Research Spotlight

Posted August 15th 2016

Amikacin optimal exposures targets in the hollow fiber system model of tuberculosis.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Srivastava, S., C. Modongo, C. W. Siyambalapitiyage Dona, J. G. Pasipanodya, D. Deshpande and T. Gumbo (2016). “Amikacin optimal exposures targets in the hollow fiber system model of tuberculosis.” Antimicrob Agents Chemother: 2016 Jul [Epub ahead of print].

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Aminoglycosides such as amikacin are currently used for the treatment of multidrug-resistant tuberculosis (MDR-TB). However, formal pharmacokinetic/pharmacodynamics (PK/PD) studies to identify amikacin exposures and dosing schedules that optimize Mycobacterium tuberculosis (Mtb) killing have not been performed. It is believed that aminoglycosides do not work well under acidic conditions, which if true would mean poor sterilizing effect activity against semidormant bacilli at low pH. We performed time kill studies to compare the bactericidal effect of amikacin in log-phase growth bacilli versus sterilizing effect in semidormant bacilli at pH 5.8 in broth. In log-phase growth Mtb at normal pH versus semidormant Mtb at pH 5.8, the maximal kill (Emax) estimate and 95% confidence intervals (CI) were 5.39 (95% CI: 4.91-5.63) versus 4.88 (CI: 4.46-5.22) log10 CFU/mL, while the concentration mediating 50% of Emax (EC50) was 1.0 (CI: 0. 0.86-1.12) versus 0.60 (CI: 0.50-0.66) times MIC, respectively. Thus, the optimal exposures and kill rates identified for log-phase growth Mtb will be optimal even for semidormant bacilli. Next, we performed exposure-response and dose-scheduling studies in the hollow fiber system model of tuberculosis using log-phase growth Mtb. We recapitulated amikacin concentration-time profiles observed in lungs of patients treated over 28 days. The PK/PD index linked to Mtb kill was peak concentration (Cmax)-to-MIC ratio (r2>0.99), closely followed by the 0-24hour area under the concentration-time curve (AUC0-24)-to-MIC ratio (r2=0.98). The EC90 was a Cmax/MIC of 10.13 (95% CI: 7.73-12.48). The EC90 is the dosing target for intermittent therapy that optimizes cure in TB Programs for MDR-TB patients.


Posted August 15th 2016

Effect of Antifibrinolytic Therapy on Complications, Thromboembolic Events, Blood Product Utilization, and Fusion in Adult Spinal Deformity Surgery.

Richard Hostin M.D.

Richard Hostin M.D.

Soroceanu, A., J. H. Oren, J. S. Smith, R. Hostin, C. I. Shaffrey, G. M. Mundis, C. P. Ames, D. C. Burton, S. Bess, M. C. Gupta, V. Deviren, F. J. Schwab, V. Lafage and T. J. Errico (2016). “Effect of antifibrinolytic therapy on complications, thromboembolic events, blood product utilization, and fusion in adult spinal deformity surgery.” Spine (Phila Pa 1976) 41(14): E879-886.

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STUDY DESIGN: A multicenter, prospective, consecutive database of surgical patients with adult spinal deformity (ASD). OBJECTIVE: This study investigated the use of antifibrinolytic (AF) therapy in ASD surgery. SUMMARY OF BACKGROUND DATA: AF therapy has been shown to be effective in preventing blood loss in some settings. Its effect on major and minor perioperative complications, blood product utilization, vascular events, and postoperative fusion in patients undergoing ASD surgery remains unclear. METHODS: All patients with data on AF use were included. Parameters of blood utilization included transfusion rates and units of packed red blood cells and fresh frozen plasma transfused. Thromboembolic events included stroke, deep vein thrombosis, and pulmonary embolus. Multivariate regression was used, accounting for confounders. RESULTS: Four hundred three patients were included. One hundred thirty-seven patients received aminocaproic acid (EACA), 81 received tranexamic acid (TXA), and 185 received no AFs. The use of AF was associated with a decrease in transfusion (EACA: odds ratio [OR] = 0.38, P = 0.043; TXA: OR = 0.31, P = 0.047), a decrease in the number of units of packed red blood cells transfused (EACA: incidence risk ratio [IRR] = 0.45, P = 0.0005; TXA: IRR = 0.7, P = 0.0005), and a decrease in the number of fresh frozen plasma transfused (EACA: IRR = 0.65, P = 0.003; TXA: IRR = 0.67, P = 0.006). AF use was associated with an increase in minor intraoperative complications (EACA: IRR = 2.15, P = 0.008; TXA: IRR = 2.12, P = 0.011). TXA use (but not EACA) was associated with a decrease in the incidence of major perioperative complications compared with no AF (IRR = 0.37, P = 0.019). There was no difference in the incidence of thromboembolic events. CONCLUSION: TXA or EACA use was associated with increased minor intraoperative complications. TXA was associated with decreased major perioperative complications. AF was associated with decreased utilization of blood products without an increased rate of thromboembolic events. Given the nature of this study, transfusion threshold was not standardized. Future studies with rigid criteria for transfusion should be prospectively performed to better evaluate the impact of AF during ASD surgery.


Posted August 15th 2016

MiR-375 and miR-200c as predictive biomarkers of islet isolation and transplantation in total pancreatectomy with islet autotransplantation.

Bashoo Naziruddin Ph.D.

Bashoo Naziruddin Ph.D.

Yoshimatsu, G., M. Takita, M. A. Kanak, W. Z. Haque, C. Chang, S. P. Balaji, M. C. Lawrence, M. F. Levy and B. Naziruddin (2016). “Mir-375 and mir-200c as predictive biomarkers of islet isolation and transplantation in total pancreatectomy with islet autotransplantation.” J Hepatobiliary Pancreat Sci: 2016 Jul [Epub ahead of print].

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BACKGROUND: Total pancreatectomy with islet autotransplantation (TPIAT) is a promising treatment for refractory chronic pancreatitis. Predictable biomarkers for the endocrine function after transplantation would be helpful in selecting patients for TPIAT. This study aims to identify novel biomarkers for predicting the outcome of islet isolation and transplantation in TPIAT patients. METHODS: This paper studied microRNA of 31 TPIAT patients and 11 deceased donors from plasma samples before TPIAT. MiR-7, miR-200a, miR-200c, miR-320, and miR-375 were analyzed along with patient characteristics and the outcomes of islet isolation and transplantation via univariate and multivariate regression analysis. RESULTS: MiR-375 before TPIAT showed a significant correlation with C-peptide (r = -0.396, P = 0.03) and post-digestion islet count (r = -0.372, P = 0.04). And also miR-200c was significantly correlated with insulin requirement, C-peptide, and SUITO index at 1 year after transplantation. Moreover it was confirmed that miR-200c was a predictable factor of endocrine outcome in multi regression analysis (coefficient = -7.081, P = 0.001). CONCLUSIONS: We concluded that miR-375 and miR-200c could potentially serve as novel biomarkers in predicting the islet yield in islet isolation and the metabolic function after transplantation for chronic pancreatitis patients.


Posted August 15th 2016

Therapeutic HPV cancer vaccine targeted to CD40 elicits effective CD8+ T-cell immunity.

SangKon Oh Ph.D.

SangKon Oh Ph.D.

Yin, W., D. Duluc, H. Joo, Y. Xue, C. Gu, Z. Wang, L. Wang, R. Ouedraogo, L. Oxford, A. Clark, F. Parikh, S. Kim-Schulze, L. Thompson-Snipes, S. Y. Lee, C. Beauregard, J. H. Woo, S. Zurawski, A. G. Sikora, G. Zurawski and S. Oh (2016). “Therapeutic hpv cancer vaccine targeted to cd40 elicits effective cd8+ t-cell immunity.” Cancer Immunol Res: 2016 Aug [Epub ahead of print].

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Human papillomavirus (HPV), particularly HPV16 and HPV18, can cause cancers in diverse anatomical sites, including the anogenital and oropharyngeal (throat) regions. Therefore, development of safe and clinically effective therapeutic vaccines is an important goal. Herein, we show that a recombinant fusion protein of a humanized antibody to CD40 fused to HPV16.E6/7 (alphaCD40-HPV16.E6/7) can evoke HPV16.E6/7-specific CD8+ and CD4+ T-cell responses in head-and-neck cancer patients in vitro and in human CD40 transgenic (hCD40tg) mice in vivo. The combination of alphaCD40-HPV16.E6/7 and poly(I:C) efficiently primed HPV16.E6/7-specific T-cells, particularly CD8+ T-cells, in hCD40tg mice. Inclusion of montanide enhanced HPV16.E6/7-specific CD4+, but not CD8+, T-cell responses. Poly(I:C) plus alphaCD40-HPV16.E6/7 was sufficient to mount both preventative and therapeutic immunity against TC-1 tumors in hCD40tg mice, significantly increasing the frequency of HPV16-specific CD8+ CTLs in the tumors, but not in peripheral blood. In line with this, tumor volume inversely correlated with the frequency of HPV16.E6/7-specific CD8+ T-cells in tumors, but not in blood. These data suggest that CD40-targeting vaccines for HPV-associated malignancies can provide a highly immunogenic platform with a strong likelihood of clinical benefit. Data from this study offer strong support for the development of CD40-targeting vaccines for other cancers in the future.


Posted August 15th 2016

Liver transplantation around the world.

James F. Trotter M.D.

James F. Trotter M.D.

Trotter, J. F. and A. Cardenas (2016). “Liver transplantation around the world.” Liver Transpl 22(8): 1059-1061.

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In the recent issues of Liver Transplantation, we have asked transplant doctors and colleagues from around the world to share insights about the state of liver transplantation in their countries. The purpose of these articles is to provide a perspective for each of us to learn how our colleagues organize and provide transplant services based on the challenges and opportunities in their different settings. By learning from the experience of these different countries, we hope that individual physicians might improve their own programs or appreciate the benefits that they might enjoy. To a great extent, the practice of liver transplantation within each country is a reflection of its own unique culture. Western countries are more organized, regulated, and have reached a plateau of transplant volume, whereas emerging countries are less systematic and growing rapidly in both their capabilities and volumes. We hope that these reviews will help provide a better appreciation for the practice of liver transplant within each of our countries by reviewing the experiences reported by Australia, New Zealand, Brazil, Germany, India, Ireland, Japan, Spain, and the United Kingdom. In future issues, authors from more countries around the globe will be invited to also share their experiences.