EASL-EORTC clinical practice guidelines : management of hepatocellular carcinoma

Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

Interleukin-10 and the interleukin-10 receptor.

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

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Nitric Oxide and Peroxynitrite in Health and Disease

Gastric cancer was the world’s third leading cause of cancer mortality in 2012, responsible for 723,000 deaths1. The vast majority of gastric cancers are adenocarcinomas, which can be further subdivided into intestinal and diffuse types according to the Lauren classification2. An alternative system, proposed by the World Health Organization, divides gastric cancer into papillary, tubular, mucinous (colloid) and poorly cohesive carcinomas3. These classification systems have little clinical utility, making the development of robust classifiers that can guide patient therapy an urgent priority.

The majority of gastric cancers are associated with infectious agents, including the bacterium Helicobacter pylori4 and Epstein–Barr virus (EBV). The distribution of histological subtypes of gastric cancer and the frequencies of H. pylori and EBV associated gastric cancer vary across the globe5. A small minority of gastric cancer cases are associated with germline mutation in E-cadherin (CDH1)6 or mismatch repair genes7 (Lynch syndrome), whereas sporadic mismatch repair-deficient gastric cancers have epigenetic silencing of MLH1 in the context of a CpG island methylator phenotype (CIMP)8. Molecular profiling of gastric cancer has been performed using gene expression or DNA sequencing9–12, but has not led to a clear biologic classification scheme. The goals of this study by The Cancer Genome Atlas (TCGA) were to develop a robust molecular classification of gastric cancer and to identify dysregulated pathways and candidate drivers of distinct classes of gastric cancer.

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Comprehensive molecular characterization of gastric adenocarcinoma

5-fluorouracil (5-FU) is widely used in the treatment of cancer. Over the past 20 years, increased understanding of the mechanism of action of 5-FU has led to the development of strategies that increase its anticancer activity. Despite these advances, drug resistance remains a significant limitation to the clinical use of 5-FU. Emerging technologies, such as DNA microarray profiling, have the potential to identify novel genes that are involved in mediating resistance to 5-FU. Such target genes might prove to be therapeutically valuable as new targets for chemotherapy, or as predictive biomarkers of response to 5-FU-based chemotherapy.

5-Fluorouracil: mechanisms of action and clinical strategies

In developing organs, epithelial tissue structures are mostly developed by the perinatal period. However, it is unknown whether epithelial cells are already functionally mature and whether they are fixed in their lineage. Here we show that epithelial cells alter their plasticity during postnatal development by examining the differentiation potential of epithelial cell adhesion molecule (EpCAM)(+) cholangiocytes (biliary epithelial cells) isolated from neonatal and adult mouse livers. We found that neonatal cholangiocytes isolated from 1-week-old liver converted into functional hepatocytes in the presence of oncostatin M and Matrigel®. In contrast, neither morphological changes nor expression of hepatocyte markers were induced in adult cholangiocytes. The transcription factors hepatocyte nuclear factor 4α and CCAAT/enhancer binding protein α (C/EBPα), which are necessary for hepatocytic differentiation, were induced in neonatal cholangiocytes but not in adult cells, whereas grainyhead-like 2 (Grhl2) and hairy-enhance of slit 1 (Hes1), which are implicated in cholangiocyte differentiation, were continuously expressed in adult cells. Overexpression of C/EBPα and Grhl2 promoted and inhibited hepatocytic differentiation, respectively. Furthermore, adult cholangiocytes formed a monolayer with higher barrier function than neonatal ones did, suggesting that cholangiocytes are still in the process of epithelial maturation even after forming tubular structures during the neonatal period. Taken together, these results suggest that cholangiocytes lose plasticity to convert into hepatocytes during epithelial maturation. They lose competency to upregulate hepatocytic transcription factors and downregulate cholagiocytic ones under conditions inducing hepatocytic differentiation. Our results suggest that a molecular machinery augmenting epithelial integrity limits lineage plasticity of epithelial cells.

Hepatic biliary epithelial cells acquire epithelial integrity but lose plasticity to differentiate into hepatocytes in vitro during development

症例は57歳の女性. 2005年8月頃より肛門周囲に硬結を触知していたが放置していた. 2006年6月頃よりの排便困難と疼痛を主訴に近医受診となった. 会陰部皮下に硬い腫瘍を触知し, 生検にて顆粒細胞腫の診断となり, 2006年9月下旬に手術目的に当科入院となった. 術前精査にて腫瘍は肛門管を取り囲むように会陰部に存在した. 左側では一部, 外肛門括約筋への浸潤が疑われた. 術前に良性と診断されたことから可及的に周囲組織の損傷を最小限におさえて腫瘍を摘出した. 左側の外肛門括約筋は合併切除とした. 自験例では良性腫瘍であったため可能な限り肛門機能温存を念頭においた手術を行った結果, 切除断端近傍にまで腫瘍は存在した. 腫瘍の悪性化は約2%に生じるとされ慎重な経過観察が必要である. 自験例の腫瘍径は65mmで, これまでの報告の中では最大であり, 肛門部に発生した稀な顆粒細胞腫であった. 肛門診察の際に皮下や粘膜下に硬結を認めた時には稀であるが本腫瘍も念頭におくべきであると思われた.

A case of granular cell tumor of the anus

症例は61歳，女性．肝右葉と膵尾部の嚢胞性病変について1992年から前医にて経過観察されていたが，肝嚢胞性病変の増大が著しく2005年手術目的に入院した．腹部超音波検査では，肝右葉と膵尾部に境界明瞭で，内部に隔壁様構造や隆起性病変を伴わない単房性嚢胞を認め，腹部CTでは両病変に壁肥厚や石灰化，壁外浸潤所見を認めなかった．これまでのCT画像を経時的に比較検討したところ，膵嚢胞性病変に関しては嚢胞径の増大に伴い，造影効果を認める明瞭な被膜の消失を認めた．以上より，典型的画像所見を欠くものの腫瘍性膵嚢胞である，粘液性嚢胞腫瘍を疑い，肝嚢胞開窓術と尾側膵切除術を施行した．病理組織学的には，異型性に乏しい粘液産生性の円柱上皮と卵巣様間質を認め，膵粘液性嚢胞腺腫と診断された．興味深い画像変化を示し，膵嚢胞性病変の鑑別診断を考える上で示唆に富む，単房性膵粘液性嚢胞腺腫の一例を経験したため報告する．

Koichi Hirata

Papers

Hepatic biliary epithelial cells acquire epithelial integrity but lose plasticity to differentiate into hepatocytes in vitro during development

A case of granular cell tumor of the anus

A case of unilocular mucinous cystadenoma of the pancreas showing an interesting change by CT observation

Mapping and localization for autonomous ship using LiDAR SLAM on the sea

Study of Inguinal Hernia following Open Radical Retropubic Prostatectomy