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Doi S.A.R.,University of Queensland | Barendregt J.J.,University of Queensland | Onitilo A.A.,University of Queensland | Onitilo A.A.,Marshfield Clinic Weston Center | Onitilo A.A.,Marshfield Clinic Research Foundation
Journal of Evaluation in Clinical Practice | Year: 2013

Background A unique challenge in meta-analysis of observational studies is bias adjustment. Two different approaches have been proposed for doing this - using summary scores versus component scores. The prevailing view on this matter is that summary quality scores are inaccurate because information from its components can cancel each other out. Methods A head-to-head comparison of the component score adjustment with our method using summary scores is undertaken, using data reported by the authors of the component method. Results It is demonstrated that the consideration of components or of aggregate scores does indeed lead to the same conclusions. Yet, the latter does not require imputation of the direction and magnitude of changes to effect sizes. Conclusions The summary quality score used for bias adjustment within the context of an appropriate model may be most expedient. Implications for the bias adjustment of meta-analyses of observational studies are discussed. © 2012 John Wiley & Sons Ltd. Source


Onitilo A.A.,Marshfield Clinic Weston Center | Engel J.M.,Marshfield Clinic Cancer Care at St Michaels | Stankowski R.V.,Marshfield Clinic Research Foundation
Therapeutic Advances in Drug Safety | Year: 2014

Before the advent of the human epidermal growth factor receptor 2 (HER2)-targeted monoclonal antibody trastuzumab, HER2-positive breast cancers were difficult to treat and had a poor prognosis. Adjuvant trastuzumab is now an important part of the treatment regimen for many women with HER2-positive breast cancer and has undoubtedly resulted in a significant improvement in prognosis, but it is associated with a risk for cardiotoxicity. In this review, we describe the prevalence, patient characteristics, and risk factors for cardiotoxicity associated with use of adjuvant trastuzumab. Understanding risk factors for trastuzumab-induced cardiotoxicity and appropriate patient monitoring during trastuzumab treatment allows for safe and effective use of this important adjuvant therapy. © The Author(s), 2014. Source


Onitilo A.A.,Marshfield Clinic Weston Center | Aryal G.,Marshfield Clinic | Engel J.M.,Marshfield Clinic at Ministry St. Michaels Hospital
Clinical Medicine and Research | Year: 2013

Hereditary diffuse gastric cancer (HDGC) is a rare cancer representing approximately 2% of all gastric cancers. It is caused by CDH1 gene mutations, inherited in an autosomal dominant fashion, that affect the function of E-cadherin. Approximately 38% of HDGC families have a CDH1 gene mutation. With an estimated 75% penetrance rate, carriers are at high risk for HDGC. We describe the case of a Caucasian male of German-Russian ancestry, carrying a CDH1 gene mutation, who survived for 18 months after being diagnosed with HDGC. The results of genetic testing undergone by his family members are also reported, along with a review of the current literature. Since surveillance methods for HDGC are ineffective and unreliable, total prophylactic gastrectomy is advised for individuals with the gene mutation. Additionally, a diagnosis of HDGC should lead to genetic evaluation of family members followed by preventative measures. © 2013 Marshfield Clinic. Source


Bradley D.P.,University of Wisconsin - Madison | Kulstad R.,Marshfield Clinic Weston Center | Schoeller D.A.,University of Wisconsin - Madison
Nutrition | Year: 2010

Objective: Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone mainly released from the distal ileum, jejunum, and colon in response to food ingestion. It is categorized as an incretin due to its activation of GLP-1 receptors in pancreatic β-cells leading to insulin exocytosis in a glucose-dependent manner. Exenatide (synthetic exendin-4) is a subcutaneously injected GLP-1 receptor agonist that shares 50% homology with GLP-1. It is derived from lizard venom and stimulates the GLP-1 receptor for prolonged periods. The present review aims to enumerate exenatide-instigated weight loss, summarize the known mechanisms of exenatide-induced weight loss, and elaborate on its possible application in the pharmacotherapy of obesity. Methods: A search through PubMed was performed using exenatide and weight loss as search terms. A second search was performed using exenatide and mechanisms or actions as search terms. Results: In addition to exenatide's action to increase insulin secretion in individuals with elevated levels of plasma glucose, clinical trials have reported consistent weight loss associated with exenatide treatment. Studies have found evidence that exenatide decreases energy intake and increases energy expenditure, but findings on which predominates to cause weight loss are often inconsistent and controversial. Conclusion: Further research on the effects of exenatide treatment on energy intake and expenditure are recommended to better understand the mechanisms through which exenatide causes weight loss. © 2010 Elsevier Inc. All rights reserved. Source


Onitilo A.A.,Marshfield Clinic Weston Center | Onitilo A.A.,Marshfield Clinic Research Foundation | Onitilo A.A.,University of Queensland | Engel J.M.,Marshfield Clinic Cancer Care at St Michaels | And 4 more authors.
Breast Cancer Research and Treatment | Year: 2012

Monitoring of left ventricular ejection fraction (LVEF) is the current standard for detection of trastuzumab-induced cardiotoxicity; however, time-to-diagnosis and cost of assessment are suboptimal in women with early-stage breast cancer. We assessed the utility of B-type natriuretic peptide (BNP), high-sensitivity C-reactive protein (hs-CRP), and cardiac troponin I (cTnI) as serum biomarkers for early detection of trastuzumab-induced cardiotoxicity. Fifty-four women with human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer were prospectively enrolled, and the relationship between elevated serum BNP, hs-CRP, and cTnI levels and clinically significant decreases in LVEF was examined. LVEF was monitored at 3-4 month intervals during trastuzumab treatment. Laboratory testing for candidate biomarkers was repeated every 3 weeks with each cycle of trastuzumab. Trastuzumab-induced cardiotoxicity was defined as a decrease in LVEF of >15 % or to a value below 50 %. A clinically significant decrease in LVEF was observed in 28.6 % of women. Abnormal hs-CRP (>3 mg/L) predicted decreased LVEF with a sensitivity of 92.9 % (95 % CI 66.1-99.8) and specificity of 45.7 % (95 % CI 28.8-63.4), and subjects with normal hs-CRP levels (<3 mg/L) have 94.1 % negative predictive 94.1 % (95 % CI 70.3-99.9) suggesting that normal hs-CRP levels may be associated with low future risk for decreased LVEF; however, no association with BNP or cTnI was observed. A false positive would have a relatively low associated cost in breast cancer patients undergoing adjuvant trastuzumab therapy and would indicate continuation of routine observation during treatment through traditional means. The maximum hs-CRP value was observed a median of 78 days prior to detection of cardiotoxicity by decreased LVEF, and those with normal levels were at lower risk for cardiotoxicity. Regular monitoring of hs-CRP holds promise as a biomarker for identifying women with early-stage breast cancer at low risk for asymptomatic trastuzumab-induced cardiotoxicity. To our knowledge, this is the first study documenting the utility of a less expensive, reproducible, easily obtainable biomarker with rapid results for evaluating cardiotoxicity related to trastuzumab therapy. © 2012 Springer Science+Business Media, LLC. Source

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