Hisafumi Kinoshita

Tumor Growth Suppression in Pancreatic Cancer by a Putative Metastasis Suppressor Gene Cap43/NDRG1/Drg-1 through Modulation of Angiogenesis

Cap43 has been identified as a nickel- and calcium-induced gene, and is also known as N-myc downstream-regulated gene 1 (NDRG1), Drg-1 and rit42. It is also reported that overexpression of Cap43 suppresses metastasis of some malignancies, but its precise role remains unclear. In this study, we asked how Cap43 could modulate the tumor growth of pancreatic cancer. Stable Cap43 cDNA transfectants of pancreatic cancer cells with Cap43 overexpression showed similar growth rates in culture as their control counterparts with low Cap43 protein level. By contrast, Cap43 overexpression showed a marked decrease in tumor growth rates in vivo. Moreover, a marked reduction in tumor-induced angiogenesis was observed. Gelatinolytic activity by matrix metalloproteinase-9 and invasive ability in Matrigel invasion activity were markedly decreased in pancreatic cancer cell lines with high Cap43 expression. Cellular expression of matrix metalloproteinase-9 and two major angiogenic factors, vascular endothelial growth factor and interleukin-8, were also significantly decreased in cell lines with Cap43 overexpression as compared with their parental counterparts. Immunohistochemical analysis of specimens from 65 patients with pancreatic ductal adenocarcinoma showed a significant association between Cap43 expression and tumor microvascular density (P = 0.0001) as well as depth of invasion (P = 0.0003), histopathologic grading (P = 0.0244), and overall survival rates for patients with pancreatic cancer (P = 0.0062). Thus, Cap43 could play a key role in the angiogenic on- or off-switch of tumor stroma in pancreatic ductal adenocarcinoma.

N-myc Downstream Regulated Gene 1/Cap43 Suppresses Tumor Growth and Angiogenesis of Pancreatic Cancer through Attenuation of Inhibitor of κB Kinase β Expression

N-myc downstream regulated gene 1 (NDRG1)/Cap43 expression is a predictive marker of good prognosis in patients with pancreatic cancer as we reported previously. In this study, NDRG1/Cap43 decreased the expression of various chemoattractants, including CXC chemokines for inflammatory cells, and the recruitment of macrophages and neutrophils with suppression of both angiogenesis and growth in mouse xenograft models. We further found that NDRG1/Cap43 induced nuclear factor-kappaB (NF-kappaB) signaling attenuation through marked decreases in inhibitor of kappaB kinase (IKK) beta expression and IkappaBalpha phosphorylation. Decreased IKKbeta expression in cells overexpressing NDRG1/Cap43 resulted in reduction of both nuclear translocation of p65 and p50 and their binding to the NF-kappaB motif. The introduction of an exogenous IKKbeta gene restored NDRG1/Cap43-suppressed expression of melanoma growth-stimulating activity alpha/CXCL1, epithelial-derived neutrophil activating protein-78/CXCL5, interleukin-8/CXCL8 and vascular endothelial growth factor-A, accompanied by increased phosphorylation of IkappaBalpha in NDRG1/Cap43-expressing cells. In patients with pancreatic cancer, NDRG1/Cap43 expression levels were also inversely correlated with the number of infiltrating macrophages in the tumor stroma. This study suggests a novel mechanism by which NDRG1/Cap43 modulates tumor angiogenesis/growth and infiltration of macrophages/neutrophils through attenuation of NF-kappaB signaling.

Clinicopathological features and prognosis of mucin‐producing bile duct tumor and mucinous cystic tumor of the liver: a multi‐institutional study by the Japan Biliary Association

The aim of this study was to determine the clinicopathological features and surgical outcomes of mucinous cystic neoplasm of the liver (MCN) and mucin‐producing intraductal papillary neoplasm of the intrahepatic bile duct (M‐IPNB).

Classification of biliary tract cancers established by the Japanese Society of Hepato‐Biliary‐Pancreatic Surgery: 3rd English edition

The 3rd English edition of the Japanese classification of biliary tract cancers was released approximately 10 years after the 5th Japanese edition and the 2nd English edition. Since the first Japanese edition was published in 1981, the Japanese classification has been in extensive use, particularly among Japanese surgeons and pathologists, because the cancer status and clinical outcomes in surgically resected cases have been the main objects of interest. However, recent advances in the diagnosis, management and research of the disease prompted the revision of the classification that can be used by not only surgeons and pathologists but also by all clinicians and researchers, for the evaluation of current disease status, the determination of current appropriate treatment, and the future development of medical practice for biliary tract cancers. Furthermore, during the past 10 years, globalization has advanced rapidly, and therefore, internationalization of the classification was an important issue to revise the Japanese original staging system, which would facilitate to compare the disease information among institutions worldwide. In order to achieve these objectives, the new Japanese classification of the biliary tract cancers principally adopted the 7th edition of staging system developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC). However, because there are some points pending in these systems, several distinctive points were also included for the purpose of collection of information for the future optimization of the staging system. Free mobile application of the new Japanese classification of the biliary tract cancers is available via http://www.jshbps.jp/en/classification/cbt15.html.

Clinical practice guidelines for the management of biliary tract cancers 2015: the 2nd English edition

The Japanese Society of Hepato‐Biliary‐Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract and ampullary carcinomas in 2008. Novel treatment modalities and handling of clinical issues have been proposed after the publication. New approaches for editing clinical guidelines, such as the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, also have been introduced for better and clearer grading of recommendations.

N-myc Downstream Regulated Gene 1 (NDRG1) Promotes Metastasis of Human Scirrhous Gastric Cancer Cells through Epithelial Mesenchymal Transition

Our recent study demonstrated that higher expression of N-myc downregulated gene 1 (NDRG1) is closely correlated with poor prognosis in gastric cancer patients. In this study, we asked whether NDRG1 has pivotal roles in malignant progression including metastasis of gastric cancer cells. By gene expression microarray analysis expression of NDRG1 showed the higher increase among a total of 3691 up-regulated genes in a highly metastatic gastric cancer cell line (58As1) than their parental low metastatic counterpart (HSC-58). The highly metastatic cell lines showed decreased expression of E-cadherin, together with enhanced expression of vimentin and Snail. This decreased expression of E-cadherin was restored by Snail knockdown in highly metastatic cell lines. We next established stable NDRG1 knockdown cell lines (As1/Sic50 and As1/Sic54) from the highly metastatic cell line, and both of these cell lines showed enhanced expression of E-cadherin and decreased expression of vimentin and Snail. And also, E-cadherin promoter-driven luciferase activity was found to be increased by NDRG1 knockdown in the highly metastatic cell line. NDRG1 knockdown in gastric cancer cell showed suppressed invasion of cancer cells into surround tissues, suppressed metastasis to the peritoneum and decreased ascites accumulation in mice with significantly improved survival rates. This is the first study to demonstrate that NDRG1 plays its pivotal role in the malignant progression of gastric cancer through epithelial mesenchymal transition.

A case of IgG4-related sclerosing mesenteritis

IgG4-related disease has been recognized as a systemic syndrome characterized by mass-forming lesions with lymphoplasmacytic infiltration and sclerosis. This disease has been identified in various sites, including the pancreas, retroperitoneum, lung, head, and neck. Herein we report a case of IgG4-related sclerosing mesenteritis. An 82-year-old woman was admitted to our hospital due to persistent abdominal pain. Abdominal computed tomography demonstrated a solitary mass with a maximal diameter of 11.7cm in mesentrium of the small intestine. On her laboratory examination, only C-reactive protein level was elevated. Although the pre-operative diagnosis was indefinite, she underwent ileocecectomy. Grossly, an elastic soft mass with foci of hemorrhage was seen in the mesentrium. Microscopically, the lesion was composed of fibroblastic or myofibroblastic spindle cells with abundant stromal fibrosis and inflammatory infiltrate, such as lymphocytes and plasma cells accompanied by lymphoid follicles with a germinal center. Obstructive phlebitis was observed. Immunohistochemically, numerous IgG4-positive plasma cells were observed, and the IgG4/IgG ratio was 75.9%. The serum level of IgG4 examined at post-operation was high. These findings suggested that this lesion was consistent with IgG4-related sclerosing mesenteritis.

Influence of preoperative anti-cancer therapy on resectability and perioperative outcomes in patients with pancreatic cancer: Project study by the Japanese Society of Hepato-Biliary-Pancreatic Surgery

Little is known about the effects of neoadjuvant therapy on outcomes in patients with pancreatic cancer. This study evaluated the effects of neoadjuvant therapy on resectability and perioperative outcomes.

Gallbladder bed resection or hepatectomy of segments 4a and 5 for pT2 gallbladder carcinoma: analysis of Japanese registration cases by the study group for biliary surgery of the Japanese Society of Hepato-Biliary-Pancreatic Surgery

PurposeHepatectomy of segments 4a and 5 (S4a+5) is the recommended treatment for pT2 gallbladder cancer. However, gallbladder bed resection is also occasionally used. Using nationwide data from the Japanese Biliary Tract Cancer Registry and a questionnaire survey, we retrospectively compared these 2 methods of treatment.MethodThe study involved 85 patients with pT2, pN0 gallbladder cancer (55 treated with gallbladder bed resection, and 30, with S4a+5 hepatectomy). The prognosis and mode of tumor recurrence following treatment were analyzed retrospectively, with overall survival as the endpoint.ResultsThe 5-year survival rate did not differ significantly between the 2 groups. Univariate analysis showed that bile duct resection and perineural tumor invasion were significant prognostic factors, but the extent of hepatectomy, location of the major intramural tumor, regional lymph node excision, and histological type were not. Multivariate analysis identified perineural tumor invasion as a significant prognostic factor. Recurrence occurred most frequently in both lobes than S4a+5 of the liver following gallbladder bed resection.ConclusionIn the present study of cases of Japanese Biliary Tract Cancer Registry, it was not possible to conclude that S4a+5 hepatectomy was superior to gallbladder bed resection.

The effect of adjuvant and neoadjuvant chemo(radio)therapy on survival in 1,679 resected pancreatic carcinoma cases in Japan: report of the national survey in the 34th annual meeting of Japanese Society of Pancreatic Surgery

BACKGROUND Pancreatic carcinoma causes more than 20,000 deaths every year in Japan. The role of (neo-) adjuvant chemotherapy for pancreatic carcinoma is still controversial. METHODS At the 34th Annual Meeting of the Japanese Society of Pancreatic Surgery in 2007, questionnaires were distributed regarding the use of (neo-) adjuvant chemo(radio)therapy for pancreatic carcinoma between 2001 and 2005. RESULTS Sixty of the 146 member institutions responded to the questionnaires. There were a total of 1,846 cases of resected pancreatic carcinoma between 2001 and 2005. The study population had a greater proportion of males, and a mean age of 65.3 years (range 34-90 years). The lesion was located in the head of the pancreas in 1,204 cases (71.7%), in the body in 353 cases (21.0%), and in the tail in 111 cases (6.6%). Overall survival rates were 67.3% at 1 year, 36.0% at 2 years, and 23.9% at 3 years, respectively. Adjuvant chemotherapy (usually involving gemcitabine) was used in 66.0% of cases. The use of adjuvant chemotherapy was found to improve the overall survival rate. Interestingly, adjuvant chemotherapy only improved survival in late-stage (UICC stages IIB, III, and IV) but not early stage (IA, IB, and IIA) patients. Survival was treatment duration-dependent, with patients who received more than 12 months of therapy having a 3-year survival rate of 51.2%. CONCLUSION This high volume retrospective data indicated the promising effect of gemcitabine-based adjuvant chemotherapy and the rational duration of adjuvant chemotherapy should be determined in the future prospective studies.