Mesenchymal stem cell-derived extracellular vesicles for the treatment of acute rejection in pediatric and adult bowel transplant.

Mesenchymal stem cells are under investigation as a novel therapy to treat solid organ transplant rejection. However, significant hurdles have limited their use in humans. Mesenchymal stem cell-derived extracellular vesicles address many of these shortcomings but have not been investigated clinically. Here we report our experience treating two patients with graft rejection and inflammation following bowel transplant using mesenchymal stem cell-derived extracellular vesicles.

Trends in the Prevalence of Hepatitis C Virus Infection based on the Insurance Status in the United States from 2013 to 2018.

BACKGROUND & AIMS: With the recent improvement in the treatment of hepatitis C virus (HCV) infection, a better understanding of the infection burden is needed. We aimed to (a) estimate the trends in the national prevalence of HCV infection based on the type of health insurance coverage and (b) identify at-risk populations for HCV infection in the United States (US) general population. METHODS: Population-based analyses using the National Health and Nutrition Examination Survey (2013-2018) were performed with a focus on HCV infection. We analysed the prevalence of HCV infection based on the health insurance status before the direct-acting antiviral (DAA) era (2013-2014) and during the DAA era (2015-2018). RESULTS: The age-adjusted prevalence of active HCV infection (HCV RNA [+]) was 0.92% (95% confidence interval, 0.71%-1.19%) in the US non-institutionalized civilian population. Although the prevalence of active HCV infection has remained stable, the prevalence of resolved HCV infection has increased after the introduction of DAA. In terms of health insurance coverage, the prevalence of active HCV infection decreased, and the prevalence of resolved HCV infection increased among individuals who had health insurance, especially private health insurance. The independent risk factors of active HCV infection were 40-69 years group, male, less than high school education, unmarried, below poverty status, being born in the US, history of blood transfusion and not having private health insurance. CONCLUSION: The burden of active HCV infection has decreased among individuals who had health insurance, especially private health insurance, during the DAA era.

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.

Temporal trends in disease presentation and survival of patients with hepatocellular carcinoma: A real-world experience from 1998 to 2015.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the few cancers whose incidence continues to increase. The goal of the current study was to investigate the presentation and survival trends of patients with HCC presenting to a university hospital between 1998 and 2015. METHODS: Study data were ascertained by individual chart review with survival data also supplemented by National Death Index query up to December 31, 2015. Patients were divided into three 6-year groups by diagnosis date (1998-2003, 2004-2009, and 2010-2015). RESULTS: A total of 2106 consecutive patients with HCC were included. The majority of patients had either hepatitis C (56.7%) or hepatitis B (22.1%), but cases of nonalcoholic steatohepatitis HCC increased by 68% over the most recent time period. Screening/surveillance identified 61% of HCC cases, but only 31% of these patients underwent curative treatment, which did not increase significantly over time. The overall median survival was 29.8 months (2.48 years) and without improvement over time. On multivariable analysis, Asian or Hispanic ethnicity, meeting Milan criteria, and receiving any of the standard HCC treatments were found to be significantly associated with improved survival, but diagnosis time period and liver disease etiology were not. CONCLUSIONS: Over the last 18 years, the percentage of cases of nonalcoholic steatohepatitis HCC has increased but not overall survival. It is interesting to note that only 31% of patients with HCC identified via screening/surveillance received any curative treatment. Further research is needed to better understand the barriers to curative care for patients with HCC and the causes of the lack of improvement in survival in the more recent patient cohort. Cancer 2018;124:2588-98. © 2018 American Cancer Society.

Increased Prevalence of Metabolic Risk Factors in Asian Americans With Hepatocellular Carcinoma.

BACKGROUND: We used metabolic risk factors to estimate the prevalence and clinical significance of nonalcoholic fatty liver disease in Asian Americans with hepatocellular carcinoma (HCC). METHODS: This is a retrospective cohort study of 824 consecutive Asian HCC patients at Stanford University Medical Center from 1998 to 2015. Patients were subdivided as: Chinese, other East Asian (Japanese and Korean), South East Asian (Vietnamese, Thai, and Laotian), Maritime South East Asian (MSEA: Malaysian, Indonesian, Filipino, and Singaporean), and South West Asian (Indian, Pakistani, and Middle Eastern). Metabolic risk factors studied were body mass index, hypertension, type II diabetes, and hyperlipidemia. RESULTS: Most patients were male (76%) with mean age 63 years. Metabolic risk factors were highly prevalent on presentation and increased over time (P<0.001), as did the prevalence of cryptogenic HCC (P<0.004). Compared with other Asian subgroups, MSEAs had the highest body mass index (26.3) and higher rates of type II diabetes (44% vs. 23% to 35%, P=0.004), hypertension (59% vs. 38% to 55%, P=0.04), and cryptogenic HCC (15% vs. 4% to 10%, P=0.01). They were more likely to be symptomatic on presentation (44% vs. 32% to 58%, P=0.07), less likely to present within Milan criteria (34% vs. 35% to 63%, P<0.0001), and trended toward decreased 10-year survival rates compared with other ethnic subgroups (9% vs. 25% to 32%, P=0.07). CONCLUSIONS: Metabolic risk factors were increasingly prevalent among Asian Americans with HCC. MSEAs, who had the highest incidence of these risk factors, had more advanced tumor stage and trended toward worse survival.

Alcohol Use in Liver Transplant Recipients With Alcohol-related Liver Disease: A Comparative Assessment of Relapse Prediction Models.

BACKGROUND: The selection of liver transplant (LT) candidates with alcohol-related liver disease (ALD) is influenced by the risk of alcohol relapse (AR), yet the ability to predict AR is limited. We evaluate psychosocial factors associated with post-LT AR and compare the performance of high-risk alcoholism risk (HRAR), sustained alcohol use post-LT (SALT), and the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) scores in predicting relapse. METHODS: A retrospective analysis of ALD patients undergoing LT from 2015 to 2021 at a single US transplant center was performed. Risk factors associated with post-LT AR were evaluated and test characteristics of 3 prediction models were compared. RESULTS: Of 219 ALD LT recipients, 23 (11%) had AR during a median study follow-up of 37.5 mo. On multivariate analysis, comorbid psychiatric illness (odds ratio 5.22) and continued alcohol use after advice from a health care provider (odds ratio 3.8) were found to be significantly associated with post-LT AR. On sensitivity analysis, SIPAT of 30 was optimal on discriminating between ALD LT recipients with and without post-LT AR. SIPAT outperformed both the HRAR and SALT scores (c-statistic 0.67 versus 0.59 and 0.62, respectively) in identifying post-LT AR. However, all scores had poor positive predictive value (<25%). CONCLUSIONS: AR after LT is associated with comorbid psychiatric illness and lack of heeding health care provider advice to abstain from alcohol. Although SIPAT outperformed the HRAR and SALT scores in predicting AR, all are poor predictors. The current tools to predict post-LT AR should not be used to exclude LT candidacy.

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.

Predictors of Outcomes of Patients Referred to a Transplant Center for Urgent Liver Transplantation Evaluation.

Liver transplantation (LT) is definitive treatment for end-stage liver disease. This study evaluated factors predicting successful evaluation in patients transferred for urgent inpatient LT evaluation. Eighty-two patients with cirrhosis were transferred for urgent LT evaluation from January 2016 to December 2018. Alcohol-associated liver disease was the common etiology of liver disease (42/82). Of these 82 patients, 35 (43%) were declined for LT, 27 (33%) were wait-listed for LT, 5 (6%) improved, and 15 (18%) died. Psychosocial factors were the most common reasons for being declined for LT (49%). Predictors for listing and receiving LT on multivariate analysis included Hispanic race (odds ratio [OR], 1.89; P = 0.003), Asian race (OR, 1.52; P = 0.02), non-Hispanic ethnicity (OR, 1.49; P = 0.04), hyponatremia (OR, 1.38; P = 0.04), serum albumin (OR, 1.13; P = 0.01), and Model for End-Stage Liver Disease (MELD)-Na (OR, 1.02; P = 0.003). Public insurance (i.e., Medicaid) was a predictor of not being listed for LT on multivariate analysis (OR, 0.77; P = 0.02). Excluding patients declined for psychosocial reasons, predictors of being declined for LT on multivariate analysis included Chronic Liver Failure Consortium (CLIF-C) score >51.5 (OR, 1.26; P = 0.03), acute-on-chronic liver failure (ACLF) grade 3 (OR, 1.41; P = 0.01), hepatorenal syndrome (HRS) (OR, 1.38; P = 0.01), and respiratory failure (OR, 1.51; P = 0.01). Predictors of 3-month mortality included CLIF-C score >51.5 (hazard ratio [HR], 2.52; P = 0.04) and intensive care unit (HR, 8.25; P < 0.001). Conclusion: MELD-Na, albumin, hyponatremia, ACLF grade 3, HRS, respiratory failure, public insurance, Hispanic race, Asian race, and non-Hispanic ethnicity predicted liver transplant outcome. Lack of psychosocial support was a major reason for being declined for LT. The CLIF-C score predicted being declined for LT and mortality.

Optimizing the Nutritional Support of Adult Patients in the Setting of Cirrhosis.

AIM: The aim of this work is to develop a pragmatic approach in the assessment and management strategies of patients with cirrhosis in order to optimize the outcomes in this patient population. METHOD: A systematic review of literature was conducted through 8 July 2017 on the PubMed Database looking for key terms, such as malnutrition, nutrition, assessment, treatment, and cirrhosis. Articles and studies looking at associations between nutrition and cirrhosis were reviewed. RESULTS: An assessment of malnutrition should be conducted in two stages: the first, to identify patients at risk for malnutrition based on the severity of liver disease, and the second, to perform a complete multidisciplinary nutritional evaluation of these patients. Optimal management of malnutrition should focus on meeting recommended daily goals for caloric intake and inclusion of various nutrients in the diet. The nutritional goals should be pursued by encouraging and increasing oral intake or using other measures, such as oral supplementation, enteral nutrition, or parenteral nutrition. CONCLUSIONS: Although these strategies to improve nutritional support have been well established, current literature on the topic is limited in scope. Further research should be implemented to test if this enhanced approach is effective.

Pregnancy-Associated Plasma Protein A Levels in Late First Trimester Pregnancies with Small-for-Gestational Age Neonates: A Prospective Case-Control Study.

OBJECTIVE: We aimed to investigate the association of pregnancy associated plasma protein A (PAPP-A) levels in late first trimester with small for gestational age (SGA) neonates and adverse pregnancy outcomes in a low-income setting. METHODS: The inclusion criteria were late first trimester (11-13 + 6 weeks) women with singleton and non-anomalous pregnancy. Enrolled participants were sampled for PAPP-A and prospectively followed up for delivery outcome and antenatal complications. A multiple of median (MoM) was calculated and statistically compared between groups. RESULTS: Out of total 284 subjects, 14.54% delivered SGA babies and formed cases (Group A), 66.5% delivered appropriate for gestational age (AGA) neonates with uneventful antenatal period (controls, Group B), and 19.3% were AGA group with adverse pregnancy complications (Group C). The late first trimester median PAPP-A MoM was significantly lower (0.61) in Group A compared to Group B (1.47). Using receiver operating characteristic (ROC) curve for PAPP-A MoM, optimal cutoff value was found at 0.45 MoM, with positive predictive value of 56.2%, specificity of 92.6% and sensitivity of 45%. The median interquartile range (IQR) of PAPP-A MoM value in Group C in comparison with Group B was significantly lower except for abruption. At PAPP-A MoM cutoff value <1, <0.8, <0.6 and <0.4, the odds ratio for adverse pregnancy outcome was 8.30, 7.29, 10.97 and 10.60, respectively, indicating an inverse relationship. CONCLUSION: With 0.45 MoM cutoff of PAPP-A, the detection rate, specificity and positive predictive value for SGA were 45, 92.6 and 56.2%, respectively. As PAPP-A MoM values decreased, the odds ratio of having adverse pregnancy outcomes increased.

Sofosbuvir Use in the Setting of End-stage Renal Disease: A Single Center Experience.

Background and Aims: Patients with chronic hepatitis C (CHC) and end-stage renal disease (ESRD) who are dialysis-dependent form a unique group, in which safety, tolerability and efficacy of sofosbuvir (SOF)-based direct-acting antivirals (DAAs) need further evaluation. Methods: We performed a retrospective analysis of 14 patients with CHC and ESRD on dialysis who received 15 courses of SOF-based therapy. We evaluated dose escalation to standard-dose SOF in this proof-of-principle experience. Results: Sustained virological response (defined as undetectable viral load at 12 weeks, SVR-12) was achieved in 13 out of the 15 (86.7%) treatment courses. Seven (46.6%) patients received reduced half dose as conservative proof-of-principal to mitigate potential toxicity. In 13 out of 15 treatment courses, patients completed the designated treatment duration. One patient was treated twice and developed SVR-12 with the retreatment. One patient was lost to follow-up and counted as a non-responder. Premature discontinuations were not due to DAA-related adverse effects. There were no reports of severe adverse effects or drug interactions. Conclusion: We treated CHC patients with ESRD using dose escalation to standard-dose SOF in this proof-of-principle experience and achieved SVR rates comparable to general population.

Real-world experience with interferon-free, direct acting antiviral therapies in Asian Americans with chronic hepatitis C and advanced liver disease.

Real-life data on interferon (IFN)-free direct acting antiviral (DAA) therapies for chronic hepatitis C (CHC) is limited for Asian Americans.To evaluate sustained virologic response (SVR) and adverse events (AE) in Asian Americans treated with sofosbuvir (SOF)-based, IFN-free DAA therapies.This is a retrospective study of 110 consecutive Asian Americans with HCV genotypes 1 to 3 or 6 treated with IFN-free SOF-based regimens for 8 to 24 weeks between February 2014 and March 2016 at a university center in Northern California.Mean age was 63 ±â€Š12 years, mean BMI was 25 ±â€Š6 (kg/m), and about half (52%) were male. Most patients were infected with HCV genotype 1 (HCV-1, 64%), followed by HCV-2 (14%), HCV-6 (13%), and HCV-3 (8%). Half had cirrhosis, and the majority of these (67%) had decompensation. Overall SVR12 was 93% (102/110), and highest among patients without cirrhosis, liver transplant, or HCC (100%, 37/37). SVR12 was lower among patients with HCC (82%, 14/17), decompensated cirrhosis (84%, 31/37), or liver transplant (89%, 17/19), regardless of treatment and genotype. Most common AEs were anemia (25%), fatigue (20%), and headache (12%). Anemia was highest in patients receiving SOF/RBV (67%). There was 1 treatment-unrelated serious adverse effect (SAE). There were 7 dose reductions due to anemia or fatigue from RBV and 2 treatment discontinuations due to fatigue or loss of insurance authorization.This real-life cohort of Asian American CHC patients treated with IFN-free SOF-based therapies showed high overall treatment response and good tolerability, despite very high rates of advanced disease and prior treatment failure.

Fixed-dose combination of sofosbuvir and ledipasvir for the treatment of chronic hepatitis C genotype 1.

INTRODUCTION: The recent October 2014 approval of the fixed dose combination (FDC) of the NS5B polymerase inhibitor sofosbuvir (SOF) and the NS5A inhibitor ledipasvir (LDV) for the treatment of treatment-naive and -experienced HCV genotype 1a/1b (HCV-1) has marked a new era of IFN and ribavirin free treatment for chronic hepatitis C. SOF/LDV combination is approved for 12 weeks in treatment-naive patients with and without cirrhosis. For treatment-experienced patients, it is approved for 12 weeks in patients without cirrhosis but for 24 weeks in patients with cirrhosis. A shorter 8-week course of treatment can be considered for treatment-naive patients who have pretreatment HCV RNA of < 6 million IU/ml and do not have cirrhosis. AREAS COVERED: The purpose of this synopsis is to review the pharmacotherapy and results of pivotal clinical trials for SOF/LDV as the current standard-of-care for HCV-1 patients. We also briefly discuss emerging data with SOF/LDV for certain special populations. Preliminary data is also emerging for HCV genotypes non-1, but their discussion is beyond the scope of this synopsis. The review was done based on data from Phase I, II and III published studies as well as data presented at major national and international meetings. EXPERT OPINION: The FDC of LDV (90 mg) and SOF (400 mg) has a sustained virologic response of approximately 96% when given as a once-a-day pill for 3 months to both treatment-naive and -experienced HCV-1 patients with the exception of prior null responders with cirrhosis. The latter group of patients also achieves high sustained virologic response of 95% but with therapy for 24 weeks. In addition, emerging data suggest that this FDC regimen may be effective in the treatment of HCV-1 co-infected patients with HIV, HCV-1 and -4, patients with cirrhosis and hepatic decompensation and those with post-liver transplant HCV recurrence.

Advances in cirrhosis: Optimizing the management of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a major complication of cirrhosis resulting in significant socioeconomic burden, morbidity, and mortality. HE can be further subdivided into covert HE (CHE) and overt HE (OHE). CHE is a subclinical, less severe manifestation of HE and requires psychometric testing for diagnosis. Due to the time consuming screening process and lack of standardized diagnostic criteria, CHE is frequently underdiagnosed despite its recognized role as a precursor to OHE. Screening for CHE with the availability of the Stroop test has provided a pragmatic method to promptly diagnose CHE. Management of acute OHE involves institution of lactulose, the preferred first-line therapy. In addition, prompt recognition and treatment of precipitating factors is critical as it may result in complete resolution of acute episodes of OHE. Treatment goals include improvement of daily functioning, evaluation for liver transplantation, and prevention of OHE recurrence. For secondary prophylaxis, intolerance to indefinite lactulose therapy may lead to non-adherence and has been identified as a precipitating factor for recurrent OHE. Rifaximin is an effective add-on therapy to lactulose for treatment and prevention of recurrent OHE. Recent studies have demonstrated comparable efficacy of probiotic therapy to lactulose use in both primary prophylaxis and secondary prophylaxis.