Naoko Miura

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.

Suppressive effect of the herbal medicine Oren-gedoku-to on cyclooxygenase-2 activity and azoxymethane-induced aberrant crypt foci development in rats

The present study is part of a program to obtain effective chemopreventive agents with low toxicity from medicinal herbs and traditional herbal medicines. We previously reported that Oren (Coptidis rhizoma) and Ogon (Scutellariae radix) inhibit azoxymethane (AOM)-induced aberrant crypt foci (ACF) formation. In the present investigation, we found Sanshishi (Gardeniae fructus) and the traditional herbal medicine Oren-gedoku-to (OGT), composed of Ogon, Oren, Sanshishi and Obaku, also have preventive potential. Sanshishi and OGT decreased the numbers of ACF to 25.2 and 59.4% of the control value at 2% in the diet, respectively. Adverse effects, evidenced by body weight loss, were weaker with OGT than component herbs. To investigate their mechanisms of action, the influence on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) activities was studied. Both OGT and Sanshishi inhibited COX-2 but not COX-1, this presumably contributing to their suppressive effects on ACF development. The results suggest that OGT may be useful for colon cancer chemoprevention in terms of efficacy and toxicity.

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.

Preventive Effect of TU-100 on a Type-2 Model of Colitis in Mice: Possible Involvement of Enhancing Adrenomedullin in Intestinal Epithelial Cells.

Purpose. Crohns disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD), have histopathologically and immunologically different characteristics. We previously reported that a traditional Japanese medicine, daikenchuto (TU-100), ameliorated a trinitrobenzenesulfonic acid- (TNBS-) induced type-1 model colitis exhibiting histopathological features of CD through adrenomedullin (ADM) enhancement. Our current aims were to examine whether TU-100 ameliorates a type-2 model colitis that histologically resembles UC and identify the active ingredients. Methods. TU-100 was administered orally to mice with oxazolone- (OXN-) induced type-2 model colitis. The morbidity was evaluated by body weight loss and the macroscopic score of colonic lesions. ADM was quantified using an EIA kit. Results. TU-100 prevented weight loss and colon ulceration. ADM production by intestinal epithelial cells was increased by TU-100 addition. Screening to identify active ingredients showed that [6]-shogaol and hydroxy α-sanshool enhanced ADM production. Conclusions. TU-100 exerted a protective effect in OXN-induced type-2 model colitis, indicating that TU-100 may be a beneficial agent for treatment of UC.

Expression of mismatch repair proteins, hMLH1/hMSH2, in non-small cell lung cancer tissues and its clinical significance

hMLH1 and hMSH2 have been implicated to be involved in the DNA mismatch repair (MMR) system. The purpose of this study is to investigate the expression of hMLH1 and hMSH2 DNA MMR proteins in non‐small cell lung cancer (NSCLC) tissue and to elucidate their clinical significance.

Biological significance of the maximum standardized uptake values on positron emission tomography in non-small cell lung cancer

The 2‐[18F]‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) has recently become an important non‐invasive tool for the diagnosis and staging in several cancers. The standardized uptake value (SUV) of primary tumor has been reported to relate to cancer progression and prognosis, however, biological mechanism is still unclear.

The Prognostic Impact of Tumor Volume in Patients with Clinical Stage IA Non-Small Cell Lung Cancer

Introduction: Tumor volume promises to be an important factor for predicting the prognosis of patients with non–small cell lung cancer (NSCLC). Methods: A total of 255 patients who underwent curative surgical resection for clinical stage IA NSCLC were included. We performed semiautomated measurement of the whole tumor volume and the volume of the solid part (referred to as the solid part volume) from a volumetric analysis of chest three‐dimensional computed tomography scans using the SYNAPSE VINCENT imaging software program (Fujifilm Medical, Tokyo, Japan). We evaluated the relationships among tumor size, tumor volume, and survival. Results: The mean whole tumor size, the ratio of the maximum diameter of consolidation to the maximum tumor diameter (CTR), the whole tumor volume, and the solid part volume were 20 mm (range 0–30 mm), 0.84 (range 0–1.0), 3080 mm3 (range 123–17509 mm3), and 2032 mm3 (0–12466 mm3), respectively. The receiver operating characteristic area under the curve for the whole tumor size, CTR, whole tumor volume, and solid part volume used to identify recurrence were 0.60, 0.68, 0.58, and 0.69, respectively. A univariate analysis revealed that the whole tumor size, CTR, whole tumor volume, and solid part volume were associated with disease‐free survival (DFS). A multivariate analysis of these factors identified the solid part volume to be the only independent factor for the prediction of DFS. Conclusions: The whole tumor volume and the solid part volume were associated with DFS. In particular, the solid part volume was a very useful factor for predicting prognosis in clinical stage IA NSCLC.

Prognostic significance of immune-nutritional parameters for surgically resected elderly lung cancer patients: a multicentre retrospective study

OBJECTIVES The worlds population is rapidly ageing, and the age of patients with lung cancer will increase as well. The prognostic nutritional index, controlling nutritional status and the geriatric nutritional risk index (GNRI) are useful parameters for evaluating immune-nutritional status. We aimed to perform a multicentre retrospective study to investigate the correlations of these immune-nutritional parameters with postoperative comorbidities or surgical outcomes of elderly patients with non-small-cell lung cancer (NSCLC). METHODS We selected 272 consecutive patients with NSCLC aged >75 years treated from January 2005 to December 2012 and evaluated 3 preoperative immune-nutritional parameters as potential predictive factors of postoperative comorbidities or as prognostic factors for surgically resected elderly patients with NSCLC. RESULTS Prognostic nutritional index, GNRI, sex and preoperative respiratory comorbidities were significantly associated with postoperative comorbidities. Multivariate analyses revealed that preoperative GNRI, sex, preoperative serum carcinoembryonic antigen levels, preoperative serum cytokeratin 19 fragment levels, pathological N factor and pleural invasion were significantly associated with overall survival (OS). Abnormal GNRI was significantly associated with histology and outcomes. The Kaplan-Meier analysis of OS as a function of preoperative GNRI revealed that patients with an abnormal GNRI experienced significantly shorter OS compared with those with normal GNRI (5-year OS, 45.15% vs 64.10%, respectively; P = 0.0007, log-rank test). The controlling nutritional status score was not significantly associated with postoperative comorbidities or surgical outcomes. CONCLUSIONS Preoperative GNRI is a novel preoperative predictor of postoperative comorbidities and a prognostic factor that may identify high-risk elderly patients with NSCLC.