William Kenneth Washburn

Liver and Intestine Transplantation in the United States 1998–2007

Liver transplantation numbers in the United States remained constant from 2004 to 2007, while the number of waiting list candidates has trended down. In 2007, the waiting list was at its smallest since 1999, with adults ≥50 years representing the majority of candidates. Noncholestatic cirrhosis was most commonly diagnosed. Most age groups had decreased waiting list death rates; however, children <1 year had the highest death rate. Use of liver allografts from donation after cardiac death (DCD) donors increased in 2007. Model for end‐stage liver disease (MELD)/pediatric model for end‐stage liver disease (PELD) scores have changed very little since 2002, with MELD/PELD <15 accounting for 75% of the waiting list. Over the same period, the number of transplants for MELD/PELD <15 decreased from 16.4% to 9.8%. Hepatocellular carcinoma exceptions increased slightly. The intestine transplantation waiting list decreased from 2006, with the majority of candidates being children <5 years old. Death rates improved, but remain unacceptably high. Policy changes have been implemented to improve allocation and recovery of intestine grafts to positively impact mortality. In addition to evaluating trends in liver and intestine transplantation, we review in depth, issues related to organ acceptance rates, DCD, living donor transplantation and MELD/PELD exceptions.

Impact of Recipient MELD Score on Resource Utilization

The model for end stage liver disease (MELD) system prioritizes deceased donor organs to the sickest patients who historically require higher healthcare expenditures. Limited information exists regarding the association of recipient MELD score with resource use. Adult recipients of a primary liver allograft (n = 222) performed at a single center in the first 27 months of the MELD system were analyzed. Costs were obtained for each recipient for the 12 defined categories of resource utilization from the time of transplant until discharge. True (calculated) MELD scores were used. Inpatient transplant costs were significantly associated with recipient MELD score (r= 0.20; p = 0.002). Overall 1‐year patient survival was 85.0% and was not associated with MELD score (p = 0.57, log rank test). Recipient MELD score was significantly associated with costs for pharmacy, laboratories, radiology, dialysis and physical therapy. Multivariate linear regression revealed that MELD score was most strongly associated with cost compared to other demographic and clinical factors. Recipient MELD score is correlated with transplant costs without significantly impacting survival.

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.

TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells

Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-β1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases.

Surgical Treatment of an Extrarenal Pseudoaneurysm After Kidney Transplantation

A 69-year-old man who underwent a kidney transplantation developed a large pseudoaneurysm at the anastomosis between the right external iliac artery and renal transplant artery. After an unsuccessful attempt using percutaneous thrombin injection, the patient underwent open exploratory laparotomy and surgical ligation of the pseudoaneurysm with preservation of renal graft function.

Truth and consequences

The system for distribution of deceased donor liver allografts has undergone relatively minor modifications over the past 15 years. The local-regional-national algorithm has been modified with small changes for discrete patient groups that impact a minor percentage of the total liver transplant volume. The proliferation of transplant centers has contributed to an entrenchment of the local donation service area as the primary distribution unit, with an amplified level of competition between centers. This has resulted in the relatively infrequent occurrence where a liver is placed nationally with a center outside the region of origin of the donor.

Abstract 1567: A mass spectrometry based serum test for the detection of hepatocellular carcinoma (HCC) in high risk patients

Improved screening protocols (SP) for patients at high risk of developing HCC could lead to improved patient outcome and possibly cure if detected early. The current SPs, ultrasound with the possible addition of alphafetoprotein (AFP) measurement, suffer from insufficient sensitivity and specificity, and less than 30% of patients are diagnosed early enough to be suitable candidates for resection or transplantation. An easy to use biomarker for the early detection of HCC is clearly needed. We used mass spectrometry analysis of serum samples combined with specialized deep learning techniques to train and validate such a test. The development cohort consisted of patients undergoing transplant or resection for HCC (N = 52; median MELD = 14), and patients with advanced cirrhosis undergoing liver transplant (N = 53; median MELD = 25). Underlying cause of liver disease was 51% hepatitis C infection. The validation cohort consisted of patients with advanced HCC (N = 103; 70/26/7 Child-Pugh A/B/C) and liver disease but no HCC (N = 77; 68/7/2 Child-Pugh A/B/C), with 68% of patients having hepatitis B infection (HBV). The classifier was trained especially to avoid confounding by liver function. The resulting test showed a sensitivity/specificity of 73%/95% in cross validation in the development set overall. In the subset of T1 patients (or lesion size The developed test shows promise in the early detection of HCC as a screening tool in high risk patients independent of the cause of underlying liver disease. While further validation will be necessary to conclusively prove its clinical validity, we believe such a test could substantially improve early detection of HCC. Citation Format: Devalingam Mahalingam, William K. Washburn, Glenn Halff, Leonidas Chelis, Stylianos Kakolyris, Stylianos Vradelis, Julia Grigorieva, Carlos Oliveira, Heinrich Roder, Joanna Roder. A mass spectrometry based serum test for the detection of hepatocellular carcinoma (HCC) in high risk patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1567. doi:10.1158/1538-7445.AM2015-1567

Abstract 3259: TGFβ signaling is frequently attenuated in hepatocellular carcinomas but is retained for malignant phenotypes in some hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Its development and progression have been shown to be regulated by various cytokines including TGFβ. However, the role of TGFβ signaling in the progression of HCC remains controversial. In the current study, we examined the expression levels of TGFβ pathway components and the activation status of Smad2/3 proteins as reflected by phospho-Smad2/3 levels in human and mouse HCC tissues and human HCC cell lines. We also investigated whether abrogation of TGFβ signaling in HCC cell lines that are responsive to TGFβ affects the growth and metastasis of transplanted HCC cells in nude mice. Quantitative real-time RT-PCR and Western immune blotting analyses reveal widespread down-regulation of TGFβ signaling pathway components including Smad2/3 and TGFβ type I and II receptors in HCC tissues of patients and mice in comparison to adjacent normal tissues. Treatment of our HCC cell lines (SNU398, SNU423, HepG2, and Sk-Hep-1) with TGFβ1 revealed that the SNU398 cell line was refractory whereas the other three cell lines were sensitive to TGFβ as determined with a number of in vitro assays including Smad phosphorylation, gene transcription, and growth inhibition assays. Knockdown of TGFβ type II receptor with shRNA significantly reduced TGFβ signaling activity in the Sk-Hep-1 cell line resulting in suppressed growth of its subcutaneous tumors and reduced metastasis potential when the cells were inoculated through tail vein injection. Our results suggest that TGFβ signaling may play a suppressive role in early stage of HCC development, but a promoting role in advanced stage, which is represented by the Sk-Hep-1 cell model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3259. doi:1538-7445.AM2012-3259