Shuichi Iwahashi

Evidence for Instant Blood-Mediated Inflammatory Reaction in Clinical Autologous Islet Transplantation

A nonspecific inflammatory and thrombotic reaction termed instant blood‐mediated inflammatory reaction (IBMIR) has been reported when allogenic or xenogenic islets come into contact with blood. This reaction is known to cause significant loss of transplanted islets. We hypothesized that IBMIR occurs in patients undergoing total pancreatectomy followed by autologous islet transplantation (TP‐AIT) and tested this hypothesis in 24 patients and in an in vitro model. Blood samples drawn during the peritransplant period showed a significant and rapid increase of thrombin–anti‐thrombin III complex (TAT) and C‐peptide during islet infusion, which persisted for up to 3 h, along with a decreased platelet count. A concomitant increase in levels of inflammatory proteins IL‐6, IL‐8 and interferon‐inducible protein‐10 was observed. An in vitro model composed of pure islets plus autologous blood also demonstrated significantly increased levels of TAT (p < 0.05), C‐peptide (p < 0.05), tumor necrosis factor‐alpha (p < 0.05) and MCP‐1 (p < 0.05), as well as strong tissue factor expression in islets. Islet viability decreased significantly but was rescued by the presence of low‐molecular‐weight dextran sulfate. In conclusion, AIT‐induced elevation of TAT and destruction of islets suggests that IBMIR might occur during AIT. Modulating this process may help improve islet engraftment and the insulin independence rate in TP‐AIT patients.

Human adipose-derived stem cells: Potential clinical applications in surgery

Regenerative medicine is emerging as a rapidly evolving field of research and therapeutics. Stem cells hold great promise for future translational research and clinical applications in many fields. Much research has focused on mesenchymal stem cells isolated from bone marrow in vitro and in vivo; however, bone marrow procurement causes considerable discomfort to the patient and yields a relatively small number of harvested cells. By contrast, adipose tissue represents an abundant and easily accessible source of adult stem cells, termed adipose-derived stem cells (ADSCs), with the ability to equally differentiate along multiple lineage pathways. These stem cells have angiogenic properties, possibly because of their secretion of cytokines. They may also play a role in healing acute and chronic tissue damage. Subsequently, they have a wide range of potential clinical implications. This article reviews the potential preclinical and clinical applications of mesenchymal stem cells, especially ADSCs, in surgery.

Impact of splenectomy in patients with liver cirrhosis: Results from 18 patients in a single center experience.

Aim:  With the recent advances in medical or surgical treatments in chronic hepatic disorders, the indications for splenectomy in hepatic disorders have greatly expanded. We performed splenectomy for cirrhotic patients and investigated the effects of splenectomy on hepatic functional reserve and nutrition metabolism.

Outcome of hepatectomy in super-elderly patients with hepatocellular carcinoma.

Aim:  The aim of this study was to investigate the characteristics of super‐elderly hepatocellular carcinoma (HCC) patients aged 80 years or more who underwent hepatectomy and to clarify whether elderly patients with HCC benefit from hepatectomy.

Elevation of high-mobility group box 1 after clinical autologous islet transplantation and its inverse correlation with outcomes.

A major problem after clinical autologous islet transplantation (AIT) is the difficulty in achieving insulin independence. To follow up on our demonstration in a murine model that high-mobility group box 1 (HMGB1) was released from islets and involved in early loss of transplanted islets, we tested the role of HMGB1 in clinical AIT. Serum HMGB1 levels from 15 AIT patients were significantly elevated during islet infusion (7.6 ± 1.2 ng/ml) and 24 h after infusion (8.0 ± 1.4 ng/ml) compared to admission levels (2.4 ± 0.6 ng/ml). The first elevation of HMGB1 was associated with islet damage, but the later elevation was not. The change in the HMGB1 level from admission to first peak (ΔHMGB1) was significantly higher in the AIT group (8.1 ± 1.1 ng/ml) than in the pancreatectomy-only control (2.2 ± 0.5 ng/ml) (p < 0.05). Circulating serum levels of soluble receptor for advanced glycation end products (sRAGE) were also elevated during islet infusion. In vitro studies demonstrated that damaged human islets released HMGB1 but not sRAGE. In terms of outcomes, the insulin-free group showed significantly lower ΔHMGB1 (5.2 ± 0.6 ng/ml) and higher ΔsRAGE (2.3 ± 0.6 ng/ml) than the insulin-dependent group (10.6 ± 1.9 ng/ml and 0.7 ± 0.2 ng/ml, respectively). The ΔHMGB1 correlated with the number of white blood cell, IP-10, EGF, and eotaxin. In conclusion, serum HMGB1 was elevated in AIT and could be associated with inflammatory reactions that deteriorate islet engraftment. Therefore, anti-HMGB1 therapy might be a candidate for further improving the outcomes of clinical AIT.

High expression of cancer stem cell markers in cholangiolocellular carcinoma

PurposeCholangiolocellular carcinoma (CLC) is an extremely rare malignant liver tumor. It is thought to originate from the ductules and/or canals of Hering, where hepatic stem cells (HpSC) are located, but there are few reports on cancer stem cell markers in CLC. Thus, we evaluated the significance of cancer stem cell markers, including CD133, CD44, and EpCAM, in CLC.MethodsThe subjects of this study were three patients with CLC and one patient with an intermediate type of combined hepatocellular cholangiocarcinoma (CHC). The cancer cell markers, CK7, CK19, and EMA, were evaluated immunohistochemically.ResultsHistological examination of the CLC revealed morphologically cholangiolar features and immunohistochemical examination revealed positivity for CD133, CD44, and EpCAM. On the other hand, in the intermediate type of CHC, only CD44 was positive, whereas CD133 and EpCAM were negative.ConclusionCLC may have stronger features derived from HpSCs than an intermediate type of CHC.

Homing effect of adipose-derived stem cells to the injured liver: the shift of stromal cell-derived factor 1 expressions

Whether systemically transplanted human adipose‐derived stem cells (ADSCs) homed to the injured liver in nude mice under stress with subsequent hepatectomy (Hx) and ischemia‐reperfusion (I/R) was investigated in the present study. The types of cells in the liver that were involved in the homing of ADSCs were clarified, with focus on the stromal‐derived factor‐1 (SDF‐1)/C‐X‐C chemokine receptor type 4 (CXCR‐4) axis.

Specific miRNA expression profiles of non‐tumor liver tissue predict a risk for recurrence of hepatocellular carcinoma

It is reasonable to investigate non‐tumor liver tissues to predict a risk for development of hepatocellular carcinoma (HCC). A molecular analysis of chronically damaged liver tissues may identify specific miRNA expression profiles associated with a risk for multicentric (MC) HCC.

Role of histone deacetylase expression in intrahepatic cholangiocarcinoma

INTRODUCTION Histone deacetylase (HDAC) plays an important role in chromatin remodeling and gene expression, and in regulating cell cycle progression and differentiation. Furthermore, hypoxic conditions in the malignant tumor enhance HDAC function and increased HDAC activity is closely involved in worse malignant behavior through hypoxia inducible factor (HIF) activation. The aim of this study was to elucidate the correlation between HDAC expression and tumor malignant behavior including HIF-1α expression in intrahepatic cholangiocarcinoma (IHCC). METHODS Thirty-five patients with IHCC who underwent hepatic resection were evaluated. HDAC1 and HIF-1α expressions were determined immunohistochemically, and the patients were divided into 2 groups: the HDAC1 positive group (n = 21) and the HDAC1 negative group (n = 14). Clinicopathologic variables including HIF-1α expression were compared between the 2 groups. RESULTS HDAC1 expression correlated significantly with higher stage carcinoma, lymph node metastasis, and vascular invasion. The prognosis in the HDAC1 positive group was poorer than in the HDAC1 negative group (5-year survival: 78% vs 8%, P = .001). Furthermore, disease free survival rate in the HDAC1 positive group had significantly worse than that in the HDAC1 negative group (P = .0003). In the multivariate analysis, HDAC1 positive expression was identified as the only independent prognostic factor for disease free survival (Hazard Ratio: 7.194, P = .0018). Furthermore, there was a significant correlation between HDAC1 expression and HIF-1α expression (P = .007). CONCLUSION These findings suggested that HDAC1 positive expression was a potential new prognostic indicator of IHCC, and a possible promising molecular target through the regulation of HIF-1α.

Epigallocatechin gallate hinders human hepatoma and colon cancer sphere formation.

The long‐term survival of patients with hepatocellular carcinoma remains unsatisfactory because of the presence of cancer stem cells (CSCs), which are responsible for tumor recurrence and chemoresistance after hepatectomy. Drugs that selectively target CSCs thus offer great promise for cancer treatment. Although the antitumor effects of epigallocatechin gallate (EGCG) have been reported in some cancer cells, its effects on CSCs remain poorly studied. In this study, we investigated the effects of EGCG on human hepatoma and colon CSCs.