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Background and aims The burden of hepatocellular carcinoma (HCC) is substantial. To address gaps in HCC care, the American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) aimed to develop a standard set of process-based measures and patient-reported outcomes along the HCC care continuum. Approach and results We identified candidate process and outcomes measures for HCC care based on structured literature review. A 13-member panel with content expertise across the HCC care continuum evaluated candidate measures on importance and performance gap using a modified Delphi approach (two rounds of rating) to define the final set of measures. Candidate patient-reported outcomes (PRO) based on a structured scoping review were ranked by 74 patients with HCC across 7 diverse institutions. Out of 135 measures, 29 measures made the final set. These covered surveillance (6 measures), diagnosis (6 measures), staging (2 measures), treatment (10 measures), and outcomes (5 measures). Examples included the use of ultrasound (± alpha-fetoprotein [AFP]) every 6 months, need for surveillance in high-risk populations, diagnostic testing for patients with a new AFP elevation, multidisciplinary liver tumor board (MLTB) review of Liver Imaging-Reporting and Data System 4 lesions, standard evaluation at diagnosis, treatment recommendations based on Barcelona Clinic Liver Cancer staging, MLTB discussion of treatment options, appropriate referral for evaluation of liver transplantation candidacy, and role of palliative therapy. PROs include those related to pain, anxiety, fear of treatment, and uncertainty about the best individual treatment and the future. Conclusions The AASLD PMC has developed a set of explicit quality measures in HCC care to help bridge the gap between guideline recommendations and measurable processes and outcomes. Measurement and subsequent implementation of these metrics could be a central step in the improvement of patient care and outcomes in this high-risk population.

Cholangiocarcinoma (CCA) is a primary malignancy of the bile ducts with three anatomically and molecularly distinct entities: Intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA. As a result of phenotypic and anatomic differences they differ significantly with respect to management. For each type of CCA there have been significant changes in management over the last several years which will be discussed in this review. Although resection remains the standard of care for all types of CCA, liver transplantation has been established as curative treatment for selected patients with pCCA and is being evaluated for iCCA with early success. With respect to systemic therapy capecitabine is now first line adjuvant therapy for all biliary tract malignancies after curative intent resection. Progress in exploiting the pathologic mutations and molecular abnormalities has also yielded regulatory approval of targeted therapy for CCA in patients with acquired alterations in the fibroblast growth factor receptor. There is also increased consensus in managing malignant biliary obstruction associated with CCA where pre-operative biliary stenting is not beneficial while self-expanding metal stents have been shown to be superior to plastic stents in patients who are not surgical candidates.

This study describes the design of the TARGET‐hepatocellular carcinoma (HCC) cohort and descriptive characteristics of the patient population at diagnosis among those who were enrolled in the cohort across academic and community clinical centers. TARGET‐HCC is a 5‐year, longitudinal, observational cohort of patients with HCC receiving care in usual clinical practice. Redacted clinical information, obtained from medical records, captures the natural history and management of the disease, including the safety and efficacy of treatment interventions used in usual clinical practice. Patients can complete patient‐reported outcome measures and provide biological specimens for future translational studies. The TARGET‐HCC study includes adults with histologic, cytologic, or radiologic diagnosis of HCC from academic and community centers in both the United States and Europe. A total of 1,841 participants were enrolled between January 9, 2017, and July 23, 2019, at 67 sites in the United States and Europe. To date, the most common liver disease etiology in the cohort continues to be hepatitis C, although nearly half had a nonviral etiology, including alcohol‐related liver disease or nonalcoholic steatohepatitis. Most included patients were diagnosed at an early stage (Barcelona Clinic Liver Cancer Stage [BCLC] 0/A), but only approximately one third underwent curative treatment. Systemic therapy has been used in 7.3% of enrolled patients, including 45.7% of those with BCLC stage C tumors. Conclusion: Overall, the TARGET‐HCC cohort allows for the assessment of patient characteristics and investigation of new treatment paradigms and sequencing with existing agents as well as novel regimens for HCC., TARGET‐HCC is a 5‐year, longitudinal, observational cohort of patients with hepatocellular carcinoma receiving care in usual clinical practice. The objective of this manuscript is to describe the design of the TARGET‐HCC cohort and descriptive characteristics of the patient population at diagnosis across academic and community clinical centers.

Many patients are not candidates for liver transplant for non-tumor-related reasons including medical comorbidities and non-adherence. The prognosis of patients with hepatocellular carcinoma (HCC) who are not liver transplant candidates in the era of locoregional therapy (LRT) including y90 is not well defined. This study seeks to evaluate outcomes and the natural history of early-stage HCC in patients who were denied liver transplant listing due to non-tumor reasons and instead were treated with LRT. A retrospective evaluation was performed for all patients who completed liver transplant evaluation with their tumor within Milan criteria but were denied due to non-tumor reasons and were treated with LRT at a single tertiary referral center. The 61 patients included had a favorable overall survival, with a median survival 60.3 months (86.9% at 1 year and 52.7% at 5 years). Patients with Child–Pugh A cirrhosis (n = 34) had significantly longer overall survival compared to those with Child–Pugh B/C cirrhosis (median survival of 70.3 months versus 26.1 months, p = 0.005). Survival in patients with Child–Pugh A at 1, 3, and 5 years was 97%, 80%, and 73%, respectively, compared to 74%, 41%, and 31% in patients with Child–Pugh B/C. In a small single-center cohort, patients with HCC who were denied liver transplant due to non-tumor reasons and underwent LRT and had Child–Pugh A cirrhosis had survival approaching the national average for patients who undergo liver transplantation. Patients with Child–Pugh B/C cirrhosis had significantly worse outcomes than those with Child–Pugh A.

BACKGROUND & AIMS:The RESORCE trial showed that regorafenib improves overall survival (OS) in patients with hepatocellular carcinoma progressing during sorafenib treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.50-0.78; p

Inflammatory markers have been studied in cancers and chronic states of inflammation. They are thought to correlate with tumor pathology through disruption of normal homeostasis. Markers such as neutrophil to lymphocyte ratio (NLR) among others have shown promise as prognostic tools in various cancers. In this study, we evaluate complete blood count based inflammatory markers in hepatocellular carcinoma (HCC) to predict overall and recurrence-free survival of patients after liver transplant. Between 2001 and 2017, all HCC indicated liver transplants were retrospectively reviewed. Inclusion criteria included presence of complete blood cell counts with differential within three months prior to transplantation. Exclusion criteria included retransplantation and inadequate posttransplant followup. A total of 160 patients with HCC were included in the study. Of those, 74.4% had hepatitis C virus as the underlying cause of HCC. Calculated Model for End stage Liver Disease (MELD) scores were statistically worse in patients with elevated NLR (≥5), derived NLR (≥3), and low lymphocyte to monocyte ratio (LMR) (

The global burden of viral hepatitis remains substantial despite advances in antiviral therapy and effective vaccines. There are five hepatitis viruses (hepatitis A, B, C, D, and E). Mortality related to hepatitis B virus and hepatitis C virus infections is among the top four global infectious diseases, together with human immunodeficiency virus infection, malaria, and tuberculosis. Of those deaths, approximately 47% are attributable to hepatitis B virus, 48% to hepatitis C virus and the remainder to hepatitis A virus and hepatitis E virus. Ending hepatitis epidemics as a major public health threat is feasible with the tools and approaches currently available. Effective vaccines are available for preventing viral hepatitis A, B and E infections. New oral, well-tolerated treatment regimens for chronic hepatitis C patients can achieve cure rates of over 90%. Effective treatment is also available for people with chronic hepatitis B virus infection; although for most people such treatment needs to be long-term, and recent advanced aim at a "functional cure" of hepatitis B. In this review article, we discuss the most recent advances of the diagnosis and treatment of viral hepatitis.

Hepatocellular carcinoma is the most common primary liver malignancy and is a common indication for liver transplantation. To qualify for liver transplantation, the size and number of tumors must be within established criteria. The Milan criteria is the most well-established of these criteria, however there is evidence these criteria can be safely expanded without affecting outcomes. While awaiting liver transplantation, locoregional therapy can be used as bridging therapy to maintain the tumor burden within criteria. Locoregional therapy can also be used to decrease tumor burden within transplant criteria, a process called downstaging. For tumors

Hepatitis C virus (HCV) infection is a leading risk factor for hepatocellular carcinoma. We employed a retrospective cohort study design and analyzed 2012–2018 Medicaid claims linked with electronic health records data from the OneFlorida Data Trust, a statewide data repository containing electronic health records data for 15.07 million Floridians from 11 health care systems. Only adult patients at high-risk for HCV (n = 30,113), defined by diagnosis of: HIV/AIDS (20%), substance use disorder (64%), or sexually transmitted infections (22%) were included. Logistic regression examined factors associated with meeting the recommended sequence of HCV testing. Overall, 44.1% received an HCV test. The odds of receiving an initial test were significantly higher for pregnant females (odds ratio [OR]1.99; 95% confidence interval [CI] 1.86–2.12; P

Background Hepatorenal syndrome (HRS) remains a serious complication of cirrhosis with a high mortality rate. There is little information on the effect of standardizing albumin, midodrine and octreotide combination on treatment response in patients with HRS. Objective The aim of the study was to determine the impact of a standardized HRS treatment regimen on renal function recovery. The primary outcome was full response rate. Secondary outcomes included partial and no response rates, 30-day all-cause mortality, ICU length of stay (LOS), hospital LOS, liver transplantation and total dose of albumin. Methods This retrospective study evaluated the impact of using a standardized approach with albumin, midodrine and octreotide on treatment response rates compared to a historical group. Results Of the patients with HRS, 28 received a standardized approach with albumin, midodrine and octreotide while 60 received a nonstandardized approach. Ten percent of patients achieved full response in the prestandardization group compared with 25% in the poststandardization group (P = 0.07). Renal replacement therapy was significantly more prevalent in the prestandardization group vs. poststandardization group (45% vs. 21.4%, P = 0.03). Liver transplantation was performed significantly more often in the prestandardization group compared the poststandardization group (23% vs. 3.6%, P = 0.02). Amount of albumin used was statistically lower in the poststandardization group (425 vs. 332 g, P = 0.05). No significant differences in days of HRS treatment, mortality rate, hospital and ICU LOS were observed. Conclusion A trend towards improved treatment response rate was observed after standardizing the HRS treatment regimen. Standardized therapy led to significantly lower rates of renal replacement therapy and liver transplantation, suggesting patients in poststandardization were effectively managed medically without requiring further intervention.

Objective The objective of this study was to compare posttransplant outcomes in patients undergoing bridging locoregional therapy (LRT) with Y-90 transarterial radioembolization (TARE) based protocol compared with transarterial chemoembolization based protocol for hepatocellular carcinoma (HCC) prior liver transplantation (LT). Materials and methods Patients listed for LT with HCC within the Milan criteria at our center who had bridging LRT were treated according to transarterial chemoembolization (TACE) based protocol from May 2012 to April 2014 and a TARE based protocol from October 2014 to December 2017. Early posttransplant survival and tumor recurrence were compared between the groups. Tumor response to LRT, microvascular invasion (mVI), and the rate of delisting was also evaluated. Results One hundred three patients who were listed for LT with HCC within the Milan criteria received LRT. LT was performed in 65 patients, 28 treated with TARE protocol and 37 on TACE protocol. There were no statistical differences in baseline pretransplant characteristics and tumor recurrence. There was a trend toward improved 3-year survival in the TARE group (92.9% vs. 75.7%; P=0.052). The mVI was seen in 1/28 (3.6%) explants in the TARE group compared with 10/37 (27%) in the TACE group (P=0.013). The TARE group also required fewer LRT treatments (1.46 vs. 2.43; P=0.001) despite no difference in time on the transplant list. Conclusions Despite requiring fewer LRT treatments, there was significantly less mVI in the explants of patients treated with TARE protocol LRT as a bridge to LT as well as a trend toward improved 3-year survival. Therefore, TARE may be associated with improved tumor control and reduced post-LT recurrence.

Aim To retrospectively compare the initial response, local recurrence, and complication rates of radiofrequency ablation (RFA) vs microwave ablation (MWA) when combined with neoadjuvant bland transarterial embolization (TAE) or drug-eluting microsphere chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC). Methods A total of 35 subjects with Barcelona Clinic Liver Cancer (BCLC) very early and early-stage HCC (range: 1.2-4.1cm) underwent TAE (23) or TACE (12) with RFA (15) or microwave ablation (MWA) (20) from January 2009 to June 2015 as either definitive therapy or a bridge to transplant. TAE and TACE were performed with 40-400μm particles and 30-100μm plus either doxorubicin- or epirubicin-eluting microspheres, respectively. Initial response and local progression were evaluated using modified response evaluation criteria in solid tumors. Complications were graded using common terminology criteria for adverse events version 5.0. Results Complete response rates were 80% (12/15) for RFA + TAE/TACE and 95% (19/20) for MWA + TAE/TACE ( P = 0.29). Local recurrence rate was 30% (4/12) for RFA + TAE/TACE and 0% (0/19) for MWA + TAE/TACE. Durability of response, defined as local disease control for duration of the study, demonstrated a significant difference in favor of MWA ( P = 0.0091). There was no statistical difference in complication rates (3 vs 2). Conclusions MWA and RFA when combined with neoadjuvant TAE or TACE have similar safety and efficacy in the treatment of early-stage HCC. MWA provided more durable disease control in this study; however, prospective data remain necessary to evaluate superiority of either modality.

To assess the radiopathologic correlation following Yttrium-90 transarterial radioembolization (TARE) of hepatocellular carcinoma (HCC) using variable radiodosimetry to identify imaging surrogates of histologic response. Twelve patients with HCC underwent ablative (≥ 190 Gy) and/or non-ablative (

Gastrointestinal bleeds are a commonly observed complication after left ventricular assist device placement and usually caused by formation of arteriovenous malformations or acquired von Willebrand disease in the setting of anticoagulation use. We present a unique case of an upper GI bleed in which the cause was likely due to the impaction of a guitar pick into the duodenal bulb in the setting of continuous flow-LVAD on anticoagulation with elevated INR and discuss the pathophysiology of GI bleeds post-LVAD placement and relevant concerns about finding foreign bodies in the GI tract and their complications.

4078 Background: REG, a multikinase inhibitor, and PEMBRO, an anti-PD-1 mAb, are approved as monotherapies in advanced HCC after progression on sorafenib. This phase 1b dose-finding study investigated first-line REG plus PEMBRO in advanced HCC. Methods: Patients (pts) in the first cohort received a starting REG dose of 120 mg/day orally for 3 weeks (wks) on/1 wk off, which could be escalated (160 mg) or reduced (80 mg) in later cohorts, plus a fixed dose of PEMBRO 200 mg IV every 3 wks. Due to a high dose modification rate in the REG 120 mg cohort, an exploratory REG 80 mg cohort was introduced. Primary objective was safety and tolerability; secondary aims were to assess the maximum tolerated dose (MTD), recommended phase 2 dose, and anti-tumor activity. Results: 35 pts started on REG 120 mg/day and 22 on REG 80 mg/day. Median age was 66 yrs (range 29–81), 84% of pts were male, 70%/30% had ECOG PS 0/1, 26%/74% were BCLC stage B/C, 100% were C–P A, 46% had extrahepatic spread, and 32% had macrovascular invasion. MTD of REG was 120 mg/day. Grade (Gr) 3/4 treatment-emergent adverse events (TEAE) occurred in 86% of pts on REG 120 mg and 50% on REG 80 mg (Table). Most common Gr 3/4 TEAE for REG 120 mg/80 mg were AST increased (23%/9%), lipase increased (20%/5%), ALT increased (17%/9%), and hypertension (17%/9%). TEAE led to REG/PEMBRO dose reductions or interruptions in 71%/57% of pts on REG 120 mg and 59%/45% on REG 80 mg. Median treatment duration (range) was 3.0 months (mo; 0.2–20.5) for REG 120 mg and 3.5 mo (0.03–24.4) for PEMBRO, and 3.5 mo (0.7–10.8) for REG 80 mg and 3.5 mo (0.8–11.3) for PEMBRO. Of 32 evaluable pts on REG 120 mg, 10 (31%) had a partial response (PR) and 18 (56%) had stable disease (SD); disease control rate (DCR) was 88% (RECIST v1.1). Of 22 pts on REG 80 mg, 4 (18%) had a PR and 16 (73%) had SD; DCR was 91%. As of 17 Dec 2020, 16 pts remain on treatment (REG 120 mg n = 5; REG 80 mg n = 11); median follow up was 11.7 mo and 6.9 mo, respectively. REG pharmacokinetic exposure was as expected for 80 mg and 120 mg doses. Flow cytometry analysis of sequential peripheral blood showed changes in subsets of T-cells and monocytes, which may contribute to clinical benefit. Conclusions: First-line REG plus PEMBRO in advanced HCC showed no new safety signals and encouraging anti-tumor activity (DCR ̃90%). The REG 80 mg cohort appeared to have lower rates of dose reductions and interruptions due to TEAE vs REG 120 mg. Efficacy data for the REG 80 mg cohort are preliminary due to short follow-up. Clinical trial information: NCT03347292. [Table: see text]

323 Background: In a phase Ib study, REG 120 mg/day plus PEMBRO for first-line treatment of advanced HCC showed no unexpected safety signals and encouraging anti-tumor activity. At the maximum tolerated dose (MTD) of REG (120 mg/day), approximately three-quarters of patients (pts) had a REG dose reduction or interruption due to a treatment-emergent adverse event (TEAE). Here, we present preliminary data for the REG 80 mg/day cohort. Methods: This is an ongoing, dose-finding study in pts who had no prior systemic therapy. In the first cohort, pts received REG 120 mg/day orally for 3 weeks on/1 week off plus PEMBRO 200 mg intravenously q 3 weeks. In later cohorts, the REG dose could be escalated (160 mg/day) or reduced (80 mg/day); the PEMBRO dose is fixed. The primary objective is safety and tolerability. Secondary objectives are to define the MTD and recommended phase II dose and assess anti-tumor activity. Results: By July 24, 2020, 16 pts were treated with REG 80 mg/day. Median age was 67 years (range 56–79), 25%/75% were Barcelona Clinic Liver Cancer stage B/C, 100% Child–Pugh A, and 69%/31% had Eastern Cooperative Oncology Group performance status 0/1. Grade (Gr) 3 TEAEs occurred in 8/16 pts (50%) and there were no Gr 4 TEAEs (Table); one pt experienced Gr 5 pneumonitis (not drug related). There were no reports of Gr 3 hand–foot skin reaction or Gr 3 maculopapular rash, and one report (6%) of Gr 3 rash. TEAEs led to a REG dose reduction or interruption in 50% of pts and to a PEMBRO dose interruption in 25% of pts. Median treatment duration (range) including pts ongoing was 4.1 months (0.4–7.1) for REG and 3.8 months (0.03–7.2) for PEMBRO. Of 13 evaluable pts, 2 (15%) had a partial response and 9 (69%) had stable disease (Response Evaluation Criteria in Solid Tumors v1.1); disease control rate was 85%. Conclusions: These preliminary results for the combination of REG 80 mg/day plus PEMBRO for first-line treatment of advanced HCC were consistent with the REG 120 mg/day cohort. The combination showed no unexpected safety signals and encouraging anti-tumor activity. Assessment of REG 80 mg/day plus PEMBRO is ongoing. Clinical trial information: NCT03347292. [Table: see text]

Background The aim of this retrospective review was to evaluate the long-term survival benefits of thermal ablation versus wedge or segmental resection in solitary HCC lesions using tumor size and clinical factors. Methods Survival analysis was performed on 43,601 patients from 2004 to 2015 in the National Cancer Database with solitary HCC lesions ≤5 cm with further stratification by tumor size, fibrosis score, and type of resection. Results In patients with moderate fibrosis or less, survival benefit was seen with one-segment resection over ablation in tumors 1.1–3 cm (HR 0.54, p = 0.03) while tumors of 3.1–5 cm received survival benefit from wedge (HR 0.44, p = 0.04), one (HR 0.28, p = 0.001) and two-segment (HR 0.20, p = 0.001) resections over ablation. In patients with severe fibrosis to cirrhosis, wedge resection demonstrated survival benefit over ablation in patients with tumors 1.1–3 cm (HR 0.48, p = 0.01) with no survival benefit of any resection type in patients with tumors of 3.1–5 cm. Conclusion These findings suggest that the decision to utilize thermal ablation versus resection to extend survival in solitary HCC lesions should include tumor size, fibrosis score, and type of resection.

To date, sorafenib, a multiple tyrosine kinase inhibitor, is the only systemic agent approved by the FDA in the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Several other tyrosine kinase-inhibiting agents have been investigated in the first-line setting, either alone (sunitinib, brivanib, linifanib, and lenvatinib) or in combination with sorafenib (erlotinib and doxorubicin) in phase 3 trials. However, none of these studies demonstrated an improvement in survival over sorafenib. Many agents have also been tested in patients with HCC whose disease has progressed on sorafenib, but regorafenib is the only one to have demonstrated efficacy in this setting in a randomized, phase 3 trial. There were no clear survival benefits shown with everolimus, brivanib, or ramucirumab as second-line therapy. Nivolumab has also shown promising efficacy in patients with HCC who progressed on sorafenib, which was recently granted approval by the FDA, although larger confirmative trials may be considered. The treatment landscape for patients with advanced unresectable hepatocellular tumors has remained fairly static for the past 10 years, with multiple failed trials yield little change in the way these patients might be treated. However, recent findings for regorafenib, lenvatinib, and nivolumab have led to the most significant changes in the treatment paradigm in years.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide, and the prognosis remains poor. The currently available treatment protocols have not been able to affect the overall prognosis significantly. Immune processes have been shown to play a major role in tumorigenesis of HCC. The immune tolerance of the liver which allows liver transplant candidates to be maintained on minimal doses of immunosuppressants also contributes to HCC development and metastasis. This understanding has opened the scope of immune-based treatments in advanced HCC. Various preclinical and early clinical trials of immunotherapy in HCC, including immune checkpoint blockade, immune cell-based therapy, vaccination strategies, and combination of these approaches with conventional therapies, are ongoing. In this chapter, we discuss the immune regulation in HCC and the evolution of immune-based treatment approaches for hepatocellular carcinoma.

Liver transplantation (LT) provides a good chance of cure for selected patients with hepatocellular carcinoma (HCC) and perihilar cholangiocarcinoma (pCCA). Patients with HCC on a waiting list for LT are at risk for tumor progression and dropout. Treatment of HCC with locoregional therapies may lessen dropout due to tumor progression. Strict selection and adherence to the LT criteria for patients with pCCA before and after neoadjuvant chemotherapy are critical for optimal outcome with LT. This article reviews the existing data for the various treatment strategies used for patients with HCC and pCCA awaiting LT.

Non-islet cell tumor hypoglycemia (NICTH) is a rare and serious paraneoplastic complication of both malignant and benign tumors to consider when evaluating fasting hypoglycemia, especially in the setting of liver diseases. We present a case of NICTH in a 54-year-old male with hepatocellular carcinoma (HCC) who presented with symptomatic intractable hypoglycemia (IH) after bowel preparation and fasting for screening upper endoscopy and colonoscopy.

424 Background: Racial/ethnic (R/E) minorities and patients of low socioeconomic (SE) status are reported to have higher mortality related to HCC than their counterparts. However, prior studies are limited to administrative datasets without annotation for clinical covariates or represent single-center data with limited generalizability. The aim of this analysis was to characterize geographic, R/E, and SE disparities in HCC presentation, treatment, and survival among a representative sample of HCC patients in the US. Methods: TARGET-HCC is an observational, retrospective/prospective study of patients with HCC from academic and community sites. Complete medical records from consented patients are abstracted into a secure database. Multivariable logistic regression with random intercepts for site and Cox proportional hazard models with frailty adjustment were fit with adjustment for age, sex, BMI, liver disease etiology (LDE) and history of alcohol abuse to identify factors associated with early HCC detection, receipt of curative-intent therapy (CIT) and overall survival. Results: 925 patients with HCC (63% non-Hispanic white, 21% black, and 8% Hispanic) were consented from 42 sites in the US (22% Northeast, 27% Southeast, 21% Midwest, 14% South, and 16% West). Median age was 64 years and 76% were men. The most common LDE was hepatitis C (72%), and 72% had Child Pugh A cirrhosis. Most patients were diagnosed with early-stage HCC (72% Barcelona Clinic Liver Cancer 0/A). CIT was the initial therapy in 249 (32%), including 32% of BCLC 0/A. Although early tumor detection and CIT did not differ by region or R/E, there were SE disparities in CIT. Among those with early stage HCC, patients with private insurance [OR = 0.51, 95% CI (0.29, 0.91)] or Medicaid [OR = 0.50, 95% CI (0.25, 0.97)] were significantly less likely to undergo CIT. Overall survival was associated with BCLC stage and type of HCC treatment, with no significant association with region, R/E, or insurance. Conclusions: In this sample of HCC patients, there were no geographic or R/E disparities in early detection, treatment, and survival although SE disparities in administration of CIT were identified and warrant further study.

The aim of the present study was to determine the treatment outcome and prognostic factors for survival in patients with peripheral intrahepatic cholangiocarcinoma (ICC). A retrospective chart review was performed for patients diagnosed with ICC between 2000 and 2009 at a single institution. We identified a total of 105 patients with ICC. Among them, 63.8% were older than 60 years of age, 50.5% were male and 88.6% were Caucasian. By preoperative imaging approximately half of the patients (50.5%) were surgical candidates and underwent resection. The other half of the patients (49.5%) were unresectable. The unresectable group received chemoradiotherapy (53%) and transarterial chemoembolization (7.7%) as palliative treatments while 23.0% of the patients (12/52) received best supportive care alone. The median survival rates were 16.1 months (13.1‑19.2) for the entire cohort, 27.6 months (17.7-37.6) for curative resection, 12.9 months (6.5-19.2) for palliative chemoradiotherapy and 4.9 months (0.4-9.6) for best supportive care (p0.001). Independent predictors on multivariate analysis were advanced stage at diagnosis and treatment received. In those patients who underwent resection, advanced AJCC stage and presence of microvascular invasion were also independent predictors of poor survival. We concluded that surgery offers the most beneficial curative option and outcome, emphasizing the importance of resectability as a major prognostic factor. The present study also revealed that use of chemoradiotherapy in the adjuvant setting failed to improve survival but its palliative use in those patients with unresectable ICC offered a modest survival advantage over best supportive care. The overriding factors influencing outcome were stage and the presence of microvascular invasion on pathology.

Preservation injury in the HCV liver transplant population has been reported to correlate with poorer survival outcomes compared to preservation injury in the non-HCV liver transplant population. However, determinants of progression to cirrhosis in HCV infection remain poorly defined in this population.This study aimed to determine if the presence and severity of preservation injury impact the acceleration of HCV recurrence and survival after liver transplant.We retrospectively reviewed liver transplant HCV patients over a 10-year period. Biopsies from postoperative day 7 were assessed for preservation injury and 4- and 12-month biopsies were assessed for fibrosis. Patients with Ishak fibrosis0.8 Units/year were considered rapid fibrosers.Our study group consisted of 255 patients. The mean age was 49.3 years old, 180 (70.6 %) were male, and 221 (86.7 %) were Caucasian. The incidence of preservation injury on the 7-day biopsy was 69.0 %. A strong correlation between postoperative peak AST within the first week and preservation injury was found. The overall prevalence of rapid fibrosers at 4 months, 1 and 2 years was 47.4, 75.2, and 58.9 %, respectively. The prevalence of rapid fibrosers at 4 months, 1 and 2 years between patients with or without preservation injury was not statistically significant (p = 0.39, p = 0.46, and p = 0.53, respectively). No differences were seen between patients with and without PI in terms of patient and graft survival.In this study, the presence and severity of preservation injury were not associated with development of rapid HCV recurrence or worsening in survival.

Incidentally discovered hepatocellular carcinomas (iHCC) are tumors which are discovered on the explanted liver which were not present on imaging prior to transplant. The natural history, histopathologic characteristics and prognosis of iHCC are not clearly defined. Methods: A retrospective analysis was performed to compare the characteristics of iHCC and established HCC within Milan criteria (eHCC) in patients who underwent liver transplantation at our center between 2000 and 2010. Results: During the study period a total of 975 adult patients were transplanted in our center; 124 (12.7%) patients had eHCC and 26 (2.6%) patients had iHCC. A larger number of patients with iHCC (73.1%) had ascites when compared to eHCC (41.3%) (p = 0.035). Patients with iHCC had a higher mean bilirubin (p 0.001) and mean INR (p = 0.05) than patients with eHCC. Around 70% of patients with iHCC had a Model for End Stage Liver Disease (MELD) score greater than 15 at the time of listing while only 25% of patients with eHCC had a MELD greater than 15 at listing (p 0.001).The mean alphafetoprotein (AFP) in patients with iHCC was significantly lower (11.6 ± 16.5) than the patients with eHCC (564.9 ± 2180; p = 0.024). In patients with iHCC, 30.8% had a multiple tumors and 23% had bilobar involvement. The average number of tumors was 1.6 and the cumulative tumor size was 2.1 cm (SD 1.4). The cumulative tumor size in iHCC was significantly smaller than in eHCC (mean 3.9 cm) (p = 0.035). American Joint Committee on Cancer (AJCC) T1 tumor stage was found in 58% of patients with iHCC and 48.4% of patients with eHCC (p = 0.829).The median survival was 9.47 years for iHCC (95% CI 7.0 - 11.9) and 8.7 years (95% CI 6.1 - 11.4) for eHCC (p = 0.328). While none of the patients with iHCC had recurrence of HCC, the incidence of recurrence in patients with eHCC was 6.4%. Conclusion: iHCC occurred in patients with more advanced liver disease than eHCC. AFP was usually not elevated in patients with iHCC. The cumulative tumor size of iHCC was smaller than eHCC but around a third of iHCC were multifocal, supporting the theory of multicentric hepatic carcinogenesis. Survival of patients with iHCC was similar to patients with eHCC and recurrence was not noted in patients with iHCC.

Sorafenib has been used to treat advanced hepatocellular carcinoma (HCC), but the underlying molecular mechanisms remain controversial and why some patients do not respond to this therapy is poorly understood. In this study, we show that sorafenib triggers cell growth inhibition and apoptosis in HCC cells by directly targeting the mitochondria. Treatment with sorafenib induces rapid mitochondrial fragmentation, which is associated with the deregulation of mitochondria fusion-related protein optic atrophy 1 (OPA1). Exposure of cells or isolated mitochondria to sorafenib substantially induces cytochrome c release. Our data indicate that siRNA-mediated OPA1 knockdown significantly sensitizes HCC cells to sorafenib-induced apoptosis. Furthermore, sorafenib has no apparent apoptotic toxicity to normal human primary hepatocytes. Sorafenib inhibits HCC xenograft tumor growth in vivo and murine xenograft tumor tissue analysis reveals mitochondria fusion protein. OPA1 expression levels are strongly downregulated by sorafenib treatment. Western blotting evaluation of patient HCC with matched non-tumor tissue samples demonstrates that OPA1 expression is decreased in up to 40% of HCC patients. Taken together, we have shown that sorafenib suppresses the tumorigenesis of HCC through the induction of mitochondrial injury via OPA1. Our results provide new insights into the pathogenesis of HCC and suggest that OPA1 is a novel therapeutic target in patients with HCC.

Hepatocellular carcinoma (HCC) is a difficult to treat cancer characterized by poor tumor immunity with only one approved systemic drug, sorafenib. If novel combination treatments are to be developed with immunological agents, the effects of sorafenib on tumor immunity are important to understand. In this study, we investigate the impact of sorafenib on the CD4+CD25- effector T cells (Teff) and CD4+CD25+ regulatory T cells (Tregs) from patients with HCC. We isolated Teff and Treg from peripheral mononuclear cells of HCC patients to determine immune reactivity by thymidine incorporation, ELISA and flow cytometry. Teff cultured alone or with Treg were supplemented with different concentrations of sorafenib. The effects of sorafenib on Teff responses were dose-dependent. Pharmacologic doses of sorafenib decreased Teff activation by down regulating CD25 surface expression. In contrast, sub-pharmacologic concentrations of sorafenib resulted in Teff activation. These low doses of sorafenib in the Teff cultures led to a significant increase in Teff proliferation, IL2 secretion and up-regulation of CD25 expression on the cell surface. In addition, low doses of sorafenib in the suppression Teff/Treg cocultures restored Teff responses by eliminating Treg suppression. The loss of Treg suppressive function correlated with an increase in IL2 and IL6 secretion. Our findings show that sub-pharmacologic doses of sorafenib impact subsets of T cells differently, selectively increasing Teff activation while blocking Treg function. In conclusion, this study describes novel immune activating properties of low doses of sorafenib by promoting immune responsiveness in patients with HCC.

Aim The goal of this study is to evaluate whether an elevated neutrophil–lymphocyte ratio (NLR) at the time of diagnosis predicts survival of patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). We hypothesize that the NLR is predictive of overall survival (OS) and recurrence-free survival (RFS) in patients with HCC who undergo LT. Methods This is a retrospective analysis of adult patients undergoing LT for HCC between 2000 and 2008 at our institution. We define an elevated NLR as a ratio of 5 or greater. Results We included 160 patients who underwent LT for HCC in the time period, of whom 28 had an elevated NLR. Seventeen subjects experienced recurrent HCC during the study period. The cumulative survival among subjects with an elevated NLR was significantly lower than among subjects with a normal NLR. On univariate analysis, several factors (including an elevated NLR) predicted decreased OS and RFS. However, after multivariate analysis, only three factors (including elevated NLR) remained significant as predictors of OS. Additionally, multivariate analysis revealed that an elevated NLR was the only significant independent predictor of RFS. Conclusion Preoperative NLR is a powerful independent predictor of OS and RFS in patients undergoing LT for HCC. Measurement of NLR could serve as a useful and easily obtained adjunct to the Model for End-Stage Liver Disease score and Milan criteria when evaluating this patient population and determining which patients will gain the most survival benefit from transplantation.

Hepatitis C (HCV) is the most common indication for liver transplant (LT) in the United States. HCV recurrence is universal following transplantation and leads to allograft failure in about ten percent of recipients by the fifth postoperative year.(1) In the LT setting, the factors associated with the more aggressive disease progression are complex and multi-factorial, including recipient, donor and viral components. It is likely that host immune responses, both innate and adaptive, play a pivotal role in the clearance of viral infections, ongoing liver damage, and response to antiviral therapy. Therefore, defining the mechanisms of host immune system interaction with HCV after LT is critical for understanding HCV-related allograft injury and response to antiviral treatment. This knowledge is also vital to guide immunosuppression strategies that minimize HCV disease progression and increase the overall survival of the graft. Although multiple host factors have been implicated in HCV disease progression, interleukin-28B (IL-28B) single nucleotide polymorphism (SNP) on the chromosome 19, rs12979860, seems to be strongly associated with HCV clearance and treatment response.(2) So far, this SNP is the strongest predictor for sustained viral response (SVR) to interferon (IFN)-based therapy in the HCV population. The C allele is the most frequent allele in the white population associated with SVR. Patients with CC genotype have a two-fold chance of SVR compared to patients with T alleles.(3) In a recent study of IL-28B SNP in HCV LT recipients and donors, IL-28B genotypes predicted an SVR with 83% sensitivity and 82% specificity.(4) In addition, IL-28B recipient genotype was predictive of fibrosis, with the TT allele associated with more rapid fibrosis. Similar to interferon-based therapy in non-transplant patients, the CC genotype in either recipient or donor has been associated with increased rate of SVR.(5–7) Emerging evidence suggests that both donor and recipient IL-28B SNP background may play an important role in post-transplant HCV recurrence and its response to current therapy (8), but the available data is limited. Recently, others have reported that follow up liver biopsies may not be suitable for IL-28B determination.(9) Therefore, the objective of our study was to examine the role of IL-28B polymorphism of both donor and recipient livers in HCV disease progression after LT and its response to interferon-based therapy in a well characterized group of transplant patients.

Sorafenib is currently the only approved systemic therapy shown to have efficacy in the treatment of advanced hepatocellular carcinoma (HCC). Recent studies suggest that hepatitis C (HCV)-related HCC patients derive more clinical benefit from sorafenib than other subgroups, but the mechanism for this effect is unknown. In vitro data suggest that sorafenib may exert anti-viral properties, and thus our aim in this study was to evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC.To evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC.We prospectively enrolled patients with HCV-related HCC treated with sorafenib for up to 6 months. Baseline clinical, viral and oncologic data were collected. Patients' HCV viral loads were obtained at various time points, and compared with their baseline viral levels. No patients received any known anti-viral therapy during this time.Thirty-three patients were identified with baseline and subsequent HCV levels available for analysis. Six patients completed 6 months of full dose sorafenib, and comparisons of their HCV viral loads showed no significant change at week 24 (difference of means = 0.3500, CI: -0.1799-0.8799, P = 0.150), or the interim time points. Similarly, the HCV viral loads of all patients who received sorafenib and the viral loads of those patients who had tumour response to sorafenib showed no significant changes at any time point.Despite preclinical data and previous subgroup analyses suggesting that sorafenib has an anti-viral effect against HCV, this study suggests that sorafenib lacks significant anti-viral activity in HCV patients with HCC.

To evaluate the impact of long-term outcomes of transarterial embolization (TAE) therapy in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) on the waiting list for liver transplantation (LT).We retrospectively evaluated the post-LT patients with HCV-related HCC who received TAE intervention (n=33) and those who had no treatment (n=47) while on the waiting list to determine long-term outcomes.Over a 10-year period, of the 424 patients transplanted with HCV, 80 patients had HCC with a tumor burden within Milan criteria. For the entire study cohort, the mean duration of post-LT follow-up was 3.5 years; mean time of transplant waiting list was 120 days; and median post-LT survival was 8.9 years. The survival rates at 1, 3, 5, and 10 years were 82%, 70%, 55%, and 35%, respectively. From the study cohort, 33 patients received TAE and 47 patients did not while on the waiting list. The 2 groups were well matched, except, that the intervention patients received post-LT interferon more often and had a shorter time on the waiting list (56.2 d) when compared with the no treatment group (164.6 d, P0.001). Median survival in the TAE group was 4.8 years and 8.9 years in the no treatment group. The recurrence rate was 15.6% in the treatment group and 6.9% in the no therapy group (P=0.275).Pre-LT transarterial therapy has no benefit on post-LT survival and tumor recurrence in patients with HCV-related HCC who underwent a mean waiting period of3 months to transplant.

In a previous study, we showed that the level of soluble CD25 (sCD25) was elevated in a small series of patients with hepatocellular carcinoma (HCC). In the present study, we determined the capacity of serum levels of sCD25 to detect the presence and the early stage of HCC using a larger cohort of HCC patients and evaluated the correlation between sCD25 level and tumor burden. Serum levels of sCD25 were quantified using ELISA in patients with HCC (n=145), controls with advanced fibrosis (n=61) and healthy control subjects (n=30). The levels of sCD25 in patients with HCC (median, 6,955 pg/ml) were significantly higher than those in cirrhosis-only patients (4,310 pg/ml; P

Aliment Pharmacol Ther 2011; 34: 205–213 Summary Background Standard of practice involves using transarterial therapy for multifocal hepatocellular carcinoma (HCC) alone and sorafenib only for more advanced HCC, but the sorafenib and transarterial therapy combination may provide greater efficacy. Aim To evaluate the safety and efficacy of concurrent sorafenib and transarterial therapy in HCC. Methods Consecutive cases of HCC were treated with sorafenib and transarterial therapy, receiving sorafenib 2 to 4 weeks before transarterial therapy. Baseline clinical parameters, adverse events (AEs) and survival were collected. Results A total of 47 patients received sorafenib and transarterial therapy. The majority of the patients were male (70%) with HCV (60%), median age of 60 years, good performance status (0–1), stable cirrhosis (Child: A 72%; B 28%), unresectable tumour (stage: B 81%; C 19%) and median AFP of 24 ng/mL. Median follow-up was 12 months and median time on sorafenib was 6 months. LC Bead TACE was used with a median frequency of 3. The majority of the patients (89%) experienced AEs. The most common AEs were fatigue (51%), hand-foot skin reaction (51%) and diarrhoea (43%). Grade 3 and 4 AEs included fatigue (13%) and hand-foot skin reaction (26%). Most patients required a dose reduction (66%). The main AE related to transarterial therapy was post-TACE syndrome (23%). The disease control rate was 68% at 6 months. Overall median survival rate was 18.5 months (95% CI 16.1–20.9 months). Conclusion Concurrent sorafenib and transarterial therapy is overall safe with no unexpected side effects and encouraging efficacy that warrants further study.

Aliment Pharmacol Ther 2011; 33: 235–242 Summary Background Newer therapies are needed for patients with primary biliary cirrhosis and incomplete response to ursodeoxycholic acid (UDCA). Fenofibrate is a fibric acid postulated to regulate immune response and cell proliferation. Aim To evaluate the efficacy and safety of fenofibrate in patients with primary biliary cirrhosis and incomplete response to UDCA. Methods We undertook a pilot study involving 20 patients with primary biliary cirrhosis and serum alkaline phosphatase (ALP) ≥ 2× ULN. Nonparametric statistical tests and Spearman correlation test were used as appropriate. Results Twenty patients received fenofibrate (160 mg/day) in addition to UDCA for 48 weeks. Median serum ALP decreased significantly at 48 weeks compared with baseline values [351 (214–779) U/L at baseline vs. 177 (60–384) U/L at 48 weeks, P

Purpose To determine the radiosensitivity difference of human Cluster of Differentiation (CD)4(+)CD25(+) regulatory T cells (Treg) and effector T cells to low dose gamma ray and elucidate the underlying mechanisms in vitro. Materials and methods Blood samples were collected from five health subjects and five patients with advanced hepatocellular carcinoma (HCC). Treg and CD4(+)CD25⁻ T cells were selected using magnetic microbeads. The proliferative profiles, cytokine secretion, and differential expressions of apoptosis-related proteins in Treg and CD4(+)CD25⁻ T cells were compared using [³H]-thymidine incorporation, Luminex assay and flow cytometry when treated with various low doses of γ-ray. Results A dose-dependent reduction of proliferation in response to irradiation which paralleled the induction of apoptosis existed in Treg and CD4(+)CD25⁻ T cells. Treg were more radiosensitive to low-dose irradiation (0.94 Gray [Gy]) than effector T cells. The interferon-γ (IFNγ) was significantly upregulated and interleukin 10 (IL-10) was significantly downregulated in irradiated Treg. An enhanced immune response to low dose gamma ray existed in the peripheral blood in patients with advanced HCC. Higher levels of active caspase-3, CD95, B cell lymphoma 2 (Bcl-2)-associated X protein (Bax) expression were observed in Treg compared to CD4(+)CD25⁻ T cells. In addition, gamma irradiation activated CD4(+)CD25⁻ T cells to express CD25. Conclusions These studies revealed that Treg were more radiosensitive than CD4(+)CD25⁻ T cells to low dose irradiation. Higher expressions of apoptosis-related proteins such as caspase-3, CD95 and Bax were observed in Treg when compared to CD4(+)CD25⁻ T cells. Our results suggest that treatment with low doses of gamma irradiation may be a viable strategy to enhance immune response in patients with advanced HCC.

Our previous studies showed that high levels of soluble CD25 (sCD25) in the serum of patients with hepatocellular carcinoma (HCC) correlated with blunted effector T-cells (Teff) responses, tumour burden and poor survival. Understanding the interactions between Teff, CD4+CD25+ regulatory T cells (Treg) and soluble factors can identify novel therapeutic targets. In this study, we characterize the mechanisms by which HCC serum and sCD25 mediate suppression of Teff and evaluate the effect of sCD25 on the suppression assays with normal healthy control cells (NHC) at a 1:1 Treg to Teff cell ratio to determine whether sCD25 has any impact on Treg suppression. HCC serum and sCD25 suppressed Teff proliferation and downregulated CD25 expression on HCC Teff in a dose-dependent fashion with sCD25 doses above 3000 pg/ml. Treg from HCC and cirrhosis patients suppressed proliferation of target CD4+CD25- Teff in serum-free medium (SFM). HCC Treg showed a higher degree of suppression than cirrhosis-derived Treg. In contrast, Treg from NHC did not suppress target Teff in SFM. However, isolated Treg from all three study subjects (HCC, cirrhosis and NHC) suppressed CD4+CD25- Teff in serum conditions or in the presence of sCD25 in the range 6000-12,000 pg/ml. In conclusion, downregulation of CD25 cell surface expression on Teff is part of the overall suppressive mechanism of sCD25 and HCC serum on Teff responses. The observed sCD25 and HCC serum-mediated suppression is further influenced via novel immune-inhibitory interaction between CD4+CD25+ Treg and sCD25.