Portable hypothermic oxygenated machine perfusion for organ preservation in liver transplantation: A randomized, open-label, clinical trial.

BACKGROUND AND AIMS: In liver transplantation, cold preservation induces ischemia, resulting in significant reperfusion injury. Hypothermic oxygenated machine perfusion (HMP-O 2 ) has shown benefits compared to static cold storage (SCS) by limiting ischemia-reperfusion injury. This study reports outcomes using a novel portable HMP-O 2 device in the first US randomized control trial. APPROACH AND RESULTS: The PILOT trial (NCT03484455) was a multicenter, randomized, open-label, noninferiority trial, with participants randomized to HMP-O 2 or SCS. HMP-O 2 livers were preserved using the Lifeport Liver Transporter and Vasosol perfusion solution. The primary outcome was early allograft dysfunction. Noninferiority margin was 7.5%. From April 3, 2019, to July 12, 2022, 179 patients were randomized to HMP-O 2 (n=90) or SCS (n=89). The per-protocol cohort included 63 HMP-O 2 and 73 SCS. Early allograft dysfunction occurred in 11.1% HMP-O 2 (N=7) and 16.4% SCS (N=12). The risk difference between HMP-O 2 and SCS was -5.33% (one-sided 95% upper confidence limit of 5.81%), establishing noninferiority. The risk of graft failure as predicted by Liver Graft Assessment Following Transplant score at seven days (L-GrAFT 7 ) was lower with HMP-O 2 [median (IQR) 3.4% (2.4-6.5) vs. 4.5% (2.9-9.4), p =0.024]. Primary nonfunction occurred in 2.2% of all SCS (n=3, p =0.10). Biliary strictures occurred in 16.4% SCS (n=12) and 6.3% (n=4) HMP-O 2 ( p =0.18). Nonanastomotic biliary strictures occurred only in SCS (n=4). CONCLUSIONS: HMP-O 2 demonstrates safety and noninferior efficacy for liver graft preservation in comparison to SCS. Early allograft failure by L-GrAFT 7 was lower in HMP-O 2 , suggesting improved early clinical function. Recipients of HMP-O 2 livers also demonstrated a lower incidence of primary nonfunction and biliary strictures, although this difference did not reach significance.

Simultaneous split liver/kidney transplantation: A national and single center experience report.

BACKGROUND: End-stage liver disease (ESLD) and end-stage renal disease (ESRD) are prevalent diseases for which the definitive treatment is transplantation. With limited organ supply, strategies to maximize organ availability has led to increasing rates of split liver transplantations for ESLD patients. Therefore, simultaneous split liver and kidney transplantations (SSLK) for patients with ESLD and ESRD could represent a treatment option for comorbid patients. However, current practice and outcomes after SSLK are unknown. METHODS: We aim to report national trends and our experience with patients undergoing SSLK. We performed a retrospective review of the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research file from January 2011-April 2022. Descriptive analysis of preoperative characteristics, postoperative outcomes and actuarial graft and patient survivals are reported. RESULTS: National review of the UNOS transplant registry from 2011-2021 of adult patients undergoing initial transplantation via SSLK demonstrates that this procedure remains uncommon, with only 76 such cases captured in that time. Nevertheless, survival rates at 1, 3, and 5 years remains robust, at 94%, 92%, and 90% for patients overall, 90%, 88%, 88%, for the liver graft, and 93%, 91%, 88% for the kidney graft, respectively. Review of a single center experience with three such patients from 2019-2021 has shown a safe, enduring transplant option with no graft complications seen. CONCLUSIONS: SSLK is both safe and a feasible option to optimize organ supply while allowing recipients to receive quality liver and kidney grafts and should be considered more often by transplant centers going forward.

Survival after LDLT in recipients ≥70 years old in the United States. An OPTN/UNOS liver transplant registry analysis.

BACKGROUND: Living donor liver transplantation (LDLT) in the elderly population is currently not well studied. There are single-center studies indicating that patient age should not be a barrier to LDLT, with similar outcomes compared to younger recipients. METHODS: Using UNOS/STAR data from 2010 to 2022 we retrospectively analyzed patients ≥70 years old receiving a living donor graft (LDLT ≥70y group) versus a deceased donor graft (DDLT ≥70y group). In addition, we compared recipients ≥70 years old undergoing LDLT versus patients 18-69 years old also undergoing LDLT. Donor and recipient baseline characteristics, as well as postoperative outcomes including graft and patient survival were analyzed and compared between groups. RESULTS: Recipients in the LDLT ≥70y group showed less disease burden and spent significantly less time on the waitlist when compared to recipients in the DDLT ≥70y group (102 [49-201] days versus 170 [36-336] days) respectively; p = .004. With the exception of a longer length of stay (LOS) in the LDLT ≥70y group (p ≤ .001), postoperative outcomes were comparable with recipients in the DDLT ≥70y group, including similar graft and patient survival rates at 1-, 3-, and 5-years. When compared to younger recipients of a graft from a living donor, patients in the LDLT ≥70y group had similar post-transplant functional status, re-transplant rates and similar causes contributing to graft failure. However, significantly lower graft and patient survival rates were observed. CONCLUSION: LDLT for recipients aged 70 or greater represents a faster access to transplantation in a safe and feasible manner when compared to similar- aged recipients undergoing DDLT.

Split liver transplantation with extended right grafts on adult recipients: A propensity score matching analysis.

INTRODUCTION: Split liver transplantation (SLT) emerged due to its potential to contribute to the organ pool and reduce organ shortage. However, SLT is technically challenging and has been associated with higher rates of postoperative complications leading to concerns about graft and patient survival. Moreover, there are few studies on matched-pair adult recipients of SLT and whole-liver transplant (WLT), with conflicting results. METHODS: This retrospective study analyze outcomes among adults who underwent SLT at our institution from 2010 to 2019. A 1:1 propensity score matching analysis was performed based on important donor and recipient variables. Baseline characteristics and postoperative outcomes were analyzed and compared between groups. Actuarial graft and patient survival were analyzed by KM curves. RESULTS: Out of 592 adults receiving a LT in our institution, 21 SLT adult recipients were identified and matched with 21 adults undergoing WLT. As expected donor age was significantly lower in SLT recipients (16 (15-22) vs. 32 (17-47), P = .012). Additional donor characteristics, including anthropometrics, and ischemic times were similar between groups. Baseline recipient characteristics and postoperative outcomes, including length of stay, vascular complications, biliary complications, and re-transplantation were comparable between SLT and WLT recipients. Graft (95/95/95 vs. 100/94/94, P = .98) and patient (100/100/100 vs. 100/94/94, P = .30) survival at 1-, 3-, 5-years, were similar between the SLT- and WLT group, respectively. CONCLUSION: Split liver transplantation has the potential to increase the availability of organs for adult recipients without compromising individual outcomes.

Increased use of split liver grafts in adult recipients following implementation of a pediatric liver transplant program.

BACKGROUND: Split liver transplantation (SLT) is a strategy to address organ shortage, but is a technically more demanding procedure than whole graft liver transplantation (LT). We aimed to determine the outcomes following SLT in adult recipients as well as to highlight the impact that having a pediatric LT program has on SLT implementation. METHODS: All SLTs conducted at a single-center from 2010 to 2019 were identified. Patient data was obtained through retrospective review of the electronic medical record. Kaplan-Meier analysis assessed primary outcomes of 1-,3-, and 5-year graft and patient survival. RESULTS: We identified 37 SLTs performed at our institution from 2010 to 2019. Twenty-four donated livers resulted in 21 extended right lobes and 16 left lateral segments for adults and pediatrics recipients, respectively. Eighty-one percent (30/37) of the SLTs were performed after introduction of the combined pediatric program in 2016. 13/24 donor livers were split with both grafts allocated and used at our institution and 92% occurred after introduction of the pediatric program. Graft survival rates at 1-, 3-, and 5-years were 94% in adult recipients and 100% for all time periods in pediatric recipients. Actuarial post-transplant patient survival was 100% at 1-, 3-, and 5-years in both. CONCLUSIONS: The introduction of a pediatric liver transplantation program resulted in more than a fourfold increase in the number of SLTs performed at our center. Increase in allocation and use of both grafts at our institution was also seen.

Donor Morbidity Is Equivalent Between Right and Left Hepatectomy for Living Liver Donation: A Meta-Analysis.

Maximizing liver graft volume benefits the living donor liver recipient. Whether maximizing graft volume negatively impacts living donor recovery and outcomes remains controversial. Patient randomization between right and left hepatectomy has not been possible due to anatomic constraints; however, a number of published, nonrandomized observational studies summarize donor outcomes between 2 anatomic living donor hepatectomies. This meta-analysis compares donor-specific outcomes after right versus left living donor hepatectomy. Systematic searches were performed via PubMed, Cochrane, ResearchGate, and Google Scholar databases to identify relevant studies between January 2005 and November 2019. The primary outcomes compared overall morbidity and incidence of severe complications (Clavien-Dindo >III) between right and left hepatectomy in donors after liver donation. Random effects meta-analysis was performed to derive summary risk estimates of outcomes. A total of 33 studies (3 prospective and 30 retrospective cohort) were used to identify 7649 pooled patients (5993 right hepatectomy and 1027 left hepatectomy). Proportion of donors who developed postoperative complications did not significantly differ after right hepatectomy (0.33; 95% confidence interval [CI], 0.27-0.40) and left hepatectomy (0.23; 95% CI, 0.17-0.29; P = 0.19). The overall risk ratio (RR) did not differ between right and left hepatectomy (RR, 1.16; 95% CI, 0.83-1.63; P = 0.36). The relative risk for a donor to develop severe complications showed no differences by hepatectomy side (Incidence rate ratio, 0.97; 95% CI, 0.67-1.40; P = 0.86). There is no evidence that the overall morbidity differs between right and left lobe donors. Publication bias reflects institutional and surgeon variation. A prospective, standardized, multi-institutional study would help quantify the burden of donor complications after liver donation.

Intraoperative glycemic control in patients undergoing Orthotopic liver transplant: a single center prospective randomized study.

BACKGROUND: Perioperative hyperglycemia is associated with poor outcomes yet evidence to guide intraoperative goals and treatment modalities during non-cardiac surgery are lacking. End-stage liver disease is associated with altered glucose homeostasis; patients undergoing liver transplantation display huge fluctuations in blood glucose (BG) and represent a population of great interest. Here, we conduct a randomized trial to compare the effects of strict versus conventional glycemic control during orthotopic liver transplant (OLT). METHODS: Following approval by the Institutional Review Board of the University of Michigan Medical School and informed consent, 100 adult patients undergoing OLT were recruited. Patients were randomized to either strict (target BG 80-120 mg/dL) or conventional (target BG 180-200 mg/dL) BG control with block randomization for diabetic and nondiabetic patients. The primary outcomes measured were 1-year patient and graft survival assessed on an intention to treat basis. Graft survival is defined as death or needing re-transplant (www.unos.org). Three and 5-year patient and graft survival, infectious and biliary complications were measured as secondary outcomes. Data were examined using univariate methods and Kaplan-Meir survival analysis. A sensitivity analysis was performed to compare patients with a mean BG of ≤120 mg/dL and those > 120 mg/dL regardless of treatment group. RESULTS: There was no statistically significant difference in patient survival between conventional and strict control respectively;1 year, 88% vs 88% (p-0.99), 3 years, 86% vs 84% (p- 0.77), 5 years, 82% vs 78. % (p-0.36). Graft survival was not different between conventional and strict control groups at 1 year, 88% vs 84% (p-0.56), 3 years 82% vs 76% (p-0.46), 5 years 78% vs 70% (p-0.362). CONCLUSION: There was no difference in patient or graft survival between intraoperative strict and conventional glycemic control during OLT. TRIAL REGISTRATION: Clinical trial number and registry: www.clinicaltrials.gov NCT00780026. This trial was retrospectively registered on 10/22/2008.

Intraoperative Versus Extended Antibiotic Prophylaxis in Liver Transplant Surgery: A Randomized Controlled Pilot Trial.

The appropriate duration of surgical antibiotic prophylaxis in orthotopic liver transplantation (OLT) in the presence of significant iatrogenic immunosuppression is unclear. We hypothesized that 72 hours of perioperative antibiotic prophylaxis would decrease rates of surgical site infection (SSI) in OLT patients when compared with intraoperative antibiotic prophylaxis alone. OLT recipients were randomized to receive either intraoperative antibiotics only (short antibiotics [SAs]) or 72 hours of perioperative antibiotics (extended antibiotics [EAs]). A total of 102 patients were randomized: 51 to the EA group and 51 to the SA group. Rates of SSI and nosocomial infection (NI) in the SA group were 19% and 17%, respectively, compared with 27% (SSI; P = 0.36) and 22% (NI; P = 0.47) in the EA group, although these differences were not statistically significant. Intensive care unit (ICU) length of stay (LOS), hospital LOS, 30-day mortality, and time to infection were also similar between the 2 groups. Patients developing infections had longer ICU LOS and hospital LOS and a higher association with reoperation, endoscopic retrograde cholangiopancreatography, and 30-day readmission. In conclusion, extending perioperative antibiotics to 72 hours from intraoperative dosing alone in OLT patients does not appear to decrease the incidence of SSI or NI. The results from this pilot trial with 60% power suggest that it is acceptable for OLT recipients to receive intraoperative antibiotic prophylaxis alone.

Geographic variation in liver transplantation persists despite implementation of Share35.

AIM: Geographic disparities persist in the USA despite locoregional organ sharing policies. The impact of national organ sharing policies on waiting-list mortality on a regional basis remains unknown. METHODS: Data on all adult liver transplants between 1 February 2002 and 31 March 2015 were obtained from the United Network for Organ Sharing/Organ and Transplantation Network. Multivariable Cox proportional hazards models were constructed in a time-to-event analysis to estimate waiting-list mortality for the pre- and post-Share35 eras. RESULTS: In the analyzed time period, 134 247 patients were listed for transplantation and 54 510 received organs (42.8%). Listing volume increased following the introduction of the Share35 organ sharing policy (15 976 candidates pre- vs. 18 375 post) without significant regional changes as did the number of transplants (7210 pre- vs. 8224 post). Waiting-list mortality improved from 12.2% to 8.1% (P < 0.001). Adjusted waiting-list mortality ratios remained geographically disparate. Region 10 and region 11 had lower hazard ratios (HR) but still had increased mortality (1.46, 95% confidence interval [CI] 1.34-1.60, P < 0.001; and HR 1.49, 95% CI 1.37-1.62, P < 0.001, respectively). Regions 3 and 6 had increased HR with persistently elevated waiting-list mortality (1.79, 95% CI 1.66-1.93, P < 0.001; and HR 1.29, 95% CI 1.16-1.45, P < 0.001, respectively). Model for End-state Liver Disease (MELD) exception continued to propagate a survival benefit (HR 0.65, 95% CI 0.63-0.68, P < 0.001). CONCLUSIONS: Although overall waiting-list mortality has decreased, geographic disparities persist, but appear reduced despite broader sharing policies enacted by Share35. The advantage afforded by MELD exception, while still present, was diminished by Share35 as organs are being shifted to MELD >35 candidates. The disparities highlighted by our findings imply a need to review current allocation policies to best balance local, regional, and national transplant environments.

Excess mortality on the liver transplant waiting list: unintended policy consequences and Model for End-Stage Liver Disease (MELD) inflation.

UNLABELLED: The Model for End-Stage Liver Disease (MELD) allocation system for liver transplantation provides "exceptions" for diseases such as hepatocellular carcinoma (HCC). It was the aim of this study to assess equipoise between exception candidates and nonexception candidates on the waiting list and to assess if the exception system contributes to steadily increasing regional MELD at transplant. In all, 78,595 adult liver transplant candidates between January 2005 and December 2012 were analyzed. Yearly trends in waiting list characteristics and transplantation rates were analyzed for statistical association with MELD exceptions. Regional variations in these associations and the effect of exceptions on regional MELD scores at transplant were also analyzed. 27.29% of the waiting list was occupied by candidates with exceptions. Candidates with exceptions fared much better on the waiting list compared to those without exceptions in mean days waiting (HCC 237 versus non-HCC 426), transplantation rates (HCC 79.05% versus non-HCC 40.60%), and waiting list death rates (HCC 4.49% versus non-HCC 24.63%). Strong regional variation in exception use occurred but exceptions were highly correlated with waiting list death rates, transplantation rates, and MELD score at removal in all regions. In a multivariate model predicting MELD score at transplant within regions, the percentage of HCC MELD exceptions was the strongest independent predictor of regional MELD score at transplant. CONCLUSION: Liver transplant candidates with MELD exceptions have superior outcomes compared to nonexception candidates and the current MELD exception system is largely responsible for steadily increasing MELD scores at transplant independent of geography.

Liver transplant recipients with portal vein thrombosis receiving an organ from a high-risk donor are at an increased risk for graft loss due to hepatic artery thrombosis.

We hypothesize that recipients with pretransplant portal vein thrombosis (PVT) receiving organs from high-risk donors (HRD) are at an increased risk of HAT. Data on all liver transplants in the United States from February 2002 to March 2015 were analyzed. Recipients were sorted into two groups: those with PVT and those without. HRDs were defined by donor risk index (DRI) >1.7. Multivariable logistic regression models were constructed to assess the independent risk factors for HAT with the resultant graft loss ≤90 days from transplantation. A total of 60 404 candidates underwent liver transplantation; of those recipients, 623 (1.0%) had HAT, of which 66.0% (n = 411) received organs from HRDs compared with 49.3% (n = 29 473) in recipients without HAT (P < 0.001); 2250 (3.7%) recipients had pretransplantation PVT and received organs from HRDs. On adjusted multivariable analysis, PVT with a HRD organ was the most significant independent risk factor (OR 3.56, 95% CI 2.52-5.02, P < 0.001) for the development of HAT. Candidates with pretransplant PVT who receive an organ from a HRD are at the highest risk for postoperative HAT independent of other measurable factors. Recipients with pretransplant PVT would benefit from careful donor selection and possibly anticoagulation perioperatively.

Pre-transplant portal vein thrombosis is an independent risk factor for graft loss due to hepatic artery thrombosis in liver transplant recipients.

BACKGROUND: Hepatic artery thrombosis is an uncommon but catastrophic complication following liver transplantation. We hypothesize that recipients with portal vein thrombosis are at increased risk. METHODS: Data on all liver transplants in the U.S. during the MELD era through September 2014 were obtained from UNOS. Status one, multivisceral, living donor, re-transplants, pediatric recipients and donation after cardiac death were excluded. Logistic regression models were constructed for hepatic artery thrombosis with resultant graft loss within 90 days of transplantation. RESULTS: 63,182 recipients underwent transplantation; 662 (1.1%) recipients had early hepatic artery thrombosis; of those, 91 (13.8%) had pre-transplant portal vein thrombosis, versus 7.5% with portal vein thrombosis but no hepatic artery thrombosis (p < 0.0001). Portal vein thrombosis was associated with an increased independent risk of hepatic artery thrombosis (OR 2.17, 95% CI 1.71-2.76, p < 0.001) as was donor risk index (OR 2.02, 95% CI 1.65-2.48, p < 0.001). Heparin use at cross clamp, INR, and male donors were all significantly associated with lower risk. DISCUSSION: Pre-transplant portal vein thrombosis is associated with post-transplant hepatic artery thrombosis independent of other factors. Recipients with portal vein thrombosis might benefit from aggressive coagulation management and careful donor selection. More research is needed to determine causal mechanism.

Management of the Potential Organ Donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations Consensus Statement.

This document was developed through the collaborative efforts of the Society of Critical Care Medicine, the American College of Chest Physicians, and the Association of Organ Procurement Organizations. Under the auspices of these societies, a multidisciplinary, multi-institutional task force was convened, incorporating expertise in critical care medicine, organ donor management, and transplantation. Members of the task force were divided into 13 subcommittees, each focused on one of the following general or organ-specific areas: death determination using neurologic criteria, donation after circulatory death determination, authorization process, general contraindications to donation, hemodynamic management, endocrine dysfunction and hormone replacement therapy, pediatric donor management, cardiac donation, lung donation, liver donation, kidney donation, small bowel donation, and pancreas donation. Subcommittees were charged with generating a series of management-related questions related to their topic. For each question, subcommittees provided a summary of relevant literature and specific recommendations. The specific recommendations were approved by all members of the task force and then assembled into a complete document. Because the available literature was overwhelmingly comprised of observational studies and case series, representing low-quality evidence, a decision was made that the document would assume the form of a consensus statement rather than a formally graded guideline. The goal of this document is to provide critical care practitioners with essential information and practical recommendations related to management of the potential organ donor, based on the available literature and expert consensus.

Increased risk of portal vein thrombosis in patients with cirrhosis due to nonalcoholic steatohepatitis.

Portal vein thrombosis (PVT) is a common complication of cirrhosis sometimes implicated in hepatic decompensation. There are no consistent epidemiologic data to suggest an increased risk of thrombotic complications in nonalcoholic steatohepatitis (NASH); however, research suggests an increased risk of thrombosis. Our aim was to examine the independent association between NASH cirrhosis and PVT in patients who underwent liver transplantation (LT) in a cross-sectional study. Data on all LTs occurring in the United States between January 1, 2003 and December 31, 2012 were obtained from the United Network for Organ Sharing. Multivariable models were constructed to assess the statistical associations and risk factors for the development of PVT. A total of 33,368 patients underwent transplantation. Of these, 2096 (6.3%) had PVT. Of the patients with PVT, 12.0% had NASH. When we compared these patients to a composite of all other causes of cirrhosis, an increased prevalence of PVT was again found, with 10.1% having PVT at the time of transplantation versus 6.0% without NASH (P < 0.001). The strongest risk factor independently associated with a diagnosis of PVT in a multivariable analysis was NASH cirrhosis (odds ratio, 1.55; 95% confidence interval, 1.33-1.81; P < 0.001). NASH cirrhosis appears to predispose a patient to PVT independently of other risk factors. These epidemiological findings provide support for the idea that NASH is a prothrombotic state, and they should lead to more research in treatment and prevention in this population.

Improved post-transplant survival in the United States for patients with cholangiocarcinoma after 2000.

BACKGROUND: The incidence of cholangiocarcinoma (CCA) continues to rise. Orthotopic liver transplantation (OLT) can be used for selected patients with localized but unresectable hilar CCA. Although initial post-OLT survival rates were poor, outcomes after introduction of the Mayo Clinic protocol have been more promising and there has been increased interest in OLT for CCA nationally. AIMS: The aim of this study is to determine post-transplant survival and prognostic factors for patients undergoing OLT for CCA. METHODS: A retrospective analysis of all patients with CCA listed nationwide for OLT between October 1987 and May 2008 was performed using the Scientific Registry of Transplant Recipients database. Survival curves were generated using the Kaplan-Meier method and compared using log-rank test. RESULTS: Of 595 patients with CCA listed for OLT, 359 (60.3 %) underwent OLT. Median age at OLT was 49 years, 66 % were male and 91 % were Caucasian. The median follow-up time was 2 years. There has been an increasing number of liver transplants performed for CCA since 2000. The 1- and 5-year probability of survival was 85.8 and 51.4 %, respectively. On multivariate analysis, significant prognostic factors for decreased post-OLT survival included transplant before 2000 (HR 11.25, 95 % CI 1.28-98.7) and acute cellular rejection (HR 5.64, 95 % CI 1.14-27.8). CONCLUSIONS: Survival after transplant for CCA has improved over time, and OLT is being used more frequently in the treatment of CCA. Significant predictors of post-OLT survival include a history of acute rejection and date of transplant in relation to the publication of Mayo protocol results.

Liver Transplant Costs and Activity After United Network for Organ Sharing Allocation Policy Changes.

Importance: A new liver allocation policy was implemented by United Network for Organ Sharing (UNOS) in February 2020 with the stated intent of improving access to liver transplant (LT). There are growing concerns nationally regarding the implications this new system may have on LT costs, as well as access to a chance for LT, which have not been captured at a multicenter level. Objective: To characterize LT volume and cost changes across the US and within specific center groups and demographics after the policy implementation. Design, Setting, and Participants: This cross-sectional study collected and reviewed LT volume from multiple centers across the US and cost data with attention to 8 specific center demographics. Two separate 12-month eras were compared, before and after the new UNOS allocation policy: March 4, 2019, to March 4, 2020, and March 5, 2020, to March 5, 2021. Data analysis was performed from May to December 2022. Main Outcomes and Measures: Center volume, changes in cost. Results: A total of 22 of 68 centers responded comparing 1948 LTs before the policy change and 1837 LTs postpolicy, resulting in a 6% volume decrease. Transplants using local donations after brain death decreased 54% (P < .001) while imported donations after brain death increased 133% (P = .003). Imported fly-outs and dry runs increased 163% (median, 19; range, 1-75, vs 50, range, 2-91; P = .009) and 33% (median, 3; range, 0-16, vs 7, range, 0-24; P = .02). Overall hospital costs increased 10.9% to a total of $46 360 176 (P = .94) for participating centers. There was a 77% fly-out cost increase postpolicy ($10 600 234; P = .03). On subanalysis, centers with decreased LT volume postpolicy observed higher overall hospital costs ($41 720 365; P = .048), and specifically, a 122% cost increase for liver imports ($6 508 480; P = .002). Transplant centers from low-income states showed a significant increase in hospital (12%) and import (94%) costs. Centers serving populations with larger proportions of racial and ethnic minority candidates and specifically Black candidates significantly increased costs by more than 90% for imported livers, fly-outs, and dry runs despite lower LT volume. Similarly, costs increased significantly (>100%) for fly-outs and dry runs in centers from worse-performing health systems. Conclusions and Relevance: Based on this large multicenter effort and contrary to current assumptions, the new liver distribution system appears to place a disproportionate burden on populations of the current LT community who already experience disparities in health care. The continuous allocation policies being promoted by UNOS could make the situation even worse.

Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia.

The Abl kinase inhibitor imatinib mesylate is the preferred treatment for Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but is much less effective in CML blast crisis or Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Here, we show that Bcr-Abl activated the Src kinases Lyn, Hck and Fgr in B-lymphoid cells. BCR-ABL1 retrovirus-transduced marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL in recipients. The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML. The combination of CGP76030 and imatinib was superior to imatinib alone in this regard. The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl. These results implicate Src family kinases as therapeutic targets in Ph(+) B-ALL and suggest that simultaneous inhibition of Src and Bcr-Abl kinases may benefit individuals with Ph(+) acute leukemia.

A prospective, randomized trial of complete avoidance of steroids in liver transplantation with follow-up of over 7 years.

OBJECTIVES: Steroids are a mainstay of treatment in orthotopic liver transplantation (OLT) and are associated with significant morbidity. This trial was conducted to assess the efficacy of steroids avoidance. METHODS: Patients undergoing OLT between June 2002 and April 2005 were entered into a prospective, randomized trial of complete steroids avoidance and followed until November 2011. Recipients received either standard therapy (n = 50) or complete steroids avoidance (n = 50). Analyses were performed on an intention-to-treat basis. The mean follow-up of all recipients was 2095 ± 117 days. Sixteen (32%) recipients randomized to the steroids avoidance group ultimately received steroids for clinical indications. RESULTS: Incidences of diabetes and hypertension prior to or after OLT were similar in both groups, as was the incidence of rejection. Patient and graft survival rates at 1, 3 and 5 years were lower in the steroids avoidance group than in the standard therapy group (patient survival: 1-year, 80% versus 86%; 3-year, 68% versus 76%; 5-year, 60% versus 72%; graft survival: 1-year, 76% versus 76%; 3-year, 64% versus 74%; 5-year, 56% versus 72%), but the differences were not statistically different. CONCLUSIONS: Complete steroids avoidance provides liver transplant recipients with minimal benefit and appears to result in a concerning trend towards decreased graft and recipient survival. The present data support the use of at least a short course of steroids after liver transplantation.

Incidence and risk factors of hepatocellular carcinoma recurrence after liver transplantation in the MELD era.

BACKGROUND AND AIMS: Deceased donor liver transplantation (DDLT) rates for candidates with hepatocellular carcinoma (HCC) have significantly increased in the MELD era because of the extra priority given to these candidates. We examined the incidence and pre-DDLT radiological and donor factors associated with post-DDLT HCC recurrence in the MELD era. METHODS: Outcomes of HCC candidates aged ≥18 years that underwent DDLT between 2/28/02 and 6/30/08 (n = 94) were reviewed. The primary outcome was biopsy-proven post-LT HCC recurrence at any site. Kaplan-Meier analysis was used to calculate the cumulative incidence and Cox regression was used to identify the predictors of post-LT HCC recurrence. RESULTS: The median age of the 94 candidates who met the study criteria was 54 years, 64% had hepatitis C, median lab MELD was 13, and median pre-LT AFP was 47 ng/dl. Based upon pre-DDLT imaging, 94% candidates met the Milan criteria. The median waiting time to transplant was 47 days and 27% received pre-DDLT loco-regional therapy. Seventeen (18%) developed HCC recurrence after 2.1 median years with a cumulative incidence of 6.8, 12, and 19% at 1, 2, and 3 years post-DDLT. The pre-DDLT number of lesions (p = 0.015), largest lesion diameter (p = 0.008), and higher donor age (p = 0.002) were the significant predictors of HCC recurrence after adjusting for pre-LT loco-regional therapy and waiting time. Post-LT HCC recurrence (p < 0.0001) and higher donor age (p = 0.029) were associated with lower post-LT survival. CONCLUSIONS: Post-LT HCC recurrence is higher in our MELD era cohort than the reported rate of 8% at 4 years in Mazzaferro et al.'s study. The risk of HCC recurrence was significantly associated with the number of lesions and size of the largest lesion at the time of DDLT as well as with older donor age. Risk stratification using a predictive model for post-LT HCC recurrence based on pre-LT imaging and donor factors may help guide candidate selection and tailoring of HCC surveillance strategies after LT.

Eliminated routine postorthotopic liver transplant antibiotics in uncomplicated patients leads to equivalent safety outcomes.

Objective: The purpose of this retrospective study was to evaluate safety and efficacy end points of a postoperative antibiotic prophylaxis protocol in liver transplant (LT) patients, which was revised to limit antibiotic use. Methods: In the routine antibiotics group (RA), patients routinely received prophylactic antibiotics for around 3 days postoperatively for a variety of rationales, versus the limited antibiotics group (LA), in which patients received antibiotics for the treatment of secondary peritonitis. Patients were included if they were 18 or older and underwent liver transplant between January 2016 and September 2019. In total, 216 patients remained after exclusion: 118 patients in the RA group and 98 patients in the LA group. Results: We detected a significant difference in the primary end point of postoperative antibiotic days of therapy. The median days of therapy was 2 for the RA group and 0 for the LA group (P < 0.005). Significantly fewer patients received only intraoperative antibiotics in the RA group versus the LA group: 42 (35.6%) versus 76 (73.5%) respectively (P < .005). There was no significant difference in secondary or safety outcomes, including surgical site infections. Conclusions: This study provides evidence that limiting the duration of prophylactic antibiotics postoperatively and treating most patients with only intraoperative antibiotics is safe.