Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Fission yeast polycystin Pkd2p promotes cell size expansion and antagonizes the Hippo-related SIN pathway.

Polycystins are conserved mechanosensitive channels whose mutations lead to the common human renal disorder autosomal dominant polycystic kidney disease (ADPKD). Previously, we discovered that the plasma membrane-localized fission yeast polycystin homolog Pkd2p is an essential protein required for cytokinesis; however, its role remains unclear. Here, we isolated a novel temperature-sensitive pkd2 mutant, pkd2-B42. Among the strong growth defects of this mutant, the most striking was that many mutant cells often lost a significant portion of their volume in just 5 min followed by a gradual recovery, a process that we termed 'deflation'. Unlike cell lysis, deflation did not result in plasma membrane rupture and occurred independently of cell cycle progression. The tip extension of pkd2-B42 cells was 80% slower than that of wild-type cells, and their turgor pressure was 50% lower. Both pkd2-B42 and the hypomorphic depletion mutant pkd2-81KD partially rescued mutants of the septation initiation network (SIN), a yeast Hippo-related signaling pathway, by preventing cell lysis, enhancing septum formation and doubling the number of Sid2p and Mob1p molecules at the spindle pole bodies. We conclude that Pkd2p promotes cell size expansion during interphase by regulating turgor pressure and antagonizes the SIN during cytokinesis. This article has an associated First Person interview with the first author of the paper.

Incidence and risk factors for chronic rejection in pediatric liver transplantation.

Chronic rejection (CR) is a progressive immunological injury that frequently leads to long-term liver allograft dysfunction and loss. Although CR remains an important indication for retransplantation, as transplant immunosuppression has evolved, its prevalence in adults undergoing liver transplantation (LT) has declined. However, the incidence and factors that lead to CR in pediatric LT are poorly defined. Therefore, we sought to systematically measure CR's incidence and assess both the risk factors for developing CR and outcomes in a large cohort of pediatric recipients of LT. In this single-center study, we retrospectively analyzed and compared relevant recipient characteristics, surgical details, immunosuppression, graft, and patient survival in the CR and control groups over a 17-year period. After a median time of 1.9 years after LT, 19/356 recipients of LT (5.3%) developed CR in our cohort. Posttransplant lymphoproliferative disorder ( p = 0.01), infections ( p = 0.02), autoimmune liver diseases (HR = 7.3, p = <0.01), Black race (HR = 11.5, p = 0.01), and 2 or more episodes of T cell mediated rejection (HR = 5.1, p = <0.01) were associated with CR development. The retransplantation rate among CR cases was 15.8% at a median follow-up time of 4.1 years. Overall, patient survival was lower in the CR group (78.9%) versus controls (91.1%). While CR incidence in our pediatric cohort was lower than previously reported rates of >12%, the CR group had a higher graft failure rate that required retransplantation and lower overall patient survival. Thus, identifying risk factors may warrant specialized immunosuppression protocols and closer posttransplantation monitoring to reduce the risk of morbidity and mortality from CR.

Identifying drivers of cost in pediatric liver transplantation.

Understanding the economics of pediatric liver transplantation (LT) is central to high-value care initiatives. We examined cost and resource utilization in pediatric LT nationally to identify drivers of cost and hospital factors associated with greater total cost of care. We reviewed 3295 children (<21 y) receiving an LT from 2010 to 2020 in the Pediatric Health Information System to study cost, both per LT and service line, and associated mortality, complications, and resource utilization. To facilitate comparisons, patients were stratified into high-cost, intermediate-cost, or low-cost tertiles based on LT cost. The median cost per LT was $150,836 [IQR $104,481-$250,129], with marked variance in cost within and between hospital tertiles. High-cost hospitals (HCHs) cared for more patients with the highest severity of illness and mortality risk levels (67% and 29%, respectively), compared to intermediate-cost (60%, 21%; p <0.001) and low-cost (51%, 16%; p <0.001) hospitals. Patients at HCHs experienced a higher prevalence of mechanical ventilation, total parental nutrition use, renal comorbidities, and surgical complications than other tertiles. Clinical (27.5%), laboratory (15.1%), and pharmacy (11.9%) service lines contributed most to the total cost. Renal comorbidities ($69,563) and total parental nutrition use ($33,192) were large, independent contributors to total cost, irrespective of the cost tertile ( p <0.001). There exists a significant variation in pediatric LT cost, with HCHs caring for more patients with higher illness acuity and resource needs. Studies are needed to examine drivers of cost and associated outcomes more granularly, with the goal of defining value and standardizing care. Such efforts may uniquely benefit the sicker patients requiring the strategic resources located within HCHs to achieve the best outcomes.

Independent Risk Factors and Economic Burden Associated With Delayed Extubation Following Pediatric Liver Transplantation.

BACKGROUND: Successful early extubation (EE) after liver transplant (LT) has been shown to reduce intensive care unit (ICU) and hospital length of stay and infectious, vascular, and sedation-related complications in adults. EE may not always be feasible in children, and many may require prolonged mechanical ventilation. Limited data exists regarding the candidacy of EE, risk factors, consequences, and hospital costs of delayed extubation (DE) in pediatric LT. METHODS: We conducted a retrospective review to investigate predictive factors and associated costs of EE and DE in infants and children after orthotopic LT at our institution between 2011 and 2021. RESULTS: Of 338 LT (median age 39 months, 54% females), 246 (73%) had EE (within 24 h of LT), while 27% had DE. Age < 1 year (p = 0.0019), diagnosis of biliary atresia (0.02), abnormal pre-LT echocardiogram (0.02), and patients with ongoing hospital admission before LT (0.0001) were independently associated with DE. Hospital costs were significantly (∼3-fold) higher (p < 0.0001) in the DE group. In addition, factors associated with increased total hospital costs were age < 1 year and hospitalization before LT. CONCLUSION: EE post-LT is feasible and merits a trial. The prevalence of DE though modest is associated with increased resource utilization and hospital costs. Children who can be extubated early and those at risk for DE can be identified pre-operatively for optimal planning and allocation of resources.

Intraoperative renal replacement therapy during liver transplantation in children: Safety, efficacy and impact on survival.

BACKGROUND: Intraoperative Continuous Renal Replacement Therapy (iCRRT) can prevent life-threatening complications, facilitate fluid management, and maintain metabolic homeostasis during liver transplantation (LT) in adults. There is a paucity of data in pediatric LT. We evaluated the safety, efficacy, and impact on survival of iCRRT in pediatric LT. METHODS: We conducted a retrospective cohort study of all children requiring CRRT pre-OLT at a quaternary children's hospital from 2014 to 2022. Demographic characteristics, intraoperative events, and post-LT outcomes were compared between those who received iCRRT and those who did not. RESULTS: Out of 306 patients who received LT, 30 (10%) were supported with CRRT at least 24 h prior to LT, of which 11 (36%) received iCRRT. The two cohorts were similar in demographics, diagnosis of liver disease, and severity of illness. The iCRRT patients experienced massive blood loss and increased transfusion requirements. There was no difference in intraoperative metabolic balance. One-year post-LT mortality rates were similar. CONCLUSION: ICRRT is safe in critically ill children with pre-LT renal dysfunction. It optimizes fluid and blood product resuscitation while maintaining metabolic homeostasis. Candidates need to be carefully chosen for this highly resource-intensive therapy to benefit this fragile population.

Risk Index Predicts Pediatric Heart Allograft Non-Utilization.

BACKGROUND: Children listed for heart transplantation face the highest waitlist mortality among all solid organ transplant patients (14%). Attempts at decreasing donor allograft non-utilization (41.5%) could potentially decrease waitlist mortality for pediatric heart transplant patients. Our aim was to quantify the non-utilization risk of pediatric donor heart allografts at the time of initial offering. METHODS: Using the United Network of Organ Sharing (UNOS) database, we retrospectively analyzed 8823 deceased donors (≤18 years old) data through univariable and multivariable analysis and logistic regression models. These factors were divided into a training (n = 5882) and validation set (n = 2941). Donor clinical characteristics and laboratory values were used to predict non-utilization of donor hearts. The multivariable analysis used factors that were significant from the univariable analysis (p-value < .05), and the pediatric non-utilization risk index (pDRSI) included significant factors from the multivariable analysis, producing an overall risk score for non-utilization. With these data, we created a non-utilization risk index to predict likelihood of donor allograft non-utilization. RESULTS: From the 24 potential factors that were identified from univariable analysis, 17 were significant predictors (p < .05) of pediatric heart non-utilization in the multivariable analysis. Low left ventricular ejection fraction (odds ratio (OR)-35.3), hepatitis C positive donor (OR-23.3), high left ventricular ejection fraction (OR-3.29), and hepatitis B positive donor (OR-3.27) were the most significant risk factors. The phDSRI has a C-statistic of 0.80 for the training set and 0.80 for the validation set. CONCLUSION: Using over 8000 donors, the phDSRI uses 17 significant risk factors to predict risk of pediatric heart donor allograft non-utilization.

Constructing an Intent-to-Treat Score Index to Predict Survival Outcomes in Pediatric Liver Transplant Recipients.

BACKGROUND: Waitlist and posttransplant outcomes have been widely reported for pediatric liver transplantation. Yet, analyzing these metrics individually fails to provide a holistic perspective for patients and their families. Intent-to-treat (ITT) analysis fills this gap by studying the associations between waitlist outcomes, organ availability, and posttransplant outcomes. Our study aimed to construct a predictive index utilizing ITT analysis for pediatric liver transplant recipients (Pedi-ITT). METHODS: We performed a retrospective analysis utilizing de-identified data provided by the United Network for Organ Sharing (UNOS) from March 1, 2002, to December 31, 2021. We analyzed data for 12 926 pediatric recipients (age <18). We conducted a univariate and multivariable logistic regression to find the significant predictive factors affecting ITT survival. A scoring index was constructed to stratify outcome risk on the basis of the significant factors identified by regression analysis. RESULTS: Multivariable analysis found the following factors to be significantly associated with death on the waitlist or after transplant: gender, diagnosis, UNOS region, ascites, diabetes mellitus, age at the time of listing, serum sodium at the time of listing, total bilirubin at the time of listing, serum creatinine at the time of listing, INR at the time of listing, history of ventilator use, and history of re-transplantation. Using receiver operator characteristic analysis, the Pedi-ITT index had a c-statistic of 0.79 (95% confidence interval [CI]: 0.76-0.82). The c-statistics of the Model for End-Stage Liver Disease/Pediatric for End-Stage Liver Disease and pediatric version of the Survival Outcomes Following Liver Transplantation score indices were 0.74 (CI: 0.71-0.76) and 0.69 (CI: 0.66-0.72), respectively. CONCLUSIONS: The Pedi-ITT index provides an additional prognostic model with moderate predictive power to assess outcomes associated with pediatric liver transplantation. Further analysis should focus on increasing the predictive power of the index.

Postoperative outcomes of acute-on-chronic liver failure in infants and children with biliary atresia.

INTRODUCTION: Acute-on-chronic liver failure (ACLF) is associated with increased mortality and morbidity in patients with biliary atresia (BA). Data on impact of ACLF on postoperative outcomes, however, are sparse. METHOD: We performed a retrospective analysis of patients with BA aged <18 years who underwent LT between 2011 and 2021 at our institution. ACLF was defined using the pediatric ACLF criteria: ≥1 extra-hepatic organ failure in children with decompensated cirrhosis. RESULTS: Of 107 patients (65% female; median age 14 [9-31] months) who received a LT, 13 (12%) had ACLF during the index admission prior to LT. Two (15%) had Grade 1; 4 (30%) had Grade 2; and 7 (55%) had Grade ≥3 ACLF. ACLF cohort was younger at time of listing (5 [4-8] vs. 9 [6-24] months; p < .001) and at LT (8 [8-11] vs. 16 [10-40] months, p < .001) compared to no-ACLF group. Intraoperatively, ACLF patients had higher blood loss (40 [20-53] vs. 10 [6-19] mL/kg; p < .001) and blood transfusion requirements (33 [21-69] vs. 18 [7-25] mL/kg; p = .004). Postoperatively, they needed higher vasopressor support (31% vs. 10.6%; p = .04) and had higher total hospital length of stay (106 [45-151] vs. 13 [7-30] days; p = .023). Rate of return to the operating room, hospital readmission rates, and 1-year post-LT survival rates were comparable between the groups. CONCLUSION: Despite higher perioperative complications, survival outcomes for ACLF in BA after LT are favorable and comparable to those without ACLF. These encouraging data reiterate prioritization during organ allocation of these critically ill children for LT.

Estimating risk of prolonged mechanical ventilation after liver transplantation in children: PROVE-ALT score.

BACKGROUND: Children at high risk for prolonged mechanical ventilation (PMV) after liver transplantation (LT) need to be identified early to optimize pulmonary support, allocate resources, and improve surgical outcomes. We aimed to develop and validate a metric that can estimate risk for Prolonged Ventilation After LT (PROVE-ALT). METHODS: We identified preoperative risk factors for PMV by univariable analysis in a retrospective cohort of pediatric LT recipients between 2011 and 2017 (n = 205; derivation cohort). We created the PROVE-ALT score by mapping multivariable logistic regression coefficients as integers, with cutoff values using the Youden Index. We validated the score by C-statistic in a retrospectively collected separate cohort of pediatric LT recipients between 2018 and 2021 (n = 133, validation cohort). RESULTS: Among total 338 patients, 21% (n = 72) were infants; 49% (n = 167) had cirrhosis; 8% (n = 27) required continuous renal replacement therapy (CRRT); and 32% (n = 111) required management in hospital (MIH) before LT. Incidence of PMV post-LT was 20% (n = 69) and 3% (n = 12) required tracheostomy. Independent risk factors (OR [95% CI]) for PMV were cirrhosis (3.8 [1-14], p = .04); age <1-year (8.2 [2-30], p = .001); need for preoperative CRRT (6.3 [1.2-32], p = .02); and MIH before LT (12.4 [2.1-71], p = .004). PROVE-ALT score ≥8 [Range = 0-21] accurately predicted PMV in the validation cohort with 73% sensitivity and 80% specificity (AUC: 0.81; 95% CI: 0.71-0.91). CONCLUSION: PROVE-ALT can predict PMV after pediatric LT with a high degree of sensitivity and specificity. Once externally validated in other centers, PROVE-ALT will empower clinicians to plan patient-specific ventilation strategies, provide parental anticipatory guidance, and optimize hospital resources.

Improved Survival After Liver Transplantation for Patients With Human Immunodeficiency Virus (HIV) and HIV/Hepatitis C Virus Coinfection in the Integrase Strand Transfer Inhibitor and Direct-Acting Antiviral Eras.

BACKGROUND: People with human immunodeficiency virus (HIV) with and without hepatitis C virus (HCV) coinfection had poor outcomes after liver transplant (LT). Integrase strand transfer inhibitors (INSTIs) and direct-acting antivirals (DAAs) have changed the treatment landscape for HIV and HCV, respectively, but their impact on LT outcomes remains unclear. METHODS: This retrospective analysis of adults with HIV monoinfection (n = 246) and HIV/HCV coinfection (n = 286) who received LT compared mortality in patients with HIV who received LT before versus after approval of INSTIs and in patients with HIV/HCV coinfection who received LT before versus after approval of DAAs. In secondary analysis, we compared the outcomes in the different eras with those of propensity score-matched control cohorts of LT recipients without HIV or HCV infection. RESULTS: LT recipients with HIV monoinfection did not experience a significant improvement in survival between the pre-INSTI and INSTI recipients with HIV (adjusted hazard ratio [aHR], 0.70 [95% confidence interval {CI}, .36-1.34]). However, recipients with HIV/HCV coinfection in the DAA era had a 47% reduction (aHR, 0.53 [95% CI, .31-9.2] in 1-year mortality compared with coinfected recipients in the pre-DAA era. Compared to recipients without HIV or HCV, HIV-monoinfected recipients had higher mortality during the pre-INSTI era, but survival was comparable between groups during the INSTI era. HIV/HCV-coinfected recipients also experienced comparable survival during the DAA era compared to recipients without HCV or HIV. CONCLUSIONS: Post-LT survival for people with HIV monoinfection and HIV/HCV coinfection has improved with the introduction of INSTI and DAA therapy, suggesting that LT has become safer in these populations.

Innate immune cell dysfunction and systemic inflammation in children with chronic liver diseases undergoing transplantation.

Advanced liver diseases (ALD) can affect immune function and compromise host defense against infections. In this study, we examined the phenotypic and functional alterations in circulating monocyte and dendritic cells (DCs) in children with ALD undergoing liver transplantation (LT). Children were stratified into 2 clusters, C1 (mild) and C2 (severe), on the basis of laboratory parameters of ALD and compared with healthy pediatric controls. Children in C2 had a significant reduction in frequencies of nonclassical monocytes and myeloid DCs. Children in C2 displayed monocyte and DC dysfunction, characterized by lower human leucocyte antigen DR expression and reduced interleukin 12 production, and had an increased incidence of infections before and after LT. Children in C2 demonstrated immune dysregulation with elevations of pro- and anti-inflammatory cytokines in plasma. Alterations of innate immune cells correlated with multiple laboratory parameters of ALD, including plasma bile acids. In vitro, monocytes cultured with specific bile acids demonstrated a dose-dependent reduction in interleukin 12 production, similar to alterations in children with ALD. In conclusion, a cohort of children with ALD undergoing LT exhibited innate immune dysfunction, which may be related to the chronic elevation of serum bile acids. Identifying at-risk patients may permit personalized management pre- and post-transplant, thereby reducing the incidence of infection-related complications.

Acute liver failure and unique challenges of pediatric liver transplantation amidst a worldwide cluster of adenovirus-associated hepatitis.

Investigation into a recent cluster of acute hepatitis in children from the southeastern United States identified human adenovirus (HAdV) DNAemia in all 9 cases. Molecular genotyping in 5 of 9 (56%) children identified HAdV type 41 in all cases (100%). Importantly, 2 children from this cluster progressed rapidly to pediatric acute liver failure (PALF) and required liver transplantation. HAdV type 41, a known cause of self-limited gastroenteritis, has not previously been associated with severe cholestatic hepatitis and liver failure in healthy children. Adenovirus polymerase chain reaction assay and sequencing of amplicons performed on DNA extracted from formalin-fixed, paraffin-embedded liver tissue also identified adenovirus species F (HAdV type 40 or 41) in these 2 children with PALF. Transplant considerations and successful liver transplantation in such situations remain scarce. In this report, we describe the clinical course, laboratory results, liver pathology, and treatment of 2 children with PALF associated with HAdV type 41, one of whom developed secondary hemophagocytic lymphohistiocytosis. Their successful posttransplant outcomes demonstrate the importance of early multidisciplinary medical management and the feasibility of liver transplantation in some children with PALF and HAdV DNAemia.

Reduction in Racial and Ethnic Disparity in Survival Following Liver Transplant for Hepatocellular Carcinoma in the Direct-acting Antiviral Era.

BACKGROUND & AIMS: Black patients with hepatocellular cancer (HCC), often attributed to hepatitis C virus (HCV) infection, have suboptimal survival following liver transplant (LT). We evaluated the impact of direct-acting antiviral (DAA) availability on racial and ethnic disparities in wait list burden post-LT survival for candidates with HCC. METHODS: Using the United Network for Organ Sharing registry, we identified patients with HCC who were listed and/or underwent LT from 2009 to 2020. Based on date of LT, patients were categorized into 2 era-based cohorts: the pre-DAA era (LT between 2009 and 2011) and DAA era (LT between 2015 and 2017, with follow-up through 2020). Kaplan-Meier and Cox proportional hazards analyses were used to compare post-LT survival, stratified by era and race and ethnicity. RESULTS: Annual wait list additions for HCV-related HCC decreased significantly in White and Hispanic patients during the DAA era, with no change (P = .14) in Black patients. Black patients had lower 3-year survival than White patients in the pre-DAA era (70.6% vs 80.1%, respectively; P < .001) but comparable survival in the DAA era (82.1% vs 85.5%, respectively; P = .16). 0n multivariable analysis, Black patients in the pre-DAA era had a 53% higher risk (adjusted hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.28-1.84), for mortality than White patients, but mortality was comparable in the DAA era (adjusted HR, 1.23; 95% CI, 0.99-1.52). In a stratified analysis in Black patients, HCV-related HCC carried more than a 2-fold higher risk of mortality in the pre-DAA era (adjusted HR, 2.86; 95% CI, 1.50-5.43), which was reduced in the DAA era (adjusted HR, 1.34; 95% CI, 0.78-2.30). CONCLUSIONS: With the availability of DAA therapy, racial disparities in post-LT survival have improved.

Long-term outcomes and trends in liver transplantation for hereditary hemochromatosis in the United States.

There have been conflicting data regarding liver transplantation (LT) outcomes for hereditary hemochromatosis (HH), with no recent data on LT outcomes in patients with HH in the past decade. Using the United Network for Organ Sharing registry, we evaluated waitlist and post-LT survival in all adult patients listed for HH without concomitant liver disease from 2003 to 2019. Post-LT survival for HH was compared with a propensity-matched (recipient and donor factors) cohort of recipients with chronic liver disease (CLD). From 2003 to 2019, 862 patients with HH were listed for LT, of which 55.6% ( n = 479) patients underwent LT. The 1- and 5-year post-LT survival rates in patients with HH were 88.7% (95% confidence interval [CI], 85.4%-91.4%) and 77.5% (95% CI, 72.8%-81.4%), respectively, and were comparable with those in the propensity-matched CLD cohort ( p value = 0.96). Post-LT survival for HH was lower than for Wilson's disease, another hereditary metabolic liver disease with similar LT volume ( n = 365). Predictors for long-term (5-year) post-LT mortality included presence of portal vein thrombosis (hazard ratio [HR], 1.96; 95% CI, 1.07-3.58), obesity measurements greater than Class II (HR, 1.98; 95% CI, 1.16-3.39), and Karnofsky performance status (HR, 0.98; 95% CI, 0.97-0.99) at the time of LT. The leading cause of post-LT death ( n = 145) was malignancy (25.5%), whereas cardiac disease was the cause in less than 10% of recipients. In conclusion, short- and long-term survival rates for HH are excellent and comparable with those of other LT recipients. Improving extrahepatic metabolic factors and functional status in patients with HH prior to LT may improve outcomes.

Survival Benefit of Solid-Organ Transplantation: 10-Year Update.

IMPORTANCE: Transplantation has transformed into a burgeoning field that is rapidly evolving to optimize organ distribution and survival outcomes. The years since 2012 (the last comprehensive study) have seen changes in transplantation, such as advances in immunotherapy and novel indices, that necessitate an updated analysis of survival benefit. DESIGN: Our goal was to determine the survival benefit for solid-organ transplants in the United Network for Organ Sharing (UNOS) database for a three decade period and provide updates on advancements since 2012. Our retrospective analysis examined data containing U.S. patient records from September 1, 1987, to September 1, 2021. RESULTS: We found that 3,430,272 life-years were saved over our transplant period (4.33 life-years saved per patient); kidney-1,998,492 life-years; liver -767,414; heart-435,312; lung-116,625; pancreas-kidney-123,463; pancreas-30,575; intestine-7901. After matching, 3,296,851 life-years were saved. Life-years saved and median survival increased for all organs between 2012 and 2021. Compared to 2012, median survival increased in kidney (from 12.4 to 14.76 years), liver (from 11.6 to 14.59), heart (9.5 to 11.73), lung (5.2 to 5.63), pancreas-kidney (from 14.5 to 16.88), pancreas (from 13.3 to 16.10). When compared to 2012, the percent transplanted increased in kidney, liver, heart, lung, and intestine, while pancreas-kidney and pancreas show decreased percent transplanted. CONCLUSION: Our study underscores the tremendous survival benefits of solid organ transplantation (over 3.4 million life-years saved) and shows improvements since 2012. Our study also highlights areas of transplantation, notably pancreas transplants, that may necessitate reinvigorated attention.

Hepatoblastomas with carcinoma features represent a biological spectrum of aggressive neoplasms in children and young adults.

BACKGROUND & AIMS: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS. METHODS: We tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8). RESULTS: Molecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (∼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes. CONCLUSIONS: Our study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms. LAY SUMMARY: We molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.

Impact of COVID-19 Pandemic on Liver Transplantation and Alcohol-Associated Liver Disease in the USA.

BACKGROUND AND AIMS: The surge in unhealthy alcohol use during the COVID-19 pandemic may have detrimental effects on the rising burden of alcohol-associated liver disease (ALD) on liver transplantation (LT) in the USA. We evaluated the effect of the pandemic on temporal trends for LT including ALD. APPROACH AND RESULTS: Using data from United Network for Organ Sharing, we analyzed wait-list outcomes in the USA through March 1, 2021. In a short-period analysis, patients listed or transplanted between June 1, 2019, and February 29, 2020, were defined as the "pre-COVID" era, and after April 1, 2020, were defined as the "COVID" era. Interrupted time-series analyses using monthly count data from 2016-2020 were constructed to evaluate the rate change for listing and LT before and during the COVID-19 pandemic. Rates for listings (P = 0.19) and LT (P = 0.14) were unchanged during the pandemic despite a significant reduction in the monthly listing rates for HCV (-21.69%, P < 0.001) and NASH (-13.18%; P < 0.001). There was a significant increase in ALD listing (+7.26%; P < 0.001) and LT (10.67%; P < 0.001) during the pandemic. In the COVID era, ALD (40.1%) accounted for more listings than those due to HCV (12.4%) and NASH (23.4%) combined. The greatest increase in ALD occurred in young adults (+33%) and patients with severe alcohol-associated hepatitis (+50%). Patients with ALD presented with a higher acuity of illness, with 30.8% of listings and 44.8% of LT having a Model for End-Stage Liver Disease-Sodium score ≥30. CONCLUSIONS: Since the start of COVID-19 pandemic, ALD has become the most common indication for listing and the fastest increasing cause for LT. Collective efforts are urgently needed to stem the rising tide of ALD on health care resources.

Trends in marginal lung allograft survival: Advanced-age donors improve.

INTRODUCTION: Although lung demand continues to outpace supply, 75% of potential donor lungs are discarded without being transplanted in the United States. To identify the discarded cohorts best suited to alleviate the lung shortage and reduce waitlist mortality, we explored changes in survival over time for five marginal donor definitions: age >60 years, smoking history >20 pack-years, PaO2 /FiO2  < 300 mmHg, purulent bronchoscopic secretions, and chest radiograph infiltrates. METHODS: Our retrospective cohort study separated 27 803 lung recipients in the UNOS Database into three 5-year eras by transplant date: 2005-2009, 2010-2014, and 2015-2019. Multivariable Cox proportional hazards regression and Kaplan-Meier analysis with log-rank test were used to compare survival across the eras. RESULTS: Three definitions-low PaO2 /FiO2 , purulent bronchoscopic secretions, and abnormal chest radiographs-did not bear out as truly marginal, demonstrating lack of significantly elevated risk. Advanced donor age demonstrated considerable survival improvement (HR (95% CI): 1.47 (1.26-1.72) in 2005-2009 down to 1.14 (.97-1.35) for 2015-2019), with protective factors being recipients <60 years, moderate recipient BMI, and low Lung Allocation Score (LAS). Donors with smoking history failed to demonstrate any significant improvement (HR (95% CI): 1.09 (1.01-1.17) in 2005-2009 increasing to 1.22 (1.08-1.38) in 2015-2019). CONCLUSIONS: Advanced donor age, previously the most significant risk factor, has improved to near-benchmark levels, demonstrating the possibility for matching older donors to healthier non-elderly recipients in selected circumstances. Low PaO2 /FiO2 , bronchoscopic secretions, and abnormal radiographs demonstrated survival on par with standard donors. Significant donor smoking history, a moderate risk factor, has failed to improve.

Marginal allografts in liver transplantation have a limited impact on length of stay.

The study of marginal liver transplant outcomes, including post-transplant length of stay (LOS), is necessary for determining the practicality of their use. 50 155 patients who received transplants from 2012 to 2020 were retrospectively analyzed with data from the Scientific Registry of Transplant Recipients database using Kaplan-Meier survival curves and multivariable Cox regression. Six different definitions were used to classify an allograft as being marginal: 90th percentile Donor Risk Index (DRI) allografts, donation after cardiac death (DCD) donors, national share donors, donors over 70, donors with > 30% macrovesicular steatosis, or 90th percentile Discard Risk Index donors. 24% (n = 12 124) of subjects received marginal allografts. Average LOS was 15.6 days among those who received standard allografts. Among those who received marginal allografts, LOS was found to be highest in those who received 90th percentile DRI allografts at 15.6 days, and lowest in those who received DCD allografts at 12.7 days. Apart from fatty livers (95% CI .86-.98), marginal allografts were not associated with a prolonged LOS. We conclude that accounting for experience and recipient matching, transplant centers may be more aggressive in their use of extended criteria donors with limited fear of increasing LOS and its associated costs.