Lung neoplasm, in place of gastric cancer, is the major cause of cancer mortality in Japan as well as in the USA (Travis et al, 1995). Despite the advances in diagnostic techniques for the early detection of lung cancer and the significant improvement in surgical procedures, the survival rate of lung cancer patients is poor even in the early stages of cancer as compared to the other malignant neoplasms. From a clinical point of view, one of the most troublesome impediments for treatment of lung cancer is the metastasis to mediastinal lymph nodes (n = 2 and n = 3 lung cancer) from the primary lesion (Jefferson et al, 1996). If metastases were inhibited by the present and/or new therapies, the prognosis of patients with lung cancer would improve. According to new TNM revisions (Mountain, 1997), it is difficult to say if the 5-year survival rate of n ³ 2 in lung cancer patients is an improvement, although a standard operative technique has been established to resect mediastinal lymph nodes (Vansteenkiste et al, 1997), except for aortic lymph node metastasis (Nakanishi et al, 1997). Therefore, biological approaches and studies, such as interference with lymph node metastasis or management of downstaging to the patients with lymph node metastasis, combined with surgery are required for lung cancer therapy. To do this, suitable animal models that conform to the clinical features are also necessary to search for novel therapies of lung cancer and to evaluate the efficacy of new drugs. However, there are few models for the formation of a solitary pulmonary nodule by orthotopic implantation of lung cancer cells and subsequent lymph node metastasis. In the present study, we attempted to establish a simple model for a solitary lung tumour and its lymph node metastasis by intrapulmonary implantation of Lewis lung carcinoma (LLC) cells in mice. MATERIAL AND METHODS AnimalsSpecific pathogen-free female C57BL/6 mice at 6 weeks old, were purchased from Japan SLC, Inc, Hamamatsu, Japan. They were maintained in the Laboratory for Animal Experiments, Research Institute for Wakan-Yaku Toyama Medical and Pharmaceutical University, under laminar air-flow conditions. All animals had free access to standard laboratory mouse food and water ad libitum. Housing was temperature controlled with a 12-h light and dark cycle. This study was conducted in accordance with the standards established by the Guidelines for the Care and Use of Laboratory Animals of Toyama Medical and Pharmaceutical University. Summary This study is designed to establish a pulmonary tumour model to investigate the biology and therapy of lung cancer in mice. Current methods for forming a solitary intrapulmonary nodule and subsequent metastasis to mediastinal lymph nodes are not well defined. Lewis lung carcinoma (LLC) cell suspensions were orthotopically introduced into the lung parenchyma of C57/BL6 mice via a limited skin incision without thoracotomy followed by direct puncture through the intercostal space. The implantation process was performed within approximately ...

To develop new therapy strategies for lung cancer, we established an animal model, which reflects the clinical features of mediastinal lymph node metastasis of lung cancer. This study was designed to determine whether CCL21 induced biological functions associated with the metastasis of highly lymph node metastatic human non-small cell lung cancer (NSCLC) selected by our model. Orthotopic intrapulmonary implantation of human NSCLC (Lu-99 and A549) was performed to analyze the metastatic characteristics of these cells. The expression of CCR7, which is a receptor of CCL21, was detected using CCL19 [also called EBI1-ligand chemokine (ELC)]-Fc chimera by flow cytometric analysis. The effects of CCL21 on the migration, adhesion and growth of human NSCLC were investigated. After orthotopic implantation of human NSCLC cell lines, Lu-99, but not A549, metastasized to mediastinal lymph nodes, forming large size nodules, and expressed CCR7 on the surface. Accordingly, its ligand CCL21 induced chemotactic migration and α4ß1-mediated adhesion to VCAM-1 of Lu-99. The expression of CCR7 and vigorous responses to its ligand CCL21 potentially account for lymph node metastasis of a human NSCLC line Lu-99.

Preoperative use of hypnotic medication, the thoracotomy approach, and duration of surgery ≥2.5 hours are associated with increased risk of neuropathic pain after thoracic surgery. The complete VATS approach could decrease the incidence of postoperative neuropathic pain, regardless of the duration of surgery.

Activation of numerous pathways has been documented in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) has emerged as a common therapeutic target. The mitogen-activated protein kinase (MAPK) and AKT signaling pathways are downstream of EGFR and deregulated via genetic and epigenetic mechanisms in many human cancers. We evaluated selected markers in the EGFR pathway with reference to outcome. Tissues from 220 cases of NSCLC patients presented in a tissue microarray were assayed with immunohistochemistry for phosphorylated AKT, phosphorylated MAPK, phosphorylated mTOR, and EGFR and then quantified by automated image analysis. Individually, the biomarkers did not predict. Combined as ratios, p-mTOR/p-AKT, and p-MAPK/EGFR function as prognostic markers of survival (p=0.008 and p=0.029, respectively), however, no significance was found after adjustment (p=0.221, p=0.103). The sum of these ratios demonstrates a stronger correlation with survival (p<0.001) and remained statistically significant after adjustment (p=0.026). The algebraic combination of biomarkers offer the capacity to understand factors that predict outcome better than current approaches of evaluating biomarkers individually or in pairs. Our results show the sum of p-mTOR/p-AKT and p-MAPK/EGFR is a potential predictive marker of survival in NSCLC patients.