. In monotherapy arm, TF was more frequent in HCV-co-infected patients (64% vs 28%; p=0.041). In the secondary analysis (ITT; re-intensification=success), 82% (41/50) in monotherapy arm and 63% (32/51) in triple-therapy arm were on study at week 96 (difference +19.3%, 95% CI 2.2–36.3). SAEs occurred in four (8%) patients in the monotherapy arm (one left basal pneumonia, one acute coronary stenosis, one traumatic lesion, one nephrolithiasis) and two (4%) in the triple therapy arm (one sepsis, one renal failure). Drug-related adverse events (AEs) leading to discontinuation were three (6%) in the monotherapy arm (two AEs occurred in patients after successful re

  4. Phase I/II trial of capecitabine, oxaliplatin, and irinotecan in combination with bevacizumab in first line treatment of metastatic colorectal cancer

    PubMed Central

    Bazarbashi, Shouki; Aljubran, Ali; Alzahrani, Ahmad; Mohieldin, Ahmed; Soudy, Hussein; Shoukri, Mohammed

    2015-01-01

    Phase III studies have demonstrated the efficacy of FOLFOXIRI regimens (5-fluorouracil/leucovorin, oxaliplatin, irinotecan) with/without bevacizumab in metastatic colorectal cancer (mCRC). Capecitabine is an orally administered fluoropyrimidine that may be used instead of 5-fluorouracil/leucovorin. We evaluated a triple-chemotherapy regimen of capecitabine, oxaliplatin, and irinotecan, plus bevacizumab in 53 patients with mCRC. A Phase I study identified the maximum tolerated dose of irinotecan as 150 mg/m2. Median follow-up in a subsequent Phase II study using this dose was 28 months (74% progressed). For all patients, a complete response was achieved in 4% and a partial response in 60%; median progression-free survival (PFS) was 16 months and median overall survival (OS) was 28 months. Median PFS was longer for patients with an early treatment response (28 vs. 9 months for others; P = 0.024), or early tumor shrinkage (25 vs. 9 months for others; P = 0.006), or for patients suitable for surgical removal of metastases with curative intent (median not reached vs. 9 months for others; P = 0.001). Median OS was longer for patients with early tumor shrinkage (median not reached vs. 22 months for others; P = 0.006) or surgery (median not reached vs. 22 months for others, P = 0.002). K-ras mutations status did not influence PFS (P = 0.88) or OS (P = 0.82). Considerable Grade 3/4 toxicity was encountered (36% for diarrhea, 21% for vomiting and 17% for fatigue). In conclusion, the 3-weekly triple-chemotherapy regimen of capecitabine, oxaliplatin, and irinotecan, plus bevacizumab, was active in the first-line treatment of mCRC, although at the expense of a high level of toxicity. PMID:26207614

  5. Low Incidence of Renal Dysfunction among HIV-Infected Patients on a Tenofovir-Based First Line Antiretroviral Treatment Regimen in Myanmar

    PubMed Central

    Kyaw, Nang Thu Thu; Antierens, Annick; Soe, Kyi Pyar; Woodman, Mike; Das, Mrinalini; Zuu, Moe Khine Lwin; Htwe, Pyae Sone

    2015-01-01

    Background Since 2004, Médecins Sans Frontières-Switzerland has provided treatment and care for people living with HIV in Dawei, Myanmar. Renal function is routinely monitored in patients on tenofovir (TDF)-based antiretroviral treatment (ART), and this provides an opportunity to measure incidence and risk factors for renal dysfunction. Methods We used routinely collected program data on all patients aged ≥15 years starting first-line TDF-based ART between January 2012 and December 2013. Creatinine clearance (CrCl) was assessed at base line and six-monthly, with renal dysfunction defined as CrCl < 50ml/min/1.73m2. We calculated incidence of renal dysfunction and used Cox regression analysis to identify associated risk factors. Results There were 1391 patients, of whom 1372 had normal renal function at baseline. Of these, 86 (6.3%) developed renal dysfunction during a median time of follow-up 1.14 years with an incidence rate of 5.4 per 100 person-years: 78 had CrCl between 30–50ml/min/1.73m2 and were maintained on TDF–based ART, but 5 were changed to another regimen: 4 because of CrCl <30ml/min/1.73m2. Risk factors for renal dysfunction included age ≥45 years, diagnosed diabetes, underlying renal disease, underweight and CD4 count <200cells/mm3. There were 19 patients with baseline renal dysfunction and all continued on TDF-based ART: CrCl stayed between 30–49 ml/min/1.73m2 in five patients while the remainder regained normal renal function. Conclusions In a resource-poor country like Myanmar, the low incidence of renal toxicity in our patient cohort suggests that routine assessment of CrCl may not be needed and could be targeted to high risk groups if resources permit. PMID:26301416

  6. Phase II study of gemcitabine, doxorubicin and paclitaxel (GAT) as first-line chemotherapy for metastatic breast cancer: a translational research experience

    PubMed Central

    Passardi, Alessandro; Massa, Ilaria; Zoli, Wainer; Gianni, Lorenzo; Milandri, Carlo; Zumaglini, Federica; Nanni, Oriana; Maltoni, Roberta; Frassineti, Giovanni Luca; Amadori, Dino

    2006-01-01

    Background Patients with metastatic breast cancer are frequently treated with anthracyclines and taxanes, which are among the most active agents in this disease. Gemcitabine is an interesting candidate for a three-drug combination because of its different mechanism of action and non-overlapping toxicity with respect to the other two drugs. We aimed to evaluate the activity and toxicity of the GAT (gemcitabine, doxorubicin and paclitaxel) regimen, derived from experimental preclinical studies, as first-line chemotherapy in patients with stage IIIB-IV breast cancer. Methods Patients with locally advanced or metastatic breast cancer and at least one bidimensionally measurable lesion were included in the present study. Adequate bone marrow reserve, normal cardiac, hepatic and renal function, and an ECOG performance status of 0 to 2 were required. Only prior adjuvant non anthracycline-based chemotherapy was permitted. Treatment consisted of doxorubicin 50 mg/m2 on day 1, paclitaxel 160 mg/m2 on day 2 and gemcitabine 800 mg/m2 on day 6, repeated every 21–28 days. Results Thirty-three consecutive breast cancer patients were enrolled onto the trial (7 stage IIIB and 26 stage IV). All patients were evaluable for toxicity and 29 were assessable for response. A total of 169 cycles were administered, with a median of 6 cycles per patient (range 1–8 cycles). Complete and partial responses were observed in 6.9% and 48.3% of patients, respectively, for an overall response rate of 55.2%. A response was reported in all metastatic sites, with a median duration of 16.4 months. Median time to progression and overall survival were 10.2 and 36.4 months, respectively. The most important toxicity was hematological, with grade III-IV neutropenia observed in 69% of patients, sometimes requiring the use of granulocyte colony-stimulating factor (27%). Non hematological toxicity was rare and mild. One patient died from sepsis during the first treatment cycle before the administration of

  7. Sunitinib Plus Paclitaxel Versus Bevacizumab Plus Paclitaxel for First-Line Treatment of Patients With Advanced Breast Cancer: A Phase III, Randomized, Open-Label Trial

    PubMed Central

    Robert, Nicholas J.; Saleh, Mansoor N.; Paul, Devchand; Generali, Daniele; Gressot, Laurent; Copur, Mehmet S.; Brufsky, Adam M.; Minton, Susan E.; Giguere, Jeffrey K.; Smith, John W.; Richards, Paul D.; Gernhardt, Diana; Huang, Xin; Liau, Katherine F.; Kern, Kenneth A.; Davis, John

    2015-01-01

    Introduction A multicenter, open-label phase III study was conducted to test whether sunitinib plus paclitaxel prolongs progression-free survival (PFS) compared with bevacizumab plus paclitaxel as first-line treatment for patients with HER2− advanced breast cancer. Patients and Methods Patients with HER2− advanced breast cancer who were disease free for ≥ 12 months after adjuvant taxane treatment were randomized (1:1; planned enrollment 740 patients) to receive intravenous (I.V.) paclitaxel 90 mg/m2 every week for 3 weeks in 4-week cycles plus either sunitinib 25 to 37.5 mg every day or bevacizumab 10 mg/kg I.V. every 2 weeks. Results The trial was terminated early because of futility in reaching the primary endpoint as determined by the independent data monitoring committee during an interim futility analysis. At data cutoff, 242 patients had been randomized to sunitinib-paclitaxel and 243 patients to bevacizumab-paclitaxel. Median PFS was shorter with sunitinib-paclitaxel (7.4 vs. 9.2 months; hazard ratio [HR] 1.63 [95% confidence interval (CI), 1.18–2.25]; 1-sided P = .999). At a median follow-up of 8.1 months, with 79% of sunitinib-paclitaxel and 87% of bevacizumab-paclitaxel patients alive, overall survival analysis favored bevacizumab-paclitaxel (HR 1.82 [95% CI, 1.16–2.86]; 1-sided P = .996). The objective response rate was 32% in both arms, but median duration of response was shorter with sunitinib-paclitaxel (6.3 vs. 14.8 months). Bevacizumab-paclitaxel was better tolerated than sunitinib-paclitaxel. This was primarily due to a high frequency of grade 3/4, treatment-related neutropenia with sunitinib-paclitaxel (52%) precluding delivery of the prescribed doses of both drugs. Conclusion The sunitinib-paclitaxel regimen evaluated in this study was clinically inferior to the bevacizumab-paclitaxel regimen and is not a recommended treatment option for patients with advanced breast cancer. PMID:21569994

  8. Review of US Comparative Economic Evidence for Treatment of Metastatic Renal Cell Carcinoma after Failure of First-Line VEGF Inhibitor Therapy

    PubMed Central

    Wong, Michael K.; Wang, Xufang; Chulikavit, Maruit J.; Liu, Zhimei

    2013-01-01

    Background In 2006, the economic burden of metastatic renal cell carcinoma (mRCC) was estimated to be up to $1.6 billion worldwide and has since grown annually. With the continuing increase of the economic burden of this disease in the United States, there is a growing need for economic analyses to guide treatment and policy decisions for this patient population. Objective To evaluate available comparative economic data on targeted therapies for patients with mRCC who have failed first-line targeted therapies. Method A broad and comprehensive literature review was conducted of US-based studies between January 1, 2005, and February 11, 2013, evaluating comparative economic evidence for targeted agents that are used as second-line therapy or beyond. Based on the specific search parameters that focused on cost-effectiveness and economic comparisons between vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFr) inhibitors and mammalian target of rapamycin (mTOR) inhibitors, only 7 relevant, US-based economic evaluations were found appropriate for inclusion in the analysis. All authors, who are experts in the health economics and outcomes research field, reviewed the search results. Studies of interest were those with a targeted agent, VEGF/VEGFr or mTOR inhibitor, in at least 1 study arm. Discussion As a group, targeted therapies were found to be cost-effective options in treating patients with refractory mRCC in the United States. Oral therapies showed an economic advantage over intravenous agents, presumably because oral therapies have a lower impact on outpatient resources. Based on 3 studies, everolimus has been shown to have an economic advantage over temsirolimus and to be cost-effective compared with sorafenib. No economic comparison between everolimus and axitinib, the only 2 drugs with a National Comprehensive Cancer Network category 1 recommendation for use after the failure of VEGFr tyrosine kinase inhibitors, is available. Conclusion The limited

  9. Role of Kras Status in Patients with Metastatic Colorectal Cancer Receiving First-Line Chemotherapy plus Bevacizumab: A TTD Group Cooperative Study

    PubMed Central

    Díaz-Rubio, Eduardo; Gómez-España, Auxiliadora; Massutí, Bartomeu; Sastre, Javier; Reboredo, Margarita; Manzano, José Luis; Rivera, Fernando; Safont, MªJosé; Montagut, Clara; González, Encarnación; Benavides, Manuel; Marcuello, Eugenio; Cervantes, Andrés; Martínez de Prado, Purificación; Fernández-Martos, Carlos; Arrivi, Antonio; Bando, Inmaculada; Aranda, E.; Gómez, A.; Massutí, B.; Yuste, A.; Rubio, E. Díaz; Sastre, J.; Valladares, M.; Abad, A.; Rivera, F.; Safont, MªJosé; Gallén, M.; González, E.; Benavides, M.; Marcuello, E.; Tobeña, M.; Cervantes, A.; Martínez de Prado, P.; Fernández-Martos, C.; Arrivi, A.; López-Ladrón, A.; Lacasta, A.; Llanos, M.; Remón, J.; Anton, A.; Vicent, J. Mª.; Gala´n, A.; Dueñas, R.; Tabernero, J. Mª.; Manzano, H.; Gómez, Mª. J.; Alfaro, J.; Losa, F.; Escudero, P.; García, T.; García López, J. L.; de Paredes, Mª L. García; Velasco, A.; Almenar, D.; Vera, R.; García Puche, J. L.; Carrato, A.; Lescure, A. Rodriguez; Jiménez, E.; Alberola, V.; García-Foncillas, J.; Constenla, M.; Ruiz, A.; Bueso, P.; Cabrera, E.; del Río,, L.; Ponce, J.; Oltra, A.; Checa, T.; Etxeberría, A.; Alonso, C.

    2012-01-01

    Background In the MACRO study, patients with metastatic colorectal cancer (mCRC) were randomised to first-line treatment with 6 cycles of capecitabine and oxaliplatin (XELOX) plus bevacizumab followed by either single-agent bevacizumab or XELOX plus bevacizumab until disease progression. An additional retrospective analysis was performed to define the prognostic value of tumour KRAS status on progression-free survival (PFS), overall survival (OS) and response rates. Methodology/Principal Findings KRAS data (tumour KRAS status and type of mutation) were collected by questionnaire from participating centres that performed KRAS analyses. These data were then cross-referenced with efficacy data for relevant patients in the MACRO study database. KRAS status was analysed in 394 of the 480 patients (82.1%) in the MACRO study. Wild-type (WT) KRAS tumours were found in 219 patients (56%) and mutant (MT) KRAS in 175 patients (44%). Median PFS was 10.9 months for patients with WT KRAS and 9.4 months for patients with MT KRAS tumours (p = 0.0038; HR: 1.40; 95% CI:1.12–1.77). The difference in OS was also significant: 26.7 months versus 18.0 months for WT versus MT KRAS, respectively (p = 0.0002; HR: 1.55; 95% CI: 1.23–1.96). Univariate and multivariate analyses showed that KRAS was an independent variable for both PFS and OS. Responses were observed in 126 patients (57.5%) with WT KRAS tumours and 76 patients (43.4%) with MT KRAS tumours (p = 0.0054; OR: 1.77; 95% CI: 1.18–2.64). Conclusions/Significance This analysis of the MACRO study suggests a prognostic role for tumour KRAS status in patients with mCRC treated with XELOX plus bevacizumab. For both PFS and OS, KRAS status was an independent factor in univariate and multivariate analyses. PMID:23174912

  10. Uracil/ftorafur/leucovorin combined with irinotecan (TEGAFIRI) or oxaliplatin (TEGAFOX) as first-line treatment for metastatic colorectal cancer patients: results of randomised phase II study

    PubMed Central

    Bajetta, E; Di Bartolomeo, M; Buzzoni, R; Mariani, L; Zilembo, N; Ferrario, E; Lo Vullo, S; Aitini, E; Isa, L; Barone, C; Jacobelli, S; Recaldin, E; Pinotti, G; Iop, A

    2007-01-01

    This randomised phase II study evaluates the safety and efficacy profile of uracil/tegafur/leucovorin combined with irinotecan (TEGAFIRI) or with oxaliplatin (TEGAFOX). One hundred and forty-three patients with measurable, non-resectable metastatic colorectal cancer were randomised in a multicentre study to receive TEGAFIRI (UFT 250 mg m−2 day days 1–14, LV 90 mg day days 1–14, irinotecan 240 mg m−2 day 1; q21) or TEGAFOX (UFT 250 mg m−2 day days 1–14, LV 90 mg day days 1–14, oxaliplatin 120 mg m−2 day 1; q21). Among 143 randomised patients, 141 were analysed (68 received TEGAFIRI and 73 TEGAFOX). The main characteristics of the two arms were well balanced. The most common grade 3–4 treatment-related adverse events were neutropenia (13% of cases with TEGAFIRI; 1% in the TEGAFOX group). Diarrhoea was prevalent in the TEGAFIRI arm (16%) vs TEGAFOX (4%). Six complete remission (CR) and 19 partial remission (PR) were recorded in the TEGAFIRI arm (odds ratio (OR): 41.7; 95% confidence limit (CL), 29.1–55.1%), and six CR and 22 PR were recorded in the TEGAFOX group, (OR: 38.9; 95% CL, 27.6–51.1). At a median time follow-up of 17 months (intequartile (IQ) range 12–23), a median survival probability of 20 and 19 months was obtained in the TEGAFIRI and TEGAFOX groups, respectively. Median time to progression was 8 months for both groups. TEGAFIRI and TEGAFOX are both effective and tolerable first-line therapies in MCRC patients. The employment of UFT/LV given in doublet combination is interesting and the presented data appear comparable to equivalent infusion regimens described in the literature. The safety profile of the two combinations also allows an evaluation with other biological agents such as monoclonal antibodies. PMID:17245343

  11. Peripheral neuropathy in HIV patients in sub-Saharan Africa failing first-line therapy and the response to second-line ART in the EARNEST trial.

    PubMed

    Arenas-Pinto, Alejandro; Thompson, Jennifer; Musoro, Godfrey; Musana, Hellen; Lugemwa, Abbas; Kambugu, Andrew; Mweemba, Aggrey; Atwongyeire, Dickens; Thomason, Margaret J; Walker, A Sarah; Paton, Nicholas I

    2016-02-01

    Sensory peripheral neuropathy (PN) remains a common complication in HIV-positive patients despite effective combination anti-retroviral therapy (ART). Data on PN on second-line ART is scarce. We assessed PN using a standard tool in patients failing first-line ART and for 96 weeks following a switch to PI-based second-line ART in a large Randomised Clinical Trial in Sub-Saharan Africa. Factors associated with PN were investigated using logistic regression. Symptomatic PN (SPN) prevalence was 22% at entry (N = 1,251) and was associated (p < 0.05) with older age (OR = 1.04 per year), female gender (OR = 1.64), Tuberculosis (TB; OR = 1.86), smoking (OR = 1.60), higher plasma creatinine (OR = 1.09 per 0.1 mg/dl increase), CD4 count (OR = 0.83 per doubling) and not consuming alcohol (OR = 0.55). SPN prevalence decreased to 17% by week 96 (p = 0.0002) following similar trends in all study groups (p = 0.30). Asymptomatic PN (APN) increased over the same period from 21 to 29% (p = 0.0002). Signs suggestive of PN (regardless of symptoms) returned to baseline levels by week 96. At weeks 48 and 96, after adjusting for time-updated associations above and baseline CD4 count and viral load, SPN was strongly associated with TB (p < 0.0001). In summary, SPN prevalence was significantly reduced with PI-based second-line therapy across all treatment groups, but we did not find any advantage to the NRTI-free regimens. The increase of APN and stability of PN-signs regardless of symptoms suggest an underlying trend of neuropathy progression that may be masked by reduction of symptoms accompanying general health improvement induced by second-line ART. SPN was strongly associated with isoniazid given for TB treatment. PMID:26323809

  12. Estimating quality adjusted progression free survival of first-line treatments for EGFR mutation positive non small cell lung cancer patients in The Netherlands

    PubMed Central

    2012-01-01

    gefitinib. Conclusions In the Dutch health care setting, the previously established progression free survival benefit of first-line gefitinib in advanced NSCLC EGFR M+ patients in comparison to standard doublet chemotherapy is further supported by the Quality Adjusted PFS, which takes into account the additional health-related quality of life benefits of gefitinib over doublet chemotherapy. PMID:22963131

  13. Phase II study of weekly vinorelbine and 24-h infusion of high-dose 5-fluorouracil plus leucovorin as first-line treatment of advanced breast cancer

    PubMed Central

    Yeh, K H; Lu, Y S; Hsu, C H; Lin, J F; Chao, H J; Huang, T C; Chung, C Y; Chang, C S; Yang, C H; Cheng, A L

    2005-01-01

    We prospectively investigated the efficacy and safety of combining weekly vinorelbine (VNB) with weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV) in the treatment of patients with advanced breast cancer (ABC). Vinorelbine 25 mg m−2 30-min intravenous infusion, and high-dose 5-FU 2600 mg m−2 plus LV 300 mg m−2 24-h intravenous infusion (HDFL regimen) were given on days 1 and 8 every 3 weeks. Between June 1999 and April 2003, 40 patients with histologically confirmed recurrent or metastatic breast cancer were enrolled with a median age of 49 years (range: 36–68). A total of 25 patients had recurrent ABC, and 15 patients had primary metastatic diseases. The overall response rate for the intent-to-treat group was 70.0% (95% CI: 54–84%) with eight complete responses and 20 partial responses. All 40 patients were evaluated for survival and toxicities. Among a total of 316 cycles of VNB–HDFL given (average: 7.9: range: 4–14 cycles per patient), the main toxicity was Gr3/4 leucopenia and Gr3/4 neutropenia in 57 (18.0%) and 120 (38.0%) cycles, respectively. Gr1/2 infection and Gr1/2 stomatitis were noted in five (1.6%) and 59 (18.7%) cycles, respectively. None of the patients developed Gr3/4 stomatitis or Gr3/4 infection. Gr2/3 and Gr1 hand–foot syndrome was noted in two (5.0%) and 23 (57.5%) patients, respectively. Gr1 sensory neuropathy developed in three patients. The median time to progression was 8.0 months (range: 3–25.5 months), and the median overall survival was 25.0 months with a follow-up of 5.5 to 45+ months. This VNB–HDFL regimen is a highly active yet well-tolerated first-line treatment for ABC. PMID:15770209

  14. Evaluating immunologic response and clinical deterioration in treatment-naïve patients initiating first-line therapies infected with HIV-1 CRF01_AE and subtype B

    PubMed Central

    Oyomopito, Rebecca A.; Li, Patrick CK.; Sungkanuparph, Somnuek; Phanuphak, Praphan; Tee, Kok Keng; Sirisanthana, Thira; Kantipong, Pacharee; Oka, Shinichi; Lee, Chris KC.; Kamarulzaman, Adeeba; Choi, Jun Yong; Sohn, Annette H.; Law, Matthew; Chen, Yi-Ming A.

    2012-01-01

    Background HIV-1 group M viruses diverge 25%–35% in envelope, important for viral attachment during infection, and 10–15% in the pol region, under selection pressure from common antiretrovirals. In Asia, subtypes B and CRF01_AE are common genotypes. Our objectives were to determine whether clinical, immunologic or virologic treatment responses differed by genotype in treatment-naïve patients initiating first-line therapy. Methods Prospectively collected, longitudinal data from patients in Thailand, Hong Kong, Malaysia, Japan, Taiwan and South Korea were provided for analysis. Covariates included demographics, hepatitis B and C coinfections, baseline CD4 T lymphocyte count and plasma HIV-1 RNA levels. Clinical deterioration (a new diagnosis of CDC category B/AIDS-defining illness or death) was assessed by proportional hazards models. Surrogate endpoints were 12-month change in CD4 cell count and virologic suppression post-therapy, evaluated by linear and logistic regression, respectively. Results Of 1105 patients, 1036 (93.8%) infected with CRF01_AE or subtype B were eligible for inclusion in clinical deterioration analyses and contributed 1546.7 person-years of follow-up (median:413 days, IQR:169–672 days). Patients >40 years demonstrated smaller immunological increases (p=0.002) and higher risk of clinical deterioration (HR=2.17; p=0.008). Patients with baseline CD4 cell counts >200 cells/μL had lower risk of clinical deterioration (HR=0.373; p=0.003). A total of 532 patients (48.1% of eligible) had CD4 counts available at baseline and 12 months post-therapy for inclusion in immunolgic analyses. Patients infected with subtype B had larger increases in CD4 counts at 12 months (p=0.024). A total of 530 patients (48.0% of eligible) were included in virologic analyses with no differences in response found between genotypes. Conclusions Results suggest that patients infected with CRF01_AE have reduced immunologic response to therapy at 12 months, compared to

  15. High-Dose-Rate Interstitial Brachytherapy as Monotherapy for Clinically Localized Prostate Cancer: Treatment Evolution and Mature Results

    SciTech Connect

    Zamboglou, Nikolaos; Tselis, Nikolaos; Baltas, Dimos; Buhleier, Thomas; Martin, Thomas; Milickovic, Natasa; Papaioannou, Sokratis; Ackermann, Hanns; Tunn, Ulf W.

    2013-03-01

    Purpose: To report the clinical outcome of high-dose-rate (HDR) interstitial (IRT) brachytherapy (BRT) as sole treatment (monotherapy) for clinically localized prostate cancer. Methods and Materials: Between January 2002 and December 2009, 718 consecutive patients with clinically localized prostate cancer were treated with transrectal ultrasound (TRUS)-guided HDR monotherapy. Three treatment protocols were applied; 141 patients received 38.0 Gy using one implant in 4 fractions of 9.5 Gy with computed tomography-based treatment planning; 351 patients received 38.0 Gy in 4 fractions of 9.5 Gy, using 2 implants (2 weeks apart) and intraoperative TRUS real-time treatment planning; and 226 patients received 34.5 Gy, using 3 single-fraction implants of 11.5 Gy (3 weeks apart) and intraoperative TRUS real-time treatment planning. Biochemical failure was defined according to the Phoenix consensus, and toxicity was evaluated using Common Toxicity Criteria for Adverse Events version 3. Results: The median follow-up time was 52.8 months. The 36-, 60-, and 96-month biochemical control and metastasis-free survival rates for the entire cohort were 97%, 94%, and 90% and 99%, 98%, and 97%, respectively. Toxicity was scored per event, with 5.4% acute grade 3 genitourinary and 0.2% acute grade 3 gastrointestinal toxicity. Late grade 3 genitourinary and gastrointestinal toxicities were 3.5% and 1.6%, respectively. Two patients developed grade 4 incontinence. No other instance of grade 4 or greater acute or late toxicity was reported. Conclusion: Our results confirm IRT-HDR-BRT is safe and effective as monotherapy for clinically localized prostate cancer.

  16. Pegylated Interferon Mono-Therapy of Chronic Hepatitis C in the Dialysis Population: Systematic Review and Meta-Analysis.

    PubMed

    Fabrizi, Fabrizio; Dixit, Vivek; Messa, Piergiorgio; Martin, Paul

    2015-12-01

    The medical literature on mono-therapy with pegylated interferon for chronic hepatitis C in dialysis patients is mostly based on small clinical studies and the efficacy and safety of such approach is still unclear. A systematic review of the literature with a meta-analysis of clinical studies was performed in order to evaluate the efficacy and safety of mono-therapy with pegylated interferon of chronic hepatitis C in patients on regular dialysis. The primary outcome was sustained viral response (as a measure of efficacy); the secondary outcome was drop-out rate (as a measure of tolerability). The random-effects model of Der Simonian and Laird was used, with heterogeneity and sensitivity analyses. Twenty-four clinical studies (N = 744 unique patients) were retrieved; five (21%) being randomized controlled trials. The summary estimate for sustained viral response and drop-out rate was 0.40 (95% confidence interval [CI], 0.35; 0.46) and 0.14 (95% CI, 0.09; 0.20), respectively. The most frequent side-effects requiring discontinuation of treatment were hematological (31/83 = 37%) and gastrointestinal (9/31 = 10.8%). Meta-regression analysis showed a detrimental role of ageing on the frequency of sustained virological response (P = 0.01); drop-out rate was greater in diabetics (P < 0.005). Important heterogeneity was seen with regard to drop-out rate only. In summary, pegylated interferon monotherapy of hepatitis C in dialysis patients resulted unsatisfactory in terms of efficacy and safety. Studies with novel direct-acting antiviral agents in combination with pegylated interferon and ribavirin for the treatment of hepatitis C virus in dialysis population are under way. PMID:26197927

  17. {sup 125}I Monotherapy Using D90 Implant Doses of 180 Gy or Greater

    SciTech Connect

    Kao, Johnny; Stone, Nelson N.; Lavaf, Amir Dumane, Vishruta; Cesaretti, Jamie A.; Stock, Richard G.

    2008-01-01

    Purpose: The purpose of this study was to characterize the oncologic results and toxicity profile of patients treated with {sup 125}I implants using the dose delivered to 90% of the gland from the dose-volume histogram (D90) of greater than 144 Gy. Methods and Materials: From June 1995 to Feb 2005, a total of 643 patients were treated with {sup 125}I monotherapy for T1-T2 prostate cancer with a D90 of 180 Gy or greater (median, 197 Gy; range, 180-267 Gy). Implantations were performed using a real-time ultrasound-guided seed-placement method and intraoperative dosimetry to optimize target coverage and homogeneity by using modified peripheral loading. We analyzed biochemical disease-free survival (bDFS) of 435 patients who had a minimum 2-year prostate-specific antigen follow-up (median follow-up, 6.7 years; range, 2.0-11.1 years). Results: Five-year bDFS rates for the entire cohort using the American Society for Therapeutic Radiology and Oncology and Phoenix definitions were 96.9% and 96.5%, respectively. Using the Phoenix definition, 5-year bDFS rates were 97.3% for low-risk patients and 92.8% for intermediate/high-risk patients. The positive biopsy rate was 4.1%. The freedom rate from Grade 2 or higher rectal bleeding at 5 years was 88.5%. Acute urinary retention occurred in 10.7%, more commonly in patients with high pretreatment International Prostate Symptom Scores (p < 0.01). In patients who were potent before treatment, 73.4% remained potent at 5 years after implantation. Conclusions: Patients with a minimum D90 of 180 Gy had outstanding local control based on prostate-specific antigen control and biopsy data. Toxicity profiles, particularly for long-term urinary and sexual function, were excellent and showed that D90 doses of 180 Gy or greater performed using the technique described were feasible and tolerable.

  18. Invasive aspergillosis successfully treated by combined antifungal therapy and immunosuppressive monotherapy two months following heart transplantation

    PubMed Central

    Żabicki, Bartłomiej; Baszyńska-Wachowiak, Hanna; Straburzyńska-Migaj, Ewa; Juszkat, Robert; Grajek, Stefan; Jemielity, Marek

    2016-01-01

    Invasive aspergillosis is becoming increasingly prevalent, especially following transplantation. Invasive aspergillosis is associated with mortality. Successful therapy is related to early diagnosis and proper therapy. We present the case of a 61-year-old man suffering from invasive aspergillosis 2 months following heart transplantation. He was suffering from hypertrophic cardiomyopathy and he underwent orthotropic heart transplantation. He was readmitted to the Department of Cardiology 69 days following transplantation due to symptoms of productive cough for 5 days. It was accompanied by chest pain, shortness of breath, and fever up to 39°C. He was slightly cyanotic and confused on physical examination. The patient's status deteriorated within the following 2 days. On bronchoscopic specimen examinations Aspergillus mould filaments were detected and the serum galactomannan index was 12.162. His blood saturation decreased to 85%. C-reactive protein serum level increased to 273 mg/l. The patient was admitted to the intensive care unit and intubated due to severe respiratory insufficiency. Computed tomography revealed massive, mostly homogeneous consolidation. The patient was treated with 200 mg of voriconazole and 50 mg of caspofungin daily. Caspofungin therapy was continued for 23 days and voriconazole was administered parenterally for 62 days. Voriconazole therapy was continued orally for 9 months. During combined antifungal therapy, the galactomannan serum index constantly decreased from 12.1 to 0.33 (end-point of caspofungin therapy) and to 0.23 (end-point of voriconazole parenteral administration). His immunosuppressive therapy was limited to calcineurin inhibitor (tacrolimus) monotherapy. Post-treatment imaging 9 months after diagnosis confirmed the efficacy of therapy as a lack of pulmonary infiltration associated with left apical peribronchial scarring as a result of treatment. The present case proved the efficiency of combined (voriconazole and caspofungin

  19. Outcome in patients with idiopathic retroperitoneal fibrosis treated with corticosteroid or tamoxifen monotherapy

    PubMed Central

    van der Bilt, Floor E.; Hendriksz, Tadek R.; van der Meijden, Wilbert A.G.; Brilman, Lisette G.; van Bommel, Eric F.H.

    2016-01-01

    Background Although corticosteroids (CS) are used primarily in idiopathic retroperitoneal fibrosis (iRPF), tamoxifen (TMX) may be a suitable alternative. We compared outcome with CS or TMX monotherapy for first presentation in a large group of patients with iRPF disease. Methods Of all patients with iRPF disease who were seen at our tertiary care referral centre from February 1999 to December 2011, 118 patients were eligible for this retrospective study. Treatment success was defined as the composite of (i) amelioration of symptoms, (ii) computed tomography (CT)-documented mass regression and, if applicable, (iii) definitive removal of ureteral stent or nephrostomy tube. Recurrence was defined as recurrence of signs and symptoms and/or CT-documented mass increase after initial treatment success with primary treatment. Results Presenting signs and symptoms did not differ between patients treated with CS (n = 50) or TMX (n = 68). Time to amelioration of symptoms after treatment initiation was shorter in CS-treated patients [CS, 2.0 (0.8–3.8) weeks versus TMX, 4.0 (2.0–6.0) weeks; P < 0.01]. Short-term percentual decrease in acute-phase reactant levels (P < 0.001 for both erythrocyte sedimentation rate and C-reactive protein) and serum creatinine level (P < 0.01) following treatment initiation was greater in CS-treated patients compared with that in TMX-treated patients. Mass regression at first follow-up CT scan was observed more frequently in CS-treated patients (CS, 84.0% versus TMX, 68.3%; P = 0.05) with no difference in time interval from treatment initiation to first follow-up CT between groups [CS, 5 (2–7) months versus TMX, 4 (4–5) months; P = 0.34]. Definite treatment success was non-significantly higher in CS-treated patients (CS, 72.7% versus TMX, 58.3%; P = 0.15). In patients with initial treatment success with primary treatment, recurrence rate was lower in TMX-treated patients (CS, 62.5% versus TMX, 21.4%; P < 0.01). Conclusions CS are superior

  20. First-line antiretroviral therapy durability in a 10-year cohort of naïve adults started on treatment in Uganda

    PubMed Central

    Castelnuovo, Barbara; Kiragga, Agnes; Mubiru, Frank; Kambugu, Andrew; Kamya, Moses; Reynolds, Steven J

    2016-01-01

    Introduction The majority of studies from resource-limited settings only report short-term virological outcomes of patients on antiretroviral treatment (ART). We aim to describe the long-term durability of first-line ART and identify factors associated with long-term virological outcomes. Methods At the Infectious Diseases Institute in Kampala, Uganda, 559 adult patients starting ART in 2004 were enrolled into a research cohort and monitored with viral load (VL) testing every six months for 10 years. We report the proportion and cumulative probability of 1) achieving virologic suppression (at least one VL <400 copies/ml); 2) experiencing virologic failure in patients who achieved suppression (two consecutive VLs >1000 copies/ml or one VL >5000, for those without a subsequent one); 3) treatment failure (not attaining virologic suppression or experiencing virologic failure). We used Cox regression methods to determine the characteristics associated with treatment failure. We included gender, baseline age, WHO stage, body mass index, CD4 count, propensity score for initial ART regimen, VL, time-dependent CD4 count and adherence. Results Of the 559 patients enrolled, 472 (84.8%) had at least one VL (67 died, 13 were lost to follow-up, 4 transferred, 2 had no VL available); 73.6% started on d4T/3TC/nevirapine and 26.4% on AZT/3TC/efavirenz. Patients in the two groups had similar characteristics, except for the higher proportion of patients in WHO Stage 3/4 and higher VL in the efavirenz-based group. Four hundred thirty-nine (93%) patients achieved virologic suppression with a cumulative probability of 0.94 (confidence interval (CI): 0.92–0.96); 74/439 (16.9%) experienced virologic failure with a cumulative probability of 0.18 (CI: 0.15–0.22). In the multivariate analysis, initial d4T/3TC/nevirapine regimen (hazard ratio (HR): 3.02; CI: 3.02 (1.66–5.44, p<0.001)) and baseline VL ≥5 log10 copies/ml (HR: 2.29; CI: 1.29–4.04) were associated with treatment

  1. Atherosclerotic effects of long-term old and new antiepileptic drugs monotherapy: a cross-sectional comparative study.

    PubMed

    El-Farahaty, Reham M; El-Mitwalli, Ashraf; Azzam, Hanan; Wasel, Yasser; Elrakhawy, Mohamed M; Hasaneen, Bothina Mohammed

    2015-03-01

    This work aimed to evaluate the metabolic and atherogenic effects of long-term antiepileptic drugs in a group of Egyptian epileptic patients. Sixty-nine epileptic patients on antiepileptic drug monotherapy for at least 2 years and 34 control subjects were recruited in this study. Patients were divided into 5 subgroups according to antiepileptic drugs used (valproate, carbamazepine, lamotrigine, topiramate, and levetiracetam). Fasting lipid profile (total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), lipoprotein(a), homocysteine, free thyroxine, thyroid-stimulating hormone, and common carotid artery intima-media thickness were measured for all subjects. Significant higher mean values of low-density lipoprotein cholesterol, low-density lipoprotein / high-density lipoprotein ratio, lipoprotein(a), homocysteine, significantly lower mean value of high-density lipoprotein cholesterol, and significantly larger diameter of common carotid artery intima-media thickness were observed in each drug-treated group versus control group. Our study supports that long-term monotherapy treatment with valproate, carbamazepine, lamotrigine, and topiramate had altered markers of vascular risk that might enhance atherosclerosis, whereas levetiracetam exerted minimal effect. PMID:25342306

  2. Prospective open-label study of add-on and monotherapy topiramate in civilians with chronic nonhallucinatory posttraumatic stress disorder

    PubMed Central

    Berlant, Jeffrey L

    2004-01-01

    Background In order to confirm therapeutic effects of topiramate on posttraumatic stress disorder (PTSD) observed in a prior study, a new prospective, open-label study was conducted to examine acute responses in chronic, nonhallucinatory PTSD. Methods Thirty-three consecutive newly recruited civilian adult outpatients (mean age 46 years, 85% female) with DSM-IV-diagnosed chronic PTSD, excluding those with concurrent auditory or visual hallucinations, received topiramate either as monotherapy (n = 5) or augmentation (n = 28). The primary measure was a change in the PTSD Checklist-Civilian Version (PCL-C) score from baseline to 4 weeks, with response defined as a ≥ 30% reduction of PTSD symptoms. Results For those taking the PCL-C at both baseline and week 4 (n = 30), total symptoms declined by 49% at week 4 (paired t-test, P < 0.001) with similar subscale reductions for reexperiencing, avoidance/numbing, and hyperarousal symptoms. The response rate at week 4 was 77%. Age, sex, bipolar comorbidity, age at onset of PTSD, duration of symptoms, severity of baseline PCL-C score, and monotherapy versus add-on medication administration did not predict reduction in PTSD symptoms. Median time to full response was 9 days and median dosage was 50 mg/day. Conclusions Promising open-label findings in a new sample converge with findings of a previous study. The use of topiramate for treatment of chronic PTSD, at least in civilians, warrants controlled clinical trials. PMID:15315714

  3. Effects of lamotrigine on cognition and behavior compared to carbamazepine as monotherapy for children with partial epilepsy.

    PubMed

    Eun, So-Hee; Eun, Baik-Lin; Lee, Joon Soo; Hwang, Yong Seung; Kim, Ki Joong; Lee, Young-Mock; Lee, In Goo; Lee, Munhyang; Ko, Tae-Sung; Kim, Jeong Tae; Eom, Soyong; Kim, Heung Dong

    2012-11-01

    To compare the cognitive and behavioral effects of lamotrigine (LTG) to carbamazepine (CBZ) as monotherapy for pediatric epilepsy. A multicenter, randomized, open-label, parallel-group clinical trial was conducted in children with partial-onset seizures. LTG or CBZ was prescribed as monotherapy for previously untreated children and titrated over 8 weeks, followed by maintenance for 24 weeks. Outcome measures were change in cognition and behavior in a combined analysis of standardized measures from screening to the end of the maintenance phase, as well as antiepileptic efficacy and tolerability. A total of 67 children completed the study, including 32 of 43 (74.4%) treated with LTG and 35 of 41 (85.4%) treated with CBZ. Seizure-free outcomes did not differ between the intent-to-treat populations (53.5% LTG, 56.1% CBZ; p=0.81). There were no statistically significant differences in the intelligence of the two groups after treatment. Externalizing behavior problems improved in the CBZ group (p<0.05). However, there were no significant differences between the two groups in terms of externalizing behavior. The parents' report on the Conner scale showed an improvement in the CBZ group compared to the LTG group (p<0.05). LTG and CBZ showed similar efficacy and cognitive effects in treating childhood partial epilepsy. However, CBZ showed more benefits in improving externalizing behaviors. PMID:22521904

  4. Gray matter increases in fronto-parietal regions of depression patients with aripiprazole monotherapy: An exploratory study.

    PubMed

    Lai, Chien-Han; Wu, Yu-Te; Chen, Cheng-Yu; Hou, Yi-Cheng

    2016-08-01

    We investigated the treatment effects of aripiprazole monotherapy in first-episode medication-naïve patients with major depressive disorder (MDD). The accompanying changes in the gray matter volume (GMV) were also explored.Fifteen patients completed the trial and received structural scans by 3-Tesla magnetic resonance imaging at baseline and partially responding state (sixth week). To account for the test-retest bias, 27 healthy controls were scanned twice within 6 weeks. We utilized optimized voxel-based morphometry with different comparisons between groups.The partially responding patients with MDD had greater GMV in left middle frontal gyrus and left superior parietal gyrus when compared with baseline. However, they had decreases in the GMV of right orbitofrontal gyrus and right inferior temporal gyrus after response. The partially responding patients with MDD still had residual GMV deficits in right superior frontal gyrus when compared with controls. However, the lack of second patient group without aripiprazole intervention would be a significant limitation to interpret the aripiprazole-specific effects on GMV.The changes in the GMV of fronto-parieto-temporal regions and residual GMV deficits in the superior frontal gyrus might represent "state-dependent brain changes" and "residual-deficit brain regions," respectively, for aripiprzole monotherapy in MDD. PMID:27559967

  5. [Breast Cancer with Multiple Liver Metastases Successfully Treated with Capecitabine Monotherapy after Failure of Combination Therapy Comprising Bevacizumab and Paclitaxel].

    PubMed

    Ooe, Asako; Suganuma, Yasushi

    2016-03-01

    We report a case of breast cancer with multiple liver metastases successfully treated with capecitabine monotherapy after failure of combination therapy comprising bevacizumab (Bev) and paclitaxel (PTX). In March 2012, a 67-year-old woman was diagnosed with Stage IV breast cancer with massive pleural effusion. Histological examination showed invasive ductal carcinoma (scirrhous carcinoma) that was positive for hormonal receptor but negative for HER2 expression, and the nuclear grade was 1. She first received chemotherapy to decrease the tumor volume followed by hormonal therapy. After progression, imaging studies showed increased multiple lung and liver metastases and pleural effusion. Subsequently, treatment with combination of Bev and PTX was started from July 2014. After 4 courses of the combination therapy, multiple liver metastases were unchanged, but her liver function was impaired. Hence, she received capecitabine monotherapy (1,800 mg bis in die [BID]; 2-week administration followed by a week of rest). Her liver function improved early, and a partial response (PR) in the multiple liver metastases was achieved 3 months after initiation of therapy. Furthermore, the metastatic lesions were well controlled 4 months later. These findings suggest that the sensitivity to an anticancer agent greatly varies among patients. PMID:27067853

  6. [A Case of Virchow's Lymph Node Recurrence of Gastric Cancer Who Had Underwent Gastrectomy, and Treated with S-1 Monotherapy Leading to Complete Response (CR)].

    PubMed

    Tanaka, Shinichi; Sanefuji, Kensaku; Kabashima, Akira; Maekawa, Souichirou

    2016-04-01

    We report the case of a 67-year-old male with Virchow's lymph node recurrence of gastric cancer, who underwent distal gastrectomy for type 2 forecourt part of pylorus gastric cancer, showing complete response(CR)in response to S-1 monotherapy. The tumor was pathologically diagnosed as Stage IIIb(well to poorly differentiated adenocarcinoma, T3[SE], N2 [20/51], M0). Virchow's lymph node metastasis was confirmed 2 months after surgery. One week after S-1 administration, a reduction in lymph node size was observed. After 5 courses of S-1 monotherapy, he achieved CR. The patient maintained CR for 2 years, before we switched to uracil and tegafur(UFT)monotherapy. The patient maintained CR for 2 years, after which UFT was discontinued. No relapse was observed 22 months after discontinuation. PMID:27220793

  7. Immunological failure of first-line and switch to second-line antiretroviral therapy among HIV-infected persons in Tanzania: analysis of routinely collected national data

    PubMed Central

    Vanobberghen, Fiona M; Kilama, Bonita; Wringe, Alison; Ramadhani, Angela; Zaba, Basia; Mmbando, Donan; Todd, Jim

    2015-01-01

    Objectives Rates of first-line treatment failure and switches to second-line therapy are key indicators for national HIV programmes. We assessed immunological treatment failure defined by WHO criteria in the Tanzanian national HIV programme. Methods We included adults initiating first-line therapy in 2004–2011 with a pre-treatment CD4 count, and ≥6-months of follow-up. We assessed subhazard ratios (SHR) for immunological treatment failure, and subsequent switch to second-line therapy, using competing risks methods to account for deaths. Results Of 121 308 adults, 7% experienced immunological treatment failure, and 2% died without observed immunological treatment failure, over a median 1.7 years. The 6-year cumulative probability of immunological treatment failure was 19.0% (95% CI 18.5, 19.7) and of death, 5.1% (4.8, 5.4). Immunological treatment failure predictors included earlier year of treatment initiation (P < 0.001), initiation in lower level facilities (SHR = 2.23 [2.03, 2.45] for dispensaries vs. hospitals), being male (1.27 [1.19, 1.33]) and initiation at low or high CD4 counts (for example, 1.78 [1.65, 1.92] and 5.33 [4.65, 6.10] for <50 and ≥500 vs. 200–349 cells/mm3, respectively). Of 7382 participants in the time-to-switch analysis, 6% switched and 5% died before switching. Four years after immunological treatment failure, the cumulative probability of switching was 7.3% (6.6, 8.0) and of death, 6.8% (6.0, 7.6). Those who immunologically failed in dispensaries, health centres and government facilities were least likely to switch. Conclusions Immunological treatment failure rates and unmet need for second-line therapy are high in Tanzania; virological monitoring, at least for persons with immunological treatment failure, is required to minimise unnecessary switches to second-line therapy. Lower level government health facilities need more support to reduce treatment failure rates and improve second-line therapy uptake to sustain the

  8. Cerebrospinal fluid analysis for HIV replication and biomarkers of immune activation and neurodegeneration in long-term atazanavir/ritonavir monotherapy treated patients

    PubMed Central

    Ferretti, Francesca; Bigoloni, Alba; Passeri, Laura; Galli, Laura; Longo, Valeria; Gerevini, Simonetta; Spagnuolo, Vincenzo; Gisslen, Magnus; Zetterberg, Henrik; Fuchs, Dietmar; Cattaneo, Dario; Caramatti, Giada; Lazzarin, Adriano; Cinque, Paola; Castagna, Antonella

    2016-01-01

    Abstract Background: Cerebrospinal fluid (CSF) viral escape is a concern in ritonavir-boosted protease inhibitors monotherapy. The aim was to assess HIV-RNA, biomarkers of immune activation and neurodegeneration, and atazanavir concentrations in CSF of patients on successful long-term atazanavir/ritonavir (ATV/r) monotherapy. Methods: This is a substudy of the multicentric, randomized, open-label, noninferiority trial monotherapy once a day with atazanavir/ritonavir (NCT01511809), comparing the ongoing ATV/r along with 2 nucleoside retrotranscriptase inhibitors (NRTIs) regimen to a simplified ATV/r monotherapy. Patients with plasma HIV-RNA < 50 copies/mL after at least 96 study weeks were eligible. We assessed HIV-RNA, soluble (s)CD14, sCD163, CCL2, CXCL10, interleukin-6, and YKL40 by enzyme-linked immunosorbent assay; neopterin, tryptophan, kynurenine, and neurofilament by immunoassays; and ATV concentrations by liquid chromatography–mass spectrometry in paired plasma and CSF samples. Variables were compared with Wilcoxon rank-sum or Fisher exact test, as appropriate. Results: HIV-RNA was detected in the CSF of 1/11 patients on ATV/r monotherapy (114 copies/mL), without neurological symptoms, who was successfully reintensified with his previous 2NRTIs, and in none of the 12 patients on ATV/r + 2NRTIs. CSF biomarkers and ATV concentrations did not differ between the 2 arms. Conclusions: CSF escape was uncommon in patients on long-term ATV/r monotherapy and was controlled with reintensification. PMID:27428202

  9. Monotherapy with darunavir/ritonavir is effective and safe in clinical practice

    PubMed Central

    Pasquau, Juan; López-Cortés, Luis; Isabel Mayorga, Maria; Viciana, Pompeyo; del Mar Arenas, María; José Ríos, Maria; Hernández-Quero, José; Castaño, Manuel; Dolores Merino, María; Márquez, Manuel; Vergara, Antonio; Terrón, Alberto; Téllez, Francisco; Hidalgo-Tenorio, Carmen

    2014-01-01

    Introduction Monotherapy against HIV has undoubted theoretical advantages and has good scientific fundaments. However, it is still controversial and here we will analyze the efficacy and safety of MT with darunavir with ritonavir (DRV/r) on patients who have received this treatment in our hospitals. Materials and Methods Observational retrospective study that includes patients from 10 Andalusian hospitals that have received DRV/r in MT and that have been followed over a minimum of 12 months. We carried out a statistical descriptive analysis based on the profile of patients who had been prescribed MT and the efficacy and safety that were observed, paying special attention to treatment failure and virological evolution. Results DRV/r was prescribed to 604 patients, of which 41.1% had a CD4 nadir <200/mmc. 33.1% had chronic hepatitis caused by HCV, had received an average of five lines of previous treatment and had a history of treatment failure to analogues in 33%, to non-analogues 22 and protease inhibitors (PI) in 19.5%. 76.6% proceeded from a previous treatment with PI. The simplification was the main criteria for the instauration of MT in the 81.5% and the adverse effects in the 18.5%. We managed to maintain MT in 84% of cases, with only 4.8% of virological failure (VF) with viral load (VL) >200 c/mL and 3.6% additional losses due to VF with VL between 50 and 200 copies/mL. Thirty three genotypes were performed after failure without findings of resistance mutations to DRV/r or other IPs. Only 23.7% of patients presented some blips during the period of exposition to MT. Eighty seven percent of all determinations of VL had <50 copies/mL, and only 4.99% had >200 copies/mL. Although up to 14.9% registered at some point an AE, only 2.6% abandoned MT because of AE and 1.2% because of voluntary decision. Although the average of total and LDL cholesterol increases 10 mg/dL after 2 years of follow-up, so did HDL cholesterol in 3mg/dL and the values of triglycerides (−14

  10. Individual Patient Data Analysis of Progression-Free Survival Versus Overall Survival As a First-Line End Point for Metastatic Colorectal Cancer in Modern Randomized Trials: Findings From the Analysis and Research in Cancers of the Digestive System Database

    PubMed Central

    Shi, Qian; de Gramont, Aimery; Grothey, Axel; Zalcberg, John; Chibaudel, Benoist; Schmoll, Hans-Joachim; Seymour, Matthew T.; Adams, Richard; Saltz, Leonard; Goldberg, Richard M.; Punt, Cornelis J.A.; Douillard, Jean-Yves; Hoff, Paulo M.; Hecht, Joel Randolph; Hurwitz, Herbert; Díaz-Rubio, Eduardo; Porschen, Rainer; Tebbutt, Niall C.; Fuchs, Charles; Souglakos, John; Falcone, Alfredo; Tournigand, Christophe; Kabbinavar, Fairooz F.; Heinemann, Volker; Van Cutsem, Eric; Bokemeyer, Carsten; Buyse, Marc; Sargent, Daniel J.

    2015-01-01

    Purpose Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination. Methods Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti–epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R2 statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models. Results Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R2, 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy. Conclusion In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents. PMID:25385741

  11. Prospective Evaluation of First-Line Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Carrying an Activating EGFR Mutation: A Multicenter Academic Phase II Study in Caucasian Patients (FIELT)

    PubMed Central

    De Grève, Jacques; Van Meerbeeck, Jan; Vansteenkiste, Johan F.; Decoster, Lore; Meert, Anne-Pascale; Vuylsteke, Peter; Focan, Christian; Canon, Jean-Luc; Humblet, Yves; Berchem, Guy; Colinet, Benoit; Galdermans, Danny; Bosquée, Lionel; Vermeij, Joanna; Dewaele, Alex; Geers, Caroline; Schallier, Denis; Teugels, Erik

    2016-01-01

    Introduction Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibition is the preferred first-line treatment of advanced adenocarcinoma of the lung that harbors EGFR activating tyrosine kinase domain mutations. Most data available pertain to Asian populations in which such mutations are more prevalent. We report on the long-term results of first-line treatment with erlotinib in Caucasian patients with advanced adenocarcinoma of the lung that have a somatic EGFR mutation in their tumor. Methods Multicenter academic prospective phase II study with erlotinib in patients with an activating EGFR tyrosine kinase (TK) domain somatic mutation (any exon encoding the kinase domain) in the tumor and no prior treatment for their advanced disease. Results Phenotypic preselecting of 229 patients led to a high EGFR mutation detection rate of 24% of which 46 patients were included in the phase II study. With a progression free survival (PFS) of 81% at three months the study met its primary endpoint for presumed superiority over chemotherapy. With an overall median PFS of 11 months and a median overall survival (OS) of 23 months, the results compare favorably with results obtained in randomized studies using TKI in first line in EGFR mutation positive adenocarcinoma of the lung. Conclusion The present study reinforces the use of EGFR tyrosine kinase inhibition (TKI) as a first line treatment of choice for advanced adenocarcinoma of the lung carrying an activating EGFR mutation. The mutation rate in preselected Caucasian patients is higher than previously reported. Issues relevant for clinical practice are discussed. Trial Registration ClinicalTrials.gov NCT00339586 PMID:27032107

  12. Efficacy of Statin Monotherapy or in Combination With Coenzyme A Capsule in Patients With Metabolic Syndrome and Mixed Dyslipidemia

    PubMed Central

    Lai, Jiangtao; Wu, Bifeng; Xuan, Tianming; Xia, Shudong; Liu, Zhong; Chen, Junzhu

    2015-01-01

    Background Patients with metabolic syndrome are at increased risk for cardiovascular disease. Combination lipid-lowering therapy is often needed in patients with metabolic syndrome and mixed dyslipidemia. The aim of this study was to compare the effect of statin combined with a new hypolipidemic agent, coenzyme A (CoA) with moderate-dose statin monotherapy in subjects with metabolic syndrome and mixed dyslipidemia by evaluating data from a subgroup of patients with metabolic syndrome and mixed dyslipidemia from a previously conducted randomized study. Methods In the present post hoc analysis, 212 patients were included, receiving statin monotherapy (n = 94) or statin combined with CoA 400 U/day (n = 118) for 8 weeks. The lipoprotein profile was determined at baseline and week 8 visits. Attainment of low-density lipoprotein-cholesterol (LDL-C) < 100 mg/dL, non-high-density lipoprotein-cholesterol (HDL-C) < 130 mg/dL, and the combined goal of these two parameters was also evaluated. Results The mean percent change was more prominent with CoA plus statin compared with placebo plus statin in triglyceride (TG) (-32.5% vs. -8.7%, respectively; P = 0.0002), total cholesterol (-9.6% vs. -3.6%, P = 0.013), LDL-C (-7.5% vs. 2.1%, P = 0.033), and non-HDL-C (-14.3% vs. -6.4%, P = 0.011). Treatment with CoA plus statin resulted in larger percentages of participants attaining lipid goals for LDL-C (70.3% vs. 56.4%, P = 0.044), non-HDL-C (60.2% vs. 45.7%, P = 0.039), and the combined goal of LDL-C and non-HDL-C (57.6% vs. 42.6%, P = 0.038) than statin monotherapy. Conclusion These results demonstrate that CoA plus statin therapy was more effective in improving lipoprotein parameters than statin alone in patients with metabolic syndrome and mixed hyperlipidemia. PMID:25883708

  13. An Economic Evaluation of the Posttreatment Prophylactic Effect of Dihydroartemisinin-Piperaquine Versus Artemether-Lumefantrine for First-Line Treatment of Plasmodium falciparum Malaria Across Different Transmission Settings in Africa.

    PubMed

    Pfeil, Johannes; Borrmann, Steffen; Bassat, Quique; Mulenga, Modest; Talisuna, Ambrose; Tozan, Yesim

    2015-11-01

    Malaria disproportionately affects young children. Clinical trials in African children showed that dihydroartemisinin-piperaquine (DP) is an effective antimalarial and has a longer posttreatment prophylactic (PTP) effect against reinfections than other artemisinin-based combination therapies, including artemether-lumefantrine (AL). Using a previously developed Markov model and individual patient data from a multicenter African drug efficacy trial, we assessed the economic value of the PTP effect of DP versus AL in pediatric malaria patients from health-care provider's perspective in low-to-moderate and moderate-to-high transmission settings under different drug co-payment scenarios. In low-to-moderate transmission settings, first-line treatment with DP was highly cost-effective with an incremental cost-effectiveness ratio of US$5 (95% confidence interval [CI] = -76 to 196) per disability-adjusted life year (DALY) averted. In moderate-to-high transmission settings, DP first-line treatment led to a mean cost saving of US$1.09 (95% CI = -0.88 to 3.85) and averted 0.05 (95% CI = -0.08 to 0.22) DALYs per child per year. Our results suggested that DP might be superior to AL for first-line treatment of uncomplicated childhood malaria across a range of transmission settings in Africa. PMID:26240155

  14. A systematic review and mixed treatment comparison of monotherapy in early Parkinson's disease: implications for Latin America.

    PubMed

    Márquez-Cruz, Maribel; Díaz-Martínez, Juan Pablo; Soto-Molina, Herman; De Saráchaga, Adib Jorge; Cervantes-Arriaga, Amin; Llorens-Arenas, Rodrigo; Rodríguez-Violante, Mayela

    2016-01-01

    Parkinson's disease (PD) is the second most common neurodegenerative disease. There are no clinical trials comparing all available pharmacological therapies for the treatment of early PD. The objective of this review is to indirectly analyze the efficacy of antiparkinson drugs currently available in Latin America. A systematic review was performed exploring only placebo-controlled randomized trials comparing antiparkinson monotherapy (levodopa, pramipexole, rasagiline, or selegiline) in patients with PD on Hoehn and Yahr stages I through III published from January 1994 to May 2014. The primary outcome was the mean change in the Unified PD Rating Scale (UPDRS) I, II and III. A mixed treatment comparison analysis (indirect comparisons) through a random-effects model was performed. Levodopa demonstrated the highest effects in terms of UPDRS score improvement both from baseline and when compared to other treatments. Levodopa showed a 60.1% probability of granting the greatest reduction in UPDRS I, II and III. PMID:26731410

  15. Outcome of advanced chronic lymphocytic leukemia following different first-line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group (GCLLSG)

    PubMed Central

    Cramer, Paula; Isfort, Susanne; Bahlo, Jasmin; Stilgenbauer, Stephan; Döhner, Hartmut; Bergmann, Manuela; Stauch, Martina; Kneba, Michael; Lange, Elisabeth; Langerbeins, Petra; Pflug, Natali; Kovacs, Gabor; Goede, Valentin; Fink, Anna-Maria; Elter, Thomas; Fischer, Kirsten; Wendtner, Clemens-Martin; Hallek, Michael; Eichhorst, Barbara

    2015-01-01

    To evaluate the effect of first-line and subsequent therapies, the outcome of 1,558 patients with chronic lymphocytic leukemia from five prospective phase II/III trials conducted between 1999 and 2010 was analyzed. The 3-year overall survival rate was higher after first-line treatment with chemoimmunotherapies such as fludarabine/cyclophosphamide/rituximab (87.9%) or bendamustine/rituximab (90.7%) compared to chemotherapies without an antibody (fludarabine/cyclophosphamide: 84.6%; fludarabine: 77.5%; chlorambucil: 77.4%). Furthermore, the median overall survival was longer in patients receiving at least one antibody-containing regimen in any treatment line (94.4 months) compared to the survival in patients who never received an antibody (84.3 months, P<0.0001). Univariate Cox regression analysis demonstrated that patients who did receive antibody treatment had a 1.42-fold higher risk of death (hazard ratio, 1.42; 95% confidence interval: 1.185–1.694). Therapies administered at relapse were very heterogeneous. Only 55 of 368 patients (14.9%) who started second-line treatment >24 months after first-line therapy repeated the first-line regimen. Among 315 patients requiring treatment ≤24 months after first-line therapy, cyclophosphamide/doxorubicin/vincristine/prednisone with or without rituximab as well as alemtuzumab were the most commonly used therapies. In these early relapsing patients, the median overall survival was shorter following therapies containing an anthracycline and/or three or more cytotoxic agents (e.g. cyclophosphamide/doxorubicin/vincristine/prednisone or fludarabine/cyclophosphamide/mitoxantrone, 30.0 months) compared to single agent chemotherapy (e.g. fludarabine; 39.6 months) and standard chemoimmunotherapy (e.g. fludarabine/cyclophosphamide/rituximab: 61.6 months). In conclusion, the analysis confirms the superior efficacy of chemoimmunotherapies in patients with chronic lymphocytic leukemia. Moreover, the use of aggressive chemo

  16. Effect on intraocular pressure of switching from latanoprost and travoprost monotherapy to timolol fixed combinations in patients with normal-tension glaucoma.

    PubMed

    Igarashi, Ryoko; Togano, Tetsuya; Sakaue, Yuta; Yoshino, Takaiko; Ueda, Jun; Fukuchi, Takeo

    2014-01-01

    Purpose. To evaluate the effect on intraocular pressure (IOP) of switching from latanoprost and travoprost monotherapy to timolol fixed combinations in Japanese patients with normal-tension glaucoma (NTG). Methods. 27 NTG patients (54 eyes) were compared IOP, superficial punctuate keratitis (SPK) scores, and conjunctival injection scores in eyes treated with prostaglandin (PG) or PG analog/beta-blocker (PG/b) fixed-combination 6 months after the change in therapy. Results. The mean baseline intraocular pressure was 17.4 ± 1.59 mmHg in eyes receiving PG therapy only and 17.4 ± 1.69 mmHg in eyes switched to PG/b. Switching to fixed combination therapy from PG monotherapy, the mean IOP was 13.1 ± 1.79 mmHg (P < 0.001)  (-24.71% reduction from baseline) at 6 months. The mean conjunctival injection score was 0.69 for eyes on PG monotherapy and 0.56 for eyes on fixed combination therapy (P = 0.028). The mean SPK scores were 0.46 and 0.53. This difference was not statistically significant (P = 0.463). Conclusions. Switching from PG monotherapy to PG/b fixed combination therapy for NTG resulted in a greater intraocular pressure reduction than PG alone without increasing the number of instillations. PMID:25505978

  17. Respiratory failure and acalculous cholecystitis in a patient with AIDS and disseminated tuberculosis: masking effect of fluoroquinolone monotherapy and immune restoration syndrome.

    PubMed

    Chen, Po-Lin; Lee, Hsin-Chun; Shan, Yan-Shen; Ko, Nai-Ying; Lee, Nan-Yao; Chang, Chia-Ming; Wu, Chi-Jung; Lee, Ching-Chi; Ko, Wen-Chien

    2009-07-01

    The clinical presentation of Mycobacterium tuberculosis infection varies in patients with AIDS. We report a case of disseminated tuberculosis in an AIDS patient. The initial manifestation was masked by fluoroquinolone monotherapy, and subsequently complicated by acalculous cholecystitis and immune restoration syndrome after antiretroviral therapy. PMID:19008140

  18. Linagliptin and pioglitazone combination therapy versus monotherapy with linagliptin or pioglitazone: A randomised, double-blind, parallel-group, multinational clinical trial.

    PubMed

    Nauck, Michael Albrecht; di Domenico, Maximiliano; Patel, Sanjay; Kobe, Maureen; Toorawa, Robert; Woerle, Hans-Juergen

    2016-07-01

    Linagliptin plus pioglitazone single-pill combinations were evaluated. Patients (n = 936) with insufficient glycaemic control, despite lifestyle interventions, were randomised for 30 weeks to either monotherapy with linagliptin 5 mg; pioglitazone 15, 30 or 45 mg; or single-pill combination with linagliptin 5 mg plus pioglitazone 15, 30 or 45 mg. An extension (⩽54 weeks) planned to evaluate linagliptin plus pioglitazone 30 or 45 mg single-pill combinations was not completed due to a protocol amendment. Adjusted mean (95% confidence interval) differences in HbA1c change from baseline at week 30 for linagliptin plus pioglitazone 15, 30 and 45 mg were -0.17% (-0.41, 0.07), -0.37% (-0.60, -0.14) and -0.41% (-0.64, -0.18) versus pioglitazone monotherapies, respectively, and -0.44% (-0.67, -0.20), -0.68% (-0.91, -0.44) and -0.89% (-1.12, -0.66) versus linagliptin monotherapy, respectively. Single-pill combinations were generally well tolerated. Hypoglycaemia frequency was ⩽1.5% per group. Linagliptin plus pioglitazone combinations were efficacious, with safety profiles comparable to the individual monotherapies. PMID:27190087

  19. Efficacy and Tolerability of Telmisartan Plus Amlodipine in Asian Patients Not Adequately Controlled on Either Monotherapy or on Low-Dose Combination Therapy

    PubMed Central

    Zhu, Dingliang; Gao, Pingjin; Yagi, Nobutaka

    2014-01-01

    Objective. To evaluate the efficacy and safety of the telmisartan plus amlodipine (T/A) single-pill combination (SPC) in Asian patients with hypertension whose blood pressure (BP) was not adequately controlled on either monotherapy or on low-dose combination therapy. Patients and Methods. Data are presented from five Boehringer Ingelheim-sponsored phase 3, double-blind, 8-week, studies: two studies in nonresponders to amlodipine (data pooled for amlodipine), two studies on nonresponders to telmisartan (pooled data), and one on nonresponders to low-dose T/A SPC. Results. After 8 weeks' treatment, mean reductions from the reference baseline in diastolic BP (DBP; primary endpoint), systolic BP (SBP), and SBP, DBP goal, and response rates were higher with the T/A SPC than respective monotherapies. The T80/A5 SPC resulted in greater reductions in DBP and SBP, and higher DBP goal and response rate than the low-dose T40/A5 SPC. Peripheral edema incidence was low (amlodipine 0.5%, telmisartan 0.0%, and T/A SPC 0.7%). Discussion and Conclusion. In Asian patients whose BP is not adequately controlled with telmisartan or amlodipine monotherapy, T/A SPC treatment results in greater BP reduction, and higher DBP and SBP goal and response rates. The safety and tolerability of the T/A SPC are comparable to those of the respective monotherapies and consistent with those reported in previous studies. PMID:24719757

  20. Pharmacokinetics and pharmacodynamics of fosmidomycin monotherapy and combination therapy with clindamycin in the treatment of multidrug resistant falciparum malaria

    PubMed Central

    Na-Bangchang, Kesara; Ruengweerayut, Ronnatrai; Karbwang, Juntra; Chauemung, Anurak; Hutchinson, David

    2007-01-01

    Background The study investigated the pharmacokinetics of fosmidomycin when given alone and in combination with clindamycin in patients with acute uncomplicated falciparum malaria. Methods A total of 15 and 18 patients with acute uncomplicated Plasmodium falciparum malaria who fulfilled the enrollment criteria were recruited from out-patient department of Mae Sot Hospital, Tak Province, Thailand. Patients were treated with monotherapy with fosmidomycin at the dose of 1,200 mg every 8 hours for 7 days (n = 15) or combination therapy with fosmidomycin (900 mg every 12 hours for 7 days) and clindamycin (600 mg every 12 hours for 7 days) (n = 18). Blood samples were taken for pharmacokinetic investigations of clindamycin and/or fosmidomycin and 24-hour urine samples were collected during dosing period. Efficacy assessments included clinical and parasitological evaluation. Safety and tolerability were assessed based on clinical and laboratory investigations. Results Both mono- and combination therapy regimens of fosmidomycin were well tolerated with no serious adverse events. Combination therapy with fosmidomycin and clindamycin was proven highly effective with 100% cure rate, whereas cure rate of monotherapy was 22% (28-day follow up). Pharmacokientics of fosmidomycin following mono- and combination therapy were similar except Vz/F and CL/F, which were significantly smaller in the combination regimen. Plasma concentration-time profiles of both fosmidomycin and clindamycin were best fit with a one-compartment open model with first-order absorption and elimination and with absorption lag time. Steady-state plasma concentrations of fosmidomycin and clindamycin were attained at about the second or third dose. There was no evidence of dose accumulation during multiple dosing. Urinary recovery of fosmidomycin was 18.7 and 20% following mono- and combination therapy, respectively. Conclusion Pharmacokinetic dose optimization of fosmidomycin-clindamycin combination therapy

  1. A single-blinded phenobarbital-controlled trial of levetiracetam as mono-therapy in dogs with newly diagnosed epilepsy.

    PubMed

    Fredsø, N; Sabers, A; Toft, N; Møller, A; Berendt, M

    2016-02-01

    Treatment of canine epilepsy is problematic. Few antiepileptic drugs have proven efficacy in dogs and undesirable adverse effects and pharmacoresistance are not uncommon. Consequently, the need for investigation of alternative treatment options is ongoing. The objective of this study was to investigate the efficacy and tolerability of levetiracetam as mono-therapy in dogs with idiopathic epilepsy. The study used a prospective single-blinded parallel group design. Twelve client-owned dogs were included and were randomised to treatment with levetiracetam (30 mg/kg/day or 60 mg/kg/day divided into three daily dosages) or phenobarbital (4 mg/kg/day divided twice daily). Control visits were at days 30, 60 and then every 3 months for up to 1 year. Two or more seizures within 3 months led to an increase in drug dosage (levetiracetam: 10 mg/kg/day, phenobarbital: 1 mg/kg/day). Five of six levetiracetam treated dogs and one of six phenobarbital treated dogs withdrew from the study within 2-5 months due to insufficient seizure control. In the levetiracetam treated dogs there was no significant difference in the monthly number of seizures before and after treatment, whereas in the phenobarbital treated dogs there were significantly (P = 0.013) fewer seizures after treatment. Five phenobarbital treated dogs were classified as true responders (≥50% reduction in seizures/month) whereas none of the levetiracetam treated dogs fulfilled this criterion. Adverse effects were reported in both groups but were more frequent in the phenobarbital group. In this study levetiracetam was well tolerated but was not effective at the given doses as mono-therapy in dogs with idiopathic epilepsy. PMID:26639829

  2. Prevention of arterial thrombosis by edoxaban, an oral factor Xa inhibitor in rats: monotherapy and in combination with antiplatelet agents.

    PubMed

    Honda, Yuko; Kamisato, Chikako; Morishima, Yoshiyuki

    2016-09-01

    In addition to platelet aggregation, coagulation activation is considered to be involved in arterial thrombosis. In this study, we determined antithrombotic effects of edoxaban, an oral factor Xa (FXa) inhibitor, as both a monotherapy and in combination with antiplatelet agents in a rat model of arterial thrombosis. We further examined its effects on a procoagulant biomarker and bleeding. Arterial thrombosis was induced by topical application of 15% ferric chloride to rat abdominal aortas. Bleeding time was measured by a tail incision method. Edoxaban, clopidogrel, and aspirin were orally administered 30min, 4h, and 2h before thrombus or bleeding induction. As a biomarker of coagulation activation, plasma thrombin-antithrombin complex (TAT) was measured. Edoxaban dose-dependently prevented arterial thrombosis in a manner comparable to clopidogrel and aspirin. The combination of edoxaban plus clopidogrel or edoxaban plus aspirin significantly potentiated the antithrombotic effects compared with these drugs alone. The combination of edoxaban and clopidogrel was more potent than clopidogrel and aspirin. Plasma TAT concentration was elevated after thrombus induction and suppressed by edoxaban and clopidogrel, but not by aspirin, suggesting P2Y12 receptor-mediated platelet procoagulant activity. Bleeding time was prolonged by the coadministration of edoxaban and clopidogrel, but not by edoxaban and aspirin. In conclusion, the present study demonstrates that the monotherapy with edoxaban and combination therapy with edoxaban plus clopidogrel or edoxaban plus aspirin are promising options for the prevention of arterial thrombosis as effective as the standard antiplatelet agents; however, a combination of edoxaban and clopidogrel increased the risk of bleeding. PMID:27288116

  3. Outpatient treatment of low-risk venous thromboembolism with monotherapy oral anticoagulation: patient quality of life outcomes and clinician acceptance

    PubMed Central

    Kline, Jeffrey A; Kahler, Zachary P; Beam, Daren M

    2016-01-01

    Background Oral monotherapy anticoagulation has facilitated home treatment of venous thromboembolism (VTE) in outpatients. Objectives The aim of this study was to measure efficacy, safety, as well as patient and physician perceptions produced by a protocol that selected VTE patients as low-risk patients by the Hestia criteria, and initiated home anticoagulation with an oral factor Xa antagonist. Methods Patients were administered the Venous Insufficiency Epidemiological and Economic Study Quality of life/Symptoms questionnaire [VEINEs QoL/Sym] and the physical component summary [PCS] from the Rand 36-Item Short Form Health Survey [SF36]). The primary outcomes were VTE recurrence and hemorrhage at 30 days. Secondary outcomes compared psychometric test scores between patients with deep vein thrombosis (DVT) to those with pulmonary embolism (PE). Patient perceptions were abstracted from written comments and physician perceptions specific to PE outpatient treatment obtained from structured survey. Results From April 2013 to September 2015, 253 patients were treated, including 67 with PE. Within 30 days, 2/253 patients had recurrent DVT and 2/253 had major hemorrhage; all four had DVT at enrollment. The initial PCS scores did not differ between DVT and PE patients (37.2±13.9 and 38.0±12.1, respectively) and both DVT and PE patients had similar improvement over the treatment period (42.2±12.9 and 43.4±12.7, respectively), consistent with prior literature. The most common adverse event was menorrhagia, present in 15% of women. Themes from patient-written responses reflected satisfaction with increased autonomy. Physicians’ (N=116) before-to-after protocol comfort level with home treatment of PE increased 48% on visual analog scale. Conclusion Hestia-negative VTE patients treated with oral monotherapy at home had low rates of VTE recurrence and bleeding, as well as quality of life measurements similar to prior reports. PMID:27143861

  4. Ketanserin in essential hypertension: use as monotherapy and in combination with a diuretic or beta-adrenoceptor antagonist.

    PubMed Central

    Cameron, H A; Waller, P C; Ramsay, L E

    1987-01-01

    1. The antihypertensive efficacy and tolerability of twice-daily treatment with the 5-hydroxytryptamine antagonist ketanserin were examined in a double-blind, placebo-controlled trial of 7 weeks duration in 56 hypertensive patients. Twenty were untreated, 20 were already taking bendrofluazide 5 mg daily, and 16 were already taking atenolol 100 mg daily. Randomisation was stratified to compare ketanserin with placebo as monotherapy (n = 20), when added to bendrofluazide (n = 20), and when added to atenolol (n = 16). 2. The antihypertensive effect of ketanserin in all patients completing the study (mean daily dose 71 mg) was 10/6 mm Hg supine (P less than 0.01/P less than 0.01) and 6/6 mm Hg standing (NS/P less than 0.01) when blood pressure was measured 2 h after the morning dose. Responses were similar in patients taking ketanserin as monotherapy, in addition to bendrofluazide, and in addition to atenolol, with reductions in mean arterial pressure of 4.6, 7.4 and 8.9 mm Hg respectively. 3. Ketanserin had no antihypertensive effect when measured 14 h after the last dose. The rise in blood pressure between 2 and 14 h after dosing was 11/4 mm Hg supine (P less than 0.01/NS) and 8/5 mm Hg standing (P less than 0.05/P less than 0.05). 4. The antihypertensive response to ketanserin was positively related to initial blood pressure and, independent of this, to age. It was not related to plasma concentrations of ketanserin or ketanserinol. 5. Five of 28 patients taking ketanserin discontinued treatment because of side-effects, compared with one of 28 patients taking placebo.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2894215

  5. Ondansetron-droperidol combination vs. ondansetron or droperidol monotherapy in the prevention of postoperative nausea and vomiting

    PubMed Central

    Angelidi, Maria; Pandazi, Aggeliki; Tzirogiannis, Konstantinos N.; Panoutsopoulos, Georgios I.; Kostopanagiotou, Georgia

    2015-01-01

    Introduction Laparoscopic cholecystectomy is associated with a high incidence of postoperative nausea and vomiting. In this study we investigated comparatively the efficacy of combination therapy with ondansetron plus droperidol versus monotherapy with each agent alone in preventing postoperative nausea and vomiting following elective laparoscopic cholecystectomy. Material and methods One hundred twenty-seven patients who underwent elective laparoscopic cholecystectomy under general anesthesia were included in the study, and assigned to one of the following three groups according to the antiemetic drug given intravenously at the end of the surgery: droperidol 1.25 mg in group D, ondansetron 4 mg in group O, and a combination of droperidol and ondansetron at the doses mentioned above in group D + O. Incidence of postoperative nausea and vomiting, and doses of given rescue antiemetics were recorded during the first postoperative day. The total drug cost per patient spent for postoperative nausea and vomiting management (including prophylactic antiemetics plus rescue postoperative antiemetics) was calculated. Results Combination therapy significantly reduced postoperative nausea and vomiting at 30 min, 3 h and 6 h after surgery compared with group D (p < 0.01 for all time points) and O (p < 0.01 at 30 min, p < 0.05 at 3 h) and required less rescue antiemetic treatment (p < 0.01). Total antiemetic cost analyses revealed no significant differences among the three groups (p > 0.05). Conclusions Pretreatment with ondansetron plus droperidol is more effective than monotherapy in preventing postoperative nausea and vomiting following laparoscopic cholecystectomy, without increasing the cost comparatively. PMID:25995753

  6. Effects of either LT4 monotherapy or LT4/LT3 combined therapy in patients totally thyroidectomized for thyroid cancer.

    PubMed

    Regalbuto, Concetto; Maiorana, Raffaella; Alagona, Corradina; Paola, Roberto Di; Cianci, Michelangela; Alagona, Giovanna; Sapienza, Salvatore; Squatrito, Sebastiano; Pezzino, Vincenzo

    2007-04-01

    After total thyroidectomy all thyroid cancer patients require lifelong treatment with thyroid hormones; the treatment of choice is synthetic levothyroxine (LT4). The question of whether these patients might benefit from the combined LT4 and liothyronine (LT3) treatment has been addressed with conflicting conclusions. The aim of the present study was to compare the effects of combined low LT4/LT3 molar ratio therapy versus LT4 monotherapy on various target organs and tissues in patients thyroidectomized for thyroid cancer. Urine collection (24 hour), a fasting blood sample for laboratory examinations, thyroid function clinical score, and cardiovascular, neurological, and neuropsychological evaluations were obtained. Clinical parameters and peripheral markers of thyroid function were measured during the two different treatment regimens in 20 patients. Mean serum aspartate aminotransferase, alanine aminotransferase, sex hormone binding globulin, and osteocalcin values were significantly higher during the combined treatment. No significant differences in the clinical score, the systolic and diastolic performance, and the neurological and neuropsychological evaluations were observed between the two treatment regimens. Moreover, no alteration due to subclinical hyperthyroidism or to the fluctuations in serum T3 concentrations during the combined therapy was observed. In conclusion, we found no evidence that combined therapy with a low LT4/LT3 molar ratio resulted in improved well-being and cognitive function or in increased thyroid hormone action on peripheral tissues in respect to LT4 monotherapy. Until future large, blind, randomized, and controlled trials prove otherwise, LT4 should remain the standard treatment for thyroid cancer patients. PMID:17465862

  7. Antihypertensive efficacy and tolerability of aliskiren/amlodipine single- pill combinations in patients with an inadequate response to aliskiren monotherapy.

    PubMed

    Glorioso, Nicola; Thomas, Mathew; Troffa, Chiara; Argiolas, Giuseppe; Patel, Samir; Baek, Inyoung; Zhang, Jack

    2012-11-01

    Many patients with hypertension will require multiple antihypertensive drugs to achieve blood pressure (BP) control. This double-blind study evaluated the efficacy and safety of aliskiren/amlodipine single-pill combinations (SPCs) in patients with mild-to-moderate hypertension who were non-responsive to aliskiren monotherapy. After a 4-week run-in with aliskiren 300 mg, patients with mean sitting diastolic BP (msDBP) ≥ 90 and < 110 mmHg were randomized to oncedaily aliskiren/ amlodipine 300/10 mg or 300/5 mg, or aliskiren 300 mg for 8 weeks. Aliskiren/amlodipine SPCs provided significantly greater mean reductions in mean sitting systolic BP/msDBP (300/10 mg, 18.0/13.1 mmHg; 300/5 mg, 14.4/10.5 mmHg) than aliskiren 300 mg (6.4/5.8 mmHg) at week 8 endpoint. This represents additional mean reductions of 11.6/7.2 mmHg (300/10 mg) and 8.0/4.7 mmHg (300/5 mg) over aliskiren alone (both p < 0.0001). Significantly more patients achieved BP control ( < 140/90 mmHg) with aliskiren/amlodipine 300/10 mg (65.5%) and 300/5 mg (56.6%) than with aliskiren (31.5% both p < 0.0001). Aliskiren, alone and in combination with amlodipine, was well tolerated, with a slightly higher incidence of adverse events with SPCs (29.0-30.1%) than with monotherapy (22.7%). In conclusion, aliskiren/amlodipine SPCs offer an effective next step for patients who have an inadequate BP response to aliskiren alone. PMID:22303910

  8. Comparison of the efficacy of anti-VEGF monotherapy versus PDT and intravitreal anti-VEGF combination treatment in AMD: a Meta-analysis and systematic review

    PubMed Central

    Tong, Yao; Zhao, Ke-Ke; Feng, Dong; Biswal, Manas; Zhao, Pei-Quan; Wang, Zhao-Yang; Zhang, Yun

    2016-01-01

    AIM To compare the effect of anti-vascular endothelial growth factor (VEGF) monotherapy versus photodynamic therapy (PDT) and anti-VEGF combination treatment in age-related macular degeneration (AMD). METHODS A computerized online search was performed using PubMed, Web of Science and the Cochrane Library. Studies that compared anti-VEGF monotherapy with PDT and anti-VEGF combination treatment of AMD and were designed as randomized controlled trials were included. The means and standard deviations of the best-corrected visual acuity (BCVA), central retinal thickness (CRT), number of treatments and proportions of patients who gained BCVA ≥15, 10, 5, or 0 letters at 12th month were extracted. A systematic review and Meta-analysis of the comparison of the two approaches was conducted using Review Manager 5.2. Subgroup. A sensitivity analysis was also performed. RESULTS Eight studies were included. When the subgroup and sensitivity analysis was conducted, the results indicated that in the findings that included the monotherapy group and PDT (standard fluence, SF) group of Kaiser's study, the patients in the monotherapy group had a better BCVA compared with the combination group at 12th month in the PDT (SF) subgroup [weighted mean difference (WMD): 3.54; 95%CI: 0.36 to 6.73; P=0.03], and there were more patients who gained ≥15 letters of BCVA in the monotherapy group compared with the combination group in the total result [odds ratio (OR): 1.41; 95%CI: 1.02 to 1.95; P=0.04]. The same conclusion was obtained in the total result that included the monotherapy group and PDT (reduced fluence, RF) group of Kaiser's study (OR: 1.56; 95%CI: 1.13 to 2.15; P=0.007). However, there were no significant differences in the other indexes between the two therapies. CONCLUSION We found that anti-VEGF monotherapy is more effective on the recovery of visual acuity than combination therapy and more researches with lager sample size should be performed to study on the effect of the two

  9. Meta-analysis of the efficacy and safety of adding an angiotensin receptor blocker (ARB) to a calcium channel blocker (CCB) following ineffective CCB monotherapy

    PubMed Central

    Ma, Jin; Wang, Xiao-Yan; Hu, Zhi-De; Zhou, Zhi-Rui; Schoenhagen, Paul

    2015-01-01

    Background We conducted this meta-analysis to systematically review and analyze the clinical benefits of angiotensin receptor blocker (ARB) combined with calcium channel blocker (CCB) following ineffective CCB monotherapy. Methods PubMed was searched for articles published until August 2015. Randomized controlled trials (RCTs) evaluating the clinical benefits of ARB combined with CCB following ineffective CCB monotherapy were included. The primary efficacy endpoint of the studies was normal rate of blood pressure, the secondary efficacy endpoints were the response rate and change in blood pressure from baseline. The safety endpoint of the studies was incidence of adverse events. Differences are expressed as relative risks (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and weighted mean differences (WMDs) with 95% CIs for continuous outcomes. Heterogeneity across studies was tested by using the I2 statistic. Results Seven RCTs were included and had sample sizes ranging from 185 to 1,183 subjects (total: 3,909 subjects). The pooled analysis showed that the on-target rate of hypertension treatment was significantly higher in the amlodipine + ARB group than in the amlodipine monotherapy group (RR =1.59; 95% CI, 1.31–1.91; P<0.01). The response rate of systolic blood pressure (SBP) (RR =1.28; 95% CI, 1.04–1.58; P<0.01) and diastolic blood pressure (DBP) (RR =1.27; 95% CI, 1.12–1.44; P=0.04) were significantly higher in the amlodipine + ARB group than in the amlodipine monotherapy group. The change in SBP (RR =−3.56; 95% CI, −7.76–0.63; P=0.10) and DBP (RR =−3.03; 95% CI, −6.51–0.45; P=0.09) were higher in hypertensive patients receiving amlodipine + ARB but the difference did not reach statistical significance. ARB + amlodipine treatment carried a lower risk of adverse events relative to amlodipine monotherapy (RR =0.88; 95% CI, 0.80-0.96; P<0.01). Conclusions The results of our meta-analysis demonstrate that adding an ARB to CCB

  10. Valsartan 160 mg/Amlodipine 5 mg Combination Therapy versus Amlodipine 10 mg in Hypertensive Patients with Inadequate Response to Amlodipine 5 mg Monotherapy

    PubMed Central

    Sung, Jidong; Jeong, Jin-Ok; Kwon, Sung Uk; Won, Kyung Heon; Kim, Byung Jin; Cho, Byung Ryul; Kim, Myeong-Kon; Lee, Sahng; Kim, Hak Jin; Lim, Seong-Hoon; Park, Seung Woo

    2016-01-01

    Background and Objectives When monotherapy is inadequate for blood pressure control, the next step is either to continue monotherapy in increased doses or to add another antihypertensive agent. However, direct comparison of double-dose monotherapy versus combination therapy has rarely been done. The objective of this study is to compare 10 mg of amlodipine with an amlodipine/valsartan 5/160 mg combination in patients whose blood pressure control is inadequate with amlodipine 5 mg. Subjects and Methods This study was conducted as a multicenter, open-label, randomized controlled trial. Men and women aged 20-80 who were diagnosed as having hypertension, who had been on amlodipine 5 mg monotherapy for at least 4 weeks, and whose daytime mean systolic blood pressure (SBP) ≥135 mmHg or diastolic blood pressure (DBP) ≥85 mmHg on 24-hour ambulatory blood pressure monitoring (ABPM) were randomized to amlodipine (A) 10 mg or amlodipine/valsartan (AV) 5/160 mg group. Follow-up 24-hour ABPM was done at 8 weeks after randomization. Results Baseline clinical characteristics did not differ between the 2 groups. Ambulatory blood pressure reduction was significantly greater in the AV group compared with the A group (daytime mean SBP change: -14±11 vs. -9±9 mmHg, p<0.001, 24-hour mean SBP change: -13±10 vs. -8±8 mmHg, p<0.0001). Drug-related adverse events also did not differ significantly (A:AV, 6.5 vs. 4.5 %, p=0.56). Conclusion Amlodipine/valsartan 5/160 mg combination was more efficacious than amlodipine 10 mg in hypertensive patients in whom monotherapy of amlodipine 5 mg had failed. PMID:27014353

  11. Optimized combination therapies with adefovir dipivoxil (ADV) and lamivudine, telbivudine, or entecavir may be effective for chronic hepatitis B patients with a suboptimal response to ADV monotherapy

    PubMed Central

    Li, Xiangyong; Jie, Yusheng; You, Xu; Shi, Hong; Zhang, Min; Wu, Yuankai; Lin, Guoli; Li, Xinhua; Gao, Zhiliang; Chong, Yutian

    2015-01-01

    Objective: To identify high risk factors in chronic hepatitis B (CHB) patients for suboptimal response to adefovir dipivoxil (ADV) monotherapy, and to assess the efficacy of optimized therapy combining ADV with lamivudine (LAM), telbivudine (LdT), or entecavir (ETV) in patients with a suboptimal response to ADV alone. Methods: Suboptimal response to ADV monotherapy was defined as having a decline in serum hepatitis B virus (HBV) DNA level of more than 1 log compared to baseline, but with viremia still detectable (HBV DNA ≥ 100 IU/mL), after 48 weeks of therapy. All patients who received ADV monotherapy in our clinic were analyzed retrospectively. Both univariate and multivariate logistic regression models were applied for risk factor analysis. Patients who showed suboptimal response completed at least 12 months of optimized combination therapy consisting of ADV plus LAM, ADV plus LdT, ADV plus ETV, or continuous ADV monotherapy. The primary outcome measurement was complete viral suppression, indicated by a reduction of HBV DNA to undetectable levels (CVS, with HBV DNA < 100 IU/mL). Secondary outcome measures were HBeAg seroconversion for HBeAg-positive patients, HBsAg loss, alanine aminotransferase (ALT) normalization and virological breakthrough rates. Results: Of 521 patients who received ADV monotherapy, 170 showed a suboptimal response. These were grouped for continued therapy as follows: 34 in group A (continuous ADV monotherapy), 55 in group B (ADV plus LAM), 38 in group C (ADV plus LdT), and 43 in group D (ADV plus ETV). Using a logistic model, five conditions were identified as high risk factors for suboptimal response: presence of the tyrosine-methionine-aspartate-aspartate (YMDD) HBV DNA polymerase mutation; being HBeAg positive; having a high baseline level of HBV DNA; having a primary virological non-response to ADV; and [initial virological response] to ADV. After 48 weeks of ADV monotherapy, there were no withdrawn patients who had experienced side

  12. Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRTI-based ART: a multicohort European case–control study using centralized ultrasensitive 454 pyrosequencing

    PubMed Central

    Cozzi-Lepri, Alessandro; Noguera-Julian, Marc; Di Giallonardo, Francesca; Schuurman, Rob; Däumer, Martin; Aitken, Sue; Ceccherini-Silberstein, Francesca; D'Arminio Monforte, Antonella; Geretti, Anna Maria; Booth, Clare L.; Kaiser, Rolf; Michalik, Claudia; Jansen, Klaus; Masquelier, Bernard; Bellecave, Pantxika; Kouyos, Roger D.; Castro, Erika; Furrer, Hansjakob; Schultze, Anna; Günthard, Huldrych F.; Brun-Vezinet, Francoise; Paredes, Roger; Metzner, Karin J.; Paredes, Roger; Metzner, Karin J.; Cozzi-Lepri, Alessandro; Schuurman, Rob; Brun-Vezinet, Francoise; Günthard, Huldrych; Ceccherini-Silberstein, Francesca; Kaiser, Rolf; Geretti, Anna Maria; Brockmeyer, Norbert; Masquelier, Bernard; Dabis, F.; Bruyand, M.; Chêne, G.; Dabis, F.; Lawson-Ayayi, S.; Thiébaut, R.; Wittkop, L.; André, K.; Bonnal, F.; Bonnet, F.; Bernard, N.; Caunègre, L.; Cazanave, C.; Ceccaldi, J.; Chossat, I.; Courtaud, K.; Dauchy, F. A.; De Witte, S.; Dupon, M.; Dupont, A.; Duffau, P.; Dutronc, H.; Farbos, S.; Gaborieau, V.; Gemain, M. C.; Gerard, Y.; Greib, C.; Hessamfar, M.; Lacoste, D.; Lataste, P.; Lazaro, E.; Longy-Boursier, M.; Malvy, D.; Meraud, J. P.; Mercié, P.; Monlun, E.; Morlat, P.; Neau, D.; Ochoa, A.; Pellegrin, J. L.; Pistone, T.; Receveur, M. C.; Schmeltz, J. Roger; Tchamgoué, S.; Vandenhende, M. A.; Vareil, M.O.; Viallard, J. F.; Moreau, J. F.; Pellegrin, I.; Fleury, H.; Lafon, M. E.; Masquelier, B.; Reigadas, S.; Trimoulet, P.; Bouchet, S.; Breilh, D.; Molimard, M.; Titier, K.; Haramburu, F.; Miremont-Salamé., G.; Blaizeau, M. J.; Decoin, M.; Delaune, J.; Delveaux, S.; D'Ivernois, C.; Hanapier, C.; Leleux, O.; Lenaud, E.; Uwamaliya-Nziyumvira, B.; Sicard, X.; Geffard, S.; Le Marec, F.; Conte, V.; Frosch, A.; Leray, J.; Palmer, G.; Touchard, D.; Bonnet, F.; Breilh, D.; Chêne, G.; Dabis, F.; Dupon, M.; Fleury, H.; Malvy, D.; Mercié, P.; Morlat, P.; Neau, D.; Pellegrin, I.; Pellegrin, J. L.; Bouchet, S.; Gaborieau, V.; Lacoste, D.; Tchamgoué, S.; Thiébaut, R.; Losso, M.; Kundro, M.; Ramos Mejia, J. M.; Vetter, N.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Suetnov, O.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Kostov, K.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Nielsen, J.; Kronborg, G.; Benfield, T.; Larsen, M.; Gerstoft, J.; Katzenstein, T.; Hansen, A.-B. E.; Skinhøj, P.; Pedersen, C.; Ostergaard, L.; Dragsted, U. B.; Nielsen, L. N.; Zilmer, K.; Smidt, Jelena; Ristola, M.; Katlama, C.; Viard, J. P.; Girard, P. M.; Vanhems, P.; Pradier, C.; Dabis, F.; Neau, D.; Duvivier, C.; Rockstroh, J.; Schmidt, R.; van Lunzen, J.; Degen, O.; Stellbrink, H. J.; Bickel, M.; Bogner, J.; Fätkenheuer, G.; Kosmidis, J.; Gargalianos, P.; Xylomenos, G.; Perdios, J.; Sambatakou, H.; Banhegyi, D.; Gottfredsson, M.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Pollack, S.; HassounRambam, G.; Elinav, H.; HaouziHadassah, M.; EspositoI, R.; Mazzotta, F.; Vullo, V.; Moroni, M.; Andreoni, M.; Angarano, G.; Antinori, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; von Schloesser, F.; Viale, P.; Monforte, A. D'Arminio; Antinori, A.; Castagna, A.; Ceccherini-Silberstein, F.; Cozzi-Lepri, A.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Andreoni, M.; Ammassari, A.; Antinori, A.; Balotta, C.; Bonfanti, P.; Bonora, S.; Borderi, M.; Capobianchi, M. R.; Castagna, A.; Ceccherini-Silberstein, F.; Cingolani, A.; Cinque, P.; Cozzi-Lepri, A.; De Luca, A.; Di Biagio, A.; Girardi, E.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Lo Caputo, S.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Mussini, C.; Puoti, M.; Quiros Roldan, E.; Rusconi, S.; Cozzi-Lepri, A.; Cicconi, P.; Fanti, I.; Formenti, T.; Galli, L.; Lorenzini, P.; Carletti, F.; Carrara, S.; Castrogiovanni, A.; Di Caro, A.; Petrone, F.; Prota, G.; Quartu, S.; Giacometti, A.; Costantini, A.; Mazzoccato, S.; Angarano, G.; Monno, L.; Santoro, C.; Maggiolo, F.; Suardi, C.; Viale, P.; Vanino, E.; Verucchi, G.; Castelli, F.; Quiros Roldan, E.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Lo Caputo, S.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Bonfanti, P.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Galli, M.; Lazzarin, A.; Rizzardini, G.; Puoti, M.; D'Arminio Monforte, A.; Ridolfo, A. L.; Piolini, R.; Castagna, A.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Marchetti, G.; Mussini, C.; Puzzolante, C.; Gori, A.

    2015-01-01

    Objectives It is still debated if pre-existing minority drug-resistant HIV-1 variants (MVs) affect the virological outcomes of first-line NNRTI-containing ART. Methods This Europe-wide case–control study included ART-naive subjects infected with drug-susceptible HIV-1 as revealed by population sequencing, who achieved virological suppression on first-line ART including one NNRTI. Cases experienced virological failure and controls were subjects from the same cohort whose viraemia remained suppressed at a matched time since initiation of ART. Blinded, centralized 454 pyrosequencing with parallel bioinformatic analysis in two laboratories was used to identify MVs in the 1%–25% frequency range. ORs of virological failure according to MV detection were estimated by logistic regression. Results Two hundred and sixty samples (76 cases and 184 controls), mostly subtype B (73.5%), were used for the analysis. Identical MVs were detected in the two laboratories. 31.6% of cases and 16.8% of controls harboured pre-existing MVs. Detection of at least one MV versus no MVs was associated with an increased risk of virological failure (OR = 2.75, 95% CI = 1.35–5.60, P = 0.005); similar associations were observed for at least one MV versus no NRTI MVs (OR = 2.27, 95% CI = 0.76–6.77, P = 0.140) and at least one MV versus no NNRTI MVs (OR = 2.41, 95% CI = 1.12–5.18, P = 0.024). A dose–effect relationship between virological failure and mutational load was found. Conclusions Pre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART. PMID:25336166

  13. Can EGFR-TKIs be used in first line treatment for advanced non-small cell lung cancer based on selection according to clinical factors ? -- A literature-based meta-analysis

    PubMed Central

    2012-01-01

    Background In the first line treatment of non-small cell lung cancer (NSCLC), several clinical trials have shown that not all NSCLC patients can benefit from treatment with tyrosine kinase inhibitors (TKIs) than receiving chemotherapy. Some trials treated patients with TKI according to their clinical characteristics. A few studies only chose patients with an epidermal grouth factor receptor (EGFR) mutation for TKI therapy. We aimed to determine whether patients could be treated with TKIs based on clinical factors in the first-line setting. Methods We performed a meta-analysis of randomized trials involving patients with advanced NSCLC treated with chemotherapy or TKIs by different selections. Efficacy outcomes of interest were the objective response rate (ORR), progression-free survival (PFS) and the overall survival (OS) of each treatment arm. Results Four trials enrolled unselected patients, and two trials selected East Asian patients using the clinical factors of gender and smoking history. Five trials chose patients with an EGFR mutation who were randomized for treatment with TKI or chemotherapy. For unselected patients, the risk ratio (RR) of the ORR was 3.52, the hazard ratio (HR) of the PFS was 1.29 and the HR of the OS was 1.35. For the clinically selected patients, the RR of the ORR was 0.64. The HRs of the PFS and OS were 0.83 and 0.92, respectively. The ORR and PFS were better for TKIs than for chemotherapy in patients with an EGFR mutation. The ORR was 0.47, and the HRs of the PFS and OS were 0.36 and 1.00, respectively. Conclusions Advanced NSCLC patients with an EGFR mutation benefit most from TKIs. EGFR-TKI treatment is justified for patients with unknown EGFR status,and those who cannot tolerate chemotherapy owing to age, poor performance status (PS) or other medical conditions, when selected according to clinical factors in the first-line setting. PMID:23050865

  14. Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomised placebo controlled trial

    PubMed Central

    Gerards, A; Landewe, R; Prins, A; Bruijn, G; Goei, T; Laan, R; Dijkmans, B

    2003-01-01

    Patients and methods: 120 patients with active RA, rheumatoid factor positive and/or erosive, were randomly allocated to receive CsA with MTX (n=60) or CsA with placebo (n=60). Treatment with CsA was started in all patients at 2.5 mg/kg/day and increased to a maximum of 5 mg/kg/day in 16 weeks. MTX was started at 7.5 mg/week and increased to a maximal dose of 15 mg/week at week 16. Primary outcomes were clinical remission (Pinals criteria) and radiological damage (Larsen score), at week 48. Results: Treatment was discontinued prematurely in 27 patients in the monotherapy group (21 because of inefficacy, and six because of toxicity) and in 26 patients in the combination therapy group (14 and 12, respectively). At week 48, clinical remission was achieved in four patients in the monotherapy group and in six patients in the combination therapy group (p=0.5). The median Larsen score increased to 10 (25th, 75th centiles: 3.5; 13.3) points in the monotherapy group and to 4 (1.0; 10.5) points in the combination therapy group (p=0.004). 28/60 (47%) of patients in the monotherapy group v 34/60 (57%) of patients in the combination therapy group had reached an American college of Rheumatology 20% (ACR20) response (p=0.36) at week 48; 15/60 (25%) v 29/60 (48%) of patients had reached an ACR50 response (p=0.013); and 7 (12%) v 12 (20%) of patients had reached an ACR70 response (p=0.11).Their was a tendency towards more toxicity in the combination therapy group. Conclusions: In patients with early RA, neither CsA plus MTX combination therapy nor CsA monotherapy is very effective in inducing clinical remission. Combination therapy is probably better at improving clinical disease activity, and definitely better at slowing radiological progression. Combination therapy should still be compared with methotrexate monotherapy. PMID:12634224

  15. Efficacy of Intravenous Immunoglobulin Monotherapy in Patients with Cutaneous Lupus Erythematosus: Results of Proof-of-Concept Study.

    PubMed

    Ky, Christa; Swasdibutra, Brian; Khademi, Shaadi; Desai, Sheetal; Laquer, Vivian; Grando, Sergei A

    2015-03-16

    Cutaneous lupus erythematosus (CLE) is a chronic inflammatory autoimmune skin disease. Evidence-based therapy for CLE is lacking in the most part. Intravenous immunoglobulin (IVIg) is being increasingly utilized as off-label therapy for a variety of autoimmune and inflammatory conditions, especially in dermatology. The usefulness of IVIg in CLE is not well established. The goal of the present study was to obtain the proof-of-concept evidence that IVIg can control acute CLE and thus replace current systemic immunosuppressive therapy that causes severe side effects and adverse reactions. Sixteen patients who tried and failed various systemic treatments for CLE were screened and consented to use IVIg as a monotherapy. The IVIg was administered at 500 mg/kg/day on 4 consecutive days up to a total of 2 g/kg/month for 3 months, and the subjects were monitored for additional 6 months off any drug for a possible relapse. The cumulative results revealed an overall improvement, as evinced by a decrease of both objective and subjective measures of disease activity. The most sensitive and specific objective and subjective instruments for assessment of the therapeutic effect of IVIg were CLASI-A (Cutaneous Lupus Erythematosus Disease Area and Severity Index) measuring disease activity and Skindex-29 scores, respectively. The CLASI-A score dropped down from the initial value taken as 100%, and remained in the range of approximately 70% until the last visit. Three patients (18.8%) had a temporary flare of CLE symptoms but recovered within a month from the relapse. No serious side effects and adverse reactions occurred. Thus, IVIg monotherapy in CLE allowed to achieve: i) rapid and persistent decreased in disease activity; ii) steady improvement of patients' quality of life assessed by Skindex-29; iii) low relapse rate; and iv) mild nature and short duration of relapses. Since healing was maintained for months after IVIg treatment, it is possible that the IVIgtriggered molecular

  16. Atheroprotective lipoprotein effects of a niacin-simvastatin combination compared to low- and high-dose simvastatin monotherapy

    PubMed Central

    Airan-Javia, Subha L.; Wolf, Ronald L.; Wolfe, Megan L.; Tadesse, Mahlet; Mohler, Emile; Reilly, Muredach P.

    2011-01-01

    Background Niacin has multiple lipoprotein effects that may provide cardiovascular benefit when added to statin monotherapy. Methods In this randomized, placebo-controlled trial (n = 75) of magnetic resonance imaging of carotid atherosclerosis, we performed a secondary comparison of combination niacin-statin (simvastatin 20 mg/Niacin-ER 2G [S20/N]) to monotherapy with moderate (20 mg [S20]) and high-dose (80 mg [S80]) simvastatin on lipids, apolipoproteins (apo), low density lipoprotein (LDL) and high density lipoprotein (HDL) particle subclasses, and inflammatory markers. Results At baseline, average age was 71, 72% were male, 62.5% used statins, and average LDL-cholesterol was 111 mg/dL. At 12 months, S20/N, compared to S80, significantly reduced apoB (−36.6% vs −11.9%; P = .05) and lipoprotein(a) (−18% vs +3.5%; P = .001) and had at least an equivalent effect on LDL-cholesterol (−39.3% vs −24.3%; P = .24). The combination reduced the proportion of subjects with atherogenic LDL pattern-B (50% to 11.5%) compared to S80 (56% to 56%) (P = .01). Despite increases in plasma free fatty acids (+62.4%; F = 5.65, P = .005 vs S20 and S80), plasma triglycerides (−29.4%; F = 6.88, P = .002 vs S20 and S80), and very-low-density lipoprotein (−44.2%; F = 7.94, P < .001 vs S20 and S80), levels were reduced by S20/N. S20/N increased HDL-cholesterol levels (+18.1%) as compared to S20 (0%) and S80 (+5.9%) (P < .001 vs both statin arms), largely due to an increase in HDL particle size (+4.6%; P = .01 vs both statin arms). Conclusions We demonstrate that full-dose niacin/moderate-dose simvastatin combination has sustained benefits on atherogenic apoB lipoproteins, at least comparable to high-dose simvastatin, while also raising HDL-cholesterol. Results of large clinical trials will inform whether niacin-statin combinations reduce cardiovascular disease events. PMID:19332196

  17. High-Dose-Rate Brachytherapy as a Monotherapy for Favorable-Risk Prostate Cancer: A Phase II Trial

    SciTech Connect

    Barkati, Maroie; Williams, Scott G.; Foroudi, Farshad; Tai, Keen Hun; Chander, Sarat; Dyk, Sylvia van; See, Andrew; Duchesne, Gillian M.

    2012-04-01

    Purpose: There are multiple treatment options for favorable-risk prostate cancer. High-dose-rate (HDR) brachytherapy as a monotherapy is appealing, but its use is still investigational. A Phase II trial was undertaken to explore the value of such treatment in low-to-intermediate risk prostate cancer. Methods and Materials: This was a single-institution, prospective study. Eligible patients had low-risk prostate cancer features but also Gleason scores of 7 (51% of patients) and stage T2b to T2c cancer. Treatment with HDR brachytherapy with a single implant was administered over 2 days. One of four fractionation schedules was used in a dose escalation study design: 3 fractions of 10, 10.5, 11, or 11.5 Gy. Patients were assessed with the Common Terminology Criteria for Adverse Events version 2.0 for urinary toxicity, the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scoring schema for rectal toxicity, and the Expanded Prostate Cancer Index Composite (EPIC) questionnaire to measure patient-reported health-related quality of life. Biochemical failure was defined as a prostate-specific antigen (PSA) nadir plus 2 ng/ml. Results: Between 2003 and 2008, 79 patients were enrolled. With a median follow-up of 39.5 months, biochemical relapse occurred in 7 patients. Three- and 5-year actuarial biochemical control rates were 88.4% (95% confidence interval [CI], 78.0-96.2%) and 85.1% (95% CI, 72.5-94.5%), respectively. Acute grade 3 urinary toxicity was seen in only 1 patient. There was no instance of acute grade 3 rectal toxicity. Rates of late grade 3 rectal toxicity, dysuria, hematuria, urinary retention, and urinary incontinence were 0%, 10.3%, 1.3%, 9.0%, and 0%, respectively. No grade 4 or greater toxicity was recorded. Among the four (urinary, bowel, sexual, and hormonal) domains assessed with the EPIC questionnaire, only the sexual domain did not recover with time. Conclusions: HDR brachytherapy as a monotherapy for favorable

  18. Efficacy of Intravenous Immunoglobulin Monotherapy in Patients with Cutaneous Lupus Erythematosus: Results of Proof-of-Concept Study

    PubMed Central

    Ky, Christa; Swasdibutra, Brian; Khademi, Shaadi; Desai, Sheetal; Laquer, Vivian; Grando, Sergei A.

    2015-01-01

    Cutaneous lupus erythematosus (CLE) is a chronic inflammatory autoimmune skin disease. Evidence-based therapy for CLE is lacking in the most part. Intravenous immunoglobulin (IVIg) is being increasingly utilized as off-label therapy for a variety of autoimmune and inflammatory conditions, especially in dermatology. The usefulness of IVIg in CLE is not well established. The goal of the present study was to obtain the proof-of-concept evidence that IVIg can control acute CLE and thus replace current systemic immunosuppressive therapy that causes severe side effects and adverse reactions. Sixteen patients who tried and failed various systemic treatments for CLE were screened and consented to use IVIg as a monotherapy. The IVIg was administered at 500 mg/kg/day on 4 consecutive days up to a total of 2 g/kg/month for 3 months, and the subjects were monitored for additional 6 months off any drug for a possible relapse. The cumulative results revealed an overall improvement, as evinced by a decrease of both objective and subjective measures of disease activity. The most sensitive and specific objective and subjective instruments for assessment of the therapeutic effect of IVIg were CLASI-A (Cutaneous Lupus Erythematosus Disease Area and Severity Index) measuring disease activity and Skindex-29 scores, respectively. The CLASI-A score dropped down from the initial value taken as 100%, and remained in the range of approximately 70% until the last visit. Three patients (18.8%) had a temporary flare of CLE symptoms but recovered within a month from the relapse. No serious side effects and adverse reactions occurred. Thus, IVIg monotherapy in CLE allowed to achieve: i) rapid and persistent decreased in disease activity; ii) steady improvement of patients’ quality of life assessed by Skindex-29; iii) low relapse rate; and iv) mild nature and short duration of relapses. Since healing was maintained for months after IVIg treatment, it is possible that the IVIgtriggered molecular

  19. Trastuzumab as a preoperative monotherapy does not inhibit HER2 downstream signaling in HER2-positive breast cancer

    PubMed Central

    Lion, Maëva; Harlé, Alexandre; Salleron, Julia; Ramacci, Carole; Campone, Mario; Merlin, Jean-Louis

    2016-01-01

    Human epidermal growth factor 2 (HER2) is overexpressed in 15–20% of breast carcinomas. The overexpression of HER2 was previously associated with a poor prognosis until the development of the first anti-HER2 therapy, trastuzumab, which drastically improves the prognosis of HER2-overexpressing breast cancers. However, its mechanism of action remains not fully understood. Several studies have proposed that the behavior and mechanism of action of trastuzumab may be drastically altered in vitro and in vivo. The present study assesses the ability of trastuzumab to inhibit the phosphorylation of the key-proteins of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin and Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways in vitro, in breast cancer cell lines and in tumor biopsies obtained from patients treated with trastuzumab preoperative monotherapy as part of the Unicancer GEP04 RADHER phase II clinical trial. HER2-positive SKBR3 and HER2-negative MCF-7 cell lines were exposed to trastuzumab for 72 h. In total, 41 patients received trastuzumab alone for 6 weeks of preoperative treatment. Biopsies were collected at the baseline and at surgery. A total of 19 pairs of associated baseline and surgery tumor specimens were eligible for protein extraction and comparative phosphoprotein expression analysis, prior to and subsequent to treatment. The expression of phosphoproteins was quantitatively assessed using a multiplex immunoassay. In the SKBR3 cell line, a statistically significant decrease of the expression level of phosphorylated (p-)AKT, p-ribosomal protein S6 kinase B1, p-extracellular signal regulated kinase 1/2 and p-mitogen-activated protein kinase kinase 1 was observed after exposure to trastuzumab. In contrast, no statistically significant variations for levels expression of these phosphoproteins were observed in patients following treatment. The lack of downregulation of PI3K and MAPK pathways could probably

  20. GATA3 mRNA expression, but not mutation, associates with longer progression-free survival in ER-positive breast cancer patients treated with first-line tamoxifen for recurrent disease.

    PubMed

    Liu, Jingjing; Prager-van der Smissen, Wendy J C; Look, Maxime P; Sieuwerts, Anieta M; Smid, Marcel; Meijer-van Gelder, Marion E; Foekens, John A; Hollestelle, Antoinette; Martens, John W M

    2016-06-28

    In breast cancer, GATA3 mutations have been associated with a favorable prognosis and the response to neoadjuvant aromatase inhibitor treatment. Therefore, we investigated whether GATA3 mutations predict the outcome of tamoxifen treatment in the advanced setting. In a retrospective study consisting of 235 hormone-naive patients with ER-positive breast cancer who received tamoxifen as first-line treatment for recurrent disease, GATA3 mutations (in 14.0% of patients) did not significantly associate with either the overall response rate (ORR) or with the length of progression-free survival (PFS) after the start of tamoxifen therapy. Interestingly, among 148 patients for whom both mutation and mRNA expression data were available, GATA3 mutations associated with an increased expression of GATA3. However, only 23.7% of GATA3 high tumors had a mutation. Evaluation of the clinical significance of GATA3 mRNA revealed that it was associated with prolonged PFS, but not with the ORR, also in multivariate analysis. Thus, GATA3 mRNA expression, but not GATA3 mutation, is an independent predictor of prolonged PFS in ER-positive breast cancer patients who received first-line tamoxifen for recurrent disease. Besides GATA3 mutation, other mechanisms must exist that underlie increased GATA3 levels. PMID:27018307

  1. Comparative Metabolomic Profiling of Hepatocellular Carcinoma Cells Treated with Sorafenib Monotherapy vs. Sorafenib-Everolimus Combination Therapy

    PubMed Central

    Zheng, Jian-feng; Lu, Juan; Wang, Xiao-zhong; Guo, Wu-hua; Zhang, Ji-xiang

    2015-01-01

    Background Sorafenib-everolimus combination therapy may be more effective than sorafenib monotherapy for hepatocellular carcinoma (HCC). To better understand this effect, we comparatively profiled the metabolite composition of HepG2 cells treated with sorafenib, everolimus, and sorafenib-everolimus combination therapy. Material/Methods A 2D HRMAS 1H-NMR metabolomic approach was applied to identify the key differential metabolites in 3 experimental groups: sorafenib (5 μM), everolimus (5 μM), and combination therapy (5 μM sorafenib +5 μM everolimus). MetaboAnalyst 3.0 was used to perform pathway analysis. Results All OPLS-DA models displayed good separation between experimental groups, high-quality goodness of fit (R2), and high-quality goodness of predication (Q2). Sorafenib and everolimus have differential effects with respect to amino acid, methane, pyruvate, pyrimidine, aminoacyl-tRNA biosynthesis, and glycerophospholipid metabolism. The addition of everolimus to sorafenib resulted in differential effects with respect to pyruvate, amino acid, methane, glyoxylate and dicarboxylate, glycolysis or gluconeogenesis, glycerophospholipid, and purine metabolism. Conclusions Sorafenib and everolimus have differential effects on HepG2 cells. Sorafenib preferentially affects glycerophospholipid and purine metabolism, while the addition of everolimus preferentially affects pyruvate, amino acid, and glucose metabolism. This phenomenon may explain (in part) the synergistic effects of sorafenib-everolimus combination therapy observed in vivo. PMID:26092946

  2. High dose rate brachytherapy as monotherapy for localised prostate cancer: a hypofractionated two-implant approach in 351 consecutive patients

    PubMed Central

    2013-01-01

    Background To report the clinical outcome of high dose rate brachytherapy as sole treatment for clinically localised prostate cancer. Methods Between March 2004 and January 2008, a total of 351 consecutive patients with clinically localised prostate cancer were treated with transrectal ultrasound guided high dose rate brachytherapy. The prescribed dose was 38.0 Gy in four fractions (two implants of two fractions each of 9.5 Gy with an interval of 14 days between the implants) delivered to an intraoperative transrectal ultrasound real-time defined planning treatment volume. Biochemical failure was defined according to the Phoenix Consensus and toxicity evaluated using the Common Toxicity Criteria for Adverse Events version 3. Results The median follow-up time was 59.3 months. The 36 and 60 month biochemical control and metastasis-free survival rates were respectively 98%, 94% and 99%, 98%. Toxicity was scored per event with 4.8% acute Grade 3 genitourinary and no acute Grade 3 gastrointestinal toxicity. Late Grade 3 genitourinary and gastrointestinal toxicity were respectively 3.4% and 1.4%. No instances of Grade 4 or greater acute or late adverse events were reported. Conclusions Our results confirm high dose rate brachytherapy as safe and effective monotherapy for clinically organ-confined prostate cancer. PMID:23656899

  3. Combined Iron Chelator and Antioxidant Exerted Greater Efficacy on Cardioprotection Than Monotherapy in Iron-Overloaded Rats

    PubMed Central

    Wongjaikam, Suwakon; Kumfu, Sirinart; Khamseekaew, Juthamas; Sripetchwandee, Jirapas; Srichairatanakool, Somdet; Fucharoen, Suthat; Chattipakorn, Siriporn C.; Chattipakorn, Nipon

    2016-01-01

    Background Iron chelators are used to treat iron overload cardiomyopathy patients. However, a direct comparison of the benefits of three common iron chelators (deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX)) or an antioxidant (N-acetyl cysteine (NAC)) with a combined DFP and NAC treatments on left ventricular (LV) function with iron overload has not been investigated. Methods and Findings Male Wistar rats were fed with either a normal diet or a high iron diet (HFe group) for 4 months. After 2 months, the HFe-fed rats were divided into 6 groups to receive either: a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day) or the combined DFP and NAC for 2 months. Our results demonstrated that HFe rats had increased plasma non-transferrin bound iron (NTBI), malondialdehyde (MDA), cardiac iron and MDA levels and cardiac mitochondrial dysfunction, leading to LV dysfunction. Although DFO, DFP, DFX or NAC improved these parameters, leading to improved LV function, the combined DFP and NAC therapy caused greater improvement, leading to more extensively improved LV function. Conclusions The combined DFP and NAC treatment had greater efficacy than monotherapy in cardioprotection through the reduction of cardiac iron deposition and improved cardiac mitochondrial function in iron-overloaded rats. PMID:27428732

  4. Polymyxin B in Combination with Antimicrobials Lacking In Vitro Activity versus Polymyxin B in Monotherapy in Critically Ill Patients with Acinetobacter baumannii or Pseudomonas aeruginosa Infections.

    PubMed

    Rigatto, Maria Helena; Vieira, Fabiane J; Antochevis, Laura C; Behle, Tainá F; Lopes, Natane T; Zavascki, Alexandre P

    2015-10-01

    There is no clinical evidence supporting the use of polymyxin B in combination with another antimicrobial for infections caused by extensively drug-resistant Acinetobacter baumannii or Pseudomonas aeruginosa isolates. We developed a cohort study of patients in two intensive care units from teaching hospitals to evaluate treatment with intravenous polymyxin B for ≥48 h for severe A. baumannii or P. aeruginosa infections. Covariates potentially associated with 30-day mortality were evaluated in a Cox proportional hazards model. A total of 101 patients were included; 33 (32.7%) were treated with polymyxin B in combination with an antimicrobial lacking in vitro activity and 68 (67.3%) with polymyxin B in monotherapy. The overall 30-day mortality was 59.4% (60 patients), comprising 42.4% (14 of 33) and 67.6% (46 of 68) in combination and monotherapy groups, respectively (P = 0.03). The mortality rates were 18.5/1,000 patient days and 36.4/1,000 patient days in the combination and monotherapy groups, respectively (P = 0.02). Combination therapy was independently associated with lower 30-day mortality (hazard ratio, 0.33; 95% confidence interval, 0.17 to 0.64; P = 0.001). Creatinine clearance of ≥60 ml/min was also a protective factor, while a higher acute physiology and chronic health evaluation (APACHE II) score and polymicrobial infection were associated with increased mortality. The results did not change after adding a propensity score for prescribing combination therapy into the model. The protective effect remained when only combination with β-lactam or carbapenem was considered and in both subgroups of patients: those with A. baumannii infection and those with lower respiratory tract infections. To our knowledge, this is the first clinical study to show a benefit of combination over monotherapy with polymyxin B for severe extensively drug-resistant A. baumannii or P. aeruginosa infections. PMID:26259799

  5. Short Communication: Efficacy and Safety of Treatment Simplification to Lopinavir/Ritonavir or Darunavir/Ritonavir Monotherapy: A Randomized Clinical Trial.

    PubMed

    Santos, José R; Llibre, Josep M; Bravo, Isabel; García-Rosado, Dácil; Cañadas, Mari Paz; Pérez-Álvarez, Nuria; Paredes, Roger; Clotet, Bonaventura; Moltó, José

    2016-05-01

    Antiretroviral treatment simplification strategies based on monotherapy with darunavir/ritonavir (DRV/r) or lopinavir/ritonavir (LPV/r) have not been directly compared in clinical trials. We evaluated the 48-week efficacy and safety of DRV/r versus LPV/r monotherapy as a treatment simplification strategy in a multicenter, randomized open-label study. Maintenance of viral suppression in cerebrospinal fluid (CSF) and semen was also explored. An intention to treat efficacy analysis was performed considering missing equals to failure (ITT:M = F). Virological failure (VF) was defined as a confirmed increase in plasma HIV-1 RNA >50 copies/mL. A total of 75 patients were enrolled: 40 were allocated to DRVr and 33 to LPVr. In the ITT: M = F analysis, 77.5% of patients on DRV/r and 66.6% of patients on LPV/r maintained HIV-1 RNA <50 copies/mL at week 48 (p = .302, treatment difference 10.8% [95% CI,-12.6 to 34.2]). In the DRV/r arm, no patients developed VF and 15.0% discontinued treatment due to adverse events. In the LPV/r arm, 2 (6.1%) patients developed VF and 18.2% discontinued monotherapy due to adverse events. Gastrointestinal disturbances were experienced by 18.2% and 2.5% of patients in the LPV/r and DRV/r arms, respectively (p = .019). Two patients had detectable HIV-1 RNA ≥50 copies/mL in CSF or semen. Monotherapy with LPV/r or DRV/r seems to be virologically effective in selected HIV-1-infected patients with sustained viral suppression. Differences between both regimens seem driven mainly by the better tolerability profile of DRV/r. PMID:26781004

  6. Effectiveness of Duloxetine Monotherapy Compared to Combination Therapy with Other Antidepressants in Patients with Major Depressive Disorder: A Short-Term, Retrospective Study

    PubMed Central

    Cheon, Eun-Jin; Lee, Jun-Yeob; Choi, Joong-Hyeon; Lee, Young-Ji

    2016-01-01

    Objective The purpose of this study was to compare duloxetine monotherapy to combination therapy with other antidepressants in patients with major depressive disorder in a clinical, real world setting. Methods An eight-week, retrospective, multi-center study of outpatients with major depressive disorder was undertaken. After screening 415 patients, enrolled in this study from July 2009 to June 2014 were 82 patients from among three centers who had been taking duloxetine with or without other antidepressant and not administered with atypical antipsychotics. We compared the mean changes of the Clinical Global Impression-Severity Scale (CGI-S) as a primary measure and the discontinuation rate as a secondary measure between the duloxetine monotherapy group (n=36, 43.9%) and the combination therapy with other antidepressants group (n=46, 56.1%) at baseline, one, two, four and eight weeks. Results There were no significant differences across the demographic characteristics between two groups. There was, however, a statistically greater improvement on the CGI-S at weeks 2, 4 and 8 in the combination group compared with the monotherapy group. There were no significant differences in discontinuation rate and adverse events between two groups. No serious adverse events were reported in both groups during the study period. Conclusion This result suggests that the duloxetine combination therapy with other antidepressants could improve effectiveness and have comparable tolerability with the monotherapy in the treatment of outpatients with major depressive disorders in a naturalistic setting. Adequately powered, well-controlled clinical trials are strongly warranted to confirm our findings due to methodological shortcomings. PMID:27482247

  7. Differences in the efficacy of S-1 monotherapy according to histological type in pretreated patients with advanced non-small cell lung cancer

    PubMed Central

    Hisamatsu, Yasushi; Murakami, Haruyasu; Akamatsu, Hiroaki; Kimura, Madoka; Mori, Keita; Imai, Hisao; Ono, Akira; Shukuya, Takehito; Taira, Tetsuhiko; Kenmotsu, Hirotsugu; Naito, Tateaki; Endo, Masahiro; Nakajima, Takashi; Takahashi, Toshiaki; Yamamoto, Nobuyuki

    2014-01-01

    Background S-1 is a novel antimetabolic agent that inhibits thymidylate synthase. The expression of thymidylate synthase is higher in squamous (Sq) non-small cell lung cancer (NSCLC) than in non-Sq NSCLC. The aim of this retrospective study was to assess the efficacy of S-1 monotherapy for advanced NSCLC according to the histological subtype. Methods We reviewed the clinical records of patients with advanced NSCLC treated with S-1 monotherapy as second- or third-line therapy between May 2005 and July 2012 at the Shizuoka Cancer Center. Results A total of 71 patients were included in this retrospective study. Patient characteristics were similar in the Sq NSCLC (n = 15) and non-Sq NSCLC (n = 56) groups, except with regard to gender and smoking status. The overall response rates were 0% (95% confidence interval [CI] 0–17%) for Sq NSCLC and 11% (95% CI 3–19%) for non-Sq NSCLC (P = 0.33). For Sq NSCLC and non-Sq NSCLC, the median progression-free survival times were 2.1 and 2.8 months (P = 0.02), respectively, and the median overall survival times were 6.1 and 10.1 months (P = 0.01), respectively. Conclusion S-1 monotherapy may be more effective in patients with non-Sq NSCLC than in those with Sq NSCLC. PMID:26766988

  8. Combined treatment with low-dose interferon plus vinblastine is associated with less toxicity than conventional interferon monotherapy in patients with metastatic renal cell carcinoma.

    PubMed

    Tsavaris, N; Skarlos, D; Bacoyiannis, C; Aravantinos, G; Kosmas, C; Retalis, G; Panopoulos, C; Vadiaka, M; Dimitrakopoulos, A; Kostantinidis, K; Mitropoulos, D; Bougas, D; Pantazopoulos, D; Kosmidis, P

    2000-08-01

    The outcome of treatment of advanced renal cell carcinoma is disappointing. In interferon (IFN)-treated patients, the high incidence of adverse effects causes many patients to withdraw from treatment. This 12-week randomized study compared the incidence of toxicity associated with high-dose IFN monotherapy (15 x 10(6) U thrice weekly) and treatment with the combination of low-dose IFN (5 x 10(6) U thrice weekly) and 6 mg/m2 vinblastine (VBL) every 14 days in 100 consecutive patients. There was no significant difference in response rate between treatment arms (42% IFN vs. 34% IFN + VBL) or between subgroups (by tumor location). Combined treatment was associated with a significantly lower incidence of fever, fatigue, and weight loss but with a higher incidence of leukopenia. There was no significant difference in the incidence of other events. More patients treated with IFN monotherapy required bed rest, and overall treatment costs were 60% higher than for combined treatment. It is concluded that combined treatment with low-dose IFN and VBL, without loss of short-term efficacy, is better tolerated and less expensive than high-dose IFN monotherapy. PMID:10954911

  9. Real-world hospital costs for nonchemotherapy drugs and nondrug care associated with platinum-based doublets in the first-line setting for advanced nonsquamous non-small-cell lung cancer in Chinese patients: a retrospective cohort study

    PubMed Central

    Chen, Jianhua; Wu, Shengqi; Hu, Chenping; Yang, Yicheng; Rajan, Narayan; Chen, Yun; Yang, Canjuan; Li, Jianfeng; Chen, Wendong

    2016-01-01

    Objective The objective of this study was to compare hospital costs per treatment cycle (HCTC) for nonchemotherapy drugs and nondrug care associated with platinum-based doublets in the first-line setting for advanced nonsquamous non-small-cell lung cancer (AdvNS-NSCLC) in Chinese patients. Methods Patients receiving platinum-based doublets in the first-line setting for AdvNS-NSCLC from 2010 to 2012 in two Chinese tertiary hospitals were identified to create the retrospective study cohort. Propensity score methods were used to create matched treatment groups for head-to-head comparisons on HCTC between pemetrexed–platinum and other platinum-based doublets. Multiple linear regression analyses were performed to rank studied platinum-based doublets for their associations with the log10 scale of HCTC for nonchemotherapy drugs and nondrug care. Results Propensity score methods created matched treatment groups for pemetrexed–platinum versus docetaxel–platinum (61 pairs), paclitaxel–platinum (39 pairs), gemcitabine–platinum (93 pairs), and vinorelbine–platinum (73 pairs), respectively. Even though the log10 scale of HCTC for nonchemotherapy drugs and nondrug care associated with pemetrexed–platinum was ranked lowest in all patients (coefficient −0.174, P=0.015), which included patients experiencing any hematological adverse events (coefficient −0.199, P=0.013), neutropenia (coefficient −0.426, P=0.021), or leukopenia (coefficient −0.406, P=0.001), pemetrexed–platinum had the highest total HCTC (median difference from RMB 1,692 to RMB 7,400, P<0.001) among platinum-based do