https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1053/jhep.2003.50047

Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival

EASL–EORTC Clinical Practice Guidelines (CPG) on the management of hepatocellular carcinoma (HCC) define the use of surveillance, diagnosis, and therapeutic strategies recommended for patients with this type of cancer. This is the first European joint effort by the European Association for the Study of the Liver (EASL) and the European Organization for Research and Treatment of Cancer (EORTC) to provide common guidelines for the management of hepatocellular carcinoma. These guidelines update the recommendations reported by the EASL panel of experts in HCC published in 2001 [1]. Several clinical and scientific advances have occurred during the past decade and, thus, a modern version of the document is urgently needed. The purpose of this document is to assist physicians, patients, health-care providers, and health-policy makers from Europe and worldwide in the decision-making process according to evidencebased data. Users of these guidelines should be aware that the recommendations are intended to guide clinical practice in circumstances where all possible resources and therapies are available. Thus, they should adapt the recommendations to their local regulations and/or team capacities, infrastructure, and cost– benefit strategies. Finally, this document sets out some recommendations that should be instrumental in advancing the research and knowledge of this disease and ultimately contribute to improve patient care. The EASL–EORTC CPG on the management of hepatocellular carcinoma provide recommendations based on the level of evidence and the strength of the data (the classification of evidence is adapted from National Cancer Institute [2]) (Table 1A) and the strength of recommendations following previously reported systems (GRADE systems) (Table 1B).

http://www.bclc.cat/download/easl-guidelines.pdf

EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma European Association for the Study of the Liver ⇑ , European Organisation for Research and Treatment of Cancer

The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

/pdf/hepatic-stellate-cells-protean-multifunctional-and-enigmatic-1ctrvjmfhn.pdf

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products. Here we report that the intestinal bacterial microflora and a functional Toll-like receptor 4 (TLR4), but not TLR2, are required for hepatic fibrogenesis. Using Tlr4-chimeric mice and in vivo lipopolysaccharide (LPS) challenge, we demonstrate that quiescent hepatic stellate cells (HSCs), the main precursors for myofibroblasts in the liver, are the predominant target through which TLR4 ligands promote fibrogenesis. In quiescent HSCs, TLR4 activation not only upregulates chemokine secretion and induces chemotaxis of Kupffer cells, but also downregulates the transforming growth factor (TGF)-beta pseudoreceptor Bambi to sensitize HSCs to TGF-beta-induced signals and allow for unrestricted activation by Kupffer cells. LPS-induced Bambi downregulation and sensitization to TGF-beta is mediated by a MyD88-NF-kappaB-dependent pathway. Accordingly, Myd88-deficient mice have decreased hepatic fibrosis. Thus, modulation of TGF-beta signaling by a TLR4-MyD88-NF-kappaB axis provides a novel link between proinflammatory and profibrogenic signals.

TLR4 enhances TGF-beta signaling and hepatic fibrosis.

There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17beta-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor alpha and beta depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.

/pdf/the-complex-role-of-estrogens-in-inflammation-29aw75ptuv.pdf

The complex role of estrogens in inflammation

PURPOSE: To evaluate the effectiveness of radio-frequency (RF) ablation and percutaneous microwave coagulation (PMC) for treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Seventy-two patients with 94 HCC nodules were randomly assigned to RF ablation and PMC groups. Thirty-six patients with 48 nodules were treated with RF ablation, and 36 patients with 46 nodules were treated with PMC. Therapeutic effect, residual foci of untreated disease, and complications of RF ablation and PMC were prospectively evaluated with statistical analyses. RESULTS: The number of treatment sessions per nodule was significantly lower in the RF ablation group than in the PMC group (1.1 vs 2.4; P < .001). Complete therapeutic effect was achieved in 46 (96%) of 48 nodules treated with RF ablation and in 41 (89%) of 46 nodules treated with PMC (P = .26). Major complications occurred in one patient treated with RF ablation and in four patients treated with PMC (P = .36). During follow-up (range, 6–27 months), residu...

Small hepatocellular carcinoma: comparison of radio-frequency ablation and percutaneous microwave coagulation therapy.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.20684

A novel 3D hepatectomy simulation based on liver circulation: Application to liver resection and transplantation

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.20603

Contribution of Toll-like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration.

The relationship among gender, lipopolysaccharide (LPS), and liver disease is complex. Accordingly, the effect of estrogen on activation of Kupffer cells by endotoxin was studied. All rats given es...

Estrogen increases sensitivity of hepatic Kupffer cells to endotoxin

Background: Liver cirrhosis, which is caused by the accumulation of extracellular matrix materials, is a serious clinical problem that can progress to hepatic failure. Transforming growth factor-β (TGFβ) plays a pivotal role in extracellular matrix production, but bone morphogenetic protein (BMP)-7, a member of the TGFβ superfamily, can antagonise the fibrogenic activity of TGFβ. Aim: In this study, we examined whether adenovirus-mediated overexpression of BMP-7 (Ad-BMP-7) antagonised the effect of TGFβ in vitro and in vivo. Methods and results: In primary cultured rat stellate cells and the LX-2 human stellate cell line, induction of BMP-7 by Ad-BMP-7 infection decreased the expression of collagen 1A2 mRNA and smooth muscle α-actin in the presence or absence of TGFβ, via Smad 1/5/8 phosphorylation. BMP-7 triggered the mRNA expression of inhibitors of differentiation 2 (Id2) in LX-2. Although endogenous expression of BMP-7 was hardly detectable, Smad1 and Id2 overexpression increased BMP-7 expression in LX-2. A liver fibrosis model was induced by the repetitive intraperitoneal injection of thioacetamide (200 mg/kg body weight) twice per week for up to 7 weeks. In rats administered Ad-BMP-7 via the tail vein, hydroxyproline content and the areas stained by Sirius red dye in the liver were significantly reduced compared to controls. Ad-Id2 also reduced fibrosis. Conclusion: These data demonstrate that BMP-7, Smad 1/5/8 and Ids interact to antagonise hepatic fibrogenesis.

/pdf/adenovirus-mediated-expression-of-bmp-7-suppresses-the-mu28mx5kxd.pdf

Yuji Iimuro

Papers

Small hepatocellular carcinoma: comparison of radio-frequency ablation and percutaneous microwave coagulation therapy.

A novel 3D hepatectomy simulation based on liver circulation: Application to liver resection and transplantation

Contribution of Toll-like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration.

Estrogen increases sensitivity of hepatic Kupffer cells to endotoxin

Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats