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There are parallels between the history of Enhanced Recovery after Surgery (ERAS) and liver transplantation. Both have been established and advanced by innovative individuals, often going against perceived wisdom and convention. Liver transplantation has traditionally been considered too complex for ERAS pathways, despite a small number of trials showing them to be both safe and of benefit. To date, there are very few randomized controlled trials and cohort studies publishing outcomes on liver transplant patients enrolled in comprehensive ERAS pathways. To progress our field, the 2022 International Liver Transplantation Society's Consensus Conference has created expert panels to analyze the evidence in 32 domains of the liver transplantation pathway using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach to generate expert recommendations. These recommendations will be voted on by the international community to gain consensus using the Danish model, and create the ERAS4OLT.org Enhanced Recovery after Liver Transplantation Pathway. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia has gained momentum as a potential risk‐stratification tool in liver transplantation (LT). While LT recipients recently have more advanced end‐stage liver disease, the impact of sarcopenia in high acuity recipients with a high model for end‐stage liver disease (MELD) score remains unclear. Methods: We retrospectively assessed sarcopenia by calculating skeletal muscle index (SMI) from cross‐sectional area at third lumbar vertebra (cm2) and height (m2) in 296 patients with a CT ≤ 30 days prior to LT. Sex‐specific SMI cut‐offs were developed, and its impact was assessed in patients with MELD ≥ 35. Results: In patients with MELD ≥ 35 (n = 217), men with a SMI < 30 cm2/m2 had significantly higher rates of bacteremia (P =.021) and a longer hospital stay (P <.001). Women with a SMI < 34 cm2/m2 had a longer hospital stay (P =.032). There were no relationships between SMI and survival in men and women with MELD ≥ 35. Conclusions: This series examined sarcopenia with a focus on high MELD patients. Although decreased SMI contributed to higher post‐LT hospital stay, it did not impact patient survival, suggesting that while SMI alone may not aid in patient selection for LT, it certainly may guide perioperative care‐planning in this challenging patient population. [ABSTRACT FROM AUTHOR]

Transcriptomic profiling of tumor tissues introduces a large database, which has led to improvements in the ability of cancer diagnosis, treatment, and prevention. However, performing tumor transcriptomic profiling in the clinical setting is very challenging since the procurement of tumor tissues is inherently limited by invasive sampling procedures. Here, the feasibility of purifying hepatocellular carcinoma (HCC) circulating tumor cells (CTCs) from clinical patient samples is demonstrated with improved molecular integrity using Click Chips in conjunction with a multimarker antibody cocktail. The purified CTCs are then subjected to messenger RNA profiling by NanoString nCounter platform, targeting 64 HCC‐specific genes, which are generated from an integrated data analysis framework with eight tissue‐based prognostic gene signatures from seven publicly available HCC transcriptomic studies. After bioinformatics analysis and comparison, the HCC CTC‐derived gene signatures show high concordance with HCC tissue‐derived gene signatures from the Cancer Genome Atlas database, suggesting that HCC CTCs purified by Click Chips can enable the translation of HCC tissue molecular profiling into a noninvasive setting. [ABSTRACT FROM AUTHOR]

Introduction: Liver transplantation (LT) is a life‐saving treatment for end‐stage liver disease patients that requires significant resources. We used national data to evaluate LT outcomes and factors associated with hospital resource use. Methods: Using the National Inpatient Sample, we identified all patients undergoing LT from 2009 to 2017 and defined high‐resource use (HRU) as having costs ≥ 90th percentile. Hierarchical regression models were used to assess factors associated with length of stay (LOS) and HRU. Results: Over the study period, approximately 53,000 patients underwent LT, increasing from 5,582 in 2009 to 7,095 in 2017 (nptrend < 0.001). Morbidity and mortality were 42.2% and 3.9%, respectively, with a median post‐LT LOS of 10 days. Hospitalization costs increased from $106,866 to $145,868 (nptrend < 0.001). Acute kidney injury (β:4.7 days, P <.001) and end‐stage renal disease (ESRD) with dialysis (β:4.3 days, P <.001) were associated with greater LOS while the Northeast region (AOR:5.2, P <.001), ESRD with dialysis (AOR:3.4, P <.001), heart failure (AOR:2.5, P <.001), and fulminant liver disease (AOR:1.8, P =.01) were associated with HRU. Conclusion: The cost of LT has increased over time. Renal dysfunction, regional practice patterns, and patient acuity were associated with greater resource use. Transplanting patients before health deterioration may help contain costs, mitigate resource use, and improve LT outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Increased societal prevalence of marijuana continues to challenge liver transplant (LT) programs. This study aimed to examine the potential effects of marijuana use on outcomes. Methods: This retrospective study included recipients who underwent LT between 1/2012 and 6/2018. According to pre‐LT marijuana use, patients were classified into recent (≤6 months of LT), former (chronic use but not ≤6 months), or non‐users. Additionally, the impact of post‐LT marijuana use on survival was assessed. Results: Of 926 eligible patients, 184 were pre‐LT marijuana users (42 recent; 142 former) (median follow‐up: 30.3 months). Pre‐users were more likely to be male, White, and have histories of tobacco, alcohol, and illicit drug use. Additionally, recent users were of higher acuity, with higher MELD and requiring ICU admission. Patient survival at 1‐year was 89% in non‐users, 94% (HR: 0.494, 95% CI: 0.239–1.022 vs. non‐users) in former users, and 83% (HR: 1.516, 95% CI: 0.701–3.282) in recent users. Post‐operative complications in pre‐LT users and the survival analysis for post‐LT marijuana users vs. non‐users did not show significance. Conclusions: Our results demonstrated that marijuana use did not have an adverse impact on post‐LT outcomes; however, further studies utilizing larger cohorts are warranted. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a leading cause of mortality. Checkpoint inhibitors of programmed cell death protein‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) have shown great efficacy, but lack biomarkers that predict response. Circulating tumor cells (CTCs) have promise as a liquid‐biopsy biomarker; however, data on HCC CTCs expressing PD‐L1 have not been reported. We sought to detect PD‐L1‐expressing HCC‐CTCs and investigated their role as a prognostic and predictive biomarker. Using an antibody‐based platform, CTCs were enumerated/phenotyped from a prospective cohort of 87 patients with HCC (49 early‐stage, 22 locally advanced, and 16 metastatic), 7 patients with cirrhosis, and 8 healthy controls. Immunocytochemistry identified total HCC CTCs (4′,6‐diamidino‐2‐phenylindole–positive [DAPI+]/cytokeratin‐positive [CK+]/clusters of differentiation 45–negative [CD45−]) and a subpopulation expressing PD‐L1 (DAPI+/CK+/PD‐L1+/CD45−). PD‐L1+ CTCs were identified in 4 of 49 (8.2%) early‐stage patients, but 12 of 22 (54.5%) locally advanced and 15 of 16 (93.8%) metastatic patients, accurately discriminating early from locally advanced/metastatic HCC (sensitivity = 71.1%, specificity = 91.8%, area under the receiver operating characteristic curve = 0.807; P < 0.001). Compared to patients without PD‐L1+ CTCs, patients with PD‐L1+ CTCs had significantly inferior overall survival (OS) (median OS = 14.0 months vs. not reached, hazard ratio [HR] = 4.0, P = 0.001). PD‐L1+ CTCs remained an independent predictor of OS (HR = 3.22, P = 0.010) even after controlling for Model for End‐Stage Liver Disease score (HR = 1.14, P < 0.001), alpha‐fetoprotein (HR = 1.55, P < 0.001), and overall stage/tumor burden (beyond University of California, San Francisco, HR = 7.19, P < 0.001). In the subset of 10 patients with HCC receiving PD‐1 blockade, all 5 responders demonstrated PD‐L1+ CTCs at baseline, compared with only 1 of 5 nonresponders, all of whom progressed within 4 months of starting treatment. Conclusion: We report a CTC assay for the phenotypic profiling of HCC CTCs expressing PD‐L1. PD‐L1+ CTCs are predominantly found in advanced‐stage HCC, and independently prognosticate OS after controlling for Model for End‐Stage Liver Disease, alpha‐fetoprotein, and tumor stage. In patients with HCC receiving anti‐PD‐1 therapy, there was a strong association with the presence of PD‐L1+ CTCs and favorable treatment response. Prospective validation in a larger cohort will better define the utility of PD‐L1+ CTCs as a prognostic and predictive biomarker in HCC. [ABSTRACT FROM AUTHOR]

Esophageal perforation in liver transplant recipients is a rare phenomenon. We herein report a case of an esophageal perforation due to Sengstaken–Blakemore tube in a liver-transplant recipient diagnosed 6 weeks post-transplant. A 2.5-cm mid-esophageal perforation communicating with large complex fluid collection in the pleural space was found. During endoscopy, 16Fr Salem Sump nasopleural tube (NP) was placed traversing through esophageal perforation into inferior aspect of the collection. Over the following 4 weeks, NP decompressed the cavity, allowed its closure and the tube was slowly retracted. By the end of 4 weeks, NP was removed with follow-up esophagogram showing no extravasation of contrast and a healed perforation. Hence, the esophageal perforation was successfully treated via this unique nonoperative approach without the need for major surgery. In instances of chronic leak with a stable patient, this nonoperative strategy should be considered even in immunocompromised patients. [ABSTRACT FROM AUTHOR]

Somatic copy number alterations (SCNAs) are important genetic drivers of many cancers. We investigated the feasibility of obtaining SCNA profiles from circulating tumor cells (CTCs) as a molecular liquid biopsy for hepatocellular carcinoma (HCC). CTCs from ten HCC patients underwent SCNA profiling. The Cancer Genome Atlas (TCGA) SCNA data were used to develop a cancer origin classification model, which was then evaluated for classifying 44 CTCs from multiple cancer types. Sequencing of 18 CTC samples (median: 4 CTCs/sample) from 10 HCC patients using a low-resolution whole-genome sequencing strategy (median: 0.88 million reads/sample) revealed frequent SCNAs in previously reported HCC regions such as 8q amplifications and 17p deletions. SCNA profiling revealed that CTCs share a median of 80% concordance with the primary tumor. CTCs had SCNAs not seen in the primary tumor, some with prognostic implications. Using a SCNA profiling model, the tissue of origin was correctly identified for 32/44 (73%) CTCs from 12/16 (75%) patients with different cancer types. [ABSTRACT FROM AUTHOR]

Farnesoid X receptor (FXR) is the nuclear receptor of bile acids and is involved in innate immune regulation. FXR agonists have been shown to protect multiple organs from inflammatory tissue injuries. Because liver expresses high levels of FXR, we explored the potential therapeutic benefits and underlying mechanisms of pharmacologic FXR activation in a murine model of partial liver warm ischemia. Pretreatment of mice with FXR agonist 3‐(2,6‐dichlorophenyl)‐4‐(3′‐carboxy‐2‐chlorostilben‐4‐yl)oxymethyl‐5‐isopropylisoxazole (GW4064) attenuated liver ischemia/reperfusion injuries (IRIs) in wild‐type but not FXR knockout mice. Posttreatment with GW4064 facilitated liver recovery from IRI. Mechanistically, Kupffer cells (KCs) expressed much higher levels of FXR than bone marrow‐derived macrophages (BMMs). Pretreatment of KCs but not BMMs with GW4064 resulted in lower tumor necrosis factor α but higher interleukin‐10 expressions following toll‐like receptor stimulation. FXR‐targeted gene small heterodimer partner (SHP) was critical for the regulation of KC response by GW4064. In vivo, the depletion of KCs but not cluster of differentiation (CD) 11b+ cells or knockdown of SHP diminished the immune regulatory effect of GW4064 in liver IRI. Thus, FXR activation protects liver from IRI by up‐regulating SHP in KCs to inhibit the liver proinflammatory response. [ABSTRACT FROM AUTHOR]

Background: Kidney delayed graft function (kDGF) remains a challenging problem following simultaneous liver and kidney transplantation (SLKT) with a reported incidence up to 40%. Given the scarcity of renal allografts, it is crucial to minimize the development of kDGF among SLKT recipients to improve patient and graft outcomes. We sought to assess the role of preoperative recipient and donor/graft factors on developing kDGF among recipients of SLKT. Methods: A retrospective review of 194 patients who received SLKT in the period from January 2004 to March 2017 in a single center was performed to assess the effect of preoperative factors on the development of kDGF. Results: Kidney delayed graft function was observed in 95 patients (49%). Multivariate analysis revealed that donor history of hypertension, cold static preservation of kidney grafts [versus using hypothermic pulsatile machine perfusion (HPMP)], donor final creatinine, physiologic MELD, and duration of delay of kidney transplantation after liver transplantation were significant independent predictors for kDGF. kDGF is associated with worse graft function and patient and graft survival. Conclusions: Kidney delayed graft function has detrimental effects on graft function and graft survival. Understanding the risks and combining careful perioperative patient management, proper recipient selection and donor matching, and graft preservation using HPMP would decrease kDGF among SLKT recipients. [ABSTRACT FROM AUTHOR]

Background & Aims: With the rising prevalence of alcoholism, obesity and metabolic syndrome, steatohepatitis will become the leading cause of end‐stage liver disease and hepatocellular carcinoma in the United States by 2025. Patients with non‐alcoholic steatohepatitis and alcoholic liver disease have similar clinical and histopathological presentations, whether these similarities persist in non‐alcoholic steatohepatitis and alcoholic liver disease patients with hepatocellular carcinoma remains unknown. Methods: A retrospective analysis of the clinical features of adult patients from a large transplant center who underwent liver transplantation for steatohepatitis due to non‐alcoholic steatohepatitis and alcoholic causes (alcoholic liver disease) between 1/1/02 and 1/1/12 was performed. Clinical features, explant histopathology, and clinical outcomes were compared. Results: Hepatocellular carcinoma was present in 80 of 317 patients, who underwent liver transplantation for steatohepatitis with equivalent distribution in non‐alcoholic steatohepatitis and alcoholic liver disease patients (24% vs 26%; P = 0.8). On multivariate analysis, significant predictors of hepatocellular carcinoma included age, ethnicity (Hispanic), and diabetes, but not BMI, hypertension or smoking. A lower risk of hepatocellular carcinoma was associated with a clinical history of hyperlipidemia. Clinical parameters were similar between patients with alcoholic liver disease ‐ hepatocellular carcinoma and non‐alcoholic steatohepatitis‐hepatocellular carcinoma, except sex and presence of metabolic syndrome. non‐alcoholic steatohepatitis‐hepatocellular carcinoma livers retained histopathological features of non‐alcoholic steatohepatitis such as ballooning and Mallory bodies, while alcoholic liver disease‐hepatocellular carcinoma livers did not. There were no significant differences in hepatocellular carcinoma recurrence rates or post‐transplant overall survival. Conclusions: We report the largest single‐center study evaluating clinical, histopathological and outcome measures of patients undergoing liver transplantation for steatohepatitis. Older patients, diabetics, and Hispanics may warrant more frequent cancer screening due to increased risk of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Abstract: Background: As the population of patients with a Fontan palliation grows so does, the number of patients with cardiac failure necessitating orthotopic heart transplant (OHT) and combined heart–liver transplant (CHLT). There is recent evidence that current era cardiac transplant in Fontan patients has improved outcomes, but most studies have a preponderance of pediatrics patients in their cohorts. We examine our institutional experience with adult OHT and CHLT transplantation for failed Fontan physiology. Methods and Results: Retrospective analysis of patients at the Ahmanson/UCLA Adult Congenital Heart Disease Center who underwent OHT or CHLT for failing Fontan physiology from January 1, 2002 to May 31, 2017. We identified 20 patients with single‐ventricle physiology and Fontan palliation who underwent OHT or CHLT. The median age was 29.5 years (range 19‐44). Five patients underwent CHLT because of biopsy proven hepatic cirrhosis. The median length of hospital stay was 23 days (range 8‐76) post‐OHT and 51 days (range 26‐77) post‐CHLT. During a median follow‐up of 56 months (range 2‐178), there was one mortality occurring at 34 months post‐OHT due to coronary vasculopathy. Most frequent early postoperative complications included bleeding and infection (55% and 20%, respectively) and surgical reintervention for bleeding complications (n = 8, 40%). One CHLT patient experienced clinically significant hepatic rejection requiring admission and steroid treatment. Conclusions: Despite inherent risks and complexities of OHT or CHLT in patients with a failed Fontan, transplant is a reasonable therapy. Peri‐ and postoperative complications are common and may require surgical reintervention. Continued observation of practices and unifying themes may help improve patient selection, pre‐ and postoperative treatment and ultimately outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Post‐transplant lymphoproliferative disease (PTLD) has the highest incidence following intestinal transplantation (ITx). Our center has seen a recent increase in PTLD. Our aim was to review a single‐center PTLD experience with a focus on clinical characteristics and outcomes. We completed a retrospective review of biopsy‐proven PTLD cases using a prospectively maintained database of 115 ITx recipients transplanted between 1991 and 2014. Nineteen (17%) ITx recipients developed 25 PTLD cases during a median follow‐up time of 6.4 (1.6‐14.6) years. The incidence of early PTLD was 6% (n = 7). There was a trend toward increased risk of PTLD in children compared with adults (P = .11) and a significantly increased risk of PTLD in re‐ITx compared with primary ITx recipients (P = .03). Most PTLD cases were diagnosed between 2010 and 2014 (n = 14). All early PTLD cases were EBV+ on in situ hybridization. Overall graft and patient survival are 68% and 74%, respectively. Second episodes of PTLD were diagnosed in 43% of surviving pediatric patients. Our program has a low incidence of early PTLD with overall excellent graft and patient survival following diagnosis. However, we have also seen a rising incidence of late PTLD. The cause of the increase is unknown as no major changes in immunosuppression protocols have occurred since 1999. [ABSTRACT FROM AUTHOR]

Abstract: The significance of post‐transplant HLA DSA and chronic AMR in LT is an emerging field of study. Although OPV has previously been described as a histopathologic finding in DSA‐positive adult LT recipients, it was not included in the recent Banff criteria for chronic AMR. Our aim was to describe the association between OPV and chronic AMR in pediatric LT recipients. A retrospective review of 67 liver biopsies performed between November 2014 and April 2016 in 45 pediatric LT recipients identified four patients with OPV. Clinical status, liver biochemistry, the presence of DSA, and available non‐HLA antibody testing, as well as histopathologic features of chronic AMR, were assessed. All four patients with OPV had class II DSA and histopathologic features of chronic AMR based on the Banff criteria. Two patients were noted to have non‐HLA antibodies. Three patients are undergoing treatment with IVIG but have persistent DSA. Two patients have graft failure and are awaiting retransplantation. In conclusion, OPV is a histopathologic finding associated with chronic AMR in pediatric LT recipients. Further studies are needed to elucidate whether OPV is reversible and/or amenable to medical therapy. [ABSTRACT FROM AUTHOR]