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.

A multicentre outcome analysis to define global benchmarks for donation after circulatory death liver transplantation.

BACKGROUND & AIMS: The concept of benchmarking is established in the field of transplant surgery; however, benchmark values for donation after circulatory death (DCD) liver transplantation are not available. Thus, we aimed to identify the best possible outcomes in DCD liver transplantation and to propose outcome reference values. METHODS: Based on 2,219 controlled DCD liver transplantations, collected from 17 centres in North America and Europe, we identified 1,012 low-risk, primary, adult liver transplantations with a laboratory MELD score of ≤20 points, receiving a DCD liver with a total donor warm ischemia time of ≤30 minutes and asystolic donor warm ischemia time of ≤15 minutes. Clinically relevant outcomes were selected and complications were reported according to the Clavien-Dindo-Grading and the comprehensive complication index (CCI). Corresponding benchmark cut-offs were based on median values of each centre, where the 75th-percentile was considered. RESULTS: Benchmark cases represented between 19.7% and 75% of DCD transplantations in participating centres. The 1-year retransplant and mortality rates were 4.5% and 8.4% in the benchmark group, respectively. Within the first year of follow-up, 51.1% of recipients developed at least 1 major complication (≥Clavien-Dindo-Grade III). Benchmark cut-offs were ≤3 days and ≤16 days for ICU and hospital stay, ≤66% for severe recipient complications (≥Grade III), ≤16.8% for ischemic cholangiopathy, and ≤38.9 CCI points 1 year after transplant. Comparisons with higher risk groups showed more complications and impaired graft survival outside the benchmark cut-offs. Organ perfusion techniques reduced the complications to values below benchmark cut-offs, despite higher graft risk. CONCLUSIONS: Despite excellent 1-year survival, morbidity in benchmark cases remains high. Benchmark cut-offs targeting morbidity parameters offer a valid tool to assess the protective value of new preservation technologies in higher risk groups and to provide a valid comparator cohort for future clinical trials. LAY SUMMARY: The best possible outcomes after liver transplantation of grafts donated after circulatory death (DCD) were defined using the concept of benchmarking. These were based on 2,219 liver transplantations following controlled DCD donation in 17 centres worldwide. Donor and recipient combinations with higher risk had significantly worse outcomes. However, the use of novel organ perfusion technology helped high-risk patients achieve similar outcomes as the benchmark cohort.

Liver Transplantation Following Yttrium-90 Radioembolization: 15-Year Experience in 207-Patient Cohort.

BACKGROUND AND AIMS: Radioembolization (yttrium-90 [Y90]) is used in hepatocellular carcinoma (HCC) as a bridging as well as downstaging liver-directed therapy to curative liver transplantation (LT). In this study, we report long-term outcomes of LT for patients with HCC who were bridged/downstaged by Y90. APPROACH AND RESULTS: Patients undergoing LT following Y90 between 2004 and 2018 were included, with staging by United Network for Organ Sharing (UNOS) tumor-node-metastasis criteria at baseline pre-Y90 and pre-LT. Post-Y90 toxicities were recorded. Histopathological data of HCC at explant were recorded. Long-term outcomes, including overall survival (OS), recurrence-free survival (RFS), disease-specific mortality (DSM), and time-to-recurrence, were reported. Time-to-endpoint analyses were estimated using Kaplan-Meier. Univariate and multivariate analyses were performed using a log-rank test and Cox proportional-hazards model, respectively. During the 15-year period, 207 patients underwent LT after Y90. OS from LT was 12.5 years, with a median time to LT of 7.5 months [interquartile range, 4.4-10.3]. A total of 169 patients were bridged, whereas 38 were downstaged to LT. Respectively, 94 (45%), 60 (29%), and 53 (26%) patients showed complete, extensive, and partial tumor necrosis on histopathology. Three-year, 5-year, and 10-year OS rates were 84%, 77%, and 60%, respectively. Twenty-four patients developed recurrence, with a median RFS of 120 (95% confidence interval, 69-150) months. DSM at 3, 5, and 10 years was 6%, 11%, and 16%, respectively. There were no differences in OS/RFS for patients who were bridged or downstaged. RFS was higher in patients with complete/extensive versus partial tumor necrosis (P < 0.0001). For patients with UNOS T2 treated during the study period, 5.2% dropped out because of disease progression. CONCLUSIONS: Y90 is an effective treatment for HCC in the setting of bridging/downstaging to LT. Patients who achieved extensive or complete necrosis had better RFS, supporting the practice of neoadjuvant treatment before LT.

Safety and Efficacy of Segmental Yttrium-90 Radioembolization for Hepatocellular Carcinoma after Transjugular Intrahepatic Portosystemic Shunt Creation.

PURPOSE: To evaluate safety and efficacy of segmental yttrium-90 (Y90) radioembolization for hepatocellular carcinoma (HCC) after transjugular intrahepatic portosystemic shunt (TIPS) placement. The hypothesis was liver sparing segmental Y90 for HCC after TIPS would provide high antitumor response with a tolerable safety profile. MATERIALS AND METHODS: This single-arm retrospective study included 39 patients (16 women, 23 men) with ages 49-81 years old who were treated with Y90. Child-Pugh A/B liver dysfunction was present in 72% (28/39) with a median Model for End-stage Liver Disease score of 18 (95% confidence interval, 16.4-19.4). Primary outcomes were clinical and biochemical toxicities and antitumor imaging response by World Health Organization (WHO) and European Association for the Study of the Liver (EASL) criteria. Secondary outcomes were orthotopic liver transplantation (OLT), time to progression (TTP), and overall survival (OS) estimates by the Kaplan-Meier method. RESULTS: The 30-day mortality was 0%. Grade 3+ clinical adverse events and grade 3+ hyperbilirubinemia occurred in 5% (2/39) and 0% (0/39), respectively. Imaging response was achieved in 58% (22/38, WHO criteria) and 74% (28/38, EASL criteria), respectively. Median TTP was 16.1 months for any cause and 27.5 months for primary index lesions. OLT was completed in 88% (21/24) of listed patients at a median time of 6.1 months (range, 0.9-11.7 months). Median OS was 31.6 months and 62.9 months censored and uncensored to OLT, respectively. CONCLUSIONS: Segmental Y90 for HCC appears safe and efficacious in patients after TIPS. Preserved transplant eligibility suggests that Y90 is a useful tool for bridging these patients to liver transplantation.

Temporary Balloon Occlusion for Hepatic Arterial Flow Redistribution during Yttrium-90 Radioembolization.

This case series describes an approach for radiation segmentectomy-style treatment of hepatic tumors fed by arteries unsuitable for catheterization. The 15-patient cohort (17 cases from 2015 to 2018) included those diagnosed with liver tumors (14 hepatocellular carcinoma, 1 cholangiocarcinoma, 1 renal-cell carcinoma, and 1 metastatic colorectal carcinoma) and chosen for radioembolization via a multimodal approach. In each case, a balloon microcatheter was used to temporarily redistribute intrahepatic flow during infusion for enhanced radioembolic agent delivery to the tumor. A median of 199 Gy was delivered to a median of 3% of total liver volume. Based on modified Response Evaluation Criteria In Solid Tumors, 11 cases had complete responses and 6 had partial responses.

Diagnosis and successful surgical management of posterior nutcracker syndrome in a patient with loin pain hematuria.

The syndrome of loin pain hematuria in the absence of stones is poorly understood but must be considered in the differential diagnosis for patients with clinical manifestations resembling nephrolithiasis. A 22-year-old white female with a 4-year history of left flank pain and hematuria underwent an extensive workup with normal renal ultrasound and cystourethroscopies. CT scan and MRI revealed a retro-aortic left renal vein. Posterior nutcracker syndrome was considered the most likely diagnosis. The patient underwent a left laparoscopic nephrectomy with auto-transplantation in the right iliac fossa. She developed azotemia shortly after, which resolved and since then has become asymptomatic.

Organ Utilization Rates from Non-Ideal Donors for Solid Organ Transplant in the United States.

Background: Non-ideal donors provide acceptable allografts and may expand the donor pool. This study evaluates donor utilization across solid organs over 15-years in the United States. Methods: We analyzed the OPTN STAR database to identify potential donors across three donor eras: 2005-2009, 2010-2014, and 2015-2019. Donors were analyzed by a composite Donor Utilization Score (DUS), comprised of donor age and comorbidities. Outcomes of interest were overall and organ-specific donor utilization. Descriptive analyses and multivariable logistic regression modeling were performed. p-values < 0.01 considered significant. Results: Of 132,465 donors, 32,710 (24.7%) were identified as non-ideal donors (NID), based on a DUS ≥ 3. Compared to ideal donors (ID), NID were older (median 56 years, IQR 51-64 years vs. 35 years, 22-48 years, p < 0.001) and more frequently female (44.3% vs. 39.1%, p < 0.001), Black (22.1% vs. 14.6%, p < 0.001) and obese (60.7% vs. 19.6%, p < 0.001). The likelihood of overall DBD utilization from NID increased from Era 1 to Era 2 (OR 1.227, 95% CI 1.123-1.341, p < 0.001) and Era 3 (OR 1.504, 1.376-1.643, p < 0.001), while DCD donor utilization in NID was not statistically different across Eras. Compared to Era 1, the likelihood of DBD utilization from NID for kidney transplantation was lower in Era 2 (OR 0.882, 0.822-0.946) and Era 3 (OR 0.938, 0.876-1.004, p = 0.002). The likelihood of NID utilization increased in Era 3 compared to Era 1 for livers (OR 1.511, 1.411-1.618, p < 0.001), hearts (OR 1.623, 1.415-1.862, p < 0.001), and lungs (OR 2.251, 2.011-2.520, p < 0.001). Conclusions: Using a universal definition of NID across organs, NID donor utilization is increasing; however, use of DUS may improve resource utilization in identifying donors at highest likelihood for multi-organ donation.

Percutaneous Biliary Interventions via the Modified Hutson Loop in Patients with Biliary-Enteric Anastomoses: A Retrospective Study.

PURPOSE: This study aimed to present the institutional experience and algorithm for performing biliary interventions in liver transplant patients using the modified Hutson loop access (MHLA) and the impact of percutaneous endoscopy via the MHLA on these procedures. METHODS: Over 13 years, 201 MHLA procedures were attempted on 52 patients (45 liver transplants; 24 living and 21 deceased donors) for diagnostic (e.g., cholangiography) and therapeutic (e.g., stent/drain insertion and cholangioplasty) purposes. The most common indications for MHLA were biliary strictures (60%) and bile leaks (23%). Percutaneous endoscopy was used to directly visualize the biliary-enteric anastomosis, diagnose pathology (e.g., ischemic cholangiopathy), and help in biliary hygiene (removing debris/casts/stones/stents) in 138/201 (69%) procedures. Technical success was defined as cannulating the biliary-enteric anastomosis and performing diagnostic/therapeutic procedure via the MHLA. RESULTS: The technical success rate was 95% (190/201). The failure rate among procedures performed with and without endoscopy was 2% (3/138) versus 13% (8/63) (P = 0.0024), and the need for new transhepatic access (to aid the procedure) was 12% (16/138) versus 30% (19/63) (P = 0.001). Despite endoscopy, failure in 2% of the cases resulted from inflamed/friable anastomosis (1/3) and high-grade stricture (2/3) obstructing retrograde cannulation of biliary-enteric anastomosis. Major adverse events (bowel perforation and injury) occurred in 1% of the procedures, with no procedure-related mortality. CONCLUSIONS: MHLA-based percutaneous biliary intervention is a safe and effective alternative to managing complications after liver transplant. Percutaneous endoscopy via the MHLA improves success rates and may reduce the need for new transhepatic access. Level of Evidence Level 4.

Portal Vein Recanalization-Transjugular Intrahepatic Portosystemic Shunt (PVR-TIPS) Facilitates Liver Transplantation in Cirrhotic Patients with Occlusive Portal Vein Thrombosis.

Portal vein thrombosis (PVT) is a heterogeneous condition with multiple possible etiologies and to varying degrees has historically limited candidacy for liver transplant (LT) in the cirrhotic patient population due to resultant difficulties in constructing a robust portal vein anastomosis. While intraoperative approaches to managing PVT are well-described, methods which approximate normal portal physiology are not always feasible depending on the extent of PVT, and other nonphysiologic techniques are linked with substantial morbidity and poor long-term outcomes. Portal vein recanalization-transjugular intrahepatic portosystemic shunt (PVR-TIPS) creation is an efficacious method of restoring physiologic portal flow in cirrhotic patients prior to LT allowing for end-to-end PV anastomosis, and is the product of decades-long institutional expertise in TIPS/LT and the support of a multidisciplinary liver tumor board. To follow is a review of the pertinent pathophysiology of PVT in cirrhosis, the rationale leading to the development and subsequent evolution of the PVR-TIPS procedure, technical lessons learned, and a summary of outcomes to date.

Imaging Evaluation of the Living Liver Donor: A Systems-Based Approach.

Liver transplant is the definitive treatment of end-stage liver disease and early hepatocellular carcinoma. The number of liver transplant surgeries done is highly affected by the number and availability of deceased donor organs. Living donor liver transplantation has emerged as an alternative source of donors, increasing the availability of organs for transplant. Many factors must be considered when choosing living donor candidates to maintain a high level of donor safety and organ survival. To that end, potential donors undergo a rigorous pre-donation workup.

A Retrospective Evaluation of Changing Health Characteristics Amongst Deceased Organ Donors in the United States.

BACKGROUND: The availability of suitable donor organs remains a limiting factor to performing life-saving transplant operations. This study evaluates changes in the health of the donor population and its influence on organ use in the United States. METHODS: A retrospective analysis was performed using the OPTN STAR data file from 2005 to 2019. Three donor eras were defined: 1) 2005 to 2009, 2) 2010 to 2014, and 3) 2015 to 2019. The primary outcome was donor use, defined as transplantation of at least one solid organ. Descriptive analyses were performed, and associations of donor use were examined with multivariable logistic regression models. P values <.01 were considered significant. RESULTS: The cohort included 132,783 potential donors of which 124,729 (93.9%) were used for transplantation. Donor median age was 42 years (interquartile range 26-54), 53,566 (40.3%) were female, and 88,209 (66.4%) were White, 21,834 (16.4%) were black, and 18,509 (13.9%) were Hispanic. Compared with donors from Eras 1 and 2, donors in Era 3 were younger (P < .001), had higher body mass index (BMI) (P < .001), increased rates of diabetes mellitus (DM) (P < .001), hepatitis C virus (HCV) positivity (P < .001) and more comorbidities (P < .001). Multivariable modeling found donor BMI, DM, hypertension, and HCV status as health factors significantly associated with donor use. Compared with Era 1, there was increased use in Era 3 of donors with BMI ≥30 kg/m2, DM, hypertension, HCV-positive status, and donors with ≥3 comorbidities. CONCLUSIONS: Despite an increasing prevalence of chronic health problems in the donor population, donors with multiple comorbid conditions are more likely to be used for transplantation in recent years.

Personality Traits in Patients With Cirrhosis Are Different From Those of the General Population and Impact Likelihood of Liver Transplantation.

BACKGROUND: Personality traits influence clinical outcomes in chronic diseases, but their impact in cirrhosis is unknown. We studied the personality of patients with cirrhosis undergoing liver transplant (LT) evaluation and determined their correlation to clinical outcomes. METHODS: A multicenter' prospective study of adult patients undergoing LT evaluation was performed from January 2018 to October 2019. The "Big Five" personality traits of conscientiousness, extraversion, openness, neuroticism, and agreeableness plus agency were assessed with the Midlife Development Inventory Personality Scale and compared with the general population. Frailty was assessed with the Liver Frailty Index. RESULTS: Two hundred sixty-three LT candidates were enrolled. Twenty-four percent had hepatitis C virus, 25% nonalcoholic steatohepatitis, and 25% ethyl alcohol (mean model for end-stage liver disease = 15.7). Compared with the general population, LT candidates had higher openness (3.1 versus 2.9; P < 0.001), extraversion (3.2 versus 3.1; P < 0.001), agreeableness (3.5 versus 3.4; P = 0.04), agency (2.9 versus 2.6; P < 0.001), neuroticism (2.2 versus 2.1; P = 0.001), and lower conscientiousness (3.3 versus 3.4; P = 0.007). Patients with higher conscientiousness were more likely to receive an LT (HR = 2.76; P = 0.003). CONCLUSIONS: Personality traits in LT candidates differ significantly from the general population, with higher conscientiousness associated with a higher likelihood of receiving a transplant.

A Clinical Tool to Guide Selection and Utilization of Marginal Donor Livers With Graft Steatosis in Liver Transplantation.

BACKGROUND: Donor liver biopsy (DLBx) in liver transplantation provides information on allograft quality; however, predicting outcomes from these allografts remains difficult. METHODS: Between 2006 and 2015, 16 691 transplants with DLBx were identified from the Standard Transplant Analysis and Research database. Cox proportional hazard regression analyses identified donor and recipient characteristics associated with 30-d, 90-d, 1-y, and 3-y graft survival. A composite model, the Liver Transplant After Biopsy (LTAB) score, was created. The Mini-LTAB was then derived consisting of only donor age, macrosteatosis on DLBx, recipient model for end-stage liver disease score, and cold ischemic time. Risk groups were identified for each score and graft survival was evaluated. P values <0.05 were considered significant. RESULTS: The LTAB model used 14 variables and 5 risk groups and identified low-, mild-, moderate-, high-, and severe-risk groups. Compared with moderate-risk recipients, severe-risk recipients had increased risk of graft loss at 30 d (hazard ratio, 3.270; 95% confidence interval, 2.568-4.120) and at 1 y (2.258; 1.928-2.544). The Mini-LTAB model identified low-, moderate-, and high-risk groups. Graft survival in Mini-LTAB high-risk transplants was significantly lower than moderate- or low-risk transplants at all time points. CONCLUSIONS: The LTAB and Mini-LTAB scores represent guiding principles and provide clinically useful tools for the successful selection and utilization of marginal allografts in liver transplantation.

Use of Computed Tomography Coronary Calcium Score for Coronary Artery Disease Risk Stratification During Liver Transplant Evaluation.

Background: End-stage liver disease (ESLD) is not considered a risk factor for atherosclerotic cardiovascular disease (ASCVD). However, lifestyle characteristics commonly associated with increased ASCVD risk are highly prevalent in ESLD. Emerging literature shows a high burden of asymptomatic coronary artery disease (CAD) in patients with ESLD and a high ASCVD risk in liver transplantation (LT) recipients. Coronary artery calcium score (CAC) is a noninvasive test providing reliable CAD risk stratification. We implemented an LT evaluation protocol with CAC playing a central role in triaging and determining the need for further CAD assessment. Here, we inform our results from this early experience. Methods: Patients with ESLD referred for LT evaluation were prospectively studied. We compared accuracy of CAC against that of CAD risk factors/scores, troponin I, dobutamine stress echocardiogram (DSE), and single-photon emission computed tomography (SPECT) to detect coronary stenosis ≥70 (CAD ≥ 70) per left heart catheterization (LHC). Thirty-day post-LT cardiac outcomes were also analyzed. Results: One hundred twenty-four of 148 (84%) patients underwent CAC, 106 (72%) DSE/SPECT, and 50 (34%) LHC. CAC ≥ 400 was found in 35 (28%), 100 to 399 in 17 (14%), and <100 in 72 (58%). LHC identified CAD ≥ 70% in 8 of 29 (28%), 2 of 9 (22%), and 0 of 4, respectively. Two acute coronary syndromes occurred after LT in a patient with CAC 811 (CAD < 70%), and one with CAC 347 (CAD ≥ 70%). No patients with CAC < 100 presented with acute coronary syndrome after LT. When using CAD ≥ 70% as primary endpoint of LT evaluation, CAC ≥ 346 was the only test showing predictive usefulness (negative predictive value 100%). Conclusions: CAC is a promising tool to guide CAD risk stratification and need for LHC during LT evaluation. Patients with a CAC < 100 can safely undergo LT without the need for LHC or cardiac stress testing, whereas a CAC < 346 accurately rules out significant CAD stenosis (≥70%) on LHC, outperforming other CAD risk-stratification strategies.

Usefulness of Controlled Attenuation Parameter and Liver Stiffness Measurement for the Identification of Extended-criteria Donors and Risk-assessment in Liver Transplantation.

BACKGROUND: Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) are noninvasive surrogates for hepatic steatosis and fibrosis, respectively, and could help identify extended criteria donors in liver transplantation (LT). We aimed to determine the accuracy of CAP/LSM in deceased donors along with post-LT changes. METHODS: Accuracy of preprocurement CAP/LSM to grade/stage steatosis/fibrosis was determined using liver biopsy as reference. Transplant outcomes, including primary nonfunction (PNF) and early allograft dysfunction, were recorded. Recipients underwent CAP/LSM as outpatients. Areas under the receiver operating characteristic curve and regression models were constructed to analyze data. RESULTS: We prospectively evaluated 160 allografts (138 transplanted). Same-probe paired baseline/post-LT CAP was 231 dB/m (181-277)/225 (187-261) (P = 0.61), and LSM 7.6 kPa (6.3-10.8)/5.9 (4.6-8.7) (P = 0.002), respectively. CAP reading was affected by BMI and LSM by ALT, race and bilirubin. Although CAP did not correlate with steatosis from frozen sections (ρ = 0.08, P = 0.47), it correlated with steatosis from permanent sections (ρ = 0.32, P < 0.001) and with oil red O histomorphometry (ρ = 0.35, P = 0.001). CAP identified moderate-to-severe steatosis with an areas under the receiver operating characteristic curve curve of 0.79 (0.66-0.91), for a negative predictive value of 100% at a cutoff value of 230 dB/m. LSM correlated with fibrosis staging (ρ = 0.22, P = 0.007) and it identified discarded allografts with advanced fibrosis/cirrhosis. Patients with no to minimal fibrosis had an LSM of 7.6 (6-10.1) kPa. CONCLUSIONS: Our results are proof-of-concept of the utility of CAP/LSM during organ procurement. Establishing the precise role of these noninvasive tools in the organ allocation process mandates confirmatory studies.

Preoperative portal vein recanalization-transjugular intrahepatic portosystemic shunt for chronic obliterative portal vein thrombosis: Outcomes following liver transplantation.

High-grade portal vein thrombosis (PVT) is often considered to be a technically challenging scenario for liver transplantation (LT) and in some centers a relative contraindication. This study compares patients with chronic obliterative PVT who underwent portal vein recanalization-transjugular intrahepatic portosystemic shunt (PVR-TIPS) and subsequent LT to those with partial nonocclusive PVT who underwent LT without an intervention. This institutional review board-approved study analyzed 49 patients with cirrhosis with PVT from 2000 to 2020 at our institution. Patients were divided into two groups, those that received PVR-TIPS due to anticipated surgical challenges from chronic obliterative PVT and those who did not because of partial PVT. Demographic data and long-term outcomes were compared. A total of 35 patients received PVR-TIPS while 14 did not, with all receiving LT. Patients with PVR-TIPS had a higher Yerdel score and frequency of cavernoma than those that did not. PVR-TIPS was effective in decreasing portosystemic gradient (16 down to 8 mm HG; p < 0.05). Both groups allowed for end-to-end anastomoses in >90% of cases. However, veno-veno bypass was used significantly more in patients who did not receive PVR-TIPS. Additionally, patients without PVR-TIPS required significantly more intraoperative red blood cells. Overall survival was not different between groups. PVR-TIPS demonstrated efficacy in resolving PVT and allowed for end-to-end portal vein anastomoses. PVR-TIPS is a viable treatment option for chronic obliterative PVT with or without cavernoma that simplifies the surgical aspects of LT.

Single Center Experience with Incidence, Impact and Predictors of Biliary Complications in Donation After Circulatory Death Liver Transplantation.

Introduction: Utilizing allografts from donors after cardiac death (DCD) has improved organ availability, and DCD livers comprise a growing proportion of transplantations. However, it has been suggested that DCD transplantations have worse outcomes. Research Questions: We aimed to characterize outcomes in a large cohort of DCD transplantations, identify trends in outcomes over time, and identify factors associated with the development of biliary complications. Design: We conducted an observational retrospective cohort study of patients receiving DCD liver allografts within a large academic teaching hospital with a high transplantation volume. Consecutive patients who underwent Type III DCD liver transplantation from 2006-2016 were included in our cohort. Re-transplantations and multi-organ transplant recipients were excluded. Results: Ninety-six type III DCD transplantations occurred between 2006-2016. We report a 1one-year patient survival of 90.6% (87) and a 5five-year patient survival of 69.8% (67). Twenty-nine (30.2%) patients experienced any biliary complication in the first year following discharge, with 17 (17.7%) experiencing ischemic cholangiopathy. Five-year patient (P = 0.04) and graft (P = 0.005) survival improved over time. Post-operative biliary complications experienced during index admission and prior to discharge were found to be associated with the development of biliary complications (P = 0.005) and ischemic cholangiopathy (P = 0.01) following discharge. Conclusion: Our data suggested that outcomes using DCD allografts have improved, however biliary complications remain a significant issue in DCD transplantation. Patients who experienced post-operative biliary complications during index admission may require more frequent screening to allow the initiation of earlier treatment for biliary complications.

Triptolide induces cell death in pancreatic cancer cells by apoptotic and autophagic pathways.

BACKGROUND & AIMS: Pancreatic adenocarcinoma, among the most lethal human malignancies, is resistant to current chemotherapies. We previously showed that triptolide inhibits the growth of pancreatic cancer cells in vitro and prevents tumor growth in vivo. This study investigates the mechanism by which triptolide kills pancreatic cancer cells. METHODS: Cells were treated with triptolide and viability and caspase-3 activity were measured using colorimetric assays. Annexin V, propidium iodide, and acridine orange staining were measured by flow cytometry. Immunofluorescence was used to monitor the localization of cytochrome c and Light Chain 3 (LC3) proteins. Caspase-3, Atg5, and Beclin1 levels were down-regulated by exposing cells to their respective short interfering RNA. RESULTS: We show that triptolide induces apoptosis in MiaPaCa-2, Capan-1, and BxPC-3 cells and induces autophagy in S2-013, S2-VP10, and Hs766T cells. Triptolide-induced autophagy has a pro-death effect, requires autophagy-specific genes, atg5 or beclin1, and is associated with the inactivation of the Protein kinase B (Akt)/mammalian target of Rapamycin/p70S6K pathway and the up-regulation of the Extracellular Signal-Related Kinase (ERK)1/2 pathway. Inhibition of autophagy in S2-013 and S2-VP10 cells results in cell death via the apoptotic pathway whereas inhibition of both autophagy and apoptosis rescues cell death. CONCLUSIONS: This study shows that triptolide kills pancreatic cancer cells by 2 different pathways. It induces caspase-dependent apoptotic death in MiaPaCa-2, Capan-1, and BxPC-3, and induces caspase-independent autophagic death in metastatic cell lines S2-013, S2-VP10, and Hs766T, thereby making it an attractive chemotherapeutic agent against a broad spectrum of pancreatic cancers.

PKC-alpha inhibitor MT477 slows tumor growth with minimal toxicity in in vivo model of non-Ras-mutated cancer via induction of apoptosis.

MT477 is a novel thiopyrano[2,3-c]quinoline with anti-cancer activity. The purpose of the present study was to evaluate different doses and treatment schedules of MT477 in an in vivo xenograft model of non-Ras-mutated cancer, as well as determine its biological effects and mechanism of action via the four conventional PKC isoforms: α, ßI, ßII, and γ. Here, we show that MT477 inhibits the activity of PKC-α and its downstream targets, ERK1/2 and Akt, before it has an effect on Ras activity. MT477 treatment of cultured H226 cells induced apoptosis and increased focal cell adhesion and formation of actin stress fibers. H226 tumor size in mice continuously treated with intraperitoneal MT477 (1 mg/kg) was 62.1 ± 15.3% smaller than the average tumor size in control mice. Blood serum chemistry revealed minimal toxicity in mice. Taken together, these results support the conclusion that MT477 acts as a direct PKC-α inhibitor in non-Ras mutated cancer, with maximum effectiveness when given in a continuous treatment schedule.

Heat shock protein 70 inhibits apoptosis in cancer cells through simultaneous and independent mechanisms.

BACKGROUND & AIMS: Heat shock proteins (HSPs) are highly conserved and serve a multitude of functions that mediate cell survival. HSP70, the only inducible form of the 70-kilodalton subfamily of HSPs, is overexpressed in pancreatic cancer cells and has been shown to inhibit caspase-dependent apoptosis. We aimed to elucidate the mechanism by which HSP70 inhibits apoptosis in cancer cells. METHODS: HSP70 expression was down-regulated in cultured pancreatic cancer cells by exposure to quercetin, triptolide, or short interfering RNAs. Intracellular Ca2+, cytosolic cathepsin B activity, caspase-3 activity, cell viability, and lysosome integrity were measured using colorimetric assays. Immunofluorescence assays were used to localize cathepsin B and Lamp2. BAPTA-AM was used to chelate intracellular Ca2+. RESULTS: Inhibition of HSP70 increased intracellular Ca2+ levels in pancreatic and colon cancer cell lines and led to loss of lysosome integrity in pancreatic cancer cells. The release of intracellular Ca2+ and lysosomal enzymes activated caspase-dependent apoptosis independently and simultaneously. CONCLUSIONS: HSP70 inhibits apoptosis in cancer cells by 2 mechanisms: attenuation of cytosolic calcium and stabilization of lysosomes. HSP70-mediated cell survival might occur in other types of cancer cells.