Research Spotlight

Posted July 15th 2016

The evolution of systemic therapy in metastatic renal cell carcinoma.

Thomas Hutson D.O.

Thomas Hutson D.O.

Hutson, T. E., G. R. Thoreson, R. A. Figlin and B. I. Rini (2016). “The evolution of systemic therapy in metastatic renal cell carcinoma.” Am Soc Clin Oncol Educ Book 35: 113-117.

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The treatment landscape for renal cell carcinoma (RCC) is a dynamic process that has seen considerable change in recent years. We have seen a rebirth of original breakthroughs with immune checkpoint inhibitors showing promise in patients with treatment-refractory disease. The optimal sequencing of treatments and incorporation of novel therapeutics are actively being investigated and have yet to be determined. The clinical challenges of this evolving treatment paradigm can be attributed to cost considerations, toxicity, and defining endpoints in the management of advanced RCC. As novel therapeutics emerge, finding the optimal treatment regimen for patients will have an increasing focus on patient-centered outcomes and improvement in quality of life in addition to improving survival.


Posted July 15th 2016

Central venous thrombosis in children with intestinal failure on long-term parenteral nutrition.

Jessica Gonzalez-Hernandez M.D.

Jessica Gonzalez-Hernandez M.D.

Gonzalez-Hernandez, J., Y. Daoud, J. Styers, J. M. Journeycake, N. Channabasappa and H. G. Piper (2016). “Central venous thrombosis in children with intestinal failure on long-term parenteral nutrition.” J Pediatr Surg 51(5): 790-793.

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PURPOSE: Central venous thrombosis (CVT) is a serious complication of long-term central venous access for parenteral nutrition (PN) in children with intestinal failure (IF). We reviewed thse incidence of CVT and possible risk factors. METHODS: Children with IF on home PN (2010-2014) with central venous imaging were reviewed. Patient demographics, catheter characteristics and related complications, and markers of liver function were compared between children with and without CVT. Serum thrombophilia markers were reviewed for patients with CVT. RESULTS: Thirty children with central venous imaging were included. Seventeen patients had thrombosis of >/=1 central vein, and twelve had >/=2 thrombosed central veins. Patients with and without CVT had similar demographics and catheter characteristics. Patients with CVT had a significantly lower albumin level (2.76+/-0.38g/dL vs. 3.12+/-0.41g/dL, p=0.0223). The most common markers of thrombophilia in children with CVT were antithrombin, protein C and S deficiencies, and elevated factor VIII. There was a statistically significant correlation between a combined protein C and S deficiency and having >1 CVT. CONCLUSIONS: Children with IF on long-term PN are at high risk for CVT potentially owing to low levels of natural anticoagulant proteins and elevated factor FVIII activity, likely a reflection of liver insufficiency and chronic inflammation.


Posted July 15th 2016

An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with fabry disease who are naive to enzyme replacement therapy.

Raphael Schiffmann M.D.

Raphael Schiffmann M.D.

Goker-Alpan, O., N. Longo, M. McDonald, S. P. Shankar, R. Schiffmann, P. Chang, Y. Shen and A. Pano (2016). “An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with fabry disease who are naive to enzyme replacement therapy.” Drug Des Devel Ther 10: 1771-1781.

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BACKGROUND: Following a drug manufacturing process change, safety/efficacy of agalsidase alfa were evaluated in enzyme replacement therapy (ERT)-naive children with Fabry disease. METHODS: In an open-label, multicenter, Phase II study (HGT-REP-084; Shire), 14 children aged >/=7 years received 0.2 mg/kg agalsidase alfa every other week for 55 weeks. Primary endpoints: safety, changes in autonomic function (2-hour Holter monitoring). Secondary endpoints: estimated glomerular filtration rate, left ventricular mass index (LVMI), midwall fractional shortening, pharmacodynamic parameters, and patient-reported quality-of-life. RESULTS: Among five boys (median 10.2 [range 6.7, 14.4] years) and nine girls (14.8 [10.1, 15.9] years), eight patients experienced infusion-related adverse events (vomiting, n=4; nausea, n=3; dyspnea, n=3; chest discomfort, n=2; chills, n=2; dizziness, n=2; headache, n=2). One of these had several hypersensitivity episodes. However, no patient discontinued for safety reasons and no serious adverse events occurred. One boy developed immunoglobulin G (IgG) and neutralizing antidrug antibodies. Overall, no deterioration in cardiac function was observed in seven patients with low/abnormal SDNN (standard deviation of all filtered RR intervals; <100 ms) and no left ventricular hypertrophy: mean (SD) baseline SDNN, 81.6 (20.9) ms; mean (95% confidence interval [CI]) change from baseline to week 55, 17.4 (2.9, 31.9) ms. Changes in SDNN correlated with changes in LVMI (r=-0.975). No change occurred in secondary efficacy endpoints: mean (95% CI) change from baseline at week 55 in LVMI, 0.16 (-3.3, 3.7) g/m(2.7); midwall fractional shortening, -0.62% (-2.7%, 1.5%); estimated glomerular filtration rate, 0.15 (-11.4, 11.7) mL/min/1.73 m(2); urine protein, -1.8 (-6.0, 2.4) mg/dL; urine microalbumin, 0.6 (-0.5, 1.7) mg/dL; plasma globotriaosylceramide (Gb3), -5.71 (-10.8, -0.6) nmol/mL; urinary Gb3, -1,403.3 (-3,714.0, 907.4) nmol/g creatinine, or clinical quality-of-life outcomes. CONCLUSION: Fifty-five weeks' agalsidase alfa ERT at 0.2 mg/kg every other week was well tolerated. Disease progression may be slowed when ERT is started prior to major organ dysfunction.


Posted July 15th 2016

Failure to Rescue Rates After Coronary Artery Bypass Grafting: An Analysis From The Society of Thoracic Surgeons Adult Cardiac Surgery Database.

Mitchell J. Magee M.D.

Mitchell J. Magee M.D.

Edwards, F. H., V. A. Ferraris, P. A. Kurlansky, K. W. Lobdell, X. He, S. M. O’Brien, A. P. Furnary, J. S. Rankin, C. M. Vassileva, F. L. Fazzalari, M. J. Magee, V. Badhwar, Y. Xian, J. P. Jacobs, M. C. Wyler von Ballmoos and D. M. Shahian (2016). “Failure to rescue rates after coronary artery bypass grafting: An analysis from the society of thoracic surgeons adult cardiac surgery database.” Ann Thorac Surg: 2016 Jun [Epub ahead of print].

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BACKGROUND: Failure to rescue (FTR) is increasingly recognized as an important quality indicator in surgery. The Society of Thoracic Surgeons National Database was used to develop FTR metrics and a predictive FTR model for coronary artery bypass grafting (CABG). METHODS: The study included 604,154 patients undergoing isolated CABG at 1,105 centers from January 2010 to January 2014. FTR was defined as death after four complications: stroke, renal failure, reoperation, and prolonged ventilation. FTR was determined for each complication and a composite of the four complications. A statistical model to predict FTR was developed. RESULTS: FTR rates were 22.3% for renal failure, 16.4% for stroke, 12.4% for reoperation, 12.1% for prolonged ventilation, and 10.5% for the composite. Mortality increased with multiple complications and with specific combinations of complications. The multivariate risk model for prediction of FTR demonstrated a C index of 0.792 and was well calibrated, with a 1.0% average difference between observed/expected (O/E) FTR rates. With centers grouped into mortality terciles, complication rates increased modestly (11.4% to 15.7%), but FTR rates more than doubled (6.8% to 13.9%) from the lowest to highest terciles. Centers in the lowest complication rate tercile had an FTR O/E of 1.14, whereas centers in the highest complication rate tercile had an FTR O/E of 0.91. CONCLUSIONS: CABG mortality rates vary directly with FTR, but complication rates have little relation to death. FTR rates derived from The Society of Thoracic Surgeons data can serve as national benchmarks. Predicted FTR rates may facilitate patient counseling, and FTR O/E ratios have promise as valuable quality metrics.


Posted July 15th 2016

Comorbidity correlates of death among new veterans of iraq and afghanistan deployment.

Laurel A. Copeland Ph.D.

Laurel A. Copeland Ph.D.

Copeland, L. A., E. P. Finley, M. J. Bollinger, M. E. Amuan and M. J. Pugh (2016). “Comorbidity correlates of death among new veterans of iraq and afghanistan deployment.” Med Care: 2016 June [Epub ahead of print].

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BACKGROUND: Veterans of the wars in Iraq and Afghanistan who receive care in the Veterans Health Administration (VA) have high disease burden. Distinct comorbidity patterns have been shown to be differentially associated with adverse outcomes, including death. This study determined correlates of 5-year mortality. MATERIALS AND METHODS: VA demographic, military, homelessness, and clinical measures informed this retrospective analysis. Previously constructed comorbidity classifications over 3 years of care were entered into a Cox proportional hazards model of death. RESULTS: There were 164,933 veterans in the cohort, including African Americans (16%), Hispanics (11%), and whites (65%). Most were in their 20s at baseline (60%); 12% were women; 4% had attempted suicide; 4% had been homeless. Having clustered disorders of pain, posttraumatic stress disorder, and traumatic brain injury was associated with death [hazard ratio (HR)=2.0]. Mental disorders including substance abuse were similarly associated (HR=2.1). Prior suicide attempt (HR=2.2) or drug overdose (HR=3.0) considerably increased risk of death over 5 years. CONCLUSIONS: As congressional actions such as Veterans Choice Act offer more avenues to seek care outside of VA, coordination of care, and suicide prevention outreach for recent veterans may require innovative approaches to preserve life.