Ronald T. Cotton

Trans-ancestry mutational landscape of hepatocellular carcinoma genomes

Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.

An Early Regional Experience with Expansion of Milan Criteria for Liver Transplant Recipients

The Milan Criteria (MC) showed that orthotopic liver transplantation (OLT) was an effective treatment for patients with nonresectable, nonmetastatic HCC. There is growing evidence that expanding the MC does not adversely affect patient or allograft survival following OLT.

Liver transplantation with donation after cardiac death donors: A comprehensive update

BACKGROUND Use of donation after cardiac death (DCD) donors has been proposed as an effective way to expand the availability of hepatic allografts used in orthotopic liver transplantation (OLT); yet, there remains no consensus in the medical literature as to how to choose optimal recipients and donors based on available information. METHODS We queried the United Network of Organ Sharing/Organ Procurement and Transplantation Network database for hepatic DCD allografts used in OLT. As of March 31, 2011, 85,148 patients received hepatic allografts from donation-after-brain-death (DBD) donors, and 2351 patients received hepatic allografts from DCD donors. We performed survival analysis using log-rank and Kaplan-Meier tests. We performed univariate and multivariate analyses using the Cox proportional hazards model. All statistics were performed with SPSS 15.0. RESULTS Patients receiving hepatic DCD allografts had significantly worse survival compared with patients receiving hepatic DBD allografts. Pediatric patients who received a hepatic DCD allograft had similar survival to those who received a hepatic DBD allograft. The optimal recipient-related characteristics were age <50 y, International Normalized Ratio <2.0, albumin >3.5 gm/dL, and cold ischemia time <8 h; optimal donor-related characteristics included age <50 y and donor warm ischemia time <20 min. CONCLUSIONS By identifying certain characteristics, the transplant clinicians decision-making process can be assisted so that similar survival outcomes after OLT can be achieved with the use of hepatic DCD allografts.

Pediatric liver transplantation for primary malignant liver tumors with a focus on hepatic epithelioid hemangioendothelioma: The UNOS experience

Guiteau JJ, Cotton RT, Karpen SJ, O’Mahony CA, Goss JA. Pediatric liver transplantation for primary malignant liver tumors with a focus on hepatic epithelioid hemangioendothelioma: The UNOS experience.
Pediatr Transplantation 2010: 14: 326–331.

Pediatric Liver Transplant Center Volume and the Likelihood of Transplantation.

BACKGROUND: Low case volume has been associated with poorer surgical outcomes in a multitude of surgical procedures. We studied the association among low case volume, outcomes, and the likelihood of pediatric liver transplantation. METHODS: We studied a cohort of 6628 candidates listed in the Organ Procurement and Transplantation Network for primary pediatric liver transplantation between 2002 and 2012; 4532 of the candidates went on to transplantation. Candidates were divided into groups according to the average volume of yearly transplants performed in the listing center over 10 years: >15, 10 to 15, 5 to 9, and <5. We used univariate and multivariate Cox regression analyses with bootstrapping on transplant recipient data and identified independent recipient and donor risk factors for wait-list and posttransplant mortality. RESULTS: 38.5% of the candidates were listed in low-volume centers, those in which <5 transplants were performed annually. These candidates had severely reduced likelihood of transplantation with only 41% receiving a transplant. For the remaining candidates, listed at higher volume centers, the transplant rate was 85% (P < .001). Being listed at a low-volume center was a significant risk factor in multivariate Cox regression analysis for both wait-list mortality (hazard ratio, 3.27; confidence interval, 2.53–4.23) and posttransplant mortality (hazard ratio, 2.21; confidence interval, 1.43–3.40). CONCLUSIONS: 38.5% of pediatric transplant candidates are listed in low-volume transplant centers and have lower likelihood of transplantation and poorer outcomes. If further studies substantiated these findings, we would advocate consolidating pediatric liver transplantation in higher volume centers.

Building a Comprehensive Genomic Program for Hepatocellular Carcinoma

BackgroundHepatocellular carcinoma (HCC) is the most common primary liver cancer, causing approximately 660,000 deaths worldwide annually. The preferred treatment of HCC is surgical resection or orthotopic liver transplantation (OLT) for patients meeting specific criteria. For patients outside these criteria, options are limited and include medical therapy, radiofrequency ablation, chemoembolization, or palliative measures, and these result in poor outcomes. Various centers at Baylor are elucidating the genomics of HCC to improve treatment options, with a focus on three etiologies: hepatitis C virus, hepatitis B virus, and non-viral.MethodsThrough collaborative efforts, we have established an effective specimen biobanking protocol, and we are using several techniques to analyze HCC, including whole genome sequencing, whole exome sequencing, gene-specific analysis, gene expression, and epigenetic analysis.ResultsWe have completed whole genome sequencing on two patient samples, whole exome sequencing on 47 patient samples, gene-specific analysis on 94 patient samples, gene expression on 4 patient samples, and epigenetic analysis on 1 patient sample.ConclusionsWe hope to use these results to define novel genetic therapeutic strategies that may work in conjunction with surgical approaches to improve long-term patient and graft survival rates in patients with HCC. We also aim to provide a functional framework of a comprehensive program for genomic analysis that may be imitated by other institutions and for other tumors in the global quest toward personalized genomic medicine.

Effects of an early referral system on liver transplantation for hepatoblastoma at Texas Children's Hospital.

The purposes of this study were to analyze the effects of an ERS on time to transplantation and to describe our centers experience with OLT for HB. Patients who received OLT for HB between 2000 and 2013 were included. Patient and allograft characteristics, chemotherapy regimens, and prior surgical therapies were examined. The interval between diagnosis and OLT prior to and following the institution of an ERS for transplant was compared. Survival and tumor recurrence were analyzed. Nineteen patients received OLT for HB (mean age 33 months). All children received grafts from deceased donors. Two patients underwent prior resections. Tumor recurred in four patients (21.1%). Both patients who received salvage transplants experienced post‐OLT recurrence. Three of the four recurrences occurred in spite of adjuvant chemotherapy. There were three deaths: two from metastatic disease. One‐ and five‐yr survivals were 86.1% and 73.8%. After the institution of the ERS, the mean interval between tissue diagnosis and OLT was significantly reduced. Our series of 19 patients demonstrates a 21% recurrence of HB following OLT despite chemotherapy. Five‐yr survival reached 73.8%. A system of early referral can effectively reduce times between diagnosis and transplant.

Survival Outcomes Following Pediatric Liver Transplantation (Pedi-SOFT) Score: A Novel Predictive Index

A prognostic index to predict survival after liver transplantation could address several clinical needs. Here, we devised a scoring system that predicts recipient survival after pediatric liver transplantation. We used univariate and multivariate analysis on 4565 pediatric liver transplant recipients data and identified independent recipient and donor risk factors for posttransplant mortality at 3 months. Multiple imputation was used to account for missing variables. We identified five factors as significant predictors of recipient mortality after pediatric liver transplantation: two previous transplants (OR 5.88, CI 2.88–12.01), one previous transplant (OR 2.54, CI 1.75–3.68), life support (OR 3.68, CI 2.39–5.67), renal insufficiency (OR 2.66, CI 1.84–3.84), recipient weight under 6 kilograms (OR 1.67, CI 1.12–2.36) and cadaveric technical variant allograft (OR 1.38, CI 1.03–1.83). The Survival Outcomes Following Pediatric Liver Transplant score assigns weighted risk points to each of these factors in a scoring system to predict 3‐month recipient survival after liver transplantation with a C‐statistic of 0.74. Although quite accurate when compared with other posttransplant survival models, we would not advocate individual clinical application of the index.

Comparing Outcomes for Rare Primary Hepatic Tumors after Liver Transplantation

Aim: Liver transplantations (LT) have proven to be a successful treatment for many tumors of the liver. The goal of this study was to evaluate the outcomes of liver transplantations in patients with primary liver tumors with a focus on rarer malignancies. Methods: The UNOS database catalogues all adult patients who underwent LT for a primary liver tumor from 1992-2008. Of the 73,231 liver transplantations, 5,682 patients with liver tumors were identified and categorized by indication for LT: hepatocellular carcinoma (HCC, n=5272), hepatic epithelioid hemangioendothelioma (HEH, n=85), cholangiocarcinoma (n=249), sarcomas (n= 11) and combined HCC-Cholangiocarcinomas (HCC-CC, n=12). Survivals were calculated using Kaplan-Meier and log rank tests. Results: 5,629 patients received LT for solid liver tumors. HCC patients and their allografts survived longer than those transplanted for cholangiocarcinomas (p=0.001, 0.002) or for HCC-CC (p=0.025, 0.004). Overall survival rates of HCC patients were 86.4%, 71.3%, and 61.2% at 1, 3 and 5 years, respectively. Cholangiocarcinoma patients had survival rates of 79.7%, 60.3% and 45.5% at 1-, 3- and 5-years from transplant. HCC-CC patients had the worst overall survival of 72.9%, 39.1% and 39.1% at 1, 3 and 5 years. Allograft survival in HCC-CC patients was comparatively low, averaging 65.6%, 35.2% and 0% at 1-, 3- and 5-years. HEH patients and their allografts survived the longest with overall survival of 83.9%, 77.8% and 73.5% at 1, 3 and 5 years, respectively, and allograft survival at 76.8%, 69.8% and 64.3%. Conclusion: Our data reveals overall survival was significantly better in HEH patients when compared to HCC, cholangiocarcinoma and HCC-CC patients after LT. In fact, HCC-CC patients fared the worst, both in patient and allograft survival, as compared to HCC and HEH. Results of cholangiocarcinoma patients show worse survival after LT compared to HCC and HEH, though recent evidence suggests adjuvant therapy will change outcomes for the future. Our findings suggest transplantation for HCC-CC may not be sufficient treatment. Other forms of adjuvant and neoadjuvant therapy may be indicated, warranting further research.

Liver transplant length of stay (LOS) index: A novel predictive score for hospital length of stay following liver transplantation

An index to predict hospital length of stay after liver transplantation could address unmet clinical needs. Length of stay is an important surrogate for hospital costs and efforts to limit stays can preserve our healthcare resources. Here, we devised a scoring system that predicts hospital length of stay following liver transplantation. We used univariate and multivariate analyses on 73 635 adult liver transplant recipient data and identified independent recipient and donor risk factors for prolonged hospital stay (>30 days). Multiple imputation was used to account for missing variables. We identified 22 factors as significant predictors of prolonged hospital stay, including the most significant risk factors: intensive care unit (ICU) admission (OR 1.75, CI 1.58‐1.95) and previous transplant (OR 1.60, CI 1.47‐1.75). The length of stay (LOS) index assigns weighted risk points to each significant factor in a scoring system to predict prolonged hospital stay after liver transplantation with a c‐statistic of 0.75. The LOS index demonstrated good discrimination across the entire population, dividing the cohort into tertiles, which had odds ratios of 2.25 (CI 2.06‐2.46) and 7.90 (7.29‐8.56) for prolonged hospital stay (>30 days). The LOS index utilizes 22 significant donor and recipient factors to accurately predict hospital length of stay following liver transplantation. The index further demonstrates the basis for a clear clinical recommendation to mitigate risk of long hospitalization by minimizing cold ischemia time.