Research Spotlight

VanWagner, L. B., M. E. Harinstein, J. R. Runo, C. Darling, M. Serper, S. Hall, J. A. Kobashigawa and L. L. Hammel (2017). “Multidisciplinary approach to cardiac and pulmonary vascular disease risk assessment in liver transplantation: An evaluation of the evidence and consensus recommendations.” Am J Transplant: 2017 Oct [Epub ahead of print].

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Liver transplant (LT) candidates today are older, have greater medical severity of illness, and have more cardiovascular comorbidities than ever before. In addition, there are specific cardiovascular responses in cirrhosis that can be detrimental to the LT candidate. Cirrhotic cardiomyopathy, a condition characterized by increased cardiac output and a reduced ventricular response to stress, is present in up to 30% of patients with cirrhosis thus challenging perioperative management. Current noninvasive tests that assess for subclinical coronary and myocardial disease have low sensitivity, and altered hemodynamics during the LT surgery can unmask latent cardiovascular disease either intraoperatively or in the immediate postoperative period. Therefore, this review, assembled by a group of multidisciplinary experts in the field and endorsed by the American Society of Transplantation Liver and Intestine and Thoracic and Critical Care Communities of Practice, provides a critical assessment of the diagnosis of cardiac and pulmonary vascular disease and interventions aimed at managing these conditions in LT candidates. Key points and practice-based recommendations for the diagnosis and management of cardiac and pulmonary vascular disease in this population are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations.

Wolchok, J. D., V. Chiarion-Sileni, R. Gonzalez, P. Rutkowski, J. J. Grob, C. L. Cowey, C. D. Lao, J. Wagstaff, D. Schadendorf, P. F. Ferrucci, M. Smylie, R. Dummer, A. Hill, D. Hogg, J. Haanen, M. S. Carlino, O. Bechter, M. Maio, I. Marquez-Rodas, M. Guidoboni, G. McArthur, C. Lebbe, P. A. Ascierto, G. V. Long, J. Cebon, J. Sosman, M. A. Postow, M. K. Callahan, D. Walker, L. Rollin, R. Bhore, F. S. Hodi and J. Larkin (2017). “Overall survival with combined nivolumab and ipilimumab in advanced melanoma.” N Engl J Med 377(14): 1345-1356.

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BACKGROUND: Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. METHODS: We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS: At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone.

White, H. D., S. Ghamande and A. C. Arroliga (2017). “Therapeutic hypothermia for acute respiratory distress syndrome.” Crit Care Med 45(11): e1202-e1203.

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In a recent issue of Critical Care Medicine, Slack et al (1) published findings of a pilot feasibility study focused on the usage of therapeutic hypothermia (TH) for moderate to severe acute respiratory distress syndrome (ARDS). Patients treated with TH in their study (1) were more likely to survive compared with historic controls with a similar level of severity. We applaud Slack et al (1) for shinning new light on this application of TH. Despite progress in treatment of ARDS, morbidity and mortality of this disease remain substantial, and development of new treatment approaches is necessary (2).

Joseph, S. M., J. L. Manghelli, J. M. Vader, T. Keeney, E. L. Novak, J. Felius, S. C. Martinez, M. E. Nassif, B. Lima, S. C. Silvestry and M. W. Rich (2017). “Prospective assessment of frailty using the fried criteria in patients undergoing left ventricular assist device therapy.” Am J Cardiol 120(8): 1349-1354.

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Frail patients are more prone to adverse events after cardiac surgery, particularly after implantation of left ventricular assist devices. Thus, frailty assessment may help identify patients unlikely to benefit from left ventricular assist device therapy. The purpose was to establish a suitable measure of frailty in adults with end-stage heart failure. In a prospective cohort of 75 patients (age 58 +/- 12 years) with end-stage heart failure, we assessed the association between frailty (5-component Fried criteria) and the composite primary outcome of inpatient mortality or prolonged length of stay, as well as extubation status, time on ventilator, discharge status, and long-term mortality. Fried frailty criteria were met in 44 (59%) patients, but there was no association with the primary outcome (p = 0.10). However, an abridged set of 3 criteria (exhaustion, inactivity, and grip strength) was predictive of the primary outcome (odds ratio 2.9, 95% confidence interval 1.1 to 7.4), and of time to extubation and time to discharge. In patients with advanced heart failure, the 5-component Fried criteria may not be optimally sensitive to clinical differences. In conclusion, an abridged set of 3 frailty criteria was predictive of the primary outcome and several secondary outcomes, and may therefore be a clinically useful tool in this population.

Gonzalez, S. A. and J. F. Trotter (2017). “The rise of the opioid epidemic and hepatitis c positive organs: A new era in liver transplantation.” Hepatology: 2017 Oct [Epub ahead of print].

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The use of hepatitis C virus (HCV) positive organs in liver transplantation has increased in the era of direct-acting antiviral therapy. A rising demand for organs, the ability to effectively treat HCV infection in the transplant setting, and an unprecedented increase in HCV positive donors have all contributed to this trend. A recent abrupt rise in opioid use in the US has resulted in a surge of injection drug use, transmission of HCV, and opioid-related overdose deaths. Geographic areas most affected by the opioid epidemic have experienced a rapid increase in recovery and utilization of HCV positive donor organs, in which the proportion of deceased donor liver transplants in the US from donors who are HCV positive has increased nearly two-fold within the last three years. The prospect of expanding the organ donor pool with HCV positive donors and achieving acceptable post-transplant outcomes has generated much interest in the areas of liver, kidney, and thoracic transplantation, including the potential for transplanting organs from HCV positive donors into HCV negative recipients. Developing strategies to ensure appropriate selection of potential recipients of HCV positive organs, initiating timely antiviral therapy, and defining associated risks will be critical in achieving optimal post-transplant outcomes in this setting.