Keiichi Okano

Hepatic Resection for Metastatic Tumors From Gastric Cancer

ObjectiveTo assess the surgical results and clinicopathologic features of hepatic metastases from gastric adenocarcinoma to identify patients with a better probability of survival. Summary Background DataMany studies have reported the benefit of hepatic resection for metastatic tumors from colorectal cancer. However, indications for a surgical approach for gastric adenocarcinoma involving the liver have not been clearly defined. MethodsNinety (11%) of 807 patients with primary gastric cancer were diagnosed with synchronous (n = 78) or metachronous (n = 12) hepatic metastases. Of these, 19 underwent 20 resections intended to cure the metastatic lesion in the liver. The clinicopathologic features of the hepatic metastases in, and the surgical results for, the 19 patients were analyzed. ResultsThe actuarial 1-year, 3-year, and 5-year survival rates after hepatic resection were, respectively, 77%, 34%, and 34%, and three patients survived for more than 5 years after surgery. Solitary and metachronous metastases were significant determinants for a favorable prognosis after hepatic resection. Pathologically, a fibrous pseudocapsule between the tumor and surrounding hepatic parenchyma was found in 13 of the 19 patients (68%). The presence of a peritumoral fibrous pseudocapsule and a well-differentiated histologic type of metastatic nodule were significant prognostic factors. Factors associated with the primary lesion were not significant prognostic determinants in patients who underwent curative resection of the primary cancer. ConclusionsSolitary and metachronous metastases from gastric cancer should be treated by a surgical approach and confer a better prognosis. A new prognostic factor, the presence of a pseudocapsule, may be helpful in defining indications for postoperative adjuvant treatment.

The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo

Recent studies suggest that metformin, which is commonly used as an oral anti-hyperglycemic agent of the biguanide family, may reduce cancer risk and improve prognosis, but the mechanisms by which metformin affects various cancers, including gastric cancer, remains unknown. The goal of the present study was to evaluate the effects of metformin on human gastric cancer cell proliferation in vitro and in vivo and to study microRNAs (miRNA) associated with antitumor effect of metformin. We used MKN1, MKN45, and MKN74 human gastric cancer cell lines to study the effects of metformin on human gastric cancer cells. Athymic nude mice bearing xenograft tumors were treated with or without metformin. Tumor growth was recorded after 4 weeks, and the expression of cell-cycle-related proteins was determined. In addition, we used miRNA array tips to explore the differences among miRNAs in MKN74 cells bearing xenograft tumors treated with or without metformin in vitro and in vivo. Metformin inhibited the proliferation of MKN1, MKN45, and MKN74 in vitro. Metformin blocked the cell cycle in G0–G1 in vitro and in vivo. This blockade was accompanied by a strong decrease of G1 cyclins, especially in cyclin D1, cyclin-dependent kinase (Cdk) 4, Cdk6 and by a decrease in retinoblastoma protein (Rb) phosphorylation. In addition, metformin reduced the phosphorylation of epidermal growth factor receptor and insulin-like growth factor-1 receptor in vitro and in vivo. The miRNA expression was markedly altered with the treatment of metformin in vitro and in vivo. Various miRNAs altered by metformin also may contribute to tumor growth in vitro and in vivo. Mol Cancer Ther; 11(3); 549–60. ©2012 AACR.

Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer.

Objective: The goal of this retrospective study was to clarify the clinical implications of the status of the 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4). Background: Recent whole-exome sequencing had shown that the landscape of the pancreatic ductal adenocarcinoma (PDAC) genome is notable for 4 frequently mutated genes (KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4). Methods: We determined immunohistochemically the status of TP53, CDKN2A/p16, and SMAD4/DPC4 among the 4 genes because the KRAS gene is mutated in virtually all PDAC patients, and analyzed relationships with clinicopathological findings, including survival and patterns of disease progression, in 106 patients with PDAC undergoing radical surgery. Results: Abnormal immunolabeling of p53 was detected in 81.1% of PDACs and was significantly associated with tumor dedifferentiation (P = 0.022) and the presence of locoregional recurrence (P = 0.020). Loss of p16 and Smad4/Dpc4 immunolabeling was identified in 67.0% and 60.4%, respectively. Loss of p16 immunolabeling was associated with lymphatic invasion (P = 0.012) and postoperative widespread metastases (P < 0.001). A significant correlation was found between Smad4/Dpc4 immunolabeling and tumor size (P = 0.006), lymphatic invasion (P = 0.033), and lymph node metastasis (P = 0.006). Interestingly, all of the 6 patients demonstrating 5-year survival had intact SMAD4/DPC4. Kaplan-Meier survival analysis showed that lymph node metastasis (P = 0.001), lymphatic invasion (P = 0.008), the tumor (T) factor (T3 vs. T1/T2, P = 0.004), loss of p16 immunolabeling (P = 0.029), and loss of Smad4/Dpc4 immunolabeling (P < 0.001) were significantly associated with shorter overall survival. Multivariate analysis revealed that loss of Smad4/Dpc4 immunolabeling was an independent and significant poor prognostic factor for overall and disease-free survival. On analysis of combinations of the status of these 3 genes, increasing number of alterations reflected poorer survival. Conclusions: Genetic alterations of these 3 genes and their accumulation are strongly associated with malignant behavior of PDAC. Their immunohistochemical assessment at the time of diagnosis may provide a new prognostic tool, assisting in deciding optimal therapeutic strategies for patients.

Macroscopic intrabiliary growth of liver metastases from colorectal cancer

BACKGROUND The clinicopathologic features of colorectal liver metastases that invade the bile duct were evaluated. METHODS From 1992 to 1996, 149 patients who underwent a first hepatic resection were studied for a total of 377 colorectal liver metastases. Twenty-one second hepatic resections in these patients were also analyzed. RESULTS Bile duct invasion was histologically observed in 62 (42%) of 149 patients with first colorectal liver metastasis. Eighteen patients (12%) had gross extension of the tumor in the bile duct ranging from 4 mm to 42 mm (median 17.0 mm). Histologically, two thirds (12 of 18) of the tumors with macroscopic bile duct invasion were well-differentiated adenocarcinomas with a tendency for less vascular involvement. The actuarial 3- and 5-year survivals were 62% and 57% for patients with no bile duct invasion, 56% and 48% for patients with microscopic bile duct invasion, and 94% and 80% for patients with macroscopic bile duct invasion. The 5-year survival rate was better for patients with macroscopic bile duct invasion than for those with only microscopic (P = .02) or no bile duct invasion (P = .03). In a multivariate analysis, macroscopic bile duct invasion was an independent prognostic variable for favorable outcome after hepatic resection. CONCLUSIONS Macroscopic bile duct invasion of colorectal liver metastases may reflect an indolent biologic behavior, warrants an aggressive surgical approach, and confers a better prognosis.

Detection of Hepatocellular Carcinoma Using 11C-Choline PET: Comparison with 18F-FDG PET

The purpose of this study was to retrospectively investigate the feasibility of 11C-choline PET, compared with 18F-FDG PET, for the detection of hepatocellular carcinoma (HCC). Methods: A total of 16 HCC lesions in 12 patients were examined with both 11C-choline PET and 18F-FDG PET. Tumor lesions were identified as areas of focally increased uptake, exceeding that of surrounding noncancerous liver tissue. For semiquantitative analysis, the tumor-to-liver (T/L) ratio was calculated by dividing the maximal standardized uptake value (SUV) in HCC lesions by the mean SUV in noncancerous liver tissue. Results: 11C-choline PET showed a slightly higher detection rate than did 18F-FDG PET for detection of HCC (63% vs. 50%, respectively), although this difference was not statistically significant. 11C-choline PET had a better detection rate for moderately differentiated HCC lesions but not for those poorly differentiated (75% vs. 25%, respectively). In contrast, 18F-FDG PET exhibited the opposite behavior, with corresponding detection rates of 42% and 75%, respectively. The mean 11C-choline SUV and T/L ratio in moderately differentiated HCC lesions were higher than those in poorly differentiated HCC lesions. In contrast, the mean 18F-FDG SUV and T/L ratio in poorly differentiated HCC were higher than those in moderately differentiated HCC. These differences, however, were also not statistically significant. Conclusion: 11C-choline PET had a better detection rate for moderately differentiated HCC lesions but not for poorly differentiated HCC lesions, whereas 18F-FDG PET produced the opposite result. 11C-choline is a potential tracer to complement 18F-FDG in detection of HCC lesions.

Is preoperative portal vein embolization effective in improving prognosis after major hepatic resection in patients with advanced-stage hepatocellular carcinoma?

The impact of the use of preoperative portal vein embolization (PVE) on long‐term survival after surgery was evaluated by retrospective analysis of prognostic factors in patients with advanced‐stage hepatocellular carcinoma (HCC) who had undergone hepatic resection with or without PVE.

Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo.

Metformin is a commonly used oral anti-hyperglycemic agent of the biguanide family. Recent studies suggest that metformin may reduce cancer risk and improve prognosis. However, the antitumor mechanism of metformin in several types of cancers, including hepatocellular carcinoma (HCC), has not been elucidated. The goal of the present study was to evaluate the effects of metformin on HCC cell proliferation in vitro and in vivo, and to study microRNAs (miRNAs) associated with the antitumor effect of metformin in vitro. We used the cell lines Alex, HLE and Huh7, and normal hepatocytes to study the effects of metformin on human HCC cells. In an in vivo study, athymic nude mice bearing xenograft tumors were treated with metformin or left untreated. Tumor growth was recorded after 4 weeks, and the expression of cell cycle-related proteins was determined. Metformin inhibited the proliferation of Alex, HLE and Huh7 cells in vitro and in vivo. Metformin blocked the cell cycle in G0/G1 in vitro and in vivo. This blockade was accompanied by a strong decrease of G1 cyclins, especially cyclin D1, cyclin E and cyclin-dependent kinase 4 (Cdk4). In addition, microRNA (miRNA) expression was markedly altered by the treatment with metformin in vitro and in vivo. In addition, various miRNAs induced by metformin also may contribute to the suppression of tumor growth. Our results demonstrate that metformin inhibits the growth of HCC, possibly by inducing G1 cell cycle arrest through the alteration of microRNAs.

18F-fluorodeoxyglucose positron emission tomography in the diagnosis of small pancreatic cancer

AIM To investigate the role of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the diagnosis of small pancreatic cancer. METHODS This study involved 31 patients with proven invasive ductal cancer of the pancreas. The patients were divided into 3 groups according to the maximum diameter of the tumor: TS1 (maximum tumor size ≤ 2.0 cm), TS2 (> 2.0 cm and ≤ 4.0 cm) or TS3-4 (> 4.0 cm). The relationships between the TS and various diagnostic tools, including FDG-PET with dual time point evaluation, were analyzed. RESULTS The tumors ranged from 1.3 to 11.0 cm in diameter. Thirty of the 31 patients (97%) had a positive FDG-PET study. There were 5 patients classified as TS1, 15 as TS2 and 11 as TS3-4. The sensitivity of FDG-PET, computed tomography (CT) and magnetic resonance imaging (MRI) were 100%, 40%, 0% in TS1, 93%, 93%, 89% in TS2 and 100%, 100%, 100% in TS3-4. The sensitivity of FDG-PET was significantly higher in comparison to CT and MRI in patients with TS1 (P < 0.032). The mean standardized uptake values (SUVs) did not show a significant difference in relation to the TS (TS1: 5.8 ± 4.5, TS2: 5.7 ± 2.2, TS3-4: 8.2 ± 3.9), respectively. All the TS1 tumors (from 13 to 20 mm) showed higher SUVs in FDG-PET with dual time point evaluation in the delayed phase compared with the early phase, which suggested the lesions were malignant. CONCLUSION These results indicate that FDG-PET with dual time point evaluation is a useful modality for the detection of small pancreatic cancers with a diameter of less than 20 mm.

A simple and safe pancreas transection using a stapling device for a distal pancreatectomy

Pancreatic fistula is the most common major complication to occur after distal pancreatectomy, ranging in frequency from 5% to 40%. The appropriate technique for treating the pancreatic stump still remains controversial. Thirty-six patients underwent distal pancreatectomy in Kagawa University Hospital between January 2000 and February 2007. Their hospital records were reviewed to evaluate the usefulness of a stapling closure using several types of staplers in comparison to a suture closure. They were subdivided according to the method used to close the pancreas stump: the suture group comprised 11 patients, the staple group comprised 24 patients, including 7 patients for whom was used the new endopath stapler Echelon 60 (Ethicon Endo-surgery; Johnson & Johnson, Cincinnati, OH, USA). Overall pancreatic fistula rate was 17% (6/36) in this series. In the staple group, 3 of the 24 patients (12%) developed a pancreatic fistula, whereas in the suture group, 3 of 11 patients (27%) developed a pancreatic fistula. Of the 7 patients for whom the Echelon 60 was used, none developed a pancreatic fistula. The length of postoperative hospital stay was also significantly shorter for the patients with the Echelon 60 than in the patients either with sutures or another stapling device. These findings support the advantages of using a stapler closure in distal pancreatectomy. This method, using a new stapler device, is considered to be a simple and safe alternative to the standard suture closure technique.

Neutrophil Elastase Inhibitor (Sivelestat) Preserves Antitumor Immunity and Reduces the Inflammatory Mediators Associated with Major Surgery

PurposeTo examine the effects of the administration of perioperative sivelestat, a selective neutrophil elastase inhibitor, on tumor immunity and inflammatory mediators in patients who undergo major surgery.MethodsThirteen patients admitted to the hospital for elective surgery were equally randomized into one of two groups: the Sivelestat group (n = 6) and the control group (n = 7). Thereafter, the immunosuppressive acidic protein (IAP), serum interleukin-6 (IL-6), and type 1/type 2 T-helper cell balance were all assessed at several time points before and after surgical intervention.ResultsThe serum IL-6 values at 1 and 12 h after surgery and on postoperative days 1 and 3 were all significantly lower in the sivelestat group than in the control group. The IAP values at postoperative days 7 and 28 in the sivelestat group were also significantly lower than those in the control group. There was a significant correlation between the IL-6 level at 1 h after surgery and the IAP level at postoperative days 7 and 28.ConclusionsIn this preliminary study, the perioperative administration of sivelestat was thus suggested to reduce surgical stress by decreasing the cytokine release and preserving the antitumor immunity.