Background: SGLT2 inhibitors provide multiple benefits to patients with type 2 diabetes, including improved glycemic control and decreased risks of cardiorenal disease. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Methods: Canagliflozin (300 mg) was administered to 30 healthy volunteers. Several endpoints were measured to assess clinically relevant responses, including drug-induced increases in urinary excretion of glucose, sodium, and uric acid. Results: This pilot study confirmed that canagliflozin (300 mg) triggered acute changes in mean levels of several biomarkers: fasting plasma glucose (-4.1 mg/dL; p=6E-05), serum creatinine (+0.05 mg/dL; p=8E-04), and serum uric acid (-0.90 mg/dL; p=5E-10). The effects of sex on glucosuria depended upon how data were normalized. Whereas responses of males were ~60% greater when data were normalized to body surface area, males and females exhibited similar responses when glucosuria was expressed as grams of urinary glucose per gram-creatinine. The magnitude of glucosuria was not significantly correlated with fasting plasma glucose, estimated GFR, or age in these healthy non-diabetic individuals with estimated GFR>60 mL/min/1.73 sq.m. Conclusions: Normalizing data relative to creatinine excretion will facilitate including data from males and females in a single analysis. Furthermore, because our ongoing pharmacogenomic study (NCT02891954) is conducted in healthy individuals, this will facilitate detection of genetic associations with limited confounding by other factors such as age and renal function. Registration:NCT02462421(clinicaltrials.gov) Funding: Research grants from the National Institute of Diabetes and Digestive and Kidney Diseases: R21DK105401, R01DK108942, T32DK098107, and P30DK072488.
Background: We sought to evaluate the comprehensive patterns of failure associated with treatment for triple negative breast cancer (TNBC) at a single urban institution. Methods: A retrospective review of TNBC patients treated from 2005-2015 was conducted. Detailed patient, tumor and treatment characteristics were included. Information on patterns of treatment failure, including local, regional, distant and combinations of these three were collected. Chi-square testing was used to compare variables, while logistic regression with Kaplan-Meier estimate was used to calculate overall survival (OS) and freedom from recurrence (FFR). Results: With a median follow-up of 46 months, 32 (16%) documented failures occurred. Locoregional failures comprised 84% of failure patterns whether isolated or in combination with distant failure. 5-year OS and FFR were 76.4% and 83.8%, respectively. On univariate analysis, treatment failure was associated with insurance type, smoking status, presence of LVSI, clinical detection of tumor, increasing clinical tumor size (>2 cm), and increasing pathologic tumor stage, nodal stage, and overall staging. On multivariate analysis, pathologic nodal staging was the most significant predictor of treatment failure. Conclusion: Our work shows that with modern therapies, treatment outcomes for patients with TNBC are very good. 53% of patients failed in distant and locoregional sites simultaneously, with an additional 34% failing locally only. These results highlight the need for aggressive local therapies in high-risk patients as well as suggest a need for improved follow up care focusing on detecting locoregional failures. Integrated multidisciplinary care is essential in the management of these patients at time of failure. Keywords: Triple negative, breast cancer, failure, patterns, predictors
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