Proposal of a new staging and grading system of the liver for primary biliary cirrhosis

金沢大学医学部附属病院病理部Aims: To define a new histological staging and grading system for primary biliary cirrhosis (PBC), to provide more information reflecting clinical laboratory data and the prognosis to hepatologists. Methods and results: First, 17 histological lesions of PBC were scored in 188 needle liver biopsy specimens. Factor analysis yielded three independent groups of factors: factor 1 (fibrosis, fibrous piecemeal necrosis, orcein-positive granules, bile plugs, Mallory bodies, feathery degeneration, bile duct loss and atypical ductular proliferation); factor 2 (portal inflammation, eosinophilic infiltration, lymphoid follicles, epithelioid granulomas, interface hepatitis and chronic cholangitis); and factor 3 (interface hepatitis, lobular hepatitis, acidophilic bodies and pigmented macrophages). The eight findings of factor 1, but not factors 2 and 3, were significantly correlated with clinical laboratory data and scores in the Mayo Clinic\u27s prognostic model. Factor 1 lesions may reflect histological progression (staging), while factor 2 and 3 lesions may relate to necroinflammatory activity (grading). Then, we devised a staging and grading system using three lesions (bile duct loss, fibrosis and orcein-positive granules) from factor 1 and three from factors 2 and 3 (chronic cholangitis, interface hepatitis and lobular hepatitis). Conclusion: This new system might provide more pathological information on PBC patients for hepatologists. © 2006 The Authors

Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

Oxaliplatin-based chemotherapy plays an important role in the treatment of colorectal liver metastases. Oxaliplatin, however, causes sinusoidal obstruction syndrome (SOS), which is characterized by portal hypertension, splenomegaly, thrombocytopenia, and liver dysfunction. SOS is diagnosed histopathologically by disruption of the sinusoidal endothelium, collagen deposition, fbrosis especially around zone 3, dilatation of the sinusoidal space and congestion. This study assessed the characteristics of a rat model of SOS. SOS was induced in rats by administration of monocrotaline (MCT). Blood chemistries and macroscopic and microscopic fndings were compared in rats administered MCT and vehicle (control group). Levels of expression in the liver of CD41, P-selectin, rat endothelial cell antigen-1, CD34, and cleaved caspase-3 were analyzed immunohistochemically. Moreover, livers of these rats were analyzed by electron microscopy. Macroscopically, MCT-treated rats showed accumulation of bloody ascites and blue liver and were diagnosed with SOS histologically. Serum concentrations of aspartate aminotransferase (P=0.003), alanine aminotransferase (P=0.008), total-bilirubin (P=0.012), direct-bilirubin (P=0.007), indirect-bilirubin (P=0.003), lactate dehydrogenase (P<0.001) and hyaluronic acid (P=0.016) were signifcantly higher, and platelet counts signifcantly lower (P=0.004), in MCT-treated than in control rats. The livers of MCT-treated rats were immunohistochemically positive for CD41 and P-selectin, suggesting platelet aggregates; for rat endothelial cell antigen-1 and CD34, suggesting sinusoidal endothelial disorder; and for cleaved caspase-3, suggesting hepatocyte apoptosis. Electron microscopic fndings revealed platelet aggregation in the space of Disse in the MCT group. Extravasated platelet aggregation in Disse\u27s space may be involved in the development of SOS

Angiotensin II induces tumor progression and fibrosis in intrahepatic cholangiocarcinoma through an interaction with hepatic stellate cells

富山県立中央病院金沢大学医薬保健研究域医学系金沢大学附属病院胃腸外科Intrahepatic cholangiocarcinoma (ICC) is characterized as a highly fatal tumor with poor prognosis because of its strong progression, early invasion, widespread metastasis and rich cancerous stroma. Although it is widely accepted that fibroblasts facilitate stromal fibrosis and tumor progression, the mechanisms of the interaction between cancer cells and activated fibroblasts have not been fully elucidated thus far. In this study, we demonstrate the presence of angiotensin II (AngII) in ICC tissues and explore the interaction between hepatic stellate cells (HSCs) and ICC cells as one of the sources of stromal fibrosis and tumor progression through the interaction of the AngII/AngII type 1 receptor (AT-1) axis. The concentrations of AngII in ICC tissues were significantly higher than those of HCC and normal liver. Two human ICC cell lines (HuCCT-1, CCKS-1) and a human HSC cell line (LI-90) expressed AT-1 mRNA and protein. The proliferative activity of ICC cells and HSCs to which AngII was added dose-dependently increased and AT-1 antagonist inhibited the proliferative effects. HSCs to which AngII was added showed a higher expression of α-smooth muscle actin (α-SMA, a marker of activated HSCs and myofibroblasts), glial fibrillary acidic protein (GFAP, a specific marker of HSCs) and collagen type I than control cells. AT-1 antagonist also inhibited the activation and transformation of HSCs stimulated by AngII. These findings suggested that locally formed AngII in ICC tissues plays a role in the proliferation and activation of ICC cells and HSCs expressing AT-1 as a growth factor in autocrine and paracrine fashions. Our mechanistic findings provide the first insight into an autocrine and paracrine AngII-initiated signaling pathway that regulates ICC proliferation and fibrosis

Extravasated platelet aggregation in liver zone 3 may correlate with the progression of sinusoidal obstruction syndrome following living donor liver transplantation: A case report

Sinusoidal obstruction syndrome (SOS), previously known as veno-occlusive disease, is relatively rare subsequent to liver transplantation (LT). SOS refractory to medical therapy, however, can result in centrilobular fibrosis, portal hypertension and liver failure. Although sinusoidal endothelial cell damage around central venules (zone 3) occurs early in the development of SOS, the detailed mechanism of SOS development and its association with thrombocytopenia are not yet completely understood. The present report describes a patient who experienced SOS with unexplained thrombocytopenia following living donor LT. The progression of SOS resulted in graft dysfunction and the patient succumbed. The presence of platelets in the liver allograft was assayed immunohistochemically using antibody to the platelet marker cluster of differentiation 42b (platelet glycoprotein Ib). Platelet aggregates were found attached to hepatocytes along the sinusoid and within the cytoplasm of hepatocytes, particularly in zone 3. By contrast, no staining was observed in zone 1. These findings suggested that extravasated platelet aggregation in the space of Disse and the phagocytosis of platelets by hepatocytes were initiated by sinusoidal endothelial cell damage due to the toxicity of the immunosuppressant tacrolimus or a corticosteroid pulse, and that platelet activation and degranulation may be at least partially involved in the mechanism responsible for SOS

Case Report of an ABO-Incompatible Living-Donor Liver Transplant for a Familial Amyloid Polyneuropathy Patient

金沢大学附属病院肝胆膵・移植外科Liver transplant is a treatment for familial amyloid polyneuropathy. Few cases of ABO-incompatible living-donor liver transplant for familial amyloid polyneuropathy exist. The outcome of an ABO-incompatible living-donor liver transplant has improved recently, using local infusion therapy and rituximab prophylaxis. Here, we describe a successful ABO-incompatible living-donor liver transplant in a patient with familial amyloid polyneuropathy in whom disease progression ceased at 2 years’ follow-up. Additionally, no evidence of acute or chronic rejection, or adverse events of the immuno-suppressive therapy, was seen. As a postoperative complication, fatty changes in the grafted liver because of malnutrition or adverse events of corticosteroids were confirmed by a liver biopsy taken early after transplant. The main cause of malnutrition was considered to be gastrointestinal dysfunction caused by familial amyloid poly-neuropathy. Therefore, before deterioration of digestive function, liver transplants should be considered for familial amyloid polyneuropathy. This case suggests that an ABO-incompatible living-donor liver transplant may provide greater opportunities for familial amyloid polyneuropathy patients

Tumor-derived trypsin enhances proliferation of intrahepatic cholangiocarcinoma cells by activating protease-activated receptor-2

金沢大学医薬保健研究域医学系In primary malignant liver tumors, trypsinogen-immunoreactivity was present in 70% of intrahepatic cholangiocarcinoma (ICC) specimens, but absent in hepato-cellular carcinoma (HCC) specimens. We suggest the secretion of trypsinogen to be a key difference in biological behavior between ICC and HCC cells. The purpose of this study was to investigate the secretion of tumor-derived trypsin and the expression of its specific receptor, protease-activated receptor-2 (PAR-2), in ICC using cell lines and surgical specimens. The expression of trypsinogen-1 mRNA was observed in three of four ICC cell lines, but none of three HCC cell lines. Western blot analysis detected trypsinogen-1 in serum-free conditioned medium from one of the ICC cell lines positive for the mRNA. Gelatin zymography revealed a gelatinolytic activity for trypsin, the activated form of trypsinogen, in the same conditioned medium. PAR-2 mRNA and protein were observed in ICC cell lines. The proliferative activity of ICC cells was increased by concentrations of trypsin as low as 10 nM, and peaked at 100 nM. The effect of trypsin was suppressed by a serine protease inhibitor, gabexate mesilate. PAR-2 expression was detected in 64% of ICC surgical specimens immunohistochemically. In addition, stroma fibroblasts expressed PAR-2 in 52% of ICC specimens. These results suggest that trypsinogen-1 contributes to the growth of ICC cells and also tumor-associated fibroblasts.Embargo Period 6 month

Angiotensin II enhances epithelial-to-mesenchymal transition through the interaction between activated hepatic stellate cells and the stromal cell-derived factor-1/CXCR4 axis in intrahepatic cholangiocarcinoma

金沢大学医薬保健研究域医学系We previously reported that hepatic stellate cells (HSCs) activated by angiotensin II (AngII) facilitate stromal fibrosis and tumor progression in intrahepatic cholangiocarcinoma (ICC). AngII has been known as a growth factor which can promote epithelial-to-mesenchymal transition (EMT) in renal epithelial cells, alveolar epithelial cells and peritoneal mesothelial cells. However, in the past, the relationship between AngII and stromal cell-derived factor-1 (SDF-1) in the microenvironment around cancer and the role of AngII on EMT of cancer cells has not been reported in detail. SDF-1 and its specific receptor, CXCR4, are now receiving attention as a mechanism of cell progression and metastasis. In this study, we examined whether activated HSCs promote tumor fibrogenesis, tumor progression and distant metastasis by mediating EMT via the AngII/AngII type 1 receptor (AT-1) and the SDF-1/CXCR4 axis. Two human ICC cell lines and a human HSC line, LI-90, express CXCR4. Significantly higher concentration of SDF-1αwas released into the supernatant of LI-90 cells to which AngII had been added. SDF-1α increased the proliferative activity of HSCs and enhanced the activation of HSCs as a growth factor. Furthermore, addition of SDF-1α and AngII enhanced the increase of the migratory capability and vimentin expression, reduced E-cadherin expression, and translocated the expression of β-catenin into the nucleus and cytoplasm in ICC cells. Co-culture with HSCs also enhanced the migratory capability of ICC cells. These findings suggest that SDF-1α, released from activated HSCs and AngII, play important roles in cancer progression, tumor fibrogenesis, and migration in autocrine and paracrine fashion by mediating EMT. Our mechanistic findings may provide pivotal insights into the molecular mechanism of the AngII and SDF-1α-initiated signaling pathway that regulates fibrogenesis in cancerous stroma, tumor progression and metastasis of tumor cells expressing AT-1 and CXCR4.Embargo Period 6 month

Multiple liver metastases of pancreatic solid pseudopapillary tumor treated with resection following chemotherapy and transcatheter arterial embolization: A case report

金沢大学医薬保健研究域医学系A 33-year-old female was diagnosed with a solid pseudopapillary tumor (SPT) of the pancreas and multiple liver metastases at the Department of Gastroenterological Surgery, Ishikawa Prefectural Central Hospital (Kanazawa, Japan). Distal pancreatectomy and postoperative systemic chemotherapy with gemcitabine (GEM) and S-1, an oral fluoropyrimidine derivative, was administered, however, liver metastases became enlarged and local recurrence occurred. Therefore, the patient was referred to the Department of Gastroenterologic Surgery at the Graduate School of Medicine (Kanazawa, Japan) for hepatic arterial infusion (HAI) chemotherapy. Oral S-1 (80 mg/m2) was administered as well as HAI chemotherapy with GEM (1,000 mg/standard liver volume). Following 18 cycles, tumor sizes were reduced and 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) examination revealed obvious reduction of tumor FDG uptake. Transarterial tumor embolization (TAE) was performed for the previously unresectable right subphrenic liver tumor, and the other tumors were surgically resected. The resected tumors were diagnosed as liver metastases and a local recurrence of SPT in the postoperative pathological examination, which revealed that the resected tumors were composed of sheets of bland cells, which were positive for CD10, CD56, vimentin, neuron-specific enolase and α-antitrypsin. The postoperative course was uneventful, and the patient is currently under observation at an outpatient clinic; postoperative adjuvant chemotherapy with oral S-1 has continued, and additional TAE is planned. In the future, if the middle segment of the liver becomes enlarged, surgery for the residual right lobe tumor may be possible. This case demonstrates one method of SPT treatment: Preoperative HAI chemotherapy with GEM, plus oral S-1 and TAE. If complete resection can be achieved, the majority of patients with SPT have a favorable prognosis. In patients with unresectable metastases from SPT, it is crucial to conduct systematic multimodal treatment to maximize treatment success. © 2015, Spandidos Publications. All Rights Reserved.Embargo Period 6 month