Research Spotlight

Posted November 15th 2016

Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Deshpande, D., S. Srivastava, J. G. Pasipanodya, S. J. Bush, E. Nuermberger, S. Swaminathan and T. Gumbo (2016). “Linezolid for infants and toddlers with disseminated tuberculosis: First steps.” Clin Infect Dis 63(suppl 3): S80-s87.

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BACKGROUND: Infants and toddlers often present with disseminated and lymph node tuberculosis, in which Mycobacterium tuberculosis (Mtb) is predominantly intracellular. Linezolid, used to treat tuberculosis in adults, has not been formally studied in infants. Infants clear linezolid 5 times faster than adults and achieve lower 0- to 24-hour area under the concentration-time curves (AUC0-24). METHODS: To mimic intracellular disease, we infected human-derived THP-1 macrophages with Mtb and inoculated hollow fiber systems. We performed dose-effect and dose-scheduling studies in which we recapitulated the linezolid half-life of 3 hours encountered in infants. Repetitive sampling for linezolid pharmacokinetics, Mtb intracellular burden, viable monocyte count, and RNA sequencing reads were performed up to 28 days. RESULTS: The linezolid extracellular half-life was 2.64 +/- 0.38 hours, whereas intracellular half-life was 8.93 +/- 1.30 hours (r2 = 0.89). Linezolid efficacy was linked to the AUC0-24 to minimum inhibitory concentration (MIC) ratio (r2 = 0.98). The exposure associated with maximal Mtb kill was an AUC0-24/MIC of 23.37 +/- 1.16. We identified a 414-gene transcript on exposure to toxic linezolid doses. The largest number of genes mapped to ribosomal proteins, a signature hitherto not associated with linezolid toxicity. The second-largest number of differentially expressed genes mapped to mitochondrial enzyme inhibition. Linezolid AUC0-24 best explained the mitochondrial gene inhibition, with 50% inhibition at 94 mg x hour/L (highest r2 = 0.98). CONCLUSIONS: We identified the linezolid AUC0-24/MIC target for optimal efficacy against pediatric intracellular tuberculosis, and an AUC0-24 threshold associated with mitochondrial inhibition. These constitute a therapeutic window to be targeted for optimal linezolid doses in children with tuberculosis.


Posted November 15th 2016

Partnerships to Design Novel Regimens to Treat Childhood Tuberculosis, Sui Generis: The Road Ahead.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Gumbo, T., M. K. Makhene and J. A. Seddon (2016). “Partnerships to design novel regimens to treat childhood tuberculosis, sui generis: The road ahead.” Clin Infect Dis 63(suppl 3): S110-s115.

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There has been a recent expansion of preclinical models to predict the efficacy of regimens to treat adults with tuberculosis. Despite increasing global interest in childhood tuberculosis, these same tools have not been employed to develop pediatric regimens. Children differ from adults in bacillary burden, spectrum of disease, the metabolism and distribution of antituberculosis drugs, and the toxicity experienced. The studies documented in this series describe a proof-of-concept approach to pediatric regimen development. We propose a program of investigation that would take this forward into a systematic and comprehensive method to find optimal drug combinations to use in children, ideal exposures, and required dosing. Although the number of possible drug combinations is extensive, a series of principles could be employed to select likely effective regimens. Regimens should avoid drugs with overlapping toxicity or linked mechanisms of resistance and should aim to include drugs with different mechanisms of action and ones that are able to target different subpopulations of mycobacteria. Finally drugs should penetrate into body sites necessary for treating pediatric disease. At an early stage, this body of work would need to engage with regulatory agencies and bodies that formulate guidelines, so that once regimens and dosages are identified, translation into clinical studies and clinical practice can be rapid. The development of child-friendly drug formulations would need to be carried out in parallel so that pharmacokinetic studies can be undertaken as formulations are created. Significant research and development would be required and a wide range of stakeholders would need to be engaged. The time is right to consider a more thoughtful and systematic approach toward identifying, testing, and comparing combinations of drugs for children with tuberculosis.


Posted November 15th 2016

A randomized adaptive phase II/III study of buparlisib, a pan-Class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4).

Joyce O'Shaughnessy M.D.

Joyce O’Shaughnessy M.D.

Martin, M., A. Chan, L. Dirix, J. O’Shaughnessy, R. Hegg, A. Manikhas, M. Shtivelband, P. Krivorotko, N. Batista Lopez, M. Campone, M. Ruiz Borrego, Q. J. Khan, J. T. Beck, M. Ramos Vazquez, P. Urban, S. Goteti, E. Di Tomaso, C. Massacesi and S. Delaloge (2016). “A randomized adaptive phase ii/iii study of buparlisib, a pan-class i pi3k inhibitor, combined with paclitaxel for the treatment of her2- advanced breast cancer (belle-4).” Ann Oncol: 2016 Nov [Epub ahead of print].

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BACKGROUND: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. PATIENTS AND METHODS: BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after >/=125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. RESULTS: As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 vs 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 vs 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (>/=40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. CONCLUSIONS: Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.


Posted November 15th 2016

The Volume-Outcome Relationship Revisited: Does It Matter for High-Risk PCI?

Gregory J. Dehmer M.D.

Gregory J. Dehmer M.D.

Brindis, R. G. and G. J. Dehmer (2016). “The volume-outcome relationship revisited: Does it matter for high-risk pci?” JACC Cardiovasc Interv 9(20): 2094-2096.

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The National Cardiovascular Data Registry (NCDR) CathPCI registry collects clinical data from >90% of all PCIs performed in the United States. Excluding patients with ST-segment elevation myocardial infarctions, aggregate data from 2015 show an in-hospital mortality rate of 0.89%, while elective PCI mortality is 0.65% 5 and 6. The small number of deaths for a given operator, coupled with estimates of the case volume for operators in the United States (mean 59 cases annually, with 61% of operators performing <40 cases annually in 2008), results in a very wide confidence interval around the point estimate of PCI mortality for an operator (7). In addition, the interplay between facility and individual operator volumes, the operator’s lifetime experience, and the operator’s performance of non-PCI procedures (structural and peripheral arterial interventions) confound the assessment of a relationship between operator PCI case volume and outcomes (3). On the basis of these considerations, there are 2 possible approaches for a continuing examination of the relationship between operator volume and outcomes. One approach would require the collection of operator mortality data over many years to obtain a sample size that would allow meaningful differentiation among operators. For an individual operator, this would likely include mostly low-complexity, low-risk cases mixed with a few high-complexity, high-risk cases. Given the low and decreasing case volume for U.S. operators, the time required to obtain an adequate number of cases is impractical. The alternative approach is to focus on high-complexity, high-risk cases, for which the number of cases needed to discriminate among operators should be lower and obtainable. This latter approach was examined by Xu et al. (8) in a report in this issue of JACC: Cardiovascular Interventions.


Posted November 15th 2016

Transcatheter Mitral Annuloplasty in Chronic Functional Mitral Regurgitation: 6-Month Results With the Cardioband Percutaneous Mitral Repair System.

Paul A. Grayburn M.D.

Paul A. Grayburn M.D.

Nickenig, G., C. Hammerstingl, R. Schueler, Y. Topilsky, P. A. Grayburn, A. Vahanian, D. Messika-Zeitoun, M. Urena Alcazar, S. Baldus, R. Volker, M. Huntgeburth, O. Alfieri, A. Latib, G. La Canna, E. Agricola, A. Colombo, K. H. Kuck, F. Kreidel, C. Frerker, F. C. Tanner, O. Ben-Yehuda and F. Maisano (2016). “Transcatheter mitral annuloplasty in chronic functional mitral regurgitation: 6-month results with the cardioband percutaneous mitral repair system.” JACC Cardiovasc Interv 9(19): 2039-2047.

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OBJECTIVES: This study sought to show safety and efficacy of the Cardioband system during 6 months after treatment. BACKGROUND: Current surgical and medical treatment options for functional mitral regurgitation (FMR) are limited. The Cardioband system (Valtech Cardio, OrYehuda, Israel) is a novel transvenous, transseptal direct annuloplasty device. METHODS: Thirty-one patients (71.8 +/- 6.9 years of age; 83.9% male; EuroSCORE II: 8.6 +/- 5.9) with moderate to severe FMR, symptomatic heart failure, and depressed left ventricular function (left ventricular ejection fraction 34 +/- 11%) were prospectively enrolled. RESULTS: Procedural success rate, defined as delivery of the entire device, was 100%. There were no periprocedural deaths (0%), and mortality rate at 1 month or prior to hospital discharge and at 7 months was 5% and 9.7% respectively. Cinching of the implanted Cardioband reduced the annular septolateral dimension by >30% from 3.7 +/- 0.5 cm at baseline to 2.5 +/- 0.4 cm after 1 month and to 2.4 +/- 0.4 cm after 6 months, respectively (p < 0.001). Percentage of patients with FMR >/=3 was reduced from 77.4% to 10.7% 1 month after the procedure (p < 0.001) and 13.6% (p < 0.001) at 7 months. Percentage of patients with New York Heart Association functional class III/IV decreased from 95.5% to 18.2% after 7 months (p < 0.001); exercise capacity as assessed by 6-min walking test increased from 250 +/- 107 m to 332 +/- 118 m (p < 0.001) and quality of life (Minnesota Living With Heart Failure Questionnaire) was also significantly improved (p < 0.001). CONCLUSIONS: In this feasibility trial in symptomatic patients with FMR, transcatheter mitral annuloplasty with the Cardioband was effective in reducing MR and was associated with improvement in heart failure symptoms and demonstrated a favorable safety profile.