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Treatments of hepatocellular carcinoma (HCC) located in the caudate lobe have been difficult because of the unique anatomical location. Our objective was to evaluate the surgical outcomes of hepatic resection for a single HCC located in the caudate lobe.Between January 1999 and December 2005, 97 patients with a single HCC underwent hepatic resection at our department. Seven (7.2%) of the 97 patients had a single HCC located in the caudate lobe. The caudate lobe HCC was located in the spiegel lobe in 2 patients, the paracaval portion in 2, caudate process in 2 and a total caudate lobe in 1. The influence of the tumor location (caudate lobe origin) on the surgical outcomes was analyzed in comparison with the other site tumors.The morbidity rate after hepatic resection for a single HCC in caudate lobe and the other lobes were 57% and 20%, respectively. The morbidity rate was significantly higher in the caudate lobe group (p0.05). The 3- and 5-year cumulative survival rates of the patients with a single caudate lobe HCC and the other lobes were 83.3%, 83.3%, 89% and 85.4%, respectively. Similarly, the 3- and 5-year cumulative disease free survival rates were 51.4%, 51.4%, 59.4% and 45.5%, respectively. There was no significant difference in both the cumulative survival rate and cumulative disease free survival rate.Hepatic resection for a single HCC located in the caudate lobe was an effective treatment, being equal clinical outcomes to a single HCC in the other sites of the liver.

The purpose of this study is to evaluate the effect of radiation therapy (RT) for tumor thrombosis (TT) in the major portal vein (PV) or inferior vena cava (IVC) from unresectable hepatocellular carcinoma.Fifteen HCC patients with main PVTT (n = 10) and IVCTT (n 5) were treated with three-dimensional conformal RT between 2001 and 2004. The mean dose was 38.5 Gy (range 28 to 54Gy). The concurrent therapies to intrahepatic tumor included transcatheter arterial chemoembolization (TACE) in 7, TACE + hepatic arterial infusion in 2 and systemic chemotherapy in 1 patient. The therapeutic effect was assessed by tumor regression for TT.An objective response was observed in 3 of 15 patients (20%). There were no patients with progressive disease. The median survival time was 10 months. In 12 cases with stable disease, time to progression (TTP) estimated above 6 months were 42% (5/12 cases). In univariate analysis, therapeutic effect and TTP were affected to survival time. All patients did not have severe deterioration of liver function.In the current study, we concluded that RT was superior treatment in terms of local control capability and was useful to continue further treatment because RT did not make liver function worse.

Pancreatic carcinoma is one of the most lethal of the gastrointestinal malignant tumors. Chronic inflammation leads to cancer development and progression. Interleukin-8 (CXCL-8) is a CXC chemokine, which plays an important role in neutrophil chemotaxis and activation. We previously reported that CXCL-8 was produced by a variety of human carcinoma cells and tissues, and that CXCL-8 promoted proliferation in pancreatic carcinoma cells (SUIT-2). In the present study, we analyzed whether various cytokines affect cell proliferation by CXCL-8 expression in pancreas carcinoma cells. All examined pancreatic carcinoma cells expressed CXCL-8 and TNFRII mRNA constitutively in RPMI-1640 medium without FBS. TNF-alpha, LIF, IL-1beta, IL-6, IL-8, or IFN-beta enhanced the expression of CXCL-8 mRNA, but IL-10 did not in Hs-700T cells. Actinomycin D suppressed and cycloheximide augmented CXCL-8 mRNA which was induced by TNF-alpha or not. The half-life of CXCL-8 mRNA was 36.5 min by TNF-alpha and 35.2 min by no stimulation. In our previous study, LIF promoted cell growth in Hs-700T cells. LIF induced CXCL-8 mRNA in a dose- and time-dependent manner. Addition of recombinant CXCL-8 did not induce cell growth of Hs-700T. Anti-CXCL-8 IgG significantly suppressed cell growth. CXCL-8 would act as an autocrine growth factor in Hs-700T cells, which expressed CXCL-8 mRNA highly without stimulation. Curcumin (diferuloylmethane), NF-kappaB inhibitor, suppressed cell proliferation in Hs-700T cells. These results suggest that CXCL-8 plays a pivotal role in progression of pancreatic cancer, and its expression is influenced by inflammatory cytokines in pancreatic tumor microenvironment.

Pancreatic carcinoma is one of the most lethal of the gastrointestinal malignant tumors. Chronic inflammation leads to cancer development and progression. Interleukin-8 (CXCL-8) is a CXC chemokine, which plays an important role in neutrophil chemotaxis and activation. We previously reported that CXCL-8 was produced by a variety of human carcinoma cells and tissues, and that CXCL-8 promoted proliferation in pancreatic carcinoma cells (SUIT-2). In the present study, we analyzed whether various cytokines affect cell proliferation by CXCL-8 expression in pancreas carcinoma cells. All examined pancreatic carcinoma cells expressed CXCL-8 and TNFRII mRNA constitutively in RPMI-1640 medium without FBS. TNF-alpha, LIF, IL-1beta, IL-6, IL-8, or IFN-beta enhanced the expression of CXCL-8 mRNA, but IL-10 did not in Hs-700T cells. Actinomycin D suppressed and cycloheximide augmented CXCL-8 mRNA which was induced by TNF-alpha or not. The half-life of CXCL-8 mRNA was 36.5 min by TNF-alpha and 35.2 min by no stimulation. In our previous study, LIF promoted cell growth in Hs-700T cells. LIF induced CXCL-8 mRNA in a dose- and time-dependent manner. Addition of recombinant CXCL-8 did not induce cell growth of Hs-700T. Anti-CXCL-8 IgG significantly suppressed cell growth. CXCL-8 would act as an autocrine growth factor in Hs-700T cells, which expressed CXCL-8 mRNA highly without stimulation. Curcumin (diferuloylmethane), NF-kappaB inhibitor, suppressed cell proliferation in Hs-700T cells. These results suggest that CXCL-8 plays a pivotal role in progression of pancreatic cancer, and its expression is influenced by inflammatory cytokines in pancreatic tumor microenvironment.

Grafts used in Domino liver transplantation (LT) obtained from living donor liver transplantation (LDLT) for familial amyloid polyneuropathy (FAP) patients have been mainly used as reduced grafts. Because of small-for-size problems seen in LDLT, using whole liver grafts could improve post-LT outcome. Eight consecutive Domino LDLT using whole livers without retrohepatic inferior vena cava (IVC) from FAP patients were retrospectively analyzed. The graft weight/recipient's body weight ratio (GWRW) in the domino recipients ranged from 1.28% to 2.4% (mean: 1.52). Multiple vascular reconstructions in the whole-liver domino LT resulted in longer than usual warm ischemia time (mean: 64 min); however immediate post-operative recovery of hepatic function was uneventful. At 8-40 months after the transplant, all the FAP patients are well and all of the domino recipients are alive. Domino LT using a whole FAP liver from a LDLT for a FAP patient presents satisfactory results, even though the transplant procedure is technically complicated.

Leukemia inhibitory factor (LIF) is a pleiotrophic cytokine, which plays an important role in inducing cancer cachexia. We have previously reported that LIF promotes cell proliferation in some human carcinoma cells through c-fos, jun-B and cyclin-E expression. In the present study, we analyzed the regulation of LIF and its receptor (LIFR) expression in pancreatic carcinoma cells. Seven pancreatic carcinoma cells expressed constitutively LIF and its heterodimer receptor (LIFR and gp130) mRNA in RPMI-1640 medium without FBS. The amount of LIF immunoreactive protein was 132.5+/-52 pg/10(6) cells in culture supernatants without FBS. Pro-inflammatory cytokines, such as TNF-alpha, IL-1beta, IL-6, IL-8, or LIF, enhanced the expression of LIF mRNA in Hs-700T and Hs-766T cells. Addition of LIF significantly induced cell proliferation of Hs700T in 13 days LIF dose-dependently. However, anti-LIF IgG failed to suppress cell proliferation in Hs-700T cells. LIF acted as a paracrine growth factor in Hs-700T cells, which expressed low amount of LIF without stimuli. Cellular signal transductions by LIF was down-regulated by inhibitors of protein kinase C (PKC), protein tyrosine kinase (PTK), and Ca/Calmodulin. LIF induced phosphorylation of STAT3. Moreover, exogenous LIF upregulated the expression of LIFR mRNA. Antisense LIFR oligonucleotide significantly suppressed cell growth in the presence of LIF in Hs-700T cells. These results suggest that cytokine network might alter the expression and responsiveness to LIF in tumor microenvironment.

A 50-year-old man with multiple liver and mediastinal LN metastases from sigmoid colon cancer was admitted to our hospital in May 2005. In October 2002, a radical resection of the original tumor and liver metastases were performed at a previous hospital. Histologically, the tumor was diagnosed as Stage IV. He was treated with an oral anticancer agent as an adjuvant therapy. In January 2005, the CEA level was increased to 3.2 ng/ml and CT scan revealed a solitary liver metastasis. Partial resection of the liver was performed. On admission to our hospital, a systemic chemotherapy by FOLFOX4 was begun. The liver metastases showed 61% reduction in size and were judged to be PR. However, the intrathoracic lymph node size was not changed. Therefore, VATS extirpation of the mediastinal lymph node was performed. After 10 courses of FOLFOX4, abdominal CT revealed liver metastases remained to be almost the same size. In January 2006, radio frequency ablation (RFA) and partial hepatectomy were enforced and then, the tumor marker returned to normal. There were no serious adverse events or postoperative complications. He has been alive without any sign of recurrence for 42 months from the initial treatment. In conclusion, intensive combination therapies for remote metastases of colon cancer might be promising to obtain a long-term survival without ruining QOL.

It is necessary to select a proper method for radio-frequency ablation (RFA) therapy of the liver tumor. Especially, treating the tumor under the diaphragm is usually difficult to approach by percutaneous puncture. We have done thoracoscopic RFA in 48 cases (43 HCC, 1 adenomatous hyperplasia, and 4 metastatic liver tumors) to treat the tumor located on the surface of the liver under the diaphragma since January 1st, 2000. The average operation time was 237 minutes, the average blood loss was 29.0 ml and the average tumor diameter were 2.6 cm, and the average frequency of coagulation was 4.5 times. The cases which thoracoscopic RFA was possible with diaphragm incision were 27 cases (56%). However, there were 15 cases in which diaphragm incision was difficult by the adhesion under the diaphragm. Moreover, there were six cases with severe adhesion that was impossible by the thoracoscopic operation to convert an open chest method. There were 25 cases, which had some adhesion either in the chest or under the diaphragm, and those adhesions were considered to be related to the previous treatments such as the operation, ablation, and chemotherapy. The average length of the hospital stay post operation was 9.7 days. Only 3 cases (6%) needed additional treatments for tumor where the severe postoperative complication did not occur. Therefore, thoracoscopic RFA for tumor on the liver surface located under the diaphragm is suggested to be a feasible technique. On the other hand, it is necessary to pay attention to two kinds of adhesion taking a critical role for thoracoscopic operation procedures.

A 56-year-old man was admitted to our hospital for liver tumor of 7 cm in diameter, located mainly in the anterior segment. He underwent a hepatic resection of anterior and median segment of the liver in January 2002. Pathologically, the tumor was moderately differentiated intrahepatic cholangiocarcinoma (ICC) with vascular invasion. Hepatic arterial chemotherapy as a neoadjuvant therapy was performed. In December 2002, bone metastases in the 12th thoracic spine and iliac bone were found. Therefore, he received radiotherapy (total of 30 Gy) and a monthly bisphosphonate infusion. In May 2003, multiple intrahepatic recurrences were diagnosed. Transarterial chemoembolization for twice and an additional radio-frequency ablation were performed. Four months later, lung metastases were found, thus, he was administered TS-1. He has been alive with PS 0 for 4 and half years after the hepatic resection. No new intrahepatic recurrences were found and bone and lung metastases remained to be stable. Although only a hepatic resection is a useful therapy for ICC, such a multidisciplinary treatment may have an effect to improve the prognosis of patients with ICC.

We reported an efficacy of percutaneous transhepatic portal embolization (PTPE) for three patients with hepatocellular carcinoma (HCC) who did not receive hepatic resection. All three patients, who had HCCs in the right hepatic lobe, were given transarterial chemoembolization (TACE) and PTPE in the aim of hepatic resection. However, hepatic resection was not performed because of the refusal of operation or insufficient hypertrophy of the remnant liver. Primary lesions were well controlled by TACE in all of the cases. We recognized new HCC lesions of the liver in the clinical courses, but all tumors appeared to be in the post-PTPE area only. A possibility of prevention for transportal intrahepatic dissemination by PTPE was considered. We conclude that combination therapy including PTPE for HCC patients with tumors in the limited area is useful for the improvement of their prognosis.

Combined hepatocellular and cholangiocarcinoma (HCC-CC) is a rare type of liver cancer. We herein report a case of HCC-CC with lymph node metastases treated by multimodality therapy. The patient has been alive for more than 42 months. A 52-year-old man with a 9 cm diameter mass lesion in the liver was admitted to our hospital. The tumor was diagnosed as peripheral type of cholangiocarcinoma. Preoperative transhepatic arterial chemoenbolization (TACE) was performed. An accumulation pattern of lipiodol after TACE and an increase of serum alpha-fetoprotein led us to diagnosis of combined HCC-CC. A three segmentectomies of the liver and dissection of the local lymph nodes were performed. A histological examination of the resected specimen showed combined HCC-CC with lymph node metastases. Alpha fetoprotein, cytokeratins 7 and 19 were partially positive with immunohistochemical staining. The final diagnosis was a mixed type of combined HCC-CC. To improve a poor prognosis of combined HCC-CC, adjuvant chemotherapy with CDDP, 5 FU and radiation therapy were achieved. Fortunately, the patient is alive without any recurrence for 42 months after the operation.

Background: C5a is one of the important factors produced on complement pathway and a strong chemokine. There is emerging evidence that C5a is generated in the cancer microenvironment and C5a receptor (C5aR) is expressed in various cancer cells and associated with invasive ability in several cancer cells. However, the role of C5aR in gastric cancer (GC) is still mostly unknown. Aim: To investigate the clinical significance of C5aR expression in human GC. Method: 168 patients underwent gastrectomy after the diagnosis of gastric cancer from January 1st 2001 to December 31th 2009. C5aR-expression of GC cells was investigated in all 168 patients and was analyzed in regard to an association with clinicopathological factors and outcomes in the patients. Additionally, in vitro experiments were used to examine the proliferation and invasion of GC cells by using the GC cell lines that had high-expression of C5aR. Result: High-expression of C5aR was found in 55 patients (32.7%). High-expression of C5aR was significantly related to depth of invasion, stage, lymphatic and vascular invasion. Among the 146 patients with a tumor stage lower than stageIV, the 5-years recurrence-free and overall survival rates of patients in the high-expression of C5aR group were significantly lower than those in the low-expression of C5aR group (91.0% vs 52.4%, p = 0.007 and 87.2% vs 59.1%, p = 0.003, respectively). The high-expression of C5aR group had more frequently distant metastasis than the low-expression of C5aR group during the follow-up time, presenting itself mainly in liver metastasis and peritoneal dissemination (p = 0.020 and p = 0.026). We found that the gastric cancer cell lines MKN1 and MKN7 had the high-expression of C5aR with western blotting in vitro. Moreover, matrigel chamber assay revealed that 10 nM of recombinant C5a enhances cell invasiveness of MKN1 by 2.55-fold and the cell invasiveness of MKN7 by 2.90-fold, but such an enhancement by C5a was not observed in control cells. Conclusions: The gastric cancer patients with a high expression of C5aR were associated with poor prognosis, and the invasive ability of gastric cancer cell lines highly expressing of C5aR were promoted by C5a. Thus, targeting this C5a-C5aR axis might provide a useful therapeutic option for gastric cancer treatment. Citation Format: Takayoshi Kaida, Hidetoshi Nitta, Kota Arima, Hideaki Takeyama, Takaaki Higashi, Katunobu Taki, Hiromitsu Hayashi, Daisuke Hashimoto, Akira Chikamoto, Takatoshi Ishiko, Toru Beppu, Hideo Baba. Overexpression of C5a receptor becomes risk factor in gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4146. doi:10.1158/1538-7445.AM2015-4146

Proteinase-activated receptor-2 (PAR-2) is expressed in various tissues, including cancer lesions. However, the functional consequences of PAR-2 expression in cancer cells, especially in pancreatic cancer cells, are poorly understood. To clarify the biological significance of PAR-2 signaling in pancreatic cancer, we examined the production of growth factors and cytokines, such as IL-6, IL-8, bFGF, TGF-beta1, and VEGF, by specific ELISAs. Two human pancreatic cancer cell lines, SUIT2 and MiaPaCa2, which have been shown to express PAR-2, were stimulated by trypsin and PAR-2 activating peptide (PAR-2AP: SLIGKV-NH2). After 24 h, the culture supernatants were collected and specific ELISAs were performed. Although no significant changes were observed in the release of IL-6, bFGF, TGF-beta1, or VEGF, that of IL-8 was significantly up-regulated by PAR-2 agonists in a dose-dependent manner. In addition, IL-8 receptor expression was found in pancreatic cancer cells and fibroblasts. These results suggest that the PAR-2 signal up-regulates IL-8 release from pancreatic cancer cells. This up-regulated IL-8 has an effect on the pancreatic cancer cells in an autocrine manner and on the fibroblasts in a paracrine manner. Thus, this signal might contribute to tumor progression and characteristic fibrosis in pancreatic cancer.

We reported a 60-year-old male patient with hepatocellular carcinoma (HCC) of 5cm in diameter with advanced tumor thrombosis in the left main trunk of portal vein and bile duct. He was treated with multimodal treatments resulting in a long-term survival of more than 4 years. At first, he was treated with transcatheter arterial chemoembolization (TACE) in April 1999, but the therapeutic effect was insufficient. Therefore, we performed an extended left hepatic lobectomy in July. Since six HCCs appeared in a posterior segment in January 2000, we achieved microwave coagulation therapy under laparotomy. Because of diffuse relapse of HCCs in the same segment of the liver, we performed hepatic arterial chemotherapy (HAC) using low-dose CDDP and 5-FU. As a result, complete disappearance of the tumors was observed. A new lesion appeared in S7 in January 2001. We performed TACE, but relapsed in June, so we selected percutaneous radio-frequency ablation under CO2 angiography. Since a recurrent tumor was detected at the same therapeutic site with invasion to the diaphragm in September 2002, we performed a partial liver resection with synchronous excision of the diaphragm. We continued TACE and systemic chemotherapy for relapses in and out of the liver. Accordingly, he lived for over four years. We conclude that a long-term survival in this patient can be attributable to appropriate treatment selections and timing, such as hepatic resection, TACE, HAC and ablation therapies based on changes in diagnostic imaging and tumor markers. In addition, we have to pay attention to keep good hepatic reserve in order to continue treatment for recurrences of HCC.

We have developed a radio-frequency ablation using hand-assisted laparoscopic surgery (HALS-RFA) for hepatocellular carcinoma, and it applied for 10 patients who were difficult to be treated by common laparoscopic surgery (LS) from November 2001. The reasons for selection of HALS-RFA were severe adhesions in 3 patients, anatomical location at the hepatic dome in 3 patients, lesions adjacent to other organs or vasculatures in 3 patients, and co-operation for another organ in 1 patient. We compared efficacies of HALS to other ablation therapeutic techniques with LS and open surgery (OS). The average amount of bleeding was 85 ml in HALS, 14 ml in LS and 319 ml in OS. The amount of HALS was lesser than that of OS, but not significant. Post operative maximal CRP level was 3.2 mg/dl, 4.9 mg/dl and 10.5 mg/dl in HALS, LS, and OS, respectively, with a statistical significance between HALS and OS. Complications occurred in 2 out of 10 cases (20%) in HALS, 2 out of 62 cases (3.2%) in LS and 3 out of 9 cases (33%) in OS. Recurrence in the treated site was encountered in 1 out of 10 cases (10%) in HALS, 2 out of 62 cases (3.2%) in LS and none (0%) of OS. Based on these findings, we conclude that HALS-RFA seems to be a minimally invasive and highly effective treatment.

RFA for the hepatocellular carcinoma localized on the surface of the liver tends to have some complications such as bleeding, an ejection of tumor and a heat injury to other internal organs even if percutaneous RFA seemed to be done easily. Therefore, we should first choose the RFA treatment under endoscopic (either laparoscope or thoracoscope) surgery for the hepatocellular carcinoma localized on the surface of the liver. Moreover, a direct central puncture should be avoided from the viewpoint of securing a margin, prevention of bleeding and rise in the intratumorale pressure. Now, we selected the unique operation method of RFA: First, the tumor is confirmed under the endoscope, and the tumor range is marked with the endoscopic echo. Second, several times of RFA applied to the tumor surroundings are done, and the margin is secured with avoiding a direct central puncture. If tumor diameter is over 2.5 cm, central ablation of the tumor is considered to be necessary, we can directly puncture the center of the tumor without bleeding since the tumor already has the congelation by surrounding heat effect. We have done RFA by this way for 29 patients with HCC since April 1st, 2004. The complications such as a heat injury to the neighboring organ could be well prevented. An enough margin of ablation about 1 cm around the tumor was confirmed by the postoperative CT image. There was no local recurrence during the average observation period of 290 days, and a severe post operative complication has not occurred. The average of hospitalized period after the operation was about 10 days. Therefore, pre-surrounding ablation preceding central puncture under the endosope for hepatocellular carcinoma on the liver surface is a feasible technique.

The results of duct-to-duct biliary reconstruction in six pediatric patients who received a living donor liver transplant aged from 2 months to 11 yr old are reported. The graft was either entire or a part of the left lateral segments. The orifice of the bile duct of the graft was anastomosed to the recipients' hepatic duct in an end-to-end fashion by interrupted suture using 6-0 absorbable material. A transanastomotic external stent tube (4 Fr) was passed through the stump of the recipients' cystic duct. Mean time for reconstruction was 24 min. All the recipients survived the operation and reinitiated oral intake on postoperative day 3. There were no early biliary complications. One 5-yr-old boy suffered from an anastomotic stenosis 9 months after transplantation. He underwent re-anastomosis by Roux-en Y (R-Y) procedure and recovered uneventfully. Duct-to-duct anastomosis in pediatric living donor liver transplantation has benefits while the complication rate is comparable to R-Y reconstruction.

The patient was a 43-year-old male with bilateral multiple liver metastases, who had undergone high anterior resection for rectal cancer (ss, n 0, P 0, H 3, M (-), stage IV). Hepatic arterial infusion (HAI) of low-dose CDDP (10 mg/body) and 5-FU (250 mg/body), 5 times a week, was ineffective for the liver metastases. Consequently, HAI of levofolinate (425 mg/body) and 5-FU (1,000 mg/body), once a week, was attempted. All metastatic liver tumors diminished apparently with calcification after the treatment (PR). Tumor marker (CA19-9 and CEA) levels decreased to less than one-tenth of the pretreatment levels and stabilized for approximately seven months. Mediastinal lymph node metastases, paraaortic lymph node metastases and tumor thrombus in the inferior vena cava were successfully treated with systemic chemotherapy using levofolinate and 5-FU and/or radiotherapy. Although the liver and lung metastases showed rapid growth, the patient died 2 years after the diagnosis of liver metastases. The liver metastases were well controlled for about 20 months. It is important to select interdisciplinary therapies according to the site of the metastases due to rectal cancer.

We introduced a new therapeutic approach for hepatocellular carcinoma (HCC); Radio-frequency ablation (RFA) assisted endoscopic hepatectomy (RFA-assisted EH). Seven patients with HCC, smaller than 3 cm and located on the surface of the liver, were entered into this study. RFA on the hepatic cutting line was achieved with a 2 cm Cool-tip needle at a 1-cm interval. RFA power was gradually increased to 100 W in a minute and ablation was stopped once an impedance-out state was attained of RFA power. Hepatic resection was achieved with various items in a coagulative hepatic parenchyma. If necessary, additional RFA could be performed during the hepatectomy. Patients' characteristics were described as follows; average age: 64 years, 5 males and 2 females, liver damage A: 5, B: 2, average tumor size: 27 mm, and average tumor number: 1.3 Two thoracoscopic and 5 laparoscopic approaches were selected. One application of RFA could make an elliptical coagulative area (2 cm x 1 cm). RFA was achieved eleven times on the hepatic cutting line and three times during the hepatectomy. The average operating time and blood loss was 256 minutes and 96 g, respectively. No blood product was needed. The average postoperative hospital stay was 11 days and no operative complication was encountered. All of the patients were well and without recurrence during the observation period (average: 6 months). We positively recommend RFA-assisted EH for HCC due to its perfect radicality and safety.

Various local cancer treatments became possible in the cure of hepatocellular carcinoma. Percutaneous ethanol injection (PEIT), a local ablation therapy such as microwave and radiofrequency were added to the transcatheter arterial chemoembolization (TACE) and hepatectomy. However, it is also a well-known fact to repeat hepatic carcinogenesis by the conditions of a background liver whereas to originate in the viral hepatitis. In this point of view, liver transplantation is one of the ultimate treatments to get rid of the carcinogenic factor. A 54-year-old man patient diagnosed as HCC strongly hoped for the prospective liver transplantation surgery from the beginning. Therefore, we had to treat a liver cancer in consideration of the prospective liver transplantation. A local ablation therapy and TACE treatment were carried out with being careful not to have an influence to the transplantation surgery. Because recurrence was repeated, a patient chose a transplantation medical treatment after one year and nine months. We reported the process of local treatments against HCC in consideration of the prospective liver transplantations.

The patient was a 73-year-old male who was identified with an increase of serum PIVKA-II during a treatment for chronic hepatitis B. Hepatocellular carcinoma (HCC) of 60 mm in diameter with satellite nodules was diagnosed in segment 8 of the liver. In addition, portal vein tumor thrombosis (PVTT) of the right branch (Vp3) and metastases to bilateral lung and right adrenal gland were recognized. He received serial treatments with transcatheter arterial chemoembolization (TACE), radiation therapy and hepatic arterial chemotherapy with reservoir for primary liver tumor and PVTT. Soon after the treatments, PVTT was reduced in size and the serum level of PIVKA-II was decreased to 57 mAU/ml. After three months, the level of PIVKA-II had increased again and the size of the right adrenal metastasis grew to 50 mm in diameter. He received TACE to the right adrenal metastasis and percutaneous transhepatic portal chemoembolization to prevent further growth of PVTT. In spite of several treatments, the therapeutic effect was insufficient. Therefore, we performed right adrenalectomy and radio-frequency ablation of HCC in the liver S8. After the surgery, he received two times of TACE and the viable tumor had disappeared on CT and MRI. Prognosis of HCC with PVTT and distant metastasis is very poor. The two-year survival rate is less than 10%. However, it is possible to improve the prognosis of advanced HCC by multidisciplinary treatment with surgical intervention, local chemotherapy and radiation therapy.

In our previous investigations, mitogen-activated protein kinase kinase 2 (MEK2)/extracellular signal-regulated kinase 2 (ERK2) signaling pathway was found to be correlated with the cell dissociation induced by dissociation factor (DF) in pancreatic cancer cells. In this study, the expressions of epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), and its downstream kinases MEK1/2 and ERK1/2, were analyzed to clarify the regulatory mechanism of cell dissociation in pancreatic cancer cells. Two hamster (PC-1.0 and PC-1) and two human (AsPC-1 and Capan-2) pancreatic cancer cell lines were used. Immunocytochemical study was performed using anti-EGFR, p-EGFR, phosphorylated MEK1/2 (p-MEK1/2), and phosphorylated ERK1/2 (p-ERK1/2) antibodies. DF-treatment markedly induced the expressions of EGFR, p-EGFR, p-MEK1/2, p-ERK1/2, as well as the dissociation of cell colonies in PC-1 and Capan-2 cells. In contrast, AG1478 (an EGFR inhibitor) treatment significantly induced the cell aggregation in PC-1.0 and AsPC-1 cells which usually grew as single cells, but strongly suppressed the expressions of EGFR, p-EGFR, p-MEK1/2, and p-ERK1/2. These observations demonstrate that activation of EGFR is closely involved in cell dissociation in pancreatic cancer through activating MEK/ERK signaling pathway.

The patient was a-54-year-old man. Sigmoidectomy was performed for sigmoid colon cancer in 1991. Partial liver resection in 1992 and microwave coagulation therapy (MCT) in 1994 were carried out for liver metastasis. Complete remission of the metastasis was achieved. In June 2002, multiple liver and lung metastases were identified. 5-FU, CDDP therapy was applied as systemic chemotherapy. The liver metastasis was improved and the level of CEA was reduced. However, a new lesion appeared in the right lobe of the liver, followed by an increase of the CEA level. Although CPT-11, 5-FU, CDDP therapy was applied, it was not effective. The reason was considered to be from the decrease of drug delivery resulting from an unbalanced blood supply in the right lobe of the liver. Right lobectomy and radio-frequency ablation was performed on June 17, 2003. The level of CEA was dramatically decreased. Additionally, CPT-11, 5-FU, CDDP therapy was applied. The patient has survived for 11 years after liver metastasis was first detected.

The patient was a 69-year-old man who was found to be positive for the hepatitis C antibody in 1996. Hepatocellular carcinoma (HCC) was found in S4 and S7 in April 2000. He received treatment by transcatheter arterial chemoembolization (TACE) 3 times and by percutaneous ethanol injection therapy 1 time. At that point pulmonary metastasis was found. In November 2001 he was urgently admitted with hematemesis to the Department of Gastroenterology and Hepatology of our hospital. Bleeding from the HCC invading the stomach was found by endoscopy. Bleeding was successfully stopped by TACE. Because of the dangerousness of severe bleeding due to the disintegration of the HCC, we carried out a partial hepatectomy with partial gastrectomy and partial excision of the diaphragm. He recuperated at home after being discharged from the hospital, and sufficient QOL was maintained. In April of the same year, he vomited blood again and was readmitted. Endoscopy showed bleeding from a recurrence of the HCC in the stomach and a metastatic tumor at the lower esophagus. Bleeding was controlled by TACE and endoscopic procedures. The patient could maintain QOL under multidisciplinary therapy including surgery for the HCC, which was impossible to treat curatively. In such cases, it is important to use IVR or endoscopic procedures or a combination including them. Furthermore, in case of good hepatic reserve, surgery may then be added.

We introduce some inventive approaches in endoscopic local ablation therapy (ELAT) for patients with hepatocellular carcinoma (HCC). ELAT is applied in cases of HCC when the tumor is smaller than 3 cm on the surface of the liver (smaller than 4 cm with extrahepatic growth), and tumor numbersor = 3. Appropriate use of the laparoscopic, thoracoscopic and hand-assisted approaches, suitable preceding embolizations with the angiographic technique, a combination of ablation therapy, and the use of CO2-angio US, DIMON puncture system and cluster needle are important. If necessary, additional surgeries such as endoscopic hepatectomy, laparoscopic cholecystectomy or laparoscopic devascularization must be performed together. As a result, it will be possible to expand the indication of ELAT safely and radically.

We have performed ablation therapy for 4 patients who had hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). In order to avoid intrahepatic metastasis due to ablation, we treated portal venous embolization before ablation. After treatment, computed tomography revealed no viable area in the treated lesion and no dissemination in the portal vein. A complication was encountered in 1 patient, in the form of a collection of ascites due to portal hypertension. We conclude that ablation therapy is the choice for unresectable HCC with PVTT in multidisciplinary therapy.

Assessment of tissue microcirculation is one of the important aspects of pathological evaluation in acute pancreatitis. Severe ischemic change sometimes leads to the development of organ dysfunction and/or infectious complications.To evaluate the angiographic features of acute pancreatitis and correlate them with the severity of the disease.Retrospective study.Twenty-seven consecutive patients with acute pancreatitis who had undergone angiography were retrospectively investigated.Vascular findings and Ranson score.Ischemic changes were found in 18 patients (66.7%); 11 (40.7%) were severe changes. Pseudoaneurysm, bleeding, and staining were seen in 4 (14.8%), 2 (7.4%) and 5 (18.5%) patients, respectively. The rate of severe ischemic changes was significantly correlated with the Ranson score (P=0.012). Conclusions Angiographic findings are useful for the evaluation of severe acute pancreatitis.

With the global pandemic of hepatitis B and C infections, the incidence of Hepatocellular carcinoma (HCC) is rapidly increasing world wide. We identified glypican-3 (GPC3), a novel oncofetal gene over-expressed specifically in human HCC, as based on data of cDNA microarrays. As GPC3 is a GPI-anchored membrane protein and could be secreted, we attempted to detect secreted GPC3 protein in sera from HCC patients using Western blotting and ELISA. GPC3 protein was positive in sera of 40.0% (16/40) of HCC patients, and negative in sera from subjects with liver cirrhosis (LC) (0/13), chronic hepatitis (CH) (0/34), and healthy donors (0/60). All subjects were Japanese. Although 12 of 40 HCC patients were negative for both alpha-fetoprotein (AFP) and PIVKA-II well known tumor markers of HCC, four of these were GPC3-positive in the sera. We also observed vanishing GPC3 protein in the sera of three patients after the surgical treatment for HCC. On the other hand, immunohistochemical analysis revealed that HCC expressed GPC3 protein in all 14 HCC patients tested. In conclusion, GPC3, as defined in this study was shown to be a useful tumor marker for cancer-diagnosis for large numbers of patients with HCC.

The proteinase-activated receptor-2 (PAR-2) is a G protein-coupled receptor that is cleaved and activated by trypsin. To clarify the presence of PAR-2 in human pancreatic cancer, the expression of PAR-2 was analyzed by RT-PCR, immunoblotting and immunocytochemistry using 5 human pancreatic cancer cell lines. And to evaluate the biological significance, immunohistochemical expression of PAR-2 in malignant and non-malignant human pancreatic tissues was examined using paraffin-embedded sections. The presence of PAR-2 was confirmed in all 5 pancreatic cancer cell lines and all 21 paraffin-embedded specimens from human pancreatic cancer examined. The expression of PAR-2 was found to be higher in the tissues with infiltrative growth pattern than those with expansive growth pattern. Moreover, significantly higher expression of PAR-2 was observed in the tissues which were accompanied by severe fibrosis. Even in the same specimen, the intensity of immunoreactivity tended to be stronger in the part with severe fibrosis than that with mild fibrosis. Similarly, the higher expression of PAR-2 was observed in chronic pancreatitis with severe fibrosis than with mild fibrosis. Taken together, these results suggest that the activation of PAR-2 is involved in cancer invasion and the induction of fibrosis in human pancreatic cancer.

Pancreatic pseudocyst-portal vein fistulae are extremely rare, and cause serious complications, including life-threatening sepsis. We report a 57-year-old man with pancreatic pseudocyst who was admitted to our hospital complaining of prolonged abdominal pain. A pancreatic duct tube was placed into the main pancreatic duct, as the pseudocyst was communicated to the pancreatic duct. He fell into septic shock state two weeks later. An ultrasonography-guided percutaneous drainage of the pseudocyst was performed. The amylase level of drained pus was 80,000 U/l. Pancreatic pseudocyst-portal vein fistula was demonstrated by fisterography. Symptoms disappeared immediately after drainage. No recurrence was observed afterward.

We performed multimodal therapy for a huge hepatocellular carcinoma with tumor embolism (Vv3), for which excision was judged impossible. After treatment, a hepatectomy to the primary lesion was finally carried out and long-term survival was achieved. A 52-years-old man with right lateroabdominal pain had a huge occupied hepatocellular carcinoma that was detected in October 2000. A tumor embolism, which invaded the inferior vena cava, was also seen. The residual liver was judged to have insufficient capacity for a right hepatic lobectomy. A percutaneous transhepatic portal embolism (PTPE) was carried out against the right portal vein to increase in the left lobe capacity. The chemo-radiotherapy (36 Gy to the right hepatic vein and systemic administration of CDDP) and transcatheter arterial chemoembolization were added to the feeding arteries of the hepatic tumor. When a decrease in the postcaval vein tumor embolism was observed, the extended right hepatic lobectomy was performed. The postoperative course was good, and the patient was discharged from the hospital on postoperative day 41. Though lung metastasis and new lesions in left lobe were seen in a recurrence, two years and ten months since the start of the systemic chemotherapy. This case suggested that even if a huge liver cancer with vascular invasion is judged impossible to excise, multimodal therapy with the aim of surgical treatment helps retain the possibility to later chose hepatectomy for the primary lesion and improve prognosis.

We report a patient with bilateral adrenal metastasis from hepatocellular carcinoma (HCC) who has survived for a long period as a result of repeated resection. A 55-year-old male patient with C type hepatitis underwent transcatheter arterial chemo-embolization (TACE) for HCC in November 1997. There was no recurrence in the liver, but left adrenal metastasis was detected in January 1998, followed by right adrenal metastasis in November 1998. We performed surgical resection for bilateral adrenal metastasis in March 1999. The histological diagnosis was well approximately moderately differentiated hepatocellular carcinoma. A recurrence in the right adrenal gland was detected eight months later. As there was no distant metastasis, we performed re-operation in December 1999. Recurrence in the liver was detected in October 2000 and was treated by TACE. He has survived more than 4 years since the first detection of adrenal metastasis. We conclude that surgical treatment is useful for patients with adrenal metastasis who have no distant viable lesion.

Contrast-enhanced computed tomography (CT) is the gold standard for assessing the severity of acute pancreatitis, especially for evaluating the presence of pancreatic necrosis (poorly perfused area). However, the contrast medium used for CT is potentially toxic to the pancreas and kidney. Therefore, medical institutions without facilities for hemodialysis hesitate to acquire contrast-enhanced CT images. Diagnostic values of magnetic resonance imaging (MRI) in pancreatic diseases have been shown.To evaluate the usefulness of MRI in the assessment of the severity of acute pancreatitis.All necrotic regions in the pancreas were visualized by gadolinium-enhanced MRI. Furthermore, MRI can discriminate the poorly perfused pancreatic area, namely so-called "pancreatic necrosis" judged on CT, into three parts: 1) necrotic area of the pancreatic parenchyma, 2) perinecrotic fluid collection, and 3) hemorrhagic foci. Inflammatory changes that were required for severity grading were also evaluated sufficiently by MRI.These results suggest that MRI is useful for the assessment of severity of acute pancreatitis.

Introduction: The contact inhibition of proliferation is crucial for well-controlled organogenesis. Its disruption results in sustained cell proliferation, which is a hallmark of solid tumors. The Hippo signaling pathway has been implicated in contact inhibition of proliferation. Here, we investigated the role of TAZ (WWTR1), a key transcription co-activator of hippo-pathway, in HCC progression. Methods and Results: In HCC patients, the high TAZmRNA expression examined by real time PCR showed worsen survival outcomes compared with low expression group. Additionally, the tumor size in High TAZmRNA expression group was significantly larger than that in low expression group, and its high protein expression in HCC was deeply associated with the cell proliferative activity. A knockdown of TAZ expression in HCC cell lines attenuated the cell growth accompanying the downstream gene expressions (CTGF and CYR61). As the TAZ-mediated signaling pathway in cell growth, a knockdown of TAZ expression using RNAi inactivated the PI3K/Akt/mTOR pathway. Conclusion: Thus, TAZ plays a crucial role in tumor progression by accelerating cell growth via a PI3K/Akt/mTOR pathway, and tumoral TAZmRNA expression level may be a useful prognostic biomarker in HCC. Citation Format: Hiromitsu Hayashi, Hideyuki Kuroki, Shigeki Nakagawa, Takaaki Higashi, Keita Sakamoto, Naomi Yokoyama, Takatoshi Ishiko, Toru Beppu, Hideo Baba. TAZ (WWTR1), a key transcription co-activator of hippo-pathway, promotes hepatocellular carcinoma progression via PI3K/Akt/mTOR pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3520. doi:10.1158/1538-7445.AM2014-3520

[Background] P-cadherin belongs to the family of classic cadherin, and accumulating evidences shows hat P-cadherin is strongly associated with carcinogenesis and confers alignant phenotype of various cancers. Pancreatic cancer has a poor prognosis, with an overall 5-year survival rate of only 5%. Despite advances in therapy recently, its survival rate still remains poor. This study aimed to analyze P-cadherin expression and its prognostic value in pancreatic carcinoma and to validate the P-cadherin gene (CDH3) promoter methylation status as the mechanism of this gene regulation. [Methods] Seventy-three patients diagnosed with pancreatic cancer were enrolled in this study. P-cadherin expression was examined by immunohistochemistry, and correlated with various clinicopathological features and prognosis. Furthermore, P-cadherin expression and its promoter methylation status were analyzed in pancreatic cancer cell lines. [Results] In pancreatic tissues, 50.7% (37/73) of cases shows a high expression of P-cadherin by immunohistochemical analysis, and high expression of P-cadherin was significantly correlated with gender, posterior tissue invasion and other organs invasion. In multivariate analyses, P-cadherin expression was the independent prognostic factors for disease-free survival (relative risk:2.68, p=0.005). P-cadherin expression was found to be related to its promoter methylation status in pancreatic cancer cell lines. Furthermore, when P-cadherin was down-regulated by specific siRNA, cell migration and invasion were significantly reduced. [Conclusion] These results suggested that expression of P-cadherin is a useful prognostic marker and seems to be important in the malignant behavior in pancreatic cancer. We are now conducting experiments to validate the CDH3 methylation status in the cancerous tissues and their adjacent normal counterpart, and investigating the biological role of P-cadherin in pancreatic cancer. Note: This abstract was not presented at the meeting. Citation Format: Keita Sakamoto, Katsunori Imai, Shigeki Nakagawa, Hidetoshi Nitta, Hiromitsu Hayashi, Akira Chikamoto, Takatoshi Ishiko, Toru Beppu, Hideo BaBa. P-cadherin overexpression is associated with poor prognosis in pancreatic carcinoma and is regulated by its promoter hypomethylation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 376. doi:10.1158/1538-7445.AM2014-376

Background: Vasohibin-1 (VASH1) is isolated as an endogenous angiogenesis inhibitor produced by the vascular endothelium, and the status of VASH1 expression has been documented in various cancer prognosis. Some reports shows that VASH1 was negatively regulated by enhancer of zeste homolog 2 (EZH2) epigenetically. The aim of this study was to assess the relationship between EZH2 and VASH1, and the prognostic value of this two molecules in intrahepatic cholangiocarcinoma (ICC) patients. Method: We examine 47 cases of intrahepatic cholangiocarcinoma to which the R0 liver resection had been performed by our department between 1993 years and 2010. Immunohistochemical staining of VASH1 and EZH2 was performed using paraffin-embedded block, and we examined the relation among the expression of VASH1 and a clinicopathological factor (sex, age, tumor diameter, tumor number, differentiation level, microscopic vascular invasion, and metastasis in lymph node), EZH2 expression, recurrence-free survival (RFS) and overall survival (OS). Result: VASH1 and EZH2 positivity was observed in 24 (51.1%) and 24 (51.1%) patients respectively, and VASH1 positivity was inversely correlated with EZH2 high expression (R=0.3870, p=0.0018). VASH1 positivity was not significantly correlate with RFS or OS. On the other hands, VASH1 negative and EZH2 positive was observed in 17 (36.2%) patients, and was a significant disadvantage to both RFS (relative risk (RR) 3.39, 95% confidence interval (CI) 1.28-8.67, p=0.0157) and OS (RR 3.69, 95% CI 1.20-11.2, 0.0237) in univariate Cox hazard analysis. In multivariate analysis, VASH1 negative and EZH2 positive group was an independent risk factor for both RFS (RR 4.19, 95% CI 1.33-13.13, p=0.0150), and OS (RR 8.11, 95% CI 2.01-42.1, p=0.0030). Conclusion: The expression of VASH1 was inversely correlate with EZH2 expression. VASH1 negative and EZH2 positive was an independent risk factor for OS and DFS in ICC patients. Citation Format: Shigeki Nakagawa, Yasuo Sakamoto, Ryuma Tokunaga, Takaaki Higashi, Keita Sakamoto, Akira Chikamoto, Takatoshi Ishiko, Toru Beppu, Hideo Baba. Vasohibine-1 negative and EZH2 positive may predict the prognosis of cholangiocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4732. doi:10.1158/1538-7445.AM2014-4732

IL-10 has been shown to play a crucial role in immunosuppression in cancer patients. We explored the regulation of IL-10 production by TNF-alpha, IL-1 beta, IL-6, IL-8, and IFN-gamma in human colon carcinoma COLO205 cells. Northern analysis revealed a marked expression of IL-10 mRNA after stimulation by IL-6, and a marginal but significant expression by TNF-alpha, IL-1 beta or IFN-gamma. No IL-10 mRNA expression was observed when cells were untreated or incubated with IL-8. IL-10 in the culture supernatants showed good agreement with mRNA expression. In addition, IFN-gamma dose-dependently inhibited this IL-6-induced production of IL-10. MTT assay revealed that low dose IFN-gamma (1-10 ng/ml) had no effect on growth of COLO205 cells, but that high dose IFN-gamma (>100 ng/ml) significantly inhibited their proliferation. Northern analysis of COLO205 cells pretreated with IFN-gamma demonstrated that the IL-6R alpha chain was down-regulated. These results suggest that, in certain colon carcinoma cells, tumor-derived IL-10 production is directly regulated by systemic or local production of pro-inflammatory cytokines, such as IL-6 and IFN-gamma.

Treatment of cells with the antimetabolite 1-beta-D-arabinofuranosylcytosine (ara-C) and other genotoxic agents is associated with activation of the c-Abl protein tyrosine kinase. The functional role of c-Abl in the response to DNA damage, however, remains unclear. The present studies demonstrate that cells expressing a dominant negative, kinase-inactive c-Abl (K-R) are resistant to killing by ara-C. The expression of c-Abl (K-R) blocked ara-C-induced apoptosis by a mechanism that is at least in part independent of the p53 tumor suppressor. Cells null for c-Abl also exhibited resistance to induction of apoptosis. These findings provide support for a pro-apoptotic function of c-Abl in the response to certain genotoxic drugs.

Activation of phosphatidylinositol (PI) 3-kinase by growth factors results in phosphorylation of phosphatidylinositol lipids at the D3 position. Although PI 3-kinase is essential to cell survival, little is known about mechanisms that negatively regulate this activity. Here we show that the c-Abl tyrosine kinase interacts directly with the p85 subunit of PI 3-kinase. Activation of c-Abl by ionizing radiation exposure is associated with c-Abl-dependent phosphorylation of PI 3-kinase. We also show that phosphorylation of p85 by c-Abl inhibits PI 3-kinase activity in vitro and in irradiated cells. These findings indicate that c-Abl negatively regulates PI 3-kinase in the stress response to DNA damage.

To investigate alterations in post-operative levels of IL-6 and soluble IL-6 receptor (sIL-6R), we examined their levels in serum and samples of drainage fluids from 26 patients who underwent thoracoabdominal surgery. Serum IL-6 levels reached the maximum within the first post-operative day and decreased thereafter. The IL-6 levels in the drainage fluid were much higher than in the serum (458 +/- 101-fold; mean +/- SEM) in the early post-operative phase. A large quantity of sIL-6R levels was present in blood samples. The time course of serum sIL-6R levels in 26 patients showed no significant change. sIL-6R concentrations in the drainage fluid were significantly lower than in serum (4.5 +/- 1.1-fold; mean +/- SEM) in the early post-operative phase. We propose that IL-6 is produced in the operative field and enters the peripheral blood stream to induce elevation of serum IL-6. On the other hand, sIL-6R levels in the operative field are lower than in the serum, and the serum sIL-6R levels are not influenced by surgical trauma. These data suggest that sIL-6R is being constantly produced in areas other than the operative field, while sIL-6R level is reduced by consumption in the operative field. Mechanisms to cope with surgical stress, involving sIL-6R together with its ligand IL-6 may thus exist.

Activation of the c-Abl protein tyrosine kinase by certain DNA-damaging agents contributes to down-regulation of Cdk2 and G 1 arrest by a p53-dependent mechanism. The present work investigates the potential role of c-Abl in apoptosis induced by DNA damage. Transient transfection studies with wild-type, but not kinase-inactive, c-Abl demonstrate induction of apoptosis. Cells that stably express inactive c-Abl exhibit resistance to ionizing radiation-induced loss of clonogenic survival and apoptosis. Cells null for c- abl are also impaired in the apoptotic response to ionizing radiation. We further show that cells deficient in p53 undergo apoptosis in response to expression of c-Abl and exhibit decreases in radiation-induced apoptosis when expressing inactive c-Abl. These findings suggest that c-Abl kinase regulates DNA damage-induced apoptosis.

Background. P-cadherin belongs to the family of classic cadherin, and accumulating evidences shows that P-cadherin is strongly associated with carcinogenesis and confers malignant phenotype of various cancers including breast, pancreatic, and colon carcinomas. Intrahepatic cholangiocarcinoma (ICC) is the second most common subtype of primary hepatobillary cancer. Despite advances in therapy, its survival rate remains poor. This study aimed to analyze P-cadherin expression and its prognostic value in Intrahepatic cholangiocarcinoma and to validate the P-cadherin gene (CDH3) promoter methylation status as the mechanism of this gene regulation. Methods. Fifty-nine patients diagnosed with ICC who underwent hepatic resection in our department were enrolled in this study. Using the paraffin-embedded tumor tissues, expression status of P-cadherin was evaluated and correlated with various clinicopathological features (age, gender, tumor markers, tumor diameter and number, stage, gross type, grade of tumor differentiation, vessel invasion, and lymph node metastases) and prognosis. Furthermore, P-cadherin expression and CDH3 promoter methylation status in 8 cholangiocarcinoma cell lines (HuCCT1, YSCCC, MEC, OZ, HuH28, RBE, SSP25, and TKKK) were analyzed. Results. In ICC tissues, 50.8% (30/59) of cases shows a high expression of P-cadherin by immunohistochemical analysis, and high expression of P-cadherin was significantly correlated with tumor diameter > 3.8 cm (p=0.0006). In multivariate analyses, P-cadherin expression was the independent prognostic factors for disease-free survival (relative risk:2.72, p=0.0138) and overall survival (relative risk:3.23 p=0.0012). Of the 8 cell lines, 3 (HuCCT1, YSCCC, OZ) were found to express P-cadherin protein and mRNA. These cell lines showed complete CDH3 promoter unmethylation. However, other cell lines showed partial methylation and unmetylation. From this result, the CDH3 promoter methylation was found to be related to the expression of P-cadherin. Conclusion. These results suggested that expression of P-cadherin is a useful prognostic marker and seems to be important in the malignant behavior in ICC. We are now conducting experiments to validate the CDH3 methylation status in the cancerous tissues and their adjacent normal counterpart, and investigating the biological role of P-cadherin in ICC. Citation Format: Keita Sakamoto, Katsunori Imai, Shigeki Nakagawa, Hirohisa Okabe, Hidetoshi Nitta, Hiromitsu Hayashi, Akira Chikamoto, Takatoshi Ishiko, Toru Beppu, Hideo Baba. Prognostic impact of P-cadherin overexpression associated with CDH3 promoter hypomethylation in intrahepatic cholangiocarcinoma (ICC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3044. doi:10.1158/1538-7445.AM2013-3044

Background and Aims: Tumor-stromal interaction has been recognized to be essential for understanding tumor development. Cholangiocarcinoma shows very poor prognosis and have fibrous tumor stroma. Hepatic stellate cells are well-known to have a major role in hepatic fibrogenesis. Therefore, we have focused on the interaction of cholangiocarcinoma and hepatic stellate cells and reported their positive interaction (Ann Surg Oncol 2009, 2011). The aim of this study is to identify the key protein which is important for the interaction of cholangiocarcinoma cells and hepatic stellate cells and examine its functional role in tumor progression. Methods: Using co-culture model and proteomic analysis, we analyzed the secreted factors which were considered to be important for their interaction. The functional role of CXCL5 was examined in vitro and clinical significance was validated using human intrahepatic carcinoma samples by immunohistochemistry. Results: Using SELDI-TOF-MS and qTOF-MS/MS analysis, we identified CXCL5 which was remarkably increased when they were co-cultured. CXCL5 which was mainly produced by cholangiocarcinoma cell lines (HuCCT1 and RBE) promoted the invasion, and migration of them in the autocrine fashion. These effects were significantly decreased by inhibition of CXCR2 which was a receptor of CXCL5. IL1β was found to up-regulate in hepatic stellate cells when they were co-cultured by cytokine array analysis, we also found that IL1β accelerated the production of CXCL5 in cholangiocarcinoma cells. In human intrahepatic cholangiocarcinoma, immunohistochemical study showed that there was a significant correlation between stromal myofibroblasts and CXCL5 produced by cholangiocarcinoma cells. Since CXCL5 is identified as epithelial neutrophil activating factor-78 (ENA-78), we researched the presence of CD66b positive immune cells which have been recently reported to be tumor-associated neutrophils. CD66b positive immune cells are more abundant in CXCL5 high expression group. In addition, high CXCL5 expression group showed worse survival than low expression group. Conclusion: We conclude that CXCL5 is important for the interaction of cholangiocarcinoma and stromal myofibroblasts and that the strategies to inhibit tumor-stromal cell interactions may be beneficial in cholangiocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 41. doi:1538-7445.AM2012-41

[Background and Aims]Enhancer of Zeste Homolog 2 (EZH2) is one of the polycomb proteins and involved in the progress of several solid tumors by methylating histone3 Lysin27 (H3K27) and silencing various genes. However, the role of EZH2 in cholangiocarcinoma has not been clarified. In this study, we investigated the significance of EZH2 expression in intrahepatic and extrahepatic cholangiocarcinoma progression.[Patients and Methods]Fourty-seven intrahepatic cholangiocarcinoma (ICC) patients and 45 extrahepatic cholangiocarcinoma (ECC) patients treated with curative resection from 1993 to 2010 were enrolled. We examined the EZH2 expression by immunohistochemistry, and relationship between EZH2 expression and clinicopathological factors, such as gender, age, CA19-9, tumor diameter, tumor number, histological vascular invasion, differentiation, lymph node metastasis and prognosis. To assess whether EZH2 relates to angiogenesis and tumor growth, Ki67 expression and microvessel density (MVD) using CD34 were also examined by immunohistochemistry. EZH2 expression was investigated eight cholangiocarcinoma cell lines. Using small interfering RNA against EZH2, the influence of EZH2 knock-down on cholangiocarcinoma cell proliferation and invasion was studied in vitro. [Results]In ICC, 24 patients (51.0%) shows a high expression of EZH2 when the cutoff value was determined to be 10%. The EZH2 high expression is significantly correlated with tumor diameter > 3.5cm (P=0.0113) and MVD score (P=0.039). The high EZH2 expression group showed significantly worse overall survival (p=0.045). In ECC, 19 patients(42.2%) showed a high EZH2 expression. The EZH2 high expression is significantly correlated with positive lymph node metastasis (p=0.0469), high Ki67 expression (P=0.0017). The high EZH2 expression group showed significantly worse overall survival (P=0.0261). All of the eight cholangiocarcinoma cell lines expressed EZH2 in a various level. When we knock down the expression of EZH2 in RBE cells, the expression of H3K27 was reduced and cell growth decreased. However, EZH2 down-regulation didn't affect cell invasion.[Conclusion]EZH2 may relate to the progression of intra and extrahepatic cholangiocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1055. doi:1538-7445.AM2012-1055

290 Background: Nowadays Radiofrequency ablation (RFA) is a popular method and demonstrates favorable results for the treatment of small-sized hepatocellular carcinoma (HCC). However, whether RFA is as effective as hepatic resection (HR) for long-term outcomes remains controversial. The aim of this study is to compare HR and RFA with regard to survival and recurrence for the establishment of treatment strategy of small-sized HCC. Methods: A total of 183 patients with solitary small-sized (≤3cm) HCC were enrolled in this study: 101 patients underwent HR and 82 underwent RFA as an initial treatment. Overall survival (OS) and disease-free survival (DFS) were compared between the two groups and in subgroup analyses. Results: Patients who underwent RFA had less platelet count (HR: 15.3±7.0, RFA: 9.8±3.6, P35mIU/ml and tumor ≥2cm were significant predicting factors for DFS (RR: 2.34, P=0.01, and RR: 2.09, P=0.02, respectively). For OS, tumor ≥2cm was the only prognostic factor (RR: 2.9, P=0.04). Conclusions: RFA might be as effective as HR for the treatment of solitary HCC

319 Background: Portal vein embolization (PVE) is a multi-potential treatment for hepatocellular carcinoma (HCC). The aim of this study is to identify the efficacies of PVE for resectable and unresectable HCC patients. Methods: Until 2011, 668 HCC patients underwent hepatic resection and 102 HCC patients treated with PVE. PVE was performed with percutaneous and ipsilateral approach using ethanolamine oleate iopamidol. Preoperative future remnant liver volume (%LV) and functional liver volume (%FLV ) were assessed with our developed combined 99mTc- galactosyl human serum albumin (GSA) scintigraphy (SPECT)/CT system. In unresectable cases chemoembolization (TACE) was repeated after PVE. Results: 1. Comparison of %LV and %FLV after right-PVE (n=40). %FLV before PVE was significantly lower in PVE group (38%) compared to non-PVE group (58%), but increased remarkably after PVE (from 38% to 55%, P < 0.0001). Right hepatectomy was successfully completed in 10 patients based on %FLV, instead of conventional %LV. 2. Long-term prognosis after right-hepatectomy with /without PVE (n=60). The 3- and 5-year disease-free survival (DFS) rates in the PVE group were significantly greater than those in the non-PVE group (78% and 78% versus 20% and 0%, P = 0.01). The 3- and 5-year overall survival (OS) rates in the PVE group were also higher than those in the non-PVE group (72% and 72% versus 57% and 12%, P Conclusions: PVE can improve resectability, and might improve disease-free and overall survival for patients with both resectable and unresectable HCC.

AIM: To evaluate prognoses after cutaneous metastases, derived from pancreatic cancer. METHODS: We treated two patients with cutaneous metastases from pancreatic cancer. We reviewed 40 reported patients in addition to our cases and analyzed clinical features of cutaneous metastases from pancreatic cancer. RESULTS: The median survival time (MST) was 5 mo after diagnoses of cutaneous metastases. The cumulative 2-year survival rate was 3.5%. The most frequent site of cutaneous metastases was the umbilicus. The MST of patients who were treated with chemotherapy or chemoradiotherapy (CRT) was 6.5 mo, which was statistically longer in comparison to patients without treatment. Prognoses of cutaneous metastases are similar to other metastatic sites from pancreatic cancer. Receiving chemotherapy or CRT was the only prognostic factor of cutaneous metastases from pancreatic cancer. CONCLUSION: The prognoses of cutaneous metastases are similar to other metastatic pancreatic cancers. Receiving chemotherapy or CRT was the only prognostic factor of cutaneous metastases from pancreatic cancer.