Toshiki Kawabata

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.

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.

Robot-assisted surgery for gastric cancer: experience at our institute.

Objective: The robot-assisted surgical system was developed for minimally invasive surgery and is thought to have the potential to overcome the shortcomings of laparoscopic surgery. We introduced this system for the treatment of gastric cancer in 2008. Here we report our initial experiences of robot-assisted surgery using the da Vinci system. Methods: A retrospective review of robot-assisted gastrectomy for gastric cancer patients was performed in our institute. The clinicopathological features and surgical outcomes were analyzed. Whereas the procedures of the gastrectomy were similar to those of the usual laparoscopic surgery, several aspects such as the port placement and the role of the assistant were modified from those for conventional laparoscopic surgery. Results: From January 2008 to December 2010, 61 patients with gastric cancer underwent robot-assisted surgery. Gastrectomy was distal in 46 patients, total in 14, proximal in 1 and no operation was converted to the open procedure. D2 lymph node dissection was performed on 28 patients in the distal gastrectomy group and on 11 in the total gastrectomy group. Complications occurred in 2 cases (4%): these consisted of ruptured sutures and hemorrhage from the anastomotic site. Conclusions: This study demonstrated that robot-assisted gastrectomy using the da Vinci system can be applied safely and effectively for patients with gastric cancer.

Immunohistochemical and genetic features of gastric and metastatic liver gastrointestinal stromal tumors: Sequential analyses

Metastatic gastrointestinal stromal tumors (GIST) have an extremely poor prognosis; however, their immunohistochemical and genetic features have not been assessed satisfactorily and the mechanisms responsible for their high malignant potential remain unclear. We examined the immunohistochemical differences between gastric GIST and metastatic lesions in the liver of four patients who had undergone a postgastrectomy hepatectomy for metachronous liver metastases. We also carried out genetic analysis of the tumors in three of the four cases. In all cases, the immunoreactivity profiles, including KIT (CD117), CD34, smooth muscle actin (SMA), desmin, S‐100 and vimentin, were similar between the gastric and metastatic tumors, but the Ki67 labeling index in the metastatic GIST was higher than that of the primary GIST. Interestingly, in the case who had received neoadjuvant imatinib therapy before gastrectomy, its therapeutic effect was observed in most of the primary lesion, with the exception of a specific small area with high cellularity. Genetic analysis revealed no acquired mutations in the c‐kit or PDGFRA genes in the metastatic lesions in any of the patients, but loss of heterozygosity (LOH) of the c‐kit gene was observed mainly in the metastatic tumors in two of the three cases. Furthermore, in the case of neoadjuvant imatinib therapy, LOH of the c‐kit gene was shown in the high cellularity area in the primary lesion and metastatic liver GIST. It is suggested that LOH of the c‐kit gene is an important event that leads to imatinib resistance and metastatic progression of GIST. In conclusion, both gastric and metastatic GIST had almost the same immunohistochemical features, except for their proliferative activity, and LOH of the c‐kit gene played an important role in the process of liver metastasis. (Cancer Sci 2006; 97: 127 – 132)

TSU68, an antiangiogenic receptor tyrosine kinase inhibitor, induces tumor vascular normalization in a human cancer xenograft nude mouse model

PurposeCombination therapy using antiangiogenic and cytotoxic agents is a useful strategy for advanced cancer, but the mechanism has not yet been elucidated. Moreover, there is a persistent paradox that destroying tumor vasculature with antiangiogenic agents disturbs the delivery of cytotoxic agents. It has been hypothesized that antiangiogenic agents can lead to normalization of tumor vessels that are structurally and functionally abnormal. The normalization means enhancing the deliver of cytotoxic agents. Our purpose was to investigate whether TSU68, a multiple receptor tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), would induce the normalization of tumor vessels.MethodsTSU68 was administered for 7 days to mice with xenografted tumors. Tumors of interstitial fluid pressure (IFP) were measured before and after administration of agents. Immunofluorescence double staining for CD31 and α-SMA was performed, and a medical video endoscopy system with narrowband illumination (NBI) was used to visualize the vascular pattern.ResultsTSU68 treatment decreased IFP significantly. Immunofluorescence double staining showed a significant increase in the fraction of pericyte coverage in the TSU68-treated group. NBI endoscopy showed that many tumor vessels in TSU68-treated mice were pruned and the diameters of remaining vessels were reduced.ConclusionThe data supported our hypothesis of tumor vascular normalization by the antiangiogenic agent TSU68.

Periodic measurement of serum carcinoembryonic antigen and carbohydrate antigen 15-3 levels as postoperative surveillance after breast cancer surgery.

PurposeBreast cancer surveillance guidelines do not recommend routine tumor marker testing after surgery, despite which it is still widely performed in Japan. We investigated the clinical utility of postoperative tumor marker testing in a series of Japanese patients, in view of the fact that all the studies to date have been non-Japanese.MethodsWe retrospectively analyzed the lead time by periodic measurements of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA15-3) in 233 patients who underwent breast cancer surgery. Both tumor marker levels were measured every 3 months for the first 5 years, every 6 months for the next 5 years, then annually. Physical examination and chest X-ray were routinely done at the same time, and bone or computed tomographic scans were done if the tumor marker levels were elevated or clinical symptoms appeared.ResultsIn patients with recurrent disease, the mean lead times were −333.9 days for CEA and −210.6 days for CA15-3, respectively. Elevated tumor marker levels were found much later than recurrence.ConclusionOur results support the American Society of Clinical Oncology guidelines. Thus, the serial testing of tumor marker levels after breast cancer surgery may not be as beneficial as thought in Japan.

Long-term survival after report resection of pulmonary metastases from hepatocellular carcinoma: report of two cases.

Hepatocellular carcinoma (HCC) is often treated most effectively by resection. Although improved surgical procedures and perioperative care have made hepatic resection safe, the prognosis of patients with HCC is still poor because of the high incidence of postoperative recurrence. The most common site of extrahepatic recurrence is the lung. However, because of its multiplicity and concurrent recurrence in the liver remnant, resection of pulmonary metastases form HCC is rarely beneficial. We report two cases of long-term survival after repeated pulmonary resection of metastasis from HCC. At the time of this report the two patients were free of disease, 110 months and 107 months, respectively, after their initial hepatectomy. These case reports show that pulmonary metastases from HCC can be successfully resected in selected patients.

Pancreatoduodenal artery aneurysm resulting from median arcuate ligament compression successfully treated with laparoscopic ligament section

True aneurysms of the pancreatoduodenal arteries are frequently associated with stenosis or occlusion of the celiac trunk caused by median arcuate ligament compression. Celiac stenosis cannot be cured, even by transarterial embolization, which has recently become a good alternative to open surgical repair. To prevent recurrence, management of median arcuate ligament compression to correct hemodynamics in vascular networks should also be performed. Herein we report a case of pancreatoduodenal arterial aneurysm with median arcuate ligament compression that was successfully treated with minimally invasive laparoscopic median arcuate ligament section. The patient was discharged 4 days after surgery with no complications. Enhanced CT 1 month after surgery revealed no residual celiac trunk stenosis or aneurysm. Normalization of blood flow by laparoscopic median arcuate ligament section is a good option for some patients with a pancreatoduodenal arterial aneurysm.

Tenascin C in colorectal cancer stroma is a predictive marker for liver metastasis and is a potent target of miR-198 as identified by microRNA analysis

Background:Tumour stroma has important roles in the development of colorectal cancer (CRC) metastasis. We aimed to clarify the roles of microRNAs (miRNAs) and their target genes in CRC stroma in the development of liver metastasis.Methods:Tumour stroma was isolated from formalin-fixed, paraffin-embedded tissues of primary CRCs with or without liver metastasis by laser capture microdissection, and miRNA expression was analysed using TaqMan miRNA arrays.Results:Hierarchical clustering classified 16 CRCs into two groups according to the existence of synchronous liver metastasis. Combinatory target prediction identified tenascin C as a predicted target of miR-198, one of the top 10 miRNAs downregulated in tumour stroma of CRCs with synchronous liver metastasis. Immunohistochemical analysis of tenascin C in 139 primary CRCs revealed that a high staining intensity was correlated with synchronous liver metastasis (P<0.001). Univariate and multivariate analyses revealed that the tenascin C staining intensity was an independent prognostic factor to predict postoperative overall survival (P=0.005; n=139) and liver metastasis-free survival (P=0.001; n=128).Conclusions:Alterations of miRNAs in CRC stroma appear to form a metastasis-permissive environment that can elevate tenascin C to promote liver metastasis. Tenascin C in primary CRC stroma has the potential to be a novel biomarker to predict postoperative prognosis.

Gastroenterological surgery: esophagus.

1-1 Which stages of thoracic esophageal cancer are indicated for thoracoscopic surgery? In many facilities, thoracoscopic surgery is indicated for cStages I, II, and III, except cT4, according to the TNM Classification of Malignant Tumours, seventh edition, or cStages I–IVa, except cT4, according to the Japanese Classification of Esophageal Cancer, 10th edition, edited by the Japan Esophageal Society.