Targeting PD-L1 in cholangiocarcinoma using nanovesicle-based immunotherapy.

This study demonstrates the potential of using biological nanoparticles to deliver RNA therapeutics targeting programmed death-ligand 1 (PD-L1) as a treatment strategy for cholangiocarcinoma (CCA). RNA therapeutics offer prospects for intracellular immune modulation, but effective clinical translation requires appropriate delivery strategies. Milk-derived nanovesicles were decorated with epithelial cellular adhesion molecule (EpCAM) aptamers and used to deliver PD-L1 small interfering RNA (siRNA) or Cas9 ribonucleoproteins directly to CCA cells. In vitro, nanovesicle treatments reduced PD-L1 expression in CCA cells while increasing degranulation, cytokine release, and tumor cell cytotoxicity when tumor cells were co-cultured with T cells or natural killer cells. Similarly, immunomodulation was observed in multicellular spheroids that mimicked the tumor microenvironment. Combining targeted therapeutic vesicles loaded with siRNA to PD-L1 with gemcitabine effectively reduced tumor burden in an immunocompetent mouse CCA model compared with controls. This proof-of-concept study demonstrates the potential of engineered targeted nanovesicle platforms for delivering therapeutic RNA cargoes to tumors, as well as their use in generating effective targeted immunomodulatory therapies for difficult-to-treat cancers such as CCA.

PTEN deficiency induces an extrahepatic cholangitis-cholangiocarcinoma continuum via aurora kinase A in mice.

BACKGROUND & AIMS: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease. METHODS: The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry, reverse-transcription PCR, cell culture, and RNA sequencing. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. We also tested the effectiveness of an Aurka inhibitor. RESULTS: We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as 1 month after birth. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated disease progression, potentially by downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expression of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression. CONCLUSIONS: Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum that was dependent on Aurka. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA. IMPACT AND IMPLICATIONS: The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition, cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted disease progression. This model will be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis.

Albumin promoter-driven FlpO expression induces efficient genetic recombination in mouse liver.

Tissue-specific gene manipulations are widely used in genetically engineered mouse models. A single recombinase system, such as the one using Alb-Cre, has been commonly used for liver-specific genetic manipulations. However, most diseases are complex, involving multiple genetic changes and various cell types. A dual recombinase system is required for conditionally modifying different genes sequentially in the same cell or inducing genetic changes in different cell types within the same organism. A FlpO cDNA was inserted between the last exon and 3'-UTR of the mouse albumin gene in a bacterial artificial chromosome (BAC-Alb-FlpO). The founders were crossed with various reporter mice to examine the efficiency of recombination. Liver cancer tumorigenesis was investigated by crossing the FlpO mice with FSF-KrasG12D mice and p53frt mice (KPF mice). BAC-Alb-FlpO mice exhibited highly efficient recombination capability in both hepatocytes and intrahepatic cholangiocytes. No recombination was observed in the duodenum and pancreatic cells. BAC-Alb-FlpO-mediated liver-specific expression of mutant KrasG12D and conditional deletion of p53 gene caused the development of liver cancer. Remarkably, liver cancer in these KPF mice manifested a distinctive mixed hepatocellular carcinoma and cholangiocarcinoma phenotype. A highly efficient and liver-specific BAC-Alb-FlpO mouse model was developed. In combination with other Cre lines, different genes can be manipulated sequentially in the same cell, or distinct genetic changes can be induced in different cell types of the same organism.NEW & NOTEWORTHY A liver-specific Alb-FlpO mouse line was generated. By coupling it with other existing CreERT or Cre lines, the dual recombinase approach can enable sequential gene modifications within the same cell or across various cell types in an organism for liver research through temporal and spatial gene manipulations.

Poverty Traps and Mortality From Liver Diseases in the United States.

INTRODUCTION: Poverty traps, locations with multigenerational poverty, result from structural and economic factors that can affect health of residents within these locations. The aim of this study was to define poverty traps within the contiguous United States and their impact on outcomes from liver diseases or cancers. METHODS: A systematic census-tract level analysis was used to spatially define regions that encompassed poverty traps. Clusters of prevalent poverty and mortality from chronic liver diseases or liver cancers were identified. Temporal trends and the relationship between race and ethnicity, type of space and escape from poverty traps on disease mortality within hot spots were determined. RESULTS: The proportion of census tracts enduring multigenerational poverty within counties was strongly associated with mortality from liver disease or cancer. There was a highly significant clustering of persistent poverty and increased mortality. Hot spots of high-mortality areas correlated with factors related to income, ethnicity, and access to health care. Location or noneconomic individual factors such as race and ethnicity were important determinants of disparities within hot spots. Distinct groups of poverty traps were defined. The highly characteristic demographics and disease outcomes within each of these groups underscored the need for location-specific interventions. DISCUSSION: Poverty traps are a major and important spatially determined risk factor for mortality from liver diseases and cancers. Targeted location-specific interventions and economic development aimed at addressing the underlying causes of poverty and enhancing prosperity will be required to reduce mortality from liver diseases within poverty traps.

Association of county level poverty with mortality from primary liver cancers.

BACKGROUND: The highly variable occurrence of primary liver cancers across the United States emphasize the relevance of location-based factors. Social determinants such as income, educational attainment, housing, and other factors may contribute to regional variations in outcomes. To evaluate their impact, this study identified and analyzed clusters of high mortality from primary liver cancers and the association of location-based determinants with mortality across the contiguous United States. METHODS: A geospatial analysis of age-adjusted incidence and standardized mortality rates from primary liver cancers from 2000 to 2020 was performed. Local indicators of spatial association identified hot-spots, clusters of counties with significantly higher mortality. Temporal analysis of locations with persistent poverty, defined as high (>20%) poverty for at least 30 years, was performed. Social determinants were analyzed individually or globally using composite measures such as the social vulnerability index or social deprivation index. Disparities in county level social determinants between hot-spots and non-hot-spots were analyzed by univariate and multivariate logistic regression. RESULTS: There are distinct clusters of liver cancer incidence and mortality, with hotspots in east Texas and Louisiana. The percentage of people living below the poverty line or Hispanics had a significantly higher odds ratio for being in the top quintile for mortality rates in comparison to other quintiles and were highly connected with mortality rates. Current and persistent poverty were both associated with an evolution from non-hotspots to new hotspots of mortality. Hotspots were predominantly associated with locations with significant levels of socioeconomic vulnerability or deprivation. CONCLUSIONS: Poverty at a county level is associated with mortality from primary liver cancer and clusters of higher mortality. These findings emphasize the importance of addressing poverty and related socio-economic determinants as modifiable factors in public health policies and interventions aimed at reducing mortality from primary liver cancers.

Therapeutic restoration of miR-126-3p as a multi-targeted strategy to modulate the liver tumor microenvironment.

BACKGROUND: Impaired natural killer (NK) cell-mediated antitumor responses contribute to the growth of liver tumors. Expression of a disintegrin and metalloprotease 9 (ADAM9) increases shedding of membrane-bound major histocompatibility complex class I chain-related protein A and results in evasion from NK cell-mediated cytolysis. ADAM9 is also involved in angiogenesis and tumor progression and is a target of miR-126-3p, a tumor suppressor that is downregulated and alters tumor cell behavior in the liver and other cancers. We evaluated the restoration of miR-126-3p and modulation of the miR-126-3p/ADAM9 axis as a therapeutic approach to simultaneously enhance NK cell-mediated cytolysis while targeting both tumor cells and their microenvironment. METHODS: Precursor miRNAs were loaded into milk-derived nanovesicles to generate therapeutic vesicles (therapeutic milk-derived nanovesicles) for the restoration of functional miR-126-3p in recipient cancer cells. RESULTS: Administration of therapeutic milk-derived nanovesicles increased miR-126-3p expression and reduced ADAM9 expression in target cells and was associated with an increase in membrane-bound major histocompatibility complex class I chain-related protein A. This enhanced NK cell cytolysis in adherent tumor cells and in multicellular tumor spheroids while also impairing angiogenesis and modulating macrophage chemotaxis. Moreover, IV administration of therapeutic milk-derived nanovesicles with adoptive transfer of NK cells reduced tumor burden in orthotopic hepatocellular cancer xenografts in mice. CONCLUSION: A directed RNA therapeutic approach can mitigate NK cell immune evasion, reduce angiogenesis, and alter the tumor cell phenotype through the restoration of miR-126-3p in liver tumor cells. The pleiotropic effects elicited by this multi-targeted approach to modulate the local tumor microenvironment support its use for the treatment of liver cancer.

Therapeutic biliary stents: applications and opportunities.

INTRODUCTION: Biliary stents are used to optimize ductal patency and enable bile flow in the management of obstruction or injury related to biliary tract tumors, strictures, stones, or leaks. Although direct therapeutic applications of biliary stents are less well developed, stents can be used to deliver drugs, radioisotopes, and photodynamic therapy. AREAS COVERED: This report provides an in-depth overview of the clinical indications, and therapeutic utility of biliary stents. Unique considerations for the design of biliary stents are described. The properties and functionalities of materials used for stents such as metal alloys, plastic polymers, or biodegradable materials are described, and opportunities for design of future stents are outlined. Current and potential applications of stents for therapeutic applications for biliary tract diseases are described. EXPERT OPINION: Therapeutic biliary stents could be used to minimize inflammation, prevent stricture formation, reduce infections, or provide localized anti-cancer therapy for biliary tract cancers. Stents could be transformed into therapeutic platforms using advanced materials, 3D printing, nanotechnology, and artificial intelligence. Whilst clinical study and validation will be required for adoption, future advances in stent design and materials are expected to expand the use of therapeutic biliary stents for the treatment of biliary tract disorders.

The Effect of Varying Preoperative Hemoglobin Levels on the Risk of Major Complications and Surgical Site Infections After Single Level Lumbar Fusion.

INTRODUCTION: Blood transfusions are associated with an increased risk of complications after lumbar fusion, and current anemia hemoglobin thresholds are not surgery specific. We aimed to calculate single-level lumbar fusion-specific preoperative hemoglobin strata that observe the likelihood of 90-day transfusion and evaluate whether these strata are associated with increased risk of 90-day complications and 2-year infections. METHODS: A national database identified patients undergoing primary single-level lumbar fusion with preoperative hemoglobin values (g/dL). Stratum-specific likelihood ratio analysis calculated sex-based hemoglobin strata associated with the risk of 90-day transfusion. Incidence and risk of 90-day major complications and 2-year infections were observed between strata. RESULTS: Three female (hemoglobin strata, likelihood ratio [<10.9, 2.41; 11.0 to 12.4, 1.35; 12.5 to 17.0, 0.78]) and male (<11.9, 2.95; 12.0 to 13.4, 1.46; 13.5 to 13.9, 0.71) strata were associated with varying likelihood of 90-day blood transfusion. Increased 90-day complication risk was associated with two female strata (hemoglobin strata, relative risk [11.0 to 12.4, 1.52; <10.9, 3.40]) and one male stratum (<11.9, 2.02). Increased 2-year infection risk was associated with one female (<10.9, 3.67) and male stratum (<11.9, 2.11). CONCLUSION: Stratum-specific likelihood ratio analysis established sex-based single-level lumbar fusion-specific hemoglobin strata that observe the likelihood of 90-day transfusion and the risk of 90-day major complications and 2-year infections. These thresholds are a unique addition to the literature and can assist in counseling patients on their postoperative risk profile and in preoperative patient optimization. LEVEL OF EVIDENCE: Level III.

No Increased Risk of All-cause Revision up to 10 Years in Patients Who Underwent Bariatric Surgery Before Single-level Lumbar Fusion.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: This study aimed to assess whether prior bariatric surgery (BS) is associated with higher 10-year surgical complication and revision rates in lumbar spine fusion compared with the general population and morbidly obese patients. BACKGROUND: Obesity accelerates degenerative spine processes, often necessitating lumbar fusion for functional improvement. BS is explored for weight loss in lumbar spine cases, but its impact on fusion outcomes remains unclear. Existing literature on BS before lumbar fusion yields conflicting results, with a limited investigation into long-term spine complications. METHODS: Utilizing the PearlDiver database, we examined patients undergoing elective primary single-level lumbar fusion, categorizing them by prior BS. Propensity score matching created cohorts from (1) the general population without BS history and (2) morbidly obese patients without BS history. Using Kaplan-Meier and Cox proportional hazard modeling, we compared 10-year cumulative incidence rates and hazard ratios (HRs) for all-cause revision and specific revision indications. RESULTS: Patients who underwent BS exhibited a higher cumulative incidence and risk of decompressive laminectomy and irrigation & debridement (I&D) within 10 years postlumbar fusion compared with matched controls from the general population [decompressive laminectomy: HR = 1.32; I&D: HR = 1.35]. Compared with matched controls from a morbidly obese population, patients who underwent BS were associated with lower rates of adjacent segment disease (HR = 0.31) and I&D (HR = 0.64). However, the risk of all-cause revision within 10 years did not increase for patients who underwent BS compared with matched or unmatched controls from the general population or morbidly obese patients (P > 0.05). CONCLUSIONS: Prior BS did not elevate the 10-year all-cause revision risk in lumbar fusion compared with the general population or morbidly obese patients. However, patients who underwent BS were associated with a lower 10-year risk of I&D when compared with morbidly obese patients without BS. Our study indicates comparable long-term surgical complication rates between patients who underwent BS and these control groups, with an associated reduction in risk of infectious complications when compared with morbidly obese patients. Although BS may address medical comorbidities, its impact on long-term lumbar fusion revision outcomes is limited.

Age-related changes in hematological and biochemical profiles of Wistar rats.

BACKGROUND: Wistar rats are extensively used as the model for assessing toxicity and efficacy in preclinical research. Hematological and biochemical laboratory data are essential for evaluating specific variations in the physiological and functional profile of a laboratory animal. Establishing hematological and biochemical reference values for Wistar (han) rats at various age intervals was the goal of this work. Male and female Wistar rats (n = 660) of ages 6-8 weeks, 10-14 weeks and > 6 months were used in the experiment. Blood and serum were collected from these rats under fasting conditions. RESULTS: We observed that the majority of hematological and biochemical parameters were significantly influenced by sex and age. Hematological changes were significantly correlated to aging were increased red blood cells, hemoglobin, hematocrit, neutrophils, monocytes and eosinophils in both sexes, as well as decreased platelet, mean corpuscular volume, mean corpuscular hemoglobin and lymphocytes in both sexes. White blood cells of male rats were considerably higher than those of female rats in all age ranges. For biochemistry, increase in glucose, total protein and creatinine were seen in both sexes, along with increases in urea in females and alanine aminotransferase in males. Age was significantly associated with decreased alkaline phosphatase in both sexes. CONCLUSIONS: When using Wistar rats as a model, these reference values may be useful in evaluating the results.

Sickle Cell Disease Has No Impact on 10-Year Cumulative Incidence and Indications for Revision Lumbar Fusion.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVES: Patients with sickle cell disease (SCD) experience distinct physiological challenges that may alter surgical outcomes. There has been no research establishing 10-year lumbar fusion (LF) implant survivorship rates among individuals with SCD. This study aims to determine the 10-year cumulative incidence and indications for revision LF between patients with and without SCD. METHODS: A national database was queried to identify patients with and without SCD who underwent primary LF. SCD patients undergoing LF were propensity-score matched in a 1:4 ratio by age, gender, and Charlson Comorbidity Index (CCI) to a matched LF control. In total, 246 SCD patients were included along with 981 and 100,000 individuals in the matched and unmatched control cohorts, respectively. Kaplan-Meier survival analysis was utilized to determine the 10-year cumulative incidence rates of revision LF. Furthermore, multivariable analysis using Cox proportional hazard modeling was performed to compare indications for revisions and surgical complications between cohorts including hardware removal, drainage and evacuation, pseudoarthrosis, and mechanical failure. RESULTS: No significant differences were found in the cumulative incidence of 10-year all-cause revision LF between patients in the SCD cohort and either of the control cohorts (P > .05 for each). Additionally, there were no significant differences between the SCD cohort and either of the control cohorts in regards to the indications for revision or surgical complications in LF (P > .05 for each). CONCLUSIONS: This study indicates that SCD patients do not have increased risk for revision LF, nor any of its indications.

Higher 2-Year Cumulative Incidence of Mental Health Disorders Following Irrigation and Debridement in Primary Lumbar Fusion.

Introduction: Spinal fusion is an operation that is employed to treat spinal diseases. Surgical site infection (SSI) after lumbar fusion (LF) is a postoperative complication. SSI is treated with irrigation and debridement (I&D), which requires readmittance following discharge or prolonged hospital stays, which are deleterious to patients' mental health. The long-term relationship between treating SSI with I&D and patients' mental health is still understudied. Methods: Using the Mariner dataset from the PearlDiver Patient Records Database using Current Procedural Terminology and International Classification of Diseases procedure codes, retrospective cohort analysis was carried out. This study involved 445,480 patients who underwent LF with at least 2-year follow-up and were followed up for 2 years. Of the patients, 2,762 underwent I&D. Using univariate analysis employing Pearson Chi-square and Student t-test, where appropriate (Table 1), patient demographics between cohorts were gathered. 2-year cumulative incidence (CI) between LF and I&D cohorts was calculated using Kaplan-Meier analysis (Fig. 1, 2, 3). Cox proportional hazards were employed to observe significant differences in CI rates (Table 2). Results: For patients who received I&D, 2-year CI depression (HR: 1.72; 95% CI: 1.49-1.99; P<0.001) and stress (HR: 1.35; 95% CI: 1.02-1.79; P=0.035) rates were significantly higher than for those who did not. There was no statistically significant difference in 2-year CI anxiety rates between cohorts (HR: 0.92; 95% CI: 0.58-1.46; P=0.719). Conclusions: In conclusion, 16.8% of patients developed new-onset depression 2 years following I&D, in comparison to 10.3% of those who underwent LF. Patients who underwent I&D following LF were significantly more likely to experience depression and stress. To mitigate negative mental health outcomes, mental health services should be available to patients who underwent surgery.

Electron beam profile measurement using enhanced dual-techniques in high heat flux test facility at Institute for Plasma Research.

During operation of an ITER-like plasma fusion device, Plasma Facing Components (PFCs) of a divertor are subjected to steady-state and transient heat loads of up to 20 MW/m2. At High Heat Flux Test Facility (HHFTF) at Institute for Plasma Research, PFCs are subjected to such heat flux scenarios using 200 kW electron beam (EB). A heat flux distribution on PFCs is significantly influenced by the EB profile and scanning technique. A novel dual-technique approach is used to measure EB cross-sectional profiles in HHFTF. A single setup is designed, fabricated, and installed in HHFTF consisting of (1) the knife-edge technique involving graphite and tungsten rectangular tiles bonded on a copper block adjacent to each other to form a sharp edge and (2) the wire scanner technique wherein tungsten wires are placed at equal distances. Current collected by the setup is measured as EB is rastered across the wire and tile boundaries. Current measured as a function of EB position is used to calculate the EB profile using a customized LabVIEW software application. Experiments are conducted by varying EB power from 28 to 200 kW and correspondingly the full width at half maximum of the EB profile grows from 5.30 to 16.04 mm, as observed by both these techniques. The COMSOL Multiphysics simulation of the wire scanner technique is performed to verify the experimental results. X-ray and infra-red imaging diagnostics of HHFTF are also used to measure the EB profile in a unique and first-of-its-kind way, and they are found to agree well with the dual-technique measurements.

Epidermal Growth Factor Receptor Inhibition With Erlotinib in Liver: Dose De-Escalation Pilot Trial as an Initial Step in a Chemoprevention Strategy.

Background and Aims: Effective approaches for prevention of hepatocellular carcinoma (HCC) will have a significant impact on HCC-related mortality. There are strong preclinical data and rationale to support targeting epidermal growth factor receptor (EGFR) for HCC chemoprevention. Small molecule inhibitors of EGFR have been Food and Drug Administration-approved for cancer therapy, which provides an opportunity to repurpose one of these drugs for chemoprevention of HCC. Unfortunately, the frequency of side effects associated with administration of these drugs at oncology doses renders them ineffective for chemoprevention. This clinical trial assesses whether lower doses of one of these inhibitors, erlotinib, still engages EGFR in the liver to block signaling (eg, EGFR phosphorylation). The objective of this clinical trial was determination of a safe and minimum effective dose of erlorinib for which ≥ 50% reduction phospho-EGFR immunohistochemical staining in the liver was observed. Methods: Forty six participants were preregistered and 25 participants were registered in this multicenter trial. By dose de-escalation trial design, cohorts of participants received a 7-day course of erlotinib 75 mg/day, 50 mg/day or 25 mg/day with liver tissue acquisition prior to and after erlotinib. Results: A ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed in a minimum of 40% of participants (predetermined threshhold) at each of the dose levels. Erlotinib was very well tolerated with few side effects observed, particularly at the dose of 25 mg/day. Favorable modulation of the Prognostic Liver Signature was observed in participants who received erlotinib. Conclusion: These data support the selection of erlotinib doses as low as 25 mg/day of for a longer intervention to assess for evidence of efficacy as an HCC chemoprevention drug (ClinicalTrials.govNCT02273362).

Structure and Funding of Clinical Informatics Fellowships: A National Survey of Program Directors.

BACKGROUND: In 2011, the American Board of Medical Specialties established clinical informatics (CI) as a subspecialty in medicine, jointly administered by the American Board of Pathology and the American Board of Preventive Medicine. Subsequently, many institutions created CI fellowship training programs to meet the growing need for informaticists. Although many programs share similar features, there is considerable variation in program funding and administrative structures. OBJECTIVES: The aim of our study was to characterize CI fellowship program features, including governance structures, funding sources, and expenses. METHODS: We created a cross-sectional online REDCap survey with 44 items requesting information on program administration, fellows, administrative support, funding sources, and expenses. We surveyed program directors of programs accredited by the Accreditation Council for Graduate Medical Education between 2014 and 2021. RESULTS: We invited 54 program directors, of which 41 (76%) completed the survey. The average administrative support received was $27,732/year. Most programs (85.4%) were accredited to have two or more fellows per year. Programs were administratively housed under six departments: Internal Medicine (17; 41.5%), Pediatrics (7; 17.1%), Pathology (6; 14.6%), Family Medicine (6; 14.6%), Emergency Medicine (4; 9.8%), and Anesthesiology (1; 2.4%). Funding sources for CI fellowship program directors included: hospital or health systems (28.3%), clinical departments (28.3%), graduate medical education office (13.2%), biomedical informatics department (9.4%), hospital information technology (9.4%), research and grants (7.5%), and other sources (3.8%) that included philanthropy and external entities. CONCLUSION: CI fellowships have been established in leading academic and community health care systems across the country. Due to their unique training requirements, these programs require significant resources for education, administration, and recruitment. There continues to be considerable heterogeneity in funding models between programs. Our survey findings reinforce the need for reformed federal funding models for informatics practice and training.

Liver Transplantation for Hepatocellular Carcinoma: Impact of Wait Time at a Single Center

ABSTRACT Introduction and aim. Liver transplantation (LT) provides durable survival for hepatocellular carcinoma (HCC). However, there is continuing debate concerning the impact of wait time and acceptable tumor burden on outcomes after LT. We sought to review outcomes of LT for HCC at a single, large U.S. center, examining the influence of wait time on post-LT outcomes. Material and methods. We reviewed LT for HCC at Mayo Clinic in Florida from 1/1/2003 until 6/30/2014. Follow up was updated through 8/1/ 2015. Results. From 2003-2014,978 patients were referred for management of HCC. 376 patients were transplanted for presumed HCC within Milan criteria, and the results of these 376 cases were analyzed. The median diagnosis to LT time was 183 days (8 - 4,337), and median transplant list wait time was 62 days (0 -1815). There was no statistical difference in recurrence-free or overall survival for those with wait time of less than or greater than 180 days from diagnosis of HCC to LT. The most important predictor of long term survival after LT was HCC recurrence (HR: 18.61, p < 0.001). Recurrences of HCC as well as survival were predicted by factors related to tumor biology, including histopathological grade, vascular invasion, and pre-LT serum alpha-fetoprotein levels. Disease recurrence occurred in 13%. The overall 5-year patient survival was 65.8%, while the probability of 5-year recurrence-free survival was 62.2%. Conclusions. In this large, single-center experience with long-term data, factors of tumor biology, but not a longer wait time, were associated with recurrence-free and overall survival.