Kozo Kuribayashi

Circulating Tumor Cell as a Diagnostic Marker in Primary Lung Cancer

Purpose: To investigate the diagnostic performance of circulating tumor cells (CTC) in discrimination between primary lung cancer and nonmalignant diseases as well as in prediction of distant metastasis. Patients and Methods: We prospectively evaluated CTCs in 7.5-mL samples of peripheral blood sampled from patients with a suspicion or a diagnosis of primary lung cancer. A semiautomated system was used to capture CTCs with an antibody against epithelial cell adhesion molecule. Results: Of 150 eligible patients, 25 were finally diagnosed as having nonmalignant disease, and 125 were diagnosed as having primary lung cancer with (n = 31) or without (n = 94) distant metastasis. CTCs were detected in 30.6 of lung cancer patients and in 12.0 of nonmalignant patients. CTC count was significantly higher in lung cancer patients than in nonmalignant patients, but a receiver operating characteristic (ROC) curve analysis showed an insufficient capability of the CTC test in discrimination between lung cancer and nonmalignant diseases with an area under ROC curve of 0.598 (95 confidence interval, 0.488-0.708; P = 0.122). Among lung cancer patients, CTC count significantly increased along with tumor progression, especially with development of distant metastasis. The area under ROC curve for CTC count in prediction of distant metastasis was 0.783 (95 confidence interval, 0.679-0.886; P < 0.001). When patients with one or more CTCs were judged as having metastatic disease, sensitivity and specificity of the CTC test were 71.0 and 83.0, respectively. Conclusions: CTC is a useful surrogate marker of distant metastasis in primary lung cancer. (Clin Cancer Res 2009;15(22):69806)

IL-18 deficiency selectively enhances allergen-induced eosinophilia in mice

BACKGROUND T(H2) cytokines are associated with airway inflammation and hyperreactivity in bronchial asthma, and restoration of the T(H1)/T(H2) imbalance is a potential avenue for novel therapies. IL-18 is a cytokine secreted by activated macrophages, and it shares some of its biologic activities with IL-12, a typical T(H1)-type cytokine. Although IL-18 and IL-12 act on T cells synergistically to induce IFN-gamma production, the contribution of IL-18 T(H1)/T(H2) imbalance and to subsequent asthmatic response has not been elucidated in vivo. OBJECTIVE We studied a model of allergic asthma in IL-18-deficient mice to investigate the modulatory role of IL-18 on induction and maintenance of T(H2) mucosal immunity. We also have investigated the ability of intraperitoneal instilled IL-18 to reduce T(H2) mucosal immunity in IL-18-deficient mice. METHODS IL-18-deficient mice immunized to ovalbumin by means of intraperitoneal injection were challenged 3 times with an aerosol of ovalbumin every second day for 8 days. Recombinant (r)IL-18 was intraperitoneally administered in mice before every first challenge. Mice were analyzed for effects on lung eosinophilia, cytokines, and serum IgE levels. RESULTS In IL-18-deficient mice, levels of eosinophilia and lung damage were significantly higher than in wild-type C57/BL6 litter mates. Intraperitoneal administration of rIL-18 in deficient mice reduced these antigen-induced changes to levels seen in wild-type mice in association with a decrease in IL-4 in bronchoalveolar lavage fluid and lung tissue. However, administration of rIL-18 did not affect the IFN-gamma level and somewhat enhanced the production of IL-5. Notably, reconstitution with rIL-18 increased the numbers of cells staining for Fas ligand, as well as apoptotic cells stained by nick end-labeling in bronchial submucosa infiltrates. CONCLUSION These findings indicate that in vivo IL-18 not only inhibited antigen-specific T(H2) development but also affected apoptosis through Fas-Fas ligand interactions. These data support a role for IL-18 in the complex pathogenesis of allergic inflammation in which IL-18 limited the development of the local inflammatory response to antigen.

Clinical Significance of Serum Vascular Endothelial Growth Factor in Malignant Pleural Mesothelioma

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM has a limited response to conventional chemotherapy and radiotherapy so diagnosing MPM early is very important. Vascular endothelial growth factor (VEGF) is an autocrine growth factor for MPM. Here, we investigated the serum levels of VEGF in patients with MPM in comparison with a population that had been exposed to asbestos without developing MPM. Methods: Serum concentrations of VEGF were measured in 51 patients with MPM and 42 individuals with benign asbestos-related diseases (asbestosis or pleural plaques) or who were healthy despite asbestos exposure. Results: We demonstrated that patients with MPM had significantly higher serum levels of VEGF than a population who had been exposed to asbestos but had not developed MPM, and the patients with advanced stage MPM showed higher levels of VEGF than the early stage patients with MPM. The difference in overall survival between the groups with VEGF serum levels lower and higher than the assumed cutoff of 460 pg/ml was significant. Conclusions: Our data suggest that the VEGF serum concentration could be a useful marker for screening MPM among asbestos-exposed individuals and as a prognostic factor.

Pleural effusion VEGF levels as a prognostic factor of malignant pleural mesothelioma

BACKGROUND Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM has a limited response to conventional chemotherapy and radiotherapy so early diagnosis of MPM is very important. Vascular endothelial growth factor (VEGF), a potent mitogen for the vascular endothelium, is also known to be an autocrine growth factor for MPM. Here, we investigated the pleural effusion VEGF levels in patients with MPM and compared them to those of a population with a non-malignant pleuritis or lung cancer involving malignant pleural effusion. METHODS The pleural effusion VEGF concentrations were measured in 46 MPM patients and 45 individuals with non-MPM individuals (25 individuals with non-malignant pleural effusions, and 20 individuals with lung cancer involving malignant pleural effusion). RESULTS We demonstrated that patients with MPM had significantly higher pleural effusion VEGF levels than a population with non-malignant pleuritis or lung cancer involving malignant pleural effusion, and the patients with advanced stage MPM showed higher levels of VEGF than the early stage MPM patients. The difference in overall survival between the groups with pleural effusion VEGF levels lower and higher than the assumed cut-off of 2000pg/ml was significant. CONCLUSIONS Our data suggest that the pleural effusion VEGF concentration could be useful as an aid for the diagnosis of MPM and as a prognostic factor.

Expression of the T Cell Receptor Vβ Repertoire in a Human T Cell Resistant to Asbestos-Induced Apoptosis and Peripheral Blood T Cells from Patients with Silica and Asbestos-Related Diseases

To explore the effects of asbestos and silica on the human immune system, an experimental model of low-dose and long-term exposure was established using a human HTLV-1-immortalized polyclonal T cell line, MT-2 (MT-2Org). MT-2 cells were continuously exposed to asbestos at a concentration (10 μg/ml) which does not induce complete cell death during short-term exposure. After acquiring resistance to CB-induced apoptosis (designated MT-2Rst), an immunological comparison was made between the MT-2Org and MT-2Rst lines in terms of T cell receptor-Vβ (TcR-Vβ) expression. MT-2Rst cells showed excess expression of various TcR-Vβ, although TcR-Vβ-overpresenting cells were characterized as undergoing apoptosis due to first contact with CB. Patients with asbestos-related diseases (ARD), such as asbestosis and malignant mesothelioma, were compared with silicosis (SIL) patients as a disease control and with healthy donors (HD). SIL and ARD not only differed in their causative materials, silica and asbestos as mineral silicates, but also in terms of complications; autoimmune disorders in SIL and tumors in ARD. ARD patients showed a restricted overpresentation of TcR-Vβ without clonal expansion, whereas SIL patients revealed significant overpresentation of TcR-Vβ 7.2. These experimental and clinical analyses indicate the superantigenic and dysregulation of autoimmunity-inducing effects of asbestos and silica, respectively.

All-trans-retinoic acid inhibits tumour growth of malignant pleural mesothelioma in mice

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour of mesothelial origin associated with asbestos exposure. Because MPM has limited response to conventional chemotherapy and radiotherapy, the prognosis is very poor. Several researchers have reported that cytokines such as interleukin (IL)-6 play an important role in the growth of MPM. Previously, it was reported that all-trans-retinoic acid (ATRA) inhibited the production and function of IL-6 and transforming growth factor (TGF)-β1 in experiments using lung fibroblasts. We investigated whether ATRA had an inhibitory effect on the cell growth of MPM, the origin of which was mesenchymal cells similar to lung fibroblasts, using a subcutaneous xenograft mouse model. We estimated the tumour growth and performed quantitative measurements of IL-6, TGF-β1 and platelet-derived growth factor (PDGF) receptor (PDGFR)-β mRNA levels both of cultured MPM cells and cells grown in mice with or without the administration of ATRA. ATRA significantly inhibited MPM tumour growth. In vitro studies disclosed that the administration of ATRA reduced 1) mRNA levels of TGF-β1, TGF-β1 receptors and PDGFR-β, and 2) TGF-β1-dependent proliferation and PDGF-BB-dependent migration of MPM cells. These data may provide a rationale to explore the clinical use of ATRA for the treatment of MPM.

The 150-Kilodalton Oxygen-Regulated Protein Ameliorates Lipopolysaccharide-Induced Acute Lung Injury in Mice

The 150-kd oxygen-regulated protein is a novel stress protein that is located in the endoplasmic reticulum and contributes to cell survival when this organelle is under stress. Expression of this protein was strongly increased in alveolar macrophages and alveolar epithelial cells from mice with acute lung injury induced by lipopolysaccharide. Transgenic mice overexpressing the 150-kd protein showed decreased histological severity of this lung injury, accompanied by lower total protein concentrations, and lactate dehydrogenase activity in bronchoalveolar lavage fluid. As indicated by nick end-labeling, lipopolysaccharide induced apoptosis in fewer alveolar wall cells in transgenic than in wild-type mice. Transgenic mice also showed increased survival after lipopolysaccharide injection (a log-rank test). Thus, the 150-kd protein, an endoplasmic reticulum-related molecular chaperone, is pivotal in resisting acute lung injury from lipopolysaccharide.

Chemotherapy for advanced non-small cell lung cancer with a focus on squamous cell carcinoma

Lung cancers are broadly divided into small-cell lung cancer (SCLC) and non-SCLC (NSCLC), and the treatments for each differ. NSCLC includes squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and others. However, because there is little difference in treatment efficacy between these histological types, they have collectively been treated as a single entity. Cytotoxic anti-cancer agents, mainly platinum-based drugs, are the first-line treatment for unresectable advanced NSCLC, and the standard therapy is combination chemotherapy with two drugs, usually involving one platinum-based and one unrelated cytotoxic drug. Such regimens have been used for all the different histological types. In recent years, however, genetic abnormalities in NSCLCs known as driver mutations have been identified. These include epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocations, which are responsible for both carcinogenesis and cancer growth and survival. The advent of molecular targeted therapies that target these mutations has clearly improved the prognosis for NSCLC. However, effective molecular targeted drugs or novel anti-cancer agents that greatly prolong survival have not yet been developed to treat squamous cell carcinoma or 30% of adenocarcinomas. For patients with these types of cancers, it is important to use existing cytotoxic anti-cancer agents appropriately in their treatment. In this paper, we review the treatment options for unresectable advanced NSCLC on the basis of recent findings, with a particular focus on squamous cell carcinoma, for which groundbreaking drugs have yet to be discovered.

Heme Oxygenase-1 Promoter Polymorphism is Associated with Risk of Malignant Mesothelioma

BackgroundMalignant mesothelioma is an aggressive tumor of serosal surfaces that is closely associated with asbestos exposure which induces oxidative stress. Heme oxygenase (HO)-1, a rate-limiting enzyme of heme degradation, plays a protective role against oxidative stress. The HO-1 gene promoter carries (GT)n repeats whose number is inversely related to transcriptional activity of the HO-1 gene.MethodsTo investigate the relationship between the length polymorphism of (GT)n repeats and mesothelioma susceptibility, we analyzed the HO-1 promoter in 44 asbestos-exposed subjects without mesothelioma and 78 asbestos-exposed subjects with mesothelioma using PCR-based genotyping.ResultsThe number of repeats ranged from 16 to 38, with two peaks at 23 and 30 repeats. Polymorphisms of (GT)n repeats were grouped into two classes of alleles, short (S) (<24) and long (L) (≥24), and three genotypes: L/L, L/S, and S/S. The proportions of allele frequencies in class L as well as genotypic frequencies of L allele carriers (L/L and L/S) were significantly higher in the asbestos-exposed subjects with mesothelioma than in those without mesothelioma.ConclusionThe findings of this study suggest that long (GT)n repeats in the HO-1 gene promoter are associated with a higher risk of malignant mesothelioma in the Japanese population.

Present and future roles of FDG-PET/CT imaging in the management of lung cancer

Integrated positron emission tomography/computed tomography (PET/CT) using 2-[18F]fluoro-2-deoxy-d-glucose (18F-FDG) has emerged as a powerful tool for combined metabolic and anatomic evaluation in clinical oncologic imaging. This review discusses the utility of 18F-FDG PET/CT as a tool for managing patients with lung cancer. We discuss different patient management stages, including diagnosis, initial staging, therapy planning, early treatment response assessment, re-staging, and prognosis.