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276 Background: The aim of this study was to clarify impact of bevacizumab (Bev) on both hepatic sinusoidal injury after oxaliplatin (L-OHP)-based chemotherapy for metastatic colorectal cancer, and on liver regeneration after massive hepatectomy (Hx). Methods: Fourteen patients who underwent Hx after receiving L-OHP-based chemotherapy for liver metastases from colorectal cancer were divided into two groups (Bev group (n=8) and No-Bev group (n=7)). Histology of non-cancerous liver tissue, blood chemistry such as hyaluronic acid (HA), spleen size, and postoperative complications were compared between the two groups. Male Wister rats that underwent 90%-Hx were divided into two groups (Control group (n=7) and Bev group (n=7), in which Bev was injected intraperitoneally (5mg/kg) 7days before Hx). The following parameters were compared; blood chemistry, liver weight to body weight (Lw/Bw) ratio, and cytokines in liver tissues by RT-PCR, and survival rate. Results: Incidence of sinusoidal dilatation in Bev group was lower than that in No-Bev group (25% vs. 67%). Serum HA before Hx in Bev group (28 ng/ml).was lower than that in No-Bev group (155ng/ml). Spleen size in Bev group (174 ml) tended to be smaller than that in No-Bev group (252 ml). No significant postoperative complication was observed in Bev group, while 4 out of 7 patients had complications in No-Bev group. Liver damage such as ALT in Bev group (1471 IU/L) was smaller than that in Control group (2287 IU/L). Regeneration rate (Lw/Bw ratio) in Bev group was greater than that in Control group (0.80 vs. 0.67). Expression levels of IL-1β, MMP2 and MMP9 in Bev group tended to be lower than those in Control group. Survival rate at 72 hours after Hx in Bev group (83%) tended to be better than that in Control group (50%). Conclusions: Bev could reduce sinusoidal injury in patients with L-OHP-based chemotherapy, furthermore, Bev reduced liver injury and promoted liver regeneration after massive hepatectomy in rats. Those data strongly suggest Bev has beneficial effects for patients receiving L-OHP-based chemotherapy who undergo massive Hx.

367 Background: Prognosis of patients with advanced biliary carcinoma is still poor, and chemotherapy has been shown to have little impact. The aim of the present study was to clarify the effectiveness of GEM combined with CDDP and 5FU (GFP) therapy for advanced biliary carcinoma. The usefulness as a postoperative adjuvant chemotherapy using GFP (UMIN000006924) was evaluated. Methods: 1. Identification of independent poor prognostic factors: One hundred one patients with biliary carcinoma before induction of GFP chemotherapy, including intrahepatic cholangiocarcinoma (IHC: n=33), hilar cholangiocarcinoma (HC: n=29), and gallbladder cancer (GBC: n=39) were enrolled. The prognostic factors were investigated by multivariate analysis using Cox’s proportional hazard model. 2. Clinical usefulness of adjuvant GFP chemotherapy: One hundred forty-eight patients with biliary carcinoma (IHC: n=46, HC: n=43, GBC: n=39), who were positive for poor prognostic factors, received postoperative adjuvant GFP chemotherapy. The prognosis of these patients was compared to those not having postoperative adjuvant chemotherapy. Results: 1. In multivariate analysis, non-curative resection, lymph nodes metastasis and intrahepatic metastasis were identified as the independent prognostic factors. 2. Seventy-nine patients (53.3%) had poor prognostic factors. Of these, 22 patients received postoperative adjuvant GFP chemotherapy. The prognosis of patients with poor prognostic factors, who received postoperative adjuvant GFP chemotherapy, was significantly better than those not having such adjuvant chemotherapy (p Conclusions: Postoperative GFP adjuvant chemotherapy for patients with poor prognostic factors may improve the surgical outcomes.

530 Background: It has recently been suggested that the SDF-1/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and survival in various cancer. In this study, we investigate the possible role of SDF-1/CXCR4 axis in colorectal liver metastasis. Methods: Both primary colorectal tumors and liver metastatic tumors were obtained from 12 patients with colorectal liver metastasis. Expression levels of CXCR4 and SDF-1 were determined using RT-PCR. In 4 patients with benign liver disease, the expression level of SDF-1 in normal liver tissues was also determined. We divided the 12 patients into two groups; high expression group (n=6) and low expression group (n=6) according to each expression level of SDF-1 and CXCR4, and compared the clinicopathological factors between the two groups. Results: 1. CXCR4 expression levels in primary tumor: The frequency of the peritoneal dissemination in the CXCR4 high expression group was higher than in the low expression group (p=0.07). Moreover, overall survival rate in the CXCR4 high expression group was significantly lower than that in the low expression group (3 year-survival rate: 67% vs. 100%, p Conclusions: The present data suggest that there is a significant association of the SDF-1/CXCR4 axis with enhanced liver metastasis and poor prognosis of the patients with colorectal liver metastasis. Furthermore, an enhanced expression of SDF-1 in non-tumor liver tissues may have an important role in the formation of liver metastasis.

621 Background: Prognosis in patients with unresectable liver metastases from colorectal cancer is known to be very poor. However, thanks to progress of chemotherapy including molecular-target agents, “conversion” (from unresectable to resectable) has been sometimes seen. The aim of this preliminary study is to clarify the impact of FOLFOXIRI plus bevacizumab (Bev) on conversion and prognosis in patients with initially unresectable liver metastases from colorectal cancer. Methods: Seven patients with initially unresectable liver metastases from colorectal cancer, who received FOLFOXIRI (LOHP 85mg/m2 D1, CPT-11 150mg/m2 D1, LV 200mg/m2 D1, and 5FU 2,400mg/m2 infusion over 46 hours, D1) plus Bev 5mg/kg bolus every 2 weeks, were included in this study. Resectability, disease-free survival (DFS), and overall survival (OS) after hepatic resection were investigated in detail. In addition, completeness and adverse effects were examined in this regimen. Results: All 7 patients tolerated the regimen well, and no adverse effect of grade 3-4 was observed. Five out of 7 patients (71%) became resectable (conversion), except for 2 with multiple lung metastases and bone metastasis prior to chemotherapy. Our historical conversion rates were, 0% (0/7) in 5FU/LV regimen from 1994 to 2003, 25% (7/27) other regimens such as FOLFIRI and FOLFOX except for FOLFOXIRI plus Bev from 2004. In 5 patients who became resectable, CR was not observed, however, all had PR after 6 cycles of chemotherapy (RR 100%). All 5 patients could undergo curative (R0) hepatic resection, furthermore, all had pathological major response (grade 2). Follow-up period ranged from 8 to 18 months, with a median period of 14 months, and 2 patients relapsed (lung recurrence and peritoneal dissemination), and one died of lung metastases (1.5-year OS and DFS are 80 % and 60%). Conclusions: Our preliminary data suggested the feasibility of this new therapeutic combination in patients with initially unresectable liver metastases from colorectal cancer, and a high conversion rate and better prognosis. [Table: see text]

230 Background: Histone deacetylase (HDAC) is strongly associated with epigenetic regulation and carcinogenesis, and its inhibitors induce the differentiation or apoptosis of cancer cells. Valproic acid (VPA) is one of the clinically available HDAC inhibitors. We previously showed that VPA augmented antitumor effect of GEM in choalngiocarcinoma cell line (2010 GI Symposium); this time, we performed microarray analysis and Ingenuity Pathways Analysis (IPA) to identify the systematic mechanism of the augmentative effect of VPA. Methods: Human cholangiocarcinoma cell line (HuCCT1) was used. The anticancer effects of VPA or gemcitabine (GEM), and the effects of VPA combined with GEM were studied by MTT assay. We divided the following four groups: control group, VPA group, GEM group, VPA plus GEM combination group. The gene expressions of p21, HDAC, VEGF, and HIF-1 were evaluated by RT-PCR. And, the microarray analysis was performed, the genes were picked up using Gene Spring GX10, and then IPA was performed. Results: In GEM alone group, no effect of GEM was observed in dose of 5 mm, and 16% of proliferation-inhibitory effects were observed in dose of 10 nm. In VPA alone group, no effect of VPA was observed in dose of 0.5 mm, and 12%, 35%, and 67% of proliferation-inhibitory effects were observed in dose of 1.0, 5.0, and 10mm, respectively. GEM (5 nm) and VPA (0.5 mm) reduced by 23%, which significantly augmented the anticancer effect of GEM alone or VPA alone (p Conclusions: VPA augmented the effects of anticancer agents in a cholangiocarcinoma cell line. Such effects may be owing to the gene network of the cellular development. HDAC inhibitor may have the effect of the differentiation of cancer cell. No significant financial relationships to disclose.

228 Background: In our clinical data, we had the interesting findings that the pathologic sinusoidal obstruction syndrome and serum hyaluronic acid after neoadjuvant oxaliplatin-associated chemotherapy for liver metastatic colorectal cancer with bevacitumab (Bev) was ameliorated compared to those without Bev. The purpose of this study was to investigate the influence of bevacizumab administration on regenerating liver in rat 70% and 90% hepatectomy (Hx) model as a surrogate model of human massive hepatectomy for liver metastatic colorectal cancer. Methods: Male Wister rats weighing 180-230g were divided into the following four groups: 70%Hx, 70%Hx + Bev, 90%Hx and 90%Hx+Bev group. The rats were pretreated with intraperitoneal administration of bevacizumab (5mg/kg) 7 days before hepatectomy. The remnant liver and blood samples were taken one day after hepatectomy, and the following parameters were evaluated: blood analysis (AST, ALT, LDH, T- Bil, and hyaluronic acid), liver weight to body weight (Lw/Bw) ratio, and postoperative survival rate for three days. Results: In the 70%Hx model, there was no significant difference between the 70%Hx group and 70%Hx + Bev group in blood analysis one day after hepatectomy; AST (1928 vs. 923 IU/L), ALT (1282 vs. 670 IU/L), T-Bil (0.17 vs. 0.19 mg/dl), LDH (3822 vs. 2967 U/L) and hyaluronic acid (995.7 vs. 1026.6 ng/ml) and in Lw/Bw ratio (1.78 vs. 1.84). In 90%Hx model, AST and ALT of blood analysis in 90%Hx+Bev group significantly decreased compared to those in 90%Hx group; AST (3428 vs. 4995 IU/L, P Conclusions: The administration of bevacizumab seven days before hepatectomy did not significantly affect the liver functions and liver regeneration rate. These findings suggest that hepatectomy might be safe and feasible after the use of bevacizumab. No significant financial relationships to disclose.

219 Background: Histone deacetylase (HDAC) modulates gene expressions by chromatin remodeling during malignant transformation, and showed malignant behavior in intrahepatic cholangiocarcinoma (IHCC) (ASCO GI 2008). HDAC inhibitors have recently been found to repress the function of hypoxia inducible factors (HIF) through inducing hyperacetylation of histones. We also reported that the correlation between the expression of CD133, which was one of the cancer stem cell marker, and HIF-1α in IHCC (J Gastroenterol. 2010), and hypothesized that the cancer stem cell could be regulated by histone acetylation through the HIF-1α pathway. The aim of this study was to elucidate the potential mechanism of HDAC for the regulation of malignant behavior including the cancer stem cell in IHCC. Methods: Thirty-five patients with IHCC who underwent hepatic resection were evaluated. The expressions of HDAC1 (sc-6298 Santa Cruz Biotechnology, USA), HIF-1α (NB100-105 Novus Biologicals, USA) and CD133 (Ab27699 Abcam Inc, UK) were determined immunohistochemically, and the patients were divided into two groups: HDAC1 positive group (n=21); and negative group (n=14). Clinicopathological variables including HIF-1α and CD133 expressions were analyzed according to these expressions. Results: The HDAC1 expression correlated significantly with higher stage, lymph node metastasis, and vascular invasion. The prognosis in the HDAC1 positive group was poorer than in the HDAC1 negative group (5-year survival: 77.9% vs. 7.9%, p=0.001). In the multivariate analysis, HDAC1 positive expression was identified as the only independent prognostic factor for disease free survival (Hazard Ratio: 7.194, p=0.0018). There was a significant correlation between HDAC1 expression and HIF-1α expression (p=0.007), and also between HIF-1α expression and CD133 expression (p=0.10). Furthermore, co-expressions of these markers in same cancer cells were proven by immunofluorescent staining in the serial section. Conclusions: The findings suggested that histone acetylation regulated cancer stem cell through the HIF-1α pathway; therefore, HDAC1 might be a possible promising molecular target in IHCC. No significant financial relationships to disclose.

e14645 Background: Histone deacetylase (HDAC) is strongly associated with epigenetic regulation and carcinogenesis, and its inhibitors (HDACIs) induce the differentiation or apoptosis of cancer cel...