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1.
Factors involved in early lenvatinib dose reduction: a retrospective analysis.
Suyama, K, Tomiguchi, M, Takeshita, T, Sueta, A, Yamamoto-Ibusuki, M, Shimokawa, M, Yamamoto, Y, Iwase, H
Medical oncology (Northwood, London, England). 2018;(3):19
Abstract
Lenvatinib, a multi-tyrosine kinase inhibitor, has been proven to be an effective treatment option for patients with iodine-131-refractory thyroid cancer. Many adverse effects of lenvatinib have been reported; thus, dose reduction is common. However, a few studies have analyzed the causes of lenvatinib dose reduction in daily clinical practice. Here, we investigate the factors involved in early lenvatinib dose reduction to analyze lenvatinib dose modification. We analyzed 20 thyroid cancer patients who began receiving lenvatinib at the Kumamoto University Hospital Cancer Center from July 2015 to November 2016. Patients were classified into the following groups based on the time until first withdrawal or dose reduction in lenvatinib: group A (early, ≤ 10 days) and group B (other, > 10 days). Patients' clinical features and reasons for withdrawal or dose reduction were analyzed. The age range of patients was 54-91 years, and the median observation period was 293 days. There were no significant differences in the administered line of lenvatinib; the presence/absence of primary residual tumors; or the history of hypertension, proteinuria, and diarrhea between the two groups (A, n = 7; B, n = 13). The cause for initial withdrawal or dose reduction was grade 3 hypertension in all group A patients, which was significantly higher than that in group B (p = 0.0001). Our results suggest that early blood pressure control may be effective as a method to maintain the lenvatinib dose intensity.
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Early prediction of lenvatinib treatment efficacy by using 18F-FDG PET/CT in patients with unresectable or advanced thyroid carcinoma that is refractory to radioiodine treatment: a protocol for a non-randomized single-arm multicenter observational study.
Takeuchi, S, Shiga, T, Hirata, K, Taguchi, J, Magota, K, Ariga, S, Gouda, T, Ohhara, Y, Homma, R, Shimizu, Y, et al
BMJ open. 2018;(8):e021001
Abstract
INTRODUCTION Lenvatinib, an oral molecular targeted drug, is used to treat patients with unresectable or advanced thyroid carcinoma that is refractory to radioiodine treatment. Effective methods for evaluating molecular targeted drugs are a critical unmet need owing to their expensive costs and unique adverse events. The aim of this study is to determine whether 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT at 1 week after commencing lenvatinib can predict treatment outcomes. DESIGN AND METHODS This study is planned as a non-randomised single-arm multicentre study; patients with pathologically confirmed differentiated thyroid carcinoma (DTC) with lesions that are refractory to radioiodine treatment are eligible. The main exclusion criteria are medullary or anaplastic carcinoma, prior treatment with chemotherapy, poor general condition and thromboembolism-requiring treatment. Patients to be included in the study will be treated with lenvatinib and undergo FDG-PET/CT examination twice: before and 1 week after the initiation of treatment. Contrast-enhanced CT, the gold standard for evaluation, will be performed at least 4 weeks after the initiation of treatment. The primary objective is to evaluate the ability of the lesion maximum standard uptake value for FDG PET/CT performed 1 week after the initiation of treatment to predict outcomes compared with the response evaluation obtained via contrast-enhanced CT performed at least 4 weeks after the initiation of treatment. ETHICS AND DISSEMINATION This study is conducted in accordance with the Declaration of Helsinki and has received ethical approval from the institutional review board of the Hokkaido University Hospital (approval number: 015-402). The results of this study will be disseminated through a presentation at a conference and the publication of the data in a peer-reviewed journal. The study will be implemented and reported in line with the SPIRIT statement. TRIAL REGISTRATION NUMBER UMIN000022592.
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Rationale and Design of Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) Trial.
Miyauchi, K, Kimura, T, Shimokawa, H, Daida, H, Iimuro, S, Iwata, H, Ozaki, Y, Sakuma, I, Nakagawa, Y, Hibi, K, et al
International heart journal. 2018;(2):315-320
Abstract
Large-scale clinical trials in patients in Western countries with coronary artery disease (CAD) have found that aggressive lipid-lowering therapy using high-dose statins reduces cardiovascular (CV) events further than low-dose statins. However, such evidence has not yet been fully established in Asian populations, including in Japan. The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study addresses whether intensification of statin therapy improves clinical outcomes in Japanese patients with CAD.REAL-CAD is a prospective, multicenter, randomized, open-label, blinded-endpoint, physician-initiated phase 4 trial in Japan. The study will recruit up to 12,600 patients with stable CAD. Patients are assigned to receive either pitavastatin 1 mg/day or pitavastatin 4 mg/day. LDL-C levels are expected to reach approximate mean values of 100 mg/dL in the low-dose pitavastatin group and 80 mg/dL in the high-dose group. The primary endpoint is the time to occurrence of a major CV event, including CV death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization during an average of 5 years. The large number of patients and the long follow-up period in the REAL-CAD study should ensure that there is adequate power to definitively determine if reducing LDL-C levels to approximately 80 mg/dL by high-dose statin can provide additional clinical benefit.After the study is completed, we will have categorical evidence on the optimal statin dose and target LDL-C level for secondary prevention in Japanese patients.
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Optimisation of treatment with lenvatinib in radioactive iodine-refractory differentiated thyroid cancer.
Capdevila, J, Newbold, K, Licitra, L, Popovtzer, A, Moreso, F, Zamorano, J, Kreissl, M, Aller, J, Grande, E
Cancer treatment reviews. 2018;:164-176
Abstract
Lenvatinib has been approved for the treatment of advanced differentiated thyroid cancer (DTC) refractory to radioactive iodine (RAI) following the results of the SELECT trial which demonstrated a significant increase in progression-free survival and a high response rates. The data reported for lenvatinib in RAI-refractory DTC (RAI-R DTC) are the most significant to date in this patient population, with a RECIST objective response rate above 60% and almost 80% reduction in the risk of disease progression. Because the first indication in oncology for lenvatinib is specifically in RAI-R DTC, a period of familiarisation with its safety and efficacy profile is required. This review includes a series of specific recommendations for optimising the management of RAI-R DTC with lenvatinib, as well as specific guidelines for minimising the incidence and severity of adverse events (AEs), which enable dose intensity to be increased and this way maximise the benefits of the drug in the patient population treated. These recommendations were defined at a meeting of experts of different specialities, reviewing available scientific evidence on the drug, as well as their own direct personal experience in daily clinical practice. For toxicity to be properly managed, a multidisciplinary approach is required in which the different medical services, nursing staff and the patient and their careers are all involved. It is essential to assess the suitability of patients who are candidates for lenvatinib, as well as their clinical and physiological status prior to treatment. They must then be closely monitored to prevent and detect possible AEs. The main objective should be to maintain the dose that obtains the maximum therapeutic effect, discontinuing the treatment only if the toxicity becomes unmanageable or there is no clinical benefit.
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Phenotyping patients with chronic cough: Evaluating the ability to predict the response to anti-inflammatory therapy.
Sadeghi, MH, Wright, CE, Hart, S, Crooks, M, Morice, A
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2018;(3):285-291
Abstract
BACKGROUND Whether the fraction of exhaled nitric oxide (FeNO) measurement can predict the response to anti-inflammatory treatment in chronic cough is unknown. OBJECTIVE To explore whether the effectiveness of treatment with 10 mg of montelukast or 20 mg of prednisolone in patients with chronic cough is predicted by FeNO level. METHODS In this randomized, open-label, controlled pilot study conducted in the Clinical Trial Unit in Castle Hospital in the United Kingdom, 50 nonsmoking patients with a cough that lasted more than 8 weeks were sequentially enrolled in the study. Thirty patients with high FeNO levels (≥30 ppb) were randomized in a 1:1 ratio to receive 10 mg of montelukast or 20 mg of prednisolone for 2 weeks followed by 10 mg of montelukast for 2 weeks. Twenty patients with a low FeNO level (≤20 ppb) received 10 mg of montelukast. The primary objective was to determine the effectiveness of treatment on 24-hour cough counts. RESULTS The 24-hour cough counts decreased in both groups by approximately 50% (P < .005), indicating that FeNO did not predict treatment response. However, it was a good marker for eosinophilic inflammation with a high degree of correlation with blood and sputum eosinophilia (P < .001). CONCLUSION These results suggest that prior investigation may not predict response to anti-inflammatory treatment, which may be consequent on localized leukotriene-mediated inflammation. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02479074.
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Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer.
Gerber, DE, Socinski, MA, Neal, JW, Wakelee, HA, Shirai, K, Sequist, LV, Rosovsky, RP, Lilenbaum, RC, Bastos, BR, Huang, C, et al
Lung cancer (Amsterdam, Netherlands). 2018;:44-49
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Abstract
BACKGROUND KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P < 0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC). MATERIALS AND METHODS Previously treated patients with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360 mg twice daily) plus erlotinib (150 mg daily) (ET) or single-agent chemotherapy (investigator's choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted. RESULTS Ninety-six patients were randomly assigned to ET (n = 51) or to C (n = 45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95% CI, 0.71-1.97; P = 0.50). There was no difference in overall survival (HR 1.20; 95% CI, 0.76-1.88; P = 0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm. CONCLUSION In previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single-agent chemotherapy.
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Question 2: Is there a role for Montelukast in the management of viral-induced wheeze in preschool children?
Burman, A
Archives of disease in childhood. 2018;(5):519-520
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Comparison of the efficacy and mechanisms of intranasal budesonide, montelukast, and their combination in treatment of patients with seasonal allergic rhinitis.
Chen, H, Lou, H, Wang, Y, Cao, F, Zhang, L, Wang, C
International forum of allergy & rhinology. 2018;(11):1242-1252
Abstract
BACKGROUND Although intranasal steroids and anti-cysteinyl-leukotriene-receptor antagonists are efficacious in the treatment of seasonal allergic rhinitis (SAR), combinations of these agents have not unequivocally been demonstrated to be superior to the individual drugs. We aimed to compare the efficacy and potential mechanisms of budesonide nasal spray (BD), oral montelukast (MNT), and combination therapy comprising a half-dose of budesonide plus montelukast (hBD+MNT) in SAR patients. METHODS We performed a single-center, randomized, open-label study in SAR subjects (n = 100). Participants were randomized to receive BD (256 μg), MNT (10 mg), or hBD (128 μg)+MNT for 14 days. Symptom severity scores, nasal cavity volume (NCV), fraction of exhaled nitric oxide (FeNO), eosinophil cationic protein (ECP), histamine and cysteinyl-leukotrienes (CysLTs), and T-cell subsets were assessed before and after treatment. RESULTS All treatments significantly improved symptoms from baseline; however, hBD+MNT produced significantly greater improvements in nasal congestion compared with BD or MNT alone. The BD and hBD+MNT groups had fewer patients with uncontrolled symptoms and improved NCV to a greater level than the MNT group. FeNO was decreased to a significantly greater extent from baseline after hBD+MNT treatment than after BD and MNT treatments. ECP, histamine, and CysLTs showed significantly greater decreases after BD and hBD+MNT treatments than after MNT treatment. BD decreased T-helper 1 (Th1) and Th2 cells and increased T-regulatory (Treg) cells in nasal mucosa and MNT decreased Th1 cells and increased Treg cells in peripheral blood, and this trend was reflected with hBD+MNT. CONCLUSION The hBD+MNT combination may have an overall better efficacy profile than BD and MNT monotherapy for treatment of SAR.
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Predictive Value of Baseline High-Sensitivity C-Reactive Protein Level and Renal Function for Patients With Acute Coronary Syndrome Undergoing Aggressive Lipid-Lowering Therapy: A Subanalysis of HIJ-PROPER.
Kawada-Watanabe, E, Yamaguchi, J, Kanbayashi, K, Sekiguchi, H, Arashi, H, Ogawa, H, Hagiwara, N
The American journal of cardiology. 2018;(11):1817-1823
Abstract
The systematic inflammatory response might confound renal impairment, and both have been reported to affect clinical outcomes after acute coronary syndrome. We examined the impacts of the high-sensitivity C-reactive protein (hsCRP) level and estimated glomerular filtration rate level on the prognosis for acute coronary syndrome patients who underwent aggressive lipid-lowering therapy in contemporary practice. This was a subanalysis of the HIJ-PROPER study, and 1,734 patients were enrolled. Patients were divided into 4 groups using an hsCRP value of 10mg/L and an estimated glomerular filtration rate value of 60 ml/min/1.73 m2 as the cut-off points. Groups were defined as follows: group A, low hsCRP and normal or mild renal impairment; group B, low hsCRP and renal impairment; group C, high hsCRP and normal or mild renal impairment; and group D, high hsCRP and renal impairment. The primary end point was defined as the composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina or coronary revascularizations. The median follow-up period was 3.9years, and the follow-up rate was 99%. Compared with group A, the 2 higher hsCRP groups (groups C and D) showed a significantly higher incidence of primary end points (hazard ratio 1.36, 95% confidence interval 1.12 to 1.65, p = 0.002; and hazard ratio 1.40, 95% CI 1.10 to 1.80, p = 0.008). Such a difference was not found compared with group B. In conclusion, patients with higher hsCRP levels had worse prognoses regardless of renal impairment and aggressive lipid-lowering therapy.
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Treatment with montelukast and antidepressive medication-a symmetry analysis.
Winkel, JS, Damkier, P, Hallas, J, Henriksen, DP
Pharmacoepidemiology and drug safety. 2018;(12):1409-1415
Abstract
PURPOSE Leukotriene receptor antagonists are used in asthma and rhinitis treatment. Pharmacovigilance data have suggested an association between montelukast and depression, but the association has not been established in controlled study designs. We described the association between initiation of montelukast and depression, using prescriptions of antidepressants as a surrogate marker, and assessed whether the association was related to the underlying asthma disease. METHODS We performed a symmetry analysis, with a study period from January 1, 2000 to December 31, 2016, using 3 nationwide Danish registers. We included all adults, who filled their first prescription of montelukast and antidepressants within an interval of 1 year. In the absence of an association between montelukast and antidepressant use, a symmetrical distribution of prescriptions is expected before and after montelukast initiation (ie, a sequence ratio [rc ] of 1.0). We subcategorized the subjects after the severity of underlying asthma disease. RESULTS In total, 4450 subjects filled their first prescriptions of both montelukast and antidepressants within a 1-year interval: 2434 redeemed their first prescription of montelukast before antidepressants, and 2016 redeemed the medications in the opposite order (rc 1.21 [95% CI 1.14-1.28]). We found rc above unity in groups with long-acting asthma treatment, but no increase in antidepressant prescription, when stratifying by the asthma severity. CONCLUSION We found a weak association between the use of montelukast and the risk of being prescribed an antidepressant, unlikely to be of clinical relevance. Stratified analyses suggest that this association may relate to asthma, rather than to montelukast.