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-1α was 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 meta-stasis of tumor cells expressing AT-1 and CXCR4.

Results of surgery alone for pancreatic cancer are disappointing. We retrospectively evaluated the efficacy and tolerability of neoadjuvant chemotherapy (NAC) with gemcitabine and oral S-1 in patients with potentially resectable pancreatic cancer. A total of 34 patients with pancreatic ductal adenocarcinoma, radiologically diagnosed preoperatively as having potentially resectable tumors, underwent pancreatic resection with lymphadenectomy at Kanazawa University Hospital. NAC was administered to 13 patients (NAC group). The remaining 21 patients were surgically treated without preoperative chemotherapy (control group). Surgical results were compared between these two groups, with follow-up for at least 24 months. No statistically significant differences were found in the clinicopathological background data (tumor location, age, gender, lymph node metastases, tumor stage and tumor size) between the NAC and control groups. Following preoperative chemotherapy, no patients were judged to be unable to undergo laparotomy, i.e., neither distant metastasis nor tumor progression was observed. Radiologically, all 13 NAC group patients had stable disease, whereas, histopathologically, all tumor specimens showed evidence of tumor cells. The treatment effect was judged by Evans grading to be grade IIa in 11 patients and grade IIb in 2 patients. Toxicity was evaluated in 11 patients. Grade III side effects were regarded as hematological toxicity, i.e., leucopenia (7.7%) and thrombocytopenia (15.4%). Moreover, the incidence of perioperative complications did not differ significantly between the NAC and control groups. The one- and three-year overall survival rates of the NAC group with pancreatic head cancer were 88.9 and 55.6%, respectively, superior to 88.9 and 29.6% in the control group (p=0.055). Therefore, NAC with gemcitabine and S-1 is well tolerated and potentially effective against pancreatic head cancer. A phase I study of NAC with gemcitabine and S-1 is under way in patients with resectable pancreatic cancer.

Abstract. Intraperitoneal (i.p.) chemotherapy with paclitaxel (PTX) has been shown to be a promising treatment strategy for peritoneal metastasis. The present study focused on the comparative evaluation of the therapeutic efficacy of nanoparticle albumin-bound PTX (Nab-PTX) and i.

Abstract.Oxaliplatin-based chemotherapy plays a central role in the treatment of patients with colorectal liver metastasis (CRLM). This treatment, however, has been associated with hepatic sinusoidal obstruction syndrome (SOS), a clinically important adverse effect characterized by a bluish hue of the liver, splenomegaly and thrombocytopenia, resulting in liver dysfunction. The significant association between the sinusoidal endothelium and platelets has suggested that oxaliplatin-based chemotherapy affects platelets in the liver. This study compared platelet counts in patients who did and did not receive oxaliplatin-based neoadjuvant chemotherapy (NAC). The peripheral blood platelet count was significantly lower in the NAC group (n=17) compared to that in the non-NAC, or control group (n=15) (P<0.05). The spleen index was also higher in the NAC group, although the difference was not significant. However, the spleens of the patients in the NAC group were significantly enlarged following treatment (P<0.01). Immunostaining for the platelet surface marker CD42b (glycoprotein Ib), revealed more platelets in the liver in the NAC compared to the control group, particularly in the centrilobular zone III, adjacent to the hepatic central vein and in contact with hepatocytes (P<0.01). The platelets present in the spaces of Disse, referred to as extravasated platelet aggregation (EPA), secrete a number of growth factors, including transforming growth factor-β, vascular endothelial growth factor-A, plasminogen activator inhibitor-1 and thromboxane A2. In conclusion, EPA may play an important role in the development of hepatic SOS. Moreover, antiplatelet drugs may prevent the onset of SOS and hepatic injury in patients treated with oxaliplatin-based chemotherapy for CRLM.

Abstract. Background Sepsis is a clinical syndrome of systemic inflammatory responses arising from an infectious process with a presumed or known focus (1, 2). Severe sepsis, defined as sepsis with acute organ dysfunction, is associated with high morbidity and mortality rates (3). Inflammation and coagulation play pivotal roles in the pathogenesis of sepsis (4, 5). Sepsis-induced multiple organ failure (MOF) has numerous causes, such as various types of shock, adult respiratory distress syndrome (ARDS), and disseminated intravascular coagulation (DIC) (6). Gando et al. (7) reported that DIC is frequently associated with systemic inflammatory response syndrome (SIRS; 83%) and that such patients have a high mortality rate (63%). Ogura et al. (4) evaluated coagulation activity, organ dysfunction, and SIRS in critically-ill patients with thrombocytopenia and examined the balance between coagulopathy and systemic inflammation. In critically-ill patients with thrombocytopenia, they found that coagulopathy and organ dysfunction progressed with a significant mutual correlation, depending on the increase in SIRS scores. Thus, SIRSassociated coagulopathy may play a critical role in inducing organ dysfunction after severe insult. 1051This article is freely accessible online.Correspondence to: Tomoharu Miyashita,