Faculty Bibliography

OBJECTIVE:We sought to develop a "Model Of Recurrence After Liver transplant" (MORAL) for hepatocellular carcinoma (HCC). BACKGROUND:The Milan criteria are used to allocate livers to patients with HCC requiring liver transplantation (LT) but do not include objective measures of tumor biology. Biological markers including the neutrophil-lymphocyte ratio (NLR) and alpha-fetoprotein (AFP) have been associated with recurrence risk. METHODS:Prospective cohort study of adults undergoing LT for HCC between January 2001 and December 2012. RESULTS:A total of 339 patients were included. On multivariable Cox regression analysis, 3 preoperatively available factors were independent predictors of worse recurrence-free survival (RFS), namely, an NLR ≥ 5 (P < 0.0001, hazard ratio, HR: 6.2), AFP > 200 (P < 0.0001, HR: 3.8), and Size >3 cm (P < 0.001, HR: 3.2). The Pre-MORAL score was constructed from the hazard ratios and assigning patients points in an additive fashion, with a minimum of 0 points (no factors) and a maximum of 13 points (all 3 factors). The highest risk patients in the Pre-MORAL had a 5-year RFS of 17.9% compared with 98.6% for the low risk group (P < 0.0001). The post-MORAL was constructed similarly using the 4 postoperatively available independent predictors of worse RFS, grade 4 HCC's (P < 0.0001, HR: 5.6), vascular invasion (P = 0.019, HR: 2.0), size >3 cm (P < 0.0001, HR: 3.2) and number >3 (P = 0.048, HR: 1.8). The pre- and post-MORAL were superior to Milan at predicting recurrence with c-statistics of 0.82 and 0.87, compared with 0.63, respectively. We then combined the scores to produce a combo-MORAL, with a c-statistic of 0.91 for predicting recurrence. CONCLUSIONS:The MORAL score provides a simple, highly accurate tool for predicting recurrence and risk-stratification pre- and postoperatively.

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.

A paradigm in transplantation states that graft-infiltrating T cells are largely non-alloreactive "bystander" cells. However, the origin and specificity of allograft T cells over time has not been investigated in detail in animals or humans. Here, we use polychromatic flow cytometry and high throughput TCR sequencing of serial biopsies to show that gut-resident T cell turnover kinetics in human intestinal allografts are correlated with the balance between intra-graft host-vs-graft (HvG) and graft-vs-host (GvH) reactivities and with clinical outcomes. In the absence of rejection, donor T cells were enriched for GvH-reactive clones that persisted long-term in the graft. Early expansion of GvH clones in the graft correlated with rapid replacement of donor APCs by the recipient. Rejection was associated with transient infiltration by blood-like recipient CD28+ NKG2D^Hi CD8+ alpha beta T cells, marked predominance of HvG clones, and accelerated T cell turnover in the graft. Ultimately, these recipient T cells acquired a steady state tissue-resident phenotype, but regained CD28 expression during rejections. Increased ratios of GvH to HvG clones were seen in non-rejectors, potentially mitigating the constant threat of rejection posed by HvG clones persisting within the tissue-resident graft T cell population.

OBJECTIVE:Centers offering adult living donor liver transplantation (LDLT) mostly use right lobe grafts due to fears of providing recipients with insufficient hepatic volume, and the technical challenges presented by using left lobe grafts (LLGs). LLGs therefore represent approximately 5% of adult LDLTs performed in the United States. Here we present the largest North American experience with the use of LLG for adult LDLT. METHODS:Analysis of a prospectively maintained database of LDLTs performed from 1998 to 2015 at our institution. RESULTS:A total of 214 adult LDLTs were studied. Fifty-six patients (26%) received LLG. LLG recipients were more likely to be women, had significantly lower BMI, graft weight, and graft-weight-recipient-weight ratios (P < 0.05 for all). There were no significant differences in vascular or biliary complication between the groups. No significant differences existed in patient or graft survival at 1, 3, and 5 years (P = 0.747 and P = 0.398 respectively). Despite significantly increased risk of small-for-size syndrome in LLG, there was no increased risk of retransplant within 90-days or perioperative mortality in LLG recipients (P = 0.308 and P = 0.932 respectively). Graft type did not predict patient or graft outcomes on regression analysis (P = 0.857 and 0.399 respectively). CONCLUSIONS:Despite smaller graft sizes, outcomes of adult LDLT using LLG are comparable to right lobe grafts transplants. Left lobes can provide an important resource in an era of severe organ shortages, and these data should serve to allay the concerns of the transplant community in the United States.

Homozygous familial hypercholesterolemia (HoFH) is a rare, inherited, life-threatening, metabolic disorder of low-density lipoprotein (LDL) receptor function characterized by elevated serum LDL cholesterol (LDL-C) and rapidly progressive atherosclerotic cardiovascular disease (ACVD). Since LDL receptors are predominantly found on hepatocytes, orthotopic liver transplantation (OLT) has emerged as a viable intervention for HoFH because LDL receptor activity is restored. This study assessed the effects of OLT on ACVD and ACVD risk factors in pediatric patients with HoFH. We analyzed lipids, lipoproteins, body mass index, glucose, blood pressure, and cardiovascular imaging in 8 pediatric patients who underwent OLT for HoFH. Total serum cholesterol, LDL-C, lipoprotein (a), and apolipoprotein B/apolipoprotein A1 ratio decreased to normal values in all subjects (p values <0.001) at 1 month after OLT and were maintained for the length of follow-up (2 to 6 years). There were few complications related to surgery or immunosuppressive therapy. Two patients developed mild hypertension. In the first 4 subjects monitored for 4 to 6 years after OLT, coronary artery disease did not develop or progress except in 1 minor artery in 1 subject and actually regressed in 2 subjects with >50% stenosis. However, aortic valve stenosis progressed in 2 of 4 subjects. In conclusion, OLT is an effective therapeutic option for patients with HoFH with coronary artery disease and persistently elevated serum LDL-C despite maximum medical therapy. Aortic valvular disease may progress. Long-term data are needed to evaluate the true risk-benefit ratio of this surgical approach.

By preserving part of the native liver, auxiliary partial orthotopic liver transplantation (APOLT) provides the advantage of potential immunosuppression (ISP) withdrawal if the native liver recovers but has had limited acceptance, especially in the United States, due to technical complications and low rates of native liver regeneration. No previous study has evaluated APOLT specifically for preadolescent children with fulminant hepatic failure (FHF). This population might benefit especially based on greater capacity for liver regeneration. Data from 13 preadolescent children who underwent APOLT were compared to 13 matched controls who underwent orthotopic liver transplantation (OLT) for FHF from 1996 to 2013. There were no significant differences in patient demographics or survival between the 2 groups. However, all surviving OLT recipients (10/13) remain on ISP, while all but 1 surviving APOLT recipient (12/13) showed native liver regeneration, and the first 10 recipients (76.9%) are currently off ISP with 2 additional patients currently weaning. In our experience, APOLT produced excellent survival and high rates of native liver regeneration in preadolescent children with FHF. This represents the largest series to date to report such outcomes. Liberating these children from lifelong ISP without the downside of increased surgical morbidity makes APOLT an attractive alternative. In conclusion, we therefore propose that, with the availability of technical expertise and with the technical modifications above, APOLT for FHF should be strongly considered for preteenage children with FHF.

It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity and immunoregulation. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (T(EM)) found only in the lungs and small intestine. Additionally, regulatory T (T(reg)) cells comprise a high proportion (30-40%) of CD4(+) T cells in pediatric tissues but are present at much lower frequencies (1-10%) in adult tissues. Pediatric tissue T(reg) cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest T(reg):T(EM) cell ratios, which suggests control in situ of immune responses in early life.

New surgical procedures taking advantage of the regenerative abilities of the liver are being introduced as potential curative therapies to these patients either to provide auxiliary support while the native liver recovers or undergoes hypertrophy. For patients with hepatocellular carcinoma outside of the Milan criteria or bilobar colorectal metastases liver transplantation is not an option. Fulminant hepatic failure can be treated but requires life-long immunosuppression. These complex surgical procedures require high quality and directed imaging.