Tokujiro Yano

Prognostic significance of intratumoral blood vessel invasion in pathologic stage IA non-small cell lung cancer.

BACKGROUND The 5-year survival rate of pathologic stage IA non-small cell lung cancer (NSCLC) is excellent; however, up to 10% of patients with pathologic stage IA NSCLC still relapse postoperatively and die. This study retrospectively analyzed the clinicopathologic features of patients with pathologic stage IA NSCLC to identify the prognostic factors and investigate the effect of a combination of intratumoral vessel invasion and tumor size. METHODS From December 1991 to December 2003, 217 consecutive patients with stage IA NSCLC were selected, and disease-free survival (DFS) was analyzed. RESULTS Intratumoral blood vessel invasion (BVI) was identified as an independent poor prognostic factor (p = 0.0006). The relative risk for patients with BVI was 4.599 times higher than that for patients without BVI (95% confidence interval, 1.913 to 11.056). According to the new T N M system, the difference in DFS between the patients with and without BVI was statistically significant, not only in tumors exceeding 2 cm (T1b with BVI vs T1b without BVI, p = 0.0020) but also in tumors smaller than 2 cm (T1a with BVI vs T1a without BVI, p < 0.0001). The survival curve of T1b patients without BVI was similar to that of T1a patients without BVI (p = 0.0892). Distant recurrence was frequently observed in both T1a and T1b patients with BVI. CONCLUSIONS BVI is an independent poor prognostic factor in patients with pathologic stage IA NSCLC. These T1a and T1b patients with BVI both might benefit from adjuvant chemotherapy.

Significance of the urinary 8-OHdG level as an oxidative stress marker in lung cancer patients

OBJECTIVE In the present study, we investigated the relationship between the urinary excretion rate of the oxidized nucleoside 8-hydroxydeoxyguanosine (8-OHdG) and clinical factors in lung cancer patients. METHODS The present study included 100 patients, who underwent a lung surgery. The patients included 62 men and 38 women with a mean age of 65.5 years ranging from 35 to 82. The diagnosis included 81 primary lung cancers, 9 metastatic lung cancers and 10 benign lung diseases. Urine samples collected for 24h were analyzed for the content of 8-OHdG using an ELISA assay. RESULTS The urinary excretion rate of 8-OHdG in smokers was significantly higher than that in never-smokers. Specifically, the 8-OHdG excretion rate of current smokers was higher than that of patients who had quit smoking for longer than 1 month. Excluding current smokers, the urinary excretion rate of 8-OHdG did not relate to age or gender, but to the malignant potential of the disease. The urinary 8-OHdG level increased in the order of metastatic lung cancer, primary lung cancer and benign disease. In lung cancer patients, furthermore, the mean urinary 8-OHdG level of patients with stages II-IV disease was significantly lower than that of patients with stage I disease. CONCLUSIONS Smoking significantly increased the urinary excretion rate of 8-OHdG, suggesting that smoking causes an increased rate of oxidative DNA modifications. On the other hand, the capacity to repair oxidative DNA modifications might be impaired to some extent in cancer patients.

Current status of pulmonary metastasectomy from primary epithelial tumors

The resection of pulmonary metastases can prolong the survival of selected patients and its therapeutic value is now accepted. The criteria for eligibility have also evolved. We reviewed the recent literature on pulmonary metastasectomy for various epithelial primary tumors and tried to establish better prognostic indicators for its surgical application. In addition to the welldefined requisites for pulmonary metastasectomy, other requirements include the absence of mediastinal lymph node involvement, a limited number of pulmonary metastatic lesions, a long disease-free interval, small metastasis, and no elevation of tumor markers, although the clinical importance of each factor varies among the primary tumors. On the other hand, with the development of video-assisted thoracoscopic surgery (VATS) and advances in thoracic imaging technology, VATS metastasectomy might become an accepted treatment for metastatic nodules located in the periphery of the lung, which can be easily removed by a wedge resection. Repeat surgery is also possible during follow-up after VATS.

Benzo[a]pyrene promotes proliferation of human lung cancer cells by accelerating the epidermal growth factor receptor signaling pathway

Smoking is an independent prognostic factor of lung adenocarcinoma. Benzo[a]pyrene (B[a]P) is one of the strongest carcinogens and it is present in both the environment and cigarette smoke. In this study, the effect of B[a]P on the proliferative activity of lung adenocarcinoma cells was investigated. A lung adenocarcinoma cell line, A549, was cultured with B[a]P for various periods, and its proliferative activity was examined by an MTS assay. To investigate the intracellular events related to the proliferative activity, the gene expression profile was investigated by a microarray analysis and a quantitative RT-PCR, and the protein expression and activation status of Akt, ERK 1/2 and the epidermal growth factor receptor (EGFR) were examined by a western blot analysis. Following the culture with B[a]P for 24 weeks, the serum-independent proliferative activity was increased. A microarray analysis revealed that a reversible upregulation of the EGFR and epiregulin genes was recognized in the B[a]P treated cells, in which the overexpression of the phosphorylated EGFR protein was also recognized. The EGFR tyrosine kinase inhibitor reduced the cellular proliferation and the level of phosphorylation of ERK1/2, which is a downstream signal of the EGFR, in the B[a]P-treated A549 cells. Moreover, the B[a]P treatment increased the mRNA expressions of the ligands for EGFR such as amphiregulin and epiregulin. B[a]P increases the proliferative potential of lung adenocarcinoma cells through the EGFR signaling pathway.

Role and Relevance of TrkB Mutations and Expression in Non―Small Cell Lung Cancer

Purpose: TrkB has been involved in poor cancer outcome. TrkB mutations have been reported in non–small cell lung cancer. In this study, we aimed at characterizing the role of three potentially sensitizing TrkB mutations previously reported in lung cancer. Experimental Design: We characterized three activation loop mutants of TrkB (M713I, R715G, and R734C) in terms of pathway activation/phosphorylation, migration, anchorage-independent growth, and sensitivity to a Trk inhibitor, using NIH3T3 cells and Baf3 cells. We also sequenced the tyrosine kinase domain of TrkB in a large number of lung cancer samples of East-Asian origin and cell lines. Results: None of the mutants were constitutively active in NIH3T3 transformation and migration assays. M713I and R734C mutants showed low levels of autophosphorylation in comparison with wild-type TrkB. Although R715G showed similar level of autophosphorylation to wild-type TrkB on brain-derived neurotrophic factor stimulation, the mutant was not as competent as wild-type TrkB in supporting interleukin-3–independent growth of Baf3 cells. In addition, the Trk inhibitor AZD6918 inhibited wild-type TrkB-induced cell migration and cell growth, whereas the mutants were relatively resistant to the Trk inhibitor compared with wild-type TrkB. We could not confirm the presence of nonsynonymous mutation in 78 lung cancer samples and 29 cell lines. Conclusions: Wild-type, but not mutant, TrkB enhances cell migration and transformation. Our study suggests that TrkB mutations should not be used for selection of patients with lung cancer treated with Trk inhibitors. High expression of wild-type TrkB might be beneficial for studies of Trk inhibitors. Clin Cancer Res; 17(9); 2638–45. ©2011 AACR.

Serum carcinoembryonic antigen level is associated with epidermal growth factor receptor mutations in recurrent lung adenocarcinomas

The presence of epidermal growth factor receptor (EGFR) gene mutations is a good indicator of the clinical efficacy of gefitinib in patients with nonsmall cell lung cancer. It was recently reported that the serum carcinoembryonic antigen (CEA) level could be a predictive factor for the efficacy of gefitinib treatment; therefore, it is suggested that the EGFR gene mutation is associated with the serum CEA level. The current study analyzed the association between EGFR gene mutations and clinical features, including the serum CEA level, in patients with recurrent lung adenocarcinomas.

Results of a surgical resection of pulmonary metastasis from malignant head and neck tumor

There have been only a few reports about a surgical resection of pulmonary metastasis from malignant head and neck tumor. Here we investigate the survival after a pulmonary metastasectomy, and discuss the prognostic factors. We retrospectively reviewed 25 patients who underwent a pulmonary metastasectomy from malignant head and neck tumor at Kyushu University Hospital from 1981 through 2008. We assessed the five year overall survival by the Kaplan-Meier method and the log-rank (Mantel-Cox) test using the Stat View software program. The three- or five-year overall survival after a metastasectomy was 53.3% and 50.0%, respectively. We investigated the clinico-pathological prognostic factors including gender, age, histology, disease free interval, number or size of pulmonary metastatic tumors, and the operative procedure. Both age (older than 60 years) (P=0.0189) and pulmonary metastases from squamous cell carcinomas in either oral cavity or pharyngeal region (P=0.0002) were identified to be adverse prognostic factors. To obtain a long survival, a positive surgical resection is considered to be an effective and standard treatment for pulmonary metastasis from malignant head and neck tumor. It is also necessary, however, to elucidate fully the primary site and histology of such pulmonary metastasis.

Feasibility study of postoperative adjuvant chemotherapy with S-1 (tegaful, gimeracil, oteracil potassium) for non-small cell lung cancer—LOGIK 0601 study

INTRODUCTION The feasibility of using S-1, a novel oral dihydropyrimidine dehydrogenase (DPD)-inhibitory 5-fluorouracil, as postoperative adjuvant chemotherapy for completely resected non-small cell lung cancer (NSCLC) was analyzed. METHODS Adjuvant chemotherapy consisted of eight courses (2-week administration and 1-week withdrawal) of S-1, at 80-120 mg/body per day in an outpatient setting. From July 2006 through March 2007, 30 patients were enrolled in this multi-institutional trial. RESULTS The planned eight courses of S-1 administration were accomplished to 17 patients (56.7%; 95% confidence interval 37.4-74.5%). Two patients discontinued the treatment due to the disease recurrence, and therefore the completion rate was calculated to be 60.7%. The completion rate in patients younger than 70 years old was 78.6% while it was 42.9% in those of 70 years old or older. In seven patients including five elderly patients (> or =70 years old), S-1 administration was discontinued due to subjective symptoms, such as anorexia, during the early courses. The rate of patients with mild renal impairment (60< or =creatinine clearance<80 ml/min) tended to be higher in the elderly patients than that in the younger patients. Although grade 3 neutropenia (6.7%), anemia (6.7%), thrombocytopenia (3.3%) and digestive hemorrhage (3.3%) were observed, no grade 4 adverse events occurred. CONCLUSION Postoperative long-term administration of S-1 seems feasible as adjuvant chemotherapy for NSCLC, with few adverse events except for the early development of anorexia, especially in the elderly patients.

Expression of an X-family DNA polymerase, pol lambda, in the respiratory epithelium of non-small cell lung cancer patients with habitual smoking.

DNA polymerase lambda, pol lambda, is a eukaryotic member of the X-family DNA polymerases that is involved in two modes of DNA repair, i.e. base excision repair (BER) or non-homologous end joining (NHEJ). Using immunohistochemical approaches, we have observed pol lambda expression in human tissues, particularly in the respiratory system of lung cancer patients. pol lambda proteins were distributed in the nuclei of the epithelial cells in the bronchi, bronchioles and alveoli. Intriguingly, the level of pol lambda expression in the bronchiolar epithelia significantly correlated with the amount of habitual smoking in the individuals. Conversely, pol lambda expression in cancer tissues did not correlate with the smoking status of the patients. Pol lambda expression was sometimes discrepant between the tumor tissues and adjacent bronchioles. More importantly, tumors without pol lambda expression that occurred in heavy smokers significantly tended to be at an advanced clinical stage. Pol lambda may thus be involved in the DNA repair processes counteracting DNA damage caused by tobacco smoke in the respiratory system.

Assessing a clinical pathway to improve the quality of care in pulmonary resections

PurposeTo evaluate the efficacy of the current clinical pathway for pulmonary resections.MethodsThis study examined variances from expected clinical pathway outcomes for pulmonary resections performed between 2005 and 2009. Data on a total of 383 patients were retrospectively analyzed.ResultsThe median length of hospital stay (LOS) using the clinical pathway was 12 days (range: 1–188 days); the mean LOS was 15.5 days. The cost per day with use of the clinical pathway was 102 726 yen. Poor control of pain from intercostal neuralgia was the most frequently observed variance from expected outcomes. It affected 119 of 168 electronic clinical pathway patients (70.8%). The clinical pathway was terminated in 3.9% of patients (15/383) due to serious or life-threatening complications.ConclusionsThis study showed the single institutional experience of the clinical pathway for pulmonary resections. These findings indicate a need to revise certain aspects of the pathway, based on data from our analysis of variances.