Lee, David D

AbstractBackgroundHepatic artery stenosis (HAS) after liver transplant (LT) is a source of significant morbidity. Some reports have suggested higher arterial complications in patients who receive donation after cardiac death (DCD) livers.MethodsA total of 2860 consecutive LT were reviewed from a prospectively collected database. All angiograms performed in LT recipients were reviewed and primary patency rates determined by need for further intervention or graft loss due to HAT.ResultsHepatic artery stenosis was seen in 4.6% of DCD and donation after brain death (DBD) recipients. Recipient male gender, age at transplant, complex donor hepatic artery anatomy, and prolonged operative time were all associated with HAS, but not DCD status. While HAS in recipients of DCD grafts required more stents (1.7% vs 0.6%, P = 0.04) and had worse primary patency rates (logrank, P = 0.02), outcomes as defined by HAT, patient and graft survival were not significantly different between the recipients of DCD or DBD grafts.ConclusionWe observed no significant difference in the incidence of hepatic artery complications, patient survival, or graft survival in recipients of DCD or DBD grafts. However, HAS in DCD recipients had worse primary patency and a higher need for stent placement.

With recent changes in United Network for Organ Sharing policy, patients in the United States with hepatocellular carcinoma (HCC) are likely to spend more time on the liver transplantation (LT) waiting list. The increasing wait time will allow for an opportunity to assess tumor biology prior to LT. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) paradigm provides such a framework for this assessment, and yet little is understood of its utility as it would apply for patients listed for LT in the United States. Through a collaboration between the University of California, San Francisco, and the Mayo Clinic, Jacksonville, Florida, the experience of 772 patients listed for LT were retrospectively reviewed to study the impact of immediate mRECIST classification following locoregional therapy (LRT) on pre‐ and post‐LT outcomes. Patients who had progression of disease (PD; n = 72), failed to respond to LRT (n = 89) at any time point, or did not achieve radiologic complete response (CR; n = 224) were all at significant risk for wait‐list dropout (odds ratio [OR] = 12.11, 4.81, and 2.48; respectively). CR identified a cohort of patients who were at a reduced risk for wait‐list dropout. However, 24.9% eventually required further intervention while waiting for transplant, and as many as 82.4% were found to have residual HCC on explant pathology. Failure to respond to LRT was associated with increased risk for recurrence (OR = 3.00) more so than PD (OR = 1.36), suggesting that despite PD, patients who eventually can respond to LRT may represent favorable candidates for LT. In conclusion, for patients awaiting LT, the mRECIST assessment provides critical guidance for patient management. Although PD portends a poor prognosis, our findings suggest that further aggressive LRT should be pursued because a response to LRT may yield acceptable results for patients awaiting LT as well as after LT.

Introduction and aim: Combined hepatocellular-cholangiocarcinoma (HCC-CCA) is a rare liver malignancy distinct from either hepatocellular carcinoma (HCC) or cholangiocarcinoma. Liver transplantation (LT) is not recommended for HCC-CCA because of suboptimal outcomes. Because non-invasive diagnosis of HCC-CCA is extremely challenging, some HCC-CCAs are presumed as HCC on imaging and listed for LT with the correct diagnosis ultimately made on explant pathology. We compared HCC-CCA with HCC to determine the utility of response to pre-transplant loco-regional therapy (LRT) in predicting outcomes for HCC-CCA after LT as a potential means of identifying appropriate HCC-CCA patients for LT. Materials and methods: Retrospective review of 19 patients with pathologically confirmed HCC-CCA individually matched to 38 HCC patients based on age, sex, and Milan criteria at listing was performed. The modified response evaluation criteria in solid tumors was used to categorize patients as responders or non-responders to pre-transplant LRT based on imaging performed before and after LRT. Overall survival (OS) and recurrence-free survival (RFS) were examined. Results: OS at 3 years post-transplant was 74% for HCC-CCA and 87% for HCC. RFS at 3 years was 74% for HCC-CCA, and 87% for HCC. Among responders to LRT, the 3-year OS was 92% for HCC-CCA and 88% for HCC; among non-responders, 3-year OS was 43% for HCC-CCA and 83% for HCC. Higher 3-year OS was observed among HCC-CCA responders (77%) compared with HCC-CCA non-responders (23%). Conclusions: OS was similarly high among responders to pre-transplant LRT irrespective of tumor type. Radiologic response to LRT could potentially be used to select appropriate HCC-CCA patients for LT if the findings are validated in independent studies.

Abstract Early allograft dysfunction (EAD) identifies allografts with marginal function soon after liver transplantation (LT) and is associated with poor LT outcomes. The impact of EAD on post-LT renal recovery, however, has not been studied. Data on 69 primary LT recipients (41 with and 28 without history of renal dysfunction) who received renal replacement therapy (RRT) for a median (range) of 9 (13-41) days before LT were retrospectively analyzed. Primary outcome was renal nonrecovery defined as RRT requirement 30 days from LT. Early allograft dysfunction developed in 21 (30%) patients, and 22 (32%) patients did not recover renal function. Early allograft dysfunction was more common in the renal nonrecovery group (50% vs 21%, P = 0.016). Multivariate logistic regression analysis demonstrated that EAD (odds ratio, 7.25; 95% confidence interval, 2.0-25.8; P = 0.002) and baseline serum creatinine (odds ratio, 3.37; 95% confidence interval, 1.4-8.1; P = 0.007) were independently associated with renal nonrecovery. History of renal dysfunction, duration of renal dysfunction, and duration of RRT were not related to renal recovery ( P > 0.2 for all). Patients who had EAD and renal nonrecovery had the worst 1-, 3-, and 5-year patient survival, whereas those without EAD and recovered renal function had the best outcomes ( P < 0.001). Post-LT EAD was independently associated with renal nonrecovery in LT recipients on RRT for a short duration before LT. Furthermore, EAD in the setting of renal nonrecovery resulted in the worst long-term survival. Measures to prevent EAD should be undertaken in LT recipients on RRT at time of LT.

Although hepatocellular carcinoma (HCC) has become a common indication for liver transplantation (LT), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular carcinoma–cholangiocarcinoma (cHCC‐CCA) are historically contraindicated due to their aggressive behavior. On the basis of recent experiences, some groups have proposed a clinical trial investigating the role of LT for patients with early cholangiocarcinoma (CCA), defined as a single lesion ≤ 2 cm. The purpose of this study is to assess the clinicopathologic features and outcomes following LT for patients who were initially diagnosed with HCC and subsequently found to have either ICC or cHCC‐CCA on explant. Patients with the diagnosis of primary liver cancer (PLC) after LT from a single center were retrospectively reviewed. Outcomes for patients with early CCA were compared with patients with HCC within Milan criteria (MC). Out of 618 patients transplanted with PLC, 44 patients were found to have CCA on explant. On the basis of preoperative imaging, 12 patients met criteria for early CCA and were compared with 319 patients who had HCC within MC. The 1‐ and 5‐year overall survival for early CCA versus HCC was 63.6% versus 90.0% and 63.6% versus 70.3% (log‐rank, P = 0.25), respectively. Overall recurrence was 33.3% for early CCA versus 11% for HCC. On explant the patients with CCA were more likely understaged with higher tumor grade and vascular invasion. In conclusion, patients with CCA present a diagnostic challenge, which often leads to the finding of more aggressive lesions on explant after LT, higher recurrence rates, and worse post‐LT survival. Careful consideration of this diagnostic conundrum needs to be made before a clinical trial is undertaken. Liver Transplantation 24 634–644 2018 AASLD.

Variation in average Model for End‐Stage Liver Disease (MELD) score at liver transplantation (LT) by United Network for Organ Sharing (UNOS) regions is well documented. The present study aimed to investigate MELD variation at the interregional, intraregional, and intra–donation service area (DSA) levels. Patients undergoing LT between 2015 and 2016 were obtained from the UNOS standard analysis and research file. The distribution of allocation MELD score including median, skew, and kurtosis was examined for all transplant programs. Intraregional median allocation MELD varied significantly within all 11 UNOS regions. The largest variation between programs was seen in region 5 (MELD 24.0 versus 38.5) and region 3 (MELD 20.5 versus 32.0). Regions 1, 5, and 9 had the largest proportion of programs with a highly negative skewed MELD score (50%, 57%, and 57%, respectively), whereas regions 3, 6, 10, and 11 did not have any programs with a highly negative skew. MELD score distribution was also examined in programs located in the same DSA, where no barriers exist and theoretically no significant difference in allocation should be observed. The largest DSA variation in median allocation MELD score was seen in NYRT‐OP1 LiveOnNY (MELD score variation 11), AZOB‐OP1 Donor Network of Arizona (MELD score variation 11), MAOB‐OP1 New England Organ Bank (MELD score variation 9), and TXGC‐OP1 LifeGift Organ Donation Ctr (MELD score variation 9). In conclusion, the present study demonstrates that this MELD disparity is not only present at the interregional level but can be seen within regions and even within DSAs between programs located as close as several city blocks away. Although organ availability likely accounts for a component of this disparity, the present study suggests that transplant center behavior may also play a significant role.Liver Transplantation 24 488–496 2018AASLD.

The tragedy of the national opioid epidemic has resulted in a significant increase in the number of opioid‐related deaths and accordingly an increase in the number of potential donors designated Public Health Service (PHS) increased risk. Previous studies have demonstrated reluctance to use these PHS organs, and as a result, higher discard rates for these organs have been observed. All patients listed for liver transplantation in the United States from January 2005 to December 2016 were investigated. Patients on the waiting list were divided into 2 groups: those in which a PHS liver was used for transplantation (accepted PHS group) and those in which a PHS liver was declined and transplanted into a recipient lower on the match run (declined PHS group). Intention‐to‐treat patient survival from the time of PHS offer was significantly higher in the accepted PHS compared with the declined PHS group (P < 0.001). On Cox multivariate regression, declining a PHS donor liver was associated with a hazard ratio of 2.36 (95% confidence interval, 2.23‐2.49; P < 0.001). For patients in which a PHS organ offer was declined, 11.6% died or were delisted for being too sick within the subsequent year. Donor liver allografts implanted in the accepted PHS group were of a lower donor risk index (1.28 versus 1.44) compared with the non‐PHS organs that patients in the declined PHS group ultimately received if they underwent transplantation. In conclusion, there is a significantly higher survival for patients in which a PHS liver is accepted and used compared with those patients in which a PHS organ is declined. These data will help inform decisions about whether or not to accept a PHS donor liver for both patients and transplant professionals. Liver Transplantation 24 497–504 2018 AASLD.

Hepatic ischemia/reperfusion injury (IRI) and associated inflammation contributes to liver dysfunction and complications after liver surgery and transplantation. Mesenchymal stem cells (MSCs) have been reported to reduce hepatic IRI because of their reparative immunomodulatory effects in injured tissues. Recent studies have highlighted beneficial effects of extracellular vesicles from mesenchymal stem cells (MSC‐EV) on tissue injury. The effects of systemically administered mouse bone marrow–derived MSC‐EV were evaluated in an experimental murine model of hepatic IRI induced by cross‐clamping the hepatic artery and portal vein for 90 minutes followed by reperfusion for periods of up to 6 hours. Compared with controls, intravenous administration of MSC‐EV 30 minutes prior to IRI dramatically reduced the extent of tissue necrosis, decreased caspase 3–positive and apoptotic cells, and reduced serum aminotransferase levels. MSC‐EV increased hepatic messenger RNA (mRNA) expression of NACHT, LRR, and PYD domains‐containing protein 12, and the chemokine (C‐X‐C motif) ligand 1, and reduced mRNA expression of several inflammatory cytokines such as interleukin 6 during IRI. MSC‐EV increased cell viability and suppressed both oxidative injury and nuclear factor kappa B activity in murine hepatocytes in vitro. In conclusion, the administration of extracellular vesicles derived from bone marrow–derived MSCs may ameliorate hepatic IRI by reducing hepatic injury through modulation of the inflammatory response.Liver Transplantation 23 791–803 2017 AASLD.