Kinji Kamiya

TSU68 Prevents Liver Metastasis of Colon Cancer Xenografts by Modulating the Premetastatic Niche

The aim of this study was to investigate the inhibitory effect of TSU68 [(Z)-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid; SU6668], an inhibitor of vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor beta, and fibroblast growth factor receptor 1 (FGFR1), on colon cancer liver metastasis, and to test the hypothesis that TSU68 modulates the microenvironment in the liver before the formation of metastasis. First, we implanted the highly metastatic human colon cancer TK-4 orthotopically into the cecal walls of nude mice, followed by twice-daily administration of TSU68 (400 mg/kg/d) or vehicle. Five weeks of treatment with TSU68 significantly inhibited liver metastasis compared with the control group (P<0.001). Next, we analyzed the gene expression profile in premetastatic liver using microarrays. Microarray and quantitative reverse transcription-PCR analysis showed that mRNA levels for the chemokine CXCL1 were significantly increased in tumor-bearing mice compared with non-tumor-bearing mice. Moreover, CXCL1 expression was significantly decreased by TSU68 treatment. CXCR2 expression was detected predominantly on tumor cells in orthotopic tumors compared with ectopic tumors. The number of migrating neutrophils in premetastatic liver was significantly decreased in the TSU68-treated group (P<0.001). The amount of interleukin-12 (IL-12) p40 in the portal vein was significantly decreased by TSU68 (P=0.02). Blockade of both CXCR2 and IL-12 p40 with a neutralizing antibody significantly inhibited liver metastasis. These results suggest that the CXCL1/CXCR2 axis is important in cancer metastasis and that TSU68 may modulate the premetastatic niche in the target organ through suppression of the inflammatory response, which might be an alternative mechanism used by antiangiogenic agents.

Analysis of anatomic variants of mesenteric veins by 3-dimensional portography using multidetector-row computed tomography

BACKGROUND It is important to be aware of mesenteric venous variants to perform peripancreatic surgery. We investigated the usefulness of 3-dimensional (3-D) portography. METHODS Vessels were reconstructed using computer software in 102 patients undergoing multidetector-row computed tomography (MDCT) scheduled for gastrointestinal or hepatobiliary-pancreatic surgery. RESULTS The superior mesenteric vein (SMV) was composed of single and double trunks around the splenoportal confluence in 78 and 24 patients, respectively. The inferior mesenteric vein joined the splenic vein (68.5%), SMV (18.5%), and splenoportal confluence (7.6%). The left gastric vein joined the splenic vein (46.3%), portal vein (39.0%), and splenoportal confluence (14.7%). Seventy-nine patients showed a gastrocolic trunk, mostly composed of the right gastroepiploic vein and veins from the colonic hepatic flexure. Intraoperative findings were identical to 3-D diagnosis in 68 gastrectomized and 9 pancreatectomized patients. CONCLUSION Although mesenteric venous tributaries are complex, 3-D portography is helpful for surgeons to safely perform peripancreatic surgery.

Prevention of liver metastasis of human colon cancer by selective matrix metalloproteinase inhibitor MMI-166.

MMI-166 is a selective inhibitor of matrix metalloproteinase (MMP)-2 and MMP-9. Mice implanted a human colon cancer orthotopically received 200 mg/kg of MMI-166 orally for 5 weeks. Gelatin zymography demonstrated that the administration of MMI-166 remarkably decreased the active MMP-2 expression. Histological examination revealed that MMI-166 showed prominent effect on reduction of the invasive feature of the cancer cells and showed inhibitory effect on tumor vasculature, resulting in the significant decrease of microvessel density of the implanted tumor and liver metastasis compared with the control group. Conclusively, MMI-166 is a potent antiangiogenic oral agent for a human colon cancer.

Optical diagnosis of gastric cancer using near-infrared multichannel Raman spectroscopy with a 1064-nm excitation wavelength

BackgroundGastric cancer is one of the most common cancers in Japan. The use of endoscopy is increasing, along with the number of histological examinations of specimens obtained by endoscopy. However, it takes several days to reach a diagnosis, which increases the medical expense. Raman spectroscopy is one of the available optical techniques, and the Raman spectrum for each molecule and tissue is characteristic and specific. The present study investigated whether Raman spectroscopy can be used to diagnose gastric cancer.MethodsA total of 251 fresh biopsy specimens of gastric carcinoma and non-neoplastic mucosa were obtained from 49 gastric cancer patients at endoscopy. Without any pretreatment, the fresh specimens were measured with a near-infrared multichannel Raman spectroscopic system with an excitation wavelength of 1064 nm, and Raman spectra specific for the specimens were obtained. A principal component analysis (PCA) was performed to distinguish gastric cancer and non-neoplastic tissue, and a discriminant analysis was used to evaluate the accuracy of the gastric cancer diagnosis.ResultsThe Raman spectra for cancer specimens differed from those for non-neoplastic specimens, especially at around 1644 cm−1. Sensitivity was 66%, specificity was 73%, and accuracy was 70%. The accuracy of diagnosis using the single Raman scattering intensity at 1644 cm−1 was 70%, consistent with the PCA result.ConclusionsThe present results indicate that near-infrared multichannel Raman spectroscopy with a 1064-nm excitation wavelength is useful for gastric cancer diagnosis. Establishment of a Raman diagnostic system for gastric cancer may improve the clinical diagnosis of gastric cancer and be beneficial for patients.

The significance of circulating vascular endothelial growth factor (VEGF) protein in gastric cancer.

We examined the vascular endothelial growth factor (VEGF) levels in peripheral blood and drainage vein (plasma and serum), and then these were compared with local VEGF expression from gastric cancer. Peripheral blood plasma VEGF levels was increased in the patients with venous invasion, and moderately correlated with the number and ratio of lymph nodes with metastasis. Local VEGF expression was correlated significantly with tumor size, advanced stage and lymph node metastasis, but not correlated with peripheral VEGF levels. The level of plasma VEGF in peripheral veins is one of the sensitive markers of the status of gastric cancer.

Antitumor effect on human gastric cancer and induction of apoptosis by vascular endothelial growth factor neutralizing antibody.

Induction of apoptosis by antiangiogenic therapy has been suggested as a new anticancer strategy. To clarify the mechanism of the antitumor effect achieved by inhibition of vascular endothelial growth factor (VEGF), which is a major mediator of angiogenesis, we used an orthotopic transplantation model of human gastric carcinoma line (MT2) treated with a monoclonal VEGF neutralizing antibody (VEGF Ab). We histologically examined the microvessel density (MVD) and the apoptotic index (AI) in this model. Transplanted tumor growth was significantly inhibited by the VEGF Ab (P= 0.03), and there was a significant decrease in the number of mice with liver metastasis (P= 0.004). The MVD detected by immunohistochemical staining with ER‐MP12 antibody was 33.6 ± 8.0 in the control group and 21.1 ± 5.4 in the treated group, and the difference was significant (P < 0.0001). The AI values of the control and treated groups were 4.73 ± 1.11 and 7.26 ± 1.62, respectively, and this difference is also significant (P < 0.0001). However, the expression of VEGF mRNA in transplanted tumors did not show a significant difference between the control and treated groups. These results suggest that the antitumor effect of the VEGF Ab on human gastric carcinoma is exerted by inducing mild hypoxia followed by apoptosis, which does not influence VEGF mRNA expression in the carcinoma.

Urokinase receptor and vascular endothelial growth factor are synergistically associated with the liver metastasis of colorectal cancer

Considering recent findings that the urokinase plasniinogen activation (PA) system is involved in invasion and vascular endothelial growth factor (VEGF) is involved in angiogenesis of colorectal cancer, we evaluated these factors in the liver metastasis of primary colorectal cancer. Cancer tissues from 71 colorectal cancer patients were assayed quantitatively for antigen levels of urokinase type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor‐1 and ‐2 (PAI‐1, PAI‐2), and were also assayed immunohistochemically for expression of VEGF protein. Among the PA system factors, both the levels of uPAR and PAI‐1 were significantly higher in larger tumors than in smaller ones, and were also significantly higher in tumors that invaded subserosa, serosa or adjacent organs than in mucosal, submucosal tumors or in tumors that invaded the muscle layer. The uPAR levels were significantly higher in tumors with liver metastasis than in those without. VEGF overexpression was significantly more frequent in tumors with lymph node involvement or liver metastasis than in those without. Among the PA system factors, the uPAR levels were significantly higher in tumors with VEGF overexpression and a multivariate analysis revealed that high uPA level and VEGF overexpression were independent risk factors for liver metastasis. The combination of high uPAR level and overexpression of VEGF was associated with the worst prognosis in patients with colorectal cancer. These results suggest that uPAR and VEGF might contribute Synergistically to the liver metastasis of colorectal cancer.

Crohn's Disease of the Esophagus : Report of a Case

We report herein the case of a 27-year-old man with Crohn’s disease of the esophagus. The patient presented with large ulcers in the esophagus for which treatment based on a diagnosis of reflux esophagitis was commenced. Although his symptoms were initially resolved, the ulcers did not improve and he was readmitted to hospital 3 months later for progressive heartburn. An esophagoscopy revealed large ulcers in the esophagus, and a colonoscopy revealed a longitudinal ulcer in the terminal ileum. Histological examination of specimens from the terminal ileum showed severe inflammation without granuloma formation, which led to a diagnosis of Crohn’s disease. The oral administration of prednisolone and salazosulfapyridine controlled his symptoms and the esophageal ulcers were observed to be healing 2 weeks after this treatment was initiated. A review of the English literature revealed only 77 cases of this disease. Isolated esophageal lesions were reported in ten patients (13.0%), none of which were able to be diagnosed as Crohn’s disease preoperatively. Ileocolic lesions developed after esophageal lesions in only five patients (6.5%) including ours. In the remaining 62 patients (80.5%), ileocolic lesions had existed synchronous with or prior to the esophageal lesions. This suggests that ileocolic lesions may often coexist in Crohn’s patients with esophageal lesions, and that examination of the terminal ileum must be performed to confirm a diagnosis of Crohn’s disease of the esophagus.

Effect of miR‐122 and its target gene cationic amino acid transporter 1 on colorectal liver metastasis

Control of liver metastasis is an important issue in the treatment of colorectal cancer (CRC). MicroRNAs have been shown to be involved in the development of many cancers, but little is known about their role in the process of colorectal liver metastasis. We compared miRNA expression between primary colorectal tumors and liver metastasis to identify those involved in the process of metastasis. Cancer cells were isolated from formalin‐fixed paraffin‐embedded primary CRC samples and their corresponding metastatic liver tumors in six patients using laser capture microdissection, and miRNA expression was analyzed using TaqMan miRNA arrays. The most abundant miRNA in liver metastasis compared with primary tumors was miR‐122. Immunohistochemical analysis revealed that the expression levels of cationic amino acid transporter 1 (CAT1), a negative target gene of miR‐122, were lower in liver metastases than primary tumors (P < 0.001). Expression levels of CAT1 in 132 primary tumors were negatively correlated with the existence of synchronous liver metastasis (P = 0.0333) and tumor stage (P < 0.0001). In an analysis of 121 colon cancer patients without synchronous liver metastasis, patients with CAT1‐low colon cancer had significantly shorter liver metastasis‐free survival (P = 0.0258) but not overall survival or disease‐free survival. Overexpression of miR‐122 and concomitant suppression of CAT1 in the primary tumor appears to play important roles in the development of colorectal liver metastasis. Expression of CAT1 in the primary CRC has the potential to be a novel biomarker to predict the risk of postoperative liver metastasis of CRC patients.

Intraoperative indocyanine green fluorescence lymphography, a novel imaging technique to detect a chyle fistula after an esophagectomy: report of a case.

Intraoperative indocyanine green (ICG) lymphography was performed on a 62-year-old man, who was diagnosed to have chylothorax after an esophagectomy for esophageal cancer. After exploration of the thorax, a slowly increasing effusion was identified in the mediastinal space above the diaphragm, but the exact site of the lymph fistula could not be identified. By injecting 1.5 ml of ICG subcutaneously at the bilateral inguinal region, fluorescence images of the lymph flow in the thoracic cavity were obtained using a near-infrared camera system. The detected leakage point was sutured and the chyle ooze stopped. The postoperative course was uneventful. The patient was discharged on the 16th postoperative day. This is the first report using ICG fluorescence lymphography for the successful intraoperative detection of the exact site of a fistula causing chylothorax.