Discovery of Novel, Orally Bioavailable Pyrimidine Ether-Based Inhibitors of ELOVL1.

In our efforts to identify novel small molecule inhibitors for the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput radiometric screen for inhibitors of elongation of very long chain fatty acid 1 (ELOVL1) enzyme. We developed a series of highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorable pharmacokinetics culminating in compound 22. Compound 22 is a selective inhibitor of ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in vitro. Compound 22 reduced C26:0 lysophosphatidyl choline (LPC), a subtype of VLCFA, in the blood of ATP binding cassette transporter D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels. Compound 22 is a low-molecular-weight, potent ELOVL1 inhibitor that may serve as a useful tool for exploring therapeutic approaches to the treatment of ALD.

Comparison of Outcomes with Semi-mechanical and Circular Stapled Intrathoracic Esophagogastric Anastomosis following Esophagectomy.

BACKGROUND: Several techniques have been described for esophagogastric anastomosis following esophagectomy. This study compared the outcomes of circular stapled anastomoses with semi-mechanical technique using a linear stapler. METHODS: Perioperative data were extracted from a contemporaneously collected database of all consecutive esophagectomies for cancer with intrathoracic anastomoses performed in the Trent Oesophago-Gastric Unit between January 2015 and April 2018. Anastomotic techniques: circular stapled versus semi-mechanical, were evaluated and outcomes were compared. The primary outcome was anastomotic leak rate. Secondary outcomes included anastomotic stricture, overall complication rates, length of stay (LOS) and 30 day all-cause mortality. RESULTS: One hundred and fifty-nine consecutive esophagectomies with intrathoracic anastomosis were performed during the study period. There were no significant differences between the two groups in terms of age, American Society of Anaesthesiologists score, Charlson comorbidity index and neoadjuvant therapies received. Circular stapled anastomoses were performed in 85 patients, while 74 patients received a semi-mechanical anastomosis. Clavien-Dindo complications II or more were higher in the circular stapled group (p = 0.02). There were 16 (10%) anastomotic leaks overall, three (4%) in semi-mechanical group versus 13 (15%) in the circular stapled group (p < 0.019). There was no statistically significant difference between the two groups in terms of LOS, 30-day mortality or the need for endoscopic dilatation of the anastomosis at 3 months follow-up. CONCLUSION: The move from a circular stapled to a semi-mechanical intrathoracic anastomosis has been associated with a reduced postoperative anastomotic leak rate following esophagectomy for esophageal cancer.

Nontraumatic rupture of the costal margin: a single-center experience.

BACKGROUND: Rupture of the costal margin is uncommon. Whilst most often seen after major trauma, we describe its occurrence in patients with no direct chest trauma. METHODS: A search was performed in our thoracic surgery database for all patients with rupture of the costal margin. Patients were excluded if the injury was a result of trauma. Data were collected on sex, age, body mass index, profession, past medical history, smoking status, presenting complaint, mechanism of injury, and management. RESULTS: There were 9 patients with rupture of the costal margin that was caused in all cases by a severe coughing fit. All patients were male and the mean age was 62.5 years (range 47-76 years). Chronic obstructive pulmonary disease was present in 6 cases. Presentations included a palpable defect (5 cases), cough (9 cases), and chest pain (6 cases). On radiological examination, all patients had widening of the rib space, 4 had associated rib fractures, and 5 had lung herniation. Time from injury to presentation was 12 months (range 1-24 months). All patients underwent surgery and were followed-up for 59 months (range 8-129 months). Two patients suffered major complications in the immediate postoperative period. CONCLUSIONS: Rupture of the costal margin, in the absence of direct trauma, is characterized by pain, a palpable defect, and lung herniation. It is associated with widening of the rib space and rib fractures, and can be treated surgically with success but not without significant risks.

Multicomponent analysis of the tumour microenvironment reveals low CD8 T cell number, low stromal caveolin-1 and high tenascin-C and their combination as significant prognostic markers in non-small cell lung cancer.

The complex interplay of the tumour microenvironment (TME) and its role in disease progression and response to therapy is poorly understood. The majority of studies to date focus on individual components or molecules within the TME and so lack the power correlative analysis. Here we have performed a multi-parameter analysis of the TME in 62 resectable non-small cell lung cancer (NSCLC) specimens detailing number and location of immune infiltrate, assessing markers of cancer-associated fibroblasts, caveolin-1 and tenascin-C, and correlating with clinicopathological details, as well as markers of disease progression such as epithelial-to-mesenchymal transition (EMT). The influence of individual parameters on overall survival was determined in univariate and multivariate analysis and the combination of risk factors and interplay between components analysed. Low numbers of CD8 T cells, low stromal levels of caveolin-1 or high levels of tenascin-C were significant prognostic markers of decreased overall survival in both univariate and multivariate analysis. Patients with two or more risk factors had dramatically reduced overall survival and those with all three a median survival of just 7.5 months. In addition, low levels of tumour E-cadherin correlated with reduced immune infiltrate into the tumour nests, possibly linking EMT to the avoidance of CD8 T cell control. The multicomponent approach has allowed identification of the dominant influences on overall survival, and exploration of the interplay between different components of the TME in NSCLC.

3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors.

There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-passage patient tumor-derived tissue into basement membrane extract, ensuring a low proportion of cell death to anoikis and growth complementation by coculture with patient-derived cancer-associated fibroblasts (CAF). A range of solid tumors proved amenable to growth and pharmacologic testing in this 3D assay. A study of 30 early-stage non-small cell lung cancer (NSCLC) specimens revealed high levels of de novo resistance to a large range of standard-of-care agents, while histone deacetylase (HDAC) inhibitors and their combination with antineoplastic drugs displayed high levels of efficacy. Increased resistance was seen in the presence of patient-derived CAFs for many agents, highlighting the utility of the assay for tumor microenvironment-educated drug testing. Standard-of-care agents showed similar responses in the 3D ex vivo and patient-matched in vivo models validating the 3D-Tumor Growth Assay (3D-TGA) as a high-throughput screen for close-to-patient tumors using significantly reduced animal numbers. Mol Cancer Ther; 15(4); 753-63. ©2016 AACR.

The impact of the 'hub and spoke' model of care for lung cancer and equitable access to surgery.

OBJECTIVES: To determine the influence of where a patient is first seen (either surgical or non-surgical centre) and patient features on having surgery for non-small cell lung cancer (NSCLC). DESIGN: Cross-sectional study from individual patients, between 1January 2008 and 31March 2012. SETTING: Linked National Lung Cancer Audit and Hospital Episode Statistics datasets. PARTICIPANTS: 95,818 English patients with a diagnosis of NSCLC, of whom 12,759 (13%) underwent surgical resection. MAIN OUTCOME MEASURE: Odds of having surgery based on the empirical catchment population of the 30 thoracic surgical centres in England and whether the patient is first seen in a surgical centre or a non-surgical centre. RESULTS: Patients were more likely to be operated on if they were first seen at a surgical centre (OR 1.37; 95% CI 1.29 to 1.45). This was most marked for surgical centres with the largest catchment populations. In these surgical centres with large catchment populations, the resection rate for local patients was 18% and for patients first seen in a non-surgical centre within catchment was 12%. CONCLUSIONS: Surgical centres that serve the largest catchment populations have high resection rates for patients first seen in their own centre but, in contrast, low resection rates for patients first seen at the surrounding centres they serve. Our findings demonstrate the importance of going further than relating resection rates to hospital volume or surgeon number, and show that there is a pressing need to design lung cancer services which enable all patients, including those first seen at non-surgical centres, to have equal access to lung cancer surgery.

Isolated axillary lymph node metastasis in oesophageal adenocarcinoma.

Oesophageal adenocarcinoma metastatic to the axilla is a rare occurrence. The authors present a case of a woman who developed an axillary metastasis from a completely excised oesophageal adenocarcinoma with no prior evidence of nodal disease. With aggressive local treatment, including multiple local operations and radiotherapy, she remains alive and disease-free 12 years after her diagnosis following surgical resection of her axillary metastasis with adjuvant radiotherapy. This case report suggests that there are occasions when aggressive local treatment of apparently isolated metastases can result in a cure.

Utility of an immune cell function assay to differentiate rejection from infectious enteritis in pediatric intestinal transplant recipients.

The Cylex Immune Cell Function Assay measures cell-mediated immunity based on ATP production by stimulated CD4 + cells. We hypothesized that this test would discriminate acute cellular rejection (ACR) from infectious enteritis (IE) in pediatric intestinal transplant (ITx) recipients with allograft dysfunction. We retrospectively analyzed 224 Cylex assays drawn in 47 children who received 53 ITx. Samples were classified as stable, ACR, or IE based on clinical status. ATP values were analyzed using Kruskal-Wallis and t-tests. Overall, there was a statistically significant difference in ATP values based on clinical status (p = 0.03); however, overlap was observed between groups. The median ATP value during ACR was significantly greater than during stable periods (p = 0.02). No difference was seen in IE vs. stability (p = 0.8). The difference in median ATP value in ACR vs. IE approached significance (p = 0.1). Relative to previous levels, ACR episodes were associated with a median ATP increase of 101 ng/mL and IE episodes with a decrease of 3 ng/mL (p = 0.3). These data indicate that the Cylex assay has limited utility in differentiating ACR from IE, largely due to interpatient variability. Following longitudinal intrapatient trends may be an adjunctive tool in discriminating IE from ACR and guiding immunosuppression adjustments in select patients.

Age and neo-adjuvant chemotherapy increase the risk of atrial fibrillation following oesophagectomy.

OBJECTIVES: Atrial tachyarrhythmias occur in up to 25% of patients after major thoracic surgery. We examined risk factors for new-onset atrial fibrillation (AF) following oesophagectomy in an attempt to guide prophylactic use of anti-arrhythmic strategies. METHODS: Data were extracted from a database of patients who underwent oesophagectomy between 1991 and 2009. Patients with pre-operative arrhythmias were excluded leaving 997 patients for further analysis. Univariate and multivariate logistic regression analyses were performed to identify factors predicting AF, and receiver operating characteristic curves were generated from a model using these predictors. Statistical significance was reflected in a P-value of <0.05. RESULTS: Patients who developed AF (n = 209; 20.96%) were older (median age 70.54 years vs. 66.9 years; P < 0.01) and included 141 males (67.4%) (P = 0.11). Patients with AF were noted to have a higher in-hospital mortality rate (n = 17; 8.1% vs. n = 34; 4.8%) (P = 0.04) and a longer stay in hospital (14 days vs. 12 days; P < 0.01). Multivariate analysis identified advanced age and neo-adjuvant chemotherapy to be independent predictors of the risk of developing AF. Assessment of discriminative ability of a predictive model revealed a c-statistic of just 0.62. CONCLUSIONS: Despite the identification of age and neo-adjuvant chemotherapy as predictors of AF, the moderate discriminative ability of predictive modelling does not support the use of prophylactic anti-arrhythmic drugs. However, the high incidence of AF after major thoracic surgery makes it necessary to understand its underlying mechanisms better before prophylactic strategies are considered.

Early outcomes of surgery for oesophageal cancer in a thoracic regional unit. Can we maintain training without compromising results?

OBJECTIVES: Meaningful exposure to oesophageal cancer surgery during general thoracic surgical training is restricted to few centres in the United Kingdom. Our Regional Tertiary Unit remains a rare 'large-volume' oesophagectomy centre. We aimed to determine the proportion of patients operated by trainees and their perioperative outcomes. METHODS: From January 2004 to September 2009, 323 patients (229 male and 94 female, median age of 69 (range 40-92) years) underwent oesophagectomy for carcinoma in our Thoracic Surgical Unit. Data were complete and obtained from a prospective departmental database. The preoperative characteristics, operative data and postoperative results were compared between the 120 patients (37%) operated by a trainee (group T) and the remainder 203 patients operated by a consultant (group C). RESULTS: The overall incidence of mortality, anastomotic leak and chylothorax were 6.5%, 5.3% and 2.2%, respectively. There were no differences in terms of age, gender, tumour location, tumour staging, preoperative spirometry or use of neoadjuvant chemotherapy between the two groups. There was no significant difference between the consultant group and the trainee group in the following key outcome measures: postoperative mortality (8% vs 4%), incidence of respiratory complications (30% vs 25%), hospital stay (14 days vs 13 days) and number of lymph nodes excised (median of 16 vs 14). CONCLUSIONS: Training in oesophageal cancer surgery can be provided in a large-volume thoracic surgical unit. It does not seem to compromise outcomes or use of resources.

Comparative analysis of resection and liver transplantation for intrahepatic and hilar cholangiocarcinoma: a 24-year experience in a single center.

OBJECTIVES: To compare the survival difference between 2 surgical modalities in the treatment of locally advanced intrahepatic and hilar cholangiocarcinoma (CCA) and to identify factors that predict mortality. DESIGN: Retrospective study. SETTING: University transplant center. PATIENTS: Of the 132 patients with a diagnosis of CCA treated from February 1, 1985, through June 30, 2009, 75 had metastatic disease at presentation and were excluded from the study, whereas 57 patients were candidates for surgical therapy. Tumor type was intrahepatic in 37 patients and hilar in 20 patients. Surgical therapy included orthotopic liver transplant (OLT) in 38 patients and combined radical bile duct resection with partial hepatectomy (RR) in 19 patients. RESULTS: Tumors were locally advanced in 35 of 37 patients (95%) with intrahepatic tumors and 16 of 20 patients (80%) with hilar tumors. Adjunctive therapy was used in 35 patients (61%). The 5-year tumor recurrence-free patient survival was significantly higher in the OLT group compared with the RR group (33% vs 0%; P = .05). In the OLT group, neoadjuvant and adjuvant therapies resulted in better patient survival compared with no therapy or adjuvant therapy only (47% vs 20% vs 33%, respectively; P = .03). Multivariate factors predictive of worse survival outcomes included hilar CCA, multifocal tumors, perineural invasion, and RR as the treatment modality compared with OLT. Tumor sizes--5 cm or larger for intrahepatic and 3 cm or larger for hilar CCA--were not predictors of poor outcome. CONCLUSION: Orthotopic liver transplant in combination with neoadjuvant and adjuvant therapies is superior to RR with adjuvant therapy in locally advanced intrahepatic and hilar CCA.

Mixed incontinence and cystocele: postoperative urge symptoms are not predicted by preoperative urodynamics.

INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) frequently presents with urinary incontinence, either urge (UUI), stress (SUI), or mixed (MUI). We sought to determine the effect of high-grade prolapse repair on MUI. METHODS: A retrospective review was performed for 111 patients with anterior POP repair and sling over 4 years. RESULTS: Sixty patients (54%) presented symptomatically with MUI, 25% with SUI, and 9% with UUI, 12% asymptomatic. Occult SUI was found in 21% (UUI plus asymptomatic). Success was seen for SUI in 92% and for POP in 89%. Urge symptoms were present in 63% pre-op and 30% post-op. MUI patients were significantly more likely to experience post-op urgency (p = 0.033). Detrusor overactivity (DO) was seen in 22 MUI patients, but was not predictive of post-op urgency (p = 0.91). CONCLUSIONS: Cystocele patients with MUI are at significant risk for postoperative urge symptoms regardless of DO, and counseling regarding persistent urgency is imperative.

Pretransplant predictors of survival after intestinal transplantation: analysis of a single-center experience of more than 100 transplants.

INTRODUCTION: Outcomes after intestinal transplantation (ITx) have steadily improved. There are few studies that assess factors associated with these enhanced results. The purpose of this study was to examine peri-ITx variables and survival. METHODS: A review of a prospectively maintained database was undertaken and included all patients undergoing ITx from 1991 to 2010. The study endpoints were patient and graft survival. Data collection included 44 variables. Survival was computed using Kaplan-Meier methods. Univariate analysis was conducted (log-rank test) with significance set at P less than or equal to 0.20. Multivariate analysis of significant variables was conducted using model reduction by backward elimination variable selection method with significance set at P less than 0.05. RESULTS: Eighty-eight patients received 106 ITx. The majority of recipients were male, Latino, and children. The leading causes of intestinal and liver failure were gastroschisis and parenteral nutrition. Grafts transplanted were isolated intestine (24%), liver-intestine (62%), and multivisceral (14%). Overall 1- and 5-year patient and graft survival were 80% and 65%, and 74% and 64%, respectively. Significant univariate survival predictors were weight less than 20 kg, children, liver-inclusive allograft, panel reactive antibody less than 20%, absence of donor-specific antibody, negative crossmatch, warm ischemia time less than 60 min, absence of recipient splenectomy, interleukin-2 receptor antagonist induction, and era. Significant multivariate survival predictors were absence of donor-specific antibody, absence of recipient splenectomy, and liver-inclusive graft type. CONCLUSION: This large, single-center ITx experience confirms a marked improvement in outcome over time. Several important factors were associated with survival, and these factors can potentially be adjusted before ITx. These findings should refocus future efforts on strategies to improve treatment and prevent graft loss.

Long-term patient outcome and quality of life after liver transplantation: analysis of 20-year survivors.

OBJECTIVE: To evaluate patient survival and allograft function and health-related quality of life (HRQOL) 20 years after orthotopic liver transplantation (LT). SUMMARY OF BACKGROUND DATA: Although LT is the established treatment of choice for acute and chronic liver failure, allograft function and recipient HRQOL 20 years after LT remain undefined. METHODS: We performed a prospective, cross-sectional study of LT recipients surviving 20 years or more. Clinical data were reviewed to identify factors associated with 20-year survival. Survivors were directly contacted and offered a survey to assess HRQOL (SF-36; Liver Disease Quality of Life), social support, and cognition (Neuropsychological Impairment Scale). Logistic regression analysis was performed to identify clinical factors influencing HRQOL 20 years after LT. RESULTS: Between February 1, 1984 and December 31, 1988, a total of 293 patients (179 adults, 114 children) received 348 LTs. Of the 293 patients, 168 (56%) survived for 20 years or more. Actuarial 20-year survival was 52% (patient) and 42% (graft). Factors associated with 20-year survival included recipient age <18 (P = 0.01), nonurgent LT (P = 0.01), no retransplantation (0.02), female gender (0.03), absence of biliary complications (P = 0.04), and short total ischemia time (P = 0.05). Rejection episodes were seen in a greater proportion of 20-year survivors than in nonsurvivors (35% vs. 27%; P = 0.3). Of the 168 survivors, 87 were contacted, and 68 (78%) completed the HRQOL surveys. Compared with the general population, survivors had lower physical scores (P < 0.01) but comparable mental scores on the SF-36. Overall HRQOL was significantly better in 20-year survivors than in patients with chronic liver disease, congestive heart failure, or diabetes. Clinical factors associated with improved post-LT HRQOL were younger age at LT, allograft longevity, and strong social support. More than 90% of pediatric survivors completed high school. After LT, 34% of pediatric recipients married, and 79% remained married at 20 years' follow-up. CONCLUSIONS: More than 50% of LT recipients survive 20 years, achieve important socioeconomic milestones, and report quality of life superior to patients with liver disease or other chronic conditions. LT is a durable surgery that restores both long-term physiologic and psychologic well-being in patients with end-stage liver disease.

Guidelines on the radical management of patients with lung cancer.

A joint initiative by the British Thoracic Society and the Society for Cardiothoracic Surgery in Great Britain and Ireland was undertaken to update the 2001 guidelines for the selection and assessment of patients with lung cancer who can potentially be managed by radical treatment.

Surgical management of primary empyema of the pleural cavity: outcome of 81 patients.

Postpneumonic empyema is the most common form of empyema thoracis and is still recognised as a major cause of morbidity and prolonged hospital stay. We reviewed 106 patients retrospectively who underwent surgical management of pleural empyema over a period of three years from August 2005. We identified 81 patients (76%) (58 males, mean age 52 years) with primary empyema and 25 patients (24%) with secondary empyema. The first group of patients with primary empyema was analysed. Twenty-nine patients (36%) had stage II empyema and 52 patients (64%) had stage III. The majority of stage II empyema patients underwent thoracoscopic debridement (28 patients) and one patient had open thoracotomy and debridement. Stage III patients underwent thoracoscopic decortication (32 patients) of those six patients (19%) were converted to open decortication, open decortication (19 patients) and fenestration (one patient). Mortality rate was 0% for all procedures. Median length of hospital stay was six days for thoracoscopic debridement, five days for thoracoscopic decortication and eight days for open decortication. Patients treated with video-assisted thoracoscopic surgery (VATS) debridement or decortication spent less time in hospital and the conversion rate to open procedure for stage III empyema was only 19%, which encourages us to consider VATS debridement/decortication as a first choice treatment.

Survival in Asian Americans after treatments for hepatocellular carcinoma: a seven-year experience at UCLA.

BACKGROUND/RATIONALE: Hepatocellular carcinoma (HCC) is a common malignancy in Asians and is related to the high incidence of chronic viral hepatitis in this ethnic population. The aims of this study were to examine the tumor characteristics and liver disease status in HCC patients of Asian ancestry and determine their survival after treatments for HCC. RESULTS: Between September 2000 and December 2007, 278 patients, mean age 61.5 years, presented with HCC to the University of California Los Angeles (UCLA) Liver Cancer Center. Hepatitis B (HBV) infection was detected in up to 68% of Chinese, Korean, and Vietnamese patients, whereas 60% of Japanese patients had Hepatitis C (HCV) infection. Compared with HCC patients who presented with symptoms, those detected by surveillance had more tumors within the Milan and University of California, San Francisco (UCSF) criteria and more patients in Child-Turcotte-Pugh class A. On the basis of a predefined UCLA treatment algorithm, 83% of patients received surgical and/or loco-regional therapies. Compared with other treatments, orthotopic liver transplantation (OLT), and radiofrequency ablation had the highest overall patient survival (P<0.0001) and OLT has the highest disease free survival rates (P<0.0001). Independent baseline predictors for: (1) patient survival were HBV [hazard ratio (HR) 0.62, P=0.005], UCSF criteria (HR 0.46, P<0.0001), Child Turcotte Pugh class A (HR 0.57, P=0.005), alphafetoprotein per log10 increase (HR 1.26, P=0.0012), and alkaline phosphatase per log10 increase (HR 2.32, P=0.02); and for (2) disease free survival were UCSF criteria (HR 0.66 P=0.007), aspartate aminotransferase per log10 increase (HR 1.50, P=0.04), and age per year increase (HR=1.02, P=0.04). The 4 Asian subgroups had similar survival rates. CONCLUSIONS: HBV and Hepatitis C were associated with over 90% of HCC cases in Asian Americans. HCC detected by surveillance identified more patients eligible for surgical and loco-regional therapies, which improved the overall and disease free survival.

Janus kinase 2 inhibitors. Synthesis and characterization of a novel polycyclic azaindole.

The synthesis and characterization of a novel polycyclic azaindole based derivative is disclosed, and its binding to JAK2 is described. The compound is further evaluated for its ability to block the EPO/JAK2 signaling cascade in vitro and in vivo.

2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2.

Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.

Fulminant hepatic failure in children: superior and durable outcomes with liver transplantation over 25 years at a single center.

OBJECTIVE(S): Death occurs in half of all children with fulminant hepatic failure (FHF). Although liver transplantation (LT) is potentially life-saving, there are only a few published series with limited experience. The aim was to examine predictors of survival after LT for FHF. METHODS: Between 1984 and 2008, all LT for FHF performed in recipients less than or equal to 18 years of age were analyzed from a prospectively maintained database using 35 demographic, laboratory, and operative variables. Unique calculated variables included creatinine clearance (cCrCl) and Pediatric End-Stage Liver Disease score (PELD). Study end-points were patient and death censored graft survival. Median follow-up was 98 months. Statistical analysis involved the log-rank test and Cox proportional hazards model. RESULTS: A total of 122 children underwent 159 LTx. Cryptogenic was the primary etiology (70%) and the median age was 53 months. The significant (P < 0.05) univariate predictors of worse graft survival were: recipient age <24 months, cCrCl <60 mL/min/1.73m, PELD >25 points, and warm ischemia time >60 minutes. The significant (P < 0.05) univariate predictors of worse patient survival were: recipient African-American and Asian race, recipient age <24 months, cCrCl <60 mL/min/1.73m, and time from onset jaundice to encephalopathy <7 days. On multivariate analysis, survival was significantly impacted by 4 variables: cCrCl <60 mL/min/1.73m (GRAFT and PATIENT), PELD >25 points (GRAFT), recipient age <24 months (GRAFT), and time from onset jaundice to encephalopathy <7 days (PATIENT). While overall 5- and 10-year survival was 73% and 72% (GRAFT) and 77% and 73% (PATIENT), these were significantly worse when a combination of multivariate risk-factors were present. CONCLUSIONS: This data from a large, single-center experience demonstrates that LT is the treatment of choice for FHF and results in durable survival. Analysis revealed 4 novel outcome predictors. Young children with rapid onset acute liver failure are a high-risk subpopulation. Unique to this study, cCrCl and PELD accurately predicted the end-points. This analysis identifies patient subpopulations requiring early aggressive intervention with LT.