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Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, OVs could potentially restore ICI responsiveness via recruitment, priming, and activation of anti-tumor T cells. Here we find that on the contrary, an oncolytic vesicular stomatitis virus, expressing interferon-ß (VSV-IFNß), antagonizes the effect of anti-PD-L1 therapy in a partially anti-PD-L1-responsive model of HCC. Cytometry by Time of Flight shows that VSV-IFNß expands dominant anti-viral effector CD8 T cells with concomitant relative disappearance of anti-tumor T cell populations, which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, combination OV and anti-PD-L1 therapeutic benefit could be restored. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, through encoding tumor antigens within the virus, oncolytic virotherapy can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work. Oncolytic viruses create an inflamed tumour microenvironment allowing T cells to respond to immune checkpoint blockade therapy more efficiently. Authors here show that in a hepatocellular carcinoma model, a dominant anti-viral rather than anti-tumour T cell response is elicited by an oncolytic vesicular stomatitis virus, unless the virus is designed to express tumour antigens, which restores therapeutic benefit. [ABSTRACT FROM AUTHOR]

Summary: Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1–36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under ClinicalTrials.gov registry number NCT01364051. [ABSTRACT FROM AUTHOR]

Background: Patients with Barcelona Clinic Liver Cancer Stage C (BCLC-C) hepatocellular carcinoma (HCC) can be markedly heterogeneous with varying prognosis. This study aims to establish a new subclassification system for BCLC-C HCC to better predict overall survival (OS) and to tailor therapy. Methods: We retrospectively studied 1856 BCLC-C HCC patients between 2006 and 2017 from E-Da Hospital, Taiwan (n = 622, training cohort), Kaohsiung Medical University Hospital, Taiwan (n = 774, Taiwan validation cohort), and Stanford University Medical Center and Mayo Clinic (United States), Hanyang University Hospital (South Korea), and Ogaki Municipal Hospital (Japan) to make up the international validation cohort (n = 460). Results: In the training cohort, significant factors associated with OS were largest tumor size ≥ 10 cm, extrahepatic spread, macrovascular invasion, and Child–Pugh class, which provided the basis, together with aged ≥ 75 years, for the substaging, through C0 to C4, of BCLC-C HCC patients. The median OS for substages C0, C1, C2, C3, and C4 were 43.8 months (95% confidence interval [CI] 32.2–53.7), 20.6 months (CI 14.1–25.9), 11.5 months (CI 8.02–14.1), 5.7 months (CI 4.02–5.98), and 3.2 months (CI 2.41–3.59), respectively, (p < 0.05). OS remained distinct among the proposed substages in the Taiwan validation cohort as well as the international validation cohort. The distinction between the substages persisted in subgroup analysis by substage combined with treatment modality. In substage C0–C3, patients receiving HCC curative therapy had a significantly better median OS than those receiving sorafenib or palliative therapy. Conclusion: Our new substaging system provides more precise prognosis to better tailor therapy for BCLC-C HCC patients. [ABSTRACT FROM AUTHOR]

Purpose: To study the prognostic significance of neutrophil and lymphocyte dynamics in patients with hepatocellular carcinoma (HCC) treated with radioembolization. Methods: A retrospective, single-center review of clinical records and treatment parameters (liver volume treated, administered activity, and radiation dose) in consecutive patients who received radioembolization for HCC was performed between August 20, 2015, and May 24, 2019. Neutrophil and lymphocyte variables associated with overall survival (OS) were determined by Barcelona Clinic Liver Cancer (BCLC) stage and were correlated with radioembolization treatment parameters. Statistical methods included Wilcoxon signed-rank test, univariate, and multivariate Cox regression analysis; receiver operating characteristic analysis; and the Kaplan-Meier method. Results: One hundred sixty-three patients with a median 67.0 years of age were included for analysis. Eighty-one percent of patients received segmental radioembolization with a median treatment dose of 358 Gray (interquartile range 256–497). The post-treatment lymphocyte count decreased significantly in 94.5 % (p < 0.001) of patients but was not predictive of OS (p = 0.248). The pre-procedure neutrophil to lymphocyte ratio (NLRpre) was not predictive of OS (p = 0.891), and the 1-month post-procedure NLR was a borderline independent predictor of OS (p = 0.05). The NLR ratio (NLRR = NLRpost-procedure/NLRpre) (Hazard ratio [HR], 1.31; 95% Cl, 1.04-1.66) and change in NLR (ΔNLR= NLRpost-procedure - NLRpre) (HR, 1.09; 95% CI, 1.02–1.15) were associated with worse OS in BCLC C patients. NLRR (> 3.17) and ΔNLR (> 3.74) were independent predictors when adjusted for tumor presentation, treatment parameters, and liver function. Volume of liver treated and administered activity positively correlated with NLRR and ΔNLR (p < 0.001). Conclusion: A decrease in lymphocyte count is common after radioembolization, but of little clinical impact. Neither pre-treatment or post-treatment NLR was a predictor of survival in our study population. NLRR and ΔNLR were independent predictors of survival in BCLC stage C disease and had positive correlations with volume of liver tissue treated and administered activity. [ABSTRACT FROM AUTHOR]

In our clinical trials of oncolytic vesicular stomatitis virus expressing interferon beta (VSV-IFNβ), several patients achieved initial responses followed by aggressive relapse. We show here that VSV-IFNβ-escape tumors predictably express a point-mutated CSDE1P5S form of the RNA-binding Cold Shock Domain-containing E1 protein, which promotes escape as an inhibitor of VSV replication by disrupting viral transcription. Given time, VSV-IFNβ evolves a compensatory mutation in the P/M Inter-Genic Region which rescues replication in CSDE1P5S cells. These data show that CSDE1 is a major cellular co-factor for VSV replication. However, CSDE1P5S also generates a neo-epitope recognized by non-tolerized T cells. We exploit this predictable neo-antigenesis to drive, and trap, tumors into an escape phenotype, which can be ambushed by vaccination against CSDE1P5S, preventing tumor escape. Combining frontline therapy with escape-targeting immunotherapy will be applicable across multiple therapies which drive tumor mutation/evolution and simultaneously generate novel, targetable immunopeptidomes associated with acquired treatment resistance. Oncolytic viruses, such as vesicular stomatitis virus (VSV), are a promising class of cancer therapeutics. Here the authors report that a mutation in the CSDE1 gene renders cancer cells resistant to VSV replication and oncolysis, but a mutation-derived escape-associated neoantigen could be exploited for immunotherapy against treatment-resistant tumors. [ABSTRACT FROM AUTHOR]

Background: The ability of the pretreatment lymphocyte to monocyte ratio (LMR) to predict outcomes of patients with hepatocellular carcinoma (HCC) receiving sorafenib is not conclusively determined. Methods: We retrospectively studied patients treated with sorafenib for HCC in two tertiary referral centres in Asia and North America. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Predictive factors for the outcomes were determined by Cox proportional hazards models. A risk assessment tool was developed. Results: Compared to the North America cohort, the Asia cohort was more heavily pretreated (72.1% vs. 35.2%; p < 0.001), had higher hepatitis B virus infection (87.6% vs. 5.6%; p < 0.001), and more distant metastases (83.2% vs. 25.4%; p < 0.001). Lower monocyte count in the Asia cohort (median 462.7 vs. 600.0/μL; p = 0.023) resulted in a higher LMR (median 2.6 vs. 1.8; p < 0.001). High LMR was associated with a significantly higher OS [hazard ratio (HR) 0.88; 95% confidence interval (CI) 0.81‒0.97; p = 0.007]. This was confirmed in a sensitivity analysis including patients treated in Asia only (HR 0.89; 95% CI 0.81‒0.97; p = 0.010). An OS nomogram was constructed with the following variables selected in the multivariate Cox model: LMR, treatment location, previous treatment, performance status, alpha-fetoprotein, lymph node metastasis, and Child‒Pugh score. The concordance score was 0.71 (95% CI, 0.67‒0.75). LMR did not predict PFS. Conclusion: LMR measured before sorafenib administration predicts OS in advanced HCC patients. Our OS nomogram, incorporating LMR, can be offered to clinicians to improve their ability to assess prognosis, strengthen the prognosis-based decision-making, and inform patients in the clinic. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis has been a major target of novel drug development in hepatocellular carcinoma (HCC). It is hypothesized that the combination of two antiangiogenic agents, sorafenib and bevacizumab, will provide greater blockade of angiogenesis.Objective: To determine the optimal dose, safety, and effectiveness of dual anti-angiogenic therapy with sorafenib and bevacizumab in patients with advanced HCC.Patients and Methods: Patients with locally advanced or metastatic HCC not amenable for surgery or liver transplant were eligible. The phase I starting dose level was bevacizumab 1.25 mg/kg day 1 and 15 plus sorafenib 400 mg twice daily (BID) days 1-28. In the phase II portion, patients were randomized to receive bevacizumab and sorafenib at the maximum tolerated dose (MTD) or sorafenib 400 mg BID.Results: Seventen patients were enrolled in the phase I component. Dose-limiting toxicities included grade 3 hand/foot skin reaction, fatigue, hypertension, alanine/aspartate aminotransferase increase, dehydration, hypophosphatemia, creatinine increase, hypoglycemia, nausea/vomiting, and grade 4 hyponatremia. Seven patients were enrolled in the phase II component at the MTD: sorafenib 200 mg BID days 1-28 and bevacizumab 2.5 mg/kg every other week; 57% (4/7) had grade 3 AEs at least possibly related to treatment. No responses were observed in the phase II portion. Estimated median time to progression and survival were 8.6 months (95% CI: 0.4-16.3) and 13.3 months (95% CI 4.4 - not estimable), respectively.Conclusions: The MTD of the combination is sorafenib 200 mg twice daily on days 1-28 plus bevacizumab 2.5 mg/kg on days 1 and 15 of a 28-day cycle. In the phase II portion of the trial, concerns regarding excessive toxicity, low efficacy, and slow enrollment led to discontinuation of the trial. (Clinical Trials ID: NCT00867321.). [ABSTRACT FROM AUTHOR]

Background: Although molecular characterization of iCCA has been studied recently, integrative analysis of molecular and clinical characterization has not been fully established. If molecular features of iCCA can be predicted based on clinical findings, we can approach to distinguish targeted treatment. We analyzed RNA sequencing data annotated with clinicopathologic data to clarify molecular-specific clinical features and to evaluate potential therapies for molecular subtypes. Methods: We performed next-generation RNA sequencing of 30 surgically resected iCCA from Korean patients and the clinicopathologic features were analyzed. The RNA sequences from 32 iCCA resected from US patients were used for validation. Results: Patients were grouped into two subclasses on the basis of unsupervised clustering, which showed a difference in 5-year survival rates (48.5% vs 14.2%, p = 0.007) and similar survival outcome in the US samples. In subclass B (poor prognosis), both data sets were similar in higher carcinoembryonic antigen and cancer antigen 19-9 levels, underlying cholangitis, and bile duct-type pathology; in subclass A (better prognosis), there was more frequent viral hepatitis and cholangiolar-type pathology. On pathway analysis, subclass A had enriched liver-related signatures. Subclass B had enriched inflammation-related and TP53 pathways, with more frequent KRAS mutations. CCA cell lines with similar gene expression patterns of subclass A were sensitive to gemcitabine. Conclusions: Two molecular subtypes of iCCA with distinct clinicopathological differences were identified. Knowledge of clinical and pathologic characteristics can predict molecular subtypes, and knowledge of different subtype signaling pathways may lead to more rational, targeted approaches to treatment. [ABSTRACT FROM AUTHOR]

Purpose of Review: To review the recent consensus on the nomenclature, clinical features, diagnosis, and treatment of combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA).Recent Findings: cHCC-CCA is a primary liver carcinoma with varying degrees of hepatocytic and cholangiocytic cytology and architecture within the same tumor. The diagnosis of cHCC-CCA can only be established based on histologic examination. Surgical resection should be considered in patients with resectable tumors who do not have underlying liver disease or clinically significant portal hypertension. While treatment by liver transplantation (LT) is controversial due to the high risk of post-LT recurrence, LT should remain as a potentially curative option in a highly selected group of patients. Little data exist for the outcome of other treatments.Summary: High-quality multicenter prospective studies should be conducted to better understand this rare but increasingly recognized tumor. [ABSTRACT FROM AUTHOR]

Purpose: To describe imaging findings in biphenotypic hepatic tumors (BPT) and a proposal for new imaging classification based on contrast-enhanced imaging.Methods: Retrospective review of CT, MRI, PET/CT, and ultrasound findings in 39 patients with histologically confirmed BPT was performed. Tumor markers including AFP, L3 fraction, CA 19.9, CA 125, and CEA were recorded. Based on the dynamic enhancement features, BPT were categorized into 4 enhancement patterns (Types 1-4). Enhancement patterns were correlated with other imaging findings and tumor markers. Imaging features and tumor markers that were not consistent with diagnosis of hepatocellular carcinoma or intrahepatic cholangiocarcinoma based on enhancement pattern were considered discordant findings.Results: Enhancement patterns in 29 patients (CT/MR) included 23 Type 2 (continuous peripheral rim of late arterial hyperenhancement with washout or fade in portal venous and/or delayed phases, ±delayed central enhancement) and 2 of each Types 1, 2, and 3. Discordant imaging findings were present in two patients with Type 2 pattern and in one patient with Type 1 pattern. Both AFP and CA 19.9 were elevated in 15 of 33 of patients. Tumor markers AFP and CA 19.9 were discordant in 17 of 21 patients with Type 2 pattern, two of two patients with Type 3 pattern. Most BPTs were markedly PET avid with average SUV max of 8.2. Most frequent ultrasound appearance is peripheral hypoechogenicity and central hyperechogenicity.Conclusions: BPT most commonly present with imaging features similar to cholangiocarcinoma or metastases. BPT can be suggested when imaging findings or tumor markers are discordant with the most likely diagnosis based on enhancement pattern. [ABSTRACT FROM AUTHOR]

Venous invasion by hepatic tumors most commonly occurs with hepatocellular carcinoma and is associated with worse patient prognosis. Imaging plays an important role in the diagnosis of tumor thrombus in the liver. Moreover, differentiating between bland and tumor thrombus in the liver has important diagnostic, staging, therapeutic, and prognostic implications and may require a multimodal imaging approach including ultrasound, computed tomography, and/or magnetic resonance imaging. Treatment of hepatic malignancies with associated tumor thrombus is dependent on tumor type, disease extent within the liver, liver hemodynamics, and underlying liver function. Treatment of such tumors may involve surgical, locoregional and/or systemic therapies. The current review will focus on the imaging characteristics of venous invasion by hepatic tumors. The imaging findings most useful for differentiating hepatic venous tumor thrombus and bland thrombus will be highlighted and demonstrated with imaging examples. Imaging findings with implications for subsequent patient management will be described. [ABSTRACT FROM AUTHOR]

Purpose of Review: The aim of this review is to address the controversy around the use of biomarkers for hepatocellular carcinoma (HCC) surveillance in individuals with cirrhosis or chronic hepatitis B who are at risk for development of liver cancer. Recent Findings: Recent studies suggest that surveillance for hepatocellular carcinoma is beneficial, even after adjustment for lead time and other biases. Alpha fetoprotein (AFP) is complementary to ultrasound (US) in surveillance, particularly in obese patients and patients with infiltrative tumors. US and AFP are both associated with harms to patients from false-positive overdiagnosis, with US appearing to cause greater harms. Including patient demographic characteristics and additional biomarkers into diagnostic models is beneficial. Recent studies emphasize the advantage of time trends in biomarkers over single cross-sectional measurements. Summary: AFP and other biomarkers are complementary to US in surveillance for HCC, especially when applied in models including patient variables and incorporating time trends in biomarker levels. With advances in genetic and molecular analysis of tumors, we may be poised at the cusp of a revolution in HCC surveillance. [ABSTRACT FROM AUTHOR]

Treatment of liver and biliary tract cancer is most effective for early and localized disease. Effective screening methods for hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) will lead to early detection and treatment, and thus improvement in survival. Patients at risk of developing HCC and CCA will benefit the most from effective surveillance strategies. In this review, we provide an update on the current status of HCC and CCA surveillance and describe the recent efforts on biomarker development. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Current staging systems for perihilar cholangiocarcinoma (pCCA) are inadequate, as they are based on surgical pathology and therefore not relevant to unresectable patients. Clinical trials for potential targeted therapies for pCCA are hampered by the lack of an accurate, nonoperative staging system for predicting survival. We aimed at developing a clinical staging system for pCCA, which would be of prognostic relevance for all pCCA patients and help stratify patients for clinical trials.METHODS:Clinical information at the time of pCCA diagnosis of 413 patients seen at Mayo Clinic, Rochester, MN between 2002 and 2010 was retrospectively analyzed. A survival predictive model was developed using Cox proportional hazards analysis. The performance of the staging system was compared with the current AJCC/UICC (the American Joint Committee on Cancer/the Union for International Cancer Control) 7th tumor-node-metastasis (TNM) staging system.RESULTS:Eastern Cooperative Oncology Group (ECOG) status, tumor size and number, vascular encasement, lymph node and peritoneal metastasis and CA 19-9 level were grouped into a four-tier staging system. The median survivals of stages I, II, III, and IV patients were 48.6, 21.8, 8.6, and 2.8 months, with hazard ratios (95% confidence interval) of 1.0 (reference), 1.7 (1.1-2.6), 3.1 (2.0-4.7), and 8.7 (5.2-14.5), respectively (P<0.0001). This staging system had greater concordance statistics (standard error) than the TNM staging system (0.725 (0.018) vs. 0.614 (0.017)), indicating better performance in predicting survival.CONCLUSIONS:This staging system, based on nonoperative information at the time of pCCA diagnosis, has excellent discriminatory power to classify patients into four prognostic stages. It could be useful to clinicians and for the design of clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the potential role for CD44 and CD90 hepatocellular carcinoma (HCC) cellular subpopulations in biological response to thermal ablation-induced heat stress. Methods: This study was approved by the institutional animal care committee. The N1S1 rat HCC cell line was subjected to sublethal heat stress (45 °C) or control (37 °C) for 10 min, costained with fluorescent-labeled antibodies against CD44, CD90, and 7-AAD after a 48-h recovery and analyzed by flow cytometry to assess the percentage of live CD44 and CD90 HCC cells ( n = 4). Experiments were repeated with pretreatment of N1S1 cells with a dose titration of the dual PI3K-mTOR inhibitor BEZ235 or vehicle control ( n = 3). Rats bearing orthotopic N1S1 tumors were subjected to ultrasound-guided partial laser ablation ( n = 5) or sham ablation ( n = 3), euthanized 24 h after ablation, and liver/tumor analyzed for immunohistochemical staining of CD44 and CD90. Differences between groups were compared with an unpaired t test. Results: Sublethal heat stress induced a significant increase in the relative proportion of live CD44 and CD90 HCC cells compared to the control group: CD44CD90 (5.3-fold; p = 0.0001), CD44CD90 (2.4-fold; p = 0.003), and CD44CD90 (22.0-fold; p < 0.03). Inhibition of PI3K-mTOR prevented heat stress-induced enrichment of the population of live CD44 HCC cells ( p < 0.01), but not CD90 cells ( p > 0.10). Immunohistochemical analysis demonstrated preferential localization of clusters of CD44 cells at both the tumor margin and ablation margin. Conclusion: These studies provide experimental evidence supporting a role for HCC cells expressing the putative stem cell marker CD44 in HCC response to heat stress. [ABSTRACT FROM AUTHOR]

This article compares the models of subjectivity and identity in William Steig's 1990 picture book Shrek! and in DreamWorks' Shrek films. Steig presented his ogre hero as a model of the crises of subjectivity all children must face, and then reassured readers by showing how even a hideous figure such as Shrek can find resolution and be 'happier than ever to be exactly what he was.' DreamWorks' Shrek films, on the other hand, offer up models of identity based on consumption and rooted in commodity culture, tales which seek to transform their viewers into consumers and even into commodities themselves. As texts of commodity culture, the films must create, not resolve, anxiety and self-doubt. Has DreamWorks' adaptation of Steig's book merely replaced a self-confident ogre with an anxiety-ridden consumer? Or, can the films' humor and absurdity, their parody of familiar commodities and corporate landscapes, and their introduction of boundary-crossing characters such as Fiona offer an alternative critique of commodity culture? This article demonstrates how the films work to uphold and reinforce commodity culture, but also examines how they might also provide moments of potential subversion and critique. [ABSTRACT FROM AUTHOR]

Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas. [ABSTRACT FROM AUTHOR]

Purpose: Intermediate-stage hepatocellular carcinoma (HCC) is usually treated with locoregional therapy using transarterial chemoembolization (TACE). Transarterial radioembolization (TARE) using β-emitting yttrium-90 integral to the glass matrix of the microspheres is an alternative to TACE. This retrospective case-control study compared the outcomes and safety of TARE versus TACE in patients with unresectable HCC. Materials and Methods: Patients with unresectable HCC without portal vein thrombosis treated with TARE between 2005 and 2008 ( n = 61) were retrospectively frequency-matched by age, sex, and liver dysfunction with TACE-treated patients ( n = 55) in the Mayo Clinic Hepatobiliary Neoplasia Registry. Imaging studies were reviewed, and clinical and safety outcomes were abstracted from the medical records. Results: Complete tumor response was more common after TARE (12 %) than after TACE (4 %) ( p = 0.17). When complete response was combined with partial response and stable disease, there was no difference between TARE and TACE. Median survival did not differ between the two groups (15.0 months for TARE and 14.4 months for TACE; p = 0.47). Two-year survival rates were 30 % for TARE and 24 % for TACE. TARE patients received fewer treatments ( p < 0.001). Fifty-nine (97 %) TARE patients received outpatient treatment. In contrast, 53 (98 %) TACE patients were hospitalized for ≥1 day ( p < 0.001). Compared with TACE, TARE was more likely to induce fatigue ( p = 0.003) but less likely to cause fever ( p = 0.02). Conclusion: There was no significant difference in efficacy between TARE and TACE. TARE patients reported more fatigue but had less fever than TACE patients. Treatment with TARE required less hospitalization than treatment with TACE. These findings require confirmation in randomized trials. [ABSTRACT FROM AUTHOR]

Purpose: This study was designed to determine the tumorigenicity of the AS30D HCC cell line following orthotopic injection into rat liver and preliminarily characterize the tumor model by both magnetic resonance imaging (MRI) and ultrasound (US) as well as histopathology and immunohistochemistry.Materials: AS30D cell line in vitro proliferation was assessed by using MTT assay. Female rats (N = 5) underwent injection of the AS30D cell line into one site in the liver. Rats subsequently underwent MR imaging at days 7 and 14 to assess tumor establishment and volume. One rat underwent US of the liver at day 7. Rats were euthanized at day 7 or 14 and livers were subjected to gross, histopathologic (H&E), and immunohistochemical (CD31) analysis to assess for tumor growth and neovascularization.Results: AS30D cell line demonstrated an in vitro doubling time of 33.2 ± 5.3 h. MR imaging demonstrated hyperintense T2-weighted and hypointense T1-weighted lesions with tumor induction in five of five and three of three sites at days 7 and 14, respectively. The mean (SD) tumor volume was 126.1 ± 36.2 mm(3) at day 7 (N = 5). US of the liver demonstrated a well-circumscribed, hypoechoic mass and comparison of tumor dimensions agreed well with MRI. Analysis of H&E- and CD31-stained sections demonstrated moderate-high grade epithelial tumors with minimal tumor necrosis and evidence of diffuse intratumoral and peritumoral neovascularization by day 7.Conclusions: AS30D HCC cell line is tumorigenic following orthotopic injection into rat liver and can be used to generate an early vascularizing, slower-growing rat HCC tumor model. [ABSTRACT FROM AUTHOR]

OBJECTIVES:The epidemiology of biliary tract cancers has changed in the United States in the past several decades. The aim of this study is to evaluate biliary tract cancers with regard to the incidence rates, etiology, treatment, and survival in Olmsted County between 1976 and 2008.METHODS:Community residents over 20 years of age with a newly diagnosed biliary tract cancers were identified using the Rochester Epidemiology Project. Clinical information, including tumor stage, treatment, and survival status was abstracted from the medical records. The incidence rate was calculated considering the entire population of Olmsted County to be at risk and adjusted by age and sex according to US Census 2000 population. Temporal trends of patient survival with biliary tract cancers were assessed.RESULTS:A total of 116 subjects met the study criteria. The age-sex-adjusted incidence rate of intrahepatic cholangiocarcinoma (ICC) increased from 0.3 to 2.1 (P=0.02) but one of gall bladder (GB) cancer decreased from 4.0 to 2.2 (P=0.04) per 100,000 person-years between 1976 and 2008 (P<0.01). Overall incidence rates of remaining biliary tract cancers have not changed. Overall 59% of patients presented with stage 3 or 4 cancers and a median survival was 6.3 months. Survival in patients with biliary tract cancer has minimally improved from median survival of 4.2-7.7 months between 1976 and 2008 (P=0.05).CONCLUSIONS:In Olmsted County, the incidence of ICC and GB cancer has increased and decreased, respectively. The prognosis remains poor in community residents diagnosed with biliary tract cancers. [ABSTRACT FROM AUTHOR]

The purpose of this study was to identify the psychosocial characteristics of incarcerated girls with a substance use disorder. Profile analysis, the repeated measures extension of multivariate analysis of variance, was conducted to compare a state-based sample of incarcerated girls with ( n = 140) and without ( n = 63) a substance use disorder across multiple subscales of the Multidimensional Adolescent Assessment Scale. Girls with a substance use disorder had higher levels of problem severity. They were more likely to have problems related to alcohol use, drug use, aggression, and cognition. Incarcerated girls with a substance use disorder may benefit from intense interventions that focus on cognitive restructuring or cognitive recovery, and interventions that promote coping and stress management skills. [ABSTRACT FROM AUTHOR]

We report four patients on long-term antiepileptic drugs, without any history of anabolic steroid or oral contraceptive use, who had path-proven hepatic adenomas at our institution. Imaging review of one case is presented here. An exhaustive literature search reveals only four other such case reports, none from the North American continent. [ABSTRACT FROM AUTHOR]

Sharon Creech’s Walk Two Moons is a defining example of contemporary realistic fiction for children. This article argues that Walk Two Moons models storytelling as a tool which children need to understand their own relationship to reality and to literature. Rather than employing a grim verisimilitude, as some critics have charged, Creech has created a novel of realistic character development which also challenges any simplistic understanding of children’s realistic fiction through its complex and self-referential narrative structure and use of literary language. The result is a narrative which, in the face of painful and tragic circumstances, empowers readers toward a hopeful and optimistic view of life’s mysteries. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIMS: Standard techniques for evaluating bile duct strictures have poor sensitivity for detection of malignancy. Newer imaging modalities, such as intraductal ultrasound (IDUS), and advanced cytologic techniques, such as digital image analysis (DIA) and fluorescence in situ hybridization (FISH), identify chromosomal abnormalities, and may improve sensitivity while maintaining high specificity. Our aim was to prospectively evaluate the accuracy of these techniques in patients with indeterminate biliary strictures. METHODS: Cholangiography, routine cytology (RC), intraductal biopsy, DIA, FISH, and IDUS were performed in 86 patients with indeterminate biliary strictures. Patients were stratified based on the presence or absence of primary sclerosing cholangitis (PSC). RESULTS: RC provided low sensitivity (7–33%) but high specificity (95–100%) for PSC and non-PSC patients. The composite DIA/FISH results (when considering trisomy-7 [Tri-7] as a marker of benign disease) yielded a 100% specificity and increased sensitivity one- to fivefold in PSC patients versus RC, and two- to fivefold in patients without PSC, depending on how suspicious cytology results were interpreted. For the most difficult-to-manage patients with negative cytology and histology who were later proven to have malignancy (N = 21), DIA, FISH, composite DIA/FISH, and IDUS were able to predict malignant diagnoses in 14%, 62%, 67%, and 86%, respectively. CONCLUSIONS: DIA, FISH, and IDUS enhance the accuracy of standard techniques in evaluation of indeterminate bile duct strictures, allowing diagnosis of malignancy in a substantial number of patients with false-negative cytology and histology. These findings support the routine use of these newer diagnostic modalities in patients with indeterminate biliary strictures. [ABSTRACT FROM AUTHOR]

Human sulfatase 1 (SULF1) was recently identified and shown to desulfate cellular heparan sulfate proteoglycans (HSPGs). Since sulfated HSPGs serve as co-receptors for many growth factors and cytokines, SULF1 was predicted to modulate growth factor and cytokine signaling. The role of SULF1 in growth factor signaling and its effects on human tumorigenesis are under active investigation. Initial results show that SULF1 inhibits the co-receptor function of HSPGs in multiple receptor tyrosine kinase signaling pathways, particularly by the heparin binding growth factors—fibroblast growth factor 2, vascular endothelial growth factor, hepatocyte growth factor, PDGF, and heparin-binding epidermal growth factor (HB-EGF). SULF1 is downregulated in the majority of cancer cell lines examined, and forced expression of SULF1 decreases cell proliferation, migration, and invasion. SULF1 also promotes drug-induced apoptosis of cancer cells in vitro and inhibits tumorigenesis and angiogenesis in vivo. Strategies targeting SULF1 or the interaction between SULF1 and the related sulfatase 2 will potentially be important in developing novel cancer therapies. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CC) is a rare yet frequently fatal tumor that causes significant morbidity and mortality due to late presentation. Radiology is the mainstay of CC diagnosis; however, advances in understanding the pathogenesis of CC, including the role of oncogenes, inflammation-mediated genomic instability, and interleukin-6/STAT-3 signaling pathways, may allow development of new diagnostic and prognostic markers and targets for CC therapy. Although surgical resection is the standard of care for resectable CC, liver transplantation has shown excellent results in selected patients. The use of chemotherapy and radiotherapy are currently limited by marginal response rates, toxicity, and biliary complications. Locally ablative therapies in the form of transcatheter arterial chemoembolization and radioembolization are under investigation. Molecular therapies (eg, epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor antagonists) and immunotherapy using diabodies are also under investigation for treatment of unresectable CC. [ABSTRACT FROM AUTHOR]

The variability in the prognosis of individuals with hepatocellular carcinoma (HCC) suggests that HCC may comprise several distinct biological phenotypes. These phenotypes may result from activation of different oncogenic pathways during tumorigenesis and/or from a different cell of origin. Here we address whether the transcriptional characteristics of HCC can provide insight into the cellular origin of the tumor. We integrated gene expression data from rat fetal hepatoblasts and adult hepatocytes with HCC from human and mouse models. Individuals with HCC who shared a gene expression pattern with fetal hepatoblasts had a poor prognosis. The gene expression program that distinguished this subtype from other types of HCC included markers of hepatic oval cells, suggesting that HCC of this subtype may arise from hepatic progenitor cells. Analyses of gene networks showed that activation of AP-1 transcription factors in this newly identified HCC subtype might have key roles in tumor development. [ABSTRACT FROM AUTHOR]

Purpose: Production of reactive oxygen species (ROS) during chronic inflammation has been implicated in the progression of liver diseases and carcinogenesis. Subjects with inflammatory liver disease and one non-functional allele of the base excision repair gene, MYH, may be more susceptible to progression to cancer due to MYH haploinsufficiency in repairing oxidative damage caused by ROS. Here, we investigated the association of two common germline MYH mutations in patients with hepatocellular carcinoma (HCC) and cholangiocarcinoma. Methods: DNA from patients with HCC ( n=48) or cholangiocarcinoma ( n=84) compared to non-cancerous controls ( n=308) were genotyped for the Y165C and G382D mutations in MYH. Results: There was no significant difference in MYH mutation carrier status between patients with HCC (1/48), cholangiocarcinoma (3/84), and non-cancerous controls (4/308). Conclusions: Patients with HCC or cholangiocarcinoma do not have an increased incidence of monoallelic MYH mutations pre-disposing them to disease. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIM: The aim of this study was to assess the relative sensitivities and specificities of fluorescencein situhybridization (FISH) and routine cytology for the detection of malignancy in biliary tract strictures.METHODS: Bile duct brushing and aspirate specimens were collected from 131 patients being evaluated for possible malignant bile duct strictures. Both specimen types were assessed by FISH but only brushing specimens were assessed by cytology. The FISH assay used a mixture of fluorescently-labeled probes to the centromeres of chromosomes 3, 7, and 17 and chromosomal band 9p21 (Vysis® UroVysion) to identify cells having chromosomal abnormalities. A case was considered positive for malignancy if five or more cells exhibited polysomy.RESULTS: Sixty-six of the 131 patients had surgical pathologic and/or clinical evidence of malignancy. Thirty-nine patients had cholangiocarcinoma, 19 had pancreatic carcinoma, and 8 had other types of malignancy. The sensitivity of cytology and FISH for the detection of malignancy in bile duct brushing specimens in these patients was 15% and 34% (p < 0.01), respectively. The sensitivity of FISH for the bile aspirate specimens was 23%, and the combined sensitivity of FISH for aspirate and brushing specimens was 35%. The specificity of FISH and cytology brushings were 91% and 98% (p= 0.06), respectively.CONCLUSIONS: FISH is significantly more sensitive than and nearly as specific as conventional cytology for the detection of malignant biliary strictures in biliary brushing specimens. FISH may improve the clinical management of patients who are being evaluated for malignancy in bile duct strictures.(Am J Gastroenterol 2004;99:1675-1681) [ABSTRACT FROM AUTHOR]

Recently, we cloned a novel sulfatase domain-containing downregulated gene, HSulf-1, which modulates heparin-binding growth factor signaling in ovarian cancer. Based on the pilot data showing the loss of HSulf-1 in head and neck squamous cell carcinoma cell lines (SCCHN), we sought to employ SCCHN as a model to define the role of HSulf-1 in the molecular regulation of tumorigenecity. Three SCCHN lines (012SCC, WMMSCC, and 015SCC) had no detectable HSulf-1 mRNA. Clonal lines of HSulf-1-expressing 012SCC attenuated the activation of ERK/mitogen-activated protein kinase (MAPK) signaling mediated by fibroblast growth factor (FGF-2) and both ERK/MAPK and Akt signaling mediated by hepatocyte growth factor (HGF). Consistent with this downregulation, phosphorylation of HGF receptor, c-Met, which is frequently overexpressed in SCCHN, was also attenuated in HSulf-1 clonal 012SCC cell lines. HGF markedly enhanced the motility and migration of vector-transfected cells in a transwell invasion chamber. However, HGF-mediated motility and invasion was attenuated in HSulf-1 clonal 012SCC cell lines. In addition, transfected cells displayed significant growth inhibition concomitant with a decrease in mitogenecity, as measured by thymidine incorporation and increased sensitivity to staurosporine- and cisplatin-induced apoptosis. These data suggest that HSulf-1 normally functions as a negative regulator in cell growth and loss of HSulf-1 in SCCHN potentiates growth factor signaling, enhances motility, invasiveness and inhibits stress-induced apoptosis, with a resulting increase in tumorigenecity.Oncogene (2004) 23, 1439-1447. doi:10.1038/sj.onc.1207258 [ABSTRACT FROM AUTHOR]

Investigates the mutational status and expression of the β-catenin gene CTNNB1 and the component proteins of the Wnt signal transduction pathway AXIN1 and AXIN2 genes in both hepatocellular carcinoma and hepatoblastoma. Information on HCC and HB; Roles of CTNNB1, AXIN1 and AXIN2 in liver carcinogenesis; Details of the pathogenesis of primary liver tumors.

Cathepsins B and D appear to act as part of the effector protease cascade in hepatocyte apoptosis, both in bile salt-induced apoptosis and CPT-induced apoptosis of hepatocellular cancer cell lines. It is important to note that these proteases do not appear to participate in many models of apoptosis studied to date; in fact, cathepsin inhibitors have been used as negative controls to show that enzymes other than caspases are not involved in apoptosis. In particular, it has been shown that cathepsin B inhibitors do not prevent many models of apoptosis in lymphocytes ( 43). Further, our experiments have shown that not all models of hepatocyte apoptosis are mediated by cathepsins. For example, staurosporine-induced apoptosis is not inhibited by cathepsin B inhibitors in primary hepatocytes or in cell lines stably transfected with the cathepsin B antisense construct. Although the signaling pathways leading to activation of cathepsins B and D in hepatocyte apoptosis are not completely understood, we hypothesize that a caspase 8-like protein may be involved proximal to cathepsins D and B (Fig. 6). The precise mechanism by which cathepsin B is translocated from lysosomes to “apoptotic targets” is currently under investigation in our laboratory. Because of the relative promiscuity of cathepsin B as protease, it is likely that it is involved in nonspecific protein degradation in apoptotic bodies; however, cathepsin B has also been shown to degrade certain specific proteins, such as histones, which may be directly relevant to the apoptotic process. Further evaluation of the role of cathepsins B and D in apoptosis should include the determination of specific proteolytic targets that result in the biochemical and morphologic manifestations of apoptosis. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor related to liver carcinogenesis.

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in the world. Elevated glucose metabolism in the availability of oxygen, a phenomenon called the Warburg effect, is important for cancer cell growth. Fructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeogenesis and is frequently lost in various types of cancer. Here, we demonstrated that expression of FBP1 was downregulated in HCC patient specimens and decreased expression of FBP1 associated with poor prognosis. Low expression of FBP1 correlated with high levels of histone deacetylase 1 (HDAC1) and HDAC2 proteins in HCC patient tissues. Treatment of HCC cells with HDAC inhibitors or knockdown of HDAC1 and/or HDAC2 restored FBP1 expression and inhibited HCC cell growth. HDAC-mediated suppression of FBP1 expression correlated with decreased histone H3 lysine 27 acetylation (H3K27Ac) in the FBP1 enhancer. Restored expression of FBP1 decreased glucose reduction and lactate secretion and inhibited HCC cell growth in vitro and tumor growth in mice. Our data reveal that loss of FBP1 due to histone deacetylation associates with poor prognosis of HCC and restored FBP1 expression by HDAC inhibitors suppresses HCC growth. Our findings suggest that repression of FBP1 by HDACs has important implications for HCC prognosis and treatment. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the second-leading cause of cancer-related death worldwide, and the factors influencing HCC progression are poorly understood. Here we reveal that HCC progression via induction of epithelial-mesenchymal transition (EMT) is closely associated with the expression of CD36/fatty acid translocase and elevated free fatty acid (FFA) levels. Although obesity is manifested as elevated FFA levels, the degree of EMT was not associated with the body mass index of the patients, highlighting the specific roles of CD36 and FFA uptake. Treatment of human liver cancer cell lines with FFAs exacerbated the EMT phenotype, whereas chemical inhibition of CD36 mitigated these effects. Furthermore, the Wnt and TGF-β signaling pathways were activated upon FFA treatment, potentially acting as upstream activators of the EMT program. These results provide the first direct evidence associating CD36 and elevated FFAs with HCC progression. [ABSTRACT FROM AUTHOR]