Kazunori Shibao

Expression of UDP-N-acetyl-α-D-galactosamine–polypeptide galNAc N-acetylgalactosaminyl transferase-3 in relation to differentiation and prognosis in patients with colorectal carcinoma

Tumor development usually is accompanied by alterations of O‐glycosylation. Initial glycosylation of mucin‐type, O‐linked proteins is catalyzed by one of the UDP‐GalNAc–polypeptide N‐acetyl‐galactosaminyl transferases, such as GalNAc‐T3, which is expressed in adenocarcinoma cells. The authors investigated whether such expression influenced tumor differentiation or prognosis in patients with colorectal carcinoma.

Lymphatic Microvessel Density is an Independent Prognostic Factor in Colorectal Cancer

PurposeAlthough lymph node metastasis via lymphatic vessels often is related with an adverse outcome, it is not well known whether lymphatic spread to lymph node needs the development of the new lymphatic formation. In addition, the correlation between lymphangiogenesis and prognosis has not been well documented. This study was designed to assess the prognostic value of lymphangiogenesis and lymphatic vessel invasion in colorectal cancer.MethodsWe examined 106 colorectal cancer specimens by immunostaining for podoplanin, lymphatic endothelial specific marker. We evaluated lymphangiogenesis, as measured by lymphatic microvessel density, and lymphatic vessel invasion. We next investigated the association of these two parameters with the clinicopathologic findings and prognosis.ResultsA significant correlation was observed between high lymphatic microvessel density and positive lymphatic vessel invasion (P = 0.0003). Positive lymphatic vessel invasion was significantly associated with the presence of lymph node metastasis (P = 0.0071). The survival curves demonstrated that both high lymphatic microvessel density and positive lymphatic vessel invasion were correlated with an adverse outcome (P = 0.0004 and P = 0.009, respectively). In a univariate analysis, high lymphatic microvessel density and positive lymphatic vessel invasion were negatively associated with the overall survival (P = 0.0011 and P = 0.0118, respectively). Furthermore, high lymphatic microvessel density, but not lymphatic vessel invasion, correlated with a poor outcome in a multivariate analysis (P = 0.0114).ConclusionsOur data suggested that lymphatic vessel invasion was related with lymph node metastasis and that both lymphatic microvessel density and lymphatic vessel invasion were related with an adverse outcome in colorectal cancer. Furthermore, lymphatic microvessel density may be a useful prognostic factor in colorectal cancer.

Reticulon 4B (Nogo‐B) is a novel regulator of hepatic fibrosis

Nogo‐B, also known as Reticulon 4B, plays important roles in vascular injuries. Its function in the liver is not understood. The aim of this study was to characterize Nogo‐B in liver fibrosis and cirrhosis. Nogo‐B distribution was assessed in normal and cirrhotic human liver sections. We also determined the levels of liver fibrosis in wild‐type (WT) and Nogo‐A/B knockout (NGB KO) mice after sham operation or bile duct ligation (BDL). To investigate the mechanisms of Nogo‐Bs involvement in fibrosis, hepatic stellate cells were isolated from WT and NGB KO mice and transformed into myofibroblasts. Portal pressure was measured to test whether Nogo‐B gene deletion could ameliorate portal hypertension. In normal livers, Nogo‐B expression was found in nonparenchymal cells, whereas its expression in hepatocytes was minimal. Nogo‐B staining was significantly elevated in cirrhotic livers. Fibrosis was significantly increased in WT mice 4 weeks after BDL compared with NGB KO mice. The absence of Nogo‐B significantly reduced phosphorylation of Smad2 levels upon transforming growth factor β (TGF‐β) stimulation. Reconstitution of the Nogo‐B gene into NGB KO fibroblasts restored Smad2 phosphorylation. Four weeks after BDL, portal pressure was significantly increased in WT mice by 47%, compared with sham‐operated controls (P = 0.03), whereas such an increase in portal pressure was not observed in NGB KO mice (P = NS). Conclusion: Nogo‐B regulates liver fibrosis, at least in part, by facilitating the TGFβ/Smad2 signaling pathway in myofibroblasts. Because absence of Nogo‐B ameliorates liver fibrosis and portal hypertension, Nogo‐B blockade may be a potential therapeutic target in fibrosis/cirrhosis. (HEPATOLOGY 2011;)

The type III inositol 1,4,5-trisphosphate receptor is associated with aggressiveness of colorectal carcinoma

The inositol 1,4,5-trisphosphate receptor (InsP3R) mediates Ca(2+) signaling in epithelia and regulates cellular functions such as secretion, apoptosis and cell proliferation. Loss of one or more InsP3R isoform has been implicated in disease processes such as cholestasis. Here we examined whether gain of expression of InsP3R isoforms also may be associated with development of disease. Expression of all three InsP3R isoforms was evaluated in tissue from colorectal carcinomas surgically resected from 116 patients. Type I and II InsP3Rs were seen in both normal colorectal mucosa and colorectal cancer, while type III InsP3R was observed only in colorectal cancer. Type III InsP3R expression in the advancing margins of tumors correlated with depth of invasion, lymph node metastasis, liver metastasis, and TNM stage. Heavier expression of type III InsP3R also was associated with decreased 5-year survival. shRNA knockdown of type III InsP3R in CACO-2 colon cancer cells enhanced apoptosis, while over-expression of the receptor decreased apoptosis. Thus, type III InsP3R becomes expressed in colon cancer, and its expression level is directly related to aggressiveness of the tumor, which may reflect inhibition of apoptosis by the receptor. These findings suggest a previously unrecognized role for Ca(2+) signaling via this InsP3R isoform in colon cancer.

Prognostic significance of UDP-N-acetyl-α-D-galactosamine : polypeptide N-acetylgalactosaminyltransferase-3 (GalNAc-T3) expression in patients with gastric carcinoma

Aberrant glycosylation occurs during development of gastric carcinomas. The initiation of mucin‐type O‐glycosylation is regulated by GalNAc‐T3 (UDP‐N‐acetylgalactosamine:polypeptide N‐acetyl‐galactosaminyltransferase‐3). However, the clinical significance of GalNAc‐T3 expression in human gastric carcinoma has not yet been demonstrated. In the present study, we investigated the relationship between immunohistochemical GalNAc‐T3 expression and various clinicopathologic factors, including prognosis, in 117 gastric carcinoma patients. Of 117 gastric carcinomas examined, 59 (50.4%) showed strong expression of GalNAc‐T3. Strong expression was detected in 38 of 59 (64.4%) differentiated type and in 21 of 58 (36.2%) undifferentiated gastric carcinomas, indicating that the expression of GalNAc‐T3 correlated significantly with tumor differentiation (P=0.0023, x2 test). Overall 5‐year survival rate in patients with strong GalNAc‐T3 expression (71.0%) was significantly better than that of patients with weak expression (49.3%) (P=0.0197, log‐rank test). Multivariate analysis identified GalNAc‐T3 expression as an independent prognostic factor (P=0.0158, Cox proportional hazards model). Our data suggest that GalNAc‐T3 expression may be a useful marker for prognosis and differentiation of gastric carcinomas. (Cancer Sci 2003; 94: 32–36)

4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid inhibits angiogenesis in colon cancer through reduced expression of vascular endothelial growth factor.

4-[3,5-bis(trimethylsilyl)benzamido] Benzoic acid (TAC-101) has potent antiproliferative, antiangiogenic, and antitumor effects in vitro and in vivo. These effects might be due to TAC-101 binding to retinoic acid receptor alpha (RAR-alpha) and interfering with the binding of activator protein-1 (AP-1) to DNA. However, little is known about the detailed mechanism of TAC-101 function. We investigated the mechanism of the antiangiogenic effect of TAC-101 using a rat hepatic metastatic model in vivo and DLD-1 human colon cancer cells in vitro. Liver metastases were induced by portal injection of RCN-9 rat colonic cancer cells into F344 rats. TAC-101 (8 mg/kg) was orally administered 5 days per week for 4 weeks and then hepatic tumors were immunohistochemically evaluated for microvessel density (MVD) and vascular endothelial growth factor (VEGF). TAC-101 significantly reduced both MVD and VEGF expression. Northern blot analysis and ELISA indicated that TAC-101 efficiently inhibited production of VEGF mRNA and protein in DLD-1 cells in a time- and dose-dependent manner. These findings suggest that TAC-101 may inhibit progression and metastasis in colon cancer by interfering with tumor production of VEGF.

Risk factors for a prolonged operative time in a single-incision laparoscopic cholecystectomy

BACKGROUND A prolonged operative time is associated with adverse post-operative outcomes in laparoscopic surgery. Although a single-incision laparoscopic cholecystectomy (SILC) requires a longer operative time as compared with a conventional laparoscopic cholecystectomy, risk factors for a prolonged operative time in SILC remain unknown. METHODS A total of 20 clinical variables were retrospectively reviewed to identify factors for a prolonged operative time (longer than 3 h) in a total of 220 consecutive patients undergoing SILC. RESULTS The median operative time was 145 min (range, 55-435) and a prolonged operative time was required in 62 patients (28%). Independent factors that predict a prolonged operative time as identified through multivariate analysis were body mass index (BMI) (P = 0.009), acute cholecystitis (P < 0.001) and operator (resident or staff surgeon) (P < 0.001). Furthermore, a prolonged operative time was significantly associated with an increased amount of intra-operative blood loss (P < 0.001) and a prolonged stay after surgery (P < 0.001). CONCLUSIONS These findings suggest that a higher BMI, acute cholecystitis and a resident as an operator significantly increase the duration of SILC procedures.

A new oval multichannel port to facilitate reduced port distal gastrectomy.

Abstract Background: This report describes the techniques and outcomes of reduced port distal gastrectomy (RPDG) using a new oval multichannel port. Material and methods: We performed reduced port distal gastrectomy through the E·Z Access™ oval type device with three trocars in the umbilical incision, plus the use of additional 5 mm and 2 mm ports. All routine procedures performed in conventional laparoscopic distal gastrectomy (CLDG) were achieved in RPDG. Results: We employed this technique without the use of additional trocars or conversion to laparotomy in all 25 patients. The median length of the operation was 340 (range, 220–487) minutes, and the median estimated blood loss was 30 (range, 5–440) ml. Neither major postoperative complications, such as anastomotic leakage and stricture, nor postoperative mortality were observed. The mean length of the hospital stay was 11 days. The umbilical wound was indistinct. The patients were also highly satisfied with the cosmetic outcome. Conclusion: Reduced port surgery using the E·Z Access™ oval type device was successfully applied for gastric cancer. This method is technically feasible, produces superior cosmetic results and thus could be an attractive surgical option for gastric cancer patients.

Mitochondrial transcription factor a worsens the clinical course of patients with pancreatic cancer through inhibition of apoptosis of cancer cells.

Objective Mitochondrial transcription factor A (mtTFA) is mandatory for both the transcription and maintenance of mitochondrial DNA. This study aimed to investigate the significance of mtTFA expression in pancreatic ductal adenocarcinoma (PDAC). Methods Surgical specimens from 93 patients with PDAC who all underwent pancreatectomy were immunohistochemically stained using a polyclonal anti-mtTFA antibody. The relationship between the expression of mtTFA, clinicopathologic factors, and prognosis of these patients were evaluated. Results Positive mtTFA expression was significantly associated with lymphovascular invasion and metastatic recurrence in the liver and correlated with an advanced surgical stage. A univariate analysis showed that the patients with positive mtTFA expression had a significantly shorter survival time than those patients with negative mtTFA expression, and a multivariate analysis revealed that mtTFA expression was one of the independent prognostic factors in patients with PDAC. Positive mtTFA expression was significantly correlated with a low apoptotic index but not significantly correlated with the mind bomb homolog-1 (MIB-1) index. Conclusions The expression mtTFA worsens the clinical course of patients with PDAC through the inhibition of apoptosis of PDAC cells and is an independent marker for the poor prognosis of the patients with PDAC after pancreatectomy. Mitochondrial transcription factor A may be a novel target for the treatment of PDAC.

Pancreatic Somatostatinoma Diagnosed Preoperatively: Report of a Case

CONTEXT Somatostatinoma is a rare neoplasm of the pancreas. Preoperative diagnosis is often difficult. CASE REPORT We report a 72-year-old woman with a pancreatic head tumor measuring 37 mm in diameter, and enlargement of the lymph nodes on the anterior surface of the pancreatic head and the posterior surface of the horizontal part of the duodenum. Laboratory data showed an elevated plasma somatostatin concentration. Examination of a biopsy specimen of the pancreatic head mass obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) showed histopathological features of a neuroendocrine tumor. Immunohistochemical staining showed that the tumor cells were positive for somatostatin, leading to a preoperative diagnosis of pancreatic somatostatinoma. The patient underwent pylorus-preserving pancreaticoduodenectomy. The plasma somatostatin concentration decreased progressively after surgery. CONCLUSIONS A rare case of pancreatic somatostatinoma with lymph node metastases was presented. Immunohistochemical analysis of a biopsy specimen obtained by EUS-FNA was useful for preoperative diagnosis.