Fumihiro Shoji

Combined evaluation of Rad51 and ERCC1 expressions for sensitivity to platinum agents in non-small cell lung cancer

DNA repair enzyme expression in tumor cells possibly affects sensitivity to anti‐cancer agents. The aim of this study was to determine the relationship between expression status of DNA repair enzymes and chemosensitivity in patients with non‐small cell lung cancer (NSCLC). NSCLC tissues prepared from the surgical specimens of 41 patients were subjected to immunohistochemical analysis for Rad51 and ERCC1 proteins and to a chemosensitivity test using the MTT assay. The relationships between the expression status of the DNA repair enzymes and ex vivo chemosensitivity to various agents were evaluated. A positive expression for Rad51 and ERCC1 was observed in 17 cases (41%) and 20 cases (49%), respectively. The positivity of Rad51 was closely related to a certain histologic type of squamous cell carcinoma and poor differentiation, and the positivity of ERCC1 tended to be related to squamous cell carcinoma. In chemosensitivity tests, sensitivities to CDDP and CBDCA were significantly lower when both 2 enzymes were positive (p = 0.012 and 0.04 in CDDP, 0.014 and 0.03 in CBDCA). Both Rad51 and ERCC1 expressions showed no significant relationship with sensitivities to paclitaxel, etoposide, vinorelbine, gemcitabine, 5‐FU, or irinotecan. In conclusion, combined expression of Rad51 and ERCC1 expression is associated with resistance to platinum agents in the ex vivo study of clinical NSCLC, and evaluation of expression status of both DNA repair enzymes would be a predictor for clinical response to platinum‐based chemotherapies.

Never-smoking Nonsmall Cell Lung Cancer as a Separate Entity : Clinicopathologic Features and Survival

To propose ‘never‐smoking nonsmall cell lung cancer (NSCLC)’ as a separate entity, the clinicopathologic differences of operable NSCLC between never‐smoking patients and patients with a history of smoking were investigated.

Effects of excision repair cross-complementation group 1 (ERCC1) single nucleotide polymorphisms on the prognosis of non-small cell lung cancer patients

BACKGROUND Excision repair cross-complementation group 1 (ERCC1) is the lead enzyme in the nucleotide excision repair process. Two polymorphisms of ERCC1, T19007C (rs11615) and C8092A (rs3212986), have been reported to affect both the carcinogenesis and the survival of the patients who received platinum-based chemotherapy, but the mechanism by which these polymorphisms influence the survival is unclear. In this study, we determined the function of these ERCC1 polymorphisms in the survival of NSCLC patients. METHOD The ERCC1 T19007C and C8092A single nucleotide polymorphisms (SNPs) were evaluated in 122 Japanese non-small cell lung cancer (NSCLC) patients who underwent a complete resection and analyzed the clinicopathological significance of these SNPs. None of the patients received peri-operative platinum-based chemotherapy. The relationship between these SNPs and ERCC1 protein expression and the platinum sensitivity of the primary tumors were also examined. RESULT Regarding T19007C SNP, the distribution of the CC, CT, and TT genotypes was 45%, 48% and 7%, respectively. As for C8092A SNP, the distribution of CC and CA genotypes was 70% and 30%, respectively. The patients with C8092A CA genotype were significantly poorer disease-free survival (DFS) and overall survival (OS) than those with the CC genotype (p=0.037 and 0.004). In addition, no relationship was observed between T19007C SNP and DFS or OS. These two SNPs also did not correlate with either ERCC1 protein expression or platinum sensitivity. CONCLUSION The ERCC1 C8092A polymorphism may influence the NSCLC prognosis regardless of the ERCC1 protein expression and platinum sensitivity.

Induction of epithelial-mesenchymal transition-related genes by benzo[a]pyrene in lung cancer cells

It is believed that epithelial‐mesenchymal transition (EMT) occurs during the development and progression of cancer; however, the correlation between tobacco smoking and EMT remains to be elucidated.

Clinical Significance of PD-L1 Protein Expression in Surgically Resected Primary Lung Adenocarcinoma.

Introduction The clinicopathological features of carcinomas expressing programmed death ligand 1 (PD‐L1) and their associations with common driver mutations, such as mutations in the EGFR gene, in lung adenocarcinoma are not clearly understood. Here, we examined PD‐L1 protein expression in surgically resected primary lung adenocarcinoma and the association of PD‐L1 protein expression with clinicopathological features, EGFR mutation status, and patient outcomes. Methods The expression of PD‐L1 protein in 417 surgically resected primary lung adenocarcinomas was evaluated by immunohistochemical analysis. The cutoff value for defining PD‐L1 positivity was determined according to the histogram of proportions of PD‐L1–positive cancer cells. Results Samples from 85 patients (20.4%) and 144 patients (34.5%) were positive for PD‐L1 protein expression according to 5% and 1% PD‐L1 cutoff values, respectively. Fisher’s exact tests showed that PD‐L1 positivity was significantly associated with male sex, smoking, higher tumor grade, advanced T status, advanced N status, advanced stage, the presence of pleural and vessel invasions, micropapillary or solid predominant histological subtypes, and wild‐type EGFR. Univariate and multivariate survival analyses revealed that patients with PD‐L1 positivity had poorer prognoses than those without PD‐L1 protein expression at the 1% cutoff value (disease‐free survival p < 0.0001, overall survival p < 0.0001). Conclusions PD‐L1 protein expression was significantly higher in smoking‐associated adenocarcinoma and in EGFR mutation–negative adenocarcinoma. PD‐L1 protein expression was associated with poor survival in patients with lung adenocarcinoma. The PD‐L1/programmed cell death 1 pathway may contribute to the progression of smoking‐associated tumors in lung adenocarcinoma.

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.

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.