Yuma Ebihara

Expression of Pigment Epithelium-Derived Factor Decreases Liver Metastasis and Correlates with Favorable Prognosis for Patients with Ductal Pancreatic Adenocarcinoma

Pigment epithelium-derived factor (PEDF) is expressed in several normal organs and identified as an inhibitor of neovascularization. In the present study, we screened the expression of PEDF immunohistochemically and investigated its correlation with clinicopathological features in patients who underwent surgery for ductal pancreatic adenocarcinoma. Of the 80 patients, 22 cases (27.5%) were positive for PEDF. A significant association was found between the PEDF expression and low microvessel density (P = 0.0003). No correlation was found between PEDF expression and age, gender, depth of invasion, tumor diameter, lymphatic invasion, venous, invasion or histopathological grading. The patients in pathological stage II had a significantly higher incidence of PEDF-positive expression than those in pathological stage III or IVA (P = 0.0418). PEDF immunoreactivity was inversely associated with liver metastasis (P = 0.0422). The survival of patients that were PEDF positive was significantly longer than that of those with negative expression (P = 0.0026). Multivariate analysis using the Cox regression model indicated that PEDF-positive expression was an independent favorable prognostic factor (risk ratio, 0.394; P = 0.0016). We conclude that PEDF expression suggests a more favorable prognosis than in patients whose carcinomas lack PEDF expression.

Pigment epithelium-derived factor gene therapy inhibits human pancreatic cancer in mice.

Purpose: Pigment epithelium–derived factor (PEDF), which has recently been shown to be the most potent inhibitor of angiogenesis in the mammalian eye, is also expressed in the pancreas. Previously, we have screened the expression of PEDF by immunohistochemical analysis and showed that low expression of PEDF is associated with increased risk of hepatic metastasis and short survival. The purpose of this study was to investigate whether PEDF gene is a potent tumor suppressor and a potential candidate for cancer gene therapy. Experimental Design: We investigated both in vitro and in vivo growth characteristics of human pancreatic adenocarcinoma cell lines that were stably transfected to overexpress human PEDF and therapeutic effects of lentivirus-based vectors expressing PEDF on tumor growth in murine s.c. tumor model. Results: We discovered that cells secreted PEDF protein in the media and this exhibited strong inhibitory effects on proliferation and migration of human umbilical vein endothelial cells. The size of PEDF-overexpressing pancreatic adenocarcinoma tumors was significantly smaller than that of control tumors in s.c. tumor models. Moreover, the growth of PEDF-overexpressing pancreatic adenocarcinoma cells was significantly suppressed in comparison with control cells in peritoneal metastasis models. In gene transfer models, intratumoral injection of a lentivirus vector encoding PEDF (LV-PEDF) caused significant inhibition of tumor growth. The antitumor effect observed after treatment with LV-PEDF was associated with decreased microvessel density in tumors. Conclusion: Our data suggest that PEDF may exert a biological effect on tumor angiogenesis and PEDF gene therapy may provide a new approach for treatment of pancreatic adenocarcinoma.

Oncological benefit of preoperative endoscopic biliary drainage in patients with hilar cholangiocarcinoma

Due to advances in endoscopic equipment and techniques, preoperative endoscopic biliary drainage (EBD) has been developed to serve as an alternative to percutaneous transhepatic biliary drainage (PTBD). This study sought to clarify the benefit of EBD in comparison to PTBD in patients who underwent radical resections of hilar cholangiocarcinoma. One hundred and forty‐one patients underwent radical surgery for hilar cholangiocarcinoma between 2000 and 2008 were retrospectively divided into two groups based on the type of preoperative biliary drainage, PTBD (n = 67) or EBD (n = 74). We investigated if the different biliary drainage methods affected postoperative survival and mode of recurrence after median observation period of 82 months. The survival rate for patients who underwent EBD was significantly higher than those who had PTBD (P = 0.004). Multivariate analysis revealed that PTBD was one of the independent factors predictive of poor survival (hazard ratio: 2.075, P = 0.003). Patients with PTBD more frequently developed peritoneal seeding in comparison to those who underwent EBD (P = 0.0003). PTBD was the only independent factor predictive of peritoneal seeding. In conclusion, EBD might confer an improved prognosis over PTBD due to prevention of peritoneal seeding, and is recommended as the initial procedure for preoperative biliary drainage in patients with hilar cholangiocarcinoma.

Neoadjuvant imatinib in a gastrointestinal stromal tumor of the rectum: Report of a case

Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal tract, and of these, GISTs involving the rectum are uncommon. This report describes a case of effective neoadjuvant therapy for a rectal GIST expressing the c-kit gene, where a laparoscopic ultralow anterior resection was successfully performed, thus preserving the anus. A 57-year-old woman visited our hospital due to constipation and was found by a digital examination to have a soft mass on the right wall of the rectum. Computed tomography revealed an 8.0 × 5.0-cm mass with an unclear margin adjacent to the rectum. A biopsy specimen was positive for CD34 and the c-kit gene product, but it was not positive for smooth muscle actin or S-100 protein, and thus the tumor was diagnosed as GIST. An abdominoperineal resection is generally essential for large rectal GISTs; however, she refused this operation. Neoadjuvant treatment with Imatinib decreased the tumor size (4.0 × 3.5 cm) and the anus was preserved by a laparoscopic ultralow anterior resection with direct coloanal anastomosis. She had no evidence of disease for 24 months postoperatively. To preserve the anus, a rectal GIST expressing the c-kit gene is best treated with Imatinib as neoadjuvant therapy.

DRD2/DARPP-32 Expression Correlates with Lymph Node Metastasis and Tumor Progression in Patients with Esophageal Squamous Cell Carcinoma

BackgroundDopamine receptors (DRs) are members of seven transmembrane domain trimeric guanosine 5’-triphosphate (GTP)-binding protein-coupled receptor family. Through dopamine receptor activation, dopamine plays a significant role in regulating gene expression, such as induced tumor cell migration.Materials and MethodsWe investigated DRD1 and DRD2 expressions in patients with esophageal squamous cell carcinoma (ESCC) for immunohistochemistry and analyzed differences between DRD1, DRD2, and DARPP-32 expressions of clinicopathological features in 122 patients with ESCC.ResultsDRD1 immunostaining correlated with the pathologic grade (P = 0.0127), and DRD2 immunostaining correlated with the pathologic stage (P = 0.0432) and pN classification (P = 0.0112). A significant correlation was found between DRD1 and DRD2 expression (P = 0.0292). However, no correlation was observed between DRD1/DRD2 expression and DARPP-32 expression (P = 0.4555 and 0.4774, respectively). No correlation was observed between the DRD1/DRD2 expression and patient prognosis. To find the cooperative role between DRD1, DRD2, and DARPP-32 expressions, patients were classified into the different groups. In the DRD2/DARPP-32 combination, the (+/−) group was significantly correlated with pathologic stage (P = 0.0006), lymph node metastasis (P = 0.0001), pT (P = 0.0287), and tumor size (P = 0.0202). Moreover, patients with this combination showed a lower survival rate compared with the other three groups (P = 0.0287).ConclusionsWe conclude that DRD2/DARPP-32 expression is associated with tumor progression and that DRD2/DARPP-32 expressions may help predict prognosis in patients with ESCC.

Novel aspects of preoperative chemoradiation therapy improving anti-tumor immunity in pancreatic cancer

Pancreatic cancer is an aggressive cancer with poor prognosis. Little is known about the immune response in the tumor microenvironment after chemotherapy for initially unresectable tumor. The purpose of this study was to investigate the immunological effects of chemoradiation therapy in the tumor microenvironment of pancreatic adenocarcinoma. Seventeen patients with pancreatic adenocarcinoma with and without preoperative chemoradiation therapy were retrospectively analyzed using immunohistochemical methods for HLA class I heavy chain, CD4+, CD8+, CD45RO+ and Foxp3+ T cell infiltrations. Seven of the 17 study patients received preoperative chemoradiation therapy. There were no statistically significant differences in the number of CD4+ and CD8+ T cell infiltrations in the tumor microenvironment. However, the number of Foxp3+ T cell infiltrations was significantly lower in the neoadjuvant chemoradiation therapy group. The HLA class I expression status was the same between the two groups. In conclusion, preoperative chemoradiation therapy in pancreatic adenocarcinoma is useful for reducing regulatory T cell levels in combination with its direct cytotoxic effects.

Thoracoscopic enucleation of esophageal submucosal tumor by prone position under artificial pneumothorax by CO2 insufflation.

Recently, the usefulness of the prone position for thoracoscopic esophagectomy has been demonstrated. Thoracoscopic resection of an esophageal submucosal tumor using a prone position also offers advantages over a lateral decubitus position. We describe 2 cases operated on using the prone position for the resection of esophageal submucosal tumor. Case 1 was a 35-year-old man, who was diagnosed with a 50×20 mm leiomyoma in the middle thoracic esophagus, and underwent right thoracoscopic tumor enucleation. Case 2 was a 61-year-old female, who had 45×30 mm esophageal schwannoma in the lower thoracic esophagus with symptoms of dysphagia, and underwent left thoracoscopic tumor enucleation. No complication was observed in both cases. Thoracoscopic esophageal submucosal resection with prone position may add the merits to conventional decubitus position, such as superior visualization, and less bleeding. The side of incision should be determined according to the location of the tumor and anatomic rationality.

Advances in the surgical treatment of hilar cholangiocarcinoma

With the improvement of perioperative management and surgical techniques as well as the accumulation of knowledge on the oncobiological behavior of bile duct carcinoma, the long-term prognosis of hilar cholangiocarcinoma has been improving. In this article, the authors review the recent developments in surgical strategies for hilar cholangiocarcinoma, focusing on diagnosis for characteristic disease extension, perioperative management to reduce postoperative morbidity and mortality, surgical techniques for extended curative resection and postoperative adjuvant therapy.

Modified duodenum-preserving pancreas head resection for low-grade malignant lesion in the pancreatic head.

BACKGROUND/OBJECTIVES Our institution has utilized a duodenum-preserving pancreas head resection (DPPHR) procedure for management of low-grade malignant lesions within the head of the pancreas, but this has resulted in a higher rate of postoperative complications, including pancreatic fistula and ischemic bile duct injury. To avoid these complications we recently modified DPPHR to resect all the parenchyma around the pancreatic head and to preserve the epicholedochal plexus around the bile duct. The goal of this study was to investigate outcomes with postoperative complications and disease control following this modified procedure. METHODS Twenty-one consecutive patients underwent DPPHR between 1994 and 2011. Patients were retrospectively classified into one of two groups: the conventional DPPHR group (cDPPHR) or the modified DPPHR group (mDPPHR). Perioperative factors and postoperative complications were compared between these two groups. RESULTS The median age of the 21 patients was 61 (23-77) years, and the median follow-up period was 51 months. Intra-operational blood loss was significantly smaller and duration of hospital stay was significantly shorter in the mDPPHR group than in the cDPPHR group, respectively. The rate of pancreatic fistula was markedly lower in the mDPPHR group (2/13; 15%) than in the cDPPHR group (7/8; 88%) (P = 0.0022). For neoplastic lesions, the surgical margin was negative in all cases, and local recurrence has not occurred in either group. CONCLUSIONS For selected patients, modified DPPHR may provide clinical benefits in terms of less complications associated with shorter hospital stay.

Strategic Approach to the Splenic Artery in Laparoscopic Spleen-preserving Distal Pancreatectomy.

Background: Laparoscopic spleen-preserving distal pancreatectomy (LSPDP) is an ideal procedure in selected patients with benign or low-grade malignant tumors in the body/tail of the pancreas. We describe our procedure and experience with splenic vessel-preserving LSPDP (SVP-LSPDP) in a retrospective case series. Methods: Six consecutive patients underwent SVP-LSPDP from January 2011 to September 2013. We evaluated the courses of the splenic artery by preoperative computed tomography and applied an individualized approach (the superior approach or inferior approach) to the splenic artery. Results: All of the operations were successful. The median surgical duration was 249 minutes. The median blood loss was 0 mL. Pathologic examination revealed 4 cases of insulinoma, 1 case of solid pseudopapillary tumor, and 1 case of pancreatic metastasis from renal carcinoma. Conclusions: In performing SVP-LSPDP, it is effective to make a strategic choice between 2 different approaches according to the course of splenic artery.