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1.  Acute exacerbation of airspace enlargement with fibrosis 
In 2008, Kawabata et al. described a lesion which they termed “airspace enlargement with fibrosis” that could be included on the spectrum of smoking-related interstitial lung diseases. This group also reported that patients with airspace enlargement with fibrosis but without coexisting interstitial pneumonia of another type had no acute exacerbations and favorable prognoses on clinical follow-up. Here we describe the first case, to our knowledge, of acute exacerbation of airspace enlargement with fibrosis without coexisting interstitial pneumonia of another type. An 82-year-old man was referred to our department for worsening dyspnea and new alveolar opacities on chest radiograph following left pulmonary segmentectomy (S6) for cancer. A diagnosis of acute exacerbation of airspace enlargement with fibrosis without coexisting interstitial pneumonia of other types was made, based on pathological evidence of airspace enlargement with fibrosis and organizing diffuse alveolar damage. Treatment with high-dose methylprednisolone followed by tapered oral prednisolone resulted in gradual improvement of the clinical condition and chest radiographic findings. Clinicians should be aware that patients with airspace enlargement with fibrosis may experience acute exacerbation.
doi:10.1016/j.rmcr.2014.07.005
PMCID: PMC4246254
Acute exacerbation; Airspace enlargement with fibrosis; Smoking-related interstitial lung disease
2.  Ki-67 is a strong prognostic marker of non-small cell lung cancer when tissue heterogeneity is considered 
Background
Ki-67 expression is a well-established prognostic marker in various cancers. However, Ki-67 expression is also known as being heterogeneous. We investigated the prognostic significance of Ki-67 from the view of staining heterogeneity by the technique of Spiral Array.
Methods
100 cases of resected lung cancer from Toyama university hospital archive were collected. Spiral Array blocks were generated out of 100 cases using 100 μm thick paraffin sections. Four μm thick sections of the Array block were stained for Ki-67. Staining results in each reel were scored for areas with lowest (LS), highest (HS), and average (AS) expression, exclusively in the cancer cells. Heterogeneity score (HeS) was designed as the difference between HS and LS. The scores were divided into four grades (0–3). Clinical information was collected, and the prognostic significance of Ki-67 was analyzed.
Results
Pathological stage was available for 91 patients (43 stage IA, 22 stage IB, 2 stage IIA, 9 stage IIB, 13 stage IIIA, 1 stage IIIB, and 1 stage IV). The HS of Ki-67 score in non-small cell lung cancer was 3 in 17 cases, 2 in 27 cases, 1 in 28 cases, 0 in 21 cases, and 4 reels were lost. 78 cases had clinical follow up. 74 cases had all the information available and were analyzed for correlation between Ki-67 expression and survival. Cases with score 2 and 3 of HS and HeS showed significant poorer prognosis (both P < 0.001), whereas LS or AS did not show significance. The results were identical when analyzing adenocarcinoma and squamous cell carcinoma, separately. Cox multivariate analysis of Ki-67 showed that HS was an independent risk factor affecting overall survival.
Conclusions
Ki-67 is a strong prognostic marker for non-small cell lung cancer when the degree of highest staining frequency or heterogeneity is considered.
doi:10.1186/1472-6890-14-23
PMCID: PMC4032346  PMID: 24860257
Tissue microarray; Tissue heterogeneity; Expression; Biomarkers; Pathology; Lung cancer
3.  Synaptonemal complex protein 3 as a novel prognostic marker in early stage non-small cell lung cancer 
Human pathology  2012;44(4):472-479.
Summary
Synaptonemal complex protein 3 (SCP3) is a marker for cell transformation that has prognostic significance in various cancers. However, the prognostic significance of SCP3 has not been studied in non-small cell lung cancer (NSCLC). To investigate the potential correlation between SCP3 and various clinicopathologic parameters, we assessed the expression of SCP3 in archival tumor tissues from 258 NSCLC patients by immunohistochemical staining. By immunofluorescence, SCP3 was detected in both the cytoplasmic and nuclear fractions of NCI-H1299 cell. In tumor samples, SCP3 is detected as cytoplasmic expression pattern and observed in 50 (19.4%) clinical samples by immunohistochemical staining. SCP3 expression was correlated with T status (P=0.008), lymph node metastasis (P=0.010), tumor types (P=0.019) and pleural invasion (P=0.005). In multivariate analysis of patients with early stage disease, increased SCP3 expression predicted worse overall survival in early stage (stage I–II) with pT1 status (P=0.041). These results suggest that positive SCP3 expression is a portent of poor outcome, and may be a potential biomarker in the early stages of the NSCLC for survival and may provide clues in the identification of patients for adjuvant therapy.
doi:10.1016/j.humpath.2012.06.018
PMCID: PMC3548971  PMID: 23069255
Immunohistochemistry; Non-small cell lung cancer; Prognostic marker; Synaptonemal complex protein 3; Tissue microarray
4.  Cellular localization of protein arginine methyltransferase-5 correlates with grade of lung tumors 
Diagnostic Pathology  2013;8:201.
Background
Protein arginine methyltransferase-5 (PRMT5) is a chromatin-modifying enzyme capable of methylating histone and non-histone proteins, and is involved in a wide range of cellular processes that range from transcriptional regulation to organelle biosynthesis. As such, its overexpression has been linked to tumor suppressor gene silencing, enhanced tumor cell growth and survival.
Material and methods
Quantitative real-time polymerase chain reaction, Western immunoblot and immunohistochemistry were used to characterize PRMT5 expression in lung cancer cell lines and human tumors. Clinicopathological findings of tissue microarray based samples from 229 patients with non-small cell lung carcinomas (NSCLC) and 133 cases with pulmonary neuroendocrine tumors (NET) were analyzed with regard to nuclear and cytoplasmic PRMT5 expression.
Results
There was statistically significant difference in PRMT5 messenger RNA expression between tumors and nonneoplastic lung tissues. Immunoblot experiments showed abundant expression of PRMT5 and its symmetric methylation mark H4R3 in lung carcinoma but not in non-neoplastic human pulmonary alveolar and bronchial epithelial cell lines. More than two thirds of lung tumors expressed PRMT5. High levels of cytoplasmic PRMT5 were detected in 20.5% of NSCLC and in 16.5% of NET; high levels of nuclear PRMT5 were detected in 38.0% of NSCLC and 24.0% of NET. Cytoplasmic PRMT5 was associated with high grade in both NSCLC and pulmonary NET while nuclear PRMT5 was more frequent in carcinoid tumors (p < 0.05).
Conclusion
The observed findings support the role of PRMT5 in lung tumorigenesis and reflect its functional dichotomy in cellular compartments.
Virtual slide
The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1611895162102528
doi:10.1186/1746-1596-8-201
PMCID: PMC3933389  PMID: 24326178
Protein arginine methyltransferase-5; Lung carcinoma; Neuroendocrine tumors
5.  Difference of Morphology and Immunophenotype between Central and Peripheral Squamous Cell Carcinomas of the Lung 
BioMed Research International  2013;2013:157838.
Background. Recent agents, that is, pemetrexed and bevacizumab, have shown reproductive negative association between squamous histology. According to these agents' effectiveness, ruling out of the squamous histology is a significant issue for surgical pathologists. Several articles have proposed the distinction of peripheral type from central type of squamous cell carcinoma (SqCC) due to its similarity to adenocarcinoma, although little evidence to support the difference between these two types was published. In this study, we compared the clinicopathologic findings of central and peripheral pulmonary SqCCs. Material and Methods. 15 central and 35 peripheral types of SqCC from 2005 to 2010 were examined. Twelve morphological features were scored based on their intensity in the original H&E slides, and then, tissue microarray holding triplicated cores from 43 cases was immunohistochemically examined for cytokeratin (CK)7, CK14, TTF-1, Napsin A, p63, CK34βE12, CK5/6, and p53. Result. Most of the histological findings did not separate central and peripheral SqCCs; only the presence of emphysema, interstitial fibrosis, and entrapped pneumocytes inside the tumor showed statistic predominance in peripheral SqCC. This is the first immunophenotypic research in the central and peripheral types of SqCC.
doi:10.1155/2013/157838
PMCID: PMC3773404  PMID: 24069587
6.  Clinicopathological significance of deoxycytidine kinase expression in esophageal squamous cell carcinoma 
Molecular and Clinical Oncology  2013;1(4):716-720.
Deoxycytidine kinase (dCK) mediates the rate-limiting catabolic step in the activation of gemcitabine. Gemcitabine is a key drug for pancreatic and biliary tract cancer. However, gemcitabine is not widely used for esophageal squamous cell carcinoma (ESCC). In this study, we analyzed the expression of dCK in ESCC and evaluated the possibility of gemcitabine treatment for ESCC. In total, 76 ESCC patients who underwent esophagectomy between 1990 and 2008 were analyzed. dCK expression was analyzed immunohistochemically using tissue microarray and compared to the clinocopathological characteristics of the patients. Results identified 41 patients positive for dCK and 35 patients negative for dCK. A significant association was observed between dCK expression and gender (P=0.01), whereas the remaining factors were not associated with dCK expression. Prognosis of the patients with a high dCK expression was significantly worse than that of the patients with a low dCK expression (P=0.022). Furthermore, dCK expression was an independent prognostic factor regarding cause-specific prognosis (risk ratio, 2.2; P=0.031). In conclustion, the results of the present study suggested that dCK expression is a prognostic factor of the ESCC patients.
doi:10.3892/mco.2013.114
PMCID: PMC3915311  PMID: 24649234
esophageal squamous cell carcinoma; deoxycytidine kinase; gemcitabine; prognostic factor
7.  Glucose transporter-1 in pulmonary neuroendocrine carcinomas: expression and survival analysis 
Glucose transporter-1 (GLUT-1) mediates the transport of glucose across the cellular membrane. Its elevated levels and/or activation have been shown to be associated with malignancy. The aim of this study was to investigate GLUT-1 expression in pulmonary neuroendocrine carcinomas. Tissue microarray-based samples of 178 neuroendocrine carcinomas, including 48 typical carcinoids, 31 atypical carcinoids, 27 large cell neuroendocrine carcinomas and 72 small cell carcinomas from different patients, were studied immunohistochemically for GLUT-1 expression. Forty-seven percent (75/161) of pulmonary neuroendocrine carcinomas were immunoreactive with GLUT-1. GLUT-1 was observed in 7% (3/46) of typical carcinoid, 21% (6/29) of atypical carcinoid, 74% (17/23) of large cell neuroendocrine carcinoma and 78% (49/63) of small cell carcinoma. GLUT-1 expression correlated with increasing patient age (P = 0.01) and with neuroendocrine differentiation/tumor type (P < 0.001), but not with gender, tumor size or stage. GLUT-1 expression was seen in a characteristic membranous pattern of staining along the luminal borders or adjacent to necrotic areas. GLUT-1 expression was associated with an increased risk of death for neuroendocrine carcinomas as a group (risk ratio = 2.519; 95% confidence interval = 1.519–4.178; P < 0.001) and carcinoids (risk ratio = 4.262; 95% confidence interval = 1.472–12.343; P = 0.01). In conclusion, GLUT-1 is expressed in approximately half of the pulmonary neuroendocrine carcinomas and shows a strong correlation with neuroendocrine differentiation/grade, but not with other clinicopathologic variables. Further studies appear plausible to elucidate the prognostic significance of GLUT-1 expression in pulmonary carcinoids.
doi:10.1038/modpathol.2009.6
PMCID: PMC3616507  PMID: 19234439
GLUT-1; neuroendocrine carcinoma; carcinoid; survival; lung
8.  SMAD6 Contributes to Patient Survival in Non–Small Cell Lung Cancer and Its Knockdown Reestablishes TGF-β Homeostasis in Lung Cancer Cells 
Cancer research  2008;68(23):9686-9692.
The malignant transformation in several types of cancer, including lung cancer, results in a loss of growth inhibition by transforming growth factor-β (TGF-β). Here, we show that SMAD6 expression is associated with a reduced survival in lung cancer patients. Short hairpin RNA (shRNA)–mediated knockdown of SMAD6 in lung cancer cell lines resulted in reduced cell viability and increased apoptosis as well as inhibition of cell cycle progression. However, these results were not seen in Beas2B, a normal bronchial epithelial cell line. To better understand the mechanism underlying the association of SMAD6 with poor patient survival, we used a lentivirus construct carrying shRNA for SMAD6 to knock down expression of the targeted gene. Through gene expression analysis, we observed that knockdown of SMAD6 led to the activation of TGF-β signaling through up-regulation of plasminogen activator inhibitor-1 and phosphorylation of SMAD2/3. Furthermore, SMAD6 knockdown activated the c-Jun NH2-terminal kinase pathway and reduced phosphorylation of Rb-1, resulting in increased G0-G1 cell arrest and apoptosis in the lung cancer cell line H1299. These results jointly suggest that SMAD6 plays a critical role in supporting lung cancer cell growth and survival. Targeted inactivation of SMAD6 may provide a novel therapeutic strategy for lung cancers expressing this gene.
doi:10.1158/0008-5472.CAN-08-1083
PMCID: PMC3617041  PMID: 19047146
9.  Irinotecan Plus Mitomycin C as Second-Line Chemotherapy for Advanced Gastric Cancer Resistant to Fluoropyrimidine and Cisplatin: A Retrospective Study 
Background. S-1 plus cisplatin has been established to be standard first-line chemotherapy for advanced gastric cancer in Japan. The optimal second-line treatment refractory to S-1 plus cisplatin remains unclear. Methods. We retrospectively studied the efficacy, toxicity, and survival of irinotecan plus mitomycin C in patients with advanced gastric cancer refractory to a fluoropyrimidine plus cisplatin. Results. Twenty-four patients were studied. Prior chemotherapy was S-1 plus cisplatin in 15 patients, S-1 plus cisplatin and docetaxel in 8, and 5-fluorouracil plus cisplatin with radiotherapy in 1. The overall response rate was 17.4%. The median overall survival was 8.6 months, and the median progression-free survival was 3.6 months. Grade 3 or 4 toxicities included leukopenia (33%), neutropenia (50%), anemia (33%), thrombocytopenia (4%), anorexia (13%), diarrhea (4%), and febrile neutropenia (13%). Conclusion. A combination of irinotecan and mitomycin C is potentially effective in patients with advanced gastric cancer refractory to a fluoropyrimidine plus cisplatin.
doi:10.1155/2012/640401
PMCID: PMC3296209  PMID: 22474446
10.  Loss of Cytoplasmic CDK1 Predicts Poor Survival in Human Lung Cancer and Confers Chemotherapeutic Resistance 
PLoS ONE  2011;6(8):e23849.
The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early stage patients and individualizing therapeutic choices. We hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery.
doi:10.1371/journal.pone.0023849
PMCID: PMC3161069  PMID: 21887332
11.  MicroRNA profiling of gastric cancer patients from formalin-fixed paraffin-embedded samples 
Oncology Letters  2011;2(4):613-619.
MicroRNA (miRNA) is a small non-coding RNA that targets specific mRNA. Recent progress in the extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissues has facilitated miRNA profiling using samples stored in laboratories worldwide. In the present study, miRNA profiling of gastric cancer patients is determined using FFPE samples. First, criteria were established for determining evaluable RNA from the FFPE samples. miRNA profiling was then undertaken using miRNA oligo chips with 885 featured genes. The FFPE samples were obtained from 47 gastric cancer patients who underwent operations between 1997 and 2007. Results showed that out of 47 paired samples, 37 pairs (78.8%) were evaluable by our criteria. A total of 30 miRNAs were significantly up-regulated and 11 miRNAs were down-regulated in gastric cancer compared with those in normal gastric tissue. Among these, 14 miRNAs, including miR-21, were identified as prognostic factors of gastric cancer patients. Furthermore, miR-34a was selected as an independent prognostic factor. In conclusion, we identified miRNAs that are associated with the prognosis of gastric cancer patients. miRNA profiling using FFPE samples is a useful and promising method of evaluation for samples stored in laboratories worldwide, and can generate extremely valuable clinical data.
doi:10.3892/ol.2011.313
PMCID: PMC3406456  PMID: 22848236
formalin-fixed paraffin-embedded samples; prognosis; miRNA profiling
12.  Identification of novel gene amplifications in breast cancer and coexistence of gene amplification with an activating mutation of PIK3CA 
Cancer research  2009;69(18):7357-7365.
To identify genetic events that characterize cancer progression, we conducted a comprehensive genetic evaluation of 161 primary breast tumors. Similar to the “mountain-and-hill” view of mutations, gene amplification also shows high and low frequency alterations in breast cancers. The frequently amplified genes include the well-known oncogenes, ERBB2, FGFR1, MYC, CCND1, and PIK3CA, whereas other known oncogenes that are amplified, though less frequently, include CCND2, EGFR, FGFR2, and NOTCH3. More importantly, by honing in on minimally amplified regions containing ≤ 3 genes, we identified six new amplified genes: POLD3, IRAK4, IRX2, TBL1XR1, ASPH, and BRD4. We found that both the IRX2 and TBL1XR1 proteins showed higher expression in the malignant cell lines, MCF10CA1h and MCF10CA1a, than in their precursor, MCF10A, a normal immortalized mammary epithelial cell line. To study oncogenic roles of TBL1XR1, we performed knockdown experiments using a shRNA approach and found that depletion of TBL1XR1 in MCF10CA1h cells resulted in reduction of cell migration and invasion as well as suppression of tumorigenesis in mouse xenografts. Intriguingly, our mutation analysis showed the presence of activation mutations in the PIK3CA gene in a subset of tumors that also had DNA copy number increases in the PIK3CA locus, suggesting an additive effect of co-existing activating amino-acid substitution and dosage increase from amplification. Our gene amplification and somatic mutation analysis of breast primary tumors provides a coherent picture of genetic events, both corroborating and novel, offering insight into the genetic underpinnings of breast cancer progression.
doi:10.1158/0008-5472.CAN-09-0064
PMCID: PMC2745517  PMID: 19706770
DNA copy number; gene amplification; oncogene; somatic mutation; breast cancer
13.  Imaging of pulmonary emphysema: A pictorial review 
The term ‘emphysema’ is generally used in a morphological sense, and therefore imaging modalities have an important role in diagnosing this disease. In particular, high resolution computed tomography (HRCT) is a reliable tool for demonstrating the pathology of emphysema, even in subtle changes within secondary pulmonary lobules. Generally, pulmonary emphysema is classified into three types related to the lobular anatomy: centrilobular emphysema, panlobular emphysema, and paraseptal emphysema. In this pictorial review, we discuss the radiological – pathological correlation in each type of pulmonary emphysema. HRCT of early centrilobular emphysema shows an evenly distributed centrilobular tiny areas of low attenuation with ill-defined borders. With enlargement of the dilated airspace, the surrounding lung parenchyma is compressed, which enables observation of a clear border between the emphysematous area and the normal lung. Because the disease progresses from the centrilobular portion, normal lung parenchyma in the perilobular portion tends to be preserved, even in a case of far-advanced pulmonary emphysema. In panlobular emphysema, HRCT shows either panlobular low attenuation or ill-defined diffuse low attenuation of the lung. Paraseptal emphysema is characterized by subpleural well-defined cystic spaces. Recent topics related to imaging of pulmonary emphysema will also be discussed, including morphometry of the airway in cases of chronic obstructive pulmonary disease, combined pulmonary fibrosis and pulmonary emphysema, and bronchogenic carcinoma associated with bullous lung disease.
PMCID: PMC2629965  PMID: 18686729
pulmonary emphysema; HRCT; radiologic-pathologic correlation; pulmonary fibrosis; bronchus; lung cancer
14.  Gene Expression Signature of Cigarette Smoking and Its Role in Lung Adenocarcinoma Development and Survival 
PLoS ONE  2008;3(2):e1651.
Background
Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure.
Methodology/Principal Findings
We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p<0.001 and fold-change >1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p<0.001) and TTK (p = 0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers.
Conclusions/Significance
Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers.
doi:10.1371/journal.pone.0001651
PMCID: PMC2249927  PMID: 18297132
15.  Inactivation of LLC1 gene in nonsmall cell lung cancer 
Serial analysis of gene expression studies led us to identify a previously unknown gene, c20orf85, that is present in the normal lung epithelium, but absent or downregulated in most primary non-small cell lung cancers and lung cancer cell lines. We named this gene LLC1 for Low in Lung Cancer 1. LLC1 is located on chromosome 20q13.3 and has a 70% GC content in the promoter region. It has 4 exons and encodes a protein containing 137 amino acids. By in situ hybridization, we observed that LLC1 message is localized in normal lung bronchial epithelial cells, but absent in 13 of 14 lung adenocarcinoma and 9 out of 10 lung squamous carcinoma samples. Methylation at CpG sites of the LLC1 promoter was frequently observed in lung cancer cell lines and in a fraction of primary lung cancer tissues. Treatment with 5-aza deoxycytidine resulted in a reduced methylation of the LLC1 promoter concomitant with the increase of LLC1 expression. These results suggest that inactivation of LLC1 by means of promoter methylation is a frequent event in nonsmall cell lung cancer and may play a role in lung tumorigenesis.
doi:10.1002/ijc.22577
PMCID: PMC1907378  PMID: 17304513
nonsmall cell lung cancer; serial analysis of gene expression; promoter methylation

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