Research Spotlight

Posted April 15th 2016

Acute on chronic liver failure: definitions, treatments and outcomes.

Robert S. Rahimi M.D.

Robert S. Rahimi, M.D.

Rahimi, R. S. and D. C. Rockey (2016). “Acute on chronic liver failure: definitions, treatments and outcomes.” Curr Opin Gastroenterol. 2016 May;32(3):172-81.

Full text of this article.

PURPOSE OF REVIEW: Acute on chronic liver failure (ACLF) causes significant morbidity and mortality in patients with cirrhosis and/or chronic liver disease (CLD). The purpose of this review is to highlight recent studies that have better defined ACLF, and to highlight current outcomes and treatment strategies. RECENT FINDINGS: Currently, there are no clear definitions for ACLF; however, ACLF requires a precipitating event that occurs in the setting of cirrhosis and/or CLD, and progresses rapidly to multiorgan failure with high mortality. Most precipitants of ACLF are due to infections, leading to inflammatory cascades, hence early treatment with antibiotics in these cases might show benefit. Prognosis in ACLF typically depends on the number of extrahepatic organs affected. Potential biomarkers in ACLF may result in early detection and risk stratification; however, further research is needed. ACLF portends a poor prognosis; however, rescue therapy with liver transplantation has been considered in selected cases. SUMMARY: ACLF is a common and devastating complication of cirrhosis or CLD. ACLF usually requires a precipitating event and rapid progression to multiorgan failure with high mortality. Although signs and symptoms might overlap in patients with ACLF and those with decompensated cirrhosis, the two entities should be distinguished separately (although it is challenging to differentiate these in certain cases). Furthermore, diagnosing each entity should be based on a variety of clinical indicators, laboratory data and precipitating factors, in order to determine the best possible targeted treatment strategies. Refinement in the clinical definitions for ACLF may lead to better management and possibly better outcomes if recognized early.

Posted April 15th 2016

Unbelievable Folly of Clinical Trials in Heart Failure: The Inconvenient Truth About How Investigators and Guidelines Weigh Evidence.

Milton Packer M.D.

Milton Packer, M.D.

Packer, M. (2016). “Unbelievable Folly of Clinical Trials in Heart Failure: The Inconvenient Truth About How Investigators and Guidelines Weigh Evidence.” Circ Heart Fail April 9(4).

Full text of this article.

Despite significant advances in the treatment of chronic heart failure during the past 30 years, there is a broad consensus that new treatments are needed because morbidity and mortality in this disorder remain unacceptably high. Nevertheless, the development of new drugs for chronic heart failure has waned during the past 20 years; the quantity of novel agents in clinical testing and the number of well-designed clinical trials have diminished to a small fraction of that seen in the 1980s and 1990s. Some have suggested that investment in heart failure has declined because the primary mechanisms of the disorder are poorly understood, because the promising results of phase II trials are frequently not confirmed in large-scale definitive studies, and because the large-scale clinical trials needed for regulatory approval have often become prohibitively expensive.2,3 We know that clinical research in heart failure is extremely challenging, and so we beg innovators in the pharmaceutical and device industries to be patient, and we plead with sponsors to invest in large-scale investigations because the need is so great. Yet, when we critically examine how we react to data, it may not be too surprising that meaningful clinical trials in heart failure are becoming increasingly scarce. Do cardiologists act as if the results of clinical trials in heart failure really matter? (Excerpt from text; no abstract.)

Posted April 15th 2016

Just because you get on a scale doesn’t mean you lose weight: is Meetbaar Beter really measurably better?

Michael J. Mack M.D.

Michael J. Mack, M.D.

Mack, M. and H. Baumgarten (2016). “Just because you get on a scale doesn’t mean you lose weight: is Meetbaar Beter really measurably better?” Eur J Cardiothorac Surg. 2016 Mar 16. [Epub ahead of print]

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The article by van Veghel et al.[First results of a national initiative to enable quality improvement of cardiovascular care by transparently reporting on patient-relevant outcomes; Eur J Cardiothorac Surg., first published online March 16, 2016] describes a national initiative in the Netherlands termed ‘Meetbaar Beter’ or in English ‘Measurably Better’. The stated goal of this multicentre effort according to its website ‘aims to improve quality and transparency of care for patients with heart diseases by measuring limited patient-relevant outcome measures’ ( Those outcomes include survival, degree of health/recovery, time to recovery and return to normal activity, disutility of the care of treatment process, sustainability of health/recovery and nature of recurrences and long-term consequences of the therapy. By doing this, they are proposing to implement a ‘Value Based Healthcare Theory’ by ‘measuring patient relevant outcomes and sharing and adopting each others best practices.’ This programme that began in 2012, termed the Netherlands Joint Outcomes and Transparency Initiative is a voluntary cooperative of 14 of the 16 heart centres in the country. The initial results of that effort in 86 000 patients treated at 12 of those hospitals with one of three diseases are reported in the accompanying article. The conclusion of this study is that ‘annual data collection of patient relevant outcomes appears to be feasible’. Furthermore, the authors conclude that transparency drives quality improvement and that using a limited set of outcomes measures enables comparisons and ‘exposes the quality of decision-making’. Lastly, they conclude that transparent communication is feasible, safe, cost-effective and stimulates professional decision-making and disease management . . . While this is an ambitious national multicentre initiative that is based on achieving patient-centred healthcare value, it is not clear from this study exactly how much the ‘needle has moved’. It is also not apparent how much of any change that may have occurred is truly causation and not merely association. Don Berwick, former administrator of the Center for Medicare and Medicaid in the USA, has recently stated as the first of nine steps to improve healthcare that we must stop excessive measurement. Stated another way, just because you step on a scale does not mean you lose weight. While the goals of this programme are laudable and beyond reproach, the evidence that change is actually occurring is not evident from this report. We would encourage the leaders of this national initiative to make efforts to provide greater clarity of results actually achieved and quality improvement in patient-relevant outcomes that they can directly credit to the programme. They are stepping on the scales and weighing a lot but is any weight really being lost? (Excerpts from text; no abstract.)

Posted April 15th 2016

Recent molecular and therapeutic advances in B-cell non-Hodgkin lymphoma in children.

Stanton C. Goldman M.D.

Stanton C. Goldman, M.D.

Giulino-Roth, L. and S. Goldman (2016). “Recent molecular and therapeutic advances in B-cell non-Hodgkin lymphoma in children.” Br J Haematol. Mar 21. [Epub ahead of print]

Full text of this article.

Paediatric B-cell non-Hodgkin lymphoma (B-NHL) compromises a heterogeneous group of histological entities of which Burkitt lymphoma is the most common. In resource-rich countries, the expected cure rate is in excess of 85% with application of risk-adapted short intensive chemotherapy. In recent years, large paediatric cooperative group trials have sought to improve upon outcomes by decreasing the intensity of cytotoxic treatment as well as introducing targeted therapies, such as rituximab. These efforts have resulted in excellent outcomes, however there remains a group of high-risk patients for whom novel treatment approaches are needed. In this review, we will summarize the recent paediatric clinical trials in B-NHL as well as compare treatment approaches across the major cooperative groups. We will also highlight our current understanding of the molecular biology of paediatric B-NHL with a focus on how this may help guide future rational targeted therapy.

Posted April 15th 2016

Long-term Follow-up of Kidney Transplant Recipients in the Spare-the-Nephron-Trial.

Larry B. Melton M.D.

Larry B. Melton, M.D.

Weir, M. R., T. C. Pearson, A. Patel, V. R. Peddi, R. Kalil, J. Scandling, L. Chan, P. Baliga, L. Melton, S. Mulgaonkar, T. Waid, H. Schaefer, N. Youssef, L. Anandagoda, D. McCollum, S. Lawson and R. Gordon (2016). “Long-term Follow-up of Kidney Transplant Recipients in the Spare-the-Nephron-Trial.” Transplantation. Mar 4. [Epub ahead of print]

Full text of this article.

In the Spare-the-Nephron (STN) Study, kidney transplant recipients randomized about 115 days posttransplant to convert from CNI (calcineurin inhibitor)/MMF to sirolimus (SRL)/MMF had a significantly greater improvement in measured GFR (mGFR) at 12 months compared with those kept on CNI/MMF. The difference at 24 months was not statistically significant. From 14 top enrolling centers, 128 of 175 patients identified with a functioning graft at 2 years consented to enroll in an observational, noninterventional extension study to collect retrospectively and prospectively annual follow-up data for the interval since baseline (completion of the parent STN study at 24 months posttransplant). Overall, 11 patients died, including 5 (7.6%) in the SRL/MMF group and 6 (9.7%) in the CNI/MMF group. Twenty-two grafts have been lost including 10 (15.2%) in the SRL/MMF arm and 12 (19.4%) in the CNI/MMF arm. Death and chronic rejection were the most common causes of graft loss in both arms. There were modestly more cardiovascular events in the MMF/SRL group. Estimated creatinine clearance (Cockcroft-Gault) from baseline out to 6 additional years (8 years posttransplant, ITT analysis, SRL/MMF, n = 34; CNI/MMF, n = 26) was 63.2 +/- 28.5 mL/min/1.73 m in the SRL/MMF group and 59.2 +/- 27.2 mL/min/1.73 m in the CNI/MMF group and was not statistically significant, but there is a clinically meaningful trend for improved long-term renal function in the SRL/MMF group compared with the CNI/MMF group. The long-term decision for immunosuppression needs to be carefully individualized.