The incidence and natural history of ascites after liver transplantation.

BACKGROUND: Ascites is common in cirrhosis but uncommon after liver transplant. We aimed to characterize the incidence, natural history, and current management strategies of post-transplant ascites. METHODS: We performed a retrospective cohort study of patients who underwent liver transplantation at 2 centers. We included patients who underwent deceased donor whole graft liver transplants between 2002 and 2019. Chart review identified patients with post-transplant ascites, requiring a paracentesis between 1 and 6-month post-transplants. Detailed chart review identified clinical and transplant characteristics, evaluation of ascites etiology, and treatments. RESULTS: Of 1591 patients who successfully underwent a first-time orthotopic liver transplant for chronic liver disease, 101 (6.3%) developed post-transplant ascites. Only 62% of these patients required large volume paracentesis for ascites before transplant. 36% of patients with post-transplant ascites had early allograft dysfunction. Most patients with post-transplant ascites (73%) required a paracentesis within 2 months of transplant, but 27% had delayed ascites onset. From 2002 to 2019, ascites studies were obtained less often, and hepatic vein pressure measurement was performed more often. Diuretics were the mainstay of treatment (58%). The use of albumin infusion and splenic artery embolization to treat post-transplant ascites increased over time. Larger pre-transplant spleen size was associated with a greater number of post-transplant paracenteses (r=0.32 and p=0.003). For patients who underwent splenic intervention, paracentesis frequency was significantly reduced (1.6-0.4 paracenteses/month, p=0.0001). The majority (72%) of patients had clinical resolution of their ascites at 6-month post-transplant. CONCLUSIONS: Persistent or recurrent ascites continues to be a clinical issue in the modern era of liver transplantation. Most had clinical resolution within 6 months, some requiring intervention.

Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions.

The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors, thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathologic analysis of the samples revealed pancreatic intraepithelial neoplasia (PanIN) lesions in most individuals irrespective of age. Using a combination of multiplex IHC, single-cell RNA sequencing, and spatial transcriptomics, we provide the first-ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. SIGNIFICANCE: Precursor lesions to pancreatic cancer are poorly characterized. We analyzed donor pancreata and discovered that precursor lesions are detected at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell-intrinsic factors that restrain or, conversely, promote malignant progression. See related commentary by Hoffman and Dougan, p. 1288. This article is highlighted in the In This Issue feature, p. 1275.

Positron emission tomography myocardial perfusion imaging (PET MPI) findings predictive of post-liver transplant major adverse cardiac events.

Positron emission tomography myocardial perfusion imaging (PET MPI) is a noninvasive diagnostic test capable of detecting coronary artery disease, structural heart disease, and myocardial flow reserve (MFR). We aimed to determine the prognostic utility of PET MPI to predict post-liver transplant (LT) major adverse cardiac events (MACE). Among the 215 LT candidates that completed PET MPI between 2015 and 2020, 84 underwent LT and had 4 biomarker variables of clinical interest on pre-LT PET MPI (summed stress and difference scores, resting left ventricular ejection fraction, global MFR). Post-LT MACE were defined as acute coronary syndrome, heart failure, sustained arrhythmia, or cardiac arrest within the first 12 months post-LT. Cox regression models were constructed to determine associations between PET MPI variable/s and post-LT MACE. The median LT recipient age was 58 years, 71% were male, 49% had NAFLD, 63% reported prior smoking, 51% had hypertension, and 38% had diabetes mellitus. A total of 20 MACE occurred in 16 patients (19%) at a median of 61.5 days post-LT. One-year survival of MACE patients was significantly lower than those without MACE (54% vs. 98%, p =0.001). On multivariate analysis, reduced global MFR ≤1.38 was associated with a higher risk of MACE [HR=3.42 (1.23-9.47), p =0.019], and every % reduction in left ventricular ejection fraction was associated with an 8.6% higher risk of MACE [HR=0.92 (0.86-0.98), p =0.012]. Nearly 20% of LT recipients experienced MACE within the first 12 months of LT. Reduced global MFR and reduced resting left ventricular ejection fraction on PET MPI among LT candidates were associated with increased risk of post-LT MACE. Awareness of these PET-MPI parameters may help improve cardiac risk stratification of LT candidates if confirmed in future studies.

Successful living donor liver transplantation in a patient with hemophilia A and factor VIII inhibitor: A case report with perioperative recommendations.

Liver transplantation in patients with end-stage liver disease and coexisting hemophilia A has been described. Controversy exists over perioperative management of patients with factor VIII inhibitor predisposing patients to hemorrhage. We describe the case of a 58-year-old man with a history of hemophilia A and factor VIII inhibitor, eradicated with rituximab prior to living donor liver transplantation without recurrence of inhibitor. We also provide perioperative management recommendations from our successful multidisciplinary approach.

Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early pre-neoplastic pancreatic lesions.

The adult healthy human pancreas has been poorly studied given lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathological analysis of the samples revealed PanIN lesions in most individuals irrespective of age. Using a combination of multiplex immunohistochemistry, single cell RNA sequencing, and spatial transcriptomics, we provide the first ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts, and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. Statement of significance: The causes underlying the onset of pancreatic cancer remain largely unknown, hampering early detection and prevention strategies. Here, we show that PanIN are abundant in healthy individuals and present at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell intrinsic factors that restrain, or, conversely, promote, malignant progression.

The Utility of Noninvasive PET/CT Myocardial Perfusion Imaging in Adult Liver Transplant Candidates.

Background: The optimal cardiovascular (CV) risk stratification in liver transplant (LT) candidates remains unclear. The aim of this study was to evaluate concordance of findings between dobutamine stress echocardiography (DSE), positron emission tomography/computed tomography myocardial perfusion imaging (PET/CT MPI), and left heart catheterization in adult LT candidates. Methods: Data on 234 consecutive adult LT candidates from February 2015 to June 2018 with PET/CT MPI were reviewed. Adverse CV outcomes were adjudicated via chart review by a board-certified cardiologist. Results: Median age was 60.8, body mass index 30.2 kg/m2, and model of end-stage liver disease-sodium 14; 61% were male, and 54% had diabetes. Thirty-seven percent had nonalcoholic steatohepatitis and 29% alcohol-related liver disease. Sixty-five percent of patients had a DSE, of which 41% were nondiagnostic. No factors were independently associated with having a nondiagnostic DSE. The median global myocardial flow reserve correlated positively with hemoglobin and negatively with model of end-stage liver disease-sodium, age, ejection fraction, and body mass index. Moderate/high-risk MPIs were associated with older age and known CV disease. In patients with 2 cardiac testing modalities, findings were concordant in 87%. Eleven of 53 LT recipients experienced an adverse CV outcome, but no independent predictors were identified for this outcome. Conclusions: Results of different cardiac risk-stratification modalities were concordant across modalities the majority of the time in LT candidates, although these findings were not independently correlated with risk of post-LT CV outcomes. Given the high rates of nondiagnostic DSEs in this population, PET/CT MPI may be the preferred CV risk-stratification modality in older patients and those with known CV disease.

Adapting to the Times: Combining Microlearning Videos and Twitter to Teach Surgical Technique.

OBJECTIVE: Surgical videos are commonly utilized by trainees to prepare for surgical cases. However, currently available videos tend to be of excessive length, variable quality, and exist behind paywalls or in other exclusive formats. Our objective was to create a series of videos that would address these shortcomings, and further allow for dynamic engagement between learners and experts. DESIGN: Our group created surgical videos using principles of microlearning, an educational strategy which deconstructs content into small units and uses social media platforms where learners and educators may actively engage. We published a library of short (<3 min) videos covering various steps of abdominal transplantation operations on a YouTube channel. We leveraged Twitter to disseminate the content and engage with experts and learners from around the world. SETTING: Multi-institutional. RESULTS: Over the period from July 2020 to January 2021, 24 microlearning videos were created, stored on a YouTube channel, and posted to Twitter weekly using a newly created account. During that time period, the videos, averaging 124 seconds in length, were viewed 4393 times and watched for a total of 127 hours. The account gained 611 followers in 37 countries and 37 US states with 312,400 impressions (defined as tweet views). Twitter users who engaged with our microlearning content (favorite, retweet, or reply) included faculty (27%), residents (21%), fellows (8%), and medical students (11%). CONCLUSIONS: Broad participation with the educational material and discussion on Twitter demonstrated the potential for the microlearning technique to provide educational benefit for learners internationally. The spread of the tweets shows an opportunity to augment traditional surgical education, and the willingness of faculty to discuss alternative techniques with their peers. Our group will continue to develop a library of microlearning videos for surgical operations and engage with other institutions for collaboration and expansion.

Intraoperative risk factors of acute kidney injury after liver transplantation.

Acute kidney injury (AKI) is one of the most common complications of liver transplantation (LT). We examined the impact of intraoperative management on risk for AKI following LT. In this retrospective observational study, we linked data from the electronic health record with standardized transplant outcomes. Our primary outcome was stage 2 or 3 AKI as defined by Kidney Disease Improving Global Outcomes guidelines within the first 7 days of LT. We used logistic regression models to test the hypothesis that the addition of intraoperative variables, including inotropic/vasopressor administration, transfusion requirements, and hemodynamic markers improves our ability to predict AKI following LT. We also examined the impact of postoperative AKI on mortality. Of the 598 adult primary LT recipients included in our study, 43% (n = 255) were diagnosed with AKI within the first 7 postoperative days. Several preoperative and intraoperative variables including (1) electrolyte/acid-base balance disorder (International Classification of Diseases, Ninth Revision codes 253.6 or 276.x and International Classification of Diseases, Tenth Revision codes E22.2 or E87.x, where x is any digit; adjusted odds ratio [aOR], 1.917, 95% confidence interval [CI], 1.280-2.869; p = 0.002); (2) preoperative anemia (aOR, 2.612; 95% CI, 1.405-4.854; p = 0.002); (3) low serum albumin (aOR, 0.576; 95% CI, 0.410-0.808; p = 0.001), increased potassium value during reperfusion (aOR, 1.513; 95% CI, 1.103-2.077; p = 0.01), and lactate during reperfusion (aOR, 1.081; 95% CI, 1.003-1.166; p = 0.04) were associated with posttransplant AKI. New dialysis requirement within the first 7 days postoperatively predicted the posttransplant mortality. Our study identified significant association between several potentially modifiable variables with posttransplant AKI. The addition of intraoperative data did not improve overall model discrimination.

Graft Survival and Segment Discards Among Split-Liver and Reduced-Size Transplantations in the United States From 2008 to 2018.

Split-liver transplantation has allocation advantages over reduced-size transplantation because of its ability to benefit 2 recipients. However, prioritization of split-liver transplantation relies on the following 3 major assumptions that have never been tested in the United States: similar long-term transplant recipient outcomes, lower incidence of segment discard among split-liver procurements, and discard of segments among reduced-size procurements that would be otherwise "transplantable." We used United Network for Organ Sharing Standard Transplant Analysis and Research data to identify all split-liver (n = 1831) and reduced-size (n = 578) transplantation episodes in the United States between 2008 and 2018. Multivariable Cox proportional hazards modeling was used to compare 7-year all-cause graft loss between cohorts. Secondary analyses included etiology of 30-day all-cause graft loss events as well as the incidence and anatomy of discarded segments. We found no difference in 7-year all-cause graft loss (adjusted hazard ratio [aHR], 1.1; 95% confidence interval [CI], 0.8-1.5) or 30-day all-cause graft loss (aHR, 1.1; 95% CI, 0.7-1.8) between split-liver and reduced-size cohorts. Vascular thrombosis was the most common etiology of 30-day all-cause graft loss for both cohorts (56.4% versus 61.8% of 30-day graft losses; P = 0.85). Finally, reduced-size transplantation was associated with a significantly higher incidence of segment discard (50.0% versus 8.7%) that were overwhelmingly right-sided liver segments (93.6% versus 30.3%). Our results support the prioritization of split-liver over reduced-size transplantation whenever technically feasible.

LI-RADS Treatment Response Algorithm: Performance and Diagnostic Accuracy With Radiologic-Pathologic Explant Correlation in Patients With SBRT-Treated Hepatocellular Carcinoma.

PURPOSE: Our purpose was to evaluate the accuracy of LI-RADS Treatment Response Algorithm (LR-TRA) for assessing the viability of hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT), using explant pathology as the gold standard. METHODS AND MATERIALS: This retrospective study included patients who underwent SBRT for locoregional treatment of HCC between 2008 and 2019 with subsequent liver transplantation. Five radiologists independently assessed all treated lesions by using the LR-TRA. Imaging and posttransplant histopathology were compared. Lesions were categorized as either completely (100%) or incompletely (<100%) necrotic, and performance characteristics and predictive values for the LR-TR viable and nonviable categories were calculated for each reader. Interreader reliability was calculated using the Fleiss kappa test. RESULTS: A total of 40 treated lesions in 26 patients (median age, 63 years [interquartile range, 59.4-65.5]; 23 men) were included. For lesions treated with SBRT, sensitivity for incomplete tumor necrosis across readers ranged between 71% and 86%, specificity between 85% and 96%, and positive predictive value between 86% and 92%, when the LR-TR equivocal category was treated as nonviable, accounting for subject clustering. When the LR-TR equivocal category was treated as viable, sensitivity of complete tumor necrosis for lesions treated with SBRT ranged from 88% to 96%, specificity from 71% to 93%, and negative predictive value from 85% to 96%. Interreader reliability was fair (k = 0.22; 95% confidence interval, 0.13-0.33). Although a loss of arterial phase hyperenhancement (APHE) was highly correlated with pathologically nonviable tumor on explant, almost half of the patients with APHE had pathologically nonviable tumor on explant. CONCLUSIONS: LR-TRA v2018 performs well for predicting complete and incomplete necrosis in HCC treated with SBRT. In contrast to other locoregional therapies, the presence of APHE after SBRT does not always indicate viable tumor and suggests that observation may be an appropriate strategy for these patients.

Optimal Timing of Administration of Direct-acting Antivirals for Patients With Hepatitis C-associated Hepatocellular Carcinoma Undergoing Liver Transplantation.

OBJECTIVE: To investigate the optimal timing of direct acting antiviral (DAA) administration in patients with hepatitis C-associated hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). SUMMARY OF BACKGROUND DATA: In patients with hepatitis C (HCV) associated HCC undergoing LT, the optimal timing of direct-acting antivirals (DAA) administration to achieve sustained virologic response (SVR) and improved oncologic outcomes remains a topic of much debate. METHODS: The United States HCC LT Consortium (2015-2019) was reviewed for patients with primary HCV-associated HCC who underwent LT and received DAA therapy at 20 institutions. Primary outcomes were SVR and HCC recurrence-free survival (RFS). RESULTS: Of 857 patients, 725 were within Milan criteria. SVR was associated with improved 5-year RFS (92% vs 77%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 92%, and 82%, and 5-year RFS of 93%, 94%, and 87%, respectively. Among 427 HCV treatment-naïve patients (no previous interferon therapy), patients who achieved SVR with DAAs had improved 5-year RFS (93% vs 76%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 93%, and 78% (P < 0.01) and 5-year RFS of 93%, 100%, and 83% (P = 0.01). CONCLUSIONS: The optimal timing of DAA therapy appears to be 0 to 3 months after LT for HCV-associated HCC, given increased rates of SVR and improved RFS. Delayed administration after transplant should be avoided. A prospective randomized controlled trial is warranted to validate these results.

Associations Among Different Domains of Quality Among US Liver Transplant Programs.

Importance: US liver transplant programs have traditionally been evaluated on 1-year patient and graft survival. However, there is concern that a narrow focus on recipient outcomes may not incentivize programs to improve in other ways that would benefit patients with end-stage liver disease. Objective: To determine the correlation among different potential domains of quality for adult liver transplant programs. Design, Setting, and Participants: This retrospective cohort study was conducted from 2014 to 2019 among adult liver transplant programs included in the United Network for Organ Sharing and Scientific Registry of Transplant Recipients program-specific reports. Liver transplant programs in the United States completing at least 10 liver transplants per year were included. Data were analyzed from March 2 to August 13, 2020. Main Outcomes and Measures: The potential domains of quality examined included recipient outcomes (1-year graft and patient survival), aggressiveness (ie, marginal graft use, defined as the rate of use of donors with body mass index [calculated as weight in kilograms divided by height in meters squared] greater than 40, age older than 65 years, or deceased by cardiac death), and waiting list management (ie, waiting list mortality). The correlation among measures, aggregated at the center level, was evaluated using linear regression to control for mean Model for End Stage Liver Disease-Sodium score at organ allocation. The extent to which programs were able to achieve high quality across multiple domains was also evaluated. Results: Among 114 transplant programs that performed a total of 44 554 transplants, the mean (SD) 1-year graft and patient survival was 90.3% (3.0%) with a total range of 75.9% to 96.6%. The mean (SD) waiting list mortality rate was 16.7 (6.1) deaths per 100 person-years, with a total range of 6.3 to 53.0 deaths per 100 person years. The mean (SD) marginal graft use rate was 15.8 (8.8) donors per 100 transplants, with a total range of 0 to 49.3 donors. There was no correlation between 1-year graft and patient survival and waiting list mortality (ß = -0.053; P = .19) or marginal graft use (ß = -0.007; P = .84) after correcting for mean allocation Model for End Stage Liver Disease-Sodium scores. There were 2 transplant programs (1.8%) that performed in the top quartile on all 3 measures, while 4 transplant programs (3.6%) performed in the bottom quartile on all 3 measures. Conclusions and Relevance: This cohort study found that among US liver transplant programs, there were no correlations among 1-year recipient outcomes, measures of program aggressiveness, or waiting list management. These findings suggest that a program's performance in one domain may be independent and unrelated to its performance on others and that the understanding of factors contributing to these domains is incomplete.

Applying Administrative Data-Based Coding Algorithms for Frailty in Patients With Cirrhosis.

Frailty is a powerful prognostic tool in cirrhosis. Claims-based frailty scores estimate the presence of frailty without the need for in-person evaluation. These algorithms have not been validated in cirrhosis. Whether they measure true frailty or perform as well as frailty in outcome prediction is unknown. We evaluated 2 claims-based frailty scores-Hospital Frailty Risk Score (HFRS) and Claims-Based Frailty Index (CFI)-in 3 prospective cohorts comprising 1100 patients with cirrhosis. We assessed differences in neuromuscular/neurocognitive capabilities in those classified as frail or nonfrail based on each score. We assessed the ability of the indexes to discriminate frailty based on the Fried Frailty Index (FFI), chair stands, activities of daily living (ADL), and falls. Finally, we compared the performance of claims-based frailty measures and physical frailty measures to predict transplant-free survival using competing risk regression and patient-reported outcomes. The CFI identified neuromuscular deficits (balance, chair stands, hip strength), whereas the HFRS only identified poor chair-stand performance. The CFI had areas under the receiver operating characteristic curve (AUROCs) for identifying frailty as measured by the FFI, ADL, and falls of 0.57, 0.60, and 0.68, respectively; similarly, the AUROCs were 0.66, 0.63, and 0.67, respectively, for the HFRS. Claims-based frailty scores were associated with poor quality of life and sleep but were outperformed by the FFI and chair stands. The HFRS, per 10-point increase (but not the CFI) predicted survival of patients in the liver transplantation (subdistribution hazard ratio [SHR], 1.08; 95% confidence interval [CI], 1.03-1.12) and non-liver transplantation cohorts (SHR, 1.13; 95% CI, 1.05-1.22). Claims-based frailty scores do not adequately associate with physical frailty but are associated with important cirrhosis-related outcomes.

Marijuana use among adult liver transplant candidates and recipients.

BACKGROUND: Data regarding marijuana (MJ) use among liver transplant (LT) candidates are limited. We set out to determine the incidence and pre- and post-LT outcomes of adult LT candidates with a self-reported history of MJ use. METHODS: Baseline clinical characteristics, waitlist, and post-LT outcomes of adult LT candidates from January 2010 to March 2017 were compared. RESULTS: Among 2690 LT candidates, 630(23%) and 298(11%) reported a history of MJ use and use within the past 12 months, respectively. Although the proportion of MJ users increased over time(ß = .76, p = .03), the proportion listed and transplanted did not change. Listing for LT increased with male (OR 1.24, 95% CI 11.01-1.52), MELD score (OR 1.08, 95% CI 1.01-1.15), HCC (OR 1.83, 95% CI 1.39-2.41) but decreased among MJ users (OR 0.67, 95% CI 0.50-0.91, p = .01). The median time to listing was longer among MJ users compared to non-users (115 vs. 87 days, p < .0005). Post-LT survival was similar in 83 MJ users and 306 non-users. CONCLUSION: The proportion of MJ users among LT candidates is increasing. MJ users have a greater burden of psychosocial issues which may contribute to longer evaluations and lower rate of LT listing. Post-LT survival was not impacted by self-reported MJ use history.