The benefit of liver transplant beyond Milan criteria: An analysis using the National Cancer Database.

BACKGROUND: Published studies examining the efficacy of liver transplantation in patients presenting with hepatocellular cancer beyond the traditional Milan criteria for liver transplantation have primarily been single institution series with limited ability to compare outcomes to alternative methods of management. METHODS: We queried the National Cancer Database to identify patients presenting between 2004 and 2016 with histologically confirmed clinical stage III and IVA hepatocellular cancer. Multivariable regression was used to identify factors associated with liver transplantation. Patients undergoing liver transplantation were 1:1 propensity score-matched for age, demographics, comorbid disease, clinical stage, and histologic resection margin to those undergoing surgical resection. The Kaplan-Meier method was used to compare overall survival profiles for matched cohorts. RESULTS: Seven hundred and ninety-two patients met inclusion criteria-590 (74.5%) underwent surgical resection and 202 (25.5%) liver transplantation. On adjusted analysis, patients undergoing liver transplantation were less likely to have advanced age (>60 years; odds ratio 0.39, 95% confidence interval [0.21-0.71]) and to be of Black race (odds ratio 0.42, 95% confidence interval [0.23-0.73]) or Asian (odds ratio 0.25, 95% confidence interval [0.11-0.53]) ethnicity but were more likely to have advanced (Charlson score >2) comorbidity scores, (odds ratio 2.48, 95% confidence interval [1.58-3.90]) and more likely to have private health insurance (odds ratio 4.17, 95% confidence interval [1.31-18.66]) than those undergoing surgical resection. On Kaplan-Meier analysis of matched cohorts, patients undergoing liver transplantation demonstrated significantly better rates of 5-year overall survival (65.3% vs 26.3%, P < .0001) and longer median overall survival times than those undergoing resection (53.1 ± 2.78 vs 26.9 ± 1.20 months, P < .0001). CONCLUSION: Liver transplantation offers the potential to be an effective treatment modality in select patients presenting with stage III and IVA hepatocellular cancer.

The E3 Ubiquitin Ligase ATL9 Affects Expression of Defense Related Genes, Cell Death and Callose Deposition in Response to Fungal Infection.

Plants use diverse strategies to defend themselves from biotic stresses in nature, which include the activation of defense gene expression and a variety of signal transduction pathways. Previous studies have shown that protein ubiquitination plays a critical role in plant defense responses, however the details of its function remain unclear. Our previous work has shown that increasing expression levels of ATL9, an E3 ubiquitin ligase in Arabidopsis thaliana, increased resistance to infection by the fungal pathogen, Golovinomyces cichoracearum. In this study, we demonstrate that the defense-related proteins PDF1.2, PCC1 and FBS1 directly interact with ATL9 and are targeted for degradation to the proteasome by ATL9. The expression levels of PDF1.2, PCC1 and FBS1 are decreased in T-DNA insertional mutants of atl9 and T-DNA insertional mutants of pdf1.2, pcc1 and fbs1 are more susceptible to fungal infection. In addition, callose is more heavily deposited at infection sites in the mutants of atl9, fbs1, pcc1 and pdf1.2. Overexpression of ATL9 and of mutants in fbs1, pcc1 and pdf1.2 showed increased levels of cell death during infection. Together these results indicate that ubiquitination, cell death and callose deposition may work together to enhance defense responses to fungal pathogens.

Urinary tract infections in cystic fibrosis patients.

Improved understanding of non-respiratory infections in cystic fibrosis (CF) patients will be vital to sustaining the increased life span of these patients. To date, there has not been a published report of urinary tract infections (UTIs) in CF patients. We performed a retrospective chart review at a major academic medical center during 2010-2020 to determine the features of UTIs in 826 CF patients. We identified 108 UTI episodes during this period. Diabetes, distal intestinal obstruction syndrome (DIOS), and nephrolithiasis were correlated with increased risk of UTIs. UTIs in CF patients were less likely to be caused by Gram-negative rods compared to non-CF patients and more likely to be caused by Enterococcus faecalis. The unique features of UTIs in CF patients highlight the importance of investigating non-respiratory infections to ensure appropriate treatment.

Combined Use of Aspirin and Statin is Associated With a Decreased Incidence of Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer and cancer-related mortality worldwide. Studies have suggested that aspirin (ASA) and statins may be associated with a decrease in incident HCC. GOALS: We aimed to evaluate the effect of ASA and statin use on the incidence of HCC in a prospective cohort of patients with liver cirrhosis and to identify if there was an increased risk of esophageal variceal hemorrhage (VH) in patients with ASA use. STUDY: We conducted a retrospective study of 521 patients with data collected from July 1, 2012 to December 31, 2017. We used competing risk analysis to assess the association between risk factors and HCC; and the association between ASA and VH. RESULTS: ASA use alone was associated with a decreased incidence of HCC in the univariate and multivariate models; [hazard ratio (HR) confidence interval (CI): 0.348 (0.124-0.976); P=0.0448] and [HR (CI): 0.266 (0.094-0.755); P=0.0129, respectively]. The combination of ASA and statin use was associated with a decreased hazard of HCC [HR (CI): 0.15 (0.036-0.624); P=0.0090] and this remained statistically significant in the multivariable model [HR (CI): 0.113 (0.026-0.483); P=0.0033]. Among daily ASA users compared with non-users, there was not a significant increase in risk of VH. CONCLUSIONS: Daily ASA use was associated with a decrease risk of incident HCC. The combination of daily ASA use and statin use decreased the risk of incident HCC suggesting there is beneficial interaction. Finally, no excess VH was observed in daily ASA users compared with non-users.

Provider Attitudes and Practice Patterns for Direct-Acting Antiviral Therapy for Patients With Hepatocellular Carcinoma.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are effective against hepatitis C virus and sustained virologic response is associated with reduced incidence of hepatocellular carcinoma (HCC). However, there is controversy over the use of DAAs in patients with active or treated HCC and uncertainty about optimal management of these patients. We aimed to characterize attitudes and practice patterns of hepatology practitioners in the United States regarding the use of DAAs in patients with HCC. METHODS: We conducted a survey of hepatology providers at 47 tertiary care centers in 25 states. Surveys were sent to 476 providers and we received 279 responses (58.6%). RESULTS: Provider beliefs about risk of HCC recurrence after DAA therapy varied: 48% responded that DAAs reduce risk, 36% responded that DAAs do not change risk, and 16% responded that DAAs increase risk of HCC recurrence. However, most providers believed DAAs to be beneficial to and reduce mortality of patients with complete response to HCC treatment. Accordingly, nearly all providers (94.9%) reported recommending DAA therapy to patients with early-stage HCC who received curative treatment. However, fewer providers recommended DAA therapy for patients with intermediate (72.9%) or advanced (57.5%) HCC undergoing palliative therapies. Timing of DAA initiation varied among providers based on HCC treatment modality: 49.1% of providers reported they would initiate DAA therapy within 3 months of surgical resection whereas 45.9% and 5.0% would delay DAA initiation for 3-12 months and >1 year post-surgery, respectively. For patients undergoing transarterial chemoembolization (TACE), 42.0% of providers would provide DAAs within 3 months of the procedure, 46.7% would delay DAAs until 3-12 months afterward, and 11.3% would delay DAAs more than 1 year after TACE. CONCLUSIONS: Based on a survey sent to hepatology providers, there is variation in provider attitudes and practice patterns regarding use and timing of DAAs for patients with HCC. Further studies are needed to characterize the risks and benefits of DAA therapy in this patient population.

Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection Is Associated With Increased Survival in Patients With a History of Hepatocellular Carcinoma.

BACKGROUND & AIMS: There is controversy regarding the benefits of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection for patients with a history of hepatocellular carcinoma (HCC). We performed a multicenter cohort study to compare overall survival between patients with HCV infection treated with DAAs and patients who did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy. METHODS: We conducted a retrospective cohort study of patients with HCV-related HCC who achieved a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy, from January 2013 through December 2017 at 31 health care systems throughout the United States and Canada. We used Cox proportional hazards regression to determine the association between receipt of DAA therapy, modeled as a time-varying covariate, and all-cause mortality, accounting for informative censoring and confounding using inverse probability weighting. RESULTS: Of 797 patients with HCV-related HCC, 383 (48.1%) received DAA therapy and 414 (51.9%) did not receive treatment for their HCV infection after complete response to prior HCC therapy. Among DAA-treated patients, 43 deaths occurred during 941 person-years of follow-up, compared with 103 deaths during 526.6 person-years of follow-up among patients who did not receive DAA therapy (crude rate ratio, 0.23; 95% confidence interval [CI], 0.16-0.33). In inverse probability-weighted analyses, DAA therapy was associated with a significant reduction in risk of death (hazard ratio, 0.54; 95% CI, 0.33-0.90). This association differed by sustained virologic response to DAA therapy; risk of death was reduced in patients with sustained virologic response to DAA therapy (hazard ratio, 0.29; 95% CI, 0.18-0.47), but not in patients without a sustained virologic response (hazard ratio, 1.13; 95% CI, 0.55-2.33). CONCLUSIONS: In an analysis of nearly 800 patients with complete response to HCC treatment, DAA therapy was associated with a significant reduction in risk of death.

Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study.

BACKGROUND & AIMS: There is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort. METHODS: We conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response). RESULTS: Of 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70-1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70-1.34) after we adjusted for study site, age, sex, Child-Pugh score, α-fetoprotein level, tumor burden, and HCC treatment modality. In DAA-treated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P = .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance. CONCLUSION: In a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients.

Risk factors and outcomes of acute respiratory distress syndrome in critically ill patients with cirrhosis.

AIM: Prior randomized controlled trials of acute respiratory distress syndrome (ARDS) excluded critically ill patients with cirrhosis. Data regarding risk factors for ARDS development and outcomes from ARDS in patients with cirrhosis are scarce. We sought to characterize outcomes from ARDS in patients with cirrhosis. METHODS: An observational cohort of patients with cirrhosis admitted to an intensive care unit at a high-volume liver transplant center between 1 January 2012 and 31 December 2014 were reviewed. ARDS cases were identified according to the Berlin definition. Potential risk factors were examined in multivariable logistic regression analysis for ARDS development. Outcomes including in-hospital mortality were compared between ARDS and non-ARDS patients. RESULTS: A total of 559 patients met the inclusion criteria and 45 (8.1%) developed ARDS. Differences between ARDS and non-ARDS patients included sepsis, Model for End-Stage Liver Disease - Sodium score, and Sequential Organ Failure Assessment score. In-hospital mortality was higher in cirrhotic patients with ARDS compared with those without ARDS (82.2% vs. 27.6%, P < 0.001). In multivariable analysis, acute-on-chronic liver failure (OR 8.69, 95% CI 2.28-33.18, P < 0.01) and shock on intensive care unit admission (OR 3.13, 95% CI 1.57-6.24, P = 0.001) were associated with ARDS development, whereas etiology of cirrhosis or alcohol use were not. CONCLUSIONS: Acute-on-chronic liver failure and shock on intensive care unit admission were risk factors for ARDS development, whereas etiology of cirrhosis and alcohol were not. Mortality from ARDS was markedly increased in patients with cirrhosis. Early recognition and treatment for infection might be important for improving the high mortality in this group of patients.

Expression and regulation of ATL9, an E3 ubiquitin ligase involved in plant defense.

Plants are continually exposed to a variety of pathogenic organisms, including bacteria, fungi and viruses. In response to these assaults, plants have developed various defense pathways to protect themselves from pathogen invasion. An understanding of the expression and regulation of genes involved in defense signaling is essential to controlling plant disease. ATL9, an Arabidopsis RING zinc finger protein, is an E3 ubiquitin ligase that is induced by chitin and involved in basal resistance to the biotrophic fungal pathogen, Golovinomyces cichoracearum (G. cichoracearum). To better understand the expression and regulation of ATL9, we studied its expression pattern and the functions of its different protein domains. Using pATL9:GUS transgenic Arabidopsis lines we found that ATL9 is expressed in numerous tissues at various developmental stages and that GUS activity was induced rapidly upon wounding. Using a GFP control protein, we showed that ATL9 is a short-lived protein within plant cells and it is degraded via the ubiquitin-proteasome pathway. ATL9 contains two transmembrane domains (TM), a RING zinc-finger domain, and a PEST domain. Using a series of deletion mutants, we found that the PEST domain and the RING domain have effects on ATL9 degradation. Further infection assays with G. cichoracearum showed that both the RING domain and the TM domains are important for ATL9's resistance phenotype. Interestingly, the PEST domain was also shown to be significant for resistance to fungal pathogens. This study demonstrates that the PEST domain is directly coupled to plant defense regulation and the importance of protein degradation in plant immunity.

Early Hospital Readmissions and Mortality in Patients With Decompensated Cirrhosis Enrolled in a Large National Health Insurance Administrative Database.

BACKGROUND: Patients with decompensated cirrhosis have high rates of morbidity and mortality and frequently require hospital admission. Few studies have examined early readmission as an indicator of 90 day and overall mortality. Analysis of large databases is needed to evaluate the association between early readmission and mortality in decompensated cirrhosis. METHODS: We analyzed 5 years of private, employer-based, health insurance claims data associated with HealthCare Services Corporation on 13.5 million members over 4 states from 2010 to 2014. We defined early readmission as an admission to a general acute care hospital within 30 days of an index hospitalization and compared mortality to those who were readmitted after 30 days (late readmission). Univariable analysis was used to compare clinical and patient characteristics associated with early readmission. Cox proportional hazard models with time-varying covariates were used to assess if an early readmission was an independent risk factor for death. RESULTS: A total of 16,107 patients with decompensated cirrhosis were analyzed. During the study period, 82% of patients with decompensated cirrhosis were hospitalized at least once. Over 50% of hospitalized patients experienced an early readmission. Patients with an early readmission received blood transfusions, transjugular intrahepatic portosystemic shunt, paracentesis, thoracentesis, and upper endoscopies more frequently than those with a late readmission. Cirrhotics with an early readmission had higher rates of hepatorenal syndrome, sepsis, hepatocellular carcinoma, hepatic encephalopathy, and ascites. Patients experiencing an early readmission had greater 90 day, 1 year and overall mortality. Early readmission was an independent predictor of worse survival when adjusting for other conditions associated with mortality in patients with cirrhosis, but the impact of an early readmission dissipated after 1 year. CONCLUSIONS: Patients with decompensated cirrhosis have high rates of hospitalization and frequently experience an early readmission. An early readmission to an acute care hospital is an independent predictor of mortality in patients with decompensated cirrhosis for at least 1 year following initial hospitalization.

A Synthesis of Hepatitis C prevalence estimates in Sub-Saharan Africa: 2000-2013.

BACKGROUND: Hepatitis C (HCV) is a deleterious virus that can be cured with new, highly effective anti-viral treatments, yet more than 185 million individuals worldwide remain HCV positive (with the vast majority un-diagnosed or untreated). Of importance, HCV is a leading cause of chronic liver disease and liver cancer, especially in Sub-Saharan Africa (SSA) where the prevalence remains high but uncertain due to little population-based evidence of the epidemic. We aimed to synthesize available data to calculate and highlight the HCV disease burden in SSA. METHODS: Weighted random-effects generalized linear mixed models were used to estimate prevalence by risk cohort, African region (Southern, Eastern, Western, and Central Africa), type of assay used, publication year, and whether the estimate included children. A pooled prevalence estimate was also calculated. Multi-variable analyses were limited to cohort and region specific prevalence estimates in the adult population due to limited studies including children. Prevalence estimates were additionally weighted using the known adult population size within each region. RESULTS: We included more than 10 years of data. Almost half of the studies on HCV prevalence in SSA were from the Western region (49 %), and over half of all studies were from either blood donor (25 %) or general population cohorts (31 %). In uni-variable analyses, prevalence was lowest in Southern Africa (0.72 %), followed by Eastern Africa at 3.00 %, Western Africa at 4.14 %, and Central Africa at 7.82 %. Blood donors consistently had the lowest prevalence (1.78 %), followed by pregnant women (2.51 %), individuals with comorbid HIV (3.57 %), individuals from the general population (5.41 %), those with a chronic illness (7.99 %), and those at high risk for infection (10.18 %). After adjusting for the population size in each region, the overall adult prevalence of HCV in SSA rose from 3.82 to 3.94 %. CONCLUSION: This meta-analysis offers a timely update to the HCV disease burden in SSA and offers additional evidence of the burgeoning epidemic. The study highlights the need to account for type of cohort and region variation when describing the HCV epidemic in SSA, the need for more studies that include children, as well as the need to factor in such variations when planning public health interventions.

The role of hepatitis E virus infection in adult Americans with acute liver failure.

Acute hepatitis E virus (HEV) infection is a leading cause of acute liver failure (ALF) in many developing countries, yet rarely identified in Western countries. Given that antibody testing for HEV infection is not routinely obtained, we hypothesized that HEV-related ALF might be present and unrecognized in North American ALF patients. Serum samples of 681 adults enrolled in the U.S. Acute Liver Failure Study Group were tested for anti-HEV immunoglobulin (Ig) M and anti-HEV IgG levels. Subjects with a detectable anti-HEV IgM also underwent testing for HEV RNA. Mean patient age was 41.8 years, 32.9% were male, and ALF etiologies included acetaminophen (APAP) hepatotoxicity (29%), indeterminate ALF (23%), idiosyncratic drug-induced liver injury DILI (22%), acute hepatitis B virus infection (12%), autoimmune hepatitis (12%), and pregnancy-related ALF (2%). Three men ages 36, 39, and 70 demonstrated repeatedly detectable anti-HEV IgM, but all were HEV-RNA negative and had other putative diagnoses. The latter 2 subjects died within 3 and 11 days of enrollment whereas the 36-year-old underwent emergency liver transplantation on study day 2. At admission, 294 (43.4%) of the ALF patients were anti-HEV IgG positive with the seroprevalence being highest in those from the Midwest (50%) and lowest in those from the Southeast (28%). Anti-HEV IgG+ subjects were significantly older, less likely to have APAP overdose, and had a lower overall 3-week survival compared to anti-HEV IgG- subjects (63% vs. 70%; P = 0.018). CONCLUSION: Acute HEV infection is very rare in adult Americans with ALF (i.e., 0.4%) and could not be implicated in any indeterminate, autoimmune, or pregnancy-related ALF cases. Past exposure to HEV with detectable anti-HEV IgG was significantly more common in the ALF patients compared to the general U.S. POPULATION: (Hepatology 2016;64:1870-1880).

The Epidemiology of Cirrhosis in the United States: A Population-based Study.

BACKGROUND AND AIMS: Liver cirrhosis is an important public health concern in the United States and a significant source of morbidity and mortality. However, the epidemiology of cirrhosis is incompletely understood. The aims of this study were to estimate the prevalence of cirrhosis in the general US population, determine characteristics of affected Americans with a focus on health disparities, and calculate excess mortality attributable to cirrhosis. METHODS: National Health And Nutrition Examination Survey data conducted between 1999 and 2010 were used to estimate cirrhosis prevalence and factors associated with cirrhosis. The National Center for Health Statistics-linked death certificate data from the National Death Index were linked to the National Health And Nutrition Examination Survey database for the years 1999 to 2004, and attributable mortality was calculated using propensity score adjustment. Cirrhosis was ascertained by aspartate aminotransferase-to-platelet ratio of >2 and abnormal liver function tests. RESULTS: The prevalence of cirrhosis in the United States was approximately 0.27%, corresponding to 633,323 adults. Sixty-nine percent reported that they were unaware of having liver disease. The prevalence was higher in non-Hispanic blacks and Mexican Americans, those living below the poverty level, and those with less than a 12th grade education. Diabetes, alcohol abuse, hepatitis C and B, male sex, and older age were all independently associated with cirrhosis, with a population attributable fraction of 53.5% from viral hepatitis (mostly hepatitis C), diabetes, and alcohol abuse. Mortality was 26.4% per 2-year interval in cirrhosis compared with 8.4% in propensity-matched controls. CONCLUSIONS: The prevalence of cirrhosis is higher than previously estimated. Many cases may be undiagnosed, and more than half are potentially preventable by controlling diabetes, alcohol abuse, and viral hepatitis. Public health efforts are needed to reduce this disease burden, particularly among racial/ethnic minorities and individuals at lower socioeconomic status.

Effectiveness of hepatitis B treatment in clinical practice.

It is important to examine the effectiveness of current therapies for chronic hepatitis B in clinical practice, given the therapeutic advances over the past 15 years. A 2010 Institute of Medicine report on hepatitis and liver cancer stated that the public and health care providers have a lack of knowledge and awareness about viral hepatitis, and that there is a gap between medical innovation and community care. We review the efficacy of hepatitis B treatment, based on results from clinical trials, and discuss the effectiveness of these treatments in clinical practice. We also discuss why having efficacious treatments alone would have a small impact on the global health burden of hepatitis B, and highlight the importance of educating the public and the medical community and coordination of care.