Keisuke Eguchi

c-MET Expression in Myofibroblasts: Role in Autocrine Activation and Prognostic Significance in Lung Adenocarcinoma

Hepatocyte growth factor (HGF) plays important roles in tumor development and progression. It is currently thought that the main action of HGF is of a paracrine nature: HGF produced by mesenchymal cells acts on epithelial cells that express its receptor c-MET. In this investigation, we explored the significance of c-MET expression in myofibroblasts, both in culture and in patients with lung adenocarcinoma. We first showed that human myofibroblasts derived from primary lung cancer expressed c-MET mRNA and protein by reverse transcription-polymerase chain reaction and Western blot analysis. Proliferation of myofibroblasts was stimulated in a dose-dependent manner by exogenously added recombinant human HGF whereas it was inhibited in a dose-dependent manner by neutralizing antibody to HGF. The addition of HGF in the culture medium stimulated tyrosine phosphorylation of c-MET. The c-MET protein was immunohistochemically detected in myofibroblasts in the invasive area of lung adenocarcinoma. Finally, the prognostic significance of c-MET expression in stromal myofibroblasts was explored in patients with small-sized lung adenocarcinomas. c-MET-positive myofibroblasts were observed in 69 of 131 cases (53%). A significant relationship between myofibroblast c-MET expression and shortened patient survival was observed in a whole cohort of patients including all pathological stages (two-sided P: = 0.0089 by log-rank test) and in patients with stage IA disease (two-sided P: = 0.0019 by log-rank test). These data suggest that the HGF/c-MET system constitutes an autocrine activation loop in cancer-stromal myofibroblasts. This autocrine system may play a role in invasion and metastasis of lung adenocarcinoma.

DNA hypermethylation at the D17S5 locus is associated with gastric carcinogenesis

The aim of this study was to elucidate the significance of aberrant DNA methylation in gastric carcinogenesis. The DNA methylation status at the D17S5 locus, at which a candidate tumor suppressor gene, HIC-1, was identified, of gastric cancers and non-cancerous gastric mucosae from 42 gastric cancer patients was examined by Southern blotting using a methylation-sensitive restriction enzyme. DNA hypermethylation was observed in 15, 13, 25 and 45% of the tissues showing no remarkable histological findings, chronic gastritis without intestinal metaplasia, intestinal metaplasia and gastric cancer, respectively. The incidence of DNA hypermethylation was significantly higher in gastric cancers than in non-cancerous gastric mucosae (P < 0.05). DNA hypermethylation was often accompanied by allelic loss at the same locus in gastric cancers. DNA hypermethylation at the D17S5 locus, which was even detected in precancerous conditions, including intestinal metaplasia, may play a role in gastric carcinogenesis.

An alternative method for screening EGFR mutation using RFLP in non-small cell lung cancer patients

Introduction: Epidermal growth factor receptor (EGFR) mutations are strong determinants of tumor response to EGFR tyrosine kinase inhibitors in non-small cell lung cancers (NSCLCs). Currently available methods of EGFR mutation detection rely on direct sequencing. Here, we describe the use of an alternative way to screen EGFR mutations. Methods: A total of 109 frozen tumor specimens from NSCLC patients were obtained. For mutational analysis of EGFR exons 18, 19, and 21, reverse transcription-polymerase chain reaction was performed on the cDNA using original primers designed for restriction fragment length polymorphism (RFLP). Results: EGFR mutations were detected in 37 patients (34%) by both RFLP and direct sequencing except one case in which it was detected only by RFLP. EGFR mutations were more frequently observed to be significant by multivariate analysis in patients with adenocarcinoma (OR = 5.56), no-smoking history (OR = 4.34), and 65-year-old or younger (OR = 2.64), but not in women (OR = 1.14). Among 37 patients, 18 were treated with gefitinib and 9 responded to the treatment. One patient without any mutation responded. Conclusion: RFLP is a useful method for screening EGFR mutations and can also be applied to predicting the sensitivity of NSCLC patients to EGFR-tyrosine kinase inhibitors.

Enhanced therapeutic efficacy of oncolytic herpes vector G207 against human non-small cell lung cancer—expression of an RNA-binding protein, Musashi1, as a marker for the tailored gene therapy

Oncolytic herpes vectors like G207 have shown considerable promise in the treatment of solid tumors, but their potency must be enhanced for the full achievement of therapeutic efficacy. Deletion of the innate γ34.5 gene made these vectors extremely safe, but their efficacy was also severely attenuated. Use of tumor‐specific promoters is one method to direct toxicity and enhance efficacy against tumors. Recently, Musashi1 has been shown expressed in some tumor tissues.

Pulmonary hilar lymph nodes in lung cancer: assessment with 3D-dynamic contrast-enhanced MR imaging.

PURPOSE We performed 3D-dynamic MRI on patients with primary lung cancer to identify its usefulness for detecting hilar adenopathy shown at surgery. METHODS AND MATERIALS 30 consecutive patients with peripheral lung cancer underwent preoperative 3D-dynamic Gd-DTPA-enhanced MRI. Two thoracic radiologists blinded to histopathologic findings reviewed those studies independently for hilar adenopathy visualization. The results were correlated with surgical and histopathologic findings. Interreader agreement for the detection of hilar adenopathy was assessed by means of the kappa statistic. RESULTS Dynamic MRI demonstrated hilar adenopathy, with or without metastasis revealed at surgery, in all of 15 patients. Adenopathy without metastasis was shown in four patients. Dynamic MRI also revealed metastatic adenopathy in 11 of 12 patients with pathologically proven metastasis. There was only one case with lymph node metastasis that did not have adenopathy either on MRI or even at surgery. The diagnostic accuracy of dynamic MRI for adenopathy with or without metastases revealed at surgery were as follows; sensitivity, 100%; specificity, 100%; positive predictive value, 100%; and negative predictive value, 100%, respectively. The diagnostic accuracy of dynamic MRI for hilar lymph nodes metastasis were as follows; sensitivity, 92%; specificity, 78%; positive predictive value, 73%; and negative predictive value, 93%. Interreader agreement was substantial (kappa=0.73) for detection of hilar adenopathy. CONCLUSION Hilar adenopathy on 3D-dynamic MRI correlated well with that of surgical finding on patients with primary lung cancer. It may have the potential to make an accurate preoperative evaluation of hilar lymph node metastasis from lung cancer.

Restenosis of superior vena cava after treatment using a self-expanding metallic stent in a patient with idiopathic fibrosing mediastinitis

The use of a self-expanding metallic stent (SEMS) for the treatment of superior vena cava (SVC) syndrome arising from non-neoplastic mediastinal disease is controversial, and data on long-term clinical observations for such have not yet been accumulated. We report a case of fibrosing mediastinitis with an obstruction of the SVC 30 months after the insertion of an SEMS. The patient had a headache and temporal facial swelling when the obstruction occurred, but these symptoms disappeared within 1 month. No further treatment was required in this case.

Surface Layer-Preserving Photodynamic Therapy (SPPDT) in a Subcutaneous Mouse Model of Lung Cancer

Photodynamic therapy (PDT) may be a less invasive treatment for lung cancer. Our newly developed surface layer‐preserving PDT (SPPDT) technique enables us to irradiate deep tumor while preserving the overlying tissue. The aim of this basic study was to verify that the SPPDT technique might be applied to lung cancer.