Biodegradable biliary stents placement using a "kissing-stent" technique for management of a recalcitrant stricture post-live donor liver transplant.

BACKGROUND: Biliary complications are common in pediatric liver transplant. Strictures resistant to interventional radiology procedures can be extremely challenging to manage and may result in the need of surgery or retransplantation. METHODS: This case report illustrates the use of biodegradable stents post left lateral segment live donor liver transplant in a pediatric patient with a recalcitrant chronic stricture of the biliary-enteric anastomosis. The patient developed a high stricture requiring multiple interventions and eventual access of both the segment II and segment III ducts of the graft. RESULTS: To ensure adequate biliary drainage, two biodegradable stents were deployed using a "kissing-stent" technique. The stents were successfully deployed and allowed the patient to remain free from an internal-external biliary drain for 11 months, with eventual redeployment of an additional biodegradable stent. CONCLUSION: In patients with recalcitrant stenosis of the biliary anastomosis, biodegradable stents may provide durable drainage, optimizing graft function and delaying retransplantation in addition to keeping patients without external devices, thus improving quality of life.

Development and validation of a multivariable prediction model in pediatric liver transplant patients for predicting intensive care unit length of stay.

BACKGROUND: Liver transplantation is the life-saving treatment for many end-stage pediatric liver diseases. The perioperative course, including surgical and anesthetic factors, have an important influence on the trajectory of this high-risk population. Given the complexity and variability of the immediate postoperative course, there would be utility in identifying risk factors that allow prediction of adverse outcomes and intensive care unit trajectories. AIMS: The aim of this study was to develop and validate a risk prediction model of prolonged intensive care unit length of stay in the pediatric liver transplant population. METHODS: This is a retrospective analysis of consecutive pediatric isolated liver transplant recipients at a single institution between April 1, 2013 and April 30, 2020. All patients under the age of 18 years receiving a liver transplant were included in the study (n = 186). The primary outcome was intensive care unit length of stay greater than 7 days. RESULTS: Recipient and donor characteristics were used to develop a multivariable logistic regression model. A total of 186 patients were included in the study. Using multivariable logistic regression, we found that age < 12 months (odds ratio 4.02, 95% confidence interval 1.20-13.51, p = .024), metabolic or cholestatic disease (odds ratio 2.66, 95% confidence interval 1.01-7.07, p = .049), 30-day pretransplant hospital admission (odds ratio 8.59, 95% confidence interval 2.27-32.54, p = .002), intraoperative red blood cells transfusion >40 mL/kg (odds ratio 3.32, 95% confidence interval 1.12-9.81, p = .030), posttransplant return to the operating room (odds ratio 11.45, 95% confidence interval 3.04-43.16, p = .004), and major postoperative respiratory event (odds ratio 32.14, 95% confidence interval 3.00-343.90, p < .001) were associated with prolonged intensive care unit length of stay. The model demonstrates a good discriminative ability with an area under the receiver operative curve of 0.888 (95% confidence interval, 0.824-0.951). CONCLUSIONS: We develop and validate a model to predict prolonged intensive care unit length of stay in pediatric liver transplant patients using risk factors from all phases of the perioperative period.

Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury.

Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ11. PMR releases pro-inflammatory cytoplasmic molecules, collectively called damage-associated molecular patterns (DAMPs), that activate immune cells. Therefore, inhibiting NINJ1 and PMR may limit the inflammation that is associated with excessive cell death. Here we describe an anti-NINJ1 monoclonal antibody that specifically targets mouse NINJ1 and blocks oligomerization of NINJ1, preventing PMR. Electron microscopy studies showed that this antibody prevents NINJ1 from forming oligomeric filaments. In mice, inhibition of NINJ1 or Ninj1 deficiency ameliorated hepatocellular PMR induced with TNF plus D-galactosamine, concanavalin A, Jo2 anti-Fas agonist antibody or ischaemia-reperfusion injury. Accordingly, serum levels of lactate dehydrogenase, the liver enzymes alanine aminotransaminase and aspartate aminotransferase, and the DAMPs interleukin 18 and HMGB1 were reduced. Moreover, in the liver ischaemia-reperfusion injury model, there was an attendant reduction in neutrophil infiltration. These data indicate that NINJ1 mediates PMR and inflammation in diseases driven by aberrant hepatocellular death.

Outcomes after liver transplantation using deceased after circulatory death donors: A comparison of outcomes in the UK and the US.

BACKGROUND AND AIMS: Identifying international differences in utilization and outcomes of liver transplantation (LT) after donation after circulatory death (DCD) donation provides a unique opportunity for benchmarking and population-level insight. METHODS: Adult (≥18 years) LT data between 2008 and 2018 from the UK and US were used to assess mortality and graft failure after DCD LT. We used time-dependent Cox-regression methods to estimate hazard ratios (HR) for risk-adjusted short-term (0-90 days) and longer-term (90 days-5 years) outcomes. RESULTS: One-thousand five-hundred-and-sixty LT receipts from the UK and 3426 from the US were included. Over the study period, the use of DCD livers increased from 15.7% to 23.9% in the UK compared to 5.1% to 7.6% in the US. In the UK, DCD donors were older (UK:51 vs. US:33 years) with longer cold ischaemia time (UK: 437 vs. US: 333 min). Recipients in the US had higher Model for End-stage Liver Disease (MELD) scores, higher body mass index, higher proportions of ascites, encephalopathy, diabetes and previous abdominal surgeries. No difference in the risk-adjusted short-term mortality or graft failure was observed between the countries. In the longer-term (90 days-5 years), the UK had lower mortality and graft failure (adj.mortality HR:UK: 0.63 (95% CI: 0.49-0.80); graft failure HR: UK: 0.72, 95% CI: 0.58-0.91). The cumulative incidence of retransplantation was higher in the UK (5 years: UK: 11.9% vs. 4.6%; p < .001). CONCLUSIONS: For those receiving a DCD LT, longer-term post-transplant outcomes in the UK are superior to the US, however, significant differences in recipient illness, graft quality and access to retransplantation were seen between the two countries.

A Malignant Hepatoblastoma Mimicking a Benign Mesenchymal Hamartoma: Lessons Learned.

Differentiating hepatoblastomas from other congenital benign hepatic tumors is key to surgical management. We, herein, present an unusual case of an antenatally diagnosed liver lesion assessed in the neonatal period. Because of its predominantly cystic ultrasound/MRI appearance and borderline alpha-fetoprotein serum levels the diagnosis of mesenchymal hamartoma was favored and protocol-based tumor resection was performed. Due to the intraoperative diagnosis of a fetal subtype of hepatoblastoma with positive resection margins the child had to undergo a second laparotomy. This report raises awareness to an unusual appearance of hepatoblastoma and discusses noninvasive imaging clues to consider atypical appearances of hepatoblastoma preoperatively as they can have profound implications in patient management.

Normothermic Ex Vivo Kidney Perfusion for Human Kidney Transplantation: First North American Results.

BACKGROUND: Normothermic ex vivo kidney perfusion (NEVKP) has shown promising results for preservation, assessment, and reconditioning of kidney allografts in preclinical studies. Here, we report the first North American safety and feasibility study of deceased donor kidneys grafts transplanted following preservation with NEVKP. METHODS: Outcomes of 13 human kidney grafts that received 1 to 3 h of NEVKP after being transported in an anoxic hypothermic machine perfusion device were compared with a matched control group of 26 grafts that were preserved with anoxic hypothermic machine perfusion alone. RESULTS: Grafts were perfused for a median of 171 min (range, 44-275 min). The delayed graft function rate in NEVKP versus control patients was 30.8% versus 46.2% ( P = 0.51). During the 1-y follow-up, no differences in postoperative graft function, measured by serum creatinine, necessity for dialysis, and urine production, were found between the study group and the control group. There were no differences in 1 y posttransplantation graft or patient survival between the 2 groups. CONCLUSIONS: Our study demonstrates the safety and feasibility of NEVKP for human deceased donor kidney transplantation. Further studies are warranted to explore how this technology can minimize cold ischemia, improve posttransplant graft function, and assess and repair expanded criteria kidney grafts.

Predictors of survival following liver transplantation for pediatric hepatoblastoma and hepatocellular carcinoma: Experience from the Society of Pediatric Liver Transplantation (SPLIT).

Management of unresectable pediatric hepatoblastoma (HB) and hepatocellular carcinoma (HCC) remains challenging. The Society of Pediatric Liver Transplantation (SPLIT) database was used to study survival predictors in pediatric liver transplantation (LT) for HB and HCC. Event-free survival (EFS), associated risk factors, and postoperative complications were studied in children requiring LT for HB/HCC at 16 SPLIT centers. Three-year EFS was 81% for HB (n = 157) and 62% for HCC (n = 18) transplants. Of HB transplants, 6.9% were PRETEXT II and 15.3% were POST-TEXT I/II. Tumor extent did not impact survival (p = NS). Salvage (n = 13) and primary HB transplants had similar 3-year EFS (62% versus 78%, p = NS). Among HCC transplants, 3-year EFS was poorer in older patients (38% in ≥8-year-olds vs 86% <8-year-olds) and those with larger tumors (48% for those beyond versus 83% within Milan criteria, p = NS). Risk of infection (HR 1.5, 95% CI 1.1-2.2, p = .02) and renal injury (HR 2.4, 95% CI 1.7-3.3, p < .001) were higher in malignant versus nonmalignant LT. Survival is favorable for pediatric HB and HCC LT, including outcomes after salvage transplant. Unexpected numbers of LTs occurred in PRE/POST-TEXT I/II tumors. Judicious patient selection is critical to distinguish tumors that are potentially resectable; simultaneously, we must advocate for patients with unresectable malignancies to receive organs.

Sequential paternal haploidentical donor liver and HSCT in EPP allow discontinuation of immunosuppression post-organ transplant.

BACKGROUND: EPP is characterized by photosensitivity and by liver disease. When LT is performed in EPP, recurrence often occurs in the allograft due to ongoing protoporphyrin production in bone marrow. Therefore, curative treatment requires allogeneic HSCT after LT. Long-term immunosuppression could be spared by using the same donor for both transplants. METHODS: A 2-year-old girl with EPP in liver failure underwent liver transplant from her father. Transfusion and apheresis therapy were used to lower protoporphyrin levels before and after liver transplant. Ten weeks after liver transplant, she underwent HSCT, using the same donor. Conditioning was with treosulfan, fludarabine, cyclophosphamide, and ATG. GVHD prophylaxis was with abatacept, methotrexate, MMF, and tacrolimus. We followed the patient's erythrocyte protoporphyrin and liver and skin health for 2 years after transplant. RESULTS: After hematopoietic stem cell engraftment, a decline in protoporphyrin levels was observed, with clinical resolution of photosensitivity. Liver biopsies showed no evidence of EPP. Mild ACR occurred and responded to steroid pulse. Two years post-HSCT, the patient has been weaned off all immunosuppression and remains GVHD and liver rejection free. CONCLUSIONS: Sequential liver and HSCT from the same haploidentical donor are feasible in EPP. This strategy can allow for discontinuation of immune suppression.

Imaging and clinical features of pediatric hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is rare in children and there is limited data on its imaging features. OBJECTIVE: To describe imaging features of pediatric HCC and correlate them with clinical and laboratory findings. MATERIALS AND METHODS: We retrospectively reviewed imaging in all pediatric HCC cases seen between January 2000 and January 2019. Imaging features defined in LI-RADS (Liver Imaging Reporting and Data System) and tumor extent by PRETEXT (pretreatment extent of disease) criteria were noted by two radiologists. Patient charts were reviewed to collect clinical features, alpha-fetoprotein (AFP) level and pathology findings. RESULTS: Of the 15 children (7 boys, 8 girls; mean age: 11.8 years, age range: 6-17 years) included in the study, 12/15 had computed tomography, 9/15 had magnetic resonance imaging and 9/15 had ultrasound exams available for review. Pathological types of HCC included classic (11/15, 73%), fibrolamellar (3/15, 20%) and mixed cholangiocarcinoma-HCC (1/15, 7%). Eighty percent occurred de novo in normal liver and 67% showed elevated AFP levels. Arterial phase hyperenhancement was seen in 83% of cases, washout in 86%, capsule in 50% and tumor-in-vein in 33%. The mean tumor size was 9.8 cm and 40% were multifocal on imaging. Staging revealed PRETEXT II tumors in 47%, III in 20% and IV in 33%. There were no PRETEXT I tumors. The two most common PRETEXT annotation factors were portal vein and caudate lobe involvement in 71% and 43% of cases, respectively. Fibrolamellar HCC demonstrated central scar, normal AFP levels and normal background liver. CONCLUSION: Pediatric HCC are large heterogeneous tumors, as reflected by high PRETEXT staging, and commonly include portal vein and caudate involvement. This affects resectability of these tumors at presentation. Central scar, normal AFP level and normal liver background may help differentiate fibrolamellar HCC from other types of HCC.

Living donor liver paired exchange: A North American first.

Paired organ exchange can be used to circumvent living donor-recipient ABO incompatibilities. Herein, we present the first case of successful liver paired exchange in North America. This 2-way swap required 4 simultaneous operations: 2 living donor hepatectomies and 2 living donor liver transplants. A nondirected anonymous living donor gift initiated this domino exchange, alleviating an ABO incompatibility in the other donor-recipient pair. With careful attention to ethical and logistical issues, paired liver exchange is a feasible option to expand the donor pool for incompatible living liver donor-recipient pairs.

"The Living Monument": The Desegregation of Grady Memorial Hospital and the Changing South.

Grady Memorial Hospital is a pillar of public medical and surgical care in the Southeast. The evolution of this institution, both in its physical structure as well as its approach to patient care, mirrors the cultural and social changes that have occurred in the American South. Grady Memorial Hospital opened its doors in 1892 built in the heart of Atlanta's black community. With its separate and unequal facilities and services for black and white patients, the concept of "the Gradies" was born. Virtually, every aspect of care at Grady continued to be segregated by race until the mid-20th century. In 1958, the opening of the "New Grady" further cemented this legacy of the separate "Gradies," with patients segregated by hospital wing. By the 1960s, civil rights activists brought change to Atlanta. The Atlanta Student Movement, with the support of Dr. Martin Luther King Jr., led protests outside of Grady, and a series of judicial and legislative rulings integrated medical boards and public hospitals. Eventually, the desegregation of Grady occurred with a quiet memo that belied years of struggle: on June 1, 1965, a memo from hospital superintendent Bill Pinkston read "All phases of the hospital are on a non-racial basis, effective today." The future of Grady is deeply rooted in its past, and Grady's mission is unchanged from its inception in 1892: "It will nurse the poor and rich alike and will be an asylum for black and white."

Preemptive kidney transplantation is associated with survival benefits among pediatric patients with end-stage renal disease.

Kidney transplantation is the preferred treatment for pediatric end-stage renal disease (ESRD). Preemptive transplantation avoids the increased morbidity and mortality of dialysis. Yet, previous studies have not demonstrated significant graft or patient survival benefits for children undergoing transplantation preemptively versus nonpreemptively. These previous studies were limited by small samples sizes and low rates of adverse events. Here we compared graft failure and mortality rates using Kaplan-Meier methods and Cox regression among a large national cohort of children with ESRD undergoing preemptive versus nonpreemptive kidney transplantation between 2000 and 2012. Among 7527 pediatric kidney transplant recipients in the United States Renal Data System, 1668 underwent preemptive transplantation. Over a median 4.8 years follow-up, 1314 experienced graft failure, and over a median 5.2 years of follow-up, 334 died. Dialysis exposure versus preemptive transplantation conferred a higher risk of graft failure (hazard ratio 1.32; 95% confidence interval: 1.10-1.56) and a higher risk of death (hazard ratio 1.69; 95% confidence interval: 1.22-2.33) in multivariable analysis. Compared with children undergoing preemptive transplantation, children on dialysis for >1 year had a 52% higher risk of graft failure and those on dialysis >18 months had an 89% higher risk of death, regardless of donor source. Thus, preemptive transplantation is associated with substantial benefits in allograft and patient survival among children with ESRD, particularly when compared with children who receive dialysis for >1 year. These findings support policies to promote early access to transplantation and avoidance of dialysis for children with ESRD whenever feasible.

Pancreas transplantation in unconventional recipients.

PURPOSE OF REVIEW: Advances in surgical technique and immunosuppression have significantly improved outcomes after pancreas transplantation, and as a result pancreas transplants increasingly are being performed for indications other than type 1 diabetes mellitus. This review summarizes the current literature on pancreas transplantation in unconventional recipient populations. RECENT FINDINGS: An increasing body of work suggests that pancreas transplantation can be performed with good outcomes in patients with type 2 diabetes mellitus and those 50 years of age and older. Obesity appears detrimental to patient and pancreas graft survival, and bariatric surgery prior to transplantation may be of increasing interest and relevance. There are limited data yielding mixed outcomes on pancreas transplantation in patients with HIV or hepatitis C virus. However, rapidly improving antiviral therapies are prolonging survival in patients with HIV and chronic hepatitis C virus infections and may increase the number of candidates available for pancreas transplantation in these populations in the future. SUMMARY: Despite limited literature in these patient populations, pancreas transplantation may be a viable treatment option for endocrine pancreas failure in appropriately selected patients regardless of disease cause or age.

Utility of Prostate Cancer Screening in Kidney Transplant Candidates.

Screening recommendations for prostate cancer remain controversial, and no specific guidelines exist for screening in renal transplant candidates. To examine whether the use of prostate-specific antigen (PSA)-based screening in patients with ESRD affects time to transplantation and transplant outcomes, we retrospectively analyzed 3782 male patients ≥18 years of age undergoing primary renal transplant evaluation during a 10-year period. Patients were grouped by age per American Urological Association screening guidelines: group 1, patients <55 years; group 2, patients 55-69 years; and group 3, patients >69 years. A positive screening test result was defined as a PSA level >4 ng/ml. We used univariate analysis and Cox proportional hazards models to identify the independent effect of screening on transplant waiting times, patient survival, and graft survival. Screening was performed in 63.6% of candidates, and 1198 candidates (31.7%) received kidney transplants. PSA screening was not associated with improved patient survival after transplantation (P=0.24). However, it did increase the time to listing and transplantation for candidates in groups 1 and 2 who had a positive screening result (P<0.05). Furthermore, compared with candidates who were not screened, PSA-screened candidates had a reduced likelihood of receiving a transplant regardless of the screening outcome (P<0.001). These data strongly suggest that PSA screening for prostate cancer may be more harmful than protective in renal transplant candidates because it does not appear to confer a survival benefit to these candidates and may delay listing and decrease transplantation rates.

Cutting edge: mast cells regulate disease severity in a relapsing-remitting model of multiple sclerosis.

Mast cells (MCs) exert a significant pathologic influence on disease severity in C57BL/6 (B6) strain-dependent experimental allergic encephalomyelitis (EAE), a model of primary progressive multiple sclerosis (MS). However, relapsing-remitting MS, which is modeled in SJL mice, is the more prevalent form. Given genetically determined heterogeneity in numbers and responsiveness of MCs from various strains of mice, we asked whether these cells also influence this more clinically relevant MS model using SJL-Kit(W/W-v) mice. Similar to the commercially available WBB6F(1)-Kit(W/W-v) mice, SJL-Kit(W/W-v) mice are MC-deficient, anemic, and neutropenic and have normal T cell compartments. They exhibit significantly reduced disease severity, but retain the relapsing-remitting course, a phenotype reversed by selective MC reconstitution. These data confirm that MC influence is not confined to an isolated model of EAE and reveal a new system to study the effects of MC heterogeneity on relapsing-remitting EAE and other SJL strain-specific diseases.

Meningeal mast cells affect early T cell central nervous system infiltration and blood-brain barrier integrity through TNF: a role for neutrophil recruitment?

Mast cells contribute to the pathogenesis of experimental autoimmune encephalomyelitis, a rodent model of the human demyelinating disease multiple sclerosis. Yet their site and mode of action is unknown. In both diseases, myelin-specific T cells are initially activated in peripheral lymphoid organs. However, for disease to occur, these cells must enter the immunologically privileged CNS through a breach in the relatively impermeable blood-brain barrier. In this study, we demonstrate that a dense population of resident mast cells in the meninges, structures surrounding the brain and spinal cord, regulate basal CNS barrier function, facilitating initial T cell CNS entry. Through the expression of TNF, mast cells recruit an early wave of neutrophils to the CNS. We propose that neutrophils in turn promote the blood-brain barrier breach and together with T cells lead to further inflammatory cell influx and myelin damage. These findings provide specific targets for intervention in multiple sclerosis as well as other immune-mediated CNS diseases.