Reactive Immunomodulator Addition to Infliximab Monotherapy Restores Clinical Response in Inflammatory Bowel Disease: A Meta-Analysis.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) receiving infliximab (IFX) commonly experience immunogenic loss of response (LOR) by formation of anti-drug antibodies (ADAs). An immunomodulator (IMM) used in combination with initial IFX induction is known to reduce ADA development and improve clinical outcomes. We aimed to assess the impact of reactively adding an IMM to patients on IFX monotherapy. METHODS: We conducted a retrospective cohort study and systematic review with meta-analysis of patients with IBD demonstrating immunologic LOR, with or without clinical LOR, that had an IMM (azathioprine, 6-mercaptopurine, or methotrexate) reactively added (reactive combination therapy; rCT) to combat elevated ADAs and raise IFX level. Data were extracted for pooled effect size estimation using random-effects models, and ADA and IFX trough levels were compared pre- and post-IMM initiation. RESULTS: We identified 6 patients who received rCT due to rising ADA titers and low IFX levels. Median ADA titer decreased from 506 ng/mL (interquartile range (IQR) [416-750]) to 76.5 ng/mL (IQR [25.8-232]), an 85% decrease (p = 0.031). Median IFX trough increased from 0.4 µg/mL (IQR [0.4-0.48]) to 8.25 µg/mL (IQR [3.7-9.6]), a 20.6-fold increase (p = 0.038). Meta-analysis pooled effect size of 7 studies with 89 patients showed an 87% ADA titer reduction [95% confidence interval (CI) = 72-94%], 6.7-fold increased IFX trough (95% CI = 2.4-18.7), and 76% clinical remission rescue rate (95% CI = 59-93%). CONCLUSIONS: These results suggest rCT is a valid rescue strategy in patients with immunogenic LOR to IFX to reduce ADA titers, restore therapeutic IFX levels, and recapture clinical remission of IBD.

Stress promotes the infiltration of peripheral immune cells to the brain.

Immune cells and the brain have a privileged interaction. Here, we report changes in the hippocampal immune microenvironment at the single cell level after stress, uncovering the tight orchestration of immune cell infiltration into the hippocampus after stress to maintain homeostasis. We show the distribution of several immune cell types in the hippocampus associated with their susceptibility or resilience to the learned helplessness paradigm in a sex- and microbiota-dependent manner using single-cell RNA sequencing and bioinformatic tools, flow cytometry, and immunofluorescence. We uncovered the presence of tissue-resident memory T cells that accumulate over time in the hippocampus of learned helpless mice, and the presence of CD74-expressing myeloid cells. These cells were found by a knockdown approach to be critical to induce resilience to learned helplessness. Altogether, these findings provide a novel overview of the neuro-immune repertoire and its impact on the landscape of the hippocampus after learned helplessness.

Stressed and Inflamed, Can GSK3 Be Blamed?

Psychological stress has a pervasive influence on our lives. In many cases adapting to stress strengthens organisms, but chronic or severe stress is usually harmful. One surprising outcome of psychological stress is the activation of an inflammatory response that resembles inflammation caused by infection or trauma. Excessive psychological stress and the consequential inflammation in the brain can increase susceptibility to psychiatric diseases, such as depression, and impair learning and memory, including in some patients with cognitive deficits. An emerging target to control detrimental outcomes of stress and inflammation is glycogen synthase kinase-3 (GSK3). GSK3 promotes inflammation, partly by regulating key transcription factors in the inflammation signaling pathway, and GSK3 can impair learning by promoting inflammation and by inhibiting long-term potentiation (LTP). Drugs inhibiting GSK3 may prove beneficial for controlling mood and cognitive impairments caused by excessive stress and the associated neuroinflammation.

Glycogen synthase kinase-3 promotes T helper type 17 differentiation by promoting interleukin-9 production.

T helper type 17 (Th17) cells are recognized as important contributors to the deleterious effects of several neurological and psychiatric diseases. Clarifying mechanisms that control the production of Th17 cells may therefore provide new strategies for developing novel interventions in a broad spectrum of disorders. Th17 cell differentiation is promoted by glycogen synthase kinase-3 (GSK3), but the mechanisms for this are only beginning to be understood. Using T-cell-selective depletion of GSK3ß and multiple selective pharmacological GSK3 inhibitors, we found that GSK3 inhibition decreased C-C motif chemokine (ccl)20, C-C motif chemokine receptor (ccr)6, interleukin (IL)-9, Runt-related transcription factor (Runx)1, interferon regulatory factor (Irf)4 and c-maf mRNA expression after 2 days of Th17 cell differentiation in vitro. These effects were found to be independent of the master regulator transcription factor retinoic acid receptor-related orphan receptor γT (RORγT), as GSK3 inhibition still reduced Th17 cell differentiation in RORγT-depleted cells. Because IL-9 was approximately ninefold down-regulated in GSK3ß-/- CD4 cells, we tested if reintroduction of IL-9 during Th17 cell differentiation abolished the inhibition by GSK3 deficiency of Th17 cell differentiation. We found that IL-9 over-expression was sufficient to reverse the inhibition of Th17 cell differentiation by GSK3 inhibition or depletion. We found that IL-9 enhances Th17 cell differentiation in part through signal transducer and activator of transcription 3 (STAT3) activation, and IL-9 also enhances STAT3 binding to the IL-17a promoter. Altogether, these findings suggest that IL-9 might be an important mediator of GSK3ß-dependent enhancement of Th17 cell differentiation.

Th17 cells in depression.

T helper 17 (Th17) cells have recently been implicated in depression, which adds to the list of several other diseases of the central nervous system (CNS) that are already known to involve Th17 cells. In CNS diseases, it is thought that the signature cytokine produced by Th17 cells, interleukin-17A (IL-17A), mediates the detrimental effects of Th17 cells. In depression, although Th17 cells increase, the lack of a consistent correlation between depression severity and blood IL-17A levels suggests that Th17 cells promote depressive symptoms, which may not be entirely dependent on IL-17. However, little is known about the mechanism of action of Th17 cells or the source of CNS Th17 cells in depression. It is likely that Th17 cells promote neuroinflammation and activation of microglia and astrocytes, actions that may contribute to neuronal damage. A source of Th17 cells is the small intestine where they are regulated by the composition of the microbiome. It remains to be determined through what mechanisms of action Th17 cells affect depression and if Th17 cells can be considered a novel therapeutic target in depression.

Distinct characteristics of hippocampal pathogenic TH17 cells in a mouse model of depression.

Increasing evidence indicates that multiple actions of the immune system are closely intertwined with the development of depression and subsequent recovery processes. One of these interactions is substantial evidence that the TH17 subtype of CD4+ T cells promotes susceptibility to depression-like behaviors in mice. Comparing subtypes of CD4+ T cells, we found that administration of TH17 cells, but not TH1 cells or TREGS, promoted susceptibility to learned-helplessness depressive-like behavior and accumulated in the hippocampus of learned helpless mice. Adoptively transferred TH17 cells into Rag2-/- mice that are devoid of endogenous T cells increased susceptibility to learned helplessness, demonstrating that increased peripheral TH17 cells are capable of modulating depression-like behavior. Moreover, in wild-type mice, adoptively transferred TH17 cells accumulated in the hippocampus of learned-helpless mice and induced endogenous TH17 cell differentiation. Hippocampal TH17 cells from learned-helpless mice expressed markers of pathogenic TH17 cells (CCR6, IL-23R) and of follicular cells (CXCR5, PD-1), indicating that the hippocampal cells are TFH-17-like cells. Knockout of CCR6 blocked TH17 cells from promoting learned helplessness, which was associated with increased expression of PD-1 in CCR6-deficient TH17 cells. In summary, these results reinforce the conclusion that depression-like behaviors are selectively facilitated by TH17 cells, and revealed that these cells in the hippocampus of learned helpless mice display characteristics of TFH17-like cells, which may contribute to their pathogenic actions in promoting depression.

Morbid obesity in liver transplant recipients adversely affects longterm graft and patient survival in a single-institution analysis.

OBJECTIVE: The effects of obesity in liver transplantation remain controversial. Earlier institutional data demonstrated no significant difference in postoperative complications or 1-year mortality. This study was conducted to test the hypothesis that obesity alone has minimal effect on longterm graft and overall survival. METHODS: A retrospective, single-institution analysis of outcomes in patients submitted to primary adult orthotopic liver transplantation was conducted using data for the period from 1 January 2002 to 31 December 2012. Recipients were divided into six groups by pre-transplant body mass index (BMI), comprising those with BMIs of <18.0 kg/m(2) , 18.0-24.9 kg/m(2) , 25.0-29.9 kg/m(2) , 30.0-35.0 kg/m(2) , 35.1-40.0 kg/m(2) and >40 kg/m(2) , respectively. Pre- and post-transplant parameters were compared. A P-value of <0.05 was considered to indicate statistical significance. Independent predictors of patient and graft survival were determined using multivariate analysis. RESULTS: A total of 785 patients met the study inclusion criteria. A BMI of >35 kg/m(2) was associated with non-alcoholic steatohepatitis (NASH) cirrhosis (P < 0.0001), higher Model for End-stage Liver Disease (MELD) score, and longer wait times for transplant (P = 0.002). There were no differences in operative time, intensive care unit or hospital length of stay, or perioperative complications. Graft and patient survival at intervals up to 3 years were similar between groups. Compared with non-obese recipients, recipients with a BMI of >40 kg/m(2) showed significantly reduced 5-year graft (49.0% versus 75.8%; P < 0.02) and patient (51.3% versus 78.8%; P < 0.01) survival. CONCLUSIONS: Obesity increasingly impacts outcomes in liver transplantation. Although the present data are limited by the fact that they were sourced from a single institution, they suggest that morbid obesity adversely affects longterm outcomes despite providing similar short-term results. Further analysis is indicated to identify risk factors for poor outcomes in morbidly obese patients.

Pharmacologic Anticoagulation Is Associated With a Lower Risk of Recurrent Venous Thromboembolic Events During Janus Kinase Inhibitor Use for Patients With a Prior Thrombosis.

BACKGROUND: Janus kinase (JAK) inhibitors tofacitinib and upadacitinib are effective therapies for inflammatory bowel disease and rheumatologic disorders but currently possess a warning for increased venous thromboembolism (VTE) risk. Some patients with a history of VTE may benefit from a JAK inhibitor, but the risk of recurrent VTE with JAK inhibitor use is unclear. Our goal was to observe rates of new VTE events after starting JAK inhibitor therapy in patients with a prior VTE, and observe whether concurrent anticoagulation (AC) reduces this risk. METHODS: We conducted a review of adults prescribed tofacitinib or upadacitinib between January 1, 2000, and June 30, 2023, with a prior history of VTE. Patient charts were reviewed for demographic data, disease type, and VTE date(s), and to verify duration of JAK inhibitor use along with any concurrent AC. VTEs following JAK inhibitor initiation were identified by International Classification of Diseases-Tenth Revision code and verified by physician documentation and imaging. RESULTS: We identified 79 patients with a documented VTE history before initiating JAK inhibitors, 47 of whom began a JAK inhibitor with concurrent AC. Of these, 15 patients discontinued AC while receiving JAK inhibitors. In total, 5 new VTE events were observed during 55.42 patient-years of JAK inhibitor treatment without concurrent AC (9.0 events per 100 patient-years), while no new VTE events occurred during 65.2 patient-years of JAK inhibitor treatment with concurrent AC, demonstrating a lower risk of recurrent VTE (P = .020). CONCLUSIONS: These results suggest that for patients with a prior VTE history there is a high risk for recurrent VTE while receiving JAK inhibitors. Concurrent use of AC with JAK inhibitors appears to be protective against recurrent VTEs in this population.

Patients with a history of venous thromboembolism prior to initiation of a Janus kinase inhibitor (tofacitinib or upadacitinib) had an elevated risk (9%) of recurrent venous thromboembolism on Janus kinase inhibitor, though concurrent anticoagulation may mitigate this risk.

Organ allocation in pediatric renal transplants: is there an optimal donor?

The 2005 revised allocation scheme for pediatric renal transplantation made the decision of whether to transplant an available living-donor (LD) kidney or use a deceased-donor (DD) kidney controversial. The aim of this study was to examine kidney allograft utilization, sensitization, and outcomes of pediatric transplant recipients. Between January 2000 and December 2009, 91 consecutive pediatric kidney recipients (<20 yr) were transplanted. The LD (n = 38) and DD (n = 53) groups were similar in age, gender, dialysis status at transplant, warm ischemia time, and overall patient survival. LD recipients were more likely to be Caucasian (92 vs. 69%), receive older allografts (39 ± 10 vs. 23 ± 9 yr), and have fewer human leukocyte antigen (HLA) mismatches (3.3 ± 1.6 vs. 4.4 ± 1.5, p < 0.01 for all). Graft survival at one, three, and five yr post-transplant was longer for LD recipients (97%, 91%, 87% vs. DD 89%, 79%, 58%, respectively, p < 0.05). At the time of transplant, 17 (33%) DD recipients had an available LD (mean age 40 yr). A greater proportion of all patients were moderately (PRA 21-79%) sensitized post-transplant (p < 0.05). A multivariable analysis of graft survival indicated that the advantage in LD organs was likely due to fewer HLA mismatched in this group. Nonetheless, LD organs appear to provide optimal outcomes in pediatric renal transplants when considering the risk of becoming sensitized post-transplant complicating later use of the LD kidney.

Utilization of hepatitis B core antibody-positive donor liver grafts.

BACKGROUND: The inclusion of hepatitis B core antibody-positive (HBcAb+) liver donors is a strategy utilized to increase organ availability. This study examined HBcAb+ transplantation practices to identify specific factors influencing outcomes. METHODS: Twenty-five HBcAb+ liver transplants were identified retrospectively among 868 adult transplants performed between 1 January 1997 and 31 December 2009. Twelve (48%) recipients had hepatitis C and five (20%) had hepatitis B. Patient and donor demographics, preoperative morbidity, transplant data and outcomes were examined. Statistical analysis was completed using Student's t-test or the Kaplan-Meier method. A P-value of <0.05 was considered significant. RESULTS: There was no difference in age, body mass index or comorbidities between HBcAb+ liver recipients and control subjects. Model for End-stage Liver Disease (MELD) scores of >30 were significantly more frequent in HBcAb+ liver recipients (32% vs. 15%; P= 0.04). All patients received immunoglobulin and longterm antiviral therapy as prophylaxis against graft hepatitis B resurgence. No patients who received HBcAb+ livers developed hepatitis B infection on follow-up. Overall survival at 30 days, 1 year and 5 years in HBcAb+ liver recipients was 92%, 74% and 74%, respectively, compared with 96%, 89% and 76%, respectively, in the control group (P= not significant, log-rank test). All except one of the deaths in the HBcAb+ liver recipient group occurred within 90 days postoperatively and in patients with MELD scores >30. CONCLUSIONS: The practice of transplanting HBcAb+ grafts incurs low risk for infection using current methods of prophylaxis. The highest mortality risk was in the early postoperative period, specifically in patients with very high MELD scores. This probably reflects the practice of using positive serology grafts in emergent situations.

Management of excluded bile ducts in paediatric orthotopic liver transplant recipients of technical variant allografts.

BACKGROUND: A strategy to increase the number of size- and weight-appropriate organs and decrease the paediatric waiting list mortality is wider application of sectional orthotopic liver transplantation (OLT). These technical variants consist of living donor, deceased donor reduced and split allografts. However, these grafts have an increased risk of biliary complications. An unusual and complex biliary complication which can lead to graft loss is inadvertent exclusion of a major segmental bile duct. We present four cases and describe an algorithm to correct these complications. METHODS: A retrospective review of the paediatric orthotopic liver transplantation database (2000-2010) at Washington University in St. Louis/St. Louis Children's Hospital was conducted. RESULTS: Sixty-eight patients (55%) received technical variant allografts. Four complications of excluded segmental bile ducts were identified. Percutaneous cholangiography provided diagnostic confirmation and stabilization with external biliary drainage. All patients required interval surgical revision of their hepaticojejunostomy for definitive drainage. Indwelling biliary stents aided intra-operative localization of the excluded ducts. All allografts were salvaged. DISCUSSION: Aggressive diagnosis, percutaneous decompression and interval revision hepaticojejunostomy are the main tenets of management of an excluded bile duct. Careful revision hepaticojejunostomy over a percutaneous biliary stent can result in restoration of biliary continuity and allograft survival.

AAV8 transduction capacity is reduced by prior exposure to endosome-like pH conditions.

Adeno-associated virus (AAV) is an essential instrument in the neuroscientist's toolkit, which allows delivery of DNA to provide labeling with fluorescent proteins or genetic instructions to regulate gene expression. In the field of neural regeneration, the transduction of neurons enables the observation and regulation of axon growth and regeneration, and in the future will likely be a mechanism for delivering molecular therapies to promote sprouting and regeneration after central nervous system injury. Traditional formulations of AAV preparations permit efficient viral transduction under physiologic conditions, but an improved understanding of the mechanistic limitations of AAV transduction may facilitate production of more resilient AAV strains for investigative and therapeutic purposes. We studied AAV transduction in the context of prior exposure of AAV serotype 8 (AAV8) to environmental pH within the range encountered during endosomal endocytosis (pH 7.4 to pH 4.4), during which low pH-triggered structural and autoproteolytic changes to the viral capsid are believed to be necessary for endosome escape and virus uncoating. Due to the fundamental nature of these processes, we hypothesized that premature exposure of AAV8 particles to acidic pH would decrease viral transduction of HT1080 cells in vitro, as measured by fluorescent reporter gene expression using high-content imaging analysis. We found that increasingly acidic incubation conditions were associated with concomitant reductions in transduction efficiency, and that quantitative levels of reporter gene expression in transduced cells were similarly decreased. The biggest decrease in transduction occurred between pH 7.4 and pH 6.4, suggesting the possible co-occurrence of a pH-associated event and viral inactivation within that range. Taken together, these findings indicate that exposure of AAV8 to acidic pH for as little as 1 hour is deleterious to transduction ability. Future studies are necessary to understand the pH-associated causative mechanisms involved. This study was approved by the University of Miami Institutional Animal Care and Use Committee, USA (Protocol #18-108-LF) on July 12, 2018.

Phenotypic Screening Following Transcriptomic Deconvolution to Identify Transcription Factors Mediating Axon Growth Induced by a Kinase Inhibitor.

After injury to the central nervous system (CNS), both neuron-intrinsic limitations on regenerative responses and inhibitory factors in the injured CNS environment restrict regenerative axon growth. Instances of successful axon regrowth offer opportunities to identify features that differentiate these situations from that of the normal adult CNS. One such opportunity is provided by the kinase inhibitor RO48, which dramatically enhances neurite outgrowth of neurons in vitro and substantially increased contralateral sprouting of corticospinal tract neurons when infused intraventricularly following unilateral pyramidotomy. The authors present here a transcriptomic deconvolution of RO48-associated axon growth, with the goal of identifying transcriptional regulators associated with axon growth in the CNS. Through the use of RNA sequencing (RNA-seq) and transcription factor binding site enrichment analysis, the authors identified a list of transcription factors putatively driving differential gene expression during RO48-induced neurite outgrowth of rat hippocampal neurons in vitro. The 82 transcription factor motifs identified in this way included some with known association to axon growth regulation, such as Jun, Klf4, Myc, Atf4, Stat3, and Nfatc2, and many with no known association to axon growth. A phenotypic loss-of-function screen was carried out to evaluate these transcription factors for their roles in neurite outgrowth; this screen identified several potential outgrowth regulators. Subsequent validation suggests that the Forkhead box (Fox) family transcription factor Foxp2 restricts neurite outgrowth, while FoxO subfamily members Foxo1 and Foxo3a promote neurite outgrowth. The authors' combined transcriptomic-phenotypic screening strategy therefore allowed identification of novel transcriptional regulators of neurite outgrowth downstream of a multitarget kinase inhibitor.

Biliary strictures in pediatric liver transplant recipients - early diagnosis and treatment results in excellent graft outcomes.

Biliary complications in pediatric LT are important causes of morbidity and graft loss. We examined our recent pediatric LT experience to determine the outcome of post-LT biliary complications and their relationship to graft type. All initially isolated LTs performed at our institution between January 1, 2000 and August 20, 2007 were reviewed. Recipient data, donor type, graft survival, and biliary complications data were examined. Of 66 LTs, 32 patients received whole organ grafts, and 34 received partial grafts; 11 split, seven reduced size, and 16 live donors. Seventy-seven percent of patients had biliary reconstruction using a RYH. Overall, 17 (26%) developed biliary complications, and 15 were diagnosed within six months post-LT. Live donor and split allografts had more biliary complications than reduced size or whole allografts (50% and 36% vs. 0% and 16%, respectively). Seventy-one percent responded to percutaneous or endoscopic treatment. Five failed initial non-operative management and required reoperation (one retransplantation). These data suggest that biliary strictures occur most frequently in live donor and split allografts and that non-operative therapy is highly successful. Partial grafts are essential in pediatric LT, and a high clinical suspicion for biliary complications combined with aggressive and early diagnosis and therapy rarely results in graft loss.

Vaccination against cocaine using a modifiable dendrimer nanoparticle platform.

Pharmacological therapies for the treatment of cocaine addiction have had disappointing efficacy, and the lack of recent developments in the clinical care of cocaine-addicted patients indicates a need for novel treatment strategies. Recent studies have shown that vaccination against cocaine to elicit production of antibodies that reduce concentrations of free drug in the blood is a promising method to protect against the effects of cocaine and reduce rates of relapse. However, the poorly immunogenic nature of cocaine remains a major hurdle to active immunization. Therefore, we hypothesized that strategies to increase targeted exposure of cocaine to the immune system may produce a more effective vaccine. To specifically direct an immune response against cocaine, in the present study we have conjugated a cocaine analog to a dendrimer-based nanoparticle carrier with MHC II-binding moieties that previously has been shown to activate antigen-presenting cells necessary for antibody production. This strategy produced a rapid, prolonged, and high affinity anti-cocaine antibody response without the need for an adjuvant. Surprisingly, additional evaluation using multiple adjuvant formulations in two strains of inbred mice found adjuvants were either functionally redundant or deleterious in the vaccination against cocaine using this platform. The use of conditioned place preference in rats after administration of this vaccine provided proof of concept for the ability of this vaccine to diminish cocaine reward. Together these data demonstrate the intrinsic efficacy of an immune-targeting dendrimer-based cocaine vaccine, with a vast potential for design of future vaccines against other poorly immunogenic antigens by substitution of the conjugated cargo.

Towards minimizing immunosuppression in pediatric liver transplant recipients.

Immunosuppression regimens after liver transplantation focus mainly on preventing rejection and subsequent graft loss. However, in children, morbidity and mortality rates from infections exceed those from rejection after transplant, and immunosuppression can hinder growth, renal function, and graft tolerance. We hypothesized that early steroid withdrawal, with a primary aim of TAC monotherapy would yield no penalty in terms of rejection and graft loss, while reducing risks of infection and maximizing growth. We prospectively evaluated 64 consecutive pediatric liver transplant recipients. One yr patient/graft survival was 93/90%, respectively. At one yr post-transplant, 75.4% of patients were on TAC monotherapy. No deaths or graft losses were caused by infection. Sixty-one percent of patients had at least one episode of rejection, most within three months following transplant and 3.8% were treated for chronic rejection. One non-compliant adolescent died from chronic rejection. CMV, EBV, and lymphoproliferative disease rates were 3.1%, 5.3%, 1.8%, respectively. Pretransplant and one yr post-transplant glomerular filtration rates were unchanged. One yr improved catch-up growth was observed. We conclude that immunosuppression minimization after pediatric liver transplant yields no serious complications from rejection, and might confer advantages with respect to infection, renal function, growth, and is deserving of wider application and study.

Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation.

PURPOSE: To evaluate outcomes of downstaging patients with advanced (American liver tumor study group stage III/IV) hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) to allow eligibility for orthotopic liver transplant (OLT). METHODS: From 1999 to 2006, 202 patients with HCC were referred for transplant evaluation. Seventy-six (37.6%) patients with stage III/IV HCC were potential transplant candidates if downstaging was achieved by TACE. OLT was considered based on follow-up imaging findings. The number of patients who were successfully downstaged within the Milan criteria, tumor response using Response Evaluation Criteria in Solid Tumors criteria, findings at explant, and outcomes after transplant were tracked. RESULTS: Eighteen of 76 (23.7%) patients had adequate downstaging to qualify for OLT under the Milan criteria. By Response Evaluation Criteria in Solid Tumors, 27/76 (35.5%) patients had a partial response, 22/76 (29%) had stable disease, and 27/76 (35.5%) had progressive disease. Seventeen of 76 (22.4%) patients who met other qualifications underwent OLT after successful downstaging (13/38 stage III;4/38 stage IV). Explant review demonstrated 28 identifiable tumors in which post-TACE necrosis was greater than 90% in 21 (75%). At a median of 19.6 months (range 3.6-104.7), 16/17 (94.1%) patients who underwent OLT are alive. One patient expired 11 months after OLT secondary to medical comorbidities. One of 17 (6%) OLT patients had recurrent HCC. This patient underwent resection of a pulmonary metastasis and is alive, 63.6 months from OLT. CONCLUSION: Selected patients with stage III/IV HCC can be downstaged to Milan criteria with TACE. Importantly, patients who are successfully downstaged and transplanted have excellent midterm disease-free and overall survival, similar to stage II HCC.