Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital

Kanazawa-shi, Japan

Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital

Kanazawa-shi, Japan
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Okudela K.,Yokohama City University | Woo T.,Yokohama City University | Mitsui H.,Yokohama City University | Yazawa T.,Yokohama City University | And 5 more authors.
International Journal of Clinical and Experimental Pathology | Year: 2010

We have established a concise sub-typing system suitable for predicting the postoperative outcome in cases of stage I lung adenocarcinoma (ADC), using morphometric profiling. The association between postoperative disease recurrence and a variety of morphological features including histological architecture, cell type, cytoplasmic color/internal structure, nuclear shape/size, chromatin pattern, and nucleoli count/remarkableness, was analyzed. Histological architecture had the most prognostic value and could be subdivided into low-grade (bronchioloalveolar, papillary and tubular: "tubular" in this paper is defined as a tubular or glandular structure lined with single-layered neoplastic cells) and high-grade (acinar and solid: "acinar" is defined as a tubular or glandular structure lined with poly-layered neoplastic cells or as a fused glandular structure such as the cribriform pattern) components. The subgroups separated based on a cut-off value, 71.5% of the high-grade component comprised by a tumor, which was calculated according to a relative operating characteristic curve, exhibited a significant difference in disease recurrence [estimated 5-year disease-free survival rate, 95.3% in the low-grade group versus 66.7% in the high-grade group, hazard ratio 7.35, Log-rank test p = 0.002]. The sub-grouping system is concise and suitable for practical use. It will improve the histological classification of ADC.


Shimoyamada H.,Yokohama City University | Yazawa T.,Yokohama City University | Sato H.,Yokohama City University | Sato H.,St. Marianna University School of Medicine | And 13 more authors.
American Journal of Pathology | Year: 2010

Vascular endothelial growth factor-A (VEGF-A) is crucial for angiogenesis, vascular permeability, and metastasis during tumor development. We demonstrate here that early growth response-1 (EGR-1), which is induced by the extracellular signal-regulated kinase (ERK) pathway activation, activates VEGF-A in lung cancer cells. Increased EGR-1 expression was found in adenocarcinoma cells carrying mutant K-RAS or EGFR genes. Hypoxic culture, siRNA experiment, luciferase assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and quantitative RT-PCR using EGR-1-inducible lung cancer cells demonstrated that EGR-1 binds to the proximal region of the VEGF-A promoter, activates VEGF-A expression, and enhances hypoxia inducible factor 1α (HIF-1α)-mediated VEGF-A expression. The EGR-1 modulator, NAB-2, was rapidly induced by increased levels of EGR-1. Pathology samples of human lung adenocarcinomas revealed correlations between EGR-1/HIF-1α and VEGF-A expressions and relative elevation of EGR-1 and VEGF-A expression in mutant K-RAS- or EGFR-carrying adenocarcinomas. Both EGR-1 and VEGF-A expression increased as tumors dedifferentiated, whereas HIF-1α expression did not. Although weak correlation was found between EGR-1 and NAB-2 expressions on the whole, NAB-2 expression decreased as tumors dedifferentiated, and inhibition of DNA methyltransferase/histone deacetylase increased NAB-2 expression in lung cancer cells despite no epigenetic alteration in the NAB-2 promoter. These findings suggest that EGR-1 plays important roles on VEGF-A expression in lung cancer cells, and epigenetic silencing of transactivator(s) associated with NAB-2 expression might also contribute to upregulate VEGF-A expression. Copyright © American Society for Investigative Pathology.


Okudela K.,Yokohama City University | Yazawa T.,Yokohama City University | Tajiri M.,Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital | Omori T.,Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital | And 5 more authors.
Pathology Research and Practice | Year: 2010

We present a case of a polypoid tumor located in the right middle lobe bronchus. The tumor was composed of bi-layered glandular or ductular structures consisting of inner cuboidal cells and outer multipolar cells. Immunohistochemical examinations confirmed epithelial and myoepithelial differentiation in the inner and outer components, respectively. Consequently, the tumor was diagnosed as an epithelial-myoepithelial carcinoma. Epithelial-myoepithelial carcinomas of the bronchus are very rare neoplasms with low-grade malignant potential. To date, including our case, only 27 cases have been reported in the English literature. Here, we review the reported cases and compare them with other salivary gland-type carcinomas regarding clinical, biological, and genetic features. © 2009 Elsevier GmbH. All rights reserved.


Okudela K.,Yokohama City University | Mitsui H.,Yokohama City University | Suzuki T.,Yokohama City University | Woo T.,Yokohama City University | And 6 more authors.
International Journal of Clinical and Experimental Pathology | Year: 2014

Our previous studies identified important molecules involved in lung carcinogenesis through a comprehensive search for the downstream targets of oncogenic KRAS, and these findings suggested that an investigation into the downstream targets of oncogenic KRAS might represent a useful strategy for elucidating the common molecular bases of lung cancer. Among the downstream targets of oncogenic KRAS, a focus was placed on HDAC9, a member of the histone deacetylase family, in the present study because epigenetic modification of DNA or the histone proteins is known to play an important role in carcinogenesis. The immunohistochemical expression of HDAC9 was examined in surgically resected primary lung cancers (130 adenocarcinoma, 49 squamous cell carcinomas, one large cell carcinoma, and 6 small cell carcinomas) and potential associations between its expression level and pathologic factors were analyzed. The results showed that HDAC9 expression levels were lower in lung cancer cells than in non-tumor epithelial cells, and were also significantly lower in adenocarcinomas among the histological types. Moreover, HDAC9 expression levels were significantly lower in adenocarcinomas with lymphatic canal involvement. The restoration of HDAC9 in lung cancer cells losing its expression severely attenuated their growth activity in vitro. These results suggest that HDAC9 may be a suppressor and its downregulation might promote the progression process, especially in lung adenocarcinomas.


Okudela K.,Yokohama City University | Woo T.,Yokohama City University | Mitsui H.,Yokohama City University | Yazawa T.,Yokohama City University | And 5 more authors.
American Journal of Surgical Pathology | Year: 2010

The traditional histologic classification of lung cancer is not satisfactory to describe the morphologic characteristics of individual tumors, because it does not fully cover cytologic features. This paper describes a novel typing system using morphometric profiling that covers a variety of morphologic features including histologic architecture, cell type, cytoplasmic color and internal structure, nuclear outline, chromatin pattern, nucleoli count and remarkableness, and average and deviation of nuclear size and circularity. In all, 201 cases of lung tumors (whose sizes are <20 mm) were examined. Results of a hierarchical clustering analysis were used to draw a dendrogram. We here tentatively focused on 8 morphometric clusters and analyzed their potential association with a variety of clinicopathologic and molecular genetic features. Significant differences in postoperative recurrent risk, growth activity, oncogenic mutation (EGFR or KRAS), impairments of tumor suppressors (p53 and p16), sex predisposition, and smoking status were found among the 8 clusters. The system has the potential to improve histopathologic diagnosis and our understanding of carcinogenesis in the lung. Copyright © 2010 by Lippincott Williams & Wilkins.


Okudela K.,Yokohama City University | Okudela K.,Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital | Umeda S.,Yokohama City University | Umeda S.,Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital | And 6 more authors.
Pathology International | Year: 2014

We herein describe a case of a benign pulmonary tumor with distinctive histopathological features. A 55-year-old Japanese male presented with a well-demarcated tumor in the left upper lobe of his lung, which gradually increased in size from 18 to 21mm over 24 months. The resected tumor consisted of an epithelial component of compact irregular glands and mesenchymal component of fascicles between the glands. The differentiation of pneumocytes and smooth muscle cells was immunohistochemically detected in the epithelial component and the mesenchymal component, respectively. No mitosis, necrosis, bleeding, or invasion was observed. A histopathologic diagnosis of fibroleiomyomatous hamartoma was made. We also review previously reported tumors with similar histopathological features and discuss their differential diagnosis and histogenesis. © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.


PubMed | Yokohama City University and Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital
Type: Journal Article | Journal: Pathology international | Year: 2016

We herein investigated the potential role of cathepsin L in lung carcinogenesis. Lung cancer cell lines and surgically resected tumors were examined for the expression of the cathepsin L protein and copy number alterations in its gene locus. Cathepsin L was stably expressed in bronchiolar epithelial cells. Neoplastic cells expressed cathepsin L at various levels, whereas its expression was completely lost in most of the lung cancer cell lines (63.6%, 7/11) examined. Furthermore, expression levels were lower in a large fraction of lung tumors (69.5%, 139/200) than in bronchiolar epithelia. The expression of cathepsin L was lost in some tumors (16.0%, 32/200). In adenocarcinomas, expression levels were significantly lower in high-grade tumors than in low-grade tumors (one-way ANOVA, P<0.0500). Copy number alterations were found in 18.0% (36 [32 gain+4 loss] /200) of lung tumors. No relationship existed between cathepsin L protein expression levels and the copy number of its gene locus (Spearmans rank-order correlation, P=0.3096). Collectively, these results suggest that the down-regulated expression of cathepsin L, which is caused by an undefined mechanism other than copy number alterations, is involved in the progression of lung adenocarcinomas.


PubMed | Saiseikai Yokohamashi Nanbu Hospital, Yokohama City University and Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital
Type: Journal Article | Journal: PloS one | Year: 2016

The purpose of this study was to define histological features determining the malignant potential of EGFR-mutated lung adenocarcinoma (LADC). Surgically resected tumors (EGFR-mutated LADCs with (21) and without (79) lymph node metastasis and EGFR wild-type LADCs with (26) and without (108) lymph node metastasis) and biopsy samples from inoperably advanced tumors (EGFR-mutated LADCs (78) and EGFR wild-type LADCs (99)) were examined. In surgically resected tumors, the EGFR-mutated LADCs with lymph node metastasis had the micropapillary element in a significantly greater proportion than others (Mann-Whitney tests P 0.026). The proportion of micropapillary element was higher in the EGFR-mutated LADC at the advanced stage (stage II, III, or IV) than in the tumor at the early stage (stage I) (Mann-Whitney test, P<0.0001). In the biopsy samples from inoperably advanced LADCs (177), EGFR-mutated tumors also had micropapillary element at a higher frequency than EGFR-wild type tumors (53/78 (68%), versus 30/99 (30%), Pearson x2 test, P<0.0001). In stage I EGFR-mutated LADCs (84), the tumors with the micropapillary element (34) exhibited a significantly higher recurrence rate than tumors without micropapillary element (50) (5-year Recurrence-free survival 64.4% versus 93.3%, log-rank test P = 0.028). The micropapillary element may be an exclusive determinant of malignant potential in EGFR-mutated LADC. It is suggested that EGFR-mutated LADC may develop through a distinct histogenesis, in which the micropapillary element is important for promoting progression.

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