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OBJECTIVE To compare outcomes of fenestrated (FEVAR) and open repairs of complex abdominal aortic aneurysms (cAAA). BACKGROUND FEVAR has emerged as an alternative to open surgery for treating cAAA, but direct comparisons are limited. METHODS We studied all repairs of intact or symptomatic cAAA in the Vascular Quality Initiative between 2012 and 2018, excluding chimney/snorkels and any devices implanted under Investigational Device Exemption studies. We compared open repairs, commercially available FEVAR devices and physician-modified endografts (PMEG) using inverse probability weighting. As a secondary analysis, we compared PMEG separately. RESULTS We identified 3253 cAAA repairs: 2125 open (65%), 877 FEVAR (27%), and 251 PMEG (8%). Patients undergoing FEVAR were older, with larger aneurysms, and more comorbidities. Propensity-weighted perioperative mortality was similar between open repair and FEVAR (4.7% vs 3.3%, respectively, P = 0.17), but open repair was associated with higher rates of myocardial infarction (5.0% vs 3.0%, P = 0.03), acute kidney injury (25% vs 16%, P < 0.001), and new dialysis (4.3% vs 2.1%, P = 0.003). However, propensity-weighted long-term mortality was higher following FEVAR [Hazard Ratio (HR) 1.7 (1.1-2.6), P = 0.02]. Although outcomes of commercially available FEVAR and PMEG were similar, there was a trend toward higher long-term mortality with PMEG compared to FEVAR [HR 1.7 (0.9-3.1), P = 0.09). CONCLUSIONS In patients undergoing cAAA repair, open surgery was associated with higher overall survival than FEVAR and similar perioperative mortality, but longer lengths of stay, and higher rates of postoperative renal dysfunction and MI. PMEG were associated with similar perioperative results as commercially available FEVAR, but further study is needed to establish their long-term durability.

Background Cholestatic liver diseases are a major source of morbidity and mortality that can progress to end-stage liver disease and hyperbilirubinemia is a hallmark of cholestasis. There are few effective medical therapies for primary biliary cholangitis, primary sclerosing cholangitis and other cholestatic liver diseases, in part, due to our incomplete understanding of the pathogenesis of cholestatic liver injury. The hepatic unfolded protein response (UPR) is an adaptive cellular response to endoplasmic reticulum stress that is important in the pathogenesis of many liver diseases and recent animal studies have demonstrated the importance of the UPR in the pathogenesis of cholestatic liver injury. However, the role of the UPR in human cholestatic liver diseases is largely unknown. Methods RNA was extracted from liver biopsies from patients after liver transplantation. RNA-seq was performed to determine the transcriptional profile and hepatic UPR gene expression that is associated with liver injury and cholestasis. Results Transcriptome analysis revealed that patients with hyperbilirubinemia had enhanced expression of hepatic UPR pathways. Alternatively, liver biopsy samples from patients with acute rejection had enhanced gene expression of LAG3 and CDK1. Pearson correlation analysis of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin levels demonstrated significant correlations with the hepatic expression of several UPR genes, as well as genes involved in hepatic bile acid metabolism and inflammation. In contrast, serum alkaline phosphatase levels were correlated with the level of hepatic bile acid metabolism gene expression but not liver UPR gene expression. Conclusions Overall, these data indicate that hepatic UPR pathways are increased in cholestatic human liver biopsy samples and supports an important role of the UPR in the mechanism of human cholestatic liver injury.

Summary Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen triggers an unfolded protein response (UPR) for stress adaptation, the failure of which induces cell apoptosis and tissue/organ damage. The molecular switches underlying how the UPR selects for stress adaptation over apoptosis remain unknown. Here, we discovered that accumulation of unfolded/misfolded proteins selectively induces N6-adenosine-methyltransferase-14 (METTL14) expression. METTL14 promotes C/EBP-homologous protein (CHOP) mRNA decay through its 3′ UTR N6-methyladenosine (m6A) to inhibit its downstream pro-apoptotic target gene expression. UPR induces METTL14 expression by competing against the HRD1-ER-associated degradation (ERAD) machinery to block METTL14 ubiquitination and degradation. Therefore, mice with liver-specific METTL14 deletion are highly susceptible to both acute pharmacological and alpha-1 antitrypsin (AAT) deficiency-induced ER proteotoxic stress and liver injury. Further hepatic CHOP deletion protects METTL14 knockout mice from ER-stress-induced liver damage. Our study reveals a crosstalk between ER stress and mRNA m6A modification pathways, termed the ERm6A pathway, for ER stress adaptation to proteotoxicity.

There is limited data on the effect of antiviral therapies on clinical outcomes in HIV and hepatitis B virus (HBV)-infected individuals in sub-Saharan Africa.Single center, prospective longitudinal cohort study at Management and Development for Health supported HIV Care and Treatment clinics in Dar es Salaam, Tanzania.Between April 2014 and December 2015, HIV-infected, HBV-infected and HIV/HBV-coinfected, treatment naïve, Tanzanian adults more than 18 years of age were eligible for enrollment and followed for 10-18 months after initiating antivirals. All HIV-infected and HIV/HBV-coinfected participants received tenofovir, lamivudine and efavirenz; HBV-infected participants received lamivudine. Multivariate regression models were constructed to identify factors associated with mortality in HIV-infected and HIV/HBV-coinfected participants.A total of 265 HIV-infected, 165 HBV-infected and 64 HIV/HBV-coinfected participants were analyzed. At baseline, HBV-infected participants were younger and had a higher BMI than HIV-infected and HIV/HBV-coinfected participants. After a median of 371 (interquartile range 50) days on treatment, there were 40 deaths. Mortality was significantly higher among HIV/HBV-coinfected participants compared with HIV and HBV-infected participants [HIV/HBV-coinfected 12 of 64 (19%) vs. HIV-infected 26 of 265 (10%) and HBV-infected two of 265 (1%), P 0.01]. High baseline HIV RNA and low hemoglobin levels, but not HBV coinfection were independently associated with early mortality in multivariate analyses of HIV-infected participants.High rates of early mortality were observed after treatment initiation in HIV/HBV-coinfected individuals compared with participants with HIV or HBV alone, despite robust aspartate aminotransferase to platelet ratio index declines and high rates of virologic suppression. HIV rather than HBV-related factors are more important contributors to mortality in these individuals.

Background and aimsPrimary sclerosing cholangitis (PSC) is a heterogeneous cholangiopathy characterized by progressive biliary fibrosis. RNA sequencing of liver tissue from patients with PSC (n=74) enrolled in a 96-week clinical trial was performed to identify associations between biological pathways that were independent of fibrosis and clinical events.Approach and resultsThe effect of fibrosis was subtracted from gene expression using a computational approach. The fibrosis-adjusted gene expression patterns were associated with time to first PSC-related clinical event (e.g., cholangitis, hepatic decompensation), and differential expression based on risk groups and Ingenuity Pathway Analysis were performed. Baseline demographic data were representative of PSC: median age 48years, 71% male, 49% with inflammatory bowel disease, and 44% with bridging fibrosis or cirrhosis. The first principle component (PC1) of RNA-sequencing data accounted for 18% of variance and correlated with fibrosis stage (ρ=-0.80; P0.05). The top pathways identified by Ingenuity Pathway Analysis were eukaryotic translation inhibition factor 2 (eIF2) signaling and regulation of eIF4/p70S6K signaling. Genes involved in the unfolded protein response, activating transcription factor 6 (ATF6) and eIF2, were differentially expressed between the PSC clusters (down-regulated in the high-risk group by log-fold changes of -0.18 [P=0.02] and -0.16 [P=0.02], respectively). Clinical events were enriched in the high-risk versus low-risk group (38% [12/32] vs. 2.4% [1/42], P&nbsp

Background & aims Limited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in non-diseased human liver; however, no studies to date fully define the heterogeneous macrophage subsets during the pathogenesis of cholestasis. Here, we aim to further characterize the transcriptional profile of macrophages in pediatric cholestatic liver disease. Methods We isolated live hepatic immune cells from patients with biliary atresia (BA), Alagille syndrome (ALGS), and non-cholestatic pediatric liver by fluorescence activated cell sorting. Through single-cell RNA sequencing analysis and immunofluorescence, we characterized cholestatic macrophages. We next compared the transcriptional profile of pediatric cholestatic and non-cholestatic macrophage populations to previously published data on normal adult hepatic macrophages. Results We identified 3 distinct macrophage populations across cholestatic liver samples and annotated them as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages based on their transcriptional profile. Immunofluorescence of liver tissue using markers for each subset confirmed their presence across BA (n = 6) and ALGS (n = 6) patients. Cholestatic macrophages demonstrated reduced expression of immune regulatory genes as compared to normal hepatic macrophages and were distinct from macrophage populations defined in either healthy adult or pediatric non-cholestatic liver. Conclusions We are the first to perform single-cell RNA sequencing on human pediatric cholestatic liver and identified three macrophage subsets with distinct transcriptional signatures from healthy liver macrophages. Further analyses will identify similarities and differences in these macrophage sub-populations across etiologies of cholestatic liver disease. Taken together, these findings may allow for future development of targeted therapeutic strategies to reprogram macrophages to an immune regulatory phenotype and reduce cholestatic liver injury.

Mucormycosis infrequently may present with isolated renal involvement. Among solid organ transplant recipients, renal allograft mucormycosis has been most often associated with medical tourism or transplantation outside of the western world. We report a case of an HIV/HCV co-infected woman who underwent simultaneous liver and kidney transplantation with a Public Health Service increased risk donor organ. 16 days after transplant, she developed massive hematuria and was found to have renal allograft Rhizopus spp. involvement, we surmise to have been from donor-derived infection. Therapy included nephrectomy, debridement, liposomal amphotericin B, and posaconazole with survival. We reviewed PubMed indexed, English-language cases of isolated renal mucormycosis in general, in HIV/AIDS, and from donor-derived renal allograft infections.

NAFLD is an important public health issue closely associated with the pervasive epidemics of diabetes and obesity. Yet, despite NAFLD being among the most common of chronic liver diseases, the biological factors responsible for its transition from benign nonalcoholic fatty liver (NAFL) to NASH remain unclear. This lack of knowledge leads to a decreased ability to find relevant animal models, predict disease progression, or develop clinical treatments. In the current study, we used multiple mouse models of NAFLD, human correlation data, and selective gene overexpression of steroidogenic acute regulatory protein (StarD1) in mice to elucidate a plausible mechanistic pathway for promoting the transition from NAFL to NASH. We show that oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory oxysterols generated by the “acidic/alternative” pathway of cholesterol metabolism. Specifically, we report data showing that an inability to upregulate CYP7B1, in the setting of insulin resistance, results in the accumulation of toxic intracellular cholesterol metabolites that promote inflammation and hepatocyte injury. This metabolic pathway, initiated and exacerbated by insulin resistance, offers insight into approaches for the treatment of NAFLD.

Three dimensional (3D) printing is highly amenable to the fabrication of tissue-engineered organs of a repetitive microstructure such as the liver. The creation of uniform and geometrically repetitive tissue scaffolds can also allow for the control over cellular aggregation and nutrient diffusion. However, the effect of differing geometries, while controlling for pore size, has yet to be investigated in the context of hepatocyte function. In this study, we show the ability to precisely control pore geometry of 3D-printed gelatin scaffolds. An undifferentiated hepatocyte cell line (HUH7) demonstrated high viability and proliferation when seeded on 3D-printed scaffolds of two different geometries. However, hepatocyte specific functions (albumin secretion, CYP activity, and bile transport) increases in more interconnected 3D-printed gelatin cultures compared to a less interconnected geometry and to 2D controls. Additionally, we also illustrate the disparity between gene expression and protein function in simple 2D culture modes, and that recreation of a physiologically mimetic 3D environment is necessary to induce both expression and function of cultured hepatocytes. Statement of Significance Three dimensional (3D) printing provides tissue engineers the ability spatially pattern cells and materials in precise geometries, however the biological effects of scaffold geometry on soft tissues such as the liver have not been rigorously investigated. In this manuscript, we describe a method to 3D print gelatin into well-defined repetitive geometries that show clear differences in biological effects on seeded hepatocytes. We show that a relatively simple and widely used biomaterial, such as gelatin, can significantly modulate biological processes when fabricated into specific 3D geometries. Furthermore, this study expands upon past research into hepatocyte aggregation by demonstrating how it can be manipulated to enhance protein function, and how function and expression may not precisely correlate in 2D models.

In sub-Saharan Africa, the burden of liver disease associated with chronic hepatitis B virus (HBV) and HIV is unknown. We characterized liver disease using aspartate aminotransferase-to-platelet ratio index (APRI) and FIB-4 in patients with HIV, HBV, and HIV/HBV coinfection in Tanzania.Using a cross-sectional design, we compared the prevalence of liver fibrosis in treatment-naive HIV monoinfected, HBV monoinfected, and HIV/HBV-coinfected adults enrolled at Management and Development for Health (MDH)-supported HIV treatment clinics in Dar es Salaam, Tanzania. Risk factors associated with significant fibrosis (APRI0.5 and FIB-41.45) were examined.Two hundred sixty-seven HIV-infected, 165 HBV-infected, and 63 HIV/HBV-coinfected patients were analyzed [44% men, median age 37 (interquartile range 14), body mass index 23 (7)]. APRI and FIB-4 were strongly correlated (r = 0.78, P0.001, R = 0.61). Overall median APRI scores were low {HIV/HBV [0.36 (interquartile range 0.4)], HIV [0.23 (0.17)], HBV [0.29 (0.15)] (P0.01)}. In multivariate analyses, HIV/HBV coinfection was associated with APRI0.5 [HIV/HBV vs. HIV: odds ratio (OR) 3.78 (95% confidence interval: 1.91 to 7.50)], [HIV/HBV vs. HBV: OR 2.61 (1.26 to 5.44)]. HIV RNA per 1 log10 copies/mL increase [OR 1.53 (95% confidence interval: 1.04 to 2.26)] and HBV DNA per 1 log10 copies/mL increase [OR 1.36 (1.15, 1.62)] were independently associated with APRI0.5 in HIV-infected and HBV-infected patients, respectively.HIV/HBV coinfection is an important risk factor for significant fibrosis. Higher levels of circulating HIV and HBV virus may play a direct role in liver fibrogenesis. Prompt diagnosis and aggressive monitoring of liver disease in HIV/HBV coinfection is warranted.

Obesity or a high-fat diet represses the endoribonuclease activity of inositol-requiring enzyme 1α (IRE1α), a transducer of the unfolded protein response (UPR) in cells under endoplasmic reticulum (ER) stress. An impaired UPR is associated with hepatic steatosis and nonalcoholic fatty liver disease (NAFLD), which is caused by lipid accumulation in the liver. We found that IRE1α was critical to maintaining lipid homeostasis in the liver by repressing the biogenesis of microRNAs (miRNAs) that regulate lipid mobilization. In mice fed normal chow, the endoribonuclease function of IRE1α processed a subset of precursor miRNAs in the liver, including those of the miR-200 and miR-34 families, such that IRE1α promoted their degradation through the process of regulated IRE1-dependent decay (RIDD). A high-fat diet in mice or hepatic steatosis in patients was associated with the S-nitrosylation of IRE1α and inactivation of its endoribonuclease activity. This resulted in an increased abundance of these miRNA families in the liver and, consequently, a decreased abundance of their targets, which included peroxisome proliferator-activated receptor α (PPARα) and the deacetylase sirtuin 1 (SIRT1), regulators of fatty acid oxidation and triglyceride lipolysis. IRE1α deficiency exacerbated hepatic steatosis in mice. The abundance of the miR-200 and miR-34 families was also increased in cultured, lipid-overloaded hepatocytes and in the livers of patients with hepatic steatosis. Our findings reveal a mechanism by which IRE1α maintains lipid homeostasis through its regulation of miRNAs, a regulatory pathway distinct from the canonical IRE1α-UPR pathway under acute ER stress.

CONTEXT Neurocytoma (NC) is a rare, low-grade tumor of the central nervous system, with a 10-year survival rate of 90% and local control rate of 74%. However, 25% of NCs will be atypical, with an elevated Ki-67 labeling index >2%, and will exhibit a more aggressive course, with a high propensity for local recurrence and/or craniospinal dissemination. Although no standard treatment regimen exists for these atypical cases, adjuvant stereotactic or conventional radiotherapy and/or chemotherapy have been typically offered but have yielded inconsistent results. CASE DESCRIPTION We have described the case of a patient with a vasopressin-secreting atypical NC of the sellar and cavernous sinus region. After subtotal resection via endoscopic transsphenoidal surgery, the residual tumor showed increased fluorodeoxyglucose uptake and high somatostatin receptor (SSTR) expression on a 68Ga-DOTA-TATE positron emission tomography/CT scan. Somatostatin receptor ligand (SRL) therapy with lanreotide (120 mg every 28 days) was initiated. Four years later, the residual tumor was stable with decreased fluorodeoxyglucose tumor uptake. Immunocytochemical SSTR2 and SSTR5 expression >80% was further confirmed in a series of NC tissues. CONCLUSIONS To the best of our knowledge, we have described the first use of SRL therapy for an atypical NC. Our results support consideration of adjuvant SRL therapy for NC refractory to surgical removal. Our findings further raise the possibility of SSTR-directed peptide receptor radionuclide therapy as NC therapy.

The endocrine system is responsible for growth, development, maintaining homeostasis and for the control of many physiological processes. Due to the integral nature of its signaling pathways, it can be difficult to distinguish endocrine-mediated adverse effects from transient fluctuations, adaptive/compensatory responses, or adverse effects on the endocrine system that are caused by mechanisms outside the endocrine system. This is particularly true in toxicological studies that require generation of effects through the use of Maximum Tolerated Doses (or Concentrations). Endocrine-mediated adverse effects are those that occur as a consequence of the interaction of a chemical with a specific molecular component of the endocrine system, for example, a hormone receptor. Non-endocrine-mediated adverse effects on the endocrine system are those that occur by other mechanisms. For example, systemic toxicity, which perturbs homeostasis and affects the general well-being of an organism, can affect endocrine signaling. Some organs/tissues can be affected by both endocrine and non-endocrine signals, which must be distinguished. This paper examines in vitro and in vivo endocrine endpoints that can be altered by non-endocrine processes. It recommends an evaluation of these issues in the assessment of effects for the determination of endocrine disrupting properties of chemicals. This underscores the importance of using a formal weight of evidence (WoE) process to evaluate potential endocrine activity.

The ongoing debate concerning the regulation of endocrine disruptors, has increasingly led to questions concerning the current testing of chemicals and whether this is adequate for the assessment of potential endocrine disrupting effects. This paper describes the current testing approaches for plant protection product (PPP) active substances in the European Union and the United States and how they relate to the assessment of endocrine disrupting properties for human and environmental health. This includes a discussion of whether the current testing approaches cover modalities other than the estrogen, androgen, thyroid and steroidogenesis (EATS) pathways, sensitive windows of exposure, adequate assessment of human endocrine disorders and wildlife species, and the determination of thresholds for endocrine disruption. It is concluded, that the scope and nature of the core and triggered data requirements for PPP active substances are scientifically robust to address adverse effects mediated through endocrine mode(s) of action and to characterise these effects in terms of dose response.

Bile acids are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR), and pharmacological FXR modulators are under development for the treatment of several liver disorders. The inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the unfolded protein response (UPR) is a protective cellular signaling pathway activated in response to endoplasmic reticulum (ER) stress. We investigated the role of FXR signaling in activation of the hepatic XBP1 pathway. Mice were treated with deoxycholic acid (DCA), cholestyramine, GW4064, or underwent bile duct ligation (BDL), and hepatic UPR activation was measured. Huh7-Ntcp and HepG2 cells were treated with FXR agonists, inhibitor, small interfering RNA (siRNA), or small heterodimer partner (SHP) siRNA to determine the mechanisms of IRE1α/XBP1 pathway activation. DCA feeding and BDL increased and cholestyramine decreased expression of hepatic XBP1 spliced (XBP1s). XBP1 pathway activation increased in Huh7-Ntcp and HepG2 cells treated with bile acids, 6α-ethyl-chenodeoxycholic acid (6-ECDCA) or GW4064. This effect decreased with FXR knockdown and treatment with the FXR inhibitor guggulsterone. FXR agonists increased XBP1 splicing and phosphorylated IRE1α (p-IRE1α) expression. Overexpression of SHP similarly increased XBP1 splicing, XBP1s, and p-IRE1α protein expression. SHP knockdown attenuated FXR agonist-induced XBP1s and p-IRE1α protein expression. Co-immunoprecipitation (Co-IP) assays demonstrate a physical interaction between overexpressed green fluorescent protein (GFP)-SHP and FLAG-IRE1α in HEK293T cells. Mice treated with GW4064 had increased, and FXR and SHP null mice had decreased, basal Xbp1s gene expression. Conclusion FXR signaling activates the IRE1α/XBP1 pathway in vivo and in vitro. FXR pathway activation increases XBP1 splicing and enhances p-IRE1α expression. These effects are mediated, at least in part, by SHP. IRE1α/XBP1 pathway activation by bile acids and pharmacological FXR agonists may be protective during liver injury and may have therapeutic implications for liver diseases. (Hepatology 2018;68:304-316).

Fatty liver is associated with endoplasmic reticulum stress and activation of the hepatic unfolded protein response (UPR). Reduced hepatic expression of the UPR regulator X-box binding protein 1 spliced (XBP1s) is associated with human nonalcoholic steatohepatitis (NASH), and feeding mice a high-fat diet with fructose/sucrose causes progressive, fibrosing steatohepatitis. This study examines the role of XBP1 in nonalcoholic fatty liver injury and fatty acid-induced cell injury. Hepatocyte-specific Xbp1-deficient ( Xbp1−/−) mice were fed a high-fat/sugar (HFS) diet for up to 16 wk. HFS-fed Xbp1−/−mice exhibited higher serum alanine aminotransferase levels compared with Xbp1fl/flcontrols. RNA sequencing and Gene Ontogeny pathway analysis of hepatic mRNA revealed that apoptotic process, inflammatory response, and extracellular matrix structural constituent pathways had enhanced activation in HFS-fed Xbp1−/−mice. Liver histology demonstrated enhanced injury and fibrosis but less steatosis in the HFS-fed Xbp1−/−mice. Hepatic Col1a1 and Tgfβ1 gene expression, as well as Chop and phosphorylated JNK (p-JNK), were increased in Xbp1−/−compared with Xbp1fl/flmice after HFS feeding. In vitro, stable XBP1-knockdown Huh7 cells (Huh7-KD) and scramble control cells (Huh7-SCR) were generated and treated with palmitic acid (PA) for 24 h. PA-treated Huh7-KD cells had increased cytotoxicity measured by lactate dehydrogenase release, apoptotic nuclei, and caspase3/7 activity assays compared with Huh7-SCR cells. CHOP and p-JNK expression was also increased in Huh7-KD cells following PA treatment. In conclusion, loss of XBP1 enhances injury in both in vivo and in vitro models of fatty liver injury. We speculate that hepatic XBP1 plays an important protective role in pathogenesis of NASH.

The endoplasmic reticulum-associated protein degradation (ERAD) is responsible for recognizing and retro-translocating protein substrates, misfolded or not, from the ER for cytosolic proteasomal degradation. HMG-CoA Reductase (HMGCR) Degradation protein-HRD1-was initially identified as an E3 ligase critical for ERAD. However, its physiological functions remain largely undefined. Herein, we discovered that hepatic HRD1 expression is induced in the postprandial condition upon mouse refeeding. Mice with liver-specific HRD1 deletion failed to repress FGF21 production in serum and liver even in the refeeding condition and phenocopy the FGF21 gain-of-function mice showing growth retardation, female infertility, and diurnal circadian behavior disruption. HRD1-ERAD facilitates the degradation of the liver-specific ER-tethered transcription factor CREBH to downregulate FGF21 expression. HRD1-ERAD catalyzes polyubiquitin conjugation onto CREBH at lysine 294 for its proteasomal degradation, bridging a multi-organ crosstalk in regulating growth, circadian behavior, and female fertility through regulating the CREBH-FGF21 regulatory axis.

Background Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. Methods After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). Results For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. Conclusions Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1; initially registered 19 September 2002

A Weight-of-evidence (WoE) evaluation should be applied in assessing all the available data for the identification of endocrine disrupting (ED) properties of chemicals. The European Commission draft acts specifying criteria under the biocidal products and plant protection products regulations require that WoE is implemented for the assessment of such products. However, only some general considerations and principles of how a WoE should be conducted are provided. This paper reviews WoE approaches to distil key recommendations specifically for the evaluation of potential ED properties of chemicals. In a manner, which is consistent with existing, published WoE frameworks, the WoE evaluation of ED properties can be divided into four phases: 1) Definition of causal questions and data gathering and selection, 2) Review of individual studies, 3) Data integration and evaluation, and 4) Drawing conclusions based on inferences. Recommendations are made on how to conduct each phase robustly and transparently to help guide the WoE evaluation of potential endocrine disrupting properties of chemicals within a European regulatory context.

PURPOSE:To assess the safety and efficacy of upfront treatment using bortezomib combined with standard radiation therapy (RT) and temozolomide (TMZ), followed by adjuvant bortezomib and TMZ for ≤24 cycles, in patients with newly diagnosed glioblastoma multiforme (GBM). METHODS AND MATERIALS:Twenty-four patients with newly diagnosed GBM were enrolled. The patients received standard external beam regional RT with concurrent TMZ beginning 3 to 6weeks after surgery, followed by adjuvant TMZ and bortezomib for ≤24 cycles or until tumor progression. During RT, bortezomib was given at 1.3mg/m2 on days 1, 4, 8, 11, 29, 32, 36, and 39. After RT, bortezomib was given at 1.3mg/m2 on days 1, 4, 8, and 11 every 4weeks. RESULTS:No unexpected adverse events occurred from the addition of bortezomib. The efficacy analysis showed a median progression-free survival (PFS) of 6.2months (95% confidence interval [CI] 3.7-8.8), with promising PFS rates at ≥18months compared with historical norms (25.0% at 18 and 24months; 16.7% at 30months). In terms of overall survival (OS), the median OS was 19.1months (95% CI 6.7-31.4), with improved OS rates at ≥12months (87.5% at 12, 50.0% at 24, 34.1% at 36-60months) compared with the historical norms. The median PFS was 24.7months (95% CI 8.5-41.0) in 10 MGMT methylated and 5.1months (95% CI 3.9-6.2) in 13 unmethylated patients. The estimated median OS was 61months (95% CI upper bound not reached) in the methylated and 16.4months (95% CI 11.8-21.0) in the unmethylated patients. CONCLUSIONS:The addition of bortezomib to current standard radiochemotherapy in newly diagnosed GBM patients was tolerable. The PFS and OS rates appeared promising, with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients.

Hepatocellular carcinoma (HCC) is the third leading form of cancer worldwide, and its incidence is increasing rapidly in the United States, tripling over the past 3 decades. The current chemotherapeutic strategies against localized and metastatic HCC are ineffective. Here we report that 6-methoxyethylamino-numonafide (MEAN) is a potent growth inhibitor of murine xenografts of 2 human HCC cell lines. At the same dose and with the same treatment strategies, MEAN was more efficacious in inhibiting tumor growth in mice than sorafenib, the only approved drug for HCC. Treatment by MEAN at an effective dose for 6 wk was well tolerated by animals. Combined therapy using both sorafenib and MEAN enhanced tumor growth inhibition over monotherapy with either agent. Additional experiments revealed that MEAN inhibited tumor growth through mechanisms distinct from those of either its parent compound, amonafide, or sorafenib. MEAN suppressed C-MYC expression and increased expression of several tumor suppressor genes, including Src homology region 2 domain-containing phosphatase-1 (SHP-1) and TXNIP (thioredoxin-interacting protein). As an encouraging feature for envisioned clinical application, the IC50 of MEAN was not significantly changed in several drug-resistant cell lines with activated P-glycoprotein drug efflux pumps compared to drug-sensitive parent cells, demonstrating the ability of MEAN to be effective in cells resistant to existing chemotherapy regimens. MEAN is a promising candidate for clinical development as a single-agent therapy or in combination with sorafenib for the management of HCC.-Liu, Y., Lou, G., Norton, J. T., Wang, C., Kandela, I., Tang, S., Shank, N. I., Gupta, P., Huang, M., Avram, M. J., Green, R., Mazar, A., Appella, D., Chen, Z., Huang, S. 6-Methoxyethylamino-numonafide inhibits hepatocellular carcinoma xenograft growth as a single agent and in combination with sorafenib.

The unfolded protein response (UPR) is an adaptive response to endoplasmic reticulum stress and the inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the UPR is important in lipid metabolism. However, its role in bile acid metabolism remains unknown. We demonstrate that liver-specific Xbp1 knockout (LS-Xbp1−/−) mice had a 45% reduction in total bile acid pool. LS-Xbp1−/− mice had lower serum 7α-hydroxy-4-cholesten-3-one (C4) levels compared with Xbp1fl/fl mice, indicating reduced cholesterol 7α-hydroxylase (CYP7A1) synthetic activity. This occurred without reductions of hepatic CYP7A1 protein expression. Feeding LS-Xbp1−/− mice cholestyramine increased hepatic CYP7A1 protein expression to levels 2-fold and 8-fold greater than cholestyramine-fed and chow-fed Xbp1fl/fl mice, respectively. However, serum C4 levels remained unchanged and were lower than both groups of Xbp1fl/fl mice. In contrast, although feeding LS-Xbp1−/− mice cholesterol did not increase CYP7A1 expression, serum C4 levels increased significantly up to levels similar to chow-fed Xbp1fl/fl mice and the total bile acid pool normalized. In conclusion, loss of hepatic XBP1 decreased the bile acid pool and CYP7A1 synthetic activity. Cholesterol feeding, but not induction of CYP7A1 with cholestyramine, increased CYP7A1 synthetic activity and corrected the genotype-specific total bile acid pools. These data demonstrate a novel role of IRE1α/XBP1 regulating bile acid metabolism.

Aim: Long-term survivors (LTS)after glioma recurrence while on bevacizumab (Bev)therapy are rarely reported in the current literature. The purpose of this case series is to confirm the existence of and describe a large cohort of recurrent glioma LTS treated with Bev (Bev-LTS). Patients & methods: We identified Bev-LTS as patients with post-Bev initiation survival times of ≥3 years among 1397 Bev treated recurrent glioma patients. Results: Among 962 grade-IV,221 grade III, and214 grade II Bev-treated glioma patients, we identified 28 (2.9%),14 (6.3%) and8(3.7%)Bev-LTS patients, respectively. 45Bev-LTS patients recurred on Bev, with 36 of those patients continuing therapy.Conclusion: Our study shows that a small portion of grade-IV, -III,and -II glioma patients can have long-term survival on Bev therapy even after Bev recurrence.

The unfolded protein response (UPR) is a protective cellular response activated under conditions of endoplasmic reticulum (ER) stress. The hepatic UPR is activated in several forms of liver disease including nonalcoholic fatty liver disease (NAFLD). Recent data defining the role of the UPR in hepatic lipid metabolism have identified molecular mechanisms that may underlie the association between UPR activation and NAFLD. It has become increasingly evident that the IRE1α/Xbp1 pathway of the UPR is critical for hepatic lipid homeostasis, and dysregulation of this evolutionarily conserved pathway is associated with human nonalcoholic steatohepatitis (NASH). Although increasing evidence has delineated the importance of UPR pathway signaling in fatty liver disorders, the regulation of the hepatic UPR in normal physiology and fatty liver disorders remains incompletely understood. Understanding the role of the UPR in hepatic lipid metabolism may lead to the identification of novel therapeutic targets for the treatment of NAFLD.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Current standard treatment for GBM includes cyto-reductive surgery followed by radiation (RT) and chemotherapy with temozolomide (TMZ).1 CpG methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter has emerged as the most robust predictor of TMZ treatment outcome for newly diagnosed GBM with prognostic implications.2–6 MGMT encodes for a DNA repair enzyme that provides resistance to alkylating chemotherapies, such as TMZ. Because MGMT transcription can be silenced by promoter methylation in tumor cells,7 it is widely assumed that MGMT promoter methylation in patient tumors causes decreased MGMT protein expression, thereby abrogating DNA repair activity necessary for TMZ resistance. However, the relationship between MGMT protein expression and promoter methylation in patient tumor samples has remained controversial.8–13 Furthermore, studies examining MGMT immunohistochemistry (IHC) and survival have not shown consistent correlation with outcome.4,5,9,10,13–19 The lack of definitive evidence has been attributed primarily to difficulty with MGMT IHC scoring; however, other possible reasons include small cohort size,4,5,10,13,18 nonuniform treatments,20,21 and various IHC scoring categories and cutoffs.4,9,10,21 Because of the importance of MGMT status for predicting treatment outcome, stratifying clinical trial patients, and guiding treatment decisions, the aims of the current single-arm retrospective study were to evaluate MGMT protein expression as a prognostic marker for patients with newly diagnosed GBM who were receiving standard of care RT/TMZ, to investigate the relationship between MGMT promoter methylation and protein expression, and to optimize the assessment of MGMT status. On the basis of a large cohort of 418 patients with newly diagnosed primary GBM, 410 of whom received chemoradiation with TMZ, we show that, although MGMT IHC is prognostic of patient survival, the combination of IHC and methylation testing provides optimized assessment of MGMT status.

Objectives There are few data on the real-world experience of FDA-approved oral hepatitis C virus (HCV) direct-acting antiviral (DAA) drug combinations in HIV/HCV-coinfected patients. We evaluated the safety and efficacy of DAA therapies in a cohort of HIV/HCV patients in a large urban clinic in Chicago. Methods HIV/HCV-coinfected adults (≥18 years) enrolled in the Northwestern University Viral Hepatitis Registry between January 2013 and June 2015 were analysed. Treated patients received one of the following DAA combinations: sofosbuvir/ledipasvir, sofosbuvir/ribavirin, sofosbuvir/simeprevir or paritaprevir/ritonavir/ombitasvir/dasabuvir ± ribavirin. The primary outcome was sustained virological response at 12 weeks after DAA completion (SVR12). Results Seventy-seven HIV/HCV patients were evaluated for DAA therapy. Most patients were male (62/77, 81%) and infected with HCV genotype 1 (67/77, 87%). Some 32/77 (42%) were cirrhotic and 29/77 (38%) had received prior treatment with an IFN-containing regimen. DAA therapy was more likely to be started in Caucasians than persons of other ethnicities (P = 0.01). The overall SVR12 rate was 92% in 52 patients who completed therapy and had follow-up by the end of the study: sofosbuvir/simeprevir, 32/33 (97%); sofosbuvir/ribavirin, 4/7 (57%); sofosbuvir/ledipasvir, 11/11 (100%); and paritaprevir/ritonavir/ombitasvir/dasabuvir, 1/1 (100%). Four patients relapsed after therapy with sofosbuvir/simeprevir (n = 1) or sofosbuvir/ribavirin (n = 3). Adverse events were uncommon and did not result in DAA treatment interruption or discontinuation. Conclusions The HCV DAA combinations of sofosbuvir/ledipasvir and sofosbuvir/simeprevir were highly effective and well tolerated in this diverse population of HIV/HCV-coinfected patients, many of whom had advanced liver disease. HIV coinfection should not be considered a barrier to successful HCV treatment with DAAs.

A modern multi-functional drug carrier is critically needed to improve the efficacy of image-guided catheter-directed approaches for the treatment of hepatic malignancies. For this purpose, a nanocomposite microsphere platform was developed for selective intra-arterial transcatheter drug delivery to liver tumors. In our study, continuous microfluidic methods were used to fabricate drug-loaded multimodal MRI/CT visible microspheres that included both gold nanorods and magnetic clusters. The resulting hydrophilic, deformable and non-aggregated microspheres were mono-disperse and roughly 25 um in size. Sustained drug release and strong MRI T2 and CT contrast effects were achieved with the embedded magnetic nano-clusters and radiopaque gold nanorods. The microspheres were successfully infused through catheters selectively placed within the hepatic artery in rodent models and subsequent distribution in the targeted liver tissues and hepatic tumors confirmed with MRI and CT imaging. These multimodal nanocomposite drug carriers should be ideal for selective intra-arterial catheter-directed administration to liver tumors while permitting MRI/CT visualization for patient-specific confirmation of tumor-targeted delivery.

Anaplastic oligodendroglial tumors are rare neoplasms with no standard approach to treatment. We sought to determine patterns of treatment delivered over time and identify clinical correlates of specific strategies using an international retrospective cohort of 1013 patients diagnosed from 1981–2007. Prior to 1990, most patients received radiotherapy (RT) alone as initial postoperative treatment. After 1990, approximately 50% of patients received both RT and chemotherapy (CT) sequentially and/or concurrently. Treatment with RT alone became significantly less common (67% in 1980–1984 vs 5% in 2005–2007, P < .0001). CT alone was more frequently administered in later years (0% in 1980–1984 vs 38% in 2005–2007; P < .0001), especially in patients with 1p19q codeleted tumors (57% of codeleted vs 4% with no deletion in 2005–2007; P < .0001). Temozolomide replaced the combination of procarbazine, lomustine, and vincristine (PCV) among patients who received CT alone or with RT (87% vs 2% in 2005–2007). In the most recent time period, patients with 1p19q codeleted tumors were significantly more likely to receive CT alone (with temozolomide), whereas RT with temozolomide was a significantly more common treatment strategy than either CT or RT alone in cases with no deletion (P < .0001). In a multivariate polytomous logistic regression model, the following were significantly associated with type of treatment delivered: date (5-year interval) of diagnosis (P < .0001), 1p19q codeletion (P < .0001), pure anaplastic oligodendroglioma histology (P < .01), and frontal lobe predominance (P < .05). Limited level 1 evidence is currently available to guide treatment decisions, and ongoing phase III trials will be critical to understanding the optimal therapy.

Cholesterol 7α-hydroxylase (CYP7A1) encodes for the rate-limiting step in the conversion of cholesterol to bile acids in the liver. In response to acute cholesterol feeding, mice upregulate CYP7A1 via stimulation of the liver X receptor (LXR) α. However, the effect of a chronic high-cholesterol diet on hepatic CYP7A1 expression in mice is unknown. We demonstrate that chronic cholesterol feeding (0.2% or 1.25% w/w cholesterol for 12 weeks) in FVB/NJ mice results in a >60% suppression of hepatic CYP7A1 expression associated with a >2-fold increase in hepatic cholesterol content. In contrast, acute cholesterol feeding induces a >3-fold upregulation of hepatic CYP7A1 expression. We show that chronic, but not acute, cholesterol feeding increases the expression of hepatic inflammatory cytokines, tumor necrosis factor (TNF)α, and interleukin (IL)-1β, which are known to suppress hepatic CYP7A1 expression. Chronic cholesterol feeding also results in activation of the mitogen activated protein (MAP) kinases, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Furthermore, we demonstrate in vitro that suppression of CYP7A1 by TNFα and IL-1β is dependent on JNK and ERK signaling. We conclude that chronic high-cholesterol feeding suppresses CYP7A1 expression in mice. We propose that chronic cholesterol feeding induces inflammatory cytokine activation and liver damage, which leads to suppression of CYP7A1 via activation of JNK and ERK signaling pathways.

Background: Ependymoma is a rare type of glioma, representing 5% of all CNS malignancies. Radiotherapy (RT) is commonly administered, but there is no standard chemotherapy. At recurrence, ependymoma is notoriously refractory to therapy and the prognosis is poor. In recurrent glioblastoma, encouraging responses with bevacizumab have been observed. Methods: In this Institutional Review Board–approved study, we retrospectively analyzed the records of 8 adult patients treated for recurrent ependymoma and anaplastic ependymoma with bevacizumab containing chemotherapy regimens. We determined radiographic response (Macdonald criteria), median time to progression (TTP), and median overall survival (OS; Kaplan-Meier method). Results: There were 4 men and 4 women with a median age of 40 years (range, 20–65). Prior treatment included surgery (n = 8), RT (8), temozolomide (5), and carboplatin (4). Bevacizumab (5–15 mg/kg every 2–3 weeks) was administered alone (2) or concurrently with cytotoxic chemotherapy including irinotecan (3), carboplatin (2), or temozolomide (1). Six patients achieved a partial response (75%) and 1 remained stable for over 8 months. Median TTP was 6.4 months (95% confidence interval 1.4–7.4) and median OS was 9.4 months (95% confidence interval 7.0–not reached), with a median follow-up of 5.2 months among 5 surviving patients (63%). Conclusions: The radiographic response rate to bevacizumab-containing regimens is high. A prospective study is warranted.

Background— It has been demonstrated recently that carotid stenting can be performed safely in patients ≥80 years of age. However, it is uncertain whether these patients will derive benefit because longevity after revascularization is an important consideration. This study was conducted to determine survival and predictors of mortality of selected elderly patients after stenting. Methods and Results— One hundred forty-two consecutive elderly patients who were non–high risk for stenting underwent 153 procedures. Patients had either symptomatic stenosis ≥50% or asymptomatic stenosis ≥70%. Demographics and in-hospital outcomes were entered into a database; subsequent outcomes and mortality data were obtained retrospectively. Mean±SD age was 83.3±3.1 years. Symptomatic patients accounted for 28%. Overall survival at 3 years was 76% (85% at 2 years). At 1 year, 1 fatal stroke had occurred, with 97% of survivors (n=114) free of neurological events (neurological status was undetermined in the remaining 3%). Predictors of mortality were remote (≥6 months) transient ischemic attack or cerebrovascular accident, smoking history, and creatinine clearance (hemoglobin level showed a strong trend toward achieving significance); for the asymptomatic subgroup, predictors of mortality were smoking history, previous carotid endarterectomy, hemoglobin level, and increasing age. In particular, symptom status and sex were not independent predictors of mortality. Conclusions— This study demonstrates that in selected elderly patients, a high proportion (85%) survived 2 years and >75% survived 3 years after stenting. Carotid stenting may be considered a revascularization option in such patients. Better selection of patients using the predictors of mortality may help to reduce unwarranted procedures and to optimize survival likelihood.

The aldo-keto reductase AKR1C3, has been shown to regulate myelopoiesis via its ability to metabolise prostaglandin D2 (PGD2). Other studies have demonstrated the oxidative activation of polycyclic aromatic hydrocarbon (PAH) procarcinogens by AKR1C3 in cell-free systems. This is the first study that addresses whether AKR1C3 mediates carcinogen activation within intact living cells following manipulation of AKR1C3 by molecular intervention. Quantitative RT-PCR identified AKR1C3 as the predominant AKR1C isoform expressed in acute myeloid leukemia (AML). Exposure of K562 and KG1a myeloid cell lines to the known AKR1C3 substrate 7,12-dimethylbenz(a)anthracene-3,4-dihydrodiol (7,12-DMBA-3,4-diol) resulted in both single strand DNA breaks and oxidative DNA damage as measured using conventional and FPG-modified comet assays respectively. PGD2-keto reductase activity was shown to be correlated with relative AKR1C3 expression and together with quantitative real time PCR was used to validate the RNAi-knockdown of AKR1C3 in K562 cells. Knockdown of AKR1C3 did not alter single strand DNA breaks following 7,12-DMBA-3,4-diol exposure but significantly decreased oxidative DNA damage. A similar interrelationship between AKR1C3 activity and 7,12-DMBA-3,4-diol mediated oxidative DNA damage but not single strand breaks was observed in KG1a cells. Finally, AKR1C3 knockdown also resulted in spontaneous erythroid differentiation of K562 cells. Since K562 cells are a model of AML blast crisis of chronic myeloid leukemia (CML) the data presented here identify AKR1C3 as a novel mediator of carcinogen-induced initiation of leukemia, as a novel regulator of erythroid differentiation and paradoxically as a potential new target in the treatment of CML.

Background: Pivotal study data examining carotid stenting with embolic protection as a less invasive alternative to endarterectomy for high surgical risk patients have been acquired under controlled conditions with highly selected physicians and hospitals. This report examines outcomes of carotid stenting post-approval after diffusion of this technology to a broader cross-section of physicians and hospitals. Methods: The Carotid Acculink/Accunet Post-Approval Trial to Uncover Unanticipated or Rare Events (CAPTURE) is a prospective, multi-center registry to assess two important aspects of the post-IDE experience: the safety of carotid stenting by physicians with varying levels of experience as a measure of the adequacy of physician training, and the identification of rare/unexpected device-related complications. The primary endpoint was a composite of death, any stroke, or myocardial infarction within 30 days post-procedure. Results: 3,500 patients were enrolled by 353 physicians at 144 sites. The 30-day primary endpoint event rate was 6.3% (95% CI: 5.5–7.1%) and did not differ among the three operator experience levels (5.3%, 6.0%, and 7.4%; P = 0.31) from most to least experienced, respectively. There were no differences in outcomes among physician specialties when adjusted for case mix. There were no unanticipated device related adverse events. Conclusions: The results of the CAPTURE study compare favorably to those achieved in the predicate pivotal investigations, and suggest that the post-approval transfer of this new therapy to the community practice setting via carotid stent training programs is effective in preparing physicians with varying experience levels and specialty training backgrounds. © 2006 Wiley-Liss, Inc.

Background: The use of carotid artery stenting with embolic protection has been practiced for over a decade in the United States, and increasingly so since carotid stenting received FDA approval in 2004. While there have been attempts at establishing predictors of outcomes in carotid artery stenting, they have generally been limited to single center experiences and/or multicenter retrospective surveys. This report examines predictors of outcomes in carotid stenting in the earliest and largest prospective multicenter neurologist-adjudicated experience in the United States post device approval. Methods: The Carotid Acculink®/Accunet® Post-Approval Trial to Uncover Unanticipated or Rare Events (CAPTURE) is a prospective, multi-center registry conducted to assess outcomes of carotid artery stenting (CAS) in the noninvestigational setting following device approval for high surgical risk patients (symptomatic with ≥50% stenosis; asymptomatic ≥80% stenosis). A neurologist examined the patients before the procedure, at 24 hr and 30-days post-procedure. The primary endpoint was a composite of death, any stroke, or myocardial infarction within 30-days post-procedure. Strokes and neurological events suspected to be strokes were adjudicated by an independent Clinical Events Adjudication Committee (CEAC) using prespecified definitions. Logistic regression analysis was performed to determine clinical, procedural, and anatomic predictors of endpoint outcomes. Results: Three thousand five hundred patients were enrolled at 144 sites by 353 physicians of varying specialty backgrounds and CAS experience. The 30-day primary endpoint event rate of death, stroke and MI was 6.3% [95% CI: 5.5–7.1%], and the rate of major stroke and death 2.9% [95% CI: 2.4–3.5]. Predictors of adverse outcomes included age, symptomatic patients, predilation prior to embolic protection device placement, time from symptoms to CAS procedure, and the use of multiple stents. Conclusions: In general, carotid stenting is performed safely in patients with severe stenosis at high surgical risk, with best outcomes in younger asymptomatic patients. However, there are certain patient and procedural characteristics that are associated with poorer outcomes. In these patients, the risk of stenting should be considered vis-a-vis both the anticipated benefit as well as the alternative surgical and medical options. © 2007 Wiley-Liss, Inc.

Dissection of the ascending aorta, type A aortic dissection (TAAD), represents a surgical emergency with high morbidity and mortality. Current open surgical techniques, although state-of-the-art procedures and having improved outcomes for patients with TAAD over the last decades, confer significant risk of complications and death. Recently, endovascular techniques for repair of both the abdominal and thoracic aorta have gained acceptance within the vascular and cardiovascular surgical communities as a useful tool in select pathologies and patient populations. As development of endovascular technology proceeds ever closer to the aortic valve, thoracic endovascular repair for TAAD deserves special investigation. A comprehensive literature search for studies reporting outcomes of endovascular repair in the ascending aorta was performed. In this review, we compile the worldwide experience of thoracic endovascular repair for TAAD as well as imaging studies for patient selection and the use of hybrid (open plus endovascular) techniques. The authors discuss the remaining challenges that preclude its broader adoption in this role, namely patient selection and device specificity.

Purpose To report our early experience with the endovascular placement of stacked Zenith main body extensions (cuffs) in the treatment of focal thoracic aortic pathology in high-risk patients. Methods Between January 2003 and May 2004, 6 patients (3 men; mean age 59 years, range 37-82) with focal aortic pathology underwent endovascular repair using stacked 30 and 32-mm-diameter Zenith main body extensions. The setting was a university tertiary referral center for vascular disease. Indication for treatment included 2 descending thoracic aneurysms and individual cases of traumatic thoracic tear, diverticulum of Kommerell, thoracic pseudoaneurysm, and aortoesophageal fistula. Results All procedures were performed successfully, with a mean of 3 cuffs used. The patient with an aortoesophageal fistula expired after successful cuff placement due to sequela of massive pretreatment hemorrhage; fistula coverage was confirmed at autopsy. There were no type I endoleaks. Morbidity included an occluded right subclavian artery from traumatic passage of the device through the artery. No left subclavian arteries were covered. No neurological deficits or paraplegia was observed. The cuffs were patent in all surviving patients at an average follow-up of 7 months (range 3-12). Computed tomography in all survivors confirmed adequate cuff placement, absence of endoleak, and lack of cuff migration. Based on this experience, the following technical recommendations are offered: (1) right subclavian cutdown when needed to reach a lesion beyond the range of the sheath, (2) Dacron chimney placement, (3) stiff guidewire usage, (4) wire placement from the right subclavian artery through the common femoral artery if necessary to ease a sharp bend in the arch, and (5) cuff overlap of 25% to 50%. Conclusions In high-risk patients, focal aortic pathology can be successfully treated with off-the-shelf commercially available cuffs using a stacking technique with acceptable mortality, morbidity, and short-term durability.

Atherosclerotic renal artery stenosis is a significant cause of poorly controlled hypertension and progressive renal dysfunction leading to ischemic nephropathy and other end-organ damage. The optimal treatment of renovascular disease contributing to hypertension and renal dysfunction is not known. This study compares the anatomic and functional outcomes of both open and endovascular therapy for chronic, symptomatic atherosclerotic renal artery disease. We performed a retrospective analysis of records from patients who underwent renal arterial interventions, endovascular or open bypass, between January 1984 and January 2004. Principal indications for intervention were hypertension (51%), chronic renal insufficiency (13%), and hypertension and elevated creatinine (36%). A total of 247 patients (109 males; mean age 69 +/- 10, range 44-89 years) underwent 314 interventions (109 open procedures; 205 angioplasties, 71% with stent placement). There was a significant difference in 30-day mortality (4% vs.1%; p0.005) between the open and endoluminal groups, but not at 1, 3, or 5 years. Patients in the open group had a higher primary patency rate at 5 years (83 +/- 5% vs. 76 +/- 6%; p = 0.03), but patients in the endoluminal group had a higher assisted primary patency rate at 5 years (92 +/- 5% vs. 84 +/- 5; p = 0.03). There was no significant difference between both treatment groups in cumulative freedom from presenting symptom or in freedom from dialysis and renal-related death. Patients who presented with hypertension were more likely to have shown improvement in their blood pressure with endoluminal intervention at 1, 3, and 5 (59 +/- 6% endoluminal vs. 83 +/- 5% open; p = 0.01) years. From these results we conclude that open repair and endoluminal repair of atherosclerotic renal artery stenosis have similar immediate and long-term functional and anatomic outcomes. Patients who present with hypertension may have greater benefit with an endoluminal repair.

ObjectivesThe objectives of this study were to examine factors predictive of success or failure after percutaneous angioplasty (PTA) and stenting (S) of the superficial femoral artery (SFA) and to compare the results of PTA/S with a contemporary group of patients treated with femoropopliteal bypass.MethodsA database of patients undergoing PTA and/or S of the SFA between 1986 and 2004 was maintained. Intention-to-treat analysis was performed. Patients underwent duplex scanning follow-up at 1, 3, and every 6 months after the intervention. Angiograms were reviewed in all cases to assess lesion characteristics and preprocedure and postprocedure runoff. Results were standardized to current TransAtlantic Inter-Society Consensus (TASC) and Society for Vascular Surgery (SVS) criteria. Kaplan-Meier survival analyses were performed to assess time-dependent outcomes. Cox proportional hazard analyses were performed to assess factors associated with patient survival and treatment efficacy.ResultsThree hundred eighty total limbs underwent PTA/S in 329 patients (67% male, 33% female; average age, 65 years). Mean follow-up was 1.8 years from the date of initial intervention. Indications for intervention were claudication in 66%, rest pain in 16%, and tissue loss in 18%. Runoff at the tibial level was 2.1 ± 0.8 patent vessels. Mean SVS ischemia grade was 3.1 (range, 1 to 5). TASC lesion grades were A (48%), B (18%), C (22%), and D (12%). Angioplasty alone was used in 63% of cases. Primary treatment failure (inability to cross lesion) was seen in 7% of patients. There was one periprocedural death. Primary patency rates were 86% at 3 months, 80% at 6 months, 75% at 12 months, 66% at 24 months, 60% at 36 months, 58% at 48 months, and 52% at 60 months. Assisted primary patency rates were slightly higher (P = not significant). By Cox proportional hazards analysis, patency of PTA/S was associated with higher preoperative ankle/brachial index (P = .016) and the performance of angioplasty only (P = .011). Failed or occluded PTA/S was associated with TASC C (P < .0001) and TASC D lesions (P < .0001). Patient death was associated with the presence of congestive heart failure (P = .003). Subgroup analysis revealed that primary patency rates are highly dependent on lesion type (A > B > C > D, P < .0001). PTA/S patency for TASC A and B lesions compared favorably to prosthetic and venous femoropopliteal bypass. Surgical bypass was superior to PTA/S for TASC C and D lesions.ConclusionsPTA and stenting of the SFA can be performed safely with excellent procedural success rates. Improved patency of these interventions was seen with increased ankle/brachial index and the performance of angioplasty only. Worse patency was seen with TASC C and TASC D lesions. Patency rates were strongly dependent on lesion type, and the results of angioplasty and stenting compared favorably with surgical bypass for TASC A and B lesions.

ObjectivesThe purpose of this study was to determine whether performance on a simulator model of carotid artery stenting correlates with previous endovascular experience and to assess the effects of repetition and training.MethodsParticipants were stratified to untrained and advanced skill groups on the basis of number of endovascular procedures previously performed. Baseline performance was assessed by means of a pretest, and participants were randomized to practice and no-practice groups. Practice consisted of a 30-minute to 60-minute proctored session before taking a final test; those in the no-practice group proceeded directly to the final test without this session. Primary outcomes were completion of a standardized protocol and the length of time needed to complete all steps.ResultsTwenty-nine subjects (16 untrained, 13 advanced) participated fully in the study. Ninety-two percent of participants in the advanced group successfully completed the pretest, versus 63% in the untrained group (P = .09); mean time to successful completion was 29.9 ± 4.8 (mean ± SD) versus 48.0 ± 9.9 minutes, respectively (P < .001). Subjects who received no practice did not significantly improve their completion times between pretest and final test, whereas those who received practice did (novice, 47.9 ± 7.0 minutes vs 24.5 ± 2.9 minutes, P < .001; advanced, 29.6 ± 3.1 minutes vs 20.2 ± 4.1 minutes, P < .001). The group without previous training had significantly more time improvement from training than did the advanced group. Exit survey results showed that those who had the opportunity to practice more commonly believed that the simulator increased their endovascular skills and interest in vascular surgery (both P < .01 vs untrained group).ConclusionsPerformance on the carotid stenting simulator correlated with previous endovascular experience. Although both novice and advanced groups improved their time after a 30-minute to 60-minute proctored training session, improvement in the novice group was greater than that in the advanced group, which suggests that novices may benefit disproportionately from this type of training.

Since 1996, 41 patients have presented to our institution with deep but localized groin infection following bypass (30) or isolated femoral artery surgery (11). These patients were treated with antibiotics, debridement, and rotational muscle flap coverage either immediately or within a few days. Patients had one of three patterns: serous leak from a groin incision within a few days of operation (Acute, n = 10), early serous leak that later became grossly infected (Acute-observed, n = 8), or obvious purulent drainage following an initially normal, healed wound (Delayed, n = 23). Patients with early leak had nearly uniformly polymicrobial infections with a preponderance of gram-negative organisms, whereas most of those with late purulence had monobacterial infection with Staphylococcus aureus. At exploration, 26 of 41 suture lines were exposed. Rectus femoris flaps were used in 35 patients (85% of cases) for coverage, and graft preservation was attempted in all 8 vein grafts and 16 of 23 prosthetic grafts. Only one flap failed and there were no instances of anastomotic bleeding. There were no deaths directly attributable to reexploration and flap coverage, although 10 patients died during the index hospitalization. Durable coverage with no long-term evidence of infection was achieved in 24 patients with mean follow-up of 23 (range 10-66) months and another 12 had no evidence of local problems despite shorter follow-up; only 5 patients (12%) overall had evidence of persistent graft infection or unexplained bacteremia. In patients with attempted graft salvage, limb salvage was 97% at 6 months and 85% at 1 year. Although early mortality is high, deaths are not related to the flap procedure itself, local outcome is excellent, and graft and limb salvage are good; results are much worse if an initially draining wound is treated too late. Local rotational muscle flap closure is an excellent solution for acute infections involving the groin following vascular procedures.

Objectives This study was performed to determine whether there is deterioration in renal function during follow-up in patients who have undergone endovascular aneurysm repair (EVAR), as recommended by the device manufacturers; to determine whether suprarenal fixation correlates with impairment of renal function; and to explore the potential implication of life-long surveillance of renal function with contrast-enhanced computed tomography. Methods One hundred forty-six consecutive patients underwent EVAR at our institution. Data from 113 of these patients who were free from preoperative renal insufficiency or postoperative renal disease were analyzed. Fifty-three patients received infrarenal (IR) fixation devices, and 60 patients received suprarenal (SR) fixation devices. All SR fixation devices were placed under investigational device exemption protocols. The average follow-up was 688 days. Sixty-five consecutive patients who had undergone open repair of an abdominal aortic aneurysm (AAA) served as the control group. Results Preoperative creatinine concentration, intraoperative blood loss, contrast volume, and number of contrast-enhanced procedures were not significantly different between the IR and SR groups. Two renal artery occlusions (1 SR, 1 IR; P = NS) were identified, and 8 renal infarcts (5 SR, 3 IR; P = NS). There was an increase in mean creatinine concentration in the open AAA, IR, and SR fixation groups at each time point in the analysis. Mean elevation in creatinine concentration at 12, 24, and 36 months was 0.10, 0.10, and 0.04 mg/dL, respectively, for open AAA repair; 0.20, 0.21, and 0.28 mg/dL for IR fixation; and 0.15, 0.21, and 0.12 mg/dL for SR fixation. At life table analysis, renal impairment at 36 months was seen in 36% ± 9% of patients in the IR group, 25% ± % of patients in the SR group, and 19% ± 6% of patients in the open AAA group ( P = .04 for IR fixation vs open AAA repair). Conclusions A decrease in kidney function is seen after EVAR, regardless of fixation level, that is independent of renal disease and renal arterial occlusion. In patients with normal renal function the site of proximal fixation does not affect postoperative creatinine concentration. The decrease in renal function is likely related to the repetitive administration of contrast agent.

Objectives Treatment of abdominal aortic aneurysm is controversial in patients at high physiologic risk for open repair and high anatomic risk for endovascular repair. We compared outcome in patients at high risk because of anatomy (short or angulated neck), severe occlusive disease, or bilateral iliac aneurysms (group A) with outcome in patients at low risk (group B). Material and methods Patients at high anatomic risk who underwent treatment between October 1998 and March 2002 with the Zenith endovascular graft (group A) were compared with patients at low anatomic risk enrolled in a prospective multicenter trial (group B). Variables compared included overall mortality, need for secondary interventions, development of endoleak, and change in aneurysm sac diameter. The χ 2 test, Student t test, and proportions analysis were used to assess the data. Results Data for 493 patients (group A, 141; group B, 352) were evaluated. Mean follow-up was 9 months (range, 1-24 months). Perioperative mortality was similar for groups A and B (0.7% vs 1%). Frequency of endoleak was higher in patients with high-risk anatomy (25% vs 11%), but not significantly so ( P > .06). The rate of aneurysm shrinkage, even in the absence of endoleak, was slower in group A ( P Conclusions In physiologically challenged patients at higher anatomic risk for endovascular aneurysm repair, initial mortality rate is similar to that in patients at lower risk. Short-term technical results are acceptable. Decreased long-term survival (largely unrelated to the procedure), slightly higher frequency of endoleak, and a lower rate of sac shrinkage may temper enthusiasm for endovascular repair in this subgroup. Risks of repairing aneurysms in this patient population must be viewed in the context of expected results of intervention or medical observation.

Fibromuscular dysplasia (FMD) accounts for 10% of cases of renal artery stenosis. This study evaluates the anatomic and functional outcomes of endovascular therapy for symptomatic renal artery FMD at an academic medical center. A retrospective analysis of records from patients who underwent percutaneous transluminal renal artery angioplasty (PTRA) found 14 patients (all female) who underwent 19 interventions on 18 renal artery segments. Significant cardiovascular comorbidities were few in this patient population. The PTRA technical success rate was 95%. There were no periprocedural mortalities. Primary patency rates were 81%, 69%, 69%, and 69% at 2, 4, 6, and 8 years. Assisted primary patency rates were 87%, 87%, 87%, and 87% at 2, 4, 6, and 8 years. The restenosis rate was 25% at 8 years. Clinical benefit (improved or cured hypertension) was seen in 79% of patients overall; 65% of patients maintained this benefit at 8 years by life-table analysis. Percutaneous endovascular intervention for clinically symptomatic FMD of the renal arteries is technically successful, safe, and durable. Most patients demonstrate immediate clinical benefit and retain durable functional outcomes.

Cholesterol gallstone disease affects 40 million Americans, and evidence indicates that there is a genetic component to human gallstone disease. In a mouse model of gallstone formation, where mice are fed a lithogenic diet, QTL analysis has been employed to identify the Lith 1 locus on Chromosome (Chr) 2. In order to identify genes in which the difference in expression is independent of factors other than strain-specific genotype, we employed microarray analysis of hepatic gene expression in gallstone-susceptible (C57L/J) and gallstone-resistant (AKR/J) mice. We observed 57 genes with consistent differential expression between C57L/J and AKR/J mice, including many cytochrome, antioxidant, and lipid peroxidation genes. Analysis of differentially expressed genes identified numerous genes involved in fatty acid metabolism. Northern analysis of selected lipid metabolic genes further confirmed the strain-specific differential expression. Literature searches of common regulatory elements within antioxidant systems identified the nuclear transcription factor Nrf2, which maps to the Lith 1 loci. Hepatic Nrf2 gene and protein expression is also increased in strain AKR/J, compared with C57L/J mice, identifying Nrf2 as a putative Lith 1 gallstone gene. These data indicate that microarray analysis may complement QTL analysis to identify systems of regulation and genotypic differences responsible for polygenic diseases.

Purpose: To compare outcome after carotid endarterectomy (CEA) in patients who would have been excluded from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) or the Asymptomatic Carotid Atherosclerosis Study (ACAS) or would have been eligible for Acculink for Revascularization of Carotids in High Risk Patients (ARCHeR), a current high-risk stent registry, with outcome in a similar cohort at low risk. Methods: Records of all CEAs performed at our institution from July 1993 to December 2000 were reviewed. Patients were assigned to groups either eligible or ineligible for NASCET and ACAS or ARCHeR, and criteria were stratified according to whether risk was defined by anatomic or medical problems or whether patients were ineligible according to nonmedical protocol exclusion criteria only. Results: Preoperative and postoperative data were sufficient to determine risk status according to various study criteria in 857 patients. Stroke or death within 30 days, the primary end point, occurred in 2.1% of patients. Rates were similar in patients excluded from (2.7%) or included in (1.6%) NASCET and ACAS and in patients eligible (3.1%) or ineligible (2.1%) for ARCHeR. Rates did not differ according to whether exclusion or inclusion was based on anatomic risk, medical risk, or protocol exclusion, although trends favored worse outcome in the ARCHeR medical risk subgroup. A higher rate of minor complications was found in the elderly; however, stroke and death rates were similar according to age, gender, repeat procedure, or the presence of contralateral occlusion. Conclusions: No statistically or clinically significant differences were found in combined 30-day stroke or death rates after CEA in any group defined by previous surgical trials or current ongoing high-risk stent registry. While high-risk groups may exist, the premise that operative risk is higher in patients excluded from NASCET and ACAS or eligible for ARCHeR is not supported. (J Vasc Surg 2003;37:575-81.)

In an effort to identify preoperative and perioperative factors impacting outcome in repair of juxtarenal abdominal aortic aneurysm (JRAAA), hospital records and CT scans (for calcification, intraluminal thrombus, and aortic diameter) of all patients undergoing JRAAA repair over the past 10 years were reviewed. The 87 men and 25 women had a mean age of 72, and a mean maximal aortic diameter of 6.2 cm. Renal artery stenosis (RAS) and iliac disease were present in 13 (11%) and 40 patients (35%), respectively. Comorbidities included coronary artery disease (n = 49, 44%), COPD (n = 28, 25%), diabetes mellitus (n = 10, 9%), and preoperative renal insufficiency (PRI; Cr >1.4 mg/dL; n = 14, 12%). A midline incision was used in most of the patients (n = 98, 88%). The proximal aortic clamp was placed in the supraceliac (SC) position in 92 (82%) patients, and directly above one or both renal arteries in 20 (18%) patients. The overall mortality was 6% (n = 7). Cardiac complications occurred in 26 patients (23%); pulmonary, in 22 (20%); renal, in 14 (12%); and gastrointestinal, in 10 (9%). No patient experienced mesenteric ischemia. Mean elevation in creatinine was greater in patients with PRI (1.8 mg/dL vs. 0.13 mg/dL, p = 0.04). Mean blood loss (EBL) was 2701 +/- 189 cc, and mean LOS was 16.1 +/- 1.7 days. Age >70 was associated with increased length of stay (LOS) (12.1 days vs. 18.6 days, p = 0.05) and higher mortality (0 vs. 10%, p = 0.02); otherwise there were no significant relationships between pre- and perioperative parameters and any of the measured outcomes including death, postoperative RI, and LOS. Preferential SC clamping may substantially reduce complications of JRAAA repair (such as mesenteric and renal ischemia) related to proximal cuff disease, but cannot overcome the deleterious affects of advanced age and PRI.

Objective. We sought to assess the utility of panoramic radiography as an adjunct screening tool for detecting significant asymptomatic carotid artery stenosis. The specific aim was to correlate calcifications seen in the region of the carotid bifurcation with clinically relevant carotid artery stenosis as determined by duplex ultrasound (DUS). Study Design. Routine dental panoramic films of patients 55 and older (n = 778) at the University of Rochester Eastman Dental Center were retrospectively reviewed for calcifications around the carotid bifurcation. Patients with such calcifications were referred for DUS, and raw data were interpreted by a vascular surgeon blinded to the radiographic findings. Groups were compared by using the χ2 test. Results. Twenty-seven patients (3.5%) had suggestive radiographic calcifications on one or both sides, 20 of whom consented to DUS. Clinically significant carotid stenoses (>50% lumenal narrowing) were present in 50% of the sides with calcification compared with 21% of the sides without (P =.08, χ2). Three patients (15% of those screened with DUS) had stenoses greater than 80% and underwent 4 carotid endarterectomies as a direct result of screening. Conclusions. Data suggest that clinically significant stenosis may exist if calcifications are observed on panoramic radiographs. Incidental examination of this area carries a minimal cost and appears beneficial as a screening tool for carotid disease, although definitive testing must follow. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:768-73)

Patients without renal function are living longer than in the past, and the provision of dialysis access is a growing problem. The distal end of the greater saphenous vein can be anastomosed to the femoral artery, creating a transposed saphenous vein thigh arteriovenous fistula, which offers the theoretical advantages of autologous conduit and a native venous ‘anastomosis.’ This is a rarely performed procedure, however, in part because of the morbidity of vein harvest and the risk of groin infection. We have been favorably impressed by the reduction in morbidity and wound infection following endoscopic vein harvest for lower extremity bypass, and believe that the success of this technique merits a reevaluation of this procedure.

Advances in free-tissue transfer have allowed for lower limb salvage in patients with significant peripheral vascular disease and limb-threatening soft-tissue wounds. The authors retrospectively reviewed their 10-year experience with free flaps for limb salvage in patients with peripheral vascular disease to assess postoperative complication rates and long-term functional outcome. They identified all patients undergoing free-tissue transfer with significant peripheral vascular disease and otherwise unreconstructible soft-tissue defects. Charts were reviewed for perioperative and long-term outcome. Parameters studied included perioperative morbidity and mortality, flap success, bypass graft patency, ambulatory results, and long-term limb and patient survival. Survival data were analyzed using life-table analysis, Kaplan-Meier survival analysis, and Cox testing. A total of 79 flaps were examined in 75 patients with peripheral vascular disease from July of 1990 to November of 1999. All patients would have required a major amputation had free-tissue transfer not been performed. Mean age was 60 years, average hospital stay was 32 days, and perioperative mortality was 5 percent. Within the first 30 days after operation, there were four cases of primary flap loss, and another two were lost as the result of bypass graft failure (8 percent); five of these cases resulted in amputation. There were no primary flap failures after 30 days. Follow-up ranged to 91 months (mean, 24 months). During this time, another 14 limbs were lost, most commonly because of progressive gangrene and/or infection in sites remote from the still-viable free flap. Using Kaplan-Meier survival analysis, 5-year flap survival was 77 percent, limb salvage 63 percent, and patient survival 67 percent. Sixty-six percent of patients were able to ambulate independently with the use of their reconstructed limb at least 1 year after hospital discharge, although some of these later went on to amputation. Free-tissue transfer for lower extremity reconstruction can be performed with acceptable morbidity and mortality in patients with peripheral vascular disease. Flap loss is low, and limb salvage, ambulation, and long-term survival rates in these patients are excellent.

Background and Aims Endoplasmic reticulum (ER) stress is induced in many forms of chronic liver disease and may promote the development of hepatocellular carcinoma. The activator protein 1 (AP-1) complex is a transcription factor that promotes hepatic carcinogenesis in response to cellular stress. The aim of this study was to determine the role of ER stress in the regulation of the hepatic AP-1 complex. Methods Human hepatocellular carcinoma (HepG2) cells and C57BL/6J mice were subjected to pharmacologic ER stress and the expression of AP-1-associated genes and proteins was assessed. To determine the role of MAPK signaling in ER stress-induced AP-1 activation, ER stress was induced in JNK- and ERK-inhibited HepG2 cells. Results Induction of ER stress promoted the activation of both Jun- and Fos-related genes and proteins of the AP-1 complex in HepG2 cells and murine liver. Inhibition of ERK phosphorylation in HepG2 cells completely prevented ER stress-induced activation of the fos-related components of AP-1 whereas activation of Jun-related components was only partially attenuated. Conversely, inhibition of JNK phosphorylation in HepG2 cells reduced ER stress-induced activation of Jun-related components but did not prevent activation of fos-related components. Conclusions ER stress activates the hepatic AP-1 complex via MAPK-dependent signaling pathways. ER stress-induced activation of Fos-related components is dependent primarily on ERK activation whereas ER stress-induced activation of Jun-related components is dependent primarily on JNK activation, although there is interplay between these regulatory pathways. These data implicate a novel signaling pathway by which sustained ER stress, as observed in many chronic liver diseases, may promote hepatic carcinogenesis.