Patient randomised controlled trial of technology enabled strategies to promote treatment adherence in liver transplantation: rationale and design of the TEST trial.

BACKGROUND AND AIMS: Liver transplantation is a life-saving procedure for end-stage liver disease. However, post-transplant medication regimens are complex and non-adherence is common. Post-transplant medication non-adherence is associated with graft rejection, which can have long-term adverse consequences. Transplant centres are equipped with clinical staff that monitor patients post-transplant; however, digital health tools and proactive immunosuppression adherence monitoring has potential to improve outcomes. METHODS AND ANALYSIS: This is a patient-randomised prospective clinical trial at three transplant centres in the Northeast, Midwest and South to investigate the effects of a remotely administered adherence programme compared with usual care. The programme monitors potential non-adherence largely levering text message prompts and phenotypes the nature of the non-adhere as cognitive, psychological, medical, social or economic. Additional reminders for medications, clinical appointments and routine self-management support are incorporated to promote adherence to the entire medical regimen. The primary study outcome is medication adherence via 24-hour recall; secondary outcomes include additional medication adherence (ASK-12 self-reported scale, regimen knowledge scales, tacrolimus values), quality of life, functional health status and clinical outcomes (eg, days hospitalised). Study implementation, acceptability, feasibility, costs and potential cost-effectiveness will also be evaluated. ETHICS AND DISSEMINATION: The University of Pennsylvania Review Board has approved the study as the single IRB of record (protocol # 849575, V.1.4). Results will be published in peer-reviewed journals and summaries will be provided to study funders. TRIAL REGISTRATION NUMBER: NCT05260268.

Clinical characteristics and outcomes in those with primary extrahepatic malignancy and malignant ascites.

BACKGROUND: Malignancy-related ascites accounts for approximately 10% of causes of ascites. Our AIM was to characterize the ascites fluid and correlate clinical outcomes in those with extrahepatic malignancy and ascites. METHODS: 241 subjects with extrahepatic solid tumors and ascites were reviewed from 1/1/2000 to 12/31/2019, 119 without liver metastasis and 122 with liver metastasis. RESULTS: Ascites fluid consistent with peritoneal carcinomatosis (PC) was most common, 150/241 (62%), followed by fluid reflecting the presence of portal hypertension (PH), 69/241 (29%). 22/241 (9%) had low SAAG and low ascites fluid total protein, with evidence of PC on cytology and or imaging in 20/22. Lung cancer was the most common malignancy in subjects with ascites due to PC at 36/150 (24%), pancreatic cancer was the most common in subjects with ascites with features of PH at 16/69 (23%). Chemotherapy or immunotherapy alone was the most common management approach. Significantly higher 5-year, 3-year and 1-year mortality rate were noted in subjects with evidence of PC on cytology/imaging versus subjects with no evidence of PC, and in subjects with liver metastasis compared to subjects without liver metastasis. Subjects with pancreatic cancer and evidence of PC on cytology/imaging had higher 1 and 5-year mortality rates compared to subjects without PC. CONCLUSIONS: Ascites in solid tumor malignancy is most commonly due to PC. We also observed ascites fluid with characteristics of PH in 29% of subjects. Higher mortality rates in subjects with peritoneal carcinomatosis and liver metastasis were noted. These findings may help inform prognosis and treatment strategies.

Incidence of hepatocellular carcinoma in chronic hepatitis B virus infection in those not meeting criteria for antiviral therapy.

Chronic hepatitis B virus (HBV) infection is the leading risk factor for hepatocellular carcinoma (HCC). The aim of this study was to explore the incidence of HCC in a cohort of subjects with HBV and correlate with HBV treatment current guidance. We identified 2846 subjects with HBV over the study period. HCC was diagnosed in 386 of 2846 (14%) subjects; 209 of 386 (54%) were on nucleos(t)ide analogue (NA) therapy at time of HCC diagnosis, and 177 of 386 (46%) were not on NA therapy. Of the 177 subjects not on NAs who developed HCC during follow-up, 153 of 177 (86%) had cirrhosis. Within the 177 subjects not on NAs, 158 of 177 (89%) had undetectable HBV DNA, 10 of 177 (6%) had detectable HBV DNA < 2000 IU/L, and 9 of 177 (5%) had HBV DNA > 2000 IU/L. Of those with cirrhosis and undetectable HBV DNA, 115 of 141 had compensated cirrhosis, and 26 of 141 had decompensated cirrhosis. Significant predictors of HCC on time to event analysis included cirrhosis (hazard ratio [HR] 10, 95% confidence interval [CI] 5.8-17.5; p < 0.001), alanine aminotransferase level (HR 1.004, 95% CI 1.002-1.006; p < 0.001), age (HR 1.04, 95% CI 1.03-1.06; p < 0.001), (HR 1.9, 95% CI 1.2-3.1; p 0.007), and nonalcoholic fatty liver disease (HR 1.7, 95% CI 1.1-2.8; p 0.02). Kaplan-Meier analysis demonstrated the cumulative incidence of HCC in subjects with compensated cirrhosis receiving NA therapy was significantly lower compared to subjects with compensated cirrhosis outside current HBV treatment practice guidance (undetectable HBV DNA) (32% vs. 51%; p < 0.001). Conclusion: Those with untreated compensated cirrhosis with undetectable HBV DNA who do not meet current guidance for treatment had higher rates of HCC than those with compensated cirrhosis and suppressed HBV DNA by NA therapy. This study highlights the need for earlier diagnosis and treatment of HBV.

Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.

BACKGROUND & AIMS: Recently, international experts proposed redefining non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease (MAFLD), based on modified criteria. It is suspected that outcomes such as mortality may differ for these clinical entities. We studied the impact of MAFLD and NAFLD on all-cause and cause-specific mortality in US adults. METHODS: We analyzed data from 7,761 participants in the Third National Health and Nutrition Examination Survey and their linked mortality through 2015. NAFLD was diagnosed by ultrasonographic evidence of hepatic steatosis without other known liver diseases. MAFLD was defined based on the criteria proposed by an international expert panel. The Cox proportional hazard model was used to study all-cause mortality and cause-specific mortality between MAFLD and NAFLD, with adjustments for known risk factors. RESULTS: During a median follow-up of 23 years, individuals with MAFLD had a 17% higher risk of all-cause mortality (hazard ratio [HR] 1.17; 95% CI 1.04-1.32). Furthermore, MAFLD was associated with a higher risk of cardiovascular mortality. NAFLD per se did not increase the risk of all-cause mortality. Individuals who met both definitions had a higher risk of all-cause mortality (HR 1.13, 95% CI 1.00-1.26), while individuals who met the definition for MAFLD but not NAFLD had a 1.7-fold higher risk of all-cause mortality (HR 1.66, 95% CI 1.19-2.32). Estimates for all-cause mortality were higher for those with advanced fibrosis and MAFLD than for those with advanced fibrosis and NAFLD. CONCLUSIONS: In this US population-based study, MAFLD was associated with an increased risk of all-cause mortality, while NAFLD demonstrated no association with all-cause mortality after adjusting for metabolic risk factors. LAY SUMMARY: Our findings provide further support for the idea that non-alcoholic fatty liver disease (NAFLD) is a part of a broader multi-system disease that also includes obesity, diabetes, high blood pressure, and high cholesterol. Therefore, re-defining NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD) may help improve our understanding of predictors that increase the risk of death.

Physical Activity, Measured Objectively, Is Associated With Lower Mortality in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: The association between physical activity (PA) and all-cause and cause-specific mortality from nonalcoholic fatty liver disease (NAFLD) requires investigation. We studied whether PA, measured by accelerometer, is associated with all-cause and cause-specific mortality among individuals with NAFLD. METHODS: We performed a longitudinal analysis using the 2003 to 2006 US National Health and Nutrition Examination Survey data of adults (age, ≥20 y) and collecting mortality data through December 2015. NAFLD was defined based on the hepatic steatosis index or US fatty liver index scores, in the absence of other causes of chronic liver disease. PA was measured from participants who wore accelerometers 10 h/d for a minimum of 4 days over a 7-day period and were classified as total PA, moderate to vigorous PA (MVPA), and sedentary behavior. RESULTS: Over an average follow-up period of 10.6 years, increasing the duration of total PA was associated with a reduced risk of death, from any cause, in an age- and sex-adjusted model (hazard ratio [HR], 0.52; 95% CI, 0.32-0.86 for highest quartile vs lowest quartile; P for trend = .001) and multivariable model (HR, 0.46; 95% CI, 0.28-0.75; P for trend < .001) among individuals with NAFLD. Increasing the duration of MVPA was associated with a lower risk of death from any cause in individuals with NAFLD. Furthermore, longer total PA was associated with a lower risk for cardiovascular disease-related death in individuals with NAFLD (HR, 0.28; 95% CI, 0.08-0.98 for highest quartile vs lowest quartile; P for trend = .007). We did not find this association for cancer-related mortality in individuals with NAFLD. Increasing the duration of sedentary behavior did not affect all-cause or cause-specific mortality in individuals with NAFLD. CONCLUSIONS: Longer total PA and MVPA, measured by accelerometers over a 7-day period, are associated with lower all-cause and cardiovascular mortality in individuals with NAFLD.

Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations From the Liver Forum.

Identifying effective therapies for nonalcoholic steatohepatitis (NASH) with fibrosis is a pressing challenge, with 1%-2% of the population in developed nations at risk of developing NASH cirrhosis and its complications. The design of NASH clinical therapeutic trials is hampered by the long period of minimally symptomatic disease that typically precedes the development of decompensated cirrhosis and the accompanying uncertainties regarding the best precirrhotic trial endpoints that reliably reflect a subsequent reduction in liver-related morbidity and mortality. The Liver Forum is a multistakeholder organization comprised of academic, industry, and regulatory experts working from a regulatory science perspective to identify barriers, prioritize research, and identify solutions to accelerate therapeutic development for NASH. Past work of The Liver Forum has focused on recommendations for disease definitions and baseline parameters to be implemented in clinical trials that are designed to assess disease status and prevent progression to cirrhosis, liver transplantation, hepatocellular carcinoma, and death. The purpose of this summary is to review currently available clinical data to identify parameters that change in parallel with liver histology and are likely to reflect clinically meaningful reductions in the risk of developing cirrhosis and its complications. We review available data on exploratory histological, blood-based, and imaging pharmacodynamic biomarkers that may reflect meaningful treatment responses and provide recommendations regarding measurements to be considered in phase 2 and 3 trials as well as during postmarketing monitoring trials.

Nonalcoholic Fatty Liver Disease: Identification and Management of High-Risk Patients.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly dominant cause of liver disease worldwide. The progressive subtype, nonalcoholic steatohepatitis, is a leading indication for liver transplantation and a noteworthy cause of hepatocellular carcinoma. The overall prevalence of NAFLD is on the rise, and even more concerning data modeling predicts that an increasing percentage of those with NAFLD will develop advanced disease. This increased volume of patients with advanced liver disease will impose a significant health care burden in terms of resources and cost. Thus, the identification of patients with established fibrosis or at high risk of developing advanced liver disease is critical to effectively intervene and prevent overall and liver-related morbidity and mortality. Herein, we provide a framework to consider for the identification of patients with NAFLD at high risk of nonalcoholic steatohepatitis with advanced fibrosis and provide a critical assessment of currently accessible diagnostic and treatment modalities.

Follow-up of the Post-Liver Transplantation Patient: A Primer for the Practicing Gastroenterologist.

The focus in liver transplantation in the next 10 years will likely change from preventing viral disease recurrence to minimizing the toll of rejection and fatty liver disease, minimizing the complications from immunosuppression with withdrawal strategies, and more optimal management of long-term risks, such as malignancy, cardiovascular disease, and renal failure. In addition, now that short-term results (<1 year) have improved significantly, there will be a shift toward improving long-term patient and graft survival, as well as a focus on primary care preventive strategies.

Diarrhea Concealing a Duodenal-Cecal Fistula Secondary to Appendiceal Mucinous Neoplasm.

Primary mucinous adenocarcinoma of the appendix is a rare gastrointestinal malignancy. Fistulous tract formation is a complication that is cited in literature. An 85-year-old man with multiple comorbidities presented with several weeks of persistent non-bloody diarrhea. Laboratory work-up was non-diagnostic. Abdominal imaging with barium contrast showed an enterocolonic fistulous tract extending from the duodenum to the cecum involving an enlarged appendiceal mass. Subsequent biopsy confirmed mucinous appendiceal neoplasm with peritoneal spread to the liver and mesentery. This is the first report describing an enterocolonic fistula formation resulting from this malignancy.

Idiopathic hypereosinophilic syndrome presenting with hepatitis and achalasia.

Idiopathic hypereosinophilic syndrome (HES) is a rare diagnosis defined by the World Health Organization as a persistent eosinophilia for 6 months and resulting in end-organ dysfunction. While many patients present with nonspecific symptoms, others will present with symptoms of the affected organs, most commonly those involving the heart, skin, or nervous system. Gastrointestinal or liver involvement is estimated to affect up to one-third of patients with HES, although patients with clinically significant disease are limited to case reports. This is the first report of a patient presenting with hepatitis and achalasia related to idiopathic HES.

Examining the relationship between early axon growth and transcription factor expression in the developing cerebral cortex.

The transcription factors Satb2 (special AT-rich sequence binding protein 2) and Ctip2 (COUP-TF interacting protein 2) have been shown to be required for callosal and corticospinal axon growth respectively from subtypes of cerebral cortex projection neurons. In this study we investigated early stages of directed axon growth in the embryonic mouse cerebral cortex, and studied the possible correlation with the expression of Satb2 and Ctip2. Electroporation of an EYFP-expressing plasmid at embryonic day 13.5 to label developing projection neurons revealed that directed axon growth is first seen in radially migrating neurons in the intermediate zone (IZ), prior to migration into the cortical plate, as has been suggested previously. Onset of expression of SATB2 and CTIP2 was also observed in the IZ, correlating well with this stage of migration and initiation of axon growth. Immunohistochemical staining through embryonic and early postnatal development revealed a significant population of Satb2/Ctip2 co-expressing cells, while retrograde axon tracing from the corpus callosum at embryonic day 18.5 back-labelled many neurons with bi-directional axon processes. However, through retrograde tracing and simultaneous immunohistochemical staining we show that these bi-directional processes do not correlate with Satb2/Ctip2 co-expression. Our work shows that although expression of these transcription factors correlates well with the appearance of directed axon growth during cortical development, the transcriptional code underlying the bi-directional axonal projections of early neocortical neurons is not likely to be the result of Satb2/Ctip2 co-expression.

ASPP2 binds Par-3 and controls the polarity and proliferation of neural progenitors during CNS development.

Cell polarity plays a key role in the development of the central nervous system (CNS). Interestingly, disruption of cell polarity is seen in many cancers. ASPP2 is a haplo-insufficient tumor suppressor and an activator of the p53 family. In this study, we show that ASPP2 controls the polarity and proliferation of neural progenitors in vivo, leading to the formation of neuroblastic rosettes that resemble primitive neuroepithelial tumors. Consistent with its role in cell polarity, ASPP2 influences interkinetic nuclear migration and lamination during CNS development. Mechanistically, ASPP2 maintains the integrity of tight/adherens junctions. ASPP2 binds Par-3 and controls its apical/junctional localization without affecting its expression or Par-3/aPKC lambda binding. The junctional localization of ASPP2 and Par-3 is interdependent, suggesting that they are prime targets for each other. These results identify ASPP2 as a regulator of Par-3, which plays a key role in controlling cell proliferation, polarity, and tissue organization during CNS development.