Kei Horino

Carcinogenesis of Intraductal Papillary Mucinous Neoplasm of the Pancreas: Loss of MicroRNA-101 Promotes Overexpression of Histone Methyltransferase EZH2

BackgroundThe mechanisms of IPMN carcinogenesis are as yet unclear. This study aimed to determine whether expression of EZH2 promotes neoplastic progression of IPMN and PDCA, and to elucidate regulation of EZH2 expression by miR-101.MethodsEZH2 mRNA and protein expression were investigated in 8 human pancreatic cancer cell lines by PCR and western blotting. Pre-miR-101 and anti-miR-101 were transfected into pancreatic cancer cells to elucidate EZH2 regulation by miR-101. To evaluate whether EZH2 modulates malignant progression of IPMN, EZH2 expression in IPMN was examined by immunohistochemistry. Next, we collected malignant and benign cells from FFPE samples of IPMNs using laser capture microdissection and extracted the RNA. miR-101 expression in IPMN was assessed using real-time PCR.ResultsAll pancreatic cancer cell lines expressed EZH2 mRNA and protein. The induction of miR-101 by transfection of pre-miR-101 in MIA PaCa-2 was closely related to a reduction in EZH2 protein production compared with control, whereas there was little difference in the expression of EZH2 mRNA. Anti-miR-101 transfected pancreatic cancer cells showed an increase in EZH2 protein, while the level of EZH2 mRNA was not elevated. Immunohistochemistry revealed that the expression of EZH2 was significantly higher in malignant than benign IPMN. Expression of miR-101 was significantly lower in malignant IPMN than benign IPMN.ConclusionsMiR-101 targets EZH2 at the posttranscriptional level, and loss of miR-101 could be a trigger for the adenomacarcinoma sequence of IPMN by upregulation of EZH2. This study suggests miR-101–EZH2 blockade as a potential therapeutic target in IPMN carcinogenesis.

Intrahepatic dissemination of hepatocellular carcinoma after local ablation therapy.

BACKGROUND/PURPOSE We aimed to clarify the histological features of and risk factors for intrahepatic dissemination after local ablation therapy (LAT) for hepatocellular carcinoma (HCC). METHODS Between April 1992 and December 2005, 192 HCC patients underwent hepatic resection at our department, among whom were 17 patients who had local recurrences after LAT. Eight of these 17 patients had intrahepatic dissemination. The clinical and histological characteristics of these 8 surgically treated patients with intrahepatic dissemination were investigated. RESULTS Histologically, numerous intrahepatic metastases were observed, mainly in the same section as the treated tumor, together with main or sectional portal vein tumor thrombi. Before the ablation therapy, the average tumor diameter was 2.1 cm, and 62.5% of the tumors were adjacent to the main or sectional portal vein. In terms of therapeutic factors, 25% of the patients had a prior needle biopsy and 62.5% had insufficient safety margins. CONCLUSIONS LAT for HCCs (even those less than 3 cm in diameter) adjacent less than 5 mm to the main or sectional portal vein possibly promotes intrahepatic dissemination.

Liver Hanging Maneuver Decreases Blood Loss and Operative Time in a Right-Side Hepatectomy

BACKGROUND/AIMS To clarify the clinical benefits of the maneuver in right-side hepatectomy. METHODOLOGY Eighty-one patients with liver tumor (54 hepatocellular carcinoma, 17 metastatic liver tumor and 10 other tumors) treated with a right-side hepatectomy were prospectively analyzed. The patients were divided into the following three groups: a conventional approach (group A, n=21); liver dissection under the hanging maneuver after liver mobilization (group B, n=19) and liver dissection under the hanging maneuver prior to liver mobilization (group C, n=41). RESULTS The liver hanging maneuver was safely performed in all the patients in groups B and C. Tumor size had a significantly positive correlation with the amount of intraoperative blood loss (R=0.52, p<0.05) in group A only. The patients in groups B and C had a significantly lower intraoperative use of blood loss (both p<0.01), operation time (p<0.05 and p<0.01) and the frequency of blood product (both p<0.05), in comparison to group A, respectively. The postoperative morbidity and the mortality rates were similar in the three groups. CONCLUSIONS Liver hanging maneuver is a safe procedure, which can decrease intraoperative blood loss and administration of blood product in right-side hepatectomy.

Preoperative tumor marker doubling time is a useful predictor of recurrence and prognosis after hepatic resection of hepatocellular carcinoma

It is important to identify prognostic factors in patients with hepatocellular carcinoma (HCC) before hepatectomy. No previous studies have addressed the predictive efficacy of the preoperative doubling times of alpha‐fetoprotein (AFP) and protein induced by vitamin K absence (PIVKA‐II).

Long-term outcomes of extended radical resection combined with intraoperative radiation therapy for pancreatic cancer

BACKGROUND/PURPOSE Systemic and/or local recurrence often occurs even after curative resection for pancreatic cancer (PC). To prevent local relapse we adopted an extended radical resection combined with intraoperative radiation therapy in patients with PC, and all the patients were followed for more than 5 years. METHODS We assessed the long-term outcomes of 41 patients who underwent this combined therapy. The cumulative survival curve in this series was depicted using the Kaplan-Meier method. Statistical analyses were performed using the log-rank test. RESULTS The actual 5-year survival rate was 14.6%, with a median survival time of 17.6 months. Six patients have been 5-year survivors. Local recurrence occurred in only 2 patients (5.0%). Cancer-related death occurred in 32 patients, 18 of whom had liver metastases. The patients with liver metastases had a significantly shorter survival time than those with other cancer-related causes of death. Patients with n3 lymph node involvement, extrapancreatic nerve plexus invasion, and stage IV disease had significantly poorer prognoses than patients without these characteristics. CONCLUSIONS Our combined therapy for patients with PC contributed to local control; however, it provided no survival benefit, because of liver metastases.

Preoperative prediction of poorly differentiated components in small‐sized hepatocellular carcinoma for safe local ablation therapy

Poorly differentiated hepatocellular carcinoma (HCC) has a malignant potential such as frequent microvascular invasion even if the tumor is smaller than 3 cm in diameter. The aim of this study was to clarify the preoperative predictors of poorly differentiated HCC for safe local ablation therapy.

Cutaneous metastases secondary to pancreatic cancer

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.

Percutaneous transfistulous pancreatic duct drainage and interventional pancreatojejunostomy as a treatment option for intractable pancreatic fistula

We present 2 techniques for treatment of intractable pancreatic fistula: percutaneous transfistulous pancreatic duct drainage and interventional pancreatojejunostomy. Percutaneous transfistulous pancreatic duct drainage can be effective for intractable fistulas that communicate with the main pancreatic duct. Because drainage itself is not enough for a complete cure of this complication when it occurs in cases after pancreatoduodenectomy (PD), interventional pancreatojejunostomy is applicable.

Portal vein embolization can prevent intrahepatic metastases to non-embolized liver.

BACKGROUND/AIMS To determine the efficacy of portal vein embolization (PVE) against unresectable hepatocellular carcinoma (HCC). METHODOLOGY We conducted a comparative study using 17 patients with HCC determined to be unresectable and who received a combination of PVE and transarterial chemoembolization (TACE) (PVE group) and 22 HCC patients with tumors in the unilateral lobe, which were treated only with repeated TACE (TACE group) from January 2000 to December 2008. RESULTS There were no significant differences in background factors except for gender between the two groups. The cumulative intrahepatic recurrence rates in the non-portal-embolized area (in the contralateral lobe for the TACE group) at 1 year and 3 years was 41.1% and 58.8% in the PVE group and 77.3% and 81.8% in the TACE group, respectively. The former was significantly lower (p<0.05). The cumulative overall survival rate at 1 year, 3 and 5 years was 88.2%, 38.2% and 38.2% in the PVE group, and 68.1%, 22.7% and 8.5% in the TACE group, respectively. The former was significantly higher (p<0.05). CONCLUSIONS Although in patients with unresectable HCC, when HCC is localized in the portal-embolized area, PVE combined with TACE can prevent intrahepatic metastasis to the non-portal-embolized area and improve overall survival.

Evaluation of mass-forming intrahepatic cholangiocarcinoma with viral hepatitis.

BACKGROUND/AIMS The correlation between the mass-forming type of intrahepatic cholangiocarcinoma (ICC) and the infection of the hepatitis B virus and hepatitis C virus are poorly understood. In this study, the clinical features of 34 patients with the mass-forming type ICC were reviewed to evaluate prognostic determinants. METHODOLOGY Between January 1997 and December 2007, 34 patients underwent surgical resection for the mass-forming type of ICC in Kumamoto University Hospital. The significance of 14 clinicopathological factors consisting of age, gender, CA19-9 levels, CEA levels, size, intrahepatic metastases, portal vein invasion, bile duct invasion, histological differentiation, lymph node involvement, type B or C hepatitis, lymph node dissection, Sirius Red score of the tumor and platelet count in peripheral blood were analyzed, with regard to prognostic aspect. RESULTS Univariate analysis showed that significant risk factors for poor survival included age =65 years, CEA levels =1.6ng/mL and pathological lymph node involvement. Multivariate analysis revealed that age, CEA levels and lymph node involvement were independent and significant poor prognostic factors. CONCLUSIONS It was concluded that age, CEA levels and lymph node involvement were significantly poor prognostic factors. However, the infection with type B or C hepatitis was not a prognostic factor of the mass forming type ICC.