Seiji Oguro

Arginase II expressed in cancer-associated fibroblasts indicates tissue hypoxia and predicts poor outcome in patients with pancreatic cancer.

An adequate level of arginine in the tissue microenvironment is essential for T cell activity and survival. Arginine levels are regulated by the arginine-catabolizing enzyme, arginase (ARG). It has been reported that arginase II (ARG2), one of two ARGs, is aberrantly expressed in prostate cancer cells, which convert arginine into ornithine, resulting in a lack of arginine that weakens tumor-infiltrating lymphocytes and renders them dysfunctional. However, immune suppression mediated by ARG2-expressing cancer cells in lung cancer has not been observed. Here we studied the expression of ARG2 in pancreatic ductal carcinoma (PDC) tissue clinicopathologically by examining over 200 cases of PDC. In contrast to prostate cancer, ARG2 expression was rarely demonstrated in PDC cells by immunohistochemistry, and instead ARG2 was characteristically expressed in α-smooth muscle actin-positive cancer-associated fibroblasts (CAFs), especially those located within and around necrotic areas in PDC. The presence of ARG2-expressing CAFs was closely correlated with shorter overall survival (OS; P  = 0.003) and disease-free survival (DFS; P  = 0.0006). Multivariate Cox regression analysis showed that the presence of ARG2-expressing CAFs in PDC tissue was an independent predictor of poorer OS (hazard ratio [HR]  = 1.582, P  = 0.007) and DFS (HR  = 1.715, P  = 0.001) in PDC patients. In addition to the characteristic distribution of ARG2-expressing CAFs, such CAFs co-expressed carbonic anhydrase IX, SLC2A1, or HIF-1α, markers of hypoxia, in PDC tissue. Furthermore, in vitro experiments revealed that cultured fibroblasts extracted from PDC tissue expressed the ARG2 transcript after exposure to hypoxia, which had arginase activity. These results indicate that cancer cell-mediated immune suppression through ARG2 expression is not a general event and that the presence of ARG2-expressing CAFs is an indicator of poor prognosis, as well as hypoxia, in PDC tissue.

Clinical significance of tumor-infiltrating immune cells focusing on BTLA and Cbl-b in patients with gallbladder cancer.

The host immune system plays a significant role in tumor control, although most cancers escape immune surveillance through a variety of mechanisms. The aim of the present study was to evaluate the clinicopathological significance of a novel co‐inhibitory receptor, B and T lymphocyte attenuator (BTLA), the anergy cell marker Casitas–B‐lineage lymphoma protein‐b (Cbl‐b), and clinical implications of tumor‐infiltrating immune cells in gallbladder cancer (GBC) tissues. We investigated 211 cases of GBC, 21 cases of chronic cholecystitis (CC), and 11 cases of xanthogranulomatous cholecystitis (XGC) using immunohistochemistry to detect tissue‐infiltrating immune cells and their expression of BTLA and Cbl‐b, and carried out correlation and survival analyses. The density of infiltrating T cells was significantly higher in CC and XGC than in GBC. The density ratio of BTLA+ cells to CD8+ T cells (BTLA/CD8) and that of Cbl‐b+ cells to CD8+T cells (Cbl‐b/CD8) were significantly higher in GBC than in CC and XGC. The FOXP3/CD4, BTLA/CD8, and Cbl‐b/CD8 ratios were significantly correlated with each other, and also with malignant phenotypes. Survival analyses revealed that a lower density of tumor‐infiltrating CD8+ cells, and higher Foxp3/CD4, BTLA/CD8, and Cbl‐b/CD8 ratios were significantly associated with shorter overall survival and disease‐free survival in GBC patients. Multivariate analyses showed that M factor, perineural invasion, BTLA/CD8, and Cbl‐b/CD8 were closely associated with shorter overall survival. These findings suggest that higher ratios of BTLA/CD8 and Cbl‐b/CD8 are independent indicators of unfavorable outcome in GBC patients, and that upregulation of BTLA in cancer tissues is involved in inhibition of antitumor immunity.

Pancreatic intraglandular metastasis predicts poorer outcome in postoperative patients with pancreatic ductal carcinoma

Intraorgan metastasis of a primary cancer within the organ of origin, such as intrahepatic metastasis of hepatocellular carcinoma, is one of the key features for clinicopathologic staging of the cancer. Pancreatic intraglandular metastasis (P-IM) of pancreatic ductal carcinoma (PDC) is encountered occasionally but has not yet been evaluated. The aim of this study was to investigate the clinicopathologic characteristics and prognostic value of P-IM in patients with PDC. The histopathologic features of 393 consecutive patients with PDC who had undergone pancreatic resection at the National Cancer Center Hospital, Tokyo, between 2003 and 2010 were reviewed. For the purposes of the study, P-IM was defined as an independent tumor showing histopathologic features similar to those of the primary one. Twenty-six cases of P-IM were identified in 21 (5.3%) of the reviewed patients. The incidence of P-IM at each stage of the TNM classification was 0% (0/7) at stage IA, 17% (1/6) at stage IB, 5% (5/92) at stage IIA, 4% (11/252) at stage IIB, 0% (0/1) at stage III, and 11% (4/35) at stage IV. Univariate survival analysis showed that both overall survival and disease-free survival for patients with P-IM were significantly shorter than for those without P-IM (P<0.001 and P=0.019, respectively). Multivariate survival analysis showed that P-IM was significantly correlated with shorter overall survival (P=0.002; hazard ratio=2.239; 95% confidence interval: 1.328-3.773). Our findings suggest that the presence of P-IM in patients with PDC is an independent prognosticator and may represent aggressive tumor behavior.

Three hundred and sixty-eight consecutive pancreaticoduodenectomies with zero mortality

Only a limited number of reports have documented zero mortality in consecutive pancreaticoduodenectomy series. The aim of this study is to review and verify our management aiming to eliminate mortality after pancreaticoduodenectomy.

Liver metastases from gastric cancer represent systemic disease in comparison with those from colorectal cancer.

The aim of this retrospective study was to clarify the difference in behavior and outcome after initial hepatectomy between gastric cancer liver metastases (GCLM) and colorectal cancer liver metastases (CCLM).

Mo1455 Extended Left Hepatic Trisectionectomy as a Feasible Surgical Procedure for Advanced Perihilar Cholangiocarcinoma

Objectives: The aim of this study was to clarify the short and long term outcome of extended left hepatic trisectionectomy (LT) for perihilar cholangiocarcinoma. Methods: Patients with perihilar cholangiocarcinoma who underwent LT between January 2000 and October 2010 for perihilar cholangiocarcinoma were analyzed retrospectively. Operative variables, mortality, morbidity, recurrence sites and survival of three groups were compared among LT, right hemihepatectomy (RH) and left hemihepatectomy (LH). Results: A total 203 patients underwent surgical resection for perihilar cholangiocarcinoma, 22 (11%) of whom underwent LT, 79 (39%) underwent RH, and 84 (41%) underwent LH. No mortality occurred, but 17 patients had morbidity. Operative time and blood loss were 655 ± 142 minutes and 2100 ± 1080 ml, respectively. Blood loss in patients with LT was significantly more than in those with LH (2100ml versus 1300ml; P = 0.017). The incidence of Grade IIIa complication in patients with LT was significant higher than RH and LH (P=0.044 and P=0.014), but Grade IIIb and IV complication did not occur in patients with LT. Overall 5-year survival rate was 40% with median survival of 45.8 years. There was no significant difference in survival in patients between LT and other two procedures. Conclusions: LT for perihilar cholangiocarcinoma is feasible and can provide a comparable prognosis for advanced perihilar cholangiocarcinoma originating from left hepatic duct or segment 4 especially extending to the root of the right anterior portal pedicle or confluence of the anterior and posterior branch of the bile duct. S-1069 SSAT Abstracts Mo1456 Audit of the use of Critical View of Safety and Infundibular Cystic Technique in Cystic Duct Identification in Laparoscopic Cholecystectomy Anokha Oomman, Ashraf M. Rasheed, Karthic Rajaram, Krithika Murugan Introduction: The commonest cause of bile duct injury (BDI) during laparoscopic cholecystectomy (LC) is the confusion of bile duct with cystic duct. Operation notes must include the anatomical rationale by which the cystic duct was conclusively identified. Aim: To examine the quality of documentation and the terms used to describe the method/methods utilised to identify the cystic duct during laparoscopic cholecystectomy. Method: The documentation of the method/s used for cystic duct identification was examined in 322 consecutive nonconverted LCs that were carried out between the months of August 2010 and January 2011. Non-protocolised operation notes were studied and stratified into different groups according to the descriptive terms used. The strata included: 1). No documentation of the method used, 2). Calots triangle was dissected or demonstrated, 3) Infundibular or infundibulocystic technique used, 4). Critical view of safety (CVS) demonstrated, 5) Intra-operative cholangiogram used, or 6) Other methods. Results: Demonstration of the critical view of safety was documented in (4/310) 1.3% of the cases. Infundibular or infundibulo-cystic technique was used to define the cystic duct in (9/310) 3.4% of the notes. Calots triangle was mentioned in (255/310) 82.3% of the notes. In (43/310) 13.9% of cases, the cystic artery and duct were mentioned without any reference to critical view of safety, infundibular / infundibulo-cystic technique or Calots triangle. Conclusion: Written documentation of the method of cystic duct identification in the operation notes during LC is sub-optimal. We, hence recommend standardization of the cholecystectomy operative report, inclusion of a video clip and/ or photo image using digital information and communication in medicine (DICOM) to complement the textual operation notes and move towards structured computerised input that links to the picture archiving and communication system (PACS).

Total pancreatectomy with en bloc celiac axis resection for a pancreatic adenocarcinoma involving both the gastroduodenal artery and the celiac artery.

A pancreatic adenocarcinoma involving both the celiac artery and the gastroduodenal artery is often considered to be unresectable because the simultaneous division of both arteries may result in an acute severe ischemia of the liver and the stomach. We report here a case of total pancreatectomy with en bloc celiac axis resection for a 61-year-old female with a pancreatic adenocarcinoma involving both the celiac artery and the gastroduodenal artery. The patient had a replaced right hepatic artery from the superior mesenteric artery and a replaced left hepatic artery from the left gastric artery, which was directly arising from the aorta. Preserving these collateral arteries, neither hepatic artery reconstruction nor total gastrectomy was needed after resection. The reported incidence of similar arterial anatomy was only 0.2% but the precise evaluation of arterial anatomy is important to offer a chance of curative resection for patients with usually unresectable locally advanced pancreatic cancer.