Research Spotlight

Bellin, M. D., M. Abu-El-Haija, K. Morgan, D. Adams, G. J. Beilman, S. Chinnakotla, D. L. Conwell, T. B. Dunn, M. L. Freeman, T. Gardner, V. A. Kirchner, L. F. Lara, L. Long-Simpson, J. D. Nathan, B. Naziruddin, J. A. Nyman, T. L. Pruett, S. J. Schwarzenberg, V. K. Singh, K. Smith, J. L. Steel, M. Wijkstrom, P. Witkowski and J. S. Hodges (2018). “A multicenter study of total pancreatectomy with islet autotransplantation (TPIAT): POST (Prospective Observational Study of TPIAT).” Pancreatology. Feb 6. [Epub ahead of print].

Full text of this article.

BACKGROUND/OBJECTIVES: Total pancreatectomy with islet autotransplantation (TPIAT) is considered for managing chronic pancreatitis in selected patients when medical and endoscopic interventions have not provided adequate relief from debilitating pain. Although more centers are performing TPIAT, we lack large, multi-center studies to guide decisions about selecting candidates for and timing of TPIAT. METHODS: Multiple centers across the United States (9 to date) performing TPIAT are prospectively enrolling patients undergoing TPIAT for chronic pancreatitis into the Prospective Observational Study of TPIAT (POST), a NIDDK funded study with a goal of accruing 450 TPIAT recipients. Baseline data include participant phenotype, pancreatitis history, and medical/psychological comorbidities from medical records, participant interview, and participant self-report (Medical Outcomes Survey Short Form-12, EQ-5D, andPROMIS inventories for pain interference, depression, and anxiety). Outcome measures are collected to at least 1 year after TPIAT, including the same participant questionnaires, visual analog pain scale, pain interference scores, opioid requirements, insulin requirements, islet graft function, and hemoglobin A1c. Health resource utilization data are collected for a cost-effectiveness analysis. Biorepository specimens including urine, serum/plasma, genetic material (saliva and blood), and pancreas tissue are collected for future study. CONCLUSIONS: This ongoing multicenter research study will enroll and follow TPIAT recipients, aiming to evaluate patient selection and timing for TPIAT to optimize pain relief, quality of life, and diabetes outcomes, and to measure the procedure’s cost-effectiveness. A biorepository is also established for future ancillary studies.

Asrani, S. K., G. Saracino, J. G. O’Leary, S. Gonzales, P. Kim, G. McKenna, G. Klintmalm and J. Trotter (2018). “Recipient characteristics and morbidity and mortality after liver transplantation.” J Hepatol. Feb 14. [Epub ahead of print].

Full text of this article.

BACKGROUND: Over the last decade, liver transplantation of sicker, older non-hepatitis C cirrhotics with multiple co-morbidities has increased in the United States. METHODS: We sought to identify a parsimonious set of recipient factors among HCV negative adult transplant recipients associated with significant morbidity and mortality within 5 years after liver transplantation using national (n=31,829, 2002-2015) and center specific data. Coefficients of relevant recipient factors were converted to weighted points and scaled from 0-5. Recipient factors associated with graft failure included: ventilator support (5 pts; HR 1.59, 95% CI 1.48-1.72); recipient age >60 years (3 pts; HR 1.29, 95% CI 1.23-1.36); hemodialysis (3 pts; HR 1.26, 95% CI 1.16-1.37); diabetes (2 pts; HR 1.20, 95% CI 1.14-1.27); or serum creatinine >/=1.5mg/dL without hemodialysis (2 pts; HR 1.15, 95% CI 1.09-1.22). RESULTS: Graft survival within 5 years based on points (any combination) was 77.2% (0-4), 69.1% (5-8) and 57.9% (>8). In recipients with > 8 points, graft survival was 42% (MELD<25) and 50% (MELD 25-35) in recipients receiving donors with donor risk index >1.7. In center specific data within the first year, subjects with >/= 5 points (vs. 0-4) had longer hospitalization (11 vs. 8 days, p<0.01), higher admissions for rehabilitation (12.3% versus 2.7%, p<0.01), and higher incidence of cardiac disease (14.2% vs. 5.3%, p<0.01) and stage 3 chronic kidney disease (78.6% vs. 39.5%, p=0.03) within 5 years. CONCLUSION: The impact of co-morbidities in a MELD based organ allocation system needs to be reassessed. The proposed clinical tool may be helpful for center specific assessment of risk of graft failure in non HCV patients and discussion regarding relevant morbidity in selected subsets. LAY SUMMARY: Over the last decade, liver transplantation of sicker, older patient with multiple co-morbidities has increased. In this study, we show that a set of recipient factors (recipient age>60 years, ventilator status, diabetes, hemodialysis and creatinine>1.5mg/dL) can help identify patients that may not do well after transplant. Transplanting sicker organs in patients with certain combinations of these characteristics further leads to lower survival.

Arsalan, M., W. K. Kim, A. Van Linden, C. Liebetrau, B. D. Pollock, G. Filardo, M. Renker, H. Mollmann, M. Doss, U. Fischer-Rasokat, A. Skwara, C. W. Hamm and T. Walther (2018). “Predictors and outcome of conversion to cardiac surgery during transcatheter aortic valve implantation.” Eur J Cardiothorac Surg. Mar 1. [Epub ahead of print].

Full text of this article.

OBJECTIVES: Due to increasing clinical experience with transcatheter aortic valve implantation (TAVI) procedures, sophisticated imaging and advanced device technology, TAVI complication rates are low; however, patients requiring conversion to surgery are confronted with an increased mortality risk. In this retrospective study, we evaluated the predictors for conversion and the outcomes of these patients. METHODS: We analysed the records of all patients undergoing TAVI in our centre from 2011 to 2016 and focused on cases that required conversion to sternotomy. We investigated reasons and risk factors for conversion as well as 30-day and 1-year outcomes. RESULTS: During the study period, 32 (2.1%) of 1775 patients undergoing TAVI required immediate conversion to sternotomy. Annular rupture (5 of 32; 16%), device embolization (9 of 32; 28%) and pericardial tamponade (15 of 32; 47%) were the most common reasons for conversion. Usage of a self-expandable valve showed to be the only predictor for conversion (odds ratio 0.38, 95% confidence interval 0.16-0.90; P = 0.03). Survival at 30 days and 1 year was 56% and 41%, respectively. Patients who survived 30 days after conversion showed higher preoperative ejection fraction, shorter duration of surgery and shorter perfusion time. CONCLUSIONS: In this high-volume, single-centre experience, conversion to sternotomy during TAVI occurred in about 2%, with annular rupture, device embolization and pericardial tamponade being the most common causes. Complications requiring conversion showed to be unpredictable. However, in view of these life-threatening complications, the 30-day survival rate exceeding 50% emphasizes the importance of an experienced and well-attuned heart team providing immediate access to surgical bailout procedures.

Ameen, R., S. A. Shemmari and M. Askar (2018). “Next-generation sequencing characterization of HLA in multi-generation families of Kuwaiti descent.” Hum Immunol 79(3): 137-142.

Full text of this article.

The frequency of HLA genes in one population may not accurately represent frequencies in other populations. In this study, we characterized extended human leukocyte antigen (HLA) haplotypes in several families of Kuwaiti descent by high-resolution typing using next-generation technology. A total 81 members (including patients and related donors) from 21 families were enrolled. No haplotypes were shared among multiple families. Of 77 haplotypes identified, 23 were not listed in the HaploStats database. Two haplotypes were most common in African Americans, six in Asian Pacific Islanders, three in Caucasians, three in Hispanics, and three in Native Americans. The remaining identified haplotypes were not among the most common 200 HLA haplotypes in any of the five major populations. This cohort had 202 (19%) unique alleles, including 20 rare alleles, 16 very rare alleles, and 2 novel ones. Furthermore, no frequency data were available for 30% (23/77) of the observed haplotypes, and 6% (3/49) of B approximately C blocks identified were not available in the HaploStats database. Kuwaiti individuals carry unique HLA haplotypes that are not shared by the majority of individuals historically reported to the US National Marrow Donor Program registry.

Alter, H., T. Block, N. Brown, A. Brownstein, C. Brosgart, K. M. Chang, P. J. Chen, F. V. Chisari, C. Cohen, H. El-Serag, J. Feld, R. Gish, J. Glenn, T. Greten, H. Guo, J. T. Guo, Y. Hoshida, J. Hu, K. V. Kowdley, W. Li, J. Liang, S. Locarnini, A. S. Lok, W. Mason, B. McMahon, A. Mehta, R. Perrillo, P. Revill, C. M. Rice, J. Rinaudo, R. Schinazi, C. Seeger, K. Shetty, J. Tavis and F. Zoulim (2018). “A research agenda for curing chronic hepatitis B virus infection.” Hepatology 67(3): 1127-1131.

Full text of this article.

We encourage the scientific community to focus on research leading to discovery of a cure for chronic HBV infection based on these principles: 1) The surest way to cure HBV is to eliminate or permanently silence its cccDNA. 2) The most important impediment to this achievement is our limited understanding of the fundamental molecular mechanisms that control cccDNA biogenesis, homeostasis, and decay. 3) Understanding these mysteries is now within reach, thanks to recent technological advances that enable definition of these mechanisms. 4) Vulnerabilities in the cccDNA “life cycle” that are discovered in the course of these studies can be exploited to develop small molecule and other molecular strategies to eradicate or permanently silence the cccDNA. 5) Because these studies will explore the unknown, the outcome, like all great adventures, cannot be predicted. Thus, we suggest that in addition to approaches that directly target cccDNA, independent approaches that target other vulnerabilities in the viral life cycle and either indirectly repress HBV cccDNA or safely establish a curative antiviral immune response be pursued in parallel. 6) Such projects could include genetic approaches to cccDNA mutagenesis, epigenetic modification, or other strategies that can suppress cccDNA transcription (e.g., HBV-targeted antisense and small interfering RNA, HBV X protein inhibition, etc.) or to prevent its recycling (e.g., capsid inhibitors). (Excerpt from text, p. 1128; no abstract available.)