Pediatric liver transplant recipients are not just young adults: The importance of a structured health care transition program in adult transplant centers.

Health care transition (HCT) is a vulnerable period that continues into adulthood, even after the transfer of care. Given the growing population of pediatric liver transplant recipients reaching young adulthood, the need for a standardized and multidisciplinary approach to transition that spans from pediatric to adult care is becoming more imperative. In this article, we review the unique challenges and barriers to successful HCT that adolescent and young adults (AYAs) who have undergone liver transplant face, highlight the gap in transition care in the adult setting, and present the Six Core Elements of Health Care TransitionTM as a framework that can be used by adult providers to incorporate AYAs systematically and collaboratively into adult practice. Multidisciplinary HCT programs should be the standard of care for all AYAs with liver transplant, and while implementation is a necessary first step, ongoing efforts to increase awareness, funding, and research on HCTs into adulthood are needed.

The Crucial Role of Empowerment in Engaging Adolescents and Young Adults for Independence: Essential Strategies and Skills for a Successful Transition.

BACKGROUND: An increasing number of pediatric solid organ transplant (SOT) recipients are surviving into adolescence and young adulthood. The transition from pediatric to adult-oriented care occurs during a unique and vulnerable period. METHODS: Presented here is a structured approach to healthcare transition (HCT) for adolescent and young adult SOT recipients aimed at optimizing independence in order to assist young patients with adherence, self-management, and improved quality of life. RESULTS: Close attention must be paid to neurocognitive development, mental well-being, and social determinants of health. CONCLUSIONS: These efforts require a multidisciplinary team approach as well as collaboration between pediatric and adult providers in order to achieve these goals and patient longevity.

The Root-Lesion Nematode, Pratylenchus penetrans, Affects Early Growth and Physiology of Grafted M.9, G.41, and G.935 Apple Rootstocks Similarly Under Field Microplot Conditions.

The root-lesion nematode, Pratylenchus penetrans, is a ubiquitous parasite of roots of temperate fruit trees. It affects early growth of trees replanted into former orchard sites where populations have built up and may contribute to decline complexes of older trees. Most British Columbia, Canada, apple acreage is planted with M.9 rootstock, but growers are increasingly considering Geneva-series rootstocks such as G.41 and G.935. Among these rootstocks, responses to P. penetrans, specifically, are poorly known. To compare the resistance and tolerance to P. penetrans of G.41, G.935, and M.9 rootstocks ('Ambrosia' scion), a field microplot experiment was established in spring of 2020 at the Summerland Research and Development Centre. The experimental design was a two by three factorial combination of: P. penetrans inoculation (+/-) and rootstock (G.41, G.935, and M.9), with 20 replicate microplots of each of the six treatment combinations arranged in a randomized complete block design. The P. penetrans inoculum was 5,400 nematodes per microplot (54 P. penetrans liter-1 soil), which is below commonly accepted damage thresholds. Though P. penetrans population densities were lower for the G.41 rootstock by the end of the 2021 growing season, the effects of P. penetrans were similar among rootstocks. In the establishment year (2020), P. penetrans caused significant reductions in aboveground growth. In 2021, shoot growth and root weight were reduced by P. penetrans. The nematode also reduced rates of leaf gas exchange and stem water potential. These data suggest that while G.41 and G.935 may have other horticultural benefits over M.9, they are equally susceptible to P. penetrans at the early stages of tree growth.

Mass cytometry for the multiplexed quantification and characterization of target expression on circulating cells in whole blood.

Characterization of target abundance on cells has broad translational applications. Among the approaches for assessing membrane target expression is quantification of the number of target-specific antibody (Ab) bound per cell (ABC). ABC determination on relevant cell subsets in complex and limited biological samples necessitates multidimensional immunophenotyping, for which the high-order multiparameter capabilities of mass cytometry provide considerable advantages. In the present study, we describe the implementation of CyTOF® for the concomitant quantification of membrane markers on diverse types of immune cells in human whole blood. Specifically, our protocol relies on establishing Bmax of Ab saturable binding on cells, then converted into ABC according to a metal's transmission efficiency and number of metal atoms per Ab. Using this method, we calculated ABC values for CD4 and CD8 within the expected range for circulating T cells and in concordance with the ABC obtained in the same samples by flow cytometry. Furthermore, we successfully conducted multiplex measurements of the ABC for CD28, CD16, CD32a, and CD64, on >15 immune cell subsets in human whole blood samples. We developed a high-dimensional data analysis workflow enabling semi-automated Bmax calculation in all examined cell subsets to facilitate ABC reporting across populations. In addition, we investigated impacts of the type of metal isotope and acquisition batch effect on the ABC evaluation with CyTOF®. In summary, our findings demonstrate mass cytometry is a valuable tool for concurrent quantitative analysis of multiple targets in specific and rare cell types, thus increasing the numbers of biomeasures obtained from a single sample.

Current approach to health care transition and integration into adult care for pediatric liver transplant recipients: A call for partnership.

Despite the increased risk of non-adherence, allograft rejection, and mortality following transfer from pediatric to adult care in liver transplantation (LT), there is no standardized approach to health care transition (HCT). Two electronic national surveys were developed and distributed to members of the Society for Pediatric Liver Transplantation and all adult LT programs in the United States to examine current HCT practices. Responses were received from 40 pediatric and 79 adult centers. Pediatric centers were more likely to focus on HCT noting the presence of a transition/transfer policy (60.2% vs. 39.2%), transition clinic (51.6% vs. 16.5%), and the routine use of transition readiness assessment tools (54.8% vs. 10.2%). Perceived barriers to HCT were similar among pediatric and adult respondents and included patient willingness to transfer and participate in care, failure to show for appointments, and lack of sufficient time and staffing. These results highlight the need for an increased awareness of HCT at both pediatric and adult LT centers. The path to improvement requires a partnership between pediatric and adult providers. Recognizing the importance of a comprehensive HCT program initiated in pediatrics and continued throughout young adulthood with ongoing support by the adult team is essential.

Health Care Transition for Adolescents and Young Adults With Pediatric-Onset Liver Disease and Transplantation: A Position Paper by the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition.

Advances in medical therapies and liver transplantation have resulted in a greater number of pediatric patients reaching young adulthood. However, there is an increased risk for medical complications and morbidity surrounding transfer from pediatric to adult hepatology and transplant services. Health care transition (HCT) is the process of moving from a child/family-centered model of care to an adult or patient-centered model of health care. Successful HCT requires a partnership between pediatric and adult providers across all disciplines resulting in a transition process that does not end at the time of transfer but continues throughout early adulthood. Joint consensus guidelines in collaboration with the American Society of Transplantation are presented to facilitate the adoption of a structured, multidisciplinary approach to transition planning utilizing The Six Core Elements of Health Care Transition TM for use by both pediatric and adult specialists. This paper provides guidance and seeks support for the implementation of an HCT program which spans across both pediatric and adult hepatology and transplant centers.

Evaluation of EDB Fibronectin in Plasma, Patient-Derived Xenograft Formalin-Fixed Paraffin-Embedded and Fresh Frozen Tumor Tissues Using Immunoaffinity LC-MS/MS.

The fibronectin (FN) isoform including the extradomain B (EDB) segment (EDB + FN) is a promising tumor target and is highly expressed in some tumor types, such as breast, head, and neck cancer. To date, mostly immunohistochemistry (IHC) and Western blot have been used for the analysis of EDB + FN. However, complete quantitative measurements of EDB + FN expression in a tumor and circulation are important for the development of anti-EDB therapeutics. To this end, a method using protein enrichment followed by online antipeptide antibody enrichment coupled with a nanoflow LC-MS/MS was developed to quantify EDB + FN in human and cynomolgus plasma, patient-derived xenograft (PDX) tumors, and PDX formalin-fixed paraffin-embedded (FFPE) samples. Mouse plasma EDB + FN was analyzed using a protein immunoaffinity method followed by nanoflow LC-MS/MS. EDB + FN concentrations were 63.1 pmol/g in PDX breast cancer tumor and 49.6 pmol/g in PDX head and neck tumor. Mean plasma concentration was 1.1 nM (pmol/mL, 47.4 ng/mL) in normal healthy humans and 0.35 nM (15.1 ng/mL) in naive cynomolgus. The assay sensitivity was 0.018 nM based on calibration with recombinant human EDB + FN (rhEDB + FN).

LI-RADS Treatment Response Algorithm: Performance and Diagnostic Accuracy.

Background In 2017, the Liver Imaging Reporting and Data System (LI-RADS) included an algorithm for the assessment of hepatocellular carcinoma (HCC) treated with local-regional therapy. The aim of the algorithm was to enable standardized evaluation of treatment response to guide subsequent therapy. However, the performance of the algorithm has not yet been validated in the literature. Purpose To evaluate the performance of the LI-RADS 2017 Treatment Response algorithm for assessing the histopathologic viability of HCC treated with bland arterial embolization. Materials and Methods This retrospective study included patients who underwent bland arterial embolization for HCC between 2006 and 2016 and subsequent liver transplantation. Three radiologists independently assessed all treated lesions by using the CT/MRI LI-RADS 2017 Treatment Response algorithm. Radiology and posttransplant histopathology reports were then compared. Lesions were categorized on the basis of explant pathologic findings as either completely (100%) or incompletely (<100%) necrotic, and performance characteristics and predictive values for the LI-RADS Treatment Response (LR-TR) Viable and Nonviable categories were calculated for each reader. Interreader association was calculated by using the Fleiss κ. Results A total of 45 adults (mean age, 57.1 years ± 8.2; 13 women) with 63 total lesions were included. For predicting incomplete histopathologic tumor necrosis, the accuracy of the LR-TR Viable category for the three readers was 60%-65%, and the positive predictive value was 86%-96%. For predicting complete histopathologic tumor necrosis, the accuracy of the LR-TR Nonviable category was 67%-71%, and the negative predictive value was 81%-87%. By consensus, 17 (27%) of 63 lesions were categorized as LR-TR Equivocal, and 12 of these lesions were incompletely necrotic. Interreader association for the LR-TR category was moderate (κ = 0.55; 95% confidence interval: 0.47, 0.67). Conclusion The Liver Imaging Reporting and Data System 2017 Treatment Response algorithm had high predictive value and moderate interreader association for the histopathologic viability of hepatocellular carcinoma treated with bland arterial embolization when lesions were assessed as Viable or Nonviable. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Gervais in this issue.

Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: Results from two prospective cohort studies.

Type 2 diabetes (T2D) is a risk factor for hepatocellular carcinoma (HCC). However, it is unknown whether T2D duration or additional metabolic comorbidities further contribute to HCC risk. From the Nurses' Health Study (NHS), 120,826 women were enrolled in 1980, and from the Health Professionals Follow-up Study (HPFS), 50,284 men were enrolled in 1986 and followed through 2012. Physician-diagnosed T2D was ascertained at baseline and updated biennially. Cox proportional hazards regression models were used to calculate age- and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident HCC. Over 32 years of follow-up (4,488,410 person-years), we documented 112 cases of HCC (69 women, 43 men). T2D was associated with an increased HCC risk (multivariable HR, 4.59; 95% CI, 2.98-7.07), as was an increasing T2D duration (Ptrend < 0.001). Compared to nondiabetics, the multivariable HRs for HCC were 2.96 (95% CI, 1.57-5.60) for 0-<2 years; 6.08 (95% CI, 2.96-12.50) for 2-<10 years; and 7.52 (95% CI, 3.88-14.58) for ≥10 years. Increasing number of metabolic comorbidities (T2D, obesity, hypertension, and dyslipidemia) was associated with increased HCC risk (Ptrend < 0.001); compared to individuals without metabolic comorbidity, those with four metabolic comorbidities had an 8.1-fold increased HCC risk (95% CI, 2.48-26.7). In T2D, neither insulin use nor oral hypoglycemic use was significantly associated with HCC risk (HR, 2.04 [95% CI, 0.69-6.09] and HR, 1.45 [95% CI, 0.69-3.07], respectively). CONCLUSION: T2D is independently associated with increased risk for HCC in two prospective cohorts of U.S. men and women. This risk is enhanced with prolonged diabetes duration and with comorbid metabolic conditions, suggesting the importance of insulin resistance in the pathogenesis of HCC. (Hepatology 2018;67:1797-1806).

Outcomes of liver retransplantation in patients with primary sclerosing cholangitis.

Liver retransplantation in patients with primary sclerosing cholangitis (PSC) has not been well studied. The aims of this study were to characterize patients with PSC listed for and undergoing retransplantation and to describe the outcomes in these patients. The United Network for Organ Sharing/Organ Procurement and Transplantation Network database was used to identify all primary liver transplantations and subsequent relistings and first retransplantations in adults with PSC between 1987 and 2015. A total of 5080 adults underwent primary transplantation for PSC during this period, and of the 1803 who experienced graft failure (GF), 762 were relisted, and 636 underwent retransplantation. Younger patients and patients with GF due to vascular thrombosis or biliary complications were more likely to be relisted, whereas those with Medicaid insurance or GF due to infection were less likely. Both 5-year graft and patient survival after retransplantation were inferior to primary transplantation (P < 0.001). Five-year survival after retransplantation for disease recurrence (REC), however, was similar to primary transplantation (graft survival, P = 0.45; patient survival, P = 0.09) and superior to other indications for retransplantation (graft and patient survival, P < 0.001). On multivariate analysis, mechanical ventilation, creatinine, bilirubin, albumin, advanced donor age, and a living donor were associated with poorer outcomes after retransplantation. In conclusion, although survival after liver retransplantation in patients with PSC was overall inferior to primary transplantation, outcomes after retransplantation for PSC REC were similar to primary transplantation at 5 years. Retransplantation may therefore represent a treatment option with the potential for excellent outcomes in patients with REC of PSC in the appropriate clinical circumstances. Liver Transplantation 23 769-780 2017 AASLD.

Differences in Phenotypes and Liver Transplantation Outcomes by Age Group in Patients with Primary Sclerosing Cholangitis.

BACKGROUND: There is increasing evidence for a heterogeneity of phenotypes in primary sclerosing cholangitis (PSC), but differences across the age spectrum in adults with PSC have not been well characterized. AIMS: To characterize phenotypic variations and liver transplantation outcomes by age group in adults with PSC. METHODS: The United Network for Organ Sharing database was used to identify waitlist registrations for primary liver transplantation in adults with PSC. Patients were split into three age groups: 18-39 (young), 40-59 (middle-aged), and ≥60 (older). Their clinical characteristics and outcomes on the waitlist and post-transplant were compared. RESULTS: Overall, 8272 adults with PSC were listed for liver transplantation during the study period, of which 28.9% were young, 52.0% were middle-aged, and 19.1% were older. The young age group had the greatest male predominance (70.0 vs. 66.2 vs. 65.1%, p = 0.001), the highest proportion of black individuals (20.0 vs. 11.0 vs. 5.5%, p < 0.001), and the most patients listed with concomitant autoimmune hepatitis (2.2 vs. 1.0 vs. 0.8%, p < 0.001). Older patients experienced the greatest waitlist and post-transplant mortality. Graft survival was greatest in the middle-aged group. Young patients were most likely to experience acute rejection (31 vs. 22.8 vs. 18.0%, p < 0.001) and have graft failure due to chronic rejection or PSC recurrence (47.8 vs. 42.3 vs. 17.9%, p < 0.001). CONCLUSIONS: Age-related differences exist among adults with PSC and are associated with outcomes pre- and post-transplant. Young patients may have a more robust immune-related phenotype that is associated with poorer graft survival. Future studies are needed to further investigate these findings.

Impact of EGF, IL28B, and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study.

Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non-transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards model was used to assess time to cirrhosis, liver-related death, and retransplantation, adjusting for donor age and sustained virological response (SVR). Over a median follow-up of 6.3 yr, a trend toward increased progression to graft cirrhosis was observed among recipients of an EGF non-AA vs. AA donor liver (adjusted HR 2.01; 95% CI 0.93-4.34; p = 0.08). No other genotypes predicted cirrhosis development or graft survival. The CC IL28B variant in both recipients and donors was associated with increased rate of SVR (R-CC/D-CC 8/12[67%], R-non-CC/D-CC or R-CC/D-non-CC 23/52[44%], R-non-CC/D-non-CC 12/45[27%], p linear trend = 0.009). Recipient EGF, IL28B, and PNPLA3, and donor IL28B and PNPLA3 genotypes do not predict adverse outcomes in HCV LT recipients. A potential association exists between donor EGF genotype and cirrhosis.

A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration.

OBJECTIVE: The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression. DESIGN: We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1 mg/dL) and platelet count (<100,000/mm(3)), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10 years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8 years). RESULTS: In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001). CONCLUSIONS: A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions.

Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C.

BACKGROUND & AIMS: Therapies that slow fibrosis progression in chronic liver disease are needed. Animal models have demonstrated that statins prevent the progression of hepatic fibrosis, but human data is lacking so far. We evaluated the association between statins and fibrosis progression in the HALT-C trial cohort. METHODS: Subjects with chronic hepatitis C (CHC) and advanced hepatic fibrosis underwent serial liver biopsies over 3.5 years. The primary outcome was a ⩾ 2-point increase in the Ishak fibrosis score on at least one of two serial biopsies. We used complementary log-log regression analysis to assess the association between statins and fibrosis progression among subjects without baseline cirrhosis. RESULTS: Fibrosis progression occurred in 3/29 (10%) statin users and 145/514 (29%) non-users. The unadjusted hazard ratio (HR) for fibrosis progression among statin users compared to non-users was 0.32 (95% CI 0.10-0.99). This association remained significant after adjusting for established predictors of histological outcome, including body mass index, platelets and hepatic steatosis (adjusted HR 0.31; 95% CI 0.10-0.97). The mean change in Ishak fibrosis score over the 3.5 year study period was -0.34 (SE 0.18) for statin users compared to +0.42 (SE 0.07) for non-users (p = 0.006, after adjustment for baseline fibrosis score). CONCLUSIONS: Statin use is associated with a reduced risk of fibrosis progression in advanced CHC. Our findings suggest a potential role for statins in preventing liver disease progression.

Obstructive Sleep Apnea Is Associated with Nonalcoholic Steatohepatitis and Advanced Liver Histology.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) are growing in prevalence in the USA. Existing data on the relationship between OSA and NAFLD are conflicting and limited by the use of various histologic definitions of nonalcoholic steatohepatitis (NASH). Using a robust definition of NASH in a large, well-characterized cohort, we sought to evaluate whether OSA was associated with NASH and advanced fibrosis. METHODS: Two hundred and thirteen subjects undergoing weight loss surgery were queried for OSA and then underwent liver biopsy. NASH was defined, as recommended by the American Association for the Study of Liver Disease, by the presence of all of the following: >5 % macrovesicular steatosis, lobular inflammation, and hepatocyte ballooning. NAFLD activity score (NAS) was also determined for each subject. RESULTS: Subjects with OSA had significantly higher alanine and aspartate aminotransferase levels than subjects without OSA (ALT 54.1 vs. 37.7 U/L, P = 0.0007; AST 31.7 vs. 20.5 U/L, P = 0.0007). OSA was associated with the presence of NASH, and this remained significant after adjusting for age, gender, race, and diabetes mellitus (P = 0.03 OR 2.01; 95 %, 1.05-3.87). Steatosis grade, lobular inflammation grade, NAS score, and fibrosis stage were all significantly associated with the presence of OSA and remained so after adjustment. CONCLUSIONS: OSA is associated with elevated aminotransferase levels, the presence of NASH, and advanced NASH histology. Further studies are needed to evaluate the impact of OSA treatment on NASH.

Gaps in recognition and evaluation of incidentally identified hepatic steatosis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), the most common cause of liver disease, is frequently diagnosed incidentally on imaging. The goal of the present study was to characterize rates of documentation and evaluation of incidentally identified steatosis. METHODS: Adults who underwent abdominal computed tomography with incidentally reported steatosis from January 2008 to October 2011 and with ≥1 primary care appointment within 14 months following imaging were included. RESULTS: One hundred twenty-seven individuals with newly identified steatosis on imaging were included. Medical record documentation of newly identified steatosis occurred in only 29 individuals (22.8 %). Mention of steatosis within the "impression" section of radiology reports in addition to the report body was associated with significantly higher likelihood of primary care documentation (p = 0.007). Primary care documentation of steatosis was associated higher rates of evaluation for the etiology of steatosis include testing of aminotransferase levels (96.5 vs. 77.5 %, p = 0.025), alcohol use screening (89.6 vs. 66.3 %, p = 0.02), and hepatitis C screening (20.6 vs. 2.0 %, p = 0.002). No patient had documentation of the NAFLD fibrosis score and none were referred for specialist evaluation or for liver biopsy. However, when calculated, the NAFLD fibrosis score identified 14 patients (11 %) as high risk for advanced hepatic fibrosis. CONCLUSION: Documentation of incidentally identified steatosis is infrequent but was improved when steatosis was mentioned in the "impression" of radiographic reports. Documentation of steatosis was associated with increased rates of aminotransferase testing and alcohol use and hepatitis C screening. An important proportion of individuals with incidentally identified steatosis are at high risk of fibrosis and may benefit from additional evaluation.