Utilization of Segmental Grafts Is Associated With Higher Transplant Rates in Pediatric Patients.

INTRODUCTION: In July 2017, a policy to increase the use of segmental grafts (SGs) was implemented at our institution. The aim was to compare changes in waitlist activity after implementation of this policy. METHODS: A single-center, retrospective study. Pediatric patients on the liver waiting list between January 2015 and December 2019 were screened. Patients were classified as receiving a liver transplant (LT) before (Period 1) or after (Period 2) policy changes. Primary end points were transplant rates and time to transplant. RESULTS: Sixty five first LT performed on 65 patients were included. Twenty nine LT were performed during Period 1 and 36 during Period 2. More than half (55%) of LT in Period 2 were SG, compared to 10.3% in Period 1 (P < 0.001). Forty nine and 56 pediatric candidates on the waiting list accounted for 38.78 and 24.48 person-years during Period 1 and Period 2, respectively. Transplant rates per 100 person-years on the waiting list increased from 85.09 during Period 1 to 187.87 in Period 2 (Rate ratio: 2.20; P < 0.001). Median time to receive a LT decreased from 229 d in Period 1 to 75 d during Period 2 (P = 0.013). One-year patient survival rates were 96.6% in Period 1 and 95.7% in Period 2. One-year graft survival rates were 89.7% and 88% in Period 1 and Period 2, respectively. CONCLUSIONS: A policy to increase the use of SG was associated with significantly higher transplant rates and lower waiting times. Implementation of this policy can be done successfully with no observed negative impact on patient and graft survival.

Conversion to resection post radioembolization in patients with HCC: recommendations from a multidisciplinary working group.

BACKGROUND: Transarterial radioembolization (TARE) with yttrium-90 (90Y) glass microspheres is an efficacious option for converting appropriately selected patients with borderline-resectable hepatocellular carcinoma (HCC) to surgical candidacy. METHODS: In 2018 and 2019, a diverse multidisciplinary group of surgical and interventional experts with experience using 90Y for downstaging and bridging to liver transplant convened to review peer-reviewed literature and personal experience in the use of 90Y to convert borderline resectable liver cancer patients to surgical candidacy. The working group included surgical oncologists specializing in liver cancer, liver transplant surgeons with experience in complex hepatobiliary surgery, and interventional radiologists with experience using 90Y. RESULTS: This document presents expert recommendations based upon the group's experience and consensus. CONCLUSIONS: By combining related evidence from the literature with expert experiences with TARE in surgical candidates, these recommendations aim to demonstrate the safety, efficacy, and feasibility of TARE in converting borderline-resectable patients to surgical options. The document also addresses the concerns about potential complications associated with TARE during the surgical intervention.

Transportal Radioembolization as Salvage Hepatocellular Carcinoma Therapy to Maintain Liver Transplant Candidacy.

A 53-year-old woman with chronic hepatitis B and multifocal hepatocellular carcinoma was unable to receive transarterial radioembolization and had disease progression despite multiple chemoembolizations and systemic chemotherapy. Transportal radioembolization (TPRE) to maintain transplant candidacy was performed. Two lesions (1.7 cm, 1.4 cm) were treated with a single session of TPRE. Imaging performed at 4 months after TPRE demonstrated complete response in one lesion and stable disease in the other. This case illustrates TPRE as a salvage therapy for hepatocellular carcinoma in select patients.

Three-dimensional Liver Model Application for Liver Transplantation.

BACKGROUND: Children are removed from the liver transplant waitlist because of death or progressive illness. Size mismatch accounts for 30% of organ refusal. This study aimed to demonstrate that 3-dimensional (3D) technology is a feasible and accurate adjunct to organ allocation and living donor selection process. METHODS: This prospective multicenter study included pediatric liver transplant candidates and living donors from January 2020 to February 2023. Patient-specific, 3D-printed liver models were used for anatomic planning, real-time evaluation during organ procurement, and surgical navigation. The primary outcome was to determine model accuracy. The secondary outcome was to determine the impact of outcomes in living donor hepatectomy. Study groups were analyzed using propensity score matching with a retrospective cohort. RESULTS: Twenty-eight recipients were included. The median percentage error was -0.6% for 3D models and had the highest correlation to the actual liver explant (Pearson's R = 0.96, P < 0.001) compared with other volume calculation methods. Patient and graft survival were comparable. From 41 living donors, the median percentage error of the allograft was 12.4%. The donor-matched study group had lower central line utilization (21.4% versus 75%, P = 0.045), shorter length of stay (4 versus 7 d, P = 0.003), and lower mean comprehensive complication index (3 versus 21, P = 0.014). CONCLUSIONS: Three-dimensional volume is highly correlated with actual liver explant volume and may vary across different allografts for living donation. The addition of 3D-printed liver models during the transplant evaluation and organ procurement process is a feasible and safe adjunct to the perioperative decision-making process.

Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers.

Onset of the mitochondrial permeability transition (MPT) plays a causative role in ischemia/reperfusion (I/R) injury. Current therapeutic strategies for reducing reperfusion injury remain disappointing. Autophagy is a lysosome-mediated, catabolic process that timely eliminates abnormal or damaged cellular constituents and organelles such as dysfunctional mitochondria. I/R induces calcium overloading and calpain activation, leading to degradation of key autophagy-related proteins (Atg). Carbamazepine (CBZ), an FDA-approved anticonvulsant drug, has recently been reported to increase autophagy. We investigated the effects of CBZ on hepatic I/R injury. Hepatocytes and livers from male C57BL/6 mice were subjected to simulated in vitro, as well as in vivo I/R, respectively. Cell death, intracellular calcium, calpain activity, changes in autophagy-related proteins (Atg), autophagic flux, MPT and mitochondrial membrane potential after I/R were analyzed in the presence and absence of 20 µM CBZ. CBZ significantly increased hepatocyte viability after reperfusion. Confocal microscopy revealed that CBZ prevented calcium overloading, the onset of the MPT and mitochondrial depolarization. Immunoblotting and fluorometric analysis showed that CBZ blocked calpain activation, depletion of Atg7 and Beclin-1 and loss of autophagic flux after reperfusion. Intravital multiphoton imaging of anesthetized mice demonstrated that CBZ substantially reversed autophagic defects and mitochondrial dysfunction after I/R in vivo. In conclusion, CBZ prevents calcium overloading and calpain activation, which, in turn, suppresses Atg7 and Beclin-1 depletion, defective autophagy, onset of the MPT and cell death after I/R.

Performance of a Prospective Anticoagulation Stratification Algorithm After Liver Transplantation.

Venous thromboembolism (VTE) occurs in 0.4% to 15.5% and bleeding occurs in 20% to 35% of patients after liver transplantation (LT). Balancing the risk of bleeding from therapeutic anticoagulation and risk of thrombosis in the postoperative period is challenging. Little evidence exists regarding the best treatment strategy for these patients. We hypothesized that a subset of LT patients who develop postoperative deep vein thromboses (DVTs) could be managed without therapeutic anticoagulation. We implemented a quality improvement (QI) initiative using a standardized Doppler ultrasound-based VTE risk stratification algorithm to guide parsimonious implementation of therapeutic anticoagulation with heparin drip. Methods: In a prospective management QI initiative for DVT management, we compared 87 LT historical patients (control group; January 2016-December 2017) to 182 LT patients (study group; January 2018-March 2021). We analyzed the rates of immediate therapeutic anticoagulation after DVT diagnosis within 14 d of LT, clinically significant bleeding, return to the operating room, readmission, pulmonary embolism, and death within 30 d of LT before and after the QI initiative. Results: Ten patients (11.5%) in the control group and 23 patients (12.6%; P = 0.9) in the study group developed DVTs after LT. Immediate therapeutic anticoagulation was used in 7 of 10 and 5 of 23 patients in the control and study groups, respectively (P = 0.024). The study group had lower odds of receiving immediate therapeutic anticoagulation after VTE (21.7% versus 70%; odds ratio = 0.12; 95% confidence interval, 0.019-0.587; P = 0.013) and a lower rate of postoperative bleeding (8.7% versus 40%; odds ratio = 0.14, 95% confidence interval, 0.02-0.91; P = 0.048). All other outcomes were similar. Conclusions: Implementing a risk-stratified VTE treatment algorithm for immediate post-LT patients appears to be safe and feasible. We observed a decrease in the use of therapeutic anticoagulation and a lower rate of postoperative bleeding without adverse impacts on early outcomes.

Kidney transplant ureteroneocystostomy: comparison of full-thickness vs. Lich-Gregoir techniques.

Despite a variety of urinary tract reconstructive techniques, urinary complications are the most frequent technical adverse event following kidney transplantation. We examined outcomes of two ureteroneocystostomy techniques, the full-thickness (FT) technique and the Lich-Gregoir (LG) technique in 634 consecutive kidney-alone transplants (327 FT and 307 LG) between December 2006 and December 2010. Urological complications at one yr post-transplantation occurred in 27 cases (4.3%) including 16 ureteral strictures (2.5%), four ureteral obstructions (0.6%) owing to donor-derived stones or intrinsic hematoma, and seven urine leaks (1.1%). Compared with LG, the FT technique was associated with similar proportions of ureteral complications overall (3.9% vs. 4.6%, p = 0.70), ureteral strictures (3.7% vs. 1.3%, p = 0.08), urinary stones/hematoma (1.0% vs. 0.3%, p = 0.36), and overall urinary leaks (1.6% vs. 0.6%, p = 0.22); however, the FT technique was associated with somewhat fewer urine leaks at the ureterovesical junction (0% vs. 1.3%, p = 0.05). There were no differences between the two groups in terms of length of stay, delayed graft function, urinary tract infection with the first post-transplant year, estimated glomerular filtration rate, and overall graft and patient survival. The FT technique of ureteroneocystostomy is technically simple to perform and has a similar incidence of urinary complications compared with the LG technique.

Critical Roles of Calpastatin in Ischemia/Reperfusion Injury in Aged Livers.

Ischemia/reperfusion (I/R) injury unavoidably occurs during hepatic resection and transplantation. Aged livers poorly tolerate I/R during surgical treatment. Although livers have a powerful endogenous inhibitor of calpains, calpastatin (CAST), I/R activates calpains, leading to impaired autophagy, mitochondrial dysfunction, and hepatocyte death. It is unknown how I/R in aged livers affects CAST. Human and mouse liver biopsies at different ages were collected during in vivo I/R. Hepatocytes were isolated from 3-month- (young) and 26-month-old (aged) mice, and challenged with short in vitro simulated I/R. Cell death, protein expression, autophagy, and mitochondrial permeability transition (MPT) between the two age groups were compared. Adenoviral vector was used to overexpress CAST. Significant cell death was observed only in reperfused aged hepatocytes. Before the commencement of ischemia, CAST expression in aged human and mouse livers and mouse hepatocytes was markedly greater than that in young counterparts. However, reperfusion substantially decreased CAST in aged human and mouse livers. In hepatocytes, reperfusion rapidly depleted aged cells of CAST, cleaved autophagy-related protein 5 (ATG5), and induced defective autophagy and MPT onset, all of which were blocked by CAST overexpression. Furthermore, mitochondrial morphology was shifted toward an elongated shape with CAST overexpression. In conclusion, CAST in aged livers is intrinsically short-lived and lost after short I/R. CAST depletion contributes to age-dependent liver injury after I/R.

Hepatocellular carcinoma in a 10-month-old biliary atresia child.

We present a case of a 10-month-old boy with BA who developed HCC and was treated with liver transplantation. A four-month-old boy was referred to our institution because of persistent jaundice, hepatomegaly, and coagulopathy. He had been treated for the diagnosis of neonatal hepatitis at an outside hospital. He was evaluated and was accepted as a liver transplant candidate, and was subsequently transplanted with a deceased donor liver allograft at the age of 10 months. His native liver showed established cirrhosis because of BA with one focus of moderately differentiated HCC, measuring 0.7 cm in a diameter with microscopic vascular invasion in pathological study. The postoperative course was uneventful, and he is well without recurrence four months after liver transplantation. The occurrence of HCC in a child under one yr old is extremely rare, and only three cases are reported so far including our case.

Duplicate gallbladder arising from the left hepatic duct: report of a case.

Gallbladder duplication is a rare congenital biliary anomaly with different morphologies depending on events at embryogenesis. This case report describes a symptomatic duplicate gallbladder arising from the left intrahepatic duct 10 years after an open cholecystectomy: this is the rarest form of gallbladder duplication. The symptoms resolved following a second open cholecystectomy. This case illustrates the importance of preoperative imaging, intraoperative cholangiography, and a high index of suspicion of anomalous gallbladder anatomy in the diagnosis and management of this rare condition. We discuss the classification of anomalous gallbladder anatomy and review previous cases, to propose a modification of the common classification scheme.

Packed red blood cell donor age affects overall survival in transfused patients undergoing hepatectomy for non-hepatocellular malignancy.

BACKGROUND: Patients undergoing hepatectomy often require packed red blood cell (PRBC) transfusion, which has been associated with worse oncologic outcomes. However, limited data exist regarding the impact of PRBC donor factors. We hypothesized that PRBC donor age impacts survival after hepatectomy for non-hepatocellular malignancies. METHODS: Patients who underwent hepatectomy for non-hepatocellular malignancy from 2005 to 2014 were retrospectively evaluated. Impact of clinicopathologic and PRBC factors on oncologic outcomes were assessed. RESULTS: Of 149 identified patients, 76 received a perioperative PRBC transfusion (median 2 units). Transfusion was associated with increased median length of stay (8 vs. 6 days; p < 0.01) and median operative blood loss (700 vs. 350 mL; p < 0.01) versus non-transfused, respectively. In transfused patients, receipt of PRBC from older donors compared to younger resulted in decreased RFS (0.94 vs. 2.63 years, respectively; p = 0.02) and OS (1.94 vs. 3.44 years, respectively; p = 0.6). The PRBC donor age was an independent predictor of decreased recurrence free survival on multivariate analysis (HR 2.5, p = 0.04). CONCLUSIONS: In patients undergoing hepatectomy for non-hepatocellular malignancies and receiving perioperative transfusion, PRBC donor age may impact survival and warrants further investigation.

Angiosomal radiopathologic analysis of transarterial radioembolization for the treatment of hepatocellular carcinoma.

PURPOSE: To assess the radiopathologic correlation following Yttrium-90 transarterial radioembolization (TARE) of hepatocellular carcinoma (HCC) using variable radiodosimetry to identify imaging surrogates of histologic response. METHODS: Twelve patients with HCC underwent ablative (≥ 190 Gy) and/or non-ablative (< 190 Gy) TARE delivered in a segmental, lobar, or combined fashion as a surgical neoadjuvant or bridge to transplantation. Both targeted tumor and treatment angiosome were analyzed before and after TARE utilizing hepatocyte-specific contrast-enhanced MRI or contrast-enhanced CT. Responses were graded using EASL and mRECIST criteria. Histologic findings including percent tumor necrosis and adjacent hepatic substrate effects were correlated with imaging features. RESULTS: Complete pathologic necrosis (CPN) was observed in 7/12 tumors post-TARE. Ablative and non-ablative dosing resulted in CPN in 5/6 and 2/6 tumors, respectively. Hyperintensity on T2-weighted imaging, the absence of hepatocyte-specific gadolinium contrast uptake, and plateau or persistent enhancement kinetics in the angiosome correlated with CPN and performed similarly to EASL and mRECIST criteria in predicting CPN. CONCLUSIONS: The absence of hepatocyte-specific contrast uptake, increased signal on T2-weighted sequences, and plateau or persistent enhancement in the angiosome may represent MRI surrogates of CPN following TARE of HCC. These findings correlated with EASL and mRECIST response criteria. Further investigation is needed to determine the role of these findings as possible adjuncts to conventional imaging criteria.

Listeria monocytogenes following orthotopic liver transplantation: central nervous system involvement and review of the literature.

Listeria monocytogene is a well-recognized cause of bacteremia in immunocompromised individuals, including solid organ transplant recipients, but has been rarely reported following orthotopic liver transplantation. We describe a case of listeria meningitis that occurred within a week after liver transplantation. The patient developed a severe headache that mimicked tacrolimus encephalopathy, and was subsequently diagnosed with listeria meningitis by cerebrospinal fluid culture. The infection was successfully treated with three-week course of intravenous ampicillin. Recurrent hepatitis C followed and was successfully treated with interferon alfa and ribavirin. Fourteen cases of listeriosis after orthotopic liver transplantation have been reported in the English literature. Most reported cases were successfully treated with intravenous ampicillin. There were four cases of listeria meningitis, and the mortality of them was 50%. Early detection and treatment of listeria meningitis are the key to obtaining a better prognosis.

Mucinous Cystadenoma: A Rare Hepatic Tumor in a Child.

Mucinous cystadenomas (MCAs) of the liver (also called hepatic biliary cystadenomas) are rare tumors that comprise about 5% of cystic masses of the liver in adults. These slow-growing lesions most commonly occur in middle-aged individuals, with a female sex predominance. Herein, we present a MCA in a 6-year-old male, one of only very few such cases described in the pediatric literature to date. Although MCAs are generally considered benign lesions, malignant transformation rarely occurs. The recurrence rate is high when partial cyst excision is performed. Therefore, complete surgical cyst resection with clinical follow-up, including imaging, is warranted.

Autophagy in Ischemic Livers: A Critical Role of Sirtuin 1/Mitofusin 2 Axis in Autophagy Induction.

No-flow ischemia occurs during cardiac arrest, hemorrhagic shock, liver resection and transplantation. Recovery of blood flow and normal physiological pH, however, irreversibly injures the liver and other tissues. Although the liver has the powerful machinery for mitochondrial quality control, a process called mitophagy, mitochondrial dysfunction and subsequent cell death occur after reperfusion. Growing evidence indicates that reperfusion impairs mitophagy, leading to mitochondrial dysfunction, defective oxidative phosphorylation, accumulation of toxic metabolites, energy loss and ultimately cell death. The importance of acetylation/deacetylation cycle in the mitochondria and mitophagy has recently gained attention. Emerging data suggest that sirtuins, enzymes deacetylating a variety of target proteins in cellular metabolism, survival and longevity, may also act as an autophagy modulator. This review highlights recent advances of our understanding of a mechanistic correlation between sirtuin 1, mitophagy and ischemic liver injury.

Mitochondrial Dysfunction and Autophagy in Hepatic Ischemia/Reperfusion Injury.

Ischemia/reperfusion (I/R) injury remains a major complication of liver resection, transplantation, and hemorrhagic shock. Although the mechanisms that contribute to hepatic I/R are complex and diverse involving the interaction of cell injury in hepatocytes, immune cells, and endothelium, mitochondrial dysfunction is a cardinal event culminating in hepatic reperfusion injury. Mitochondrial autophagy, so-called mitophagy, is a key cellular process that regulates mitochondrial homeostasis and eliminates damaged mitochondria in a timely manner. Growing evidence accumulates that I/R injury is attributed to defective mitophagy. This review aims to summarize the current understanding of autophagy and its role in hepatic I/R injury and highlight the various therapeutic approaches that have been studied to ameliorate injury.

Survival With Dialysis Versus Kidney Transplantation in Adult Hemolytic Uremic Syndrome Patients: A Fifteen-Year Study of the Waiting List.

BACKGROUND: Survival data are lacking for kidney transplant recipients with rare native end-stage renal disease (ESRD) etiologies. There is currently no large registry study comparing dialysis versus kidney transplantation survival outcomes of waitlisted adults with hemolytic uremic syndrome (HUS). MATERIALS AND METHODS: We retrospectively studied adult-HUS end-stage renal disease patients (n = 559) placed on the US kidney transplant waitlist in 1996 to 2011. We analyzed 5-year transplantation and patient survival probabilities and risk factors using Kaplan-Meier and Cox hazards models, respectively. Using similar models, waitlist and transplantation outcomes of patients with diabetes mellitus (DM), hypertension (HTN), and glomerulonephritis (GN) were analyzed, and then compared with HUS patients. RESULTS: Compared with waitlisted adult HUS patients on dialysis, 5-year mortality risks were 73% and 48% lower in recipients of living (hazard ratio [HR], 0.27, 95% confidence interval [95% CI], 0.11-0.65) and standard deceased (HR, 0.52; 95% CI, 0.29-0.94) donor kidney transplants, respectively. Mortality risks over 5 years were 44%, 50%, 54%, and 55% lower in the overall transplant recipient cohorts than in the dialysis-maintained cohorts within the HUS (HR, 0.56; 95% CI, 0.35-0.91), HTN (HR, 0.50; 95% CI, 0.48-0.52), GN (HR, 0.46; 95% CI, 0.44-0.49), and DM (HR, 0.45; 95% CI, 0.44-0.47) groups, respectively. Five-year transplantation probability in the waitlisted HUS cohort was 60% versus 42% to 49% (P < 0.001) in the DM and HTN cohorts, and 62% (P = 0.93) in the GN cohort. CONCLUSIONS: Living and standard criteria deceased donor kidney transplants provide significant survival benefit over dialysis in waitlisted adults with HUS. On the waitlist, the 5-year transplantation probability was higher in HUS than in DM and HTN patients.

Combined laparoscopic placement of a PTBD demonstrating multidisciplinary problem-solving in a complex patient.

In rare cases, biliary drainage is prevented by colonic position. When these situations arise within a critically ill patient who is not a good surgical candidate, unique solutions must be found. In this case, the solution was to use laparoscopic assistance to displace the colon while the interventional radiology team successfully accessed the biliary system.

Epigenetic signatures of alcohol abuse and hepatitis infection during human hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. Deregulated DNA methylation landscapes are ubiquitous in human cancers. Interpretation of epigenetic aberrations in HCC is confounded by multiple etiologic drivers and underlying cirrhosis. We globally profiled the DNA methylome of 34 normal and 122 liver disease tissues arising in settings of hepatitis B (HBV) or C (HCV) viral infection, alcoholism (EtOH), and other causes to examine how these environmental agents impact DNA methylation in a manner that contributes to liver disease. Our results demonstrate that each 'exposure' leaves unique and overlapping signatures on the methylome. CpGs aberrantly methylated in cirrhosis-HCV and conserved in HCC were enriched for cancer driver genes, suggesting a pathogenic role for HCV-induced methylation changes. Additionally, large genomic regions displaying stepwise hypermethylation or hypomethylation during disease progression were identified. HCC-HCV/EtOH methylomes overlap highly with cryptogenic HCC, suggesting shared epigenetically deregulated pathways for hepatocarcinogenesis. Finally, overlapping methylation abnormalities between primary and cultured tumors unveil conserved epigenetic signatures in HCC. Taken together, this study reveals profound epigenome deregulation in HCC beginning during cirrhosis and influenced by common environmental agents. These results lay the foundation for defining epigenetic drivers and clinically useful methylation markers for HCC.