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BACKGROUND & AIMS The epidemiology of hepatitis B virus (HBV) infection differs between Asians and non-Asians, but little is known regarding the effect of ethnicity on outcomes of HBV-related hepatocellular carcinoma (HCC). We aim to characterize the presentation and survival outcomes in Asian and non-Asian patients with HBV-related HCC. METHODS We analyzed the baseline characteristics and long-term survival of 613 Asian and 410 non-Asian patients with HBV-related HCC from three US and one Spanish centre. RESULTS Overall, non-Asian patients were more likely to have HIV or hepatitis C co-infection, cirrhosis, decompensated liver disease and advanced BCLC stage (all P ≤ .04). Compared with Asians, non-Asians were more likely to be listed for transplantation (P

We conducted a multicenter retrospective cohort study of metabolic dysfunction‐associated hepatocellular carcinoma. In this cohort, cirrhosis was not associated with poorer survival, while history of liver imaging was., Metabolic‐associated fatty liver disease (MAFLD) is a major cause of liver‐related complications, including hepatocellular carcinoma (HCC). While MAFLD‐related HCC is known to occur in the absence of cirrhosis, our understanding of MAFLD‐related HCC in this setting is limited. Here, we characterize MAFLD‐related HCC and the impact of cirrhosis and screening on survival. This was a multicenter, retrospective, cohort study of MAFLD‐related HCC. MAFLD was defined based on the presence of race‐adjusted overweight, diabetes, or both hypertension and dyslipidemia in the absence of excess alcohol use or other underlying cause of liver disease. The primary outcome of interest was overall survival, and the primary dependent variables were cirrhosis status and prior HCC screening. We used Kaplan‐Meier methods to estimate overall survival and Cox proportional hazards models and random forest machine learning to determine factors associated with prognosis. This study included 1,382 patients from 11 centers in the United States and East/Southeast Asia. Cirrhosis was present in 62% of patients, but under half of these patients had undergone imaging within 12 months of HCC diagnosis. Patients with cirrhosis were more likely to have early stage disease but less often received curative therapy. After adjustment, cirrhosis was not associated with prognosis, but the presence of cancer‐related symptoms at diagnosis was associated with poorer prognosis. Conclusion: Cirrhosis was not associated with overall survival in this cohort of MAFLD‐related HCC, while diagnosis in the presence of symptoms was associated with poorer prognosis. The HCC surveillance rate in patients with MAFLD‐related HCC was disappointingly low in a multicenter cohort.

The clinical presentation and survival of hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) eradication as compared to HCC in viremic patients are not well characterized. We aimed to investigate the characteristics and survival between HCV patients with and without viremia at HCC diagnosis.: We retrospectively analyzed overall survival outcomes in 1389 HCV-related HCC patients, including 301 with HCC developed after HCV eradication (post-SVR HCC) and 1088 with HCV viremia at HCC diagnosis (viremic HCC). We also evaluated overall survival in the two groups using propensity score-matching methods.: At HCC diagnosis, post-SVR HCC patients were older, less obese, less likely cirrhotic, with better liver function, lower alfa-fetoprotein levels, earlier BCLC stages, and higher rate of treatment with surgery. Overall, post-SVR HCC patients had higher median survival than viremic patients (153.3 vs. 55.6 months, p &lt, 0.01), but post-SVR HCC was not independently associated with survival on multivariate analysis (adjusted HR: 1.05, 95% CI: 0.76–1.47). However, on sub-analysis, viremic HCC patients who subsequently received anti-viral treatment and achieved SVR had higher median survival than post-SVR HCC patients (p &lt, 0.01). Viremic HCC with subsequent SVR was also significantly associated with lower mortality as compared to post-SVR HCC (adjusted HR: 0.18, 95% CI: 0.11–0.29). In addition, we observed similar findings in our analysis of the propensity score-matched cohorts.: The advantages in clinical and tumor characters at HCC diagnosis determined the better overall survival of post-SVR HCC patients, however, HCV eradication after HCC development was also associated with improved survival.

BACKGROUND AND AIMS Real-world data for treatment effectiveness and renal outcomes in chronic hepatitis B (CHB) patients who were switched to the new and safer prodrug tenofovir alafenamide (TAF) from tenofovir disoproxil fumarate (TDF) are limited. Therefore, we aimed to evaluate treatment and renal outcomes of this population. APPROACH AND RESULTS We analyzed 834 patients with CHB previously treated with TDF for ≥12 months who were switched to TAF in routine practice at 13 US and Asian centers for changes in viral (HBV DNA 0.44) or mean eGFR (P > 0.83, adjusted for age, sex, baseline eGFR, and diabetes, hypertension, or cirrhosis by generalized linear modeling) remained stable. However, among those with baseline eGFR

A 54-year-old woman presented to the emergency department with several days of visual disturbance. Her medical history included alcoholic liver cirrhosis with portosystemic encephalopathy (PSE), chronic hyponatremia, and chronic pain on opioids. She had a recent hospitalization for hepatic encephalopathy, but presented now with 5 days of new visual disturbance described mostly as an inability to see and impaired ability to focus. The patient's husband corroborated that this episode was different from her past episodes of PSE and noted that she seemed unable to attend to him during their conversations and he wondered if she was looking at things that were not present. Typically her PSE episodes were characterized by lethargy, confusion, and disorientation, whereas now she was alert, oriented to herself and recognized familiar people, and was able to have a conversation despite her visual complaints.

AIM To assess the real-world effectiveness and cost of simeprevir (SMV), and/or sofosbuvir (SOF)-based therapy for chronic hepatitis C virus (HCV) infection. METHODS The real-world performance of patients treated with SMV/SOF ± ribavirin (RBV), SOF/RBV, and SOF/RBV with pegylated-interferon (PEG) were analyzed in a consecutive series of 508 patients with chronic HCV infection treated at a single academic medical center. Patients with genotypes 1 through 4 were included. Rates of sustained virological response - the absence of a detectable serum HCV RNA 12 wk after the end of treatment [sustained virological response (SVR) 12] - were calculated on an intention-to-treat basis. Costs were calculated from the payer’s perspective using Medicare/Medicaid fees and Redbook Wholesale Acquisition Costs. Patient-related factors associated with SVR12 were identified using multivariable logistic regression. RESULTS SVR12 rates were as follows: 86% (95%CI: 80%-91%) among 178 patients on SMV/SOF ± RBV; 62% (95%CI: 55%-68%) among 234 patients on SOF/RBV; and 78% (95%CI: 68%-86%) among 96 patients on SOF/PEG/RBV. Mean costs-per-SVR12 were $174442 (standard deviation: ± $18588) for SMV/SOF ± RBV; $223003 (± $77946) for SOF/RBV; and $126496 (± $31052) for SOF/PEG/RBV. Among patients on SMV/SOF ± RBV, SVR12 was less likely in patients previously treated with a protease inhibitor [odds ratio (OR): 0.20, 95%CI: 0.06-0.56]. Higher bilirubin (OR: 0.47, 95%CI: 0.30-0.69) reduced the likelihood of SVR12 among patients on SOF/RBV, while FIB-4 score ≥ 3.25 reduced the likelihood of SVR12 (OR: 0.18, 95%CI: 0.05-0.59) among those on SOF/PEG/RBV. CONCLUSION SVR12 rates for SMV and/or SOF-based regimens in a diverse real-world population are comparable to those in clinical trials. Treatment failure accounts for 27% of costs.

African-Americans (AA) have a higher incidence of hepatocellular carcinoma (HCC) and lower survival. We characterized survival rates and clinical features associated with survival in AA vs. Caucasians with HCC over the past two decades. HCC patients from three US medical centers were matched by year of diagnosis (1991–2016): AA (n = 578)/Caucasian (n = 578) and placed in one of two groups—HCC diagnosed prior to 2010 or 2010 and after. Data were obtained from chart review and the National Death Index. Multivariate and survival analysis controlling for key predictors were conducted. Prior to 2010, there was no difference in survival between Caucasians and AA (p = 0.61). After 2010, AA patients had poorer survival compared to Caucasians (35% vs. 44%, respectively, p = 0.044). Over time, survival improved for Caucasians (32% before 2010 vs. 44% after 2010, p = 0.003), but not AA (36% vs. 35%, p = 0.50). AA on presentation (in the after 2010 cohort) were more likely to have BCLC (Barcelona Clinic Liver Cancer) stage C (24% vs. 15%, p = 0.010) and less likely to receive treatment (85% vs. 93%, p = 0.002) compared to matched Caucasians. BCLC beyond stage A (aHR: 1.75, 95% CI: 1.26–2.43, p = 0.001) and child’s class C (aHR 2.05, 95% CI: 1.23–3.41, p = 0.006) were the strongest predictors of mortality, while race was not. African-Americans presented with more advanced HCC and had poorer survival compared to Caucasians after 2010. Tumor stage was an independent predictor of mortality, but ethnicity was not. Further efforts are needed to improve early HCC diagnosis for AA.

Immune checkpoint blockade therapies have been shown to induce potent and durable anti-tumor immunity in many cancer types. Nevertheless, not all patients benefit from immunotherapy, and immune-related adverse events remain a problem. Recently, it has been demonstrated that Antibody Drug Conjugates (ADCs) are not only capable of killing cancer cells but also can act to induce the immunogenic cell death of tumor cells as well as directly activate dendritic cells. These results provided a rationale to combine ADCs with immunotherapy to enhance the potential of immune checkpoint blockade therapies in a broader population of patients. CytomX Therapeutics has developed a new class of antibodies called Probody™ therapeutics, designed to widen the therapeutic window by minimizing binding to target in healthy tissue while being specifically activated in the tumor microenvironment (TME) by tumor-associated proteases. Probody technology has been evaluated in preclinical studies in several antibody formats, with efficacy and increased safety windows observed for Probody therapeutics targeting the PD-1 pathway, Probody drug conjugates (PDCs) targeting highly expressed tumor antigens, and T-cell engaging bispecific Probody therapeutics. Here we extend our evaluation of the Probody platform to the combination of CX-2009, an investigational PDC targeting human CD166, with an investigational Probody therapeutic targeting PD-1. To evaluate the anti-tumor activity of PDC CX-2009 in a syngeneic mouse model, human CD166 was overexpressed on the surface of the CT-26 murine colon carcinoma cell line. The combination treatment of CX-2009 with a surrogate mouse anti-PD-1 Probody molecule significantly inhibited tumor growth in human CD166 positive CT-26 tumor-bearing mice as compared to CX-2009 or anti-PD-1 Probody molecule alone. Tumor rejection is partially dependent on CD8+ T cells as illustrated by the evidence of a CD8+ memory T cell response in a re-challenge assay, and a reduced activity of CX-2009 alone or in combination with a mouse anti-PD-1 Probody molecule after CD8+ T cell depletion. The immunogenic potential of CX-2009 was further evaluated in multiple in vitro assays using human cancer cells and human PBMCs. In contrast to its cytotoxic activity towards CD166+ tumor cells, CX-2009 spares T cells and may enhance T cell priming. These preclinical data demonstrate the potential utility of a combination of PDC CX-2009 with a Probody therapeutic targeting the PD-1 pathway. Generally, these data highlight the potential to combine ADCs or PDCs with immune checkpoint blockade therapies. PROBODY is a trademark of CytomX Therapeutics, Inc. Citation Format: Erwan Le Scolan, Tiffany Tse, Michael Krimm, Will Garner, Hikmat Assi, Jennifer Razo, Laurie Wong, Kenneth Wong, Victoria Singson, Jennifer Leong, Linnea Diep, Jennifer Richardson, Siew Schleyer, Dylan Daniel, Marcia Belvin, Michael Kavanaugh. A probody drug conjugate targeting CD166 (ALCAM) enhances preclinical antitumor activity of a probody therapeutic targeting PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3202.

Most studies have shown that lamivudine (LAM) prophylaxis is sufficient to prevent hepatitis B virus (HBV) transmission in recipients of hepatitis B core antibody positive (HBcAb(+) ) allografts. However, de novo hepatitis B (DNHB) is known to occur in this patient population. Herein, we report a case series of four liver transplant recipients who developed DNHB after receiving HBcAb(+) allografts due to acquisition of LAM resistance mutations, suggesting that LAM prophylaxis may be suboptimal. A retrospective chart review was performed of all adult liver transplants performed at Mount Sinai from 2001 to 2010. A total of 79 patients received HBcAb(+) allografts for non-hepatitis B-related liver disease. Of these 79 recipients, four patients developed DNHB and were found to have documented LAM resistance. With the increasing use of HBcAb(+) donor livers, we suspect that there will also be a growing number of cases of DNHB due to acquisition of LAM resistance. We suggest that other agents, such as entecavir or tenofovir, be considered for use as prophylaxis in this patient population to decrease this risk.

Approximately 240 million people are chronically infected with hepatitis B. The implementation of rigorous vaccination programs has led to an overall decrease in the prevalence of this disease worldwide but this may also have led to emergence of viral mutations that can escape the protection of hepatitis B surface antibody. As this phenomenon is increasingly recognized, concern for transmission to vaccinated individuals has also been raised. Herein, we describe two cases where the suspected presence of a hepatitis B surface antigen escape mutation impacted the decision to initiate early antiviral therapy, as well as provide a brief review of these mutations. Our findings described here suggest that a lower threshold for initiating therapy in these individuals should be considered in order to reduce the risk of transmission, as vaccination does not provide protection.

To determine the safety profile of new hepatitis C virus (HCV) treatments in liver transplant (LT) recipients with recurrent HCV infection.Forty-two patients were identified with recurrent HCV infection that underwent LT at least 12 mo prior to initiating treatment with a Sofosbuvir-based regimen during December 2013-June 2014. Cases were patients who experienced hepatic decompensation and/or serious adverse events (SAE) during or within one month of completing treatment. Controls had no evidence of hepatic decompensation and/or SAE. HIV-infected patients were excluded. Cumulative incidence of decompensation/SAE was calculated using the Kaplan Meier method. Exact logistic regression analysis was used to identify factors associated with the composite outcome.Median age of the 42 patients was 60 years [Interquartile Range (IQR): 56-65 years], 33% (14/42) were female, 21% (9/42) were Hispanic, and 9% (4/42) were Black. The median time from transplant to treatment initiation was 5.4 years (IQR: 2.1-8.8 years). Thirteen patients experienced one or more episodes of hepatic decompensation and/or SAE. Anemia requiring transfusion, the most common event, occurred in 62% (8/13) patients, while 54% (7/13) decompensated. The cumulative incidence of hepatic decompensation/SAE was 31% (95%CI: 16%-41%). Risk factors for decompensation/SAE included lower pre-treatment hemoglobin (OR = 0.61 per g/dL, 95%CI: 0.40-0.88, P0.01), estimated glomerular filtration rate (OR = 0.95 per mL/min per 1.73 m(2), 95%CI: 0.90-0.99, P = 0.01), and higher baseline serum total bilirubin (OR = 2.43 per mg/dL, 95%CI: 1.17-8.65, P0.01). The sustained virological response rate for the cohort of 42 patients was 45%, while it was 31% for cases.Sofosbuvir/ribavirin will continue to be used in the post-transplant population, including those with HCV genotypes 2 and 3. Management of anemia remains an important clinical challenge.

Background Spontaneous bacterial peritonitis (SBP) carries appreciable morbidity and mortality in the pre-liver transplant (LT) setting. However, the occurrence of SBP and its consequences in the post-LT setting have not been well characterized. Methods This is a retrospective study of SBP occurring in post-LT patients between January 2007 and December 2012. Outcomes were compared to a cohort of post-LT patients with allograft failure and ascites without SBP. Results The most common indication for liver transplantation in this cohort was hepatitis C. A total of 29 episodes of SBP in 21 patients were identified. Escherichia coli (19%) and Klebsiella pneumoniae (10%) were the most frequent pathogens identified. Six patients died during their first episode of SBP. Ten patients were eventually listed for liver re-transplantation (re-LT) after their first episode of SBP; 5 of these patients were transplanted and the other 5 died. Of the 5 who were transplanted, 2 died shortly after re-transplant, and 3 are still alive. The cause of death in the majority of patients was infection (83.3%). The median time from onset of ascites to death was 214 days (range: 10-1085 days) and from the first episode of SBP to death was 50.5 days (range: 4-549 days). In contrast, the median time from onset of ascites to death in patients with allograft failure and ascites without SBP was 331.5 days (45-2400 days). Conclusions Allograft failure with ascites is a poor prognostic factor and these patients should be considered high risk for re-LT. SBP may accelerate the time to mortality.

Most studies have shown that lamivudine (LAM) prophylaxis is sufficient to prevent hepatitis B virus (HBV) transmission in recipients of hepatitis B core antibody positive (HBcAb(+) ) allografts. However, de novo hepatitis B (DNHB) is known to occur in this patient population. Herein, we report a case series of four liver transplant recipients who developed DNHB after receiving HBcAb(+) allografts due to acquisition of LAM resistance mutations, suggesting that LAM prophylaxis may be suboptimal. A retrospective chart review was performed of all adult liver transplants performed at Mount Sinai from 2001 to 2010. A total of 79 patients received HBcAb(+) allografts for non-hepatitis B-related liver disease. Of these 79 recipients, four patients developed DNHB and were found to have documented LAM resistance. With the increasing use of HBcAb(+) donor livers, we suspect that there will also be a growing number of cases of DNHB due to acquisition of LAM resistance. We suggest that other agents, such as entecavir or tenofovir, be considered for use as prophylaxis in this patient population to decrease this risk.

Alcoholic liver cirrhosis is the second most common indication for liver transplantation in the United States. Studies have shown that these patients do as well as those transplanted for nonalcoholic liver disease. Recently, transplantation of patients with alcoholic liver disease has come under closer scrutiny following an article in the New England Journal of Medicine demonstrating comparable outcomes and survival in patients transplanted for acute alcoholic hepatitis. This article reviews the literature and data on the evaluation and selection of patients with alcoholic cirrhosis for liver transplant, and discusses the most recent indication (once a contraindication), acute alcoholic hepatitis.

Sepsis is associated with an increase in circulating levels of bacterial endotoxin. Sepsis is a particularly serious problem in the geriatric population due to the associated high mortality rate. However, it remains unknown whether this phenomenon is related to an increase in apoptosis in splenic cells. To investigate this issue, male Fischer-344 rats (young, 3 months old; aged, 24 months old) were subjected to endotoxemia by injection of LPS. Splenic samples were collected 4 h thereafter. Apoptosis was determined by cleaved caspase-3 levels and TUNEL staining. The levels of proinflammatory mediators, TNF-alpha, IL-6 and high mobility group box-1 (HMGB-1), were also measured. Our results showed that, while splenic cell apoptosis increased in the young and aged rats with endotoxemia, the aged animals had much higher levels of apoptotic cell death. The elevated expression of cell cycle inhibitory protein P21 was also observed in the aged animals after treatment with LPS. Moreover, endotoxemia significantly increased TNF-alpha, IL-6 and HMGB-1. The accelerated apoptosis in the aged animals was correlated with significantly higher levels of TNF-alpha, IL-6 and HMGB-1. It is suggested that this accelerated rate of apoptosis contributes to age-related hyperinflammation in endotoxemia. To investigate the factors involving accelerated apoptosis in aged animals, we analyzed the Fas/Fas ligand (Fas-L) pathway. Our results showed that Fas and Fas-L gene expression was markedly higher in the spleen in the aged animals after LPS. Similarly, cleaved caspase-8 expression, a downstream element of Fas and Fas-L, was also significantly higher in the aged rats after LPS. Fas-L neutralizing antibodies markedly decreased apoptosis and proinflammatory cytokines in the aged animals after endotoxemia. Thus, there is substantial evidence that the Fas/Fas-L pathway may play an important role in LPS-induced accelerated apoptosis and hyperinflammation in aged animals.

Aims Sepsis is a major cause of morbidity and mortality in the elderly population. In prior studies, we have shown that in vivo, the inflammatory response in aged animals is exaggerated as compared to young animals and that this response likely accounts for the increased morbidity and mortality. Part of this uncontrolled inflammatory response in sepsis is due to the innate immune response. However, recent studies have shown that the pathogenesis of sepsis is much more complex. The adrenergic autonomic nervous system is now thought to play a key role in modulating the inflammatory response in sepsis. In this study, we hypothesize that not only is the innate immune response enhanced in response to lipopolysaccharide (LPS) in aged animals, but that the adrenergic nervous system also plays a role in the release of excess inflammatory cytokines. Main methods Male Fischer-344 rats (young: 3 months; aged: 24 months) were used. Endotoxemia was induced by intravenous injection of lipopolysaccharide (LPS, 15 mg/kg BW). Splenic tissues were harvested and mRNA and protein were extracted. The protein expression of CD14 and TLR4, key mediators of LPS in the innate response, as well as alpha-2A adrenergic receptor (α2A-AR) and phosphodiesterase 4D (PDE4D), as the means by which the autonomic nervous system exerts its effects were analyzed. Key findings Splenic tissue concentrations of α2A-AR, PDE4D, CD14, and TLR4 were significantly increased in septic aged rats as compared to aged sham rats and septic young rats. The increased expression of α2A-AR in septic aged rats was further confirmed by immunohistochemical staining of splenic tissues. Significance These data support the hypothesis that not only is the innate immune response increased in aged animals during sepsis, but that there is also an upregulated response of the adrenergic autonomic nervous system that contributes to excess proinflammatory cytokine release.

3 90-year-old woman was admitted for a 2-week history of fever and persistent peristomal leakage. A percutaneous enoscopic gastrostomy (PEG) was placed a year earlier as a result of ultiple strokes resulting in dysphagia. During the ensuing year, he gastrostomy tube was replaced multiple times at the bedside as result of minor complications. The physical exam revealed a acerated peristomal site with surrounding erythema, induration, nd serosanguineous drainage. The abdominal exam was otherise normal without evidence of obstruction. An upper endoscopy as performed for placement of a new PEG; however, on examiation, absence of the pyloric opening was noted (Figure A).1 urthermore, the PEG tube was extending from the gastrocutaneus site to the opposite wall, with torsion of the distal stomach Figure B). A subsequent gastrostomy tube study revealed contrast xtrusion into the duodenum, suggesting the balloon was inflated n the small bowel. It was suspected that as a result of persistent anipulation of the PEG tube, torsion of the distal stomach and uodenum ensued, with a resultant anatomic gastric outlet obtruction. The wound dehiscence and cellulitis were believed to be result of leakage of gastric secretions around the peristomal site aused by the obstruction. Repeat esophagogastroduodenoscopy fter deflation of the balloon bumper revealed normal anatomy. ntubation of the duodenum noted a clean based ulcer attributed o pressure necrosis from the inflated balloon. A replacement PEG ube was inserted through the tract and anchored securely to the bdominal wall without any complication. The localized wound nfection has since healed. PEG tube placement is a low-risk procedure routinely erformed for patients who are unable to take food orally. ommon indications for placement include neurologic conitions with associated impaired swallowing, oropharyngeal, aryngeal, and esophageal neoplasms, facial trauma, and the eed for supplemental feedings in patients with miscellaeous catabolic conditions. Overall, the complication rate anges from 3%–14%, and mortality approaches 1%.1 Various ajor and minor complications have been described in the iterature. Commonly encountered problems include pain at he insertion site, leakage around PEG tube, tube displaceent by patient or health care personnel, tube obstruction, nd local ulceration or wound infection.2 This case is an example of an anatomically created gastric outlet bstruction, without the typical symptoms of nausea, vomiting, nd distention. Two theories have been postulated to explain the bove. As described by Lamont and Rode,3 passage of a gastrosomy tube past the pylorus into the small bowel with insufflation f the balloon can result in fixation within the small bowel. The econd theory implicates migration of the PEG tube through the ylorus as a result of improper anchoring to the abdominal wall. ortunately in this patient, absence of obstruction at the distal tip f the gastrostomy tube allowed for unimpeded feedings, and the toma provided an exit for air release and excess gastric secretions.

A Case Report of Nephrotic Syndrome Due to Intake of Certolizumab Pegol in a Patient With Crohn's Disease