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Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer.
Reed, N, Glen, H, Gerrard, G, Good, J, Lei, M, Lyon, AR, Strachan, M, Wadsley, J, Newbold, K
Clinical oncology (Royal College of Radiologists (Great Britain)). 2020;(5):e145-e153
Abstract
AIMS: Lenvatinib is an oral multi-kinase inhibitor approved for the treatment of adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma refractory to radioactive iodine. MATERIALS AND METHODS A literature review was undertaken to inform the development of consensus-based guidance for the routine management of adverse events associated with lenvatinib. PubMed was searched on 24 October 2017; the search terms were 'lenvatinib' and 'thyroid cancer'. RESULTS Hypertension, diarrhoea, weight loss, skin toxicities and cardiovascular adverse events were considered. For grade 1/2 diarrhoea, initial treatment should be loperamide with a 1-week treatment interruption if diarrhoea persists and dose reduction if diarrhoea recurs on reinitiation of lenvatinib. Blood pressure should be monitored daily in patients with pre-existing hypertension, otherwise from 1 week after the initiation of lenvatinib and weekly for the first 2 months. For patients with systolic blood pressure ≥135 mmHg to <160 mmHg or diastolic blood pressure ≥85 mmHg to <100 mmHg, lenvatinib should be continued but antihypertensive therapy initiated/intensified. For patients who remain hypertensive, a treatment break can be considered with lenvatinib reinitiated at a reduced dose once the patient's blood pressure has stabilised for at least 48 h. Weight loss of 10% of baseline body weight or the onset of anorexia should be managed with a 1-week treatment break; patients should maintain a healthy, active lifestyle. For patients with grade 2 proteinuria, lenvatinib may be continued, but an angiotensin II receptor blocker or angiotensin converting enzyme inhibitor should be commenced. For grade >3 proteinuria, lenvatinib should be interrupted until proteinuria returns to 1+. For chronic proteinuria, lenvatinib should be stopped. Skin toxicities should be managed with moisturisers or emollients and soap substitutes. CONCLUSIONS Prophylaxis, regular monitoring and symptomatic management with appropriate short treatment breaks and, for persistent adverse events, dose reductions, are recommended to enable patients to remain on the optimal dose regimen.
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The Use of Antiepileptics in Migraine Prophylaxis.
Bagnato, F, Good, J
Headache. 2016;(3):603-15
Abstract
BACKGROUND Migraine is a chronic debilitating disorder. Selected antiepileptic drugs (AEDs) are proposed as preventives for migraine. Clinical efficacy and side effects of these AEDs are discussed. SUMMARY OF REVIEW The American Academy of Neurology and the American Society of Headache classify topiramate (TPM) and divalproex sodium (DVPX) as Level-A medications and recommend offering them to patients for migraine prophylaxis. Their mechanism(s) of actions remains not entirely known. Their recognized action as sodium channel blockers may affect the neural component of migraine pain. TPM or DVPX can be considered an obvious choice for those patients with a concomitant seizure disorder. Care must be taken to plan their treatment with their psychiatrist if a mood disorder is present. DVPX tends not to be prescribed as first/second choice due to its potential for weight gain and hepatotoxicity. TPM is generally first choice, but bears severe contraindications. Both medications require education on teratogenesis in childbearing women. Consideration of gabapentin, acetazolamide, leviteracetam, zonisamide, and carbamazipine may be given later as empiric options and in selected patients. Patients must be made aware that there is insufficient scientific support for their use in migraine. CONCLUSIONS Available AEDs to prophylactically treat migraine are few but of robust clinical efficacy. Special care needs to be exerted with respect to their side effects. Future research is needed for a better understanding of their mechanisms of action in migraine. Such research has the potential of providing some insight into the pathophysiology of migraine.
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Dose-response effects of aerobic exercise on estrogen among women at high risk for breast cancer: a randomized controlled trial.
Schmitz, KH, Williams, NI, Kontos, D, Domchek, S, Morales, KH, Hwang, WT, Grant, LL, DiGiovanni, L, Salvatore, D, Fenderson, D, et al
Breast cancer research and treatment. 2015;(2):309-18
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Abstract
UNLABELLED Medical and surgical interventions for elevated breast cancer risk (e.g., BRCA1/2 mutation, family history) focus on reducing estrogen exposure. Women at elevated risk may be interested in less aggressive approaches to risk reduction. For example, exercise might reduce estrogen, yet has fewer serious side effects and less negative impact than surgery or hormonal medications. Randomized controlled trial. Increased risk defined by risk prediction models or BRCA mutation status. Eligibility: Age 18-50, eumenorrheic, non-smokers, and body mass index (BMI) between 21 and 50 kg/m(2). 139 were randomized. Treadmill exercise: 150 or 300 min/week, five menstrual cycles. Control group maintained exercise <75 min/week. PRIMARY OUTCOME Area under curve (AUC) for urinary estrogen. Secondary measures: urinary progesterone, quantitative digitized breast dynamic contrast-enhanced magnetic resonance imaging background parenchymal enhancement. Mean age 34 years, mean BMI 26.8 kg/m(2). A linear dose-response relationship was observed such that every 100 min of exercise is associated with 3.6 % lower follicular phase estrogen AUC (linear trend test, p = 0.03). No changes in luteal phase estrogen or progesterone levels. There was also a dose-response effect noted: for every 100 min of exercise, there was a 9.7 % decrease in background parenchymal enhancement as measured by imaging (linear trend test, p = 0.009). Linear dose-response effect observed to reduce follicular phase estrogen exposure measured via urine and hormone sensitive breast tissue as measured by imaging. Future research should explore maintenance of effects and extent to which findings are repeatable in lower risk women. Given the high benefit to risk ratio, clinicians can inform young women at increased risk that exercise may blunt estrogen exposure while considering whether to try other preventive therapies.
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Women In Steady Exercise Research (WISER) Sister: study design and methods.
Schmitz, KH, Williams, NI, Kontos, D, Kurzer, MS, Schnall, M, Domchek, S, Stopfer, J, Galantino, ML, Hwang, WT, Morales, K, et al
Contemporary clinical trials. 2015;:17-30
Abstract
PURPOSE Women at elevated risk for breast cancer are motivated to reduce their risk. Current approaches rely primarily on hormonal intervention. A preventive exercise intervention might address the same hormonal issues, yet have fewer serious side effects and less negative impact on quality of life as compared to prophylactic mastectomy. WISER Sister was a randomized controlled trial which examined effects of two doses of exercise training on endogenous sex hormone exposure, hormonally active breast tissue, and other breast cancer risk factors. METHODS Subjects for this single site trial were recruited from across the U.S., in collaboration with organizations that serve women at elevated risk, via emails, flyers, and letters. Eligibility criteria included age ≥ 18, eumenorrheic, and at elevated risk for breast cancer (e.g. BRCA1 or BRCA2 mutation and/or ≥ 18% lifetime risk according to prediction models). A 1:1:1 randomization scheme was used to allocate participants into: control, low dose (150 min/week), or high dose (300 min/week) home based treadmill exercise. Participants provided first morning urine samples daily for two menstrual cycles at study beginning and end for calculation of endogenous hormone exposure. In addition, women completed breast dynamic contrast enhanced magnetic resonance imaging, a fasting blood draw, a treadmill exercise test, and surveys at baseline and follow-up. DISCUSSION WISER Sister randomized 139 women, 122 of whom completed the study. The overall drop-out rate was 12%. Findings will be useful in understanding the potential for exercise to assist with reducing risk for breast cancer among women at elevated risk.
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Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma.
Irvin, C, Zafar, I, Good, J, Rollins, D, Christianson, C, Gorska, MM, Martin, RJ, Alam, R
The Journal of allergy and clinical immunology. 2014;(5):1175-1186.e7
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Abstract
BACKGROUND TH2 cells can further differentiate into dual-positive TH2/TH17 cells. The presence of dual-positive TH2/TH17 cells in the airways and their effect on asthma severity are unknown. OBJECTIVE We sought to study dual-positive TH2/TH17 cells in bronchoalveolar lavage (BAL) fluid from asthmatic patients, examine their response to glucocorticoids, and define their relevance for disease severity. METHODS Bronchoscopy and lavage were performed in 52 asthmatic patients and 25 disease control subjects. TH2 and TH2/TH17 cells were analyzed by using multicolor flow cytometry and confocal immunofluorescence microscopy. Cytokines were assayed by means of ELISA. RESULTS Dual-positive TH2/TH17 cells were present at a higher frequency in BAL fluid from asthmatic patients compared with numbers seen in disease control subjects. High-level IL-4 production was typically accompanied by high-level IL-17 production and coexpression of GATA3 and retinoic acid receptor-related orphan receptor γt. Increased presence of TH2/TH17 cells was associated with increased IL-17 production in lavage fluid. TH2/TH17 cell counts and IL-17 production correlated with PC20 for methacholine, eosinophil counts, and FEV1. TH2/TH17 cells, unlike TH2 cells, were resistant to dexamethasone-induced cell death. They expressed higher levels of mitogen-activated protein-extracellular signal-regulated kinase kinase 1, a molecule that induces glucocorticoid resistance. On the basis of the dominance of BAL fluid TH2 or TH2/TH17 cells, we identified 3 subgroups of asthma: TH2(predominant), TH2/TH17(predominant), and TH2/TH17(low). The TH2/TH17(predominant) subgroup manifested the most severe form of asthma, whereas the TH2/TH17(low) subgroup had the mildest asthma. CONCLUSION Asthma is associated with a higher frequency of dual-positive TH2/TH17 cells in BAL fluid. The TH2/TH17(predominant) subgroup of asthmatic patients manifested glucocorticoid resistance in vitro. They also had the greatest airway obstruction and hyperreactivity compared with the TH2(predominant) and TH2/TH17(low) subgroups.
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Patterns of weight change in black Americans: pooled analysis from three behavioral weight loss trials.
Morales, KH, Kumanyika, SK, Fassbender, JE, Good, J, Localio, AR, Wadden, TA
Obesity (Silver Spring, Md.). 2014;(12):2632-40
Abstract
OBJECTIVE Differentiating trajectories of weight change and identifying associated baseline predictors can provide insights for improving behavioral obesity treatment outcomes. METHODS Secondary, observational analyses using growth mixture models were conducted in pooled data for 604 black American, primarily female adults in three completed clinical trials. Covariates of identified patterns were evaluated. RESULTS The best fitting model identified three patterns over 2 years: 1) mean weight loss of approximately 2 kg (n = 519); 2) mean weight loss of approximately 3 kg at 1 year, followed by ∼4 kg regain (n = 61); and 3) mean weight loss of ∼20 kg at 1 year followed by ∼4 kg regain (n = 24, with 23 from one study). In final multivariate analyses, higher BMI predicted having pattern 2 (OR [95% CI]) 1.10 [1.03, 1.17]) or 3 (OR [95% CI] 1.42 [1.25, 1.63]), and higher dietary fat score was predictive of a lower odds of having patterns 2 (OR [95% CI] 0.37[0.15, 0.94]) or 3 (OR [95% CI] 0.23 [0.07, 0.79]). CONCLUSIONS Findings were consistent with moderate, clinically non-significant weight loss as the predominant pattern across all studies. Results underscore the need to develop novel and more carefully targeted and tailored approaches to facilitating weight loss in black American adults.