Faculty Bibliography

Of the 1.6 million patients >70 years of age who died of stroke since 2002, donor livers were retrieved from only 2402 (0.15% yield rate). Despite reports of successful liver transplantation (LT) with elderly grafts (EG), advanced donor age is considered a risk for poor outcomes. Centers for Medicare and Medicaid Services definitions of an "eligible death" for donation excludes patients >70 years of age, creating disincentives to donation. We investigated utilization and outcomes of recipients of donors >70 through analysis of a United Network for Organ Sharing Standard Transplant Analysis and Research-file of adult LTs from 2002 to 2014. Survival analysis was conducted using Kaplan-Meier curves, and Cox regression was used to identify factors influencing outcomes of EG recipients. Three thousand one hundred four livers from donors >70, ≈40% of which were used in 2 regions: 2 (520/3104) and 9 (666/3104). Unadjusted survival was significantly worse among recipients of EG compared to recipients of younger grafts (P < .0001). Eight independent negative predictors of survival in recipients of EG were identified on multivariable analysis. Survival of low-risk recipients who received EG was significantly better than survival of recipients of younger grafts (P = .04). Outcomes of recipients of EG can therefore be optimized to equal outcomes of younger grafts. Given the large number of stroke deaths in patients >70 years of age, the yield rate of EGs can be maximized and disincentives removed to help resolve the organ shortage crisis.

Organ donors are sources of physiologically healthy organs and tissues for life-saving transplantation, and have been recently used for human immunology studies which are typically confined to the sampling of peripheral blood. Donors comprise a diverse population with different causes of death and clinical outcomes during hospitalization, and the effects of such variations on immune parameters in blood and tissues are not known. We present here a coordinate analysis of innate and adaptive immune components in blood, lymphoid (bone marrow, spleen, lymph nodes), and mucosal (lungs, intestines) sites from a population of brain-dead organ donors (2 months-93 years; n = 291) across eight clinical parameters. Overall, the blood of donors exhibited similar monocyte and lymphocyte content and low serum levels of pro-inflammatory cytokines as healthy controls; however, donor blood had increased neutrophils and serum levels of IL-8, IL-6, and MCP-1 which varied with cause of death. In tissues, the frequency and composition of monocytes, neutrophils, B lymphocytes and T cell subsets in lymphoid or mucosal sites did not vary with clinical state, and was similar in donors independent of the extent of clinical complications. Our results reveal that organ donors maintain tissue homeostasis, and are a valuable resource for fundamental studies in human immunology.

The goal of the study is to characterize the relationship between portal vein thrombosis (PVT) and hepatic atrophy in patients without cirrhosis and the effect of various types of surgical shunts on liver regeneration and splenomegaly. Patients without cirrhosis with PVT suffer from presinusoidal portal hypertension, and often hepatic atrophy is a topic that has received little attention. We hypothesized that patients with PVT have decreased liver volumes, and shunts that preserve intrahepatic portal flow enhance liver regeneration. Sixty-four adult and pediatric patients with PVT who underwent surgical shunt placement between 1998 and 2011 were included in a retrospective study. Baseline liver volumes from adult patients were compared with standard liver volume (SLV) as well as a group of healthy controls undergoing evaluation for liver donation. Clinical assessment, liver function tests, and liver and spleen volumes from cross-sectional imaging were compared before and after surgery. A total of 40 patients received portal flow-preserving shunts (32 mesoportal and 8 selective splenorenal), whereas 24 received portal flow-diverting shunts (16 nonselective splenorenal and 8 mesocaval). Baseline adult liver volumes were 26% smaller than SLV (1248 versus 1624 cm³ ; P = 0.02) and 20% smaller than the control volumes (1248 versus 1552 cm³ ; P = 0.02). Baseline adult spleen volumes were larger compared with controls (1258 versus 229 cm³ ; P < 0.001). Preserving shunts were associated with significant increase in liver volumes (886 versus 1131 cm³ ; P = 0.01), whereas diverting shunts were not. Diverting shunts significantly improved splenomegaly. In conclusion, we have demonstrated that patients without cirrhosis with PVT have significant liver atrophy and splenomegaly. Significant liver regeneration was achieved after portal flow-preserving shunts. Liver Transplantation 24 881-887 2018 AASLD.

Biliary complications are a common cause of morbidity after liver transplantation, with biliary stone formation being a known occurrence generally upstream of a stricture. A 12-year-old boy, who underwent an orthotopic liver transplantation at 11 months of age for biliary atresia, presented acutely with fever and abdominal pain. Cross-sectional imaging revealed Roux-en-Y limb dilatation and thickening. He was explored and was found to have an ischemic Roux limb secondary to an obstructing enterolith. A segmental bowel resection and revision of his hepaticojejunostomy was performed. While rare, biliary enteroliths may present as either a bowel obstruction or cholangitis and should be considered in the differential diagnosis of a patient following biliary reconstruction. Additionally, anatomic etiologies should be considered and potentially surgically corrected.

PURPOSE OF REVIEW:The aim of this study was to review the recent progress in xenotransplantation achieved through genetic engineering and discuss the potential of tolerance induction to overcome remaining barriers to extended xenograft survival. RECENT FINDINGS:The success of life-saving allotransplantation has created a demand for organ transplantation that cannot be met by the supply of human organs. Xenotransplantation is one possible solution that would allow for a nearly unlimited supply of organs. Recent genetic engineering of swine has decreased the reactivity of preformed antibodies to some, but not all, potential human recipients. Experiments using genetically modified swine organs have now resulted in survival of life-supporting kidneys for over a year. However, the grafts show evidence of antibody-mediated rejection on histology, suggesting additional measures will be required for further extension of graft survival. Tolerance induction through mixed chimerism or thymic transplantation across xenogeneic barriers would be well suited for patients with a positive crossmatch to genetically modified swine or relatively negative crossmatches to genetically modified swine, respectively. SUMMARY:This review highlights the current understanding of the immunologic processes in xenotransplantation and describes the development and application of strategies designed to overcome them from the genetic modification of the source animal to the induction of tolerance to xenografts.

BACKGROUND:Despite high survival in pediatric living donor liver transplantation (LDLT), only 10% of liver transplants in children in the United States are from living donors, reflecting reluctance to embrace this approach. In addition to optimal timing and graft quality, LDLT may offer immunologic benefit because most donors are haploidentical parents. We sought to quantify the benefit of LDLT compared to deceased donor liver transplantation (DDLT) using granular clinical and immunologic outcomes over the long term. METHODS:A retrospective cohort of children (age <18 years) surviving 1 year or longer posttransplant was evaluated to determine the impact of donor type on graft survival and immunologic outcomes. RESULTS:Two hundred forty-one children (177 DDLT and 64 LDLT) were assessed. In multivariable analysis, LDLT was associated with a lower rate of acute cellular rejection (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98; P = 0.04), a lower rate of chronic rejection (HR, 0.12; 95% CI, 0.03-0.56; P = 0.007), better graft survival on monotherapy immunosuppression at 3 years posttransplant (87.7% vs 46.7%; odds ratio, 7.41; 95% CI, 2.80-19.66; P < 0.001), and a lower rate of graft loss (HR, 0.29; 95% CI, 0.10-0.88; P = 0.03). Graft type was not an independent predictor of posttransplant mortality (LDLT HR, 0.57; 95% CI, 0.16-2.01; P = 0.38). Maternal graft LDLT was associated with a lower rate of acute cellular rejection (HR, 0.13; 95% CI, 0.03-0.64; P = 0.01) and posttransplant lymphoproliferative disorder (HR, 0.04; 95% CI, 0.004-0.44; P = 0.008) compared with paternal grafts. CONCLUSIONS:This study demonstrates the potential benefit of LDLT, particularly with maternal grafts, for pediatric liver transplant recipients on multiple clinical parameters over long-term follow-up.

OBJECTIVE:In order to minimize the impact of donation, fully laparoscopic donor hepatectomy (LDH) is being investigated at a few centers throughout the world. We report here our experience with 51 living donor pure laparoscopic hepatectomies. BACKGROUND:Adoption of minimal access techniques to living donor liver transplantation (LDLT) has been slowed by concerns about donor safety and the quality of the grafts. METHODS:Of 344 donor hepatectomies (DHs) for living donor liver transplantation (LDLT) since 1998, 51 pure LDH have been performed since 2009. We report here our experience with 51 living donor pure laparoscopic hepatectomy (LH), based on prospectively collected data. There were 31 left lateral sectionectomy and 20 full lobectomies LH. We matched full lobe LH to open DH prior to introduction of LH. RESULTS:LH increased from 21% of all DH in first 5 years of performing LH to 45% of DH in the most recent 3 years. Laparoscopic donors were more likely female, had lower body mass index, smaller total livers, and smaller allografts but longer operating room times. In the total LD experience, total 5 donors were converted to open surgery (10%), 2 donors required transfusion (4%), and there was 2 donor bile leaks (4%). Recipient patient and graft 1-year survival was 98% and 94%. CONCLUSIONS:Our experience indicates that LDH for LDLT can be safely used with appropriate attention to learning curve and progression from left lateral sectionectomy to right hepatectomy.

BACKGROUND:Infusion of recipient regulatory T (Treg) cells promotes durable mixed hematopoietic chimerism and allograft tolerance in mice receiving allogeneic bone marrow transplant (BMT) with minimal conditioning. We applied this strategy in a Cynomolgus macaque model. METHODS:CD4 CD25 Treg cells that were polyclonally expanded in culture were highly suppressive in vitro and maintained high expression of FoxP3. Eight monkeys underwent nonmyeloablative conditioning and major histocompatibility complex mismatched BMT with or without Treg cell infusion. Renal transplantation (from the same BMT donor) was performed 4 months post-BMT without immunosuppression to assess for robust donor-specific tolerance. RESULTS:Transient mixed chimerism, without significant T cell chimerism, was achieved in the animals that received BMT without Treg cells (N = 3). In contrast, 2 of 5 recipients of Treg cell BMT that were evaluable displayed chimerism in all lineages, including T cells, for up to 335 days post-BMT. Importantly, in the animal that survived long-term, greater than 90% of donor T cells were CD45RA CD31, suggesting they were new thymic emigrants. In this animal, the delayed (to 4 months) donor kidney graft was accepted more than 294 days without immunosuppression, whereas non-Treg cell BMT recipients rejected delayed donor kidneys within 3 to 4 weeks. Early CMV reactivation and treatment was associated with early failure of chimerism, regardless of Treg cell administration. CONCLUSIONS:Our studies provide proof-of-principle that, in the absence of early CMV reactivation (and BM-toxic antiviral therapy), cotransplantation of host Treg cell can promote prolonged and high levels of multilineage allogeneic chimerism and robust tolerance to the donor.

Ganglioneuromas are slow growing, clinically silent benign tumors for which surgery is considered to be the standard treatment. However, surgical excision in cases where surrounding structures are involved can be challenging. The present study reports a novel technique of ex vivo excision for the management of a retroperitoneal ganglioneuroma in a 21-year old patient, that appeared to be inoperable using standard surgical resection. Preoperative investigations revealed a large tumor with encasement of the origins of the superior mesenteric artery (SMA) and bilateral renal arteries. Initially, to prevent the need to explant the liver, the distal SMA (with takeoff of the replaced common hepatic artery) was anastomosed to the splenic artery. The bulk of the tumor along with the bilateral kidneys was mobilized from the retroperitoneum, and the aorta and inferior vena cava (IVC) were cross-clamped above and below the tumor and divided. The two kidneys were dissected free of the tumor at the back-table and were auto-transplanted in a standard technique following the reconstruction of the aorta and IVC. The patient tolerated surgery well and a one-year postoperative follow-up did not show any sign of tumor recurrence. Although technically demanding, ex vivo resection and auto-transplantation of the involved organs can be introduced as a final option for the treatment of tumors that are un-resectable using standard surgical techniques.