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1.  APOBEC3B gene overexpression in non-small-cell lung cancer 
Biomedical Reports  2014;2(3):392-395.
Recent study results have demonstrated that a subclass of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminase may induce mutation clusters in various types of cancer. From the Cancer Genome Altas, an APOBEC mutation pattern was identified in bladder, cervical, breast, head and neck and lung cancers. In the present study, APOBEC3B mRNA expression was investigated using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assay using LightCycler in surgically treated non-small-cell lung cancer (NSCLC) cases. Additionally, 88 surgically removed Japanese NSCLC cases were analyzed for mRNA level. The results showed that APOBEC3B/β-actin mRNA levels were significantly higher in lung cancer (1,598.481±6,465.781) when compared to adjacent normal lung tissues (2,116.639±8,337.331, P=0.5453). The tumor/normal (T/N) ratio of APOBEC3B/β-actin mRNA levels was not different within the gender, age, smoking status and pathological stages. The T/N ratio of APOBEC3B/β-actin mRNA levels was not significantly different in epidermal growth factor receptor (EGFR) or Kras mutation-positive cases as compared to the wild-type cases.
PMCID: PMC3990218  PMID: 24748981
APOBEC3B; mutation; lung cancer; epidermal growth factor receptor; LightCycler
2.  Prognosis of recurrent non-small cell lung cancer following complete resection 
Oncology Letters  2014;7(4):1300-1304.
Prognosis following recurrence subsequent to complete resection of non-small-cell lung cancer (NSCLC) is considered a multifactorial process dependent on clinicopathological, biological and treatment characteristics. Gefitinib was approved for lung cancer treatment in Japan in 2002. The aim of the current study was to quantify the prognostic effects of these characteristics on post-recurrence prognosis. In total, 127 NSCLC patients were analyzed who underwent complete resection and subsequently had recurrent cancer. The correlation between characteristics of the initial and recurrent disease with post-recurrence prognosis was investigated. The factors clearly associated with post-recurrence prognosis using Cox proportional hazards models were age at recurrence (those <65 years of age typically had better prognoses) and interval between initial resection and recurrence (intervals of <1 year accompanied a worse prognosis). Epidermal growth factor receptor (EGFR) mutant patients treated with EGFR tyrosine kinase inhibitors (TKIs), exhibited the longest median survival following recurrence (37.4 months) in the sample. Treatment, particularly EGFR TKIs for recurrent NSCLC, was observed to significantly prolong survival. The results of the study highlight that various treatment modalities according to the clinical background of the patient should be considered in patients with postoperative recurrent NSCLC.
PMCID: PMC3961426  PMID: 24944713
EGFR; recurrent; prognosis; tyrosine kinase inhibitor
3.  Proposal for a new mediastinal compartment classification of transverse plane images according to the Japanese Association for Research on the Thymus (JART) General Rules for the Study of Mediastinal Tumors 
Oncology Reports  2013;31(2):565-572.
There is no existing worldwide published method for mediastinum compartment classification based on transverse section images for the differential diagnosis of mediastinal tumors. Herein, we describe a new method for anatomic mediastinal compartment classification using transverse section computed tomography (CT) images and the use of this method to classify mediastinal lesions, and thus evaluate whether the method is sufficiently user-friendly and useful. In a publication of the Japanese Association for Research on the Thymus (JART), we proposed the following four mediastinal compartments based on transverse CT images: superior portion of mediastinum, anterior mediastinum (prevascular zone), middle mediastinum (peri-tracheoesophageal zone), and posterior mediastinum (paravertebral zone). In the present study, we retrospectively analyzed 445 pathologically proven mediastinal mass lesions, and categorized them into the proposed four compartments by consensus reading. Mass lesions were classified into compartments based on the location of the lesion centroid, and each lesion was satisfactorily categorized into a compartment. Almost all thymic epithelial tumors (99%, 244/246), all 24 thymic malignant lymphomas and a majority of germ cell neoplasms (93%, 54/58) were classified as being in the anterior mediastinum compartment. The majority of intrathoracic goiters (82%, 14/17) were categorized as being in the superior portion of the mediastinum compartment. Approximately two-thirds of mass lesions in the middle mediastinum were cysts, including foregut and pericardial cysts. Approximately 80% of 37 mass lesions in the posterior mediastinum were neurogenic tumors. Correspondingly, 29 of the 49 neurogenic tumors (60%) were categorized as being in the posterior mediastinum, while 10 (20%) were in the superior portion of the mediastinum, 4 (8%) in the anterior mediastinum, and 6 (12%) in the middle mediastinum. Our findings showed that the newly proposed mediastinal compartment classification using transverse images appears to be user-friendly enough for practical clinical application and may be helpful in differential diagnoses.
PMCID: PMC3896522  PMID: 24317723
mediastinum; compartment; mediastinal mass; mediastinal neoplasm; computed tomography; differential diagnosis
4.  Expression of thymidylate synthase and orotate phosphoribosyltransferase in thymic carcinoma 
Thymic carcinoma is a rare thymic epithelial tumor in which chemotherapy for advanced disease has not yet been established. Thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT) protein expression levels in thymic carcinoma were evaluated as possible indicators of the anticancer activity of 5-fluorouracil (5-FU) drugs using immunohistochemistry (IHC). A total of 24 samples of thymic carcinoma were used in the present study. The tumor sections were immunohistochemically stained for TS and OPRT. As a comparison with thymic carcinoma, we also assessed the TS and OPRT protein expression levels in 55 lung cancer samples. The TS expression was positive in 12 of 24 thymic carcinoma samples (50%) and OPRT expression was positive in 10 (42%). The association between TS and OPRT expression and Masaoka stages of thymic carcinoma was analyzed. The TS and OPRT expressions in stage IV were significantly higher compared to that in stages I, II or III. We also compared the TS and OPRT expression levels between thymic carcinoma and lung cancer (33 adenocarcinomas and 22 squamous cell carcinomas). TS expression in thymic carcinoma was significantly lower compared with lung squamous cell carcinoma. OPRT expression in thymic carcinoma was significantly higher compared to lung adenocarcinoma. The combination of a relatively low expression of TS and high expression of OPRT suggests an improved antitumor effect of 5-FU drugs in thymic carcinoma compared to in lung carcinoma.
PMCID: PMC3501379  PMID: 23170110
thymic carcinoma; thymidylate synthase; orotate phosphoribosyltransferase
5.  Keap1 mutations in lung cancer patients 
Oncology Letters  2013;6(3):719-721.
Kelch-like ECH-associated protein 1 (Keap1) inhibits nuclear factor erythroid 2-related 2 (NEF2L2; also named NRF2)-induced cytoprotection and has been hypothesized to represent a candidate tumor suppressor. We have previously reported the somatic mutations of the NRF2 gene (NFE2L2), however, the correlation between the Keap1 mutation and the clinicopathological features of lung cancer has not been well investigated. Therefore, in the present study, the Keap1 mutational status in non-small cell lung cancer (NSCLC) patients was investigated by reverse transcription PCR and direct sequencing. The study included 76 surgically-removed lung cancer cases from patients of the Nagoya City University Hospital in which the EGFR and NFE2L2 mutation status was already established. Keap1 mutations were identified in 2 (2.6%) adenocarcinoma patients with a history of heavy smoking. These mutations were identified to exist exclusively. The Keap1 mutation was only detected in patients with advanced adenocarcinoma (4.3%) and the completely exclusive status of this mutation and others, including EGFR, Kas, erbB2 and NRF2L2, is likely to improve the selection of personalized therapy for lung cancer.
PMCID: PMC3789102  PMID: 24137397
Keap1; NRF2; lung cancer; mutations; adenocarcinoma
6.  Polymorphisms of NRF2 gene correlated with decreased FEV1 in lung cancers of smokers 
Biomedical Reports  2013;1(3):484-488.
The metabolism of xenobiotics plays a fundamental role in smoking-related lung function loss and the development of pulmonary disease. An NRF2-dependent response is a key protective mechanism against oxidative stress. In the present study, we evaluated the effect of single nucleotide polymorphisms in NRF2 genes on the level of forced expiratory volume in one second (FEV1) in lung cancers of smokers. We genotyped the status of NRF2 gene polymorphisms in 209 surgically treated lung cancer cases of smokers using TaqMan polymerase chain reaction (PCR). The results demonstrated the mean FEV1 in patients with rs2364723 C/C, C/G and G/G to be 2143.9, 2294.2 and 2335.4 ml, respectively, and there was a tendency towards lower FEV1 in C/C phenotype (P=0.0944). The mean FEV1 was significantly lower in the C/C phenotype (2143.9±566.0 ml) compared to C/G or G/G (2308.9±642.9 ml, P=0.05). The mean FEV1 in patients with rs6726395 A/A, G/A and G/G was 66.7, 71.2 and 72.3%, respectively, and there was a significant difference between A/A and G/G phenotype (P=0.043). A tendency towards a lower mean FEV1 in A/A phenotype (66.7±11.7%) was observed when compared to A/G or G/G (71.9±10.7%, P=0.07). This study demonstrated that an NRF2-dependent response to cigarette smoking has the potential to affect FEV1 decrease in a lung cancer population. In conclusion, the results have shown that NRF2 genetic changes may play a role in FEV1 loss in smokers with lung cancer.
PMCID: PMC3917728  PMID: 24648973
nuclear factor (erythroid derived 2)-like 2; polymorphism; NRF2; forced expiratory volume in 1 second; smoker
7.  Post-operative acute exacerbation of pulmonary fibrosis in lung cancer patients undergoing lung resection 
Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) in lung cancer patients is a critical factor in post-operative mortality. The cause of AE development is unknown and AE may occur in patients without the diagnosis of IPF. We have conducted a retrospective study of consecutive patients who underwent lung cancer surgery since January 2004. Sixty-two patients with fibrous findings in preoperative high-resolution computed tomography were enrolled in the present study and clinicopathological factors were analysed. AE was observed in 6 of 62 patients. The frequency of AE according to the type of fibrous changes classification was 1/7 in the usual interstitial pneumonia (UIP) pattern, 1/16 in the cellular non-specific interstitial pneumonia (NSIP) pattern, 4/25 in the fibrotic NSIP pattern and 0/14 in the unclassified or focal fibrous changes pattern. Preoperative Krebs von den Lungen-6 (KL-6) was higher in patients with AE than in those without AE. In patients who underwent partial resection, AE did not develop even with high KL-6 levels. In conclusion, in patients with both the UIP and the NSIP patterns, AE development is possible. In patients with a high risk of AE, such as those with high KL-6 values, limited surgery may be an option to prevent AE development.
PMCID: PMC3279985  PMID: 22159236
Idiopathic pulmonary fibrosis; Acute exacerbation; Lung cancer; KL-6
8.  RagD gene expression and NRF2 mutations in lung squamous cell carcinomas 
Oncology Letters  2012;4(6):1167-1170.
RagD is a member of the small G protein family, which encodes a recently discovered activator of the mTOR pathway. In vitro, RagD plays an important role in the proliferation of NRF2 gene (NFE2L2) mutated cancer cells. We hypothesized that tumor RagD expression may be correlated with the mutation status of NRF2 in lung cancers. RagD mRNA levels were analyzed by quantitative real-time polymerase chain reaction (qPCR) in 90 surgically-treated lung squamous cell cancer cases, including 14 NRF2 mutation cases, and normalized by β-actin mRNA levels. Mean RagD/β-actin mRNA levels of lung squamous cell carcinoma patients did not differ with age (≤65 vs. >65), Brinkman index (<400 vs. ≥400) or gender. RagD/β-actin mRNA levels were significantly higher in stage III samples (3.204±3.623) compared to stage I samples (1.357±1.560) (P= 0.0039). In addition, higher RagD/β-actin mRNA levels were identified in NRF2 mutant samples (3.107±3.633) compared to wild-type samples (1.774±2.301) (P=0.074). These results suggest that RagD induction by NRF2 activation plays a role in the proliferation of lung squamous cell cancers.
PMCID: PMC3506764  PMID: 23226795
NRF2; lung cancer; squamous cell carcinoma; RagD; mutation
9.  Angiopoietin-like protein ANGPTL2 gene expression is correlated with lymph node metastasis in lung cancer 
Oncology Letters  2012;4(6):1325-1328.
Inflammation plays key roles at various stages of tumor development, including invasion and metastasis. In mice, the angiopoietin-like protein (ANGPTL2) gene has been implicated in inflammatory carcinogenesis. ANGPTL2 mRNA expression was investigated by real-time polymerase chain reaction (RT-PCR) assay using LightCycler in surgically treated non-small cell lung cancer (NSCLC) cases. In total, 110 surgically resected NSCLC cases were used for mRNA level analyses. The ANGPTL2/β-actin mRNA levels were not significantly different between lung cancer (1598.481±6465.781) and adjacent normal lung tissues (2116.639±8337.331, P=0.5453). The tumor/normal (T/N) ratio of ANGPTL2/β-actin mRNA levels was not different between gender, age, smoking status and pathological stages. The T/N ratio of ANGPTL2/β-actin mRNA levels was significantly higher in lymph node metastasis-positive cases (2.173±3.151) compared with lymph node metastasis-negative cases (1.212±1.778, P=0.0464). However, ANGPTL2 mRNA status was not correlated with tumor invasion status. Thus, ANGPTL2 may drive metastasis and provide a candidate for blockade of its function as a strategy to antagonize the metastatic process in NSCLC.
PMCID: PMC3506759  PMID: 23205131
ANGTL2; angiopoietin; lung cancer; metastasis; LightCycler
10.  PD-L1 gene expression in Japanese lung cancer patients 
Biomedical Reports  2012;1(1):93-96.
An imbalance in immune regulation affects tumor-specific T-cell immunity in the cancer microenvironment and reshapes tumor progression and metastasis. Blockade of interactions of immune function mediates anti-tumor activity in preclinical models. In the present study, we investigated programmed cell death 1 ligand 1 (PD-L1) mRNA expression by real-time polymerase chain reaction (RT-PCR) using a LightCycler in surgically treated non-small cell lung cancer (NSCLC) cases. This study included 123 surgically removed NSCLC cases for mRNA level analyses. The PD-L1/β-actin mRNA levels showed no marked difference in lung cancer (131.398±421.596) and adjacent normal lung tissues (78.182±254092, P=0.1482). The tumor/normal (T/N) ratio of PD-L1/β-actin mRNA levels was more than 2 in 49 cases and more than 1 in 63 cases. No difference was found in the T/N ratio of PD-L1/β actin mRNA levels among factors inlcuding gender, age, smoking status and pathological subtypes. The T/N ratio of PD-L1/β actin mRNA levels was markedly higher in pathological T4 cases (15.811±36.883) compared to T1 cases (3.492±8.494, P=0.0235). However, the PD-L1 mRNA status did not correlate with lymph node metastasis status. Thus, PD-L1 may drive tumor invasion, while providing a candidate for blockade of its function as a strategy to antagonize the progression process in NSCLC.
PMCID: PMC3956825  PMID: 24648901
programmed cell death 1 ligand 1; immunotherapy; lung cancer; tumor invasion; LightCycler
11.  Polymorphisms in intron 1 of the EGFR gene in non-small cell lung cancer patients 
The epidermal growth factor receptor (EGFR) gene is highly polymorphic and its expression and activity may be affected by various polymorphisms. There have been several studies examining associations between EGFR polymorphisms and clinical outcome of lung cancer therapy; however, the underlying mechanism is largely unknown. The present study investigated EGFR polymorphism status and its correlation with clinicopathological features in Japanese non-small cell lung cancer (NSCLC) patients. We investigated 5 polymorphisms in the EGFR gene (−216G/T, −191C/A, 8227G/A, D994D and R497K) in 274 surgically-treated NSCLC patients. TaqMan single nucleotide polymorphism (SNP) genotyping assays and a PCR-based assay were used to analyze these polymorphisms. In our cohort of patients we did not find any evidence of the −191C/A polymorphism. Our results showed that the patients with the 8227GA or AA type in intron 1 had a significantly better prognosis with the anti-EGFR therapy than the patients with the GG type (p=0.0448) in terms of recurrence of lung cancer. No significant association was observed between 3 other SNPs (−216G/T, D994D and R497K) and clinicopathological features. The EGFR 8227G/A polymorphism in intron 1 may be associated with clinical outcome in NSCLC patients treated with EGFR tyrosine kinase inhibitors.
PMCID: PMC3493703  PMID: 23226726
epidermal growth factor receptor; polymorphism; lung cancer; gefitinib therapy; 8227G/A
12.  RET expression and detection of KIF5B/RET gene rearrangements in Japanese lung cancer 
Cancer Medicine  2012;1(1):68-75.
RET encodes the tyrosine kinase receptor of growth factors belonging to the glial-derived neurotrophic factor family. Recently, RET gene rearrangements with N-terminal of KIF5B gene were identified in lung adenocarcinomas from large-scale sequencing. We investigated RET mRNA expression by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assay using LightCycler, and KIF5B/RET gene rearrangements using newly established fluorescence in situ hybridization (FISH) analysis in surgically treated nonsmall cell lung cancer (NSCLC) cases. RET protein expression was also investigated by immunohistochemistry (IHC). This study included 157 surgically removed NSCLC cases for mRNA level analyses. The RET/β actin mRNA levels were not significantly different between lung cancer (6.359 ± 15.268) and adjacent normal lung tissues (8.205 ± 28.931, P = 0.6332). Tumor/normal (T/N) ratio of RET/β actin mRNA levels was not different within gender, stage, smoking status, and pathological subtypes. T/N ratio of RET/β actin mRNA levels was significantly higher in KIF5B/RET rearrangement samples (161.763 ± 123.488) than in wild-type samples (5.9013 ± 17.148, P = 0.044). Although RET IHC positivity was not perfectly correlated with KIF5B/RET arrangement, we have detected the KIF5B/RET rearrangements using FISH analysis. Thus, we have successfully introduced FISH for diagnosing KIF5B/RET positive lung adenocarcinoma. This method facilitates the molecular evaluation for RET fusions and could be applicable in clinical practice to detect lung cancer that may be responsive to RET inhibitors.
PMCID: PMC3544433  PMID: 23342255
FISH; KIF5B/RET; lung cancer; RET expression
13.  Clinicopathological analysis of small-sized thymoma with podoplanin and Ki 67 expression analysis 
Thymoma is the most common tumor of the anterior mediastinum for which surgical resection is currently the primary form of treatment. An increase in the incidence of a small-sized (≤3 cm) thymoma (SST) has recently been noted. Clinicopathological factors and prognosis of SST have not been reported previously. In this study, the clinicopathological data of 21 SST patients were reviewed and podoplanin and Ki67 immunohistochemistry were assessed to determine the biological behavior of SSTs. Pathological diagnosis of SSTs revealed the following types: A (n=1), AB (n=8), B1 (n=5), B2 (n=6) and B3 (n=1). The Masaoka-Koga stages of 21 thymoma patients were I (n=16), II (n=3), III (n=1) and IVb (n=1). In the case of the stage IVb thymoma, phrenic nerve, mediastinal pleura invasion and anterior mediastinal lymph node metastasis were observed. The Ki67 labeling index of this stage IVb was found to be 3.2. This case was also positive for podoplanin and was one of the only 2 cases that were positive for podoplanin. This patient succumbed to thymoma. Advanced stage thymomas are possibly included in SSTs although the majority of SSTs are classified into early stages of disease. Findings of this study suggest that podoplanin analyzed by immunohistochemistry may be useful to determine the malignant behavior of SSTs.
PMCID: PMC3956257  PMID: 24649128
thymoma; small-sized; Ki67; podoplanin
14.  DDR2 polymorphisms and mRNA expression in lung cancers of Japanese patients 
Oncology Letters  2012;4(1):33-37.
Discoidin domain receptor 2, DDR2, is a tyrosine kinase receptor for fibrillar collagen that is involved in postnatal development, tissue repair and primary and metastatic cancer progression. Recently, mutations in the DDR2 kinase gene were identified in squamous cell lung cancer from large-scale Sanger sequencing. The present study investigated the DDR2 gene mutations and mRNA expression in surgically treated non-small cell lung cancer (NSCLC) of squamous histology cases. The presence or absence of DDR2 mutations at the kinase and discoidin domain was analyzed by direct sequencing. In this cohort, DDR2 mutations were not observed in the 166 patients with lung cancer, although DDR2 polymorphisms were observed (H136H, n=14) at the discoidin domain. mRNA levels of DDR2 in lung tumor samples and the adjacent normal lung samples were simultaneously analyzed. DDR2 mRNA levels were significantly decreased in tumor samples compared with normal lung samples. However, the DDR2 mRNA levels were elevated in the DDR2 polymorphism cases.
PMCID: PMC3398371  PMID: 22807955
discoidin domain receptor 2; mRNA expression; lung cancer; squamous cell carcinoma; polymorphism
15.  Braf and erbB2 mutations correlate with smoking status in lung cancer patients 
The erbB pathway involves a family of tyrosine kinases and contributes to resistance or sensitivity to chemotherapy in many tumor types. Somatic mutations of the epidermal growth factor receptor (EGFR) gene at the kinase domain have been found in lung cancer patients. These mutations are correlated with clinical response to targeted molecular therapy. Although Caucasian lung cancer patients have been shown to harbor Braf and erbB2 mutations, only a few reports exist concerning Braf and erbB2 mutations in Japanese lung cancer patients. We investigated the Braf and erbB2 mutation status in non-small cell lung cancer (NSCLC) patients by reverse transcription-polymerase chain reaction (RT-PCR) and direct sequencing. The study included 305 surgically removed lung cancer samples from the Nagoya City University Hospital, which were EGFR and Kras wild-type centric. Six Braf mutations were found in the adenocarcinoma cases. Among the adenocarcinoma cases, Braf mutations were more frequently noted in heavy smokers (Brinkman index >400, p=0.0476). We also detected five erbB2 mutations all in the non-smokers. All of these mutations existed exclusively. The erbB2 gene mutations were predominantly found in non-smokers with adenocarcinomas. However, the completely exclusive mutation status could help us design individually tailored targeted molecular therapy for lung cancer.
PMCID: PMC3438531  PMID: 22969966
Braf; epidermal growth factor receptor; lung cancer; mutations; erbB2; adenocarcinoma
16.  Thymoma associated with fatal myocarditis and polymyositis in a 58-year-old man following treatment with carboplatin and paclitaxel: A case report 
Oncology Letters  2011;3(2):300-302.
We report the case of a 58-year-old male presenting with giant cell myocarditis and myositis associated with thymoma following treatment with carboplatin and paclitaxel. The patient was diagnosed as having stage IVa thymoma. Acetylcholine receptor binding antibody titers were positive at 42 nmol/l, although the patient exhibited no symptoms of myasthenia gravis (MG). The patient was treated with a combination of carboplatin and paclitaxel. However, 18 days following administration of this second cycle of chemotherapy, the patient developed a low-grade fever. Twenty-one days after receiving the second cycle of chemotherapy, the patient was admitted to the Nagoya City University Medical School complaining of general fatigue. Serum levels of creatinine phosphokinase (7,271 U/l), alanine aminotransferase (469 U/l) and aspartate aminotransferase (561 U/l) were elevated. Electromyography revealed no evidence of a neuromuscular junction defect or myopathic process. The patient developed progressive muscle weakness and succumbed to the disease in hospital on day 9. An autopsy revealed thymoma invasion of the left parietal and visceral pleura, pericardium and diaphragm. Numerous skeletal muscle groups and myocardium exhibited diffuse lymphocytic infiltration. Although it has been suggested that myocardial disorders may occur in patients with thymoma and/or MG, the mechanism involved remains unknown. This second report may provide new data regarding giant cell myocarditis and myositis associated with thymoma following treatment with carboplatin and paclitaxel.
PMCID: PMC3362376  PMID: 22740899
thymoma; myocarditis; myositis; carboplatin; paclitaxel
17.  Increased Sox2 copy number in lung squamous cell carcinomas 
The transcription factor Sox2 is necessary for foregut morphogenesis. Sox2 is also required for the normal development of the trachea and lung. Recently, Sox2 amplifications were investigated using large-scale single nucleotide polymorphism arrays in esophageal and lung cancer. We hypothesized that Sox2 overexpression might be correlated with clinicopathological features of lung cancers. The increased copy number of the Sox2 gene was analyzed by real-time polymerase chain reaction amplifications in 127 surgically treated non-small cell lung cancer cases from Nagoya City University Hospital, Japan. A total of 87 squamous cell carcinoma (SCC) cases were involved. An increased Sox2 gene copy number was found in 42 (33.1%) lung cancer patients. Increased Sox2 copy number status was significantly correlated with gender (females, 9.5% vs. males, 34.1%; p=0.0026), smoking status (never smoker, 4.8% vs. smoker, 32.9%; p=0.0003) and pathological subtypes (squamous cell carcinoma, 44.8% vs. non-squamous cell carcinoma, 7.5%; p<0.0001). However, among the SCCs, the Sox2 copy number status was not significantly correlated with gender, smoking status, pathological stage or differentiation status. An increased Sox2 copy number is common within SCC.
PMCID: PMC3438854  PMID: 22969842
Sox2; lung cancer; squamous cell carcinoma; copy number; differentiation
18.  Expression of CD44v6 is an independent prognostic factor for poor survival in patients with esophageal squamous cell carcinoma 
Oncology Letters  2011;2(3):429-434.
CD44v6 has been causally associated with the development of metastases and with poor prognosis in various human malignancies. To elucidate the clinicopathological significance of CD44v6 expression in esophageal squamous cell carcinoma (ESCC), the present study aimed to investigate the expression of CD44v6 using immunohistological techniques. Using specific antibodies against CD44v6 and CD44s, expression of the proteins was analyzed immunohistochemically in 63 primary esophageal ESCCs, which were previously resected at the Nagoya City University Hospital without pre-operative induction therapy. Using light microscopy, the positive expression of CD44v6 was divided into a low- or high-expression group. The expression of CD44v6 in ESCC was analyzed with respect to various clinicopathological characteristics. The frequency of CD44v6 expression was 90.5% (57/63). The CD44v6 high-expression group comprised 55.6% of the patients (n=35) and the low expression group included 44.4% of the patients (n=28). In this study, no significant difference was observed between any clinicopathological factor and the immunohistochemical expression of CD44v6. In patients with high levels of CD44v6 expression, survival was markedly worse (p=0.0327). Favorable outcomes were observed for the clinicopathological characteristics of 6 patients whose tissue immunohistochemical expression of CD44v6 was not detected. Moreover, multivariate analysis confirmed that expression of CD44v6 was an independent prognostic indicator (risk ratio =2.793; p=0.0301). Overexpression of CD44v6 is a useful prognostic indicator of ESCC. Therefore, CD44v6 should be investigated as a potential target for therapy.
PMCID: PMC3410448  PMID: 22866099
CD44v6; esophageal squamous cell carcinoma; immunohistochemistry
19.  Decreased expression of FBXW7 is correlated with poor prognosis in patients with esophageal squamous cell carcinoma 
FBXW7 is a tumor suppressor gene that induces the degradation of positive cell-cycle regulators such as c-Myc, cyclin E, c-Jun and Notch. The loss of FBXW7 promotes cell-cycle progression and cell proliferation. In the present study, we investigated the relationship between FBXW7 expression and the clinicopathological characteristics of patients with esophageal squamous cell carcinoma (ESCC). The expression of FBXW7 was quantified by real-time reverse transcription polymerase chain reaction in 43 primary ESCCs and their paired normal esophageal mucosa in patients who had not received preoperative therapy. FBXW7 expression levels were significantly correlated with the progression of the cancer and with local invasiveness. In muscle-invasive tumor cases (T2–4), lymphatic invasive tumor cases and stage II–IV cases, FBXW7 expression levels were significantly decreased (P=0.0315, P=0.0336 and P=0.0289, respectively). Decreased expression of FBXW7 was correlated with poor prognosis (P=0.0255). In conclusion, this study examined the relationship between FBXW7 expression and tumor progression in ESCC. We suggest that FBXW7 is a molecular prognostic marker and can be used to elucidate the mechanism of carcinogenesis.
PMCID: PMC3445893  PMID: 22993608
esophageal cancer; prognosis; FBXW7
20.  MicroRNA-34b has an oncogenic role in esophageal squamous cell carcinoma 
Oncology Letters  2010;1(4):685-689.
Esophageal squamous cell carcinoma (ESCC) is a common malignancy and one of the more difficult diseases to diagnose in Japan due to its poor prognosis. MicroRNAs are small non-coding RNAs of 21–23 nucleotides that regulate gene expression. MicroRNA-34b (miR-34b) has been reported to be overexpressed in various types of cancer. However, its role in ESCC has yet to be extensively studied. The present study investigated the expression of miR-34b in 88 ESCC patients. The miR-34b expression in ESCC was significantly higher than that in the corresponding normal esophageal mucosa. It was more highly expressed in tumors with more advanced stages. However, its expression did not correlate with the p53 status. Transfection of anti-miR-34b to the ESCC cells suppressed cell growth in vitro. These results suggest an oncogenic role of miR in ESCC.
PMCID: PMC3436259  PMID: 22966364
microRNA-34b; esophageal squamous cell carcinoma; MTT assay
21.  Vascular endothelial growth factor C (VEGF-C) in esophageal cancer correlates with lymph node metastasis and poor patient prognosis 
The diagnosis of lymph node metastasis in esophageal cancer by the presence and number of metastatic lymph nodes is an extremely important prognostic factor. In addition, the indication of non-surgical therapy is gaining more attention. Vascular endothelial growth factor C (VEGF-C) is potentially lymphangiogenic and selectively induces hyperplasia of the lymphatic vasculature. In this study, we investigated the expression of VEGF-C and whether it correlated with various clinico-pathologic findings.
KYSE series of esophageal cancer cell lines and 106 patients with primary esophageal squamous cell carcinomas who had undergone radical esophagectomy were analyzed. VEGF-C mRNA expression was determined by quantitative RT-PCR.
High expression of VEGF-C was detected in most of the KYSE cell lines, especially KYSE410, yet, in an esophageal normal epithelium cell line, Het-1A, VEGF-C was not detected. In the clinical specimen, the expression of VEGF-C in the cancerous tissue was higher than in the corresponding noncancerous esophageal mucosa (p = 0.026). The expression of VEGF-C was found to be higher in Stage2B-4A tumors than in Stage0-2A tumors (p = 0.049). When the patients were divided into two groups according to their expression levels of VEGF-C (a group of 53 cases with high expression and a group of 53 cases with low expression), the patients with high VEGF-C expression had significantly shorter survival after surgery than the patients with low expression (p = 0.0065). Although univariate analysis showed that high expression of VEGF-C was a statistically significant prognostic factor, this was not shown in multivariate analysis. In the subgroup of patients with Tis and T1 tumors, the expression of VEGF-C was higher in N1 tumors than in N0 tumors (p = 0.029). The survival rate of patients from the high expression group (n = 10) was lower than that in the low expression group (n = 11), and all the patients in the low VEGF-C expression group survived.
The expression of VEGF-C correlates with lymph node metastasis and poor prognosis. In patients with Tis and T1 esophageal tumors, the expression of VEGF-C may be a good diagnostic factor for determining metastasis of the lymph node.
PMCID: PMC2917417  PMID: 20584281
22.  Effects of dibutyryl cyclic adenosine monophosphate on hypercapnic depression of diaphragmatic contractility in pentobarbital-anesthetized dogs 
Background: Hypercapnia is associated with diaphragm muscle dysfunction that causes a reduction of diaphragmatic force generated for a constant elective myographic activity. No published data are available concerning hypercapnic depression of diaphragmatic contractility during dibutyryl cyclic adenosine monophospate (DBcAMP) administration.
Objective: The aim of this study was to assess the effects of DBcAMP on hypercapnic depression of diaphragmatic contractility in pentobarbital-anesthetized dogs.
Methods: This experimental study was conducted from July to December 2008 at the Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan. Adult (aged >5 years) mongrel dogs weighing 10 to 15 kg were randomly divided into 3 equal groups. Hypercapnia (80–90 mm Hg) was induced with 10% carbon dioxide added to the inspired gas. When hypercapnia was established, group 1 was infused with low-dose DBcAMP (0.05 mg/kg/min); group 2 was infused with high-dose DBcAMP (0.2 mg/kg/min); and group 3 received placebo (saline). Study drug was administered intravenously for 60 minutes. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi) at baseline, induction of hypercapnia, and study drug administration.
Results: Twenty-one dogs were divided into 3 groups of 7. There were no significant differences observed at baseline. In the presence of hypercapnia, Pdi (mean [SD], cm H2O) at low- (20-Hz) and high-frequency (100-Hz) stimulation was significantly decreased from baseline in each group (all, P = 0.001). In groups 1 and 2, Pdi at both stimuli was significantly increased during DBcAMP administration compared with hypercapnia-induced values (group 1: 20-Hz, 13.5 [2.2] vs 15.0 [2.4], respectively, P = 0.001, 100-Hz, 21.2 [1.6] vs 22.5 [1.6], P = 0.001; group 2: 20-Hz, 13.7 [1.4] vs 19.2 [1.7], P = 0.001, 100-Hz, 21.0 [2.4] vs 27.2 [2.5], P = 0.001). The Pdi at both stimuli during DBcAMP administration was significantly higher in group 2 than in group 1 (20-Hz, 19.2 [1.7] vs 15.0 [2.4], P = 0.001, 100-Hz, 27.2 [2.5] vs 22.5 [1.6], P = 0.003). In group 3, Pdi did not significantly change in regard to either stimulus from hypercapnia-induced values.
Conclusion: DBcAMP, in a dose-dependent manner, was associated with improved hypercapnic depression of diaphragmatic contractility in these pentobarbital-anesthetized dogs.
PMCID: PMC3967283  PMID: 24683261
muscle; diaphragm; contractility; hypercapnia; dibutyryl cyclic adenosine monophosphate (DBcAMP)
23.  Hypermethylation of the large tumor suppressor genes in Japanese lung cancer 
Oncology Letters  2010;1(2):303-307.
Large tumor suppressor (LATS) 1 and 2 are tumor suppressor genes implicated in the regulation of the cell cycle. The methylation statuses of the promoter regions of these genes were studied in Japanese lung cancers. The methylation statuses of the promoter regions of LATS1 and LATS2 were investigated by methylation-specific PCR. The findings were compared to clinicopathological features of lung cancer. Methylation-specific PCR showed that the LATS1 promoter region was hypermethylated in 95 out of 119 (79.8%) lung cancers. The methylation status of LATS1 was significantly associated with squamous histology (p=0.0267) and smoking status (never smoker vs. smoker; p=0.0399). LATS1-ummethylated patients harbored more EGFR mutations (p=0.0143). The LATS2 promoter region was hypermethylated in 160 out of 203 (78.8%) lung cancers. However, the methylation status had no association with the clinicopathological characteristics of the lung cancers cases. Both the LATS1 and LATS2 methylation statuses did not correlate with survival of lung cancer patients. Thus, the EGFR methylation status of the LATS genes has limited value in Japanese lung cancers.
PMCID: PMC3436364  PMID: 22966299
hypermethylation; large tumor suppressor gene; lung cancer
24.  Methylation of the DLEC1 gene correlates with poor prognosis in Japanese lung cancer patients 
Oncology Letters  2010;1(2):283-287.
The incidence of chromosome 3p gene alterations is one of the most frequent and earliest documented events in lung cancer. This study aimed to investigate promoter methylation in the deleted in lung and esophageal cancer 1 (DLEC1) gene, as well as the p16 and CDH1 genes in Japanese lung cancer cases. The methylation status of the promoter regions of DLEC1, p16 and CDH1 was investigated using methylation-specific PCR. The findings were compared to the clinicopathological features of lung cancer. Methylation-specific PCR showed that the DLEC1 promoter region was methylated in 65 out of 116 (56%) lung cancers. Patients with DLEC1-methylated cancer were associated with a significantly worse prognosis than those with unmethylated cancer (p=0.0368; hazard ratio=1.83). The p16 methylation status correlated with squamous histology (p=0.03) and smoking status (never smoker vs. smoker; p=0.0122). Patients with p16 ummethylated cancer harbored more EGFR mutations (p=0.0071). The CDH1 promoter region was hypermethylated in 65 out of 118 (55.1%) lung cancer cases. However, the CDH1 methylation status was not associated with the clinicopathological characteristics of the lung cancer types. p16 and CDH1 methylation status did not correlate with survival in the lung cancer patients. Thus, in our Japanese cohort, the methylation status of the DLEC1 gene was a marker of poor prognosis independent of stage.
PMCID: PMC3436471  PMID: 22966295
methylation; DLEC1 gene; lung cancer
25.  Frequently increased epidermal growth factor receptor (EGFR) copy numbers and decreased BRCA1 mRNA expression in Japanese triple-negative breast cancers 
BMC Cancer  2008;8:309.
Triple-negative breast cancer (estrogen receptor-, progesterone receptor-, and HER2-negative) (TNBC) is a high risk breast cancer that lacks specific therapy targeting these proteins.
We studied 969 consecutive Japanese patients diagnosed with invasive breast cancer from January 1981 to December 2003, and selected TNBCs based on the immunohistochemical data. Analyses of epidermal growth factor receptor (EGFR) gene mutations and amplification, and BRCA1 mRNA expression were performed on these samples using TaqMan PCR assays. The prognostic significance of TNBCs was also explored. Median follow-up was 8.3 years.
A total of 110 (11.3%) patients had TNBCs in our series. Genotyping of the EGFR gene was performed to detect 14 known EGFR mutations, but none was identified. However, EGFR gene copy number was increased in 21% of TNBCs, while only 2% of ER- and PgR-positive, HER2-negative tumors showed slightly increased EGFR gene copy numbers. Thirty-one percent of TNBCs stained positive for EGFR protein by immunohistochemistry. BRCA1 mRNA expression was also decreased in TNBCs compared with controls. Triple negativity was significantly associated with grade 3 tumors, TP53 protein accumulation, and high Ki67 expression. TNBC patients had shorter disease-free survival than non-TNBC in node-negative breast cancers.
TNBCs have an aggressive clinical course, and EGFR and BRCA1 might be candidate therapeutic targets in this disease.
PMCID: PMC2612006  PMID: 18950515

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